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Ikpeama EU, Orish CN, Ezejiofor AN, Cirovic A, Cirovic A, Nwaogazie IL, Orisakwe OE. Selenium and zinc protect against heavy metal mixture-induced, olfactory bulb and hippocampal damage by augmenting antioxidant capacity and activation of Nrf2-Hmox-1 signaling in male rats. Int J Neurosci 2025; 135:242-256. [PMID: 38108304 DOI: 10.1080/00207454.2023.2295227] [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: 09/08/2023] [Revised: 12/02/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
PURPOSE/AIM OF THE STUDY Heavy metals and metalloids have been implicated in neurodenerative diseases. Present study has evaluated the potential protective effects of Se and Zn on heavy metals and metalloids mixture-induced (Cd, Pb, Hg and As) toxicity in the hippocampus and olfactory bulb in male rats. MATERIALS AND METHODS Five groups of Wistar rats were randomly divided in to: controls, toxic metals mixture (TMM) exposed rats (PbCl2, 20 mg·kg-1; CdCl2, 1.61 mg·kg-1; HgCl2, 0.40 mg·kg-1 and NaAsO3, 10 mg·kg-1)), TMM + Zn, TMM + Se and TMM-+Zn + Se groups and were orally treated for 60 days. RESULTS We found that in hippocampus and olfactory bulb, TMM generated increased lipid peroxidation and diminished antioxidant capacity. These adverse effects induced by TMM were alleviated by Zn and Se co-treatment; moreover, essential trace elements (Zn and Se) decreased activity of acetylcholinesterase, reduced Cd, Pb, Hg and As bioaccumulation in hippocampus and olfactory bulb and decreased levels of TNF-α in the hippocampus. TMM treated rats had lower levels of Hmox-1 (hippocampus), higher levels of Nrf2 (olfactory bulb and hippocampus) and NF-kB (olfactory bulb). TMM treated rats showed significantly highest time in locating the escape hole. Histopathological examination revealed hypertrophied granule cells in OB of TMM exposed rats. CONCLUSION Zn and Se supplementation can reverse quaternary mixture-induced (Cd, Pb, Hg and As) toxicity in hippocampus and OB in male albino rats.
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Affiliation(s)
- Evelyn U Ikpeama
- World Bank Africa Centre of Excellence in Oilfield Chemicals Research (ACE-CEFOR), University of Port Harcourt, PMB, Port Harcourt, Choba, Nigeria
| | - Chinna N Orish
- Department of Anatomy, Faculty of Basic Medical Sciences, College of Health Sciences, University of Port Harcourt, PMB, Port Harcourt, Choba, Nigeria
| | - Anthonet N Ezejiofor
- African Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port Harcourt, PMB, Port Harcourt, Choba, Nigeria
| | - Ana Cirovic
- Faculty of Medicine, Institute of Anatomy, University of Belgrade, Belgrade, Serbia
| | - Aleksandar Cirovic
- Faculty of Medicine, Institute of Anatomy, University of Belgrade, Belgrade, Serbia
| | - Ify L Nwaogazie
- World Bank Africa Centre of Excellence in Oilfield Chemicals Research (ACE-CEFOR), University of Port Harcourt, PMB, Port Harcourt, Choba, Nigeria
| | - Orish E Orisakwe
- African Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port Harcourt, PMB, Port Harcourt, Choba, Nigeria
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2
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Wen S, Wang L. Cadmium neurotoxicity and therapeutic strategies. J Biochem Mol Toxicol 2024; 38:e23670. [PMID: 38432689 DOI: 10.1002/jbt.23670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 01/26/2024] [Accepted: 02/23/2024] [Indexed: 03/05/2024]
Abstract
Cadmium (Cd) is a multitarget, carcinogenic, nonessential environmental pollutant. Due to its toxic effects at very low concentrations, lengthy biological half-life, and low excretion rate, exposure to Cd carries a concern. Prolonged exposure to Cd causes severe injury to the nervous system of both humans and animals. Nevertheless, the precise mechanisms responsible for the neurotoxic effects of Cd have yet to be fully elucidated. The accurate chemical mechanism potentially entails the destruction of metal-ion homeostasis, inducing oxidative stress, apoptosis, and autophagy. Here we review the evidence of the neurotoxic effects of Cd and corresponding strategies to protect against Cd-induced central nervous system injury.
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Affiliation(s)
- Shuangquan Wen
- Suzhou Chien-Shiung Institute of Technology, Taicang, China
- Veterinarian Clinical Diagnosis Study Group, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Liang Wang
- Suzhou Chien-Shiung Institute of Technology, Taicang, China
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Zhou T, Guo J, Zhang J, Xiao H, Qi X, Wu C, Chang X, Zhang Y, Liu Q, Zhou Z. Sex-Specific Differences in Cognitive Abilities Associated with Childhood Cadmium and Manganese Exposures in School-Age Children: a Prospective Cohort Study. Biol Trace Elem Res 2020; 193:89-99. [PMID: 30977088 DOI: 10.1007/s12011-019-01703-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 03/19/2019] [Indexed: 01/06/2023]
Abstract
To examine sex-specific associations of neonatal and childhood exposure to eight trace elements with cognitive abilities of school-age children. The association between exposure and effects was assessed among 296 school-age children from a population-based birth cohort study, who had manganese (Mn), cadmium (Cd), and lead (Pb) exposure measured in cord blood and chromium (Cr), manganese, cobalt (Co), copper (Cu), arsenic (As), selenium (Se), cadmium, and lead exposure quantified in spot urine. Cognitive abilities were assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR). Generalized linear models were performed to analyze associations of intelligence quotient (IQ) with trace element concentrations in cord blood and urinary trace element levels. General linear models were used to evaluate association between exposure fluctuation and children's IQ. Urinary Cd concentrations were negatively associated with full-scale IQ (β = - 3.469, 95% confidence interval (CI) - 6.291, - 0.647; p = 0.016) and performance IQ (β = - 4.012, 95% CI - 7.088, - 0.936; p = 0.011) in girls; however, neonatal Cd exposure expressed as Cd concentrations in cord blood was in inverse associations with verbal IQ (β = - 2.590, 95% CI - 4.570, - 0.609; p = 0.010) only in boys. Positive association between urinary Mn concentrations and performance IQ (β = 1.305, 95% CI 0.035, 2.575; p = 0.044) of children was observed, especially in girls. In addition, inverse association of urinary Cu concentrations with verbal IQ (β = - 2.200, 95% CI - 4.360, - 0.039; p = 0.046) was only found in boys. Childhood Cd exposure may adversely affect cognitive abilities, while Mn exposure may beneficially modify cognitive abilities of school-age children, particularly in girls.
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Affiliation(s)
- Tong Zhou
- School of Public Health/Key Laboratory of Public Health Safety of Ministry of Education/Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China, Fudan University, No. 130 Dong'an Road, Shanghai, 200032, China
| | - Jianqiu Guo
- School of Public Health/Key Laboratory of Public Health Safety of Ministry of Education/Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China, Fudan University, No. 130 Dong'an Road, Shanghai, 200032, China
| | - Jiming Zhang
- School of Public Health/Key Laboratory of Public Health Safety of Ministry of Education/Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China, Fudan University, No. 130 Dong'an Road, Shanghai, 200032, China
| | - Hongxi Xiao
- School of Public Health/Key Laboratory of Public Health Safety of Ministry of Education/Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China, Fudan University, No. 130 Dong'an Road, Shanghai, 200032, China
| | - Xiaojuan Qi
- School of Public Health/Key Laboratory of Public Health Safety of Ministry of Education/Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China, Fudan University, No. 130 Dong'an Road, Shanghai, 200032, China
- Zhejiang Provincial Center for Disease Control and Prevention, No. 3399, Binsheng Road, Hangzhou, 310051, China
| | - Chunhua Wu
- School of Public Health/Key Laboratory of Public Health Safety of Ministry of Education/Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China, Fudan University, No. 130 Dong'an Road, Shanghai, 200032, China
| | - Xiuli Chang
- School of Public Health/Key Laboratory of Public Health Safety of Ministry of Education/Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China, Fudan University, No. 130 Dong'an Road, Shanghai, 200032, China
| | - Yubin Zhang
- School of Public Health/Key Laboratory of Public Health Safety of Ministry of Education/Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China, Fudan University, No. 130 Dong'an Road, Shanghai, 200032, China
| | - Qiang Liu
- School of Public Health/Key Laboratory of Public Health Safety of Ministry of Education/Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China, Fudan University, No. 130 Dong'an Road, Shanghai, 200032, China
| | - Zhijun Zhou
- School of Public Health/Key Laboratory of Public Health Safety of Ministry of Education/Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China, Fudan University, No. 130 Dong'an Road, Shanghai, 200032, China.
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4
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Wang H, Zhang L, Abel GM, Storm DR, Xia Z. Cadmium Exposure Impairs Cognition and Olfactory Memory in Male C57BL/6 Mice. Toxicol Sci 2019; 161:87-102. [PMID: 29029324 DOI: 10.1093/toxsci/kfx202] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cadmium (Cd) is a heavy metal of high interest to the superfund initiative. Recent epidemiology studies have suggested a possible association between Cd exposure and cognitive as well as olfactory impairments in humans. However, studies in animal models are needed to establish a direct causal relationship between Cd exposure and impairments in cognition and olfaction. This study aims to investigate the toxic effect of Cd on cognition and olfactory function in mice. One group of 8-week-old C57BL/6 male mice was exposed to 3 mg/l Cd (in the form of CdCl2) through drinking water for 20 weeks for behavior tests and final blood Cd concentration analysis. The behavior tests were conducted before, during, and after Cd exposure to analyze the effects of Cd on cognition and olfactory function. Upon completion of behavior tests, blood was collected to measure final blood Cd concentration. Two additional groups of mice were similarly exposed to Cd for 5 or 13 weeks for peak blood Cd concentration measurement. The peak blood Cd concentration was 2.125-2.25 μg/l whereas the final blood Cd concentration was 0.18 μg/l. At this exposure level, Cd impaired hippocampus-dependent learning and memory in novel object location test, T-maze test, and contextual fear memory test. It also caused deficits in short-term olfactory memory and odor-cued olfactory learning and memory. Results in this study demonstrate a direct relationship between Cd exposure and cognitive as well as olfactory impairments in an animal model.
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Affiliation(s)
- Hao Wang
- Toxicology Program, Department of Environmental and Occupational Health Sciences
| | - Liang Zhang
- Toxicology Program, Department of Environmental and Occupational Health Sciences
| | - Glen M Abel
- Toxicology Program, Department of Environmental and Occupational Health Sciences
| | - Daniel R Storm
- Department of Pharmacology, University of Washington, Seattle, Washington 98195
| | - Zhengui Xia
- Toxicology Program, Department of Environmental and Occupational Health Sciences
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5
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Anyanwu BO, Ezejiofor AN, Igweze ZN, Orisakwe OE. Heavy Metal Mixture Exposure and Effects in Developing Nations: An Update. TOXICS 2018; 6:E65. [PMID: 30400192 PMCID: PMC6316100 DOI: 10.3390/toxics6040065] [Citation(s) in RCA: 142] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/17/2018] [Accepted: 10/23/2018] [Indexed: 01/06/2023]
Abstract
The drive for development and modernization has come at great cost. Various human activities in developed and developing countries, particularly in sub-Saharan Africa (SSA) have given rise to environmental safety concerns. Increased artisanal mining activities, illegal refining, use of leaded petrol, airborne dust, arbitrary discarding and burning of toxic waste, absorption of production industries in inhabited areas, inadequate environmental legislation, and weak implementation of policies, have given rise to the incomparable contamination and pollution associated with heavy metals in recent decades. This review evaluates the public health effects of heavy metals and their mixtures in SSA. This shows the extent and size of the problem posed by exposure to heavy metal mixtures in regard to public health.
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Affiliation(s)
- Brilliance Onyinyechi Anyanwu
- World Bank Africa Centre of Excellence in Oilfield Chemicals Research, University of Port Harcourt, PMB, 5323 Port Harcourt, Rivers State, Nigeria.
| | - Anthonet Ndidiamaka Ezejiofor
- Department of Experimental Pharmacology & Toxicology, Faculty of Pharmacy, University of Port Harcourt, PMB, 5323 Port Harcourt, Rivers State, Nigeria.
| | - Zelinjo Nkeiruka Igweze
- Department of Experimental Pharmacology & Toxicology, Faculty of Pharmacy, Madonna University Elele, PMB, 5001 Elele, Rivers State, Nigeria.
| | - Orish Ebere Orisakwe
- Department of Experimental Pharmacology & Toxicology, Faculty of Pharmacy, University of Port Harcourt, PMB, 5323 Port Harcourt, Rivers State, Nigeria.
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6
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Werner S, Nies E. Olfactory dysfunction revisited: a reappraisal of work-related olfactory dysfunction caused by chemicals. J Occup Med Toxicol 2018. [PMID: 30202422 DOI: 10.1186/s12995‐018‐0209‐6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Occupational exposure to numerous individual chemicals has been associated with olfactory dysfunction, mainly in individual case descriptions. Comprehensive epidemiological investigations into the olfactotoxic effect of working substances show that the human sense of smell may be impaired by exposure to metal compounds involving cadmium, chromium and nickel, and to formaldehyde. This conclusion is supported by the results of animal experiments. The level of evidence for a relationship between olfactory dysfunction and workplace exposure to other substances is relatively weak.
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Affiliation(s)
- Sabine Werner
- Institute for Occupational Safety and Health of the German Social Accident Insurance, Unit Toxicology of Industrial Chemicals, Alte Heerstrasse 111, 53757 Sankt Augustin, Germany
| | - Eberhard Nies
- Institute for Occupational Safety and Health of the German Social Accident Insurance, Unit Toxicology of Industrial Chemicals, Alte Heerstrasse 111, 53757 Sankt Augustin, Germany
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7
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Werner S, Nies E. Olfactory dysfunction revisited: a reappraisal of work-related olfactory dysfunction caused by chemicals. J Occup Med Toxicol 2018; 13:28. [PMID: 30202422 PMCID: PMC6124006 DOI: 10.1186/s12995-018-0209-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 07/30/2018] [Indexed: 11/10/2022] Open
Abstract
Occupational exposure to numerous individual chemicals has been associated with olfactory dysfunction, mainly in individual case descriptions. Comprehensive epidemiological investigations into the olfactotoxic effect of working substances show that the human sense of smell may be impaired by exposure to metal compounds involving cadmium, chromium and nickel, and to formaldehyde. This conclusion is supported by the results of animal experiments. The level of evidence for a relationship between olfactory dysfunction and workplace exposure to other substances is relatively weak.
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Affiliation(s)
- Sabine Werner
- Institute for Occupational Safety and Health of the German Social Accident Insurance, Unit Toxicology of Industrial Chemicals, Alte Heerstrasse 111, 53757 Sankt Augustin, Germany
| | - Eberhard Nies
- Institute for Occupational Safety and Health of the German Social Accident Insurance, Unit Toxicology of Industrial Chemicals, Alte Heerstrasse 111, 53757 Sankt Augustin, Germany
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8
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Togno-Peirce C, Limón-Morales O, Montes-López S, Rojas-Castañeda J, Márquez-Aguiluz D, Bonilla-Jaime H, Arteaga-Silva M. Pleiotropic Effects of Cadmium Toxicity on the Neuroendocrine-Immune Network. ACTA ACUST UNITED AC 2018. [DOI: 10.3233/nib-180138] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Cristián Togno-Peirce
- Department of Biology of Reproduction, DCBS, The Metropolitan Autonomous University-Iztapalapa, Mexico City, Mexico
| | - Ofelia Limón-Morales
- Department of Biology of Reproduction, DCBS, The Metropolitan Autonomous University-Iztapalapa, Mexico City, Mexico
| | - Sergio Montes-López
- Department of Neurochemistry, National Institute of Neurology and Neurosurgery “Dr. Manuel Velasco Suarez”, Mexico City, Mexico
| | | | - Darla Márquez-Aguiluz
- Department of Biology of Reproduction, DCBS, The Metropolitan Autonomous University-Iztapalapa, Mexico City, Mexico
| | - Herlinda Bonilla-Jaime
- Department of Biology of Reproduction, DCBS, The Metropolitan Autonomous University-Iztapalapa, Mexico City, Mexico
| | - Marcela Arteaga-Silva
- Department of Biology of Reproduction, DCBS, The Metropolitan Autonomous University-Iztapalapa, Mexico City, Mexico
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9
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Pi H, Li M, Xie J, Yang Z, Xi Y, Yu Z, Zhou Z. Transcription factor E3 protects against cadmium-induced apoptosis by maintaining the lysosomal-mitochondrial axis but not autophagic flux in Neuro-2a cells. Toxicol Lett 2018; 295:335-350. [PMID: 30030080 DOI: 10.1016/j.toxlet.2018.07.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 06/19/2018] [Accepted: 07/16/2018] [Indexed: 01/09/2023]
Abstract
Cadmium (Cd), is a well-known environmental and occupational hazard with a potent neurotoxic action. However, the mechanism underlying cadmium-induced neurotoxicity remains unclear. Herein, we exposed Neuro-2a cells to different concentrations of cadmium chloride (CdCl2) (12.5, 25 and 50 μM) for 24 h and found that Cd significantly induced lysosomal membrane permeabilization (LMP) with the release of cathepsin B (CTSB) to the cytosol, which in turn caused the release of mitochondrial cytochrome c (Cyt c) and eventually triggered caspase-dependent apoptosis. Interestingly, Cd decreased TFE3 expression but induced the nuclear translocation of TFE3 and TFE3 target-gene expression, which might be associated with lysosomal stress mediated by Cd. Notably, Tfe3 overexpression protected against Cd-induced neurotoxicity by maintaining the lysosomal-mitochondrial axis, and the protective effect of TFE3 is not dependent on the restoration of autophagic flux. In conclusion, our study demonstrated for the first time that lysosomal-mitochondrial axis dependent apoptosis, a neglected mechanism, may be the most important reason for Cd-induced neurotoxicity and that manipulation of TFE3 signaling may be a potential therapeutic approach for treatment of Cd-induced neurotoxicity.
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Affiliation(s)
- Huifeng Pi
- Department of Occupational Health, Third Military Medical University, Chongqing, China; School of Aerospace Medicine, Fourth Military Medical University, Xi'an, China
| | - Min Li
- Department of Occupational Health, Third Military Medical University, Chongqing, China
| | - Jia Xie
- Department of Occupational Health, Third Military Medical University, Chongqing, China
| | - Zhiqi Yang
- Brain Research Center, Third Military Medical University, Chongqing, China; Department of Neurology, Army General Hospital in Lanzhou, Lanzhou, China
| | - Yu Xi
- Department of Occupational and Environmental Medicine, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhengping Yu
- Department of Occupational Health, Third Military Medical University, Chongqing, China; State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - Zhou Zhou
- Department of Environmental Medicine, and Department of Critical Care Medicine of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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10
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Kass MD, McGann JP. Persistent, generalized hypersensitivity of olfactory bulb interneurons after olfactory fear generalization. Neurobiol Learn Mem 2017; 146:47-57. [PMID: 29104178 PMCID: PMC5886010 DOI: 10.1016/j.nlm.2017.11.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 10/16/2017] [Accepted: 11/01/2017] [Indexed: 12/25/2022]
Abstract
Generalization of fear from previously threatening stimuli to novel but related stimuli can be beneficial, but if fear overgeneralizes to inappropriate situations it can produce maladaptive behaviors and contribute to pathological anxiety. Appropriate fear learning can selectively facilitate early sensory processing of threat-predictive stimuli, but it is unknown if fear generalization has similarly generalized neurosensory consequences. We performed in vivo optical neurophysiology to visualize odor-evoked neural activity in populations of periglomerular interneurons in the olfactory bulb 1 day before, 1 day after, and 1 month after each mouse underwent an olfactory fear conditioning paradigm designed to promote generalized fear of odors. Behavioral and neurophysiological changes were assessed in response to a panel of odors that varied in similarity to the threat-predictive odor at each time point. After conditioning, all odors evoked similar levels of freezing behavior, regardless of similarity to the threat-predictive odor. Freezing significantly correlated with large changes in odor-evoked periglomerular cell activity, including a robust, generalized facilitation of the response to all odors, broadened odor tuning, and increased neural responses to lower odor concentrations. These generalized effects occurred within 24 h of a single conditioning session, persisted for at least 1 month, and were detectable even in the first moments of the brain's response to odors. The finding that generalized fear includes altered early sensory processing of not only the threat-predictive stimulus but also novel though categorically-similar stimuli may have important implications for the etiology and treatment of anxiety disorders with sensory sequelae.
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Affiliation(s)
- Marley D Kass
- Behavioral & Systems Neuroscience Section, Department of Psychology, Rutgers, The State University of New Jersey, 152 Frelinghuysen Road, Piscataway, NJ 08854, United States
| | - John P McGann
- Behavioral & Systems Neuroscience Section, Department of Psychology, Rutgers, The State University of New Jersey, 152 Frelinghuysen Road, Piscataway, NJ 08854, United States.
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11
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Saleh HM, El-Sayed YS, Naser SM, Eltahawy AS, Onoda A, Umezawa M. Efficacy of α-lipoic acid against cadmium toxicity on metal ion and oxidative imbalance, and expression of metallothionein and antioxidant genes in rabbit brain. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2017; 24:24593-24601. [PMID: 28913608 DOI: 10.1007/s11356-017-0158-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 09/07/2017] [Indexed: 06/07/2023]
Abstract
To explore the protective efficacy of α-lipoic acid (ALA) against Cd-prompted neurotoxicity, young male New Zealand rabbits (Oryctolagus cuniculus) were divided randomly into four groups. Group 1 (control) received demineralized water. Group 2 (Cd) administered cadmium chloride (CdCl2) 3 mg/kg bwt. Group 3 (ALA) administered ALA 100 mg/kg bwt. Group 4 (Cd + ALA) administered ALA 1 h after Cd. The treatments were administered orally for 30 consecutive days. Cd-induced marked disturbances in neurochemical parameters were indicated by the reduction in micro- and macro-elements (Zn, Fe, Cu, P, and Ca), with the highest reduction in Cd-exposed rabbits, followed by Cd + ALA group and then ALA group. In the brain tissues, Cd has significantly augmented the lipid hydroperoxides (LPO) and reduced the glutathione (GSH) and total antioxidant capacity (TAC), and glutathione peroxidase and glutathione S-transferase enzyme activities but had an insignificant effect on the antioxidant redox enzymes. Administration of ALA effectively restored LPO and sustained GSH and TAC contents. Moreover, Cd downregulated the transcriptional levels of Nrf2, MT3, and SOD1 genes, and upregulated that of Keap1 gene. ALA treatment, shortly following Cd exposure, downregulated Keap1, and upregulated Nrf2 and GPx1, while maintained MT3 and SOD1 mRNA gene expression in the rabbits' brain. These data indicated the ALA effectiveness in protecting against Cd-induced oxidative stress and the depletion of cellular antioxidants in the brain of rabbits perhaps due to its antioxidant, free radical scavenging, and chelating properties.
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Affiliation(s)
- Hamida M Saleh
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
| | - Yasser S El-Sayed
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
| | - Sherif M Naser
- Department of Veterinary Genetics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
| | - Abdelgawad S Eltahawy
- Department of Veterinary Economics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
| | - Atsuto Onoda
- The Center for Environmental Health Science for the Next Generation, Research Institute for Science and Technology, Tokyo University of Science, Noda, Chiba, Japan
- Department of Hygienic Chemistry, Graduate School of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan
- Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Masakazu Umezawa
- Department of Materials Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Katsushika, Tokyo, Japan
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12
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Differences in peripheral sensory input to the olfactory bulb between male and female mice. Sci Rep 2017; 7:45851. [PMID: 28443629 PMCID: PMC5405412 DOI: 10.1038/srep45851] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 03/03/2017] [Indexed: 11/21/2022] Open
Abstract
Female mammals generally have a superior sense of smell than males, but the biological basis of this difference is unknown. Here, we demonstrate sexually dimorphic neural coding of odorants by olfactory sensory neurons (OSNs), primary sensory neurons that physically contact odor molecules in the nose and provide the initial sensory input to the brain’s olfactory bulb. We performed in vivo optical neurophysiology to visualize odorant-evoked OSN synaptic output into olfactory bub glomeruli in unmanipulated (gonad-intact) adult mice from both sexes, and found that in females odorant presentation evoked more rapid OSN signaling over a broader range of OSNs than in males. These spatiotemporal differences enhanced the contrast between the neural representations of chemically related odorants in females compared to males during stimulus presentation. Removing circulating sex hormones makes these signals slower and less discriminable in females, while in males they become faster and more discriminable, suggesting opposite roles for gonadal hormones in influencing male and female olfactory function. These results demonstrate that the famous sex difference in olfactory abilities likely originates in the primary sensory neurons, and suggest that hormonal modulation of the peripheral olfactory system could underlie differences in how males and females experience the olfactory world.
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13
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Amygdalar Gating of Early Sensory Processing through Interactions with Locus Coeruleus. J Neurosci 2017; 37:3085-3101. [PMID: 28188216 DOI: 10.1523/jneurosci.2797-16.2017] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 12/18/2016] [Accepted: 01/09/2017] [Indexed: 11/21/2022] Open
Abstract
Fear- and stress-induced activity in the amygdala has been hypothesized to influence sensory brain regions through the influence of the amygdala on neuromodulatory centers. To directly examine this relationship, we used optical imaging to observe odor-evoked activity in populations of olfactory bulb inhibitory interneurons and of synaptic terminals of olfactory sensory neurons (the primary sensory neurons of the olfactory system, which provide the initial olfactory input to the brain) during pharmacological inactivation of amygdala and locus coeruleus (LC) in mice. Although the amygdala does not directly project to the olfactory bulb, joint pharmacological inactivation of the central, basolateral, and lateral nuclei of the amygdala nonetheless strongly suppressed odor-evoked activity in GABAergic inhibitory interneuron populations in the OB. This suppression was prevented by inactivation of LC or pretreatment of the olfactory bulb with a broad-spectrum noradrenergic receptor antagonist. Visualization of synaptic output from olfactory sensory neuron terminals into the olfactory bulb of the brain revealed that amygdalar inactivation preferentially strengthened the odor-evoked synaptic output of weakly activated populations of sensory afferents from the nose, thus demonstrating a change in sensory gating potentially mediated by local inhibition of olfactory sensory neuron terminals. We conclude that amygdalar activity influences olfactory processing as early as the primary sensory input to the brain by modulating norepinephrine release from the locus coeruleus into the olfactory bulb. These findings show that the amygdala and LC state actively determines which sensory signals are selected for processing in sensory brain regions. Similar local circuitry operates in the olfactory, visual, and auditory systems, suggesting a potentially shared mechanism across modalities.SIGNIFICANCE STATEMENT The affective state is increasingly understood to influence early neural processing of sensory stimuli, not just the behavioral response to those stimuli. The present study elucidates one circuit by which the amygdala, a critical structure for emotional learning, valence coding, and stress, can shape sensory input to the brain and early sensory processing through its connections to the locus coeruleus. One function of this interaction appears to be sensory gating, because inactivating the central, basolateral, and lateral nuclei of the amygdala selectively strengthened the weakest olfactory inputs to the brain. This linkage of amygdalar and LC output to primary sensory signaling may have implications for affective disorders that include sensory dysfunctions like hypervigilance, attentional bias, and impaired sensory gating.
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Karri V, Schuhmacher M, Kumar V. Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: A general review of metal mixture mechanism in brain. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2016; 48:203-213. [PMID: 27816841 DOI: 10.1016/j.etap.2016.09.016] [Citation(s) in RCA: 302] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 09/21/2016] [Accepted: 09/24/2016] [Indexed: 05/22/2023]
Abstract
Human exposure to toxic heavy metals is a global challenge. Concurrent exposure of heavy metals, such as lead (Pb), cadmium (Cd), arsenic (As) and methylmercury (MeHg) are particularly important due to their long lasting effects on the brain. The exact toxicological mechanisms invoked by exposure to mixtures of the metals Pb, Cd, As and MeHg are still unclear, however they share many common pathways for causing cognitive dysfunction. The combination of metals may produce additive/synergetic effects due to their common binding affinity with NMDA receptor (Pb, As, MeHg), Na+ - K+ ATP-ase pump (Cd, MeHg), biological Ca+2 (Pb, Cd, MeHg), Glu neurotransmitter (Pb, MeHg), which can lead to imbalance between the pro-oxidant elements (ROS) and the antioxidants (reducing elements). In this process, ROS dominates the antioxidants factors such as GPx, GS, GSH, MT-III, Catalase, SOD, BDNF, and CERB, and finally leads to cognitive dysfunction. The present review illustrates an account of the current knowledge about the individual metal induced cognitive dysfunction mechanisms and analyse common Mode of Actions (MOAs) of quaternary metal mixture (Pb, Cd, As, MeHg). This review aims to help advancement in mixture toxicology and development of next generation predictive model (such as PBPK/PD) combining both kinetic and dynamic interactions of metals.
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Affiliation(s)
- Venkatanaidu Karri
- Center of Environmental Food and Toxicological Technology (TecnATox), Departament d'Enginyeria Química, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain
| | - Marta Schuhmacher
- Center of Environmental Food and Toxicological Technology (TecnATox), Departament d'Enginyeria Química, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain
| | - Vikas Kumar
- Center of Environmental Food and Toxicological Technology (TecnATox), Departament d'Enginyeria Química, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain.
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15
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Rapisarda V, Loreto C, Malaguarnera M, Ardiri A, Proiti M, Rigano G, Frazzetto E, Ruggeri MI, Malaguarnera G, Bertino N, Malaguarnera M, Catania VE, Di Carlo I, Toro A, Bertino E, Mangano D, Bertino G. Hepatocellular carcinoma and the risk of occupational exposure. World J Hepatol 2016; 8:573-90. [PMID: 27168870 PMCID: PMC4858622 DOI: 10.4254/wjh.v8.i13.573] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 04/01/2016] [Accepted: 04/14/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The main risk factors for HCC are alcoholism, hepatitis B virus, hepatitis C virus, nonalcoholic steatohepatitis, obesity, type 2 diabetes, cirrhosis, aflatoxin, hemochromatosis, Wilson's disease and hemophilia. Occupational exposure to chemicals is another risk factor for HCC. Often the relationship between occupational risk and HCC is unclear and the reports are fragmented and inconsistent. This review aims to summarize the current knowledge regarding the association of infective and non-infective occupational risk exposure and HCC in order to encourage further research and draw attention to this global occupational public health problem.
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Affiliation(s)
- Venerando Rapisarda
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Carla Loreto
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Michele Malaguarnera
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Annalisa Ardiri
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Maria Proiti
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Giuseppe Rigano
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Evelise Frazzetto
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Maria Irene Ruggeri
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Giulia Malaguarnera
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Nicoletta Bertino
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Mariano Malaguarnera
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Vito Emanuele Catania
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Isidoro Di Carlo
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Adriana Toro
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Emanuele Bertino
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Dario Mangano
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Gaetano Bertino
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
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16
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Kass MD, Guang SA, Moberly AH, McGann JP. Changes in Olfactory Sensory Neuron Physiology and Olfactory Perceptual Learning After Odorant Exposure in Adult Mice. Chem Senses 2015; 41:123-33. [PMID: 26514410 DOI: 10.1093/chemse/bjv065] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The adult olfactory system undergoes experience-dependent plasticity to adapt to the olfactory environment. This plasticity may be accompanied by perceptual changes, including improved olfactory discrimination. Here, we assessed experience-dependent changes in the perception of a homologous aldehyde pair by testing mice in a cross-habituation/dishabituation behavioral paradigm before and after a week-long ester-odorant exposure protocol. In a parallel experiment, we used optical neurophysiology to observe neurotransmitter release from olfactory sensory neuron (OSN) terminals in vivo, and thus compared primary sensory representations of the aldehydes before and after the week-long ester-odorant exposure in individual animals. Mice could not discriminate between the aldehydes during pre-exposure testing, but ester-exposed subjects spontaneously discriminated between the homologous pair after exposure, whereas home cage control mice cross-habituated. Ester exposure did not alter the spatial pattern, peak magnitude, or odorant-selectivity of aldehyde-evoked OSN input to olfactory bulb glomeruli, but did alter the temporal dynamics of that input to make the time course of OSN input more dissimilar between odorants. Together, these findings demonstrate that odor exposure can induce both physiological and perceptual changes in odor processing, and suggest that changes in the temporal patterns of OSN input to olfactory bulb glomeruli could induce differences in odor quality.
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Affiliation(s)
- Marley D Kass
- Behavioral & Systems Neuroscience Section, Department of Psychology, Rutgers University, 152 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Stephanie A Guang
- Behavioral & Systems Neuroscience Section, Department of Psychology, Rutgers University, 152 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Andrew H Moberly
- Behavioral & Systems Neuroscience Section, Department of Psychology, Rutgers University, 152 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - John P McGann
- Behavioral & Systems Neuroscience Section, Department of Psychology, Rutgers University, 152 Frelinghuysen Road, Piscataway, NJ 08854, USA
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17
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Olfactory training induces changes in regional functional connectivity in patients with long-term smell loss. NEUROIMAGE-CLINICAL 2015; 9:401-10. [PMID: 26594622 PMCID: PMC4590718 DOI: 10.1016/j.nicl.2015.09.004] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 07/25/2015] [Accepted: 09/08/2015] [Indexed: 11/18/2022]
Abstract
Recently, olfactory training has been introduced as a promising treatment for patients with olfactory dysfunction. However, less is known about the neuronal basis and the influence on functional networks of this training. Thus, we aimed to investigate the neuroplasticity of chemosensory perception through an olfactory training program in patients with smell loss. The experimental setup included functional MRI (fMRI) experiments with three different types of chemosensory stimuli. Ten anosmic patients (7f, 3m) and 14 healthy controls (7f, 7m) underwent the same testing sessions. After a 12-week olfactory training period, seven patients (4f, 3m) were invited for follow-up testing using the same fMRI protocol. Functional networks were identified using independent component analysis and were further examined in detail using functional connectivity analysis. We found that anosmic patients and healthy controls initially use the same three networks to process chemosensory input: the olfactory; the somatosensory; and the integrative network. Those networks did not differ between the two groups in their spatial extent, but in their functional connectivity. After the olfactory training, the sensitivity to detect odors significantly increased in the anosmic group, which was also manifested in modifications of functional connections in all three investigated networks. The results of this study indicate that an olfactory training program can reorganize functional networks, although, initially, no differences in the spatial distribution of neural activation were observed.
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18
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Kass MD, Rosenthal MC, Pottackal J, McGann JP. Fear learning enhances neural responses to threat-predictive sensory stimuli. Science 2013; 342:1389-1392. [PMID: 24337299 DOI: 10.1126/science.1244916] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The central nervous system rapidly learns that particular stimuli predict imminent danger. This learning is thought to involve associations between neutral and harmful stimuli in cortical and limbic brain regions, though associative neuroplasticity in sensory structures is increasingly appreciated. We observed the synaptic output of olfactory sensory neurons (OSNs) in individual mice before and after they learned that a particular odor indicated an impending foot shock. OSNs are the first cells in the olfactory system, physically contacting the odor molecules in the nose and projecting their axons to the brain's olfactory bulb. OSN output evoked by the shock-predictive odor was selectively facilitated after fear conditioning. These results indicate that affective information about a stimulus can be encoded in its very earliest representation in the nervous system.
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Affiliation(s)
- Marley D Kass
- Behavioral and Systems Neuroscience Section, Department of Psychology, Rutgers, The State University of New Jersey, 152 Frelinghuysen Road, Piscataway, NJ 08854
| | - Michelle C Rosenthal
- Behavioral and Systems Neuroscience Section, Department of Psychology, Rutgers, The State University of New Jersey, 152 Frelinghuysen Road, Piscataway, NJ 08854
| | - Joseph Pottackal
- Behavioral and Systems Neuroscience Section, Department of Psychology, Rutgers, The State University of New Jersey, 152 Frelinghuysen Road, Piscataway, NJ 08854
| | - John P McGann
- Behavioral and Systems Neuroscience Section, Department of Psychology, Rutgers, The State University of New Jersey, 152 Frelinghuysen Road, Piscataway, NJ 08854
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19
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Haehner A, Hummel T, Wolz M, Klingelhöfer L, Fauser M, Storch A, Reichmann H. Effects of rasagiline on olfactory function in patients with Parkinson's disease. Mov Disord 2013; 28:2023-7. [DOI: 10.1002/mds.25661] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 07/25/2013] [Accepted: 08/04/2013] [Indexed: 01/02/2023] Open
Affiliation(s)
- Antje Haehner
- Smell & Taste Clinic, Department of Otorhinolaryngology; University of Dresden Medical School; Dresden Germany
| | - Thomas Hummel
- Smell & Taste Clinic, Department of Otorhinolaryngology; University of Dresden Medical School; Dresden Germany
| | - Martin Wolz
- Department of Neurology; University of Dresden Medical School; Dresden Germany
- Department of Neurology; Elblandkliniken Meissen; Meissen Germany
| | - Lisa Klingelhöfer
- Department of Neurology; University of Dresden Medical School; Dresden Germany
| | - Mareike Fauser
- Department of Neurology; University of Dresden Medical School; Dresden Germany
| | - Alexander Storch
- Division of Neurodegenerative Diseases, Department of Neurology; University of Dresden Medical School; Dresden Germany
- German Centre for Neurodegenerative Diseases (DZNE) Dresden; Dresden Germany
| | - Heinz Reichmann
- Department of Neurology; University of Dresden Medical School; Dresden Germany
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20
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Geißler K, Reimann H, Gudziol H, Bitter T, Guntinas-Lichius O. Olfactory training for patients with olfactory loss after upper respiratory tract infections. Eur Arch Otorhinolaryngol 2013; 271:1557-62. [DOI: 10.1007/s00405-013-2747-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Accepted: 09/26/2013] [Indexed: 10/26/2022]
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21
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McGann JP. Presynaptic inhibition of olfactory sensory neurons: new mechanisms and potential functions. Chem Senses 2013; 38:459-74. [PMID: 23761680 DOI: 10.1093/chemse/bjt018] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Presynaptic inhibition is the suppression of neurotransmitter release from a neuron by inhibitory input onto its presynaptic terminal. In the olfactory system, the primary sensory afferents from the olfactory neuroepithelium to the brain's olfactory bulb are strongly modulated by a presynaptic inhibition that has been studied extensively in brain slices and in vivo. In rodents, this inhibition is mediated by γ-amino butyric acid (GABA) and dopamine released from bulbar interneurons. The specialized GABAergic circuit is now well understood to include a specific subset of GAD65-expressing periglomerular interneurons that stimulate presynaptic GABAB receptors to reduce presynaptic calcium conductance. This inhibition is organized to permit the selective modulation of neurotransmitter release from specific populations of olfactory sensory neurons based on their odorant receptor expression, includes specialized microcircuits to create a tonically active inhibition and a separate feedback inhibition evoked by sensory input, and can be modulated by centrifugal projections from other brain regions. Olfactory nerve output can also be modulated by dopaminergic circuitry, but this literature is more difficult to interpret. Presynaptic inhibition of olfactory afferents may extend their dynamic range but could also create state-dependent or odorant-specific sensory filters on primary sensory representations. New directions exploring this circuit's role in olfactory processing are discussed.
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Affiliation(s)
- John P McGann
- Department of Psychology, Rutgers University, 152 Frelinghuysen Road, Piscataway, NJ 08854, USA.
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22
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Odor-specific, olfactory marker protein-mediated sparsening of primary olfactory input to the brain after odor exposure. J Neurosci 2013; 33:6594-602. [PMID: 23575856 DOI: 10.1523/jneurosci.1442-12.2013] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Long-term plasticity in sensory systems is usually conceptualized as changing the interpretation of the brain of sensory information, not an alteration of how the sensor itself responds to external stimuli. However, here we demonstrate that, in the adult mouse olfactory system, a 1-week-long exposure to an artificially odorized environment narrows the range of odorants that can induce neurotransmitter release from olfactory sensory neurons (OSNs) and reduces the total transmitter release from responsive neurons. In animals heterozygous for the olfactory marker protein (OMP), this adaptive plasticity was strongest in the populations of OSNs that originally responded to the exposure odorant (an ester) and also observed in the responses to a similar odorant (another ester) but had no effect on the responses to odorants dissimilar to the exposure odorant (a ketone and an aldehyde). In contrast, in OMP knock-out mice, odorant exposure reduced the number and amplitude of OSN responses evoked by all four types of odorants equally. The effect of this plasticity is to preferentially sparsen the primary neural representations of common olfactory stimuli, which has the computational benefit of increasing the number of distinct sensory patterns that could be represented in the circuit and might thus underlie the improvements in olfactory discrimination often observed after odorant exposure (Mandairon et al., 2006a). The absence of odorant specificity in this adaptive plasticity in OMP knock-out mice suggests a potential role for this protein in adaptively reshaping OSN responses to function in different environments.
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23
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Bernhoft RA. Cadmium toxicity and treatment. ScientificWorldJournal 2013; 2013:394652. [PMID: 23844395 PMCID: PMC3686085 DOI: 10.1155/2013/394652] [Citation(s) in RCA: 299] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 02/28/2013] [Indexed: 02/06/2023] Open
Abstract
Cadmium is a heavy metal of considerable toxicity with destructive impact on most organ systems. It is widely distributed in humans, the chief sources of contamination being cigarette smoke, welding, and contaminated food and beverages. Toxic impacts are discussed and appear to be proportional to body burden of cadmium. Detoxification of cadmium with EDTA and other chelators is possible and has been shown to be therapeutically beneficial in humans and animals when done using established protocols.
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Affiliation(s)
- Robin A Bernhoft
- Bernhoft Centers for Advanced Medicine, 11677 San Vicente Blvd, Suite 208/211, Los Angeles, CA 93023, USA.
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24
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Spatiotemporal alterations in primary odorant representations in olfactory marker protein knockout mice. PLoS One 2013; 8:e61431. [PMID: 23630588 PMCID: PMC3632605 DOI: 10.1371/journal.pone.0061431] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 03/11/2013] [Indexed: 11/19/2022] Open
Abstract
Olfactory marker protein (OMP) is highly and selectively expressed in primary olfactory sensory neurons (OSNs) across species, but its physiological function remains unclear. Previous studies in the olfactory epithelium suggest that it accelerates the neural response to odorants and may modulate the odorant-selectivity of OSNs. Here we used a line of gene-targeted mice that express the fluorescent exocytosis indicator synaptopHluorin in place of OMP to compare spatiotemporal patterns of odorant-evoked neurotransmitter release from OSNs in adult mice that were heterozygous for OMP or OMP-null. We found that these patterns, which constitute the primary neural representation of each odorant, developed more slowly during the odorant presentation in OMP knockout mice but eventually reached the same magnitude as in heterozygous mice. In the olfactory bulb, each glomerulus receives synaptic input from a subpopulation of OSNs that all express the same odor receptor and thus typically respond to a specific subset of odorants. We observed that in OMP knockout mice, OSNs innervating a given glomerulus typically responded to a broader range of odorants than in OMP heterozygous mice and thus each odorant evoked synaptic input to a larger number of glomeruli. In an olfactory habituation task, OMP knockout mice behaved differently than wild-type mice, exhibiting a delay in their onset to investigate an odor stimulus during its first presentation and less habituation to that stimulus over repeated presentations. These results suggest that the actions of OMP in olfactory transduction carry through to the primary sensory representations of olfactory stimuli in adult mice in vivo.
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25
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Haehner A, Tosch C, Wolz M, Klingelhoefer L, Fauser M, Storch A, Reichmann H, Hummel T. Olfactory training in patients with Parkinson's disease. PLoS One 2013; 8:e61680. [PMID: 23613901 PMCID: PMC3629137 DOI: 10.1371/journal.pone.0061680] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Accepted: 03/13/2013] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE Decrease of olfactory function in Parkinson's disease (PD) is a well-investigated fact. Studies indicate that pharmacological treatment of PD fails to restore olfactory function in PD patients. The aim of this investigation was whether patients with PD would benefit from "training" with odors in terms of an improvement of their general olfactory function. It has been hypothesized that olfactory training should produce both an improved sensitivity towards the odors used in the training process and an overall increase of olfactory function. METHODS We recruited 70 subjects with PD and olfactory loss into this single-center, prospective, controlled non-blinded study. Thirty-five patients were assigned to the olfactory training group and 35 subjects to the control group (no training). Olfactory training was performed over a period of 12 weeks while patients exposed themselves twice daily to four odors (phenyl ethyl alcohol: rose, eucalyptol: eucalyptus, citronellal: lemon, and eugenol: cloves). Olfactory testing was performed before and after training using the "Sniffin' Sticks" (thresholds for phenyl ethyl alcohol, tests for odor discrimination, and odor identification) in addition to threshold tests for the odors used in the training process. RESULTS Compared to baseline, trained PD patients experienced a significant increase in their olfactory function, which was observed for the Sniffin' Sticks test score and for thresholds for the odors used in the training process. Olfactory function was unchanged in PD patients who did not perform olfactory training. CONCLUSION The present results indicate that olfactory training may increase olfactory sensitivity in PD patients.
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Affiliation(s)
- Antje Haehner
- Smell & Taste Clinic, Department of Otorhinolaryngology, University of Dresden Medical School, Dresden, Germany.
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26
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Kass MD, Pottackal J, Turkel DJ, McGann JP. Changes in the neural representation of odorants after olfactory deprivation in the adult mouse olfactory bulb. Chem Senses 2012; 38:77-89. [PMID: 23125347 DOI: 10.1093/chemse/bjs081] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Olfactory sensory deprivation during development has been shown to induce significant alterations in the neurophysiology of olfactory receptor neurons (ORNs), the primary sensory inputs to the brain's olfactory bulb. Deprivation has also been shown to alter the neurochemistry of the adult olfactory system, but the physiological consequences of these changes are poorly understood. Here we used in vivo synaptopHluorin (spH) imaging to visualize odorant-evoked neurotransmitter release from ORNs in adult transgenic mice that underwent 4 weeks of unilateral olfactory deprivation. Deprivation reduced odorant-evoked spH signals compared with sham-occluded mice. Unexpectedly, this reduction was equivalent between ORNs on the open and plugged sides. Changes in odorant selectivity of glomerular subpopulations of ORNs were also observed, but only in ORNs on the open side of deprived mice. These results suggest that naris occlusion in adult mice produces substantial changes in primary olfactory processing which may reflect not only the decrease in olfactory stimulation on the occluded side but also the alteration of response properties on the intact side. We also observed a modest effect of true sham occlusions that included noseplug insertion and removal, suggesting that conventional noseplug techniques may have physiological effects independent of deprivation per se and thus require more careful controls than has been previously appreciated.
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Affiliation(s)
- Marley D Kass
- Behavioral and Systems Neuroscience Section, Department of Psychology, Rutgers, The State University of New Jersey, USA
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27
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Moberly AH, Czarnecki LA, Pottackal J, Rubinstein T, Turkel DJ, Kass MD, McGann JP. Intranasal exposure to manganese disrupts neurotransmitter release from glutamatergic synapses in the central nervous system in vivo. Neurotoxicology 2012; 33:996-1004. [PMID: 22542936 PMCID: PMC3432160 DOI: 10.1016/j.neuro.2012.04.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Revised: 03/29/2012] [Accepted: 04/14/2012] [Indexed: 11/28/2022]
Abstract
Chronic exposure to aerosolized manganese induces a neurological disorder that includes extrapyramidal motor symptoms and cognitive impairment. Inhaled manganese can bypass the blood-brain barrier and reach the central nervous system by transport down the olfactory nerve to the brain's olfactory bulb. However, the mechanism by which Mn disrupts neural function remains unclear. Here we used optical imaging techniques to visualize exocytosis in olfactory nerve terminals in vivo in the mouse olfactory bulb. Acute Mn exposure via intranasal instillation of 2-200 μg MnCl(2) solution caused a dose-dependent reduction in odorant-evoked neurotransmitter release, with significant effects at as little as 2 μg MnCl(2) and a 90% reduction compared to vehicle controls with a 200 μg exposure. This reduction was also observed in response to direct electrical stimulation of the olfactory nerve layer in the olfactory bulb, demonstrating that Mn's action is occurring centrally, not peripherally. This is the first direct evidence that Mn intoxication can disrupt neurotransmitter release, and is consistent with previous work suggesting that chronic Mn exposure limits amphetamine-induced dopamine increases in the basal ganglia despite normal levels of dopamine synthesis (Guilarte et al., J Neurochem 2008). The commonality of Mn's action between glutamatergic neurons in the olfactory bulb and dopaminergic neurons in the basal ganglia suggests that a disruption of neurotransmitter release may be a general consequence wherever Mn accumulates in the brain and could underlie its pleiotropic effects.
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Affiliation(s)
- Andrew H Moberly
- Behavioral Neuroscience Section, Department of Psychology, Rutgers, The State University of New Jersey, USA
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