|
1
|
Haidary M, Ahmadi-Soleimani SM, Ghofraninezad M, Azhdari-Zarmehri H, Beheshti F. Omega-3 fatty acids supplementation prevents learning and memory impairment induced by chronic ethanol consumption in adolescent male rats through restoration of inflammatory and oxidative responses. Int J Dev Neurosci 2024; 84:423-433. [PMID: 38803108 DOI: 10.1002/jdn.10336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/03/2024] [Accepted: 04/24/2024] [Indexed: 05/29/2024] Open
Abstract
OBJECTIVE Ethanol (Eth) intake is known to cause numerous detrimental effects on the structure and function of the brain, and it is commonly used as a psychostimulant drug by adolescents. Conversely, omega-3 (O3) can reduce the risk of cognitive decline and promote the maintenance of neurophysiological functions. In this study, we investigated the protective effects of O3 on behavioral alterations, oxidative stress, and interleukin-6 (IL-6) levels induced by chronic Eth intake during adolescence in rats. MATERIALS AND METHODS Adolescent male rats (21 days old) were divided as follows: (1) Vehicle, (2) Eth (Eth in drinking water [20%]), (3-5) Eth + O3 (50/100/150 mg/kg), and (6) O3 (150 mg/kg). After 5 weeks, Morris water maze (MWM) and passive avoidance (PA) tests were performed, and the hippocampal and cortical levels of oxidative stress markers and inflammatory indices were measured. RESULTS Adolescent Eth intake impairs learning and memory function in MWM and PA tests (groups × day, p < 0.05 and p < 0.001, respectively). It was shown that Eth induced oxidative stress and neuroinflammation. O3 improved learning and impairment induced by Eth by reducing the adverse effects of Eth on the oxidant/antioxidant balance in the hippocampi (for malondialdehyde [MDA]/thiol: p < 0.01, p < 0.001, respectively) and for superoxide dismutase (SOD)/catalase (CAT): p < 0.01 and p < 0.05, respectively). Furthermore, we found that O3 prevented the Eth-induced increase of hippocampal IL-6 (p < 0.001). CONCLUSION O3 supplementation acts as an effective approach to prevent learning and memory impairments induced by chronic Eth consumption during adolescence. In this respect, the antioxidant and anti-inflammatory properties of O3 seem to be the main underlying mechanisms of neuroprotection.
Collapse
Affiliation(s)
- Murtaza Haidary
- Student Research Committee, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - S Mohammad Ahmadi-Soleimani
- Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
- Departments of Physiology, School of Medicine, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Mina Ghofraninezad
- Student Research Committee, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Hassan Azhdari-Zarmehri
- Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
- Departments of Physiology, School of Medicine, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Farimah Beheshti
- Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
- Departments of Physiology, School of Medicine, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| |
Collapse
|
|
2
|
Rodella P, Boreski D, Luz MAM, Gabriel EA, Takase LF, Chin CM. Taurine Neuroprotection and Neurogenesis Effect in Chronic Ethanol-Induced Rats. Nutrients 2024; 16:1973. [PMID: 38931326 PMCID: PMC11206532 DOI: 10.3390/nu16121973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/15/2024] [Accepted: 06/17/2024] [Indexed: 06/28/2024] Open
Abstract
Taurine (2-aminoethanesulfonic acid) is a non-protein β-amino acid essential for cellular homeostasis, with antioxidant, anti-inflammatory, and cytoprotective properties that are crucial for life maintenance. This study aimed to evaluate the effects of taurine administration on hippocampal neurogenesis, neuronal preservation, or reverse damage in rats exposed to forced ethanol consumption in an animal model. Wistar rats were treated with ethanol (EtOH) for a 28-day period (5% in the 1st week, 10% in the 2nd week, and 20% in the 3rd and 4th weeks). Two taurine treatment protocols (300 mg/kg i.p.) were implemented: one during ethanol consumption to analyze neuroprotection, and another after ethanol consumption to assess the reversal of ethanol-induced damage. Overall, the results demonstrated that taurine treatment was effective in protecting against deficits induced by ethanol consumption in the dentate gyrus. The EtOH+TAU group showed a significant increase in cell proliferation (145.8%) and cell survival (54.0%) compared to the EtOH+Sal group. The results also indicated similar effects regarding the reversal of ethanol-induced damage 28 days after the cessation of ethanol consumption. The EtOH+TAU group exhibited a significant increase (41.3%) in the number of DCX-immunoreactive cells compared to the EtOH+Sal group. However, this amino acid did not induce neurogenesis in the tissues of healthy rats, implying that its activity may be contingent upon post-injury stimuli.
Collapse
Affiliation(s)
- Patricia Rodella
- Laboratory for Drug Design (LAPDESF), School of Pharmaceutical Sciences, University of São Paulo State (UNESP), Araraquara 14800-903, Brazil; (P.R.); (D.B.)
| | - Diogo Boreski
- Laboratory for Drug Design (LAPDESF), School of Pharmaceutical Sciences, University of São Paulo State (UNESP), Araraquara 14800-903, Brazil; (P.R.); (D.B.)
| | - Marcus Alexandre Mendes Luz
- Advanced Research Center in Medicine (CEPAM), School of Medicine, Union of the Colleges of the Great Lakes (UNILAGO), Sao Jose do Rio Preto 15030-070, Brazil; (M.A.M.L.); (E.A.G.)
| | - Edmo Atique Gabriel
- Advanced Research Center in Medicine (CEPAM), School of Medicine, Union of the Colleges of the Great Lakes (UNILAGO), Sao Jose do Rio Preto 15030-070, Brazil; (M.A.M.L.); (E.A.G.)
| | - Luiz Fernando Takase
- Morphology and Pathology Department, Federal University of São Paulo of São Carlos (UFSCar), São Carlos 13565-905, Brazil;
| | - Chung Man Chin
- Laboratory for Drug Design (LAPDESF), School of Pharmaceutical Sciences, University of São Paulo State (UNESP), Araraquara 14800-903, Brazil; (P.R.); (D.B.)
- Advanced Research Center in Medicine (CEPAM), School of Medicine, Union of the Colleges of the Great Lakes (UNILAGO), Sao Jose do Rio Preto 15030-070, Brazil; (M.A.M.L.); (E.A.G.)
| |
Collapse
|
|
3
|
Amadio P, Sandrini L, Zarà M, Barbieri SS, Ieraci A. NADPH-oxidases as potential pharmacological targets for thrombosis and depression comorbidity. Redox Biol 2024; 70:103060. [PMID: 38310682 PMCID: PMC10848036 DOI: 10.1016/j.redox.2024.103060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/06/2024] Open
Abstract
There is a complex interrelationship between the nervous system and the cardiovascular system. Comorbidities of cardiovascular diseases (CVD) with mental disorders, and vice versa, are prevalent. Adults with mental disorders such as anxiety and depression have a higher risk of developing CVD, and people with CVD have an increased risk of being diagnosed with mental disorders. Oxidative stress is one of the many pathways associated with the pathophysiology of brain and cardiovascular disease. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is one of the major generators of reactive oxygen species (ROS) in mammalian cells, as it is the enzyme that specifically produces superoxide. This review summarizes recent findings on the consequences of NOX activation in thrombosis and depression. It also discusses the therapeutic effects and pharmacological strategies of NOX inhibitors in CVD and brain disorders. A better comprehension of these processes could facilitate the development of new therapeutic approaches for the prevention and treatment of the comorbidity of thrombosis and depression.
Collapse
Affiliation(s)
- Patrizia Amadio
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy
| | - Leonardo Sandrini
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy
| | - Marta Zarà
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy
| | - Silvia S Barbieri
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy.
| | - Alessandro Ieraci
- Department of Theoretical and Applied Sciences, eCampus University, 22060, Novedrate (CO), Italy; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156, Milan, Italy.
| |
Collapse
|
|
4
|
Mendes PFS, Baia-da-Silva DC, Melo WWP, Bittencourt LO, Souza-Rodrigues RD, Fernandes LMP, Maia CDSF, Lima RR. Neurotoxicology of alcohol: a bibliometric and science mapping analysis. Front Pharmacol 2023; 14:1209616. [PMID: 37593178 PMCID: PMC10427875 DOI: 10.3389/fphar.2023.1209616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 07/11/2023] [Indexed: 08/19/2023] Open
Abstract
Alcohol consumption is common in many societies and has increased considerably, resulting in many socioeconomic and public health problems. In this sense, studies have been carried out in order to understand the mechanisms involved in alcohol consumption and related harmful effects. This study aimed to identify and map the knowledge and to perform bibliometric analysis of the neurotoxicology of alcohol based on the 100 most cited articles. A search was carried out in the Web of Science Core Collection database and information was extracted regarding the journal, authors, keywords, year of publication, number of citations, country and continent of the corresponding author. For each selected manuscript, the study design, alcohol exposure model, dose, period of exposure, and effect on the central nervous system and research hotspots were mapped. The journal with the highest number of publications was Alcoholism: Clinical and Experimental Research (n = 11 papers), the author who contributed the most was Crews FT (n = 8 papers), the studies had a total of 288 keywords and 75% of the publications were from the United States of America. The experimental studies evaluated the effects of prenatal and postnatal exposure and were conducted in rats and mice using doses ranging from 2.5 to 14 g/kg/day, with administration by subcutaneous, intraperitoneal, intragastric, or inhalation route or with free access through drinking bottles. Among the studies mapped, the oldest one (1989) aimed to understand the systemic damage and mechanisms of action involved, while the most recent focused on understanding the receptors and mechanisms involved in addiction, as well as genetic factors. Our results show the panorama of the most widespread scientific production in the scientific community on the neurotoxicology of ethanol, a high prevalence was observed in studies that addressed fetal alcohol syndrome and/or the effects of ethanol on neurodevelopment.
Collapse
Affiliation(s)
- Paulo Fernando Santos Mendes
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
| | - Daiane Claydes Baia-da-Silva
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
| | - Wallacy Watson Pereira Melo
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
| | - Leonardo Oliveira Bittencourt
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
| | - Renata Duarte Souza-Rodrigues
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
| | - Luanna Melo Pereira Fernandes
- Department of Morphology and Physiological Sciences, Center of Sciences Biological and Health, State University of Pará, Belém, Brazil
| | | | - Rafael Rodrigues Lima
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
| |
Collapse
|
|
5
|
Nalberczak-Skóra M, Beroun A, Skonieczna E, Cały A, Ziółkowska M, Pagano R, Taheri P, Kalita K, Salamian A, Radwanska K. Impaired synaptic transmission in dorsal dentate gyrus increases impulsive alcohol seeking. Neuropsychopharmacology 2023; 48:436-447. [PMID: 36182989 PMCID: PMC9852589 DOI: 10.1038/s41386-022-01464-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 02/02/2023]
Abstract
Both human and animal studies indicate that the dentate gyrus (DG) of the hippocampus is highly exploited by drug and alcohol abuse. Yet, it is poorly understood how DG dysfunction affects addiction-related behaviors. Here, we used an animal model of alcohol use disorder (AUD) in automated IntelliCages and performed local genetic manipulation to investigate how synaptic transmission in the dorsal DG (dDG) affects alcohol-related behaviors. We show that a cue light induces potentiation-like plasticity of dDG synapses in alcohol-naive mice. This process is impaired in mice trained to drink alcohol. Acamprosate (ACA), a drug that reduces alcohol relapse, rescues the impairment of dDG synaptic transmission in alcohol mice. A molecular manipulation that reduces dDG synaptic AMPAR and NMDAR levels increases impulsive alcohol seeking during cue relapse (CR) in alcohol mice but does not affect alcohol reward, motivation or craving. These findings suggest that hindered dDG synaptic transmission specifically underlies impulsive alcohol seeking induced by alcohol cues, a core symptom of AUD.
Collapse
Affiliation(s)
- Maria Nalberczak-Skóra
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland ,grid.460447.50000 0001 2161 9572Experimental Psychopathology Lab, Institute of Psychology of Polish Academy of Sciences, Warsaw, Poland
| | - Anna Beroun
- grid.419305.a0000 0001 1943 2944BRAINCITY, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Edyta Skonieczna
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Anna Cały
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Magdalena Ziółkowska
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Roberto Pagano
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Pegah Taheri
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Katarzyna Kalita
- grid.419305.a0000 0001 1943 2944BRAINCITY, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Ahmad Salamian
- grid.419305.a0000 0001 1943 2944Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Kasia Radwanska
- Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
| |
Collapse
|
|
6
|
van den Oord EJCG, Xie LY, Zhao M, Aberg KA, Clark SL. A single-nucleus transcriptomics study of alcohol use disorder in the nucleus accumbens. Addict Biol 2023; 28:e13250. [PMID: 36577731 DOI: 10.1111/adb.13250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 08/29/2022] [Accepted: 10/13/2022] [Indexed: 11/14/2022]
Abstract
Gene expression studies offer promising opportunities to better understand the processes underlying alcohol use disorder (AUD). As cell types differ in their function, gene expression profiles will typically vary across cell types. When studying bulk tissue, failure to account for this cellular diversity has a detrimental impact on the ability to detect disease associations. We therefore assayed the transcriptomes of 32,531 individual nuclei extracted from the nucleus accumbens (NAc) of nine donors with AUD and nine controls (72% male). Our study identified 17 clearly delineated cell types. We detected 26 transcriptome-wide significant differentially expressed genes (DEGs) that mainly involved medium spiny neurons with both D1-type and D2-type dopamine receptors, microglia (MGL) and oligodendrocytes. A higher than expected number of DEGs replicated in an existing single nucleus gene expression study of alcohol dependence in the prefrontal cortex (enrichment ratio 1.91, p value 0.019) with two genes remaining significant after a Bonferroni correction. Our most compelling result involved CD53 in MGL that replicated in the same cell type in the prefrontal cortex and was previously implicated in studies of DNA methylation, bulk gene expression and genetic variants. Several DEGs were previously reported to be associated with AUD (e.g., PER1 and MGAT5). The DEGs for MSN.3 seemed involved in neurodegeneration, disruption of circadian rhythms, alterations in glucose metabolism and changes in synaptic plasticity. For MGL, the DEGs implicated neuroinflammation and immune-related processes and for OLI, disruptions in myelination. This identification of the specific cell-types from which the association signals originate will be key for designing proper follow-up experiments and, eventually, novel clinical interventions.
Collapse
Affiliation(s)
- Edwin J C G van den Oord
- Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Lin Y Xie
- Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Min Zhao
- Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Karolina A Aberg
- Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Shaunna L Clark
- Department of Psychiatry & Behavioral Sciences, Texas A&M University, College Station, Texas, USA
| |
Collapse
|
|
7
|
Huang S, White DR, Marinkovic K. Alterations of theta power and synchrony during encoding in young adult binge drinkers: Subsequent memory effects associated with retrieval after 48 h and 6 months. Front Psychol 2022; 13:1061016. [PMID: 36591031 PMCID: PMC9798430 DOI: 10.3389/fpsyg.2022.1061016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 11/22/2022] [Indexed: 12/23/2022] Open
Abstract
Introduction Young emerging adults commonly engage in binge drinking which is associated with a range of neurocognitive deficits, including memory impairments. However, evidence on neural oscillations mediating episodic memory in this population is lacking. To address this gap, we recorded theta oscillatory activity in young binge (BDs) and light drinkers (LDs) during memory encoding and analyzed it prospectively as a function of subsequent retrieval. Theta underlies successful encoding of novel items in memory through corticolimbic integration. Subsequent memory effects (SMEs) are reflected in stronger theta activity during encoding of the items that are later remembered compared to those that are later forgotten. Methods In the present study, 23 BDs (age: 23.3 ± 3.3) and 24 LDs (age: 23.4 ± 3.3) rated emotionally evocative images with negative, positive, and neutral themes during implicit encoding. They performed a recognition memory task on two follow-up occasions after a short (48 h), and long retention delay (6 months). Electroencephalography (EEG) signal was recorded during the encoding session and analyzed in time-frequency domain with Morlet wavelets in theta band (4-7 Hz). To evaluate SMEs, the event-related theta oscillations acquired during encoding were analyzed based on recognition outcomes after the two retention intervals. Results The BD and LD groups did not differ on recognition memory. However, BDs showed attenuated event-related theta power during encoding of images that were successfully retained after 6 months compared to LDs. In addition, theta synchronous activity between frontal and left posterior regions during encoding successfully predicted recognition of the images after both retention delays in LDs but not in BDs. These SMEs on theta power and synchrony correlated negatively with high-intensity drinking in the previous 6 months. No differences between men and women were observed for any analysis. Discussion It has been well established that long-range neural synchrony between cortical and limbic nodes underlies successful memory encoding and retention which, in turn, depends on neural excitation/inhibition (E/I) balance. Given that binge drinking is associated with E/I dysregulation, the observed SME deficiencies are consistent with other evidence of neural hyperexcitability in BDs, and may be indicative of increased risk of developing alcohol use disorders.
Collapse
Affiliation(s)
- Siyuan Huang
- Spatio-Temporal Brain Imaging Laboratory, Department of Psychology, San Diego State University, San Diego, CA, United States
| | - David R. White
- Spatio-Temporal Brain Imaging Laboratory, Department of Psychology, San Diego State University, San Diego, CA, United States
| | - Ksenija Marinkovic
- Spatio-Temporal Brain Imaging Laboratory, Department of Psychology, San Diego State University, San Diego, CA, United States,Department of Radiology, University of California, San Diego, San Diego CA, United States,*Correspondence: Ksenija Marinkovic,
| |
Collapse
|
|
8
|
Xu Z, Zhang J, Wu J, Yang S, Li Y, Wu Y, Li S, Zhang X, Zuo W, Lian X, Lin J, Jiang Y, Xie L, Liu Y, Wang P. Lactobacillus plantarum ST-III culture supernatant ameliorates alcohol-induced cognitive dysfunction by reducing endoplasmic reticulum stress and oxidative stress. Front Neurosci 2022; 16:976358. [PMID: 36188464 PMCID: PMC9515438 DOI: 10.3389/fnins.2022.976358] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/15/2022] [Indexed: 11/28/2022] Open
Abstract
Background Long-term alcohol exposure is associated with oxidative stress, endoplasmic reticulum (ER) stress, and neuroinflammation, which may impair cognitive function. Probiotics supplements can significantly improve cognitive function in neurodegenerative diseases such as Alzheimer’s disease. Nevertheless, the effect of Lactobacillus plantarum ST-III culture supernatant (LP-cs) on alcohol-induced cognitive dysfunction remains unclear. Methods A mouse model of cognitive dysfunction was established by intraperitoneal injection of alcohol (2 g/kg body weight) for 28 days. Mice were pre-treated with LP-cs, and cognitive function was evaluated using the Morris water maze test. Hippocampal tissues were collected for biochemical and molecular analysis. Results LP-cs significantly ameliorated alcohol-induced decline in learning and memory function and hippocampal morphology changes, neuronal apoptosis, and synaptic dysfunction. A mechanistic study showed that alcohol activated protein kinase R-like endoplasmic reticulum kinase (PERK) signaling and suppressed brain derived neurotrophic factor (BDNF) levels via ER stress in the hippocampus, which LP-cs reversed. Alcohol activated oxidative stress and inflammation responses in the hippocampus, which LP-cs reversed. Conclusion LP-cs significantly ameliorated alcohol-induced cognitive dysfunction and cellular stress. LP-cs might serve as an effective treatment for alcohol-induced cognitive dysfunction.
Collapse
Affiliation(s)
- Zeping Xu
- Department of Pharmacy, Ningbo Medical Center Li Huili Hospital, The Affiliated Hospital of Ningbo University, Ningbo, China
| | - Jinjing Zhang
- Department of Pharmacy, Affiliated Cixi Hospital, Wenzhou Medical University, Wenzhou, China
| | - Junnan Wu
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
- The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, China
| | - Shizhuo Yang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yuying Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yuyu Wu
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Siyuan Li
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Xie Zhang
- Department of Pharmacy, Ningbo Medical Center Li Huili Hospital, The Affiliated Hospital of Ningbo University, Ningbo, China
| | - Wei Zuo
- The Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, China
| | - Xiang Lian
- The Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, China
| | - Jianjun Lin
- The Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, China
| | - Yongsheng Jiang
- The Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, China
| | - Longteng Xie
- The Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, China
- Longteng Xie,
| | - Yanlong Liu
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
- The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, China
- *Correspondence: Yanlong Liu,
| | - Ping Wang
- The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
- Ping Wang,
| |
Collapse
|
|
9
|
Thomas KN, Zimmel KN, Basel A, Roach AN, Mehta NA, Thomas KR, Dotson LJ, Bedi YS, Golding MC. Paternal alcohol exposures program intergenerational hormetic effects on offspring fetoplacental growth. Front Cell Dev Biol 2022; 10:930375. [PMID: 36036017 PMCID: PMC9405020 DOI: 10.3389/fcell.2022.930375] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/30/2022] [Indexed: 12/03/2022] Open
Abstract
Hormesis refers to graded adaptive responses to harmful environmental stimuli where low-level toxicant exposures stimulate tissue growth and responsiveness while, in contrast, higher-level exposures induce toxicity. Although the intergenerational inheritance of programmed hormetic growth responses is described in plants and insects, researchers have yet to observe this phenomenon in mammals. Using a physiologically relevant mouse model, we demonstrate that chronic preconception paternal alcohol exposures program nonlinear, dose-dependent changes in offspring fetoplacental growth. Our studies identify an inverse j-shaped curve with a threshold of 2.4 g/Kg per day; below this threshold, paternal ethanol exposures induce programmed increases in placental growth, while doses exceeding this point yield comparative decreases in placental growth. In male offspring, higher paternal exposures induce dose-dependent increases in the placental labyrinth layer but do not impact fetal growth. In contrast, the placental hypertrophy induced by low-level paternal ethanol exposures associate with increased offspring crown-rump length, particularly in male offspring. Finally, alterations in placental physiology correlate with disruptions in both mitochondrial-encoded and imprinted gene expression. Understanding the influence of ethanol on the paternally-inherited epigenetic program and downstream hormetic responses in offspring growth may help explain the enormous variation observed in fetal alcohol spectrum disorder (FASD) phenotypes and incidence.
Collapse
|
|
10
|
Manohar S, Chen GD, Ding D, Liu L, Wang J, Chen YC, Chen L, Salvi R. Unexpected Consequences of Noise-Induced Hearing Loss: Impaired Hippocampal Neurogenesis, Memory, and Stress. Front Integr Neurosci 2022; 16:871223. [PMID: 35619926 PMCID: PMC9127992 DOI: 10.3389/fnint.2022.871223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 03/21/2022] [Indexed: 11/17/2022] Open
Abstract
Noise-induced hearing loss (NIHL), caused by direct damage to the cochlea, reduces the flow of auditory information to the central nervous system, depriving higher order structures, such as the hippocampus with vital sensory information needed to carry out complex, higher order functions. Although the hippocampus lies outside the classical auditory pathway, it nevertheless receives acoustic information that influence its activity. Here we review recent results that illustrate how NIHL and other types of cochlear hearing loss disrupt hippocampal function. The hippocampus, which continues to generate new neurons (neurogenesis) in adulthood, plays an important role in spatial navigation, memory, and emotion. The hippocampus, which contains place cells that respond when a subject enters a specific location in the environment, integrates information from multiple sensory systems, including the auditory system, to develop cognitive spatial maps to aid in navigation. Acute exposure to intense noise disrupts the place-specific firing patterns of hippocampal neurons, "spatially disorienting" the cells for days. More traumatic sound exposures that result in permanent NIHL chronically suppresses cell proliferation and neurogenesis in the hippocampus; these structural changes are associated with long-term spatial memory deficits. Hippocampal neurons, which contain numerous glucocorticoid hormone receptors, are part of a complex feedback network connected to the hypothalamic-pituitary (HPA) axis. Chronic exposure to intense intermittent noise results in prolonged stress which can cause a persistent increase in corticosterone, a rodent stress hormone known to suppress neurogenesis. In contrast, a single intense noise exposure sufficient to cause permanent hearing loss produces only a transient increase in corticosterone hormone. Although basal corticosterone levels return to normal after the noise exposure, glucocorticoid receptors (GRs) in the hippocampus remain chronically elevated. Thus, NIHL disrupts negative feedback from the hippocampus to the HPA axis which regulates the release of corticosterone. Preclinical studies suggest that the noise-induced changes in hippocampal place cells, neurogenesis, spatial memory, and glucocorticoid receptors may be ameliorated by therapeutic interventions that reduce oxidative stress and inflammation. These experimental results may provide new insights on why hearing loss is a risk factor for cognitive decline and suggest methods for preventing this decline.
Collapse
Affiliation(s)
- Senthilvelan Manohar
- Center for Hearing and Deafness, University at Buffalo, Buffalo, NY, United States
| | - Guang-Di Chen
- Center for Hearing and Deafness, University at Buffalo, Buffalo, NY, United States
| | - Dalian Ding
- Center for Hearing and Deafness, University at Buffalo, Buffalo, NY, United States
| | - Lijie Liu
- Department of Physiology, Medical College, Southeast University, Nanjing, China
| | - Jian Wang
- School of Communication Science and Disorders, Dalhousie University, Halifax, NS, Canada
| | - Yu-Chen Chen
- Department of Radiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Lin Chen
- Auditory Research Laboratory, University of Science and Technology of China, Hefei, China
| | - Richard Salvi
- Center for Hearing and Deafness, University at Buffalo, Buffalo, NY, United States
| |
Collapse
|
|
11
|
Ahdoot-Levi H, Croitoru O, Bareli T, Sudai E, Peér-Nissan H, Jacob A, Gispan I, Maayan R, Weizman A, Yadid G. The Effect of Dehydroepiandrosterone Treatment on Neurogenesis, Astrogliosis and Long-Term Cocaine-Seeking Behavior in a Cocaine Self-Administration Model in Rats. Front Neurosci 2021; 15:773197. [PMID: 34899172 PMCID: PMC8662380 DOI: 10.3389/fnins.2021.773197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 10/25/2021] [Indexed: 11/13/2022] Open
Abstract
Cocaine addiction is an acquired behavioral state developed in vulnerable individuals after cocaine exposure. It is characterized by compulsive drug-seeking and high vulnerability to relapse even after prolonged abstinence, associated with decreased neurogenesis in the hippocampus. This addictive state is hypothesized to be a form of “memory disease” in which the drug exploits the physiological neuroplasticity mechanisms that mediate regular learning and memory processes. Therefore, a major focus of the field has been to identify the cocaine-induced neuroadaptations occurring in the usurped brain’s reward circuit. The neurosteroid dehydroepiandrosterone (DHEA) affects brain cell morphology, differentiation, neurotransmission, and memory. It also reduces drug-seeking behavior in an animal model of cocaine self-administration. Here, we examined the long-lasting effects of DHEA treatment on the attenuation of cocaine-seeking behavior. We also examined its short- and long-term influence on hippocampal cells architecture (neurons and astrocytes). Using a behavioral examination, immunohistochemical staining, and diffusion tensor imaging, we found an immediate effect on tissue density and activation of astrocytes, which has a continuous beneficial effect on neurogenesis and tissue organization. This research emphasizes the requites concert between astrocytes and neurons in the rehabilitation from addiction behavior. Thus, DHEA may serve as a treatment that corrects brain damage following exposure to and abstinence from cocaine.
Collapse
Affiliation(s)
- Hadas Ahdoot-Levi
- Neuropharmacology Laboratory, The Mina and Everard Goodman Faculty of Life Sciences, Ramat-Gan, Israel
| | - Ofri Croitoru
- Neuropharmacology Laboratory, The Mina and Everard Goodman Faculty of Life Sciences, Ramat-Gan, Israel
| | - Tzofnat Bareli
- Neuropharmacology Laboratory, The Mina and Everard Goodman Faculty of Life Sciences, Ramat-Gan, Israel
| | - Einav Sudai
- Neuropharmacology Laboratory, The Mina and Everard Goodman Faculty of Life Sciences, Ramat-Gan, Israel.,The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Ramat-Gan, Israel
| | - Hilla Peér-Nissan
- Neuropharmacology Laboratory, The Mina and Everard Goodman Faculty of Life Sciences, Ramat-Gan, Israel
| | - Avi Jacob
- Neuropharmacology Laboratory, The Mina and Everard Goodman Faculty of Life Sciences, Ramat-Gan, Israel
| | - Iris Gispan
- Neuropharmacology Laboratory, The Mina and Everard Goodman Faculty of Life Sciences, Ramat-Gan, Israel
| | - Rachel Maayan
- The Laboratory of Biological Psychiatry, Felsenstein Medical Research Center and Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel
| | - Abraham Weizman
- The Laboratory of Biological Psychiatry, Felsenstein Medical Research Center and Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel.,Research Unit, Geha Mental Health Center, Petah Tikva, Israel
| | - Gal Yadid
- Neuropharmacology Laboratory, The Mina and Everard Goodman Faculty of Life Sciences, Ramat-Gan, Israel.,The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Ramat-Gan, Israel
| |
Collapse
|
|
12
|
Dai X, Gao L, Zhang H, Wei X, Liu Z. A combination of support vector machine and voxel-based morphometry in adult male alcohol use disorder patients with cognitive deficits. Brain Res 2021; 1771:147644. [PMID: 34478708 DOI: 10.1016/j.brainres.2021.147644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 08/05/2021] [Accepted: 08/28/2021] [Indexed: 10/20/2022]
Abstract
Cognitive performance deteriorates with drinking. However, the neural basis of cognitive deficits in alcohol use disorder (AUD) is still incompletely understood. Here we examined the relationship between overall drinking, brain structural alterations and cognitive deficits in AUD. A total of 40 middle-aged AUD males and 40 healthy controls (HC) underwent high-resolution anatomical imaging scans, and the data were analyzed using voxel-based morphometry, support vector machine (SVM) classification and mediation analysis. The AUD patients demonstrated reduced gray matter (GM) volumes that included left amygdala, thalamus, hippocampus, precentral gyrus, cerebellum, calcarine, right supplementary motor area and bilateral superior temporal gyri (voxel-wise p < 0.05, FWE corrected). The SVM results could distinguish AUD from HC with satisfactory classification results (0.8275). GM volumes in the bilateral cerebellum and thalamus, left anterior medial temporal lobe, left nucleus ambiguus + parahippocampus gyrus, left fusiform gyrus, left lingual gyrus, left hippocampus, and right nucleus accumbens had positive correlations with the Montreal Cognitive Assessment (MoCA) scores. Further mediation analysis showed that left cerebellum crus 1 partially mediated the relationship between overall drinking and MoCA scores (standardized beta coefficient = -0.0973, SE = 0.0002, 95% CI = (-0.0006, 0.0000)). Our findings showed widespread GM atrophies and many of these atrophies also mirrored cognitive deficits and were robustly distinguishable. Critically, the left cerebellum crus 1 partially mediated the relationship betweem overall drinking and MoCA scores, suggesting a pathway by which alcohol abuse impairs cognition and accelerates brain ageing in middle-aged AUD males.
Collapse
Affiliation(s)
- Xiyong Dai
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510080, China; Department of Radiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China; Department of Radiology, the Third People's Hospital of Zhongshan, Zhongshan, Guangdong 528451, China
| | - Lei Gao
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, Hube 430071, China
| | - Haibo Zhang
- Department of Radiology, the Third People's Hospital of Zhongshan, Zhongshan, Guangdong 528451, China
| | - Xinhua Wei
- Department of Radiology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China.
| | - Zaiyi Liu
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510080, China; Department of Radiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China.
| |
Collapse
|
|
13
|
Role of hippocampal NF-κB and GluN2B in the memory acquisition impairment of experiences gathered prior to cocaine administration in rats. Sci Rep 2021; 11:20033. [PMID: 34625609 PMCID: PMC8501066 DOI: 10.1038/s41598-021-99448-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 09/16/2021] [Indexed: 12/24/2022] Open
Abstract
Cocaine can induce severe neurobehavioral changes, among others, the ones involved in learning and memory processes. It is known that during drug consumption, cocaine-associated memory and learning processes take place. However, much less is known about the effects of this drug upon the mechanisms involved in forgetting.The present report focuses on the mechanisms by which cocaine affects memory consolidation of experiences acquired prior to drug administration. We also study the involvement of hippocampus in these processes, with special interest on the role of Nuclear factor kappa B (NF-κB), N-methyl-D-aspartate glutamate receptor 2B (GluN2B), and their relationship with other proteins, such as cyclic AMP response element binding protein (CREB). For this purpose, we developed a rat experimental model of chronic cocaine administration in which spatial memory and the expression or activity of several proteins in the hippocampus were assessed after 36 days of drug administration. We report an impairment in memory acquisition of experiences gathered prior to cocaine administration, associated to an increase in GluN2B expression in the hippocampus. We also demonstrate a decrease in NF-κB activity, as well as in the expression of the active form of CREB, confirming the role of these transcription factors in the cocaine-induced memory impairment.
Collapse
|
|
14
|
Nawarawong NN, Thompson KR, Guerin SP, Anasooya Shaji C, Peng H, Nixon K. Reactive, Adult Neurogenesis From Increased Neural Progenitor Cell Proliferation Following Alcohol Dependence in Female Rats. Front Neurosci 2021; 15:689601. [PMID: 34594180 PMCID: PMC8477003 DOI: 10.3389/fnins.2021.689601] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 08/16/2021] [Indexed: 11/25/2022] Open
Abstract
Hippocampal neurodegeneration is a consequence of excessive alcohol drinking in alcohol use disorders (AUDs), however, recent studies suggest that females may be more susceptible to alcohol-induced brain damage. Adult hippocampal neurogenesis is now well accepted to contribute to hippocampal integrity and is known to be affected by alcohol in humans as well as in animal models of AUDs. In male rats, a reactive increase in adult hippocampal neurogenesis has been observed during abstinence from alcohol dependence, a phenomenon that may underlie recovery of hippocampal structure and function. It is unknown whether reactive neurogenesis occurs in females. Therefore, adult female rats were exposed to a 4-day binge model of alcohol dependence followed by 7 or 14 days of abstinence. Immunohistochemistry (IHC) was used to assess neural progenitor cell (NPC) proliferation (BrdU and Ki67), the percentage of increased NPC activation (Sox2+/Ki67+), the number of immature neurons (NeuroD1), and ectopic dentate gyrus granule cells (Prox1). On day seven of abstinence, ethanol-treated females showed a significant increase in BrdU+ and Ki67+ cells in the subgranular zone of the dentate gyrus (SGZ), as well as greater activation of NPCs (Sox2+/Ki67+) into active cycling. At day 14 of abstinence, there was a significant increase in the number of immature neurons (NeuroD1+) though no evidence of ectopic neurogenesis according to either NeuroD1 or Prox1 immunoreactivity. Altogether, these data suggest that alcohol dependence produces similar reactive increases in NPC proliferation and adult neurogenesis. Thus, reactive, adult neurogenesis may be a means of recovery for the hippocampus after alcohol dependence in females.
Collapse
Affiliation(s)
- Natalie N Nawarawong
- College of Pharmacy, The University of Texas at Austin, Austin, TX, United States
| | - K Ryan Thompson
- College of Pharmacy, The University of Texas at Austin, Austin, TX, United States
| | - Steven P Guerin
- College of Pharmacy, The University of Texas at Austin, Austin, TX, United States
| | | | - Hui Peng
- Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, United States
| | - Kimberly Nixon
- College of Pharmacy, The University of Texas at Austin, Austin, TX, United States
| |
Collapse
|
|
15
|
Rodrigues RS, Paulo SL, Moreira JB, Tanqueiro SR, Sebastião AM, Diógenes MJ, Xapelli S. Adult Neural Stem Cells as Promising Targets in Psychiatric Disorders. Stem Cells Dev 2021; 29:1099-1117. [PMID: 32723008 DOI: 10.1089/scd.2020.0100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The development of new therapies for psychiatric disorders is of utmost importance, given the enormous toll these disorders pose to society nowadays. This should be based on the identification of neural substrates and mechanisms that underlie disease etiopathophysiology. Adult neural stem cells (NSCs) have been emerging as a promising platform to counteract brain damage. In this perspective article, we put forth a detailed view of how NSCs operate in the adult brain and influence brain homeostasis, having profound implications at both behavioral and functional levels. We appraise evidence suggesting that adult NSCs play important roles in regulating several forms of brain plasticity, particularly emotional and cognitive flexibility, and that NSC dynamics are altered upon brain pathology. Furthermore, we discuss the potential therapeutic value of utilizing adult endogenous NSCs as vessels for regeneration, highlighting their importance as targets for the treatment of multiple mental illnesses, such as affective disorders, schizophrenia, and addiction. Finally, we speculate on strategies to surpass current challenges in neuropsychiatric disease modeling and brain repair.
Collapse
Affiliation(s)
- Rui S Rodrigues
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Sara L Paulo
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - João B Moreira
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Sara R Tanqueiro
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Ana M Sebastião
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Maria J Diógenes
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Sara Xapelli
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| |
Collapse
|
|
16
|
Nawarawong NN, Nickell CG, Hopkins DM, Pauly JR, Nixon K. Functional Activation of Newborn Neurons Following Alcohol-Induced Reactive Neurogenesis. Brain Sci 2021; 11:499. [PMID: 33921189 PMCID: PMC8071556 DOI: 10.3390/brainsci11040499] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/10/2021] [Accepted: 04/11/2021] [Indexed: 02/07/2023] Open
Abstract
Abstinence after alcohol dependence leads to structural and functional recovery in many regions of the brain, especially the hippocampus. Significant increases in neural stem cell (NSC) proliferation and subsequent "reactive neurogenesis" coincides with structural recovery in hippocampal dentate gyrus (DG). However, whether these reactively born neurons are integrated appropriately into neural circuits remains unknown. Therefore, adult male rats were exposed to a binge model of alcohol dependence. On day 7 of abstinence, the peak of reactive NSC proliferation, rats were injected with bromodeoxyuridine (BrdU) to label dividing cells. After six weeks, rats underwent Morris Water Maze (MWM) training then were sacrificed ninety minutes after the final training session. Using fluorescent immunohistochemistry for c-Fos (neuronal activation), BrdU, and Neuronal Nuclei (NeuN), we investigated whether neurons born during reactive neurogenesis were incorporated into a newly learned MWM neuronal ensemble. Prior alcohol exposure increased the number of BrdU+ cells and newborn neurons (BrdU+/NeuN+ cells) in the DG versus controls. However, prior ethanol exposure had no significant impact on MWM-induced c-Fos expression. Despite increased BrdU+ neurons, no difference in the number of activated newborn neurons (BrdU+/c-Fos+/NeuN+) was observed. These data suggest that neurons born during alcohol-induced reactive neurogenesis are functionally integrated into hippocampal circuitry.
Collapse
Affiliation(s)
| | - Chelsea G. Nickell
- Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA; (C.G.N.); (D.M.H.); (J.R.P.)
| | - Deann M. Hopkins
- Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA; (C.G.N.); (D.M.H.); (J.R.P.)
| | - James R. Pauly
- Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA; (C.G.N.); (D.M.H.); (J.R.P.)
| | - Kimberly Nixon
- College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA;
- Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA; (C.G.N.); (D.M.H.); (J.R.P.)
| |
Collapse
|
|
17
|
Shin SK, Kaiser EE, West FD. Alcohol Induced Brain and Liver Damage: Advantages of a Porcine Alcohol Use Disorder Model. Front Physiol 2021; 11:592950. [PMID: 33488396 PMCID: PMC7818780 DOI: 10.3389/fphys.2020.592950] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/01/2020] [Indexed: 12/30/2022] Open
Abstract
Alcohol is one of the most commonly abused intoxicants with 1 in 6 adults at risk for alcohol use disorder (AUD) in the United States. As such, animal models have been extensively investigated with rodent AUD models being the most widely studied. However, inherent anatomical and physiological differences between rodents and humans pose a number of limitations in studying the complex nature of human AUD. For example, rodents differ from humans in that rodents metabolize alcohol rapidly and do not innately demonstrate voluntary alcohol consumption. Comparatively, pigs exhibit similar patterns observed in human AUD including voluntary alcohol consumption and intoxication behaviors, which are instrumental in establishing a more representative AUD model that could in turn delineate the risk factors involved in the development of this disorder. Pigs and humans also share anatomical similarities in the two major target organs of alcohol- the brain and liver. Pigs possess gyrencephalic brains with comparable cerebral white matter volumes to humans, thus enabling more representative evaluations of susceptibility and neural tissue damage in response to AUD. Furthermore, similarities in the liver result in a comparable rate of alcohol elimination as humans, thus enabling a more accurate extrapolation of dosage and intoxication level to humans. A porcine model of AUD possesses great translational potential that can significantly advance our current understanding of the complex development and continuance of AUD in humans.
Collapse
Affiliation(s)
- Soo K Shin
- Regenerative Bioscience Center, University of Georgia, Athens, GA, United States.,Interdisciplinary Toxicology Program, University of Georgia, Athens, GA, United States.,Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, University of Georgia, Athens, GA, United States
| | - Erin E Kaiser
- Regenerative Bioscience Center, University of Georgia, Athens, GA, United States.,Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, University of Georgia, Athens, GA, United States.,Neuroscience Program, Biomedical and Health Sciences Institute, University of Georgia, Athens, GA, United States
| | - Franklin D West
- Regenerative Bioscience Center, University of Georgia, Athens, GA, United States.,Interdisciplinary Toxicology Program, University of Georgia, Athens, GA, United States.,Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, University of Georgia, Athens, GA, United States.,Neuroscience Program, Biomedical and Health Sciences Institute, University of Georgia, Athens, GA, United States
| |
Collapse
|
|
18
|
Nickell CG, Thompson KR, Pauly JR, Nixon K. Recovery of Hippocampal-Dependent Learning Despite Blunting Reactive Adult Neurogenesis After Alcohol Dependence. Brain Plast 2020; 6:83-101. [PMID: 33680848 PMCID: PMC7903006 DOI: 10.3233/bpl-200108] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background: The excessive alcohol drinking that occurs in alcohol use disorder (AUD) causes neurodegeneration in regions such as the hippocampus, though recovery may occur after a period of abstinence. Mechanisms of recovery are not clear, though reactive neurogenesis has been observed in the hippocampal dentate gyrus following alcohol dependence and correlates to recovery of granule cell number. Objective: We investigated the role of neurons born during reactive neurogenesis in the recovery of hippocampal learning behavior after 4-day binge alcohol exposure, a model of an AUD. We hypothesized that reducing reactive neurogenesis would impair functional recovery. Methods: Adult male rats were subjected to 4-day binge alcohol exposure and two approaches were tested to blunt reactive adult neurogenesis, acute doses of alcohol or the chemotherapy drug, temozolomide (TMZ). Results: Acute 5 g/kg doses of EtOH gavaged T6 and T7 days post binge did not inhibit significantly the number of Bromodeoxyuridine-positive (BrdU+) proliferating cells in EtOH animals receiving 5 g/kg EtOH versus controls. A single cycle of TMZ inhibited reactive proliferation (BrdU+ cells) and neurogenesis (NeuroD+ cells) to that of controls. However, despite this blunting of reactive neurogenesis to basal levels, EtOH-TMZ rats were not impaired in their recovery of acquisition of the Morris water maze (MWM), learning similarly to all other groups 35 days after 4-day binge exposure. Conclusions: These studies show that TMZ is effective in decreasing reactive proliferation/neurogenesis following 4-day binge EtOH exposure, and baseline levels of adult neurogenesis are sufficient to allow recovery of hippocampal function.
Collapse
Affiliation(s)
- Chelsea G Nickell
- University of Kentucky, Department of Pharmaceutical Sciences, Lexington, KY, USA
| | - K Ryan Thompson
- The University of Texas at Austin, College of Pharmacy, Austin, TX, USA
| | - James R Pauly
- University of Kentucky, Department of Pharmaceutical Sciences, Lexington, KY, USA
| | - Kimberly Nixon
- University of Kentucky, Department of Pharmaceutical Sciences, Lexington, KY, USA.,The University of Texas at Austin, College of Pharmacy, Austin, TX, USA
| |
Collapse
|
|
19
|
Abstract
Chronic alcohol consumption results in alcohol use disorder (AUD). Interestingly, however, sudden alcohol withdrawal (AW) after chronic alcohol exposure also leads to a devastating series of symptoms, referred to as alcohol withdrawal syndromes. One key feature of AW syndromes is to produce phenotypes that are opposite to AUD. For example, while the brain is characterized by a hypoactive state in the presence of alcohol, AW induces a hyperactive state, which is manifested as seizure expression. In this review, we discuss the idea that hippocampal neurogenesis and neural circuits play a key role in neuroadaptation and establishment of allostatic states in response to alcohol exposure and AW. The intrinsic properties of dentate granule cells (DGCs), and their contribution to the formation of a potent feedback inhibitory loop, endow the dentate gyrus with a "gate" function, which can limit the entry of excessive excitatory signals from the cortex into the hippocampus. We discuss the possibility that alcohol exposure and withdrawal disrupts structural development and circuitry integration of hippocampal newborn neurons, and that this altered neurogenesis impairs the gate function of the hippocampus. Failure of this gate function is expected to alter the ratio of excitatory to inhibitory (E/I) signals in the hippocampus and to induce seizure expression during AW. Recent functional studies have shown that specific activation and inhibition of hippocampal newborn DGCs are both necessary and sufficient for the expression of AW-associated seizures, further supporting the concept that neurogenesis-induced neuroadaptation is a critical target to understand and treat AUD and AW-associated seizures.
Collapse
Affiliation(s)
- Sreetama Basu
- Department of Neurosciences, Cleveland Clinic, Cleveland, OH, USA
| | - Hoonkyo Suh
- Department of Neurosciences, Cleveland Clinic, Cleveland, OH, USA
| |
Collapse
|
|
20
|
Alvarez Cooper I, Beecher K, Chehrehasa F, Belmer A, Bartlett SE. Tumour Necrosis Factor in Neuroplasticity, Neurogenesis and Alcohol Use Disorder. Brain Plast 2020; 6:47-66. [PMID: 33680846 PMCID: PMC7903009 DOI: 10.3233/bpl-190095] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Alcohol use disorder is a pervasive and detrimental condition that involves changes in neuroplasticity and neurogenesis. Alcohol activates the neuroimmune system and alters the inflammatory status of the brain. Tumour necrosis factor (TNF) is a well characterised neuroimmune signal but its involvement in alcohol use disorder is unknown. In this review, we discuss the variable findings of TNF's effect on neuroplasticity and neurogenesis. Acute ethanol exposure reduces TNF release while chronic alcohol intake generally increases TNF levels. Evidence suggests TNF potentiates excitatory transmission, promotes anxiety during alcohol withdrawal and is involved in drug use in rodents. An association between craving for alcohol and TNF is apparent during withdrawal in humans. While anti-inflammatory therapies show efficacy in reversing neurogenic deficit after alcohol exposure, there is no evidence for TNF's essential involvement in alcohol's effect on neurogenesis. Overall, defining TNF's role in alcohol use disorder is complicated by poor understanding of its variable effects on synaptic transmission and neurogenesis. While TNF may be of relevance during withdrawal, the neuroimmune system likely acts through a larger group of inflammatory cytokines to alter neuroplasticity and neurogenesis. Understanding the individual relevance of TNF in alcohol use disorder awaits a more comprehensive understanding of TNF's effects within the brain.
Collapse
Affiliation(s)
- Ignatius Alvarez Cooper
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
- Institute of Health and Biomedical Innovation, Translational Research Institute, Brisbane, Australia
| | - Kate Beecher
- Institute of Health and Biomedical Innovation, Translational Research Institute, Brisbane, Australia
- School of Clinical Sciences, Queensland University of Technology, Brisbane, Australia
| | - Fatemeh Chehrehasa
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
- Institute of Health and Biomedical Innovation, Translational Research Institute, Brisbane, Australia
| | - Arnauld Belmer
- Institute of Health and Biomedical Innovation, Translational Research Institute, Brisbane, Australia
- School of Clinical Sciences, Queensland University of Technology, Brisbane, Australia
| | - Selena E. Bartlett
- Institute of Health and Biomedical Innovation, Translational Research Institute, Brisbane, Australia
- School of Clinical Sciences, Queensland University of Technology, Brisbane, Australia
| |
Collapse
|
|
21
|
Tavanasefat H, Li F, Koyano K, Gourtani BK, Marty V, Mulpuri Y, Lee SH, Shin KH, Wong DTW, Xiao X, Spigelman I, Kim Y. Molecular consequences of fetal alcohol exposure on amniotic exosomal miRNAs with functional implications for stem cell potency and differentiation. PLoS One 2020; 15:e0242276. [PMID: 33196678 PMCID: PMC7668603 DOI: 10.1371/journal.pone.0242276] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 10/30/2020] [Indexed: 12/16/2022] Open
Abstract
Alcohol (ethanol, EtOH) consumption during pregnancy can result in fetal alcohol spectrum disorders (FASDs), which are characterized by prenatal and postnatal growth restriction and craniofacial dysmorphology. Recently, cell-derived extracellular vesicles, including exosomes and microvesicles containing several species of RNAs (exRNAs), have emerged as a mechanism of cell-to-cell communication. However, EtOH's effects on the biogenesis and function of non-coding exRNAs during fetal development have not been explored. Therefore, we studied the effects of maternal EtOH exposure on the composition of exosomal RNAs in the amniotic fluid (AF) using rat fetal alcohol exposure (FAE) model. Through RNA-Seq analysis we identified and verified AF exosomal miRNAs with differential expression levels specifically associated with maternal EtOH exposure. Uptake of purified FAE AF exosomes by rBMSCs resulted in significant alteration of molecular markers associated with osteogenic differentiation of rBMSCs. We also determined putative functional roles for AF exosomal miRNAs (miR-199a-3p, miR-214-3p and let-7g) that are dysregulated by FAE in osteogenic differentiation of rBMSCs. Our results demonstrate that FAE alters AF exosomal miRNAs and that exosomal transfer of dysregulated miRNAs has significant molecular effects on stem cell regulation and differentiation. Our results further suggest the usefulness of assessing molecular alterations in AF exRNAs to study the mechanisms of FAE teratogenesis that should be further investigated by using an in vivo model.
Collapse
Affiliation(s)
- Honey Tavanasefat
- Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, UCLA, Los Angeles, California, United States of America
- CSUN-UCLA Stem Cell Research Bridge Program, Department of Biology, California State University at Northridge, Northridge, California, United States of America
| | - Feng Li
- Division of Oral Biology & Medicine, UCLA School of Dentistry, Los Angeles, California, United States of America
| | - Kikuye Koyano
- Department of Integrative Biology and Physiology, Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, United States of America
| | - Bahar Khalilian Gourtani
- Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, UCLA, Los Angeles, California, United States of America
| | - Vincent Marty
- Division of Oral Biology & Medicine, UCLA School of Dentistry, Los Angeles, California, United States of America
| | - Yatendra Mulpuri
- Division of Oral Biology & Medicine, UCLA School of Dentistry, Los Angeles, California, United States of America
| | - Sung Hee Lee
- The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, California, United States of America
| | - Ki-Hyuk Shin
- The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, California, United States of America
| | - David T. W. Wong
- Division of Oral Biology & Medicine, UCLA School of Dentistry, Los Angeles, California, United States of America
| | - Xinshu Xiao
- Department of Integrative Biology and Physiology, Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, United States of America
| | - Igor Spigelman
- Division of Oral Biology & Medicine, UCLA School of Dentistry, Los Angeles, California, United States of America
| | - Yong Kim
- Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, UCLA, Los Angeles, California, United States of America
- Division of Oral Biology & Medicine, UCLA School of Dentistry, Los Angeles, California, United States of America
- UCLA Broad Stem Cell Research Center, Los Angeles, California, United States of America
| |
Collapse
|
|
22
|
Shabani Z, Jafarzadeh Gharehziaaddin M. Effects and Potential Mechanisms of Alcohol Use Disorder on the Fate Determination of Newly Born Neurons in the Hippocampus. Alcohol Alcohol 2020; 55:598-602. [PMID: 32814954 DOI: 10.1093/alcalc/agaa083] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 07/23/2020] [Accepted: 07/23/2020] [Indexed: 01/06/2023] Open
Abstract
In the adult mammalian brain, new functional neurons are generated throughout life because of sustained proliferation and differentiation of neural stem cells (NSCs). The subventricular zone (SVZ), lining the lateral ventricle, and the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus are the two major neurogenic regions in the adult brain. This process is not fixed but is highly modulated by numerous intrinsic and extrinsic factors. Neurogenesis has become in the focus of interest for its involvement in repairing the damaged brain and this motivates researchers to detect controlling mechanisms of this process. Recent evidence suggests that alcohol usage can directly influence adult hippocampal neurogenesis, but its mechanisms remain a matter for debate. Thus, this review summarizes in vivo/in vitro studies on the role of alcohol in hippocampal neurogenesis during adulthood and clarifies its underlying mechanisms by highlighting neurotransmitters and their receptors.
Collapse
Affiliation(s)
- Zahra Shabani
- Neuroscience Department, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Golgasht Street, Azadi Avenue, Tabriz 51656-87386, Iran.,Neurosciences Research Center, Tabriz University of Medical Sciences, Golgasht Street, Azadi Avenue, Tabriz 51666-14756, Iran
| | - Mohsen Jafarzadeh Gharehziaaddin
- Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, No 2, Bakeri Blvd, Tabriz 51666-14756, Iran
| |
Collapse
|
|
23
|
Buján GE, Serra HA, Molina SJ, Guelman LR. Oxidative Stress-Induced Brain Damage Triggered by Voluntary Ethanol Consumption during Adolescence: A Potential Target for Neuroprotection? Curr Pharm Des 2020; 25:4782-4790. [PMID: 31814553 DOI: 10.2174/1381612825666191209121735] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 08/23/2019] [Indexed: 12/28/2022]
Abstract
Alcohol consumption, in particular ethanol (EtOH), typically begins in human adolescence, often in a "binge like" manner. However, although EtOH abuse has a high prevalence at this stage, the effects of exposure during adolescence have been less explored than prenatal or adult age exposure. Several authors have reported that EtOH intake during specific periods of development might induce brain damage. Although the mechanisms are poorly understood, it has been postulated that oxidative stress may play a role. In fact, some of these studies revealed a decrease in brain antioxidant enzymes' level and/or an increase in reactive oxygen species (ROS) production. Nevertheless, although existing literature shows a number of studies in which ROS were measured in developing animals, fewer reported the measurement of ROS levels after EtOH exposure in adolescence. Importantly, neuroprotective agents aimed to these potential targets may be relevant tools useful to reduce EtOH-induced neurodegeneration, restore cognitive function and improve treatment outcomes for alcohol use disorders (AUDs). The present paper reviews significant evidences about the mechanisms involved in EtOH-induced brain damage, as well as the effect of different potential neuroprotectants that have shown to be able to prevent EtOH-induced oxidative stress. A selective inhibitor of the endocannabinoid anandamide metabolism, a flavonol present in different fruits (quercetin), an antibiotic with known neuroprotective properties (minocycline), a SOD/catalase mimetic, a potent antioxidant and anti-inflammatory molecule (resveratrol), a powerful ROS scavenger (melatonin), an isoquinoline alkaloid (berberine), are some of the therapeutic strategies that could have some clinical relevance in the treatment of AUDs. As most of these works were performed in adult animal models and using EtOH-forced paradigms, the finding of neuroprotective tools that could be effective in adolescent animal models of voluntary EtOH intake should be encouraged.
Collapse
Affiliation(s)
- Gustavo E. Buján
- Universidad de Buenos Aires, Facultad de Medicina, 1 Cátedra de Farmacología, Buenos Aires, Argentina.,Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Centro de Estudios Farmacológicos y Botánicos (CEFyBO, UBACONICET), Facultad de Medicina, Buenos Aires, Argentina
| | - Hector A. Serra
- Universidad de Buenos Aires, Facultad de Medicina, 1 Cátedra de Farmacología, Buenos Aires, Argentina
| | - Sonia J. Molina
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Centro de Estudios Farmacológicos y Botánicos (CEFyBO, UBACONICET), Facultad de Medicina, Buenos Aires, Argentina
| | - Laura R. Guelman
- Universidad de Buenos Aires, Facultad de Medicina, 1 Cátedra de Farmacología, Buenos Aires, Argentina.,Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Centro de Estudios Farmacológicos y Botánicos (CEFyBO, UBACONICET), Facultad de Medicina, Buenos Aires, Argentina
| |
Collapse
|
|
24
|
Enhanced neuroinflammation and oxidative stress are associated with altered hippocampal neurogenesis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated mice. Behav Pharmacol 2020; 30:689-699. [PMID: 31703031 DOI: 10.1097/fbp.0000000000000516] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Loss of midbrain dopaminergic neurons in Parkinson's disease not only induces motor impairments but also leads to the development of non-motor symptoms such as memory impairment, anxiety and depression. Dopaminergic axons directly innervate hippocampus and release dopamine in the local environment of hippocampus, and hence are directly involved in the modulation of hippocampal-dependent functions. Studies have explored the potential effect of dopamine on adult hippocampal neurogenesis. However, it is not well defined whether oxidative damage and inflammation could be associated with alteration in adult hippocampal neurogenesis. In the present study, we analyzed the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on adult hippocampal neurogenesis and how it is associated with inflammatory conditions in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease-like phenotypes. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice exhibited significantly reduced dopaminergic neurons and dopamine content that resulted in impairment of motor functions. Interestingly, the formation of endogenous neuronal precursor cells and the number of neuroblasts in the hippocampus were significantly increased following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. Net hippocampal neurogenesis was also reduced in the hippocampus after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. These effects in the hippocampus were associated with increased oxidative stress markers and a massive reactive gliosis. Taken together, our results suggest that degeneration of midbrain dopaminergic neurons directly affects the local hippocampal microenvironment by enhancing inflammatory influences. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced inflammatory reaction in the hippocampus may alter the endogenous regenerative capacity of the brain. Therefore, anti-inflammatory agents could be a potential therapy for the improvement of the endogenous regenerative capacity of the aging or neurodegenerative brain.
Collapse
|
|
25
|
Flores-Bastías O, Adriasola-Carrasco A, Karahanian E. Activation of Melanocortin-4 Receptor Inhibits Both Neuroinflammation Induced by Early Exposure to Ethanol and Subsequent Voluntary Alcohol Intake in Adulthood in Animal Models: Is BDNF the Key Mediator? Front Cell Neurosci 2020; 14:5. [PMID: 32063838 PMCID: PMC6997842 DOI: 10.3389/fncel.2020.00005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 01/10/2020] [Indexed: 12/31/2022] Open
Abstract
The concept that neuroinflammation induced by excessive alcohol intake in adolescence triggers brain mechanisms that perpetuate consumption has strengthened in recent years. The melanocortin system, composed of the melanocortin 4 receptor (MC4R) and its ligand α-melanocyte-stimulating hormone (α-MSH), has been implicated both in modulation of alcohol consumption and in ethanol-induced neuroinflammation decrease. Chronic alcohol consumption in adolescent rats causes a decrease in an α-MSH release by the hypothalamus, while the administration of synthetic agonists of MC4R causes a decrease in neuroinflammation and a decrease in voluntary alcohol consumption. However, the mechanism that connects the activation of MC4R with the decrease of both neuroinflammation and voluntary alcohol consumption has not been elucidated. Brain-derived neurotrophic factor (BDNF) has been implicated in alcohol drinking motivation, dependence and withdrawal, and its levels are reduced in alcoholics. Deficiencies in BDNF levels increased ethanol self-administration in rats. Further, BDNF triggers important anti-inflammatory effects in the brain, and this could be one of the mechanisms by which BDNF reduces chronic alcohol intake. Interestingly, MC4R signaling induces BDNF expression through the activation of the cAMP-responsive element-binding protein (CREB). We hypothesize that ethanol exposure during adolescence decreases the expression of α-MSH and hence MC4R signaling in the hippocampus, leading to a lower BDNF activity that causes dramatic changes in the brain (e.g., neuroinflammation and decreased neurogenesis) that predispose to maintain alcohol abuse until adulthood. The activation of MC4R either by α-MSH or by synthetic agonist peptides can induce the expression of BDNF, which would trigger several processes that lead to lower alcohol consumption.
Collapse
Affiliation(s)
- Osvaldo Flores-Bastías
- Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago, Chile.,Research Center for the Study of Alcohol Drinking Behavior in Adolescents, Universidad Autónoma de Chile, Santiago, Chile
| | - Alfredo Adriasola-Carrasco
- Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago, Chile
| | - Eduardo Karahanian
- Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago, Chile.,Research Center for the Study of Alcohol Drinking Behavior in Adolescents, Universidad Autónoma de Chile, Santiago, Chile
| |
Collapse
|
|
26
|
Hamidovic A, Wang Y. The P300 in alcohol use disorder: A meta-analysis and meta-regression. Prog Neuropsychopharmacol Biol Psychiatry 2019; 95:109716. [PMID: 31369766 DOI: 10.1016/j.pnpbp.2019.109716] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 12/30/2022]
Abstract
OBJECTIVE The P300 ERP component is a marker of reduced capacity in alcohol use disorder (AUD) to engage attentional mechanisms and update memory representations. No meta-analysis to date has been completed comparing effect size estimates of auditory vs. visual stimuli in AUD. In addition, there is a lack of consensus on whether the P3b in women is reduced, or whether the P3a - an earlier, more frontally distributed component - is reduced in AUD. METHODS Strict inclusion criteria and data-analysis plans were implemented. Eligible studies needed to diagnose AUD using DSM or ICD-10 and exclude patients with any psychiatric co-morbidities. Data analysis was completed using a refined variance estimator of the random effects model. RESULTS Effect size estimates were large for both auditory (Hedges' g = 1.01, p = .056) and visual (Hedges' g = 0.77, p = .040) P300 amplitudes, but only marginally significant for the auditory modality. Auditory P300 latency was significantly increased in AUD patients (Hedges' g = 0.73, p = .027). The moderator analysis did not show significant sex differences for either auditory (p = .97) or visual (p = .45) P3b. Finally, the P3a was not reduced in patients with AUD (Hedges' g = 1.01; p = .59). CONCLUSION This meta-analysis clarifies important questions related to P300 in AUD. By resolving inconsistencies, it is hoped that this information will facilitate the design of futurestudies.
Collapse
Affiliation(s)
- Ajna Hamidovic
- Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60608, United States of America.
| | - Yohyoh Wang
- Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60608, United States of America
| |
Collapse
|
|
27
|
Peroxiredoxin II Maintains the Mitochondrial Membrane Potential against Alcohol-Induced Apoptosis in HT22 Cells. Antioxidants (Basel) 2019; 9:antiox9010001. [PMID: 31861323 PMCID: PMC7023630 DOI: 10.3390/antiox9010001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/17/2019] [Accepted: 12/17/2019] [Indexed: 12/15/2022] Open
Abstract
Excessive alcohol intake can significantly reduce cognitive function and cause irreversible learning and memory disorders. The brain is particularly vulnerable to alcohol-induced ROS damage; the hippocampus is one of the most sensitive areas of the brain for alcohol neurotoxicity. In the present study, we observed significant increasing of intracellular ROS accumulations in Peroxiredoxin II (Prx II) knockdown HT22 cells, which were induced by alcohol treatments. We also found that the level of ROS in mitochondrial was also increased, resulting in a decrease in the mitochondrial membrane potential. The phosphorylation of GSK3β (Ser9) and anti-apoptotic protein Bcl2 expression levels were significantly downregulated in Prx II knockdown HT22 cells, which suggests that Prx II knockdown HT22 cells were more susceptible to alcohol-induced apoptosis. Scavenging the alcohol-induced ROS with NAC significantly decreased the intracellular ROS levels, as well as the phosphorylation level of GSK3β in Prx II knockdown HT22 cells. Moreover, NAC treatment also dramatically restored the mitochondrial membrane potential and the cellular apoptosis in Prx II knockdown HT22 cells. Our findings suggest that Prx II plays a crucial role in alcohol-induced neuronal cell apoptosis by regulating the cellular ROS levels, especially through regulating the ROS-dependent mitochondrial membrane potential. Consequently, Prx II may be a therapeutic target molecule for alcohol-induced neuronal cell death, which is closely related to ROS-dependent mitochondria dysfunction.
Collapse
|
|
28
|
Nunes PT, Kipp BT, Reitz NL, Savage LM. Aging with alcohol-related brain damage: Critical brain circuits associated with cognitive dysfunction. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2019; 148:101-168. [PMID: 31733663 PMCID: PMC7372724 DOI: 10.1016/bs.irn.2019.09.002] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alcoholism is associated with brain damage and impaired cognitive functioning. The relative contributions of different etiological factors, such as alcohol, thiamine deficiency and age vulnerability, to the development of alcohol-related neuropathology and cognitive impairment are still poorly understood. One reason for this quandary is that both alcohol toxicity and thiamine deficiency produce brain damage and cognitive problems that can be modulated by age at exposure, aging following alcohol toxicity or thiamine deficiency, and aging during chronic alcohol exposure. Pre-clinical models of alcohol-related brain damage (ARBD) have elucidated some of the contributions of ethanol toxicity and thiamine deficiency to neuroinflammation, neuronal loss and functional deficits. However, the critical variable of age at the time of exposure or long-term aging with ARBD has been relatively ignored. Acute thiamine deficiency created a massive increase in neuroimmune genes and proteins within the thalamus and significant increases within the hippocampus and frontal cortex. Chronic ethanol treatment throughout adulthood produced very minor fluctuations in neuroimmune genes, regardless of brain region. Intermittent "binge-type" ethanol during the adolescent period established an intermediate neuroinflammatory response in the hippocampus and frontal cortex, that can persist into adulthood. Chronic excessive drinking throughout adulthood, adolescent intermittent ethanol exposure, and thiamine deficiency all led to a loss of the cholinergic neuronal phenotype within the basal forebrain, reduced hippocampal neurogenesis, and alterations in the frontal cortex. Only thiamine deficiency results in gross pathological lesions of the thalamus. The behavioral impairment following these types of treatments is hierarchical: Thiamine deficiency produces the greatest impairment of hippocampal- and prefrontal-dependent behaviors, chronic ethanol drinking ensues mild impairments on both types of tasks and adolescent intermittent ethanol exposure leads to impairments on frontocortical tasks, with sparing on most hippocampal-dependent tasks. However, our preliminary data suggest that as rodents age following adolescent intermittent ethanol exposure, hippocampal functional deficits began to emerge. A necessary requirement for the advancement of understanding the neural consequences of alcoholism is a more comprehensive assessment and understanding of how excessive alcohol drinking at different development periods (adolescence, early adulthood, middle-aged and aged) influences the trajectory of the aging process, including pathological aging and disease.
Collapse
Affiliation(s)
- Polliana Toledo Nunes
- Developmental Exposure Alcohol Research Center, Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, NY, United States
| | - Brian T Kipp
- Developmental Exposure Alcohol Research Center, Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, NY, United States
| | - Nicole L Reitz
- Developmental Exposure Alcohol Research Center, Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, NY, United States
| | - Lisa M Savage
- Developmental Exposure Alcohol Research Center, Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, NY, United States.
| |
Collapse
|
|
29
|
Baliño P, Romero-Cano R, Sánchez-Andrés JV, Valls V, Aragón CG, Muriach M. Effects of Acute Ethanol Administration on Brain Oxidative Status: The Role of Acetaldehyde. Alcohol Clin Exp Res 2019; 43:1672-1681. [PMID: 31211868 DOI: 10.1111/acer.14133] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 06/11/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Ethanol (EtOH), one of the most widely consumed substances of abuse, can induce brain damage and neurodegeneration. EtOH is centrally metabolized into acetaldehyde, which has been shown to be responsible for some of the neurophysiological and cellular effects of EtOH. Although some of the consequences of chronic EtOH administration on cell oxidative status have been described, the mechanisms by which acute EtOH administration affects the brain's cellular oxidative status and the role of acetaldehyde remain to be elucidated in detail. METHODS Swiss CD-I mice were pretreated with the acetaldehyde-sequestering agent d-penicillamine (DP; 75 mg/kg, i.p.) or the antioxidant lipoic acid (LA; 50 mg/kg, i.p.) 30 minutes before EtOH (2.5 g/kg, i.p.) administration. Animals were sacrificed 30 minutes after EtOH injection. Glutathione peroxidase (GPx) mRNA levels; GPx and glutathione reductase (GR) enzymatic activities; reduced glutathione (GSH), glutathione disulfide (GSSG), glutamate, g-L-glutamyl-L-cysteine (Glut-Cys), and malondialdehyde (MDA) concentrations; and protein carbonyl group (CG) content were determined in whole-brain samples. RESULTS Acute EtOH administration enhanced GPx activity and the GSH/GSSG ratio, while it decreased GR activity and GSSG concentration. Pretreatment with DP or LA only prevented GPx activity changes induced by EtOH. CONCLUSIONS Altogether, these results show the capacity of a single dose of EtOH to unbalance cellular oxidative homeostasis.
Collapse
Affiliation(s)
- Pablo Baliño
- From the, Unitat predepartamental de Medicina, (PB, RR-C, JVS-A, VV, MM), Universitat Jaume I, Castellón de la Plana, Spain
| | - Ricard Romero-Cano
- From the, Unitat predepartamental de Medicina, (PB, RR-C, JVS-A, VV, MM), Universitat Jaume I, Castellón de la Plana, Spain
| | - Juan Vicente Sánchez-Andrés
- From the, Unitat predepartamental de Medicina, (PB, RR-C, JVS-A, VV, MM), Universitat Jaume I, Castellón de la Plana, Spain
| | - Victoria Valls
- From the, Unitat predepartamental de Medicina, (PB, RR-C, JVS-A, VV, MM), Universitat Jaume I, Castellón de la Plana, Spain
| | | | - María Muriach
- From the, Unitat predepartamental de Medicina, (PB, RR-C, JVS-A, VV, MM), Universitat Jaume I, Castellón de la Plana, Spain
| |
Collapse
|
|
30
|
Tyler RE, Kim SW, Guo M, Jang YJ, Damadzic R, Stodden T, Vendruscolo LF, Koob GF, Wang GJ, Wiers CE, Volkow ND. Detecting neuroinflammation in the brain following chronic alcohol exposure in rats: A comparison between in vivo and in vitro TSPO radioligand binding. Eur J Neurosci 2019; 50:1831-1842. [PMID: 30803059 PMCID: PMC10714130 DOI: 10.1111/ejn.14392] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 01/17/2019] [Accepted: 02/08/2019] [Indexed: 12/18/2022]
Abstract
Excessive alcohol consumption is associated with neuroinflammation, which likely contributes to alcohol-related pathology. However, positron emission tomography (PET) studies using radioligands for the 18-kDa translocator protein (TSPO), which is considered a biomarker of neuroinflammation, reported decreased binding in alcohol use disorder (AUD) participants compared to controls. In contrast, autoradiographic findings in alcohol exposed rats reported increases in TSPO radioligand binding. To assess if these discrepancies reflected differences between in vitro and in vivo methodologies, we compared in vitro autoradiography (using [3 H]PBR28 and [3 H]PK11195) with in vivo PET (using [11 C]PBR28) in male, Wistar rats exposed to chronic alcohol-vapor (dependent n = 10) and in rats exposed to air-vapor (nondependent n = 10). PET scans were obtained with [11 C]PBR28, after which rats were euthanized and the brains were harvested for autoradiography with [3 H]PBR28 and [3 H]PK11195 (n = 7 dependent and n = 7 nondependent), and binding quantified in hippocampus, thalamus, and parietal cortex. Autoradiography revealed significantly higher binding in alcohol-dependent rats for both radioligands in thalamus and hippocampus (trend level for [3 H]PBR28) compared to nondependent rats, and these group differences were stronger for [3 H]PK11195 than [3 H]PBR28. In contrast, PET measures obtained in the same rats showed no group difference in [11 C]PBR28 binding. Our in vitro data are consistent with neuroinflammation associated with chronic alcohol exposure. Failure to observe similar increases in [11 C]PBR28 binding in vivo suggests the possibility that a mechanism mediated by chronic alcohol exposure interferes with [11 C]PBR28 binding to TSPO in vivo. These data question the sensitivity of PBR28 PET as a methodology to assess neuroinflammation in AUD.
Collapse
Affiliation(s)
- Ryan E. Tyler
- National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
| | - Sung Won Kim
- National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
| | - Min Guo
- National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
| | - Yeon Joo Jang
- National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
| | - Ruslan Damadzic
- National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
| | - Tyler Stodden
- National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
| | - Leandro F. Vendruscolo
- National Institute on Drug Abuse, National Institutes of Health, NIH, Baltimore, Maryland
| | - George F. Koob
- National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
- National Institute on Drug Abuse, National Institutes of Health, NIH, Baltimore, Maryland
| | - Gene-Jack Wang
- National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
| | - Corinde E. Wiers
- National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
| | - Nora D. Volkow
- National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
- National Institute on Drug Abuse, National Institutes of Health, NIH, Baltimore, Maryland
| |
Collapse
|
|
31
|
Mai HN, Chung YH, Shin EJ, Jeong JH, Jung TW, Sharma N, Lei XG, Nah SY, Jang CG, Kim DJ, Yang BK, Kim HC. Overexpression of glutathione peroxidase-1 attenuates cocaine-induced reproductive dysfunction in male mice by inhibiting nuclear factor κB. Chem Biol Interact 2019; 307:136-146. [PMID: 31059705 DOI: 10.1016/j.cbi.2019.05.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 04/24/2019] [Accepted: 05/02/2019] [Indexed: 12/13/2022]
Abstract
Since reproductive toxicity is associated with oxidative stress, nuclear factor κB (NFκB), a redox-sensitive transcription factor, may be involved in the reproductive dysfunction induced by the abusive drug, such as cocaine. In the present study, we investigated whether NFκB mediates cocaine-induced reproductive dysfunction in male mice, and whether glutathione peroxidase (GPx)-1, a well-known enzymatic antioxidant, modulates NFκB activity to affect this reproductive dysfunction. Cocaine treatment significantly increased nuclear translocation of NFκB and its DNA binding activity in the testis of mice. Treatment with cocaine resulted in a significant increase in sperm abnormality, and in significant decreases in the sperm viability and sperm level. Furthermore, cocaine significantly reduced hypothalamic gonadotropin-releasing-hormone expression and plasma testosterone level. These alterations were more pronounced in the GPx-1 knockout (GPx-1 KO) than wild type (WT) mice, and they were less pronounced in GPx-1 overexpressing transgenic (GPx-1 TG) than in non-transgenic (non-TG) mice. Pyrrolidine dithiocarbamate (PDTC), an NFκB inhibitor, was more effective in attenuating cocaine-induced reproductive toxicity in GPx-1 KO than in WT mice. Although PDTC treatment was also significantly protective against the reproductive toxicity in non-TG mice, PDTC did not show additional positive effects against the protective potential mediated by GPx-1 overexpression in mice. Therefore, our results suggest that GPx-1 gene is a protective factor in response to reproductive dysfunction induced by cocaine in male mice, and that NFκB is a critical mediator of protective activity of GPx-1 gene in our experimental conditions.
Collapse
Affiliation(s)
- Huynh Nhu Mai
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea
| | - Yoon Hee Chung
- Department of Anatomy, College of Medicine, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Eun-Joo Shin
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Tae Woo Jung
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Naveen Sharma
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea
| | - Xin Gen Lei
- Department of Animal Science, Cornell University, Ithaca, NY, 14853, USA
| | - Seung-Yeol Nah
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul, 05029, Republic of Korea
| | - Choon-Gon Jang
- Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Dae-Joong Kim
- Department of Anatomy and Cell Biology, Medical School, Kangwon National University, Chunchon, 24341, Republic of Korea
| | - Boo-Keun Yang
- Department of Animal Resource Science, College of Animal Life Science, Kangwon National University, Chunchon, 24341, Republic of Korea
| | - Hyoung-Chun Kim
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea.
| |
Collapse
|
|
32
|
Xu H, Liu D, Chen J, Li H, Xu M, Wen W, Frank JA, Grahame NJ, Zhu H, Luo J. Effects of Chronic Voluntary Alcohol Drinking on Thiamine Concentrations, Endoplasmic Reticulum Stress, and Oxidative Stress in the Brain of Crossed High Alcohol Preferring Mice. Neurotox Res 2019; 36:777-787. [PMID: 30972556 DOI: 10.1007/s12640-019-00032-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 03/21/2019] [Accepted: 03/25/2019] [Indexed: 12/11/2022]
Abstract
Chronic alcohol drinking can damage the central nervous system via many mechanisms. One of these may involve a deficiency of an essential nutrient, thiamine, as a result of chronic alcohol exposure. Although thiamine deficiency (TD) has often been linked to the neuropathology of alcohol-related brain damage, the underlying mechanisms remain to be investigated. The crossed high alcohol preferring (cHAP) mice prefer alcohol to water when they have free access. In this study, we used cHAP mice to determine the effect of chronic voluntary alcohol exposure on thiamine levels and neuropathological changes in the brain. The male cHAP mice were given free-choice access to 10% ethanol (EtOH) and water for 7 months, sacrificed, and thiamine concentrations in the blood plasma and brain were determined by liquid chromatography-mass spectrometry (LC-MS). The expression of thiamine transporters was examined by immunoblotting. In addition, oxidative stress, endoplasmic reticulum (ER) stress, active caspase-3-dependent apoptosis, and neurogenesis in the brain were evaluated. The results indicated that chronic alcohol exposure decreased thiamine levels and thiamine transporters, and increased oxidative stress, ER stress, and neuronal apoptosis in the brains. Interestingly, alcohol exposure also stimulated neurogenesis in the hippocampus which may serve as a compensatory mechanism in response to alcohol-induced brain damage. Our data have demonstrated that cHAP mice are a useful model to study the interaction between chronic alcohol consumption and TD, as well as TD's contributions to the neuropathological processes resulting in alcohol-related brain damage.
Collapse
Affiliation(s)
- Hong Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Dexiang Liu
- Department of Medical Psychology, Shandong University School of Medicine, #44 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Jing Chen
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Hui Li
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Mei Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Wen Wen
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Jacqueline A Frank
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
| | - Nicholas J Grahame
- Department of Psychology, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202, USA
| | - Haining Zhu
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.,Lexington VA Health Care System, Research & Development, 1101 Veterans Drive, Lexington, KY, 40502, USA
| | - Jia Luo
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA. .,Lexington VA Health Care System, Research & Development, 1101 Veterans Drive, Lexington, KY, 40502, USA.
| |
Collapse
|
|
33
|
Hicks SD, Miller MW. Ethanol-induced DNA repair in neural stem cells is transforming growth factor β1-dependent. Exp Neurol 2019; 317:214-225. [PMID: 30853389 DOI: 10.1016/j.expneurol.2019.02.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 12/13/2018] [Accepted: 02/07/2019] [Indexed: 12/18/2022]
Abstract
Following neurotoxic damage, cells repair their DNA, and survive or undergo apoptosis. This study tests the hypothesis that ethanol induces a DNA damage response (DDR) in neural stem cells (NSCs) that promotes excision repair (ER) and this repair is influenced by the growth factor environment. Non-immortalized NSCs treated with fibroblast growth factor 2 or transforming growth factor (TGF) β1 were exposed to ethanol. Ethanol increased total DNA damage, reactive oxygen species, and oxidized DNA bases. TGFβ1 potentiated these toxic effects. Transcriptional analyses of cultured NSCs revealed ethanol-induced increases in transcripts related to the DDR (e.g., Hus1 and p53), base ER (e.g., Mutyh and Nthl1), and nucleotide ER (e.g., Xpc), particularly in the presence of TGFβ1. Expression and activity of ER proteins were affected by ethanol. Similar changes occurred in proliferating cells of ethanol-treated mouse fetuses. Ethanol-induced DNA repair in NSCs depends on the ambient growth factors. Gene products for DNA repair in stem cells are among the first biomarkers identifying fetal alcohol-induced damage.
Collapse
Affiliation(s)
- Steven D Hicks
- Department of Neuroscience and Physiology, State University of New York - Upstate Medical University, Syracuse, NY 13210, USA; Developmental Exposure Alcohol Research Center, Binghamton NY 13902, Cortland NY 13045, and Syracuse, NY 13210, USA
| | - Michael W Miller
- Department of Neuroscience and Physiology, State University of New York - Upstate Medical University, Syracuse, NY 13210, USA; Developmental Exposure Alcohol Research Center, Binghamton NY 13902, Cortland NY 13045, and Syracuse, NY 13210, USA; Department of Anatomy, Touro College of Osteopathic Medicine, Middletown, NY 10940, USA; Research Service, Veterans Affairs Medical Center, Syracuse, NY 13210, USA.
| |
Collapse
|
|
34
|
Rivera P, Silva-Peña D, Blanco E, Vargas A, Arrabal S, Serrano A, Pavón FJ, Bindila L, Lutz B, Rodríguez de Fonseca F, Suárez J. Oleoylethanolamide restores alcohol-induced inhibition of neuronal proliferation and microglial activity in striatum. Neuropharmacology 2019; 146:184-197. [DOI: 10.1016/j.neuropharm.2018.11.037] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 11/08/2018] [Accepted: 11/25/2018] [Indexed: 01/19/2023]
|
|
35
|
Mai HN, Chung YH, Shin EJ, Kim DJ, Sharma N, Lee YJ, Jeong JH, Nah SY, Jang CG, Kim HC. Glutathione peroxidase-1 overexpressing transgenic mice are protected from cocaine-induced drug dependence. Neurochem Int 2019; 124:264-273. [DOI: 10.1016/j.neuint.2019.01.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 01/13/2019] [Accepted: 01/22/2019] [Indexed: 11/29/2022]
|
|
36
|
Transient receptor potential melastatin 2 governs stress-induced depressive-like behaviors. Proc Natl Acad Sci U S A 2019; 116:1770-1775. [PMID: 30642955 DOI: 10.1073/pnas.1814335116] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Major depressive disorder (MDD) is a devastating disease that arises in a background of environmental risk factors, such as chronic stress, that produce reactive oxygen species (ROS) in the brain. The chronic stress-induced ROS production involves Ca2+ signals; however, the mechanism is poorly understood. Transient receptor potential melastatin type 2 (TRPM2) is a Ca2+-permeable cation channel that is highly expressed in the brain. Here we show that in animal models of chronic unpredictable stress (CUS), deletion of TRPM2 (Trpm2 -/- ) produces antidepressant-like behaviors in mice. This phenotype correlates with reduced ROS, ROS-induced calpain activation, and enhanced phosphorylation of two Cdk5 targets including synapsin 1 and histone deacetylase 5 that are linked to synaptic function and gene expression, respectively. Moreover, TRPM2 mRNA expression is increased in hippocampal tissue samples from patients with MDD. Our findings suggest that TRPM2 is a key agent in stress-induced depression and a possible target for treating depression.
Collapse
|
|
37
|
Tobore TO. On the Neurobiological Role of Oxidative Stress in Alcohol-Induced Impulsive, Aggressive and Suicidal Behavior. Subst Use Misuse 2019; 54:2290-2303. [PMID: 31369300 DOI: 10.1080/10826084.2019.1645179] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Objectives: Alcohol abuse is known to result in behavioral impairments (such as increased impulsivity, aggressive, and suicidal behavior), but the neurobiological basis for these behavioral impairments remains unknown. The objective of this review is to propose a neurobiological basis for alcohol-induced aggression, impulsivity, and suicidal behavior. Methods: Search was done by accessing PubMed/Medline, EBSCO, and PsycINFO databases. The search string used was "(Alcohol OR Alcoholism* OR Alcohol Abuse) AND (Behavior* OR Behavioral Impairment or Disorder) AND (Oxidative Stress OR Reactive Oxygen Species)." The electronic databases were searched for titles or abstracts containing these terms in all published articles between January 1, 1960, and May 31, 2019. The search was limited to studies published in English and other languages involving both animal and human subjects. Articles selected included randomized clinical trials (RCTs), observational studies, meta-analyses, and both systemic and narrative reviews, providing both quantitative and qualitative information with a measure of alcohol abuse or alcoholism as an outcome. Exclusion criteria were unpublished data of any form, including conference proceedings and dissertation. New key terms were identified (new term included: "Antioxidants, Neurotransmitters, Dopamine, Serotonin, GABA, Glutamate. Aggression, Impulsivity, Suicidal Behavior, hippocampus, prefrontal cortex, limbic system, psychiatric disorders, PTSD, Anxiety, Depression. These new terms were searched with Alcohol or Alcoholism or Alcohol Abuse and Oxidative Stress separately resulting in the identification of over 3000 articles. 196 were included in this article. Results: Multiple lines of evidence indicate that oxidative stress (OS) plays a critical underlying role in alcohol toxicity and behavioral impairments. Conclusions/Importance: People diagnosed with PTSD, anxiety disorder, depression, and those with a personality high in psychoticism as measured by the P Scale of the Eysenck Personality Questionnaire, with comorbid alcohol abuse or alcohol use disorder (AUD), may display increased impulsivity, aggression, and suicidal behavior because of the potentiating effect of alcohol-induced OS on their elevated brain oxidative status. Antioxidant therapy should be an integral part of acute alcohol intoxication and AUD treatment. Further research is necessary to fully understand the relationship between OS and alcohol-induced behavioral impairments.
Collapse
|
|
38
|
Role of glutamatergic system and mesocorticolimbic circuits in alcohol dependence. Prog Neurobiol 2018; 171:32-49. [PMID: 30316901 DOI: 10.1016/j.pneurobio.2018.10.001] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 09/08/2018] [Accepted: 10/08/2018] [Indexed: 02/06/2023]
Abstract
Emerging evidence demonstrates that alcohol dependence is associated with dysregulation of several neurotransmitters. Alterations in dopamine, glutamate and gamma-aminobutyric acid release are linked to chronic alcohol exposure. The effects of alcohol on the glutamatergic system in the mesocorticolimbic areas have been investigated extensively. Several studies have demonstrated dysregulation in the glutamatergic systems in animal models exposed to alcohol. Alcohol exposure can lead to an increase in extracellular glutamate concentrations in mesocorticolimbic brain regions. In addition, alcohol exposure affects the expression and functions of several glutamate receptors and glutamate transporters in these brain regions. In this review, we discussed the effects of alcohol exposure on glutamate receptors, glutamate transporters and glutamate homeostasis in each area of the mesocorticolimbic system. In addition, we discussed the genetic aspect of alcohol associated with glutamate and reward circuitry. We also discussed the potential therapeutic role of glutamate receptors and glutamate transporters in each brain region for the treatment of alcohol dependence. Finally, we provided some limitations on targeting the glutamatergic system for potential therapeutic options for the treatment alcohol use disorders.
Collapse
|
|
39
|
Choi SH, Lee AY, Park CH, Shin YS, Cho EJ. Protective effect of Carthamus tinctorius L. seed on oxidative stress and cognitive impairment induced by chronic alcohol consumption in mice. Food Sci Biotechnol 2018; 27:1475-1484. [PMID: 30319858 DOI: 10.1007/s10068-018-0472-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 09/07/2018] [Accepted: 09/11/2018] [Indexed: 12/23/2022] Open
Abstract
Chronic alcohol consumption induces damage to the brain that can cause various forms of dementia. An abundance of acetaldehyde is produced by excessive alcohol consumption and accumulates in the body to induce oxidative stress, apoptosis, and inflammation in neuronal cells, which results in learning and cognitive decline. In the present study, C57BL/N mice were orally administered alcohol (16%) and Carthamus tinctorius L. seed (CTS) (100 and 200 mg/kg/day). Behavioral experiments showed that memory and cognitive abilities were significantly higher in the CTS groups than the alcohol-treated control group in the T-maze test, novel object recognition test, and Morris water maze test. In addition, CTS inhibited alcohol-induced lipid peroxidation and nitric oxide production in the brain, kidney, and liver. Moreover, alcohol increased acetylcholinesterase activity in the brain, but this was significantly decreased by the administration of CTS. Therefore, CTS may play role in the prevention of alcohol-related dementia.
Collapse
Affiliation(s)
- Seung Hak Choi
- 1Department of Food Science and Nutrition, and Kimchi Research Institute, Pusan National University, Busan, 46241 Republic of Korea
| | - Ah Young Lee
- 1Department of Food Science and Nutrition, and Kimchi Research Institute, Pusan National University, Busan, 46241 Republic of Korea
| | - Chan Hum Park
- 2Department of Medicinal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong, 27709 Republic of Korea
| | - Yu Su Shin
- 2Department of Medicinal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong, 27709 Republic of Korea
| | - Eun Ju Cho
- 1Department of Food Science and Nutrition, and Kimchi Research Institute, Pusan National University, Busan, 46241 Republic of Korea
| |
Collapse
|
|
40
|
Kashem MA, Sultana N, Balcar VJ. Exposure of Rat Neural Stem Cells to Ethanol Affects Cell Numbers and Alters Expression of 28 Proteins. Neurochem Res 2018; 43:1841-1854. [PMID: 30043189 DOI: 10.1007/s11064-018-2600-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 07/17/2018] [Accepted: 07/20/2018] [Indexed: 11/28/2022]
Abstract
Developing brain cells express many proteins but little is known of how their protein composition responds to chronic exposure to alcohol and/or how such changes might relate to alcohol toxicity. We used cultures derived from embryonic rat brain (previously shown to contain mostly neural stem cells; rat NSC, rNSC), exposed them to ethanol (25-100 mM) for up to 96 h and studied how they reacted. Ethanol (50 and 100 mM) reduced cell numbers indicating either compromised cell proliferation, cytotoxicity or both. Increased lipid peroxidation was consistent with the presence of oxidative stress accompanying alcohol-induced cytotoxicity. Proteomics revealed 28 proteins as altered by ethanol (50 mM for 96 h). Some were constituents of cytoskeleton, others were involved in transcription/translation, signal transduction and oxidative stress. Nucleophosmin (NPM1) and dead-end protein homolog 1 (DND1) were further studied by immunological techniques in cultured neurons and astrocytes (derived from brain tissue at embryonic ages E15 and E20, respectively). In the case of DND1 (but not NPM1) ethanol induced similar pattern of changes in both types of cells. Given the critical role of the protein NPM1 in cell proliferation and differentiation, its reduced expression in the ethanol-exposed rNSC could, in part, explain the lower cells numbers. We conclude that chronic ethanol profoundly alters protein composition of rNSC to the extent that their functioning-including proliferation and survival-would be seriously compromised. Translated to humans, such changes could point the way towards mechanisms underlying the fetal alcohol spectrum disorder and/or alcoholism later in life.
Collapse
Affiliation(s)
- Mohammed A Kashem
- Laboratory of Neurochemistry, Bosch Institute and Discipline of Anatomy and Histology, School of Medical Sciences, Sydney Medical School, The University of Sydney, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia
| | - Nilufa Sultana
- Laboratory of Neurochemistry, Bosch Institute and Discipline of Anatomy and Histology, School of Medical Sciences, Sydney Medical School, The University of Sydney, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia
| | - Vladimir J Balcar
- Laboratory of Neurochemistry, Bosch Institute and Discipline of Anatomy and Histology, School of Medical Sciences, Sydney Medical School, The University of Sydney, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia.
| |
Collapse
|
|
41
|
Wilson S, Malone SM, Hunt RH, Thomas KM, Iacono WG. Problematic alcohol use and hippocampal volume in a female sample: disentangling cause from consequence using a co-twin control study design. Psychol Med 2018; 48:1673-1684. [PMID: 29108528 PMCID: PMC5938157 DOI: 10.1017/s0033291717003166] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Although there is extensive evidence that problematic alcohol use is associated with smaller hippocampal volume, the typical cross-sectional study design cannot determine whether hippocampal deviations reflect pre-existing liability toward problematic alcohol use or instead reflect an alcohol exposure-related effect. We used the co-twin control study design, which capitalizes upon differences within a twin pair in levels of drinking, to differentiate pre-existing liability from an effect of alcohol exposure. METHODS The sample included 100 female twins, prospectively assessed from ages 11 to 24. Problematic alcohol use was assessed dimensionally and included indicators of quantity, frequency, and density of alcohol use and intoxication. Hippocampal volume was assessed using magnetic resonance imaging. RESULTS Problematic alcohol use (proximal and cumulative) was associated with significantly smaller left and right hippocampal volume. Follow-up co-twin control analyses that partitioned individual-level alcohol effects into pre-existing, familial liability and non-shared alcohol exposure-related effects indicated that this association reflected alcohol exposure. Greater alcohol using twins had smaller hippocampal volume relative to lesser alcohol using co-twins, beyond effects of their shared genetic and environmental liability toward problematic alcohol use. Results held accounting for recent alcohol use, other substance use, externalizing and internalizing psychopathology, personality traits, trauma exposure, and menstrual phase. CONCLUSIONS The association between problematic alcohol use and smaller hippocampal volume likely reflects an alcohol exposure-related effect. Differentiating pre-existing brain deviations that confer risk for problematic alcohol use from those that reflect effects of alcohol on the brain will inform etiological models of addiction and further prevention and intervention efforts.
Collapse
Affiliation(s)
- Sylia Wilson
- Department of Psychology, University of Minnesota, 75 East River Rd, Minneapolis, MN 55455, USA
| | - Stephen M. Malone
- Department of Psychology, University of Minnesota, 75 East River Rd, Minneapolis, MN 55455, USA
| | - Ruskin H. Hunt
- Department of Psychology, University of Minnesota, 75 East River Rd, Minneapolis, MN 55455, USA
| | - Kathleen M. Thomas
- Institute of Child Development, University of Minnesota, 51 E River Rd, Minneapolis, MN 55455, USA
| | - William G. Iacono
- Department of Psychology, University of Minnesota, 75 East River Rd, Minneapolis, MN 55455, USA
| |
Collapse
|
|
42
|
Hayes DM, Nickell CG, Chen KY, McClain JA, Heath MM, Deeny MA, Nixon K. Activation of neural stem cells from quiescence drives reactive hippocampal neurogenesis after alcohol dependence. Neuropharmacology 2018; 133:276-288. [PMID: 29378214 PMCID: PMC6620048 DOI: 10.1016/j.neuropharm.2018.01.032] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 11/30/2017] [Accepted: 01/24/2018] [Indexed: 02/07/2023]
Abstract
Neural stem cell-driven adult neurogenesis contributes to the integrity of the hippocampus. Excessive alcohol consumption in alcoholism results in hippocampal degeneration that may recover with abstinence. Reactive, increased adult neurogenesis during abstinence following alcohol dependence may contribute to recovery, but the mechanism driving reactive neurogenesis is not known. Therefore, adult, male rats were exposed to alcohol for four days and various markers were used to examine cell cycle dynamics, the percentage and number of neural progenitor cell subtypes, and the percentage of quiescent versus activated progenitors. Using a screen for cell cycle perturbation, we showed that the cell cycle is not likely altered at 7 days in abstinence. As the vast majority of Bromodeoxyuridine-positive (+) cells were co-labeled with progenitor cell marker, Sox2, we then developed a quadruple fluorescent labeling scheme to examine Type-1, -2a, -2b and -3 progenitor cells simultaneously. Prior alcohol dependence indiscriminately increased all subtypes at 7 days, the peak of the reactive proliferation. An evaluation of the time course of reactive cell proliferation revealed that cells begin proliferating at 5 days post alcohol, where only actively dividing Type 2 progenitors were increased by alcohol. Furthermore, prior alcohol increased the percentage of actively dividing Sox2+ progenitors, which supported that reactive neurogenesis is likely due to the activation of progenitors out of quiescence. These observations were associated with granule cell number returning to normal at 28 days. Therefore, activating stem and progenitor cells out of quiescence may be the mechanism underlying hippocampal recovery in abstinence following alcohol dependence.
Collapse
Affiliation(s)
- Dayna M Hayes
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
| | - Chelsea G Nickell
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
| | - Kevin Y Chen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
| | - Justin A McClain
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
| | - Megan M Heath
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
| | - M Ayumi Deeny
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
| | - Kimberly Nixon
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
| |
Collapse
|
|
43
|
McGrath EL, Gao J, Kuo YF, Dunn TJ, Ray MJ, Dineley KT, Cunningham KA, Kaphalia BS, Wu P. Spatial and Sex-Dependent Responses of Adult Endogenous Neural Stem Cells to Alcohol Consumption. Stem Cell Reports 2017; 9:1916-1930. [PMID: 29129682 PMCID: PMC5785672 DOI: 10.1016/j.stemcr.2017.10.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Revised: 10/09/2017] [Accepted: 10/10/2017] [Indexed: 12/12/2022] Open
Abstract
Chronic alcohol abuse results in alcohol-related neurodegeneration, and critical gaps in our knowledge hinder therapeutic development. Neural stem cells (NSCs) are a subpopulation of cells within the adult brain that contribute to brain maintenance and recovery. While it is known that alcohol alters NSCs, little is known about how NSC response to alcohol is related to sex, brain region, and stage of differentiation. Understanding these relationships will aid in therapeutic development. Here, we used an inducible transgenic mouse model to track the stages of differentiation of adult endogenous NSCs and observed distinct NSC behaviors in three brain regions (subventricular zone, subgranular zone, and tanycyte layer) after long-term alcohol consumption. Particularly, chronic alcohol consumption profoundly affected the survival of NSCs in the subventricular zone and altered NSC differentiation in all three regions. Significant differences between male and female mice were further discovered.
Alcohol alters neural stem cell differentiation in a region-dependent manner Sex plays a role in neural stem cell response to alcohol consumption Sex contributes to regional differences of neural stem cell response to alcohol
Collapse
Affiliation(s)
- Erica L McGrath
- Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch at Galveston, Galveston 77555, USA; Institute for Translational Sciences, University of Texas Medical Branch at Galveston, Galveston 77555, USA; Center for Addiction Research, University of Texas Medical Branch at Galveston, Galveston 77555, USA; Department of Neurology, Johns Hopkins, Baltimore 21287, USA
| | - Junling Gao
- Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch at Galveston, Galveston 77555, USA
| | - Yong-Fang Kuo
- Department of Preventive Medicine and Community Health, University of Texas Medical Branch at Galveston, Galveston 77555, USA
| | - Tiffany J Dunn
- Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch at Galveston, Galveston 77555, USA
| | - Moniqua J Ray
- Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch at Galveston, Galveston 77555, USA
| | - Kelly T Dineley
- Center for Addiction Research, University of Texas Medical Branch at Galveston, Galveston 77555, USA; Department of Neurology, University of Texas Medical Branch at Galveston, Galveston 77555, USA
| | - Kathryn A Cunningham
- Center for Addiction Research, University of Texas Medical Branch at Galveston, Galveston 77555, USA; Department of Pharmacology and Toxicology, University of Texas Medical Branch at Galveston, Galveston 77555, USA
| | - Bhupendra S Kaphalia
- Department of Pathology, University of Texas Medical Branch at Galveston, Galveston 77555, USA
| | - Ping Wu
- Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch at Galveston, Galveston 77555, USA; Center for Addiction Research, University of Texas Medical Branch at Galveston, Galveston 77555, USA; Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China.
| |
Collapse
|
|
44
|
Abstract
BACKGROUND A number of studies reports reduced hippocampal volume in individuals who engage in problematic alcohol use. However, the magnitude of the difference in hippocampal volume between individuals with v. without problematic alcohol use has varied widely, and there have been null findings. Moreover, the studies comprise diverse alcohol use constructs and samples, including clinically significant alcohol use disorders and subclinical but problematic alcohol use (e.g. binge drinking), adults and adolescents, and males and females. METHODS We conducted the first quantitative synthesis of the published empirical research on associations between problematic alcohol use and hippocampal volume. In total, 23 studies were identified and selected for inclusion in the meta-analysis; effects sizes were aggregated using a random-effects model. RESULTS Problematic alcohol use was associated with significantly smaller hippocampal volume (d = -0.53). Moderator analyses indicated that effects were stronger for clinically significant v. subclinical alcohol use and among adults relative to adolescents; effects did not differ among males and females. CONCLUSIONS Problematic alcohol use is associated with reduced hippocampal volume. The moderate overall effect size suggests the need for larger samples than are typically included in studies of alcohol use and hippocampal volume. Because the existing literature is almost entirely cross-sectional, future research using causally informative study designs is needed to determine whether this association reflects premorbid risk for the development of problematic alcohol use and/or whether alcohol has a neurotoxic effect on the hippocampus.
Collapse
Affiliation(s)
- S. Wilson
- Department of Psychology, University of Minnesota, 75 E River Rd, Minneapolis, MN, USA
| | - J. L. Bair
- Department of Psychology, University of Minnesota, 75 E River Rd, Minneapolis, MN, USA
| | - K. M. Thomas
- Institute of Child Development, 51 E River Rd, Minneapolis, MN, USA
| | - W. G. Iacono
- Department of Psychology, University of Minnesota, 75 E River Rd, Minneapolis, MN, USA
| |
Collapse
|
|
45
|
Liu W, Crews FT. Persistent Decreases in Adult Subventricular and Hippocampal Neurogenesis Following Adolescent Intermittent Ethanol Exposure. Front Behav Neurosci 2017; 11:151. [PMID: 28855864 PMCID: PMC5557743 DOI: 10.3389/fnbeh.2017.00151] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 07/28/2017] [Indexed: 11/25/2022] Open
Abstract
Neurogenesis in hippocampal dentate gyrus (DG) and subventricular zone (SVZ) matures during adolescence to adult levels. Binge drinking is prevalent in adolescent humans, and could alter brain neurogenesis and maturation in a manner that persists into adulthood. To determine the impact of adolescent binge drinking on adult neurogenesis, Wistar rats received adolescent intermittent ethanol (AIE) exposure (5.0 g/kg/day, i.g., 2 days on/2 days off from postnatal day, P25–P54) and sacrificed on P57 or P95. Neural progenitor cell proliferation, differentiation, survival and maturation using immunohistochemistry was determined in the DG and SVZ. We found that AIE exposure decreased neurogenesis in both brain regions in adulthood (P95). In the DG at P57, AIE exposure resulted in a significant reduction of SOX2+, Tbr2+, Prox1+ and parvalbumin (PV)+IR expression, and at P95 decreased DCX+ and PV+IR expression. AIE exposure also reduced the expression of two cell proliferation markers (Ki67+ and BrdU+IR with 300 mg/kg, 2 h) at P95. The immune signaling molecule β-2 microglobulin+ and the cell death marker activated caspase-3+IR were significantly increased in the DG by AIE exposure. In the SVZ, AIE exposure decreased SOX2+, Mash1+, DCX+ and Dlx2+IR expression at P95, but not at P57. Thus, in adulthood both brain regions have reduced neurogenesis following AIE exposure. To assess progenitor cell survival and maturation, rats were treated with BrdU (150 mg/kg/day, 14 days) to label proliferating cells and were sacrificed weeks later on P95. In the hippocampus DG, AIE exposure increased survival BrdU+ cells which differentiated into Iba1+ microglia. In contrast, SVZ had decreased BrdU+ cells similar to decreased DCX+ neurogenesis. These data indicate that AIE exposure causes a lasting decrease in both adult hippocampal DG and forebrain SVZ neurogenesis with brain regional differences in the AIE response that persist into adulthood.
Collapse
Affiliation(s)
- Wen Liu
- Bowles Center for Alcohol Studies, University of North Carolina at Chapel HillChapel Hill, NC, United States
| | - Fulton T Crews
- Bowles Center for Alcohol Studies, University of North Carolina at Chapel HillChapel Hill, NC, United States
| |
Collapse
|
|
46
|
Maynard ME, Barton EA, Robinson CR, Wooden JI, Leasure JL. Sex differences in hippocampal damage, cognitive impairment, and trophic factor expression in an animal model of an alcohol use disorder. Brain Struct Funct 2017; 223:195-210. [PMID: 28752318 DOI: 10.1007/s00429-017-1482-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 07/20/2017] [Indexed: 12/21/2022]
Abstract
Compared to men, women disproportionally experience alcohol-related organ damage, including brain damage, and while men remain more likely to drink and to drink heavily, there is cause for concern because women are beginning to narrow the gender gap in alcohol use disorders. The hippocampus is a brain region that is particularly vulnerable to alcohol damage, due to cell loss and decreased neurogenesis. In the present study, we examined sex differences in hippocampal damage following binge alcohol. Consistent with our prior findings, we found a significant binge-induced decrement in dentate gyrus (DG) granule neurons in the female DG. However, in the present study, we found no significant decrement in granule neurons in the male DG. We show that the decrease in granule neurons in females is associated with both spatial navigation impairments and decreased expression of trophic support molecules. Finally, we show that post-binge exercise is associated with an increase in trophic support and repopulation of the granule neuron layer in the female hippocampus. We conclude that sex differences in alcohol-induced hippocampal damage are due in part to a paucity of trophic support and plasticity-related signaling in females.
Collapse
Affiliation(s)
- Mark E Maynard
- Department of Psychology, University of Houston, Houston, TX, 77204-5022, USA.,Department of Neurobiology and Anatomy, University of Texas Health Science Center, PO Box 20708, Houston, TX, 77225-0708, USA
| | - Emily A Barton
- Department of Psychology, University of Houston, Houston, TX, 77204-5022, USA
| | - Caleb R Robinson
- Department of Psychology, University of Houston, Houston, TX, 77204-5022, USA.,Department of Biology, Eastern Nazarene College, 23 E Elm Ave, Shrader Hall 30B, Quincy, MA, 02170, USA
| | - Jessica I Wooden
- Department of Psychology, University of Houston, Houston, TX, 77204-5022, USA
| | - J Leigh Leasure
- Department of Psychology, University of Houston, Houston, TX, 77204-5022, USA. .,Department of Biology and Biochemistry, University of Houston, Houston, TX, 77204-5022, USA.
| |
Collapse
|
|
47
|
Pant R, Jangra A, Kwatra M, Singh T, Kushwah P, Bezbaruah BK, Gurjar SS, Phukan S. Cognitive deficits induced by combined exposure of stress and alcohol mediated through oxidative stress-PARP pathway in the hippocampus. Neurosci Lett 2017; 653:208-214. [PMID: 28576564 DOI: 10.1016/j.neulet.2017.05.058] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Revised: 05/13/2017] [Accepted: 05/25/2017] [Indexed: 11/18/2022]
Abstract
Several studies reported that stress can enhance the consumption of alcohol in humans and animals. However, the combinatorial effect of stress and alcohol on cognitive function and neurochemical alterations is quite understudied. In the present study, we have elucidated the involvement of oxidative stress-PARP cascade in alcohol and restraint stress (RS)-exposed animals using a PARP inhibitor, 1,5-isoquinolinediol (3mg/kg for 14days). Male Swiss albino mice were given alcohol (ALC) or RS (2h per day) or both in ALC+RS group for 28days. Behavioral analysis revealed cognitive dysfunction in ALC+RS group. Furthermore, oxidative stress and raised level of pro-inflammatory cytokines were found in the hippocampus region of ALC+RS group. Semi-quantitative reverse transcriptase PCR showed overactivation of PARP-1 gene in ALC+RS group. 1,5-isoquinolinediol treatment significantly prevented cognitive deficits and aforementioned neurochemical alterations. Overall, our findings showed that ALC+RS exerted deleterious effects on the hippocampus which involves oxidative stress-PARP overactivation cascade.
Collapse
Affiliation(s)
- Rajat Pant
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam, India
| | - Ashok Jangra
- Department of Pharmacology, KIET School of Pharmacy, Krishna Institute of Engineering and Technology, Ghaziabad, Uttar Pradesh, India.
| | - Mohit Kwatra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam, India
| | - Tavleen Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam, India
| | - Pawan Kushwah
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam, India
| | | | - Satendra Singh Gurjar
- Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, Assam, India
| | - Swopna Phukan
- Department of Pharmacology, Gauhati Medical College, Guwahati, Assam, India
| |
Collapse
|
|
48
|
McAndrew A, Lawn W, Stevens T, Porffy L, Brandner B, Morgan CJA. A proof-of-concept investigation into ketamine as a pharmacological treatment for alcohol dependence: study protocol for a randomised controlled trial. Trials 2017; 18:159. [PMID: 28372596 PMCID: PMC5379743 DOI: 10.1186/s13063-017-1895-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 03/12/2017] [Indexed: 12/12/2022] Open
Abstract
Background Worldwide, alcohol abuse is a burgeoning problem. Abstinence is key to allow recovery of physical and mental health as well as quality of life, but treatment for alcohol dependence is associated with high relapse rates. Preliminary data have suggested that a combined repeated ketamine and psychological therapy programme may be effective in reducing relapse in severe alcohol use disorder. This non-commercial proof-of-concept trial is aimed at making a preliminary assessment of the effectiveness of this combined treatment in this patient group. Methods/design This is a phase II, randomised, double-blind, placebo-controlled, parallel-group clinical trial taking place in two sites in the UK: the South West of England and London. Ninety-six recently detoxified alcoholics, with comorbid depressive symptoms, will be randomised to one of four treatment arms. Patients will receive either three sessions of ketamine (0.8 mg/kg administered intravenously (IV) over 40 minutes) or placebo (50 ml saline 0.9% IV over 40 minutes) plus either seven sessions of manualised psychological therapy or an alcohol education control. Patients will be assessed at 3 and 6 months on a range of psychological and biological variables. The primary endpoints are (1) relapse rates at 6 months and (2) percentage days abstinent at 6 months. Secondary endpoints include 3 and 6 month percentage days abstinence, tolerability (indicated by dropout), adverse events, depressive symptoms, craving and quality of life. Discussion This study will provide important information on a new combined psychological and pharmacological intervention aimed at reducing relapse rates in alcoholics. The findings would have broad application given the worldwide prevalence of alcoholism and its associated medical, psychological and social problems. Trial registration ClinicalTrials.gov, NCT02649231. Registered on 5 January 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1895-6) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Amy McAndrew
- Psychopharmacology and Addiction Research Centre (PARC), College of Life and Environmental Science, University of Exeter, Washington Singer Building, Perry Road, Exeter, EX4 4QG, UK.
| | - Will Lawn
- Clinical Psychopharmacology Unit, University College London, 1-19 Torrington Place, London, WC1E 7HB, UK
| | - Tobias Stevens
- Psychopharmacology and Addiction Research Centre (PARC), College of Life and Environmental Science, University of Exeter, Washington Singer Building, Perry Road, Exeter, EX4 4QG, UK
| | - Lilla Porffy
- Clinical Psychopharmacology Unit, University College London, 1-19 Torrington Place, London, WC1E 7HB, UK
| | - Brigitta Brandner
- Anaesthetics Department, Podium 3, maple Link corridor, Unviersity College Hospital, 235 Euston Road, London, NW1 2BU, UK
| | - Celia J A Morgan
- Psychopharmacology and Addiction Research Centre (PARC), College of Life and Environmental Science, University of Exeter, Washington Singer Building, Perry Road, Exeter, EX4 4QG, UK
| |
Collapse
|
|
49
|
Gilbert ME, Goodman JH, Gomez J, Johnstone AFM, Ramos RL. Adult hippocampal neurogenesis is impaired by transient and moderate developmental thyroid hormone disruption. Neurotoxicology 2017; 59:9-21. [PMID: 28048979 PMCID: PMC11242631 DOI: 10.1016/j.neuro.2016.12.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 12/21/2016] [Accepted: 12/28/2016] [Indexed: 11/28/2022]
Abstract
The hippocampus maintains a capacity for neurogenesis throughout life, a capacity that is reduced in models of adult onset hypothyroidism. The effects of developmental thyroid hormone (TH) insufficiency on neurogenesis in the adult hippocampus, however, has not been examined. Graded degrees of TH insufficiency were induced in pregnant rat dams by administration of 0, 3 or 10ppm of 6-propylthiouracil (PTU) in drinking water from gestational day (GD) 6 until weaning. Body, brain, and hippocampal weight were reduced on postnatal day (PN) 14, 21, 78 and hippocampal volume was smaller at the 10 but not 3ppm dose level. A second experiment examined adult hippocampal neurogenesis following developmental or adult onset hypothyroidism. Two male offspring from 0 and 3ppm exposed dams were either maintained on control water or exposed to 3ppm PTU to create 4 distinct treatment conditions (Control-Control; Control-PTU, PTU-Control, PTU-PTU) based on developmental and adult exposures. Beginning on the 28th day of adult exposure to 0 or 3ppm PTU, bromodeoxyuridine (BrdU, 50mg/kg, ip) was administered twice daily for 5days, and one male from each treatment was sacrificed 24h and 28days after the last BrdU dose and brains processed for immunohistochemistry. Although no volume changes were seen in the hippocampus of the neonate at 3ppm, thinning of the granule cell layer emerged in adulthood. Developmental TH insufficiency produced a reduction in newly born cells, reducing BrdU+ve cells at 1 with no further reduction at 28-days post-BrdU. Similar findings were obtained using the proliferative cell marker Ki67. Neuronal differentiations was also altered with fewer doublecortin (Dcx) expressing cells and a higher proportion of immature Dcx phenotypes seen after developmental but not adult TH insufficiency. An impaired capacity for neurogenesis may contribute to impairments in synaptic plasticity and cognitive deficits previously reported by our laboratory and others following moderate degrees of developmental TH insufficiency induced by this PTU model.
Collapse
Affiliation(s)
- M E Gilbert
- Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC, USA.
| | - J H Goodman
- Department of Developmental Neurobiology, NY State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA; Departments of Physiology and Pharmacology and Neurology, SUNY Downstate Medical Center Brooklyn, NY 11203, USA
| | - J Gomez
- Department of Developmental Neurobiology, NY State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA
| | - A F M Johnstone
- Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC, USA
| | - R L Ramos
- Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY 11568, USA
| |
Collapse
|
|
50
|
Barcia JM, Portolés S, Portolés L, Urdaneta AC, Ausina V, Pérez-Pastor GMA, Romero FJ, Villar VM. Does Oxidative Stress Induced by Alcohol Consumption Affect Orthodontic Treatment Outcome? Front Physiol 2017; 8:22. [PMID: 28179886 PMCID: PMC5263147 DOI: 10.3389/fphys.2017.00022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 01/10/2017] [Indexed: 12/26/2022] Open
Abstract
HIGHLIGHTS Ethanol, Periodontal ligament, Extracellular matrix, Orthodontic movement. Alcohol is a legal drug present in several drinks commonly used worldwide (chemically known as ethyl alcohol or ethanol). Alcohol consumption is associated with several disease conditions, ranging from mental disorders to organic alterations. One of the most deleterious effects of ethanol metabolism is related to oxidative stress. This promotes cellular alterations associated with inflammatory processes that eventually lead to cell death or cell cycle arrest, among others. Alcohol intake leads to bone destruction and modifies the expression of interleukins, metalloproteinases and other pro-inflammatory signals involving GSKβ, Rho, and ERK pathways. Orthodontic treatment implicates mechanical forces on teeth. Interestingly, the extra- and intra-cellular responses of periodontal cells to mechanical movement show a suggestive similarity with the effects induced by ethanol metabolism on bone and other cell types. Several clinical traits such as age, presence of systemic diseases or pharmacological treatments, are taken into account when planning orthodontic treatments. However, little is known about the potential role of the oxidative conditions induced by ethanol intake as a possible setback for orthodontic treatment in adults.
Collapse
Affiliation(s)
- Jorge M. Barcia
- School of Medicine and Dentistry, Universidad Católica de Valencia San Vicente MártirValencia, Spain
| | - Sandra Portolés
- School of Medicine and Dentistry, Universidad Católica de Valencia San Vicente MártirValencia, Spain
| | - Laura Portolés
- School of Medicine and Dentistry, Universidad Católica de Valencia San Vicente MártirValencia, Spain
| | - Alba C. Urdaneta
- School of Medicine and Dentistry, Universidad Católica de Valencia San Vicente MártirValencia, Spain
| | - Verónica Ausina
- Facultad de Ciencias de la Salud, Universidad Europea de ValenciaValencia, Spain
| | - Gema M. A. Pérez-Pastor
- School of Medicine and Dentistry, Universidad Católica de Valencia San Vicente MártirValencia, Spain
| | - Francisco J. Romero
- School of Medicine and Dentistry, Universidad Católica de Valencia San Vicente MártirValencia, Spain
- Facultad de Ciencias de la Salud, Universidad Europea de ValenciaValencia, Spain
| | - Vincent M. Villar
- Department of Biomedical Sciences, Universidad Cardenal Herrera, CEUMoncada, Spain
| |
Collapse
|