Targeting the immune system has recently garnered attention in the treatment of stress- associated psychiatric disorders resistant to existing pharmacotherapeutics. While such approaches have been studied in considerable detail in depression, the role of (neuro)inflammation in anxiety-related disorders, or in anxiety as an important transdiagnostic symptom, is much less clear. In this review we first critically review clinical and in part preclinical evidence of central and peripheral immune dysregulation in anxiety disorders and post-traumatic stress disorder (PTSD) and briefly discuss proposed mechanisms of how inflammation can affect anxiety-related symptoms. We then give an overview of existing and potential future targets in inflammation-associated signal transduction pathways and discuss effects of different immune-modulatory drugs in anxiety-related disorders. Finally, we discuss key gaps in current clinical trials such as the lack of prospective studies involving anxiety patient stratification strategies based on inflammatory biomarkers. Overall, although evidence is rather limited so far, there is data to indicate that increased (neuro)inflammation is present in subgroups of anxiety disorder patients. Although exact identification of such immune subtypes of anxiety disorders and PTSD is still challenging, these patients will likely particularly benefit from therapeutic targeting of aspects of the inflammatory system. Different anti-inflammatory treatment approaches (microglia-directed treatments, pro-inflammatory cytokine inhibitors, COX-inhibitors, phytochemicals and a number of novel anti-inflammatory agents) have indeed shown some efficacy even in non-stratified anxiety patient groups and appear promising as novel alternative or complimentary therapeutic options in specific ("inflammatory") subtypes of anxiety disorder and PTSD patients.

The renin angiotensin system (RAS) is implicated in various cognitive processes relevant to anxiety. However, the role of the RAS in pattern separation, a hippocampal memory mechanism that enables discrete encoding of similar stimuli, is unclear. Given the proposed role of this mechanism in overgeneralization and the maintenance of anxiety, we explored the influence of the RAS on mnemonic discrimination, i.e., the behavioral ability arising from pattern separation.

In a double-blind experimental medicine trial, we examined the effect of losartan, an angiotensin receptor blocker, on mnemonic discrimination in N = 60 healthy volunteers aged 18-50. Participants were randomly allocated to a 50 mg losartan or placebo condition, and then completed the Mnemonic Similarity Task (MST), an established measure of mnemonic discrimination. Main outcome measures were the lure discrimination index (LDI), calculated as the rate of 'similar' responses to lures minus 'similar' responses to foils, and recognition (REC) memory, calculated as the difference between the rate of 'old' responses to targets minus 'old' responses to foils.

Data were available for N = 56 participants (N = 40 females, N = 16 males). Participants in the losartan group (N = 29) achieved significantly higher LDI scores (t(54) = 2.30, p = 0.025) compared to the placebo group (N = 27), indicating better mnemonic discrimination. No significant group differences were found in REC scores (U = 324, z = -1.10, d = 0.08; p = 0.271).

We demonstrate for the first time that losartan improves mnemonic discrimination in healthy individuals, suggesting that the RAS may influence pattern separation and anxiety.

Fear generalization, a lack of discrimination between safe and unsafe cues, is a hallmark of posttraumatic stress disorder. The phosphodiesterase 5 (PDE5) regulates the cyclic guanosine monophosphate (cGMP) pathway, which has been proposed to be involved in fear memory generalization. However, whether PDE5 activity underlies fear memory generalization remains unexplored. Considering the importance of retrieval-induced reconsolidation in memory maintenance, we aimed to investigate whether PDE5 inhibition during reconsolidation of recent fear memory affects generalization over time in adult male Wistar rats submitted to contextual fear conditioning. The PDE5 inhibition with vardenafil (VAR) 1 mg/kg i.p. during reconsolidation triggered a time-dependent fear generalization without affecting fear memory in the paired context. Fear generalization and impaired pattern separation appear to be interlinked. Likewise, an impairment of object pattern separation was observed in the VAR-treated group at the remote time point. These effects depended on memory retrieval and were restricted to the reconsolidation time window. A chemogenetic inhibition of the anterior cingulate cortex (ACC), a region involved in allocating remote memories and generalization, prevented the effects of VAR. Moreover, VAR infusion into the ACC (6 μg/0.2 μL) after retrieval also promoted fear generalization and impaired OPS in remote time point, suggesting that ACC underlies the behavioral outcomes of the treatment with VAR. In conclusion, our results suggest that inhibiting PDE5 during the reconsolidation of a recent fear memory recruits the activity of the ACC, triggering fear memory generalization and impairing object pattern separation over time.

Impairments in behavioral pattern separation (BPS)-the ability to distinguish between similar contexts or experiences-contribute to memory interference and overgeneralization seen in many neuropsychiatric conditions, including depression, anxiety, posttraumatic stress disorder, dementia, and age-related cognitive decline. Although BPS relies on the dentate gyrus and is sensitive to changes in adult hippocampal neurogenesis, its significance as a pharmacological target has not been tested.

In this study, we applied a human neural stem cell high-throughput screening cascade to identify compounds that increase human neurogenesis. One compound with a favorable profile, RO6871135, was then tested in young and aged mice for effects on BPS and anxiety-related behaviors.

Chronic treatment with RO6871135 (7.5 mg/kg) increased adult hippocampal neurogenesis and improved BPS in a fear discrimination task in both young and aged mice. RO6871135 treatment also lowered innate anxiety-like behavior, which was more apparent in mice exposed to chronic corticosterone. Ablation of adult hippocampal neurogenesis by hippocampal irradiation supported a neurogenesis-dependent mechanism for RO6871135-induced improvements in BPS. To identify possible mechanisms of action, in vitro and in vivo kinase inhibition and chemical proteomics assays were performed. These tests indicated that RO6871135 inhibited CDK8, CDK11, CaMKIIa, CaMKIIb, MAP2K6, and GSK-3β. An analog compound also demonstrated high affinity for CDK8, CaMKIIa, and GSK-3β.

These studies demonstrate a method for empirical identification and preclinical testing of novel neurogenic compounds that can improve BPS and point to possible novel mechanisms that can be interrogated for the development of new therapies to improve specific endophenotypes such as impaired BPS.

It had long been considered that no new neurons are generated in the primate brain beyond birth, but recent studies have indicated that neurogenesis persists in various locations throughout the lifespan. The dentate gyrus of the hippocampus is of particular interest due to the postulated role played by neurogenesis in memory. However, studies investigating the presence of adult hippocampal neurogenesis (AHN) have reported contradictory findings, and no systematic review of the evidence has been conducted to date. We searched MEDLINE, Embase and PsycINFO on 27th June 2023 for studies on hippocampal neurogenesis in adult primates, excluding review papers. Screening, quality assessment and data extraction was done by independent co-raters. We synthesised evidence from 112 relevant papers. We found robust evidence, primarily supported by immunohistochemical examination of tissue samples and neuroimaging, for newly generated neurons, first detected in the subgranular zone of the dentate gyrus, that mature over time and migrate to the granule cell layer, where they become functionally integrated with surrounding neuronal networks. AHN has been repeatedly observed in both humans and other primates and gradually diminishes with age. Transient increases in AHN are observed following acute insults such as stroke and epileptic seizures, and following electroconvulsive therapy, and AHN is diminished in neurodegenerative conditions. Markers of AHN correlate positively with measures of learning and short-term memory, but associations with antidepressant use and mood states are weaker. Heterogeneous outcome measures limited quantitative syntheses. Further research should better characterise the neuropsychological function of neurogenesis in healthy subjects.

Everyday experiences often overlap, challenging our ability to maintain distinct episodic memories. One way to resolve such interference is by exaggerating subtle differences between remembered events, a phenomenon known as memory repulsion. Here, we tested whether repulsion is influenced by emotional arousal, when resolving memory interference is perhaps most needed. We adapted an existing paradigm in which participants repeatedly studied object-face associations. Participants studied two different-colored versions of each object: a to-be-tested "target" and its not-to-be-tested "competitor" pair mate. The level of interference between target and competitor pair mates was manipulated by making the object colors either highly similar or less similar, depending on the participant group. To manipulate arousal, the competitor object-face associations were preceded by either a neutral tone or an aversive and arousing burst of white noise. Memory distortion for the color of the target objects was tested after each study round to examine whether memory distortions emerge after learning. We found that participants with greater sound-induced pupil dilations, an index of physiological arousal, showed greater memory attraction of target colors towards highly similar competitor colors. Greater memory attraction was also correlated with greater memory interference in the last round of learning. Additionally, individuals who self-reported higher trait anxiety showed greater memory attraction when one of the overlapping memories was associated with something aversive. Our findings suggest that memories of similar neutral and arousing events may blur together after repeated exposures, especially in individuals who show higher arousal responses and symptoms of anxiety.

Post-traumatic stress and major depressive disorders are associated with "overgeneral" autobiographical memory, or impaired recall of specific life events. Interpersonal trauma exposure, a risk factor for both conditions, may influence how symptomatic trauma-exposed (TE) individuals segment everyday events. The ability to parse experience into units (event segmentation) supports memory. Neural state transitions occur within a cortical hierarchy and play a key role in event segmentation, with regions like the occipital cortex, angular gyrus, and striatum involved in parsing event structure. We examined whether interpersonal trauma exposure was associated with alterations in the cortical hierarchy and striatal activity at neural state transitions in symptomatic TE versus healthy control (HC) individuals. Fifty older adolescents and young adults (29 TE, 21 HC) viewed the film "Partly Cloudy" during functional magnetic resonance imaging. A greedy-state boundary search algorithm assessed the optimal number of events, quality, and segmentation agreement of neural state transitions in the occipital cortex and angular gyrus. Striatal (nucleus accumbens, caudate, and putamen) activity was assessed at occipital and angular gyrus-evoked state transitions. Compared to HCs, TE participants displayed less occipital and greater angular gyrus-evoked optimal number of neural state transitions. TE participants also displayed lower quality of neural state segmentation solutions in occipital and angular cortices compared to HCs. Additionally, TE participants had less putamen activity at angular gyrus-evoked state transitions than HCs. This investigation provides neurobiological insights into aberrant event segmentation in symptomatic TE individuals, shedding light on mechanisms influencing overgeneral memory in trauma-related disorders.

Dysregulation in aversive contextual processing is believed to affect several forms of psychopathology, including post-traumatic stress disorder (PTSD). The dentate gyrus (DG) is an important brain region in contextual discrimination and disambiguation of new experiences from prior memories. The DG also receives dense projections from the locus coeruleus (LC), the primary source of norepinephrine (NE) in the mammalian brain, which is active during stressful events. However, how noradrenergic dynamics impact DG-dependent function during contextual discrimination and pattern separation remains unclear. Here, we report that aversive contextual processing in mice is linked to linear elevations in tonic norepinephrine release dynamics within the DG and report that this engagement of prolonged norepinephrine release is sufficient to produce contextual disambiguation, even in the absence of a salient aversive stimulus. These findings suggest that spatiotemporal ramping characteristics of LC-NE release in the DG during stress likely serve an important role in driving contextual processing.

A decline in hippocampal function has long been associated with the progression of cognitive impairments in patients with Alzheimer's disease (AD). The disruption of hippocampal synaptic plasticity [primarily the reduction of long-term potentiation LTP] by excess production of soluble beta-amyloid (Aβ) has long been accepted as the mechanism by which AD pathology impairs memory, at least during the early stages of AD pathogenesis. However, the premise that hippocampal LTP underpins the formation of associative, long-term memories has been challenged. Here, we consider evidence that this canonical view of LTP needs to be refined. Similarly, the view that the hippocampus simply supports memory ignores the wealth of data showing that the hippocampus is functionally heterogeneous along its septo-temporal axis. The ventral (but not the dorsal) hippocampus plays a major role in modulating emotional reactions to conflict. Here, we suggest that hippocampal LTP is not involved in forming long-term associative memories, but instead contributes to the disambiguation of overlapping memories in situations of conflict and associative interference. This conceptualisation of hippocampal synaptic plasticity may help explain how early-stage AD pathology may impact both memory and anxiety.

Research on emotion regulation often focuses on cognitively effortful self-regulation strategies, but exposure to stress has been shown to interfere with the underlying mechanisms supporting such processes. Understanding alternative strategies that potentially bolster emotion regulation under stress is an important topic of investigation. Two potential alternatives involve everyday occurrences of social processing and memory recall. Social support and past emotional experiences may help in guiding us toward appropriate neurophysiological responses through overlapping circuitry with stress and reward systems, while also buttressing cognitive regulation strategies by expanding one's perspective and allowing multiple opportunities to regulate retrospectively. In recognition that ongoing social and emotional events are often at the beginning of a cascade of both emotion regulation and memory processes, this chapter focuses on the emerging role of social relationships and autobiographical memory recall in regulating emotions under stress, highlighting opportunities and challenges associated with this process.

Emotional intensity can produce both optimal and suboptimal effects on learning and memory. While emotional events tend to be better remembered, memory performance can follow an inverted U-shaped curve with increasing intensity. The strength of Pavlovian conditioning tends to increase linearly with the intensity of the aversive outcome, but leads to greater stimulus generalization. Here, we combined elements of episodic memory and Pavlovian conditioning into a single paradigm to investigate the effects of varying outcome intensities on conditioned fear responses and episodic memory. Participants encoded trial-unique images from two semantic categories as conditioned stimuli (CS+ and CS-) before (preconditioning), during, and after (extinction) acquisition. We systematically varied the intensity of the unconditioned stimulus (US) during acquisition between-groups as a nonaversive tone, a low-intensity electrical shock, or a high-intensity electrical shock paired with a loud static noise. Results showed that conditioned skin conductance responses scaled linearly with US intensity during acquisition, with a high-intensity US leading to greater resistance to extinction and stronger 24 h fear recovery. However, 24 h recognition memory produced an inverted U-shaped relationship, with better recognition memory for CSs encoded before (retroactive), during, and following conditioning using a low-intensity US. These findings suggest a dissociation between optimal levels of emotional intensity on explicit and implicit learning and memory performance.

In response to the rising mental health concerns and cognitive decline associated with the human brain's neurogenesis, which continues until the tenth decade of life but declines with age and is suppressed by poor environments, this pilot study investigates how physical environments may influence public health proxy measures of neurogenesis in humans. This pilot study focuses on the residential environment where people spend most of their time and age in place, exploring the dependency of depression, anxiety, and cognitive impairment variations on spatial and lifestyle variables.

A total of 142 healthy adults in England completed a survey consisting of PHQ-8, GAD-7, and CFI questionnaires and other questions developed to capture the variance in spatial and lifestyle factors such as time spent at home, house type layout complexity, spaciousness, physical activity, routine and spatial novelty, and perceived loneliness.

Extensive time spent at home has adverse effects on all measures, while multi-storey houses perform better than single-story houses with positive correlations with physical activity and spatial novelty. Separate regression models on the variance in depression, as the most salient dependent variable and reliably associated with neurogenesis, reveal that getting out of the house explains 20.5% of the variance in depression symptoms. At the scale of the house, multi-storey houses explain 16.5% of the variance. Both percentages are closer to the effect of loneliness, which we found to explain 26.6% of the variance in depression.

The built environment appears to be significantly associated with changes in cognitive function and mental health symptoms associated with neurogenesis. This pilot study shows the equally important effect of physical and social enrichment, offering critically needed insights for neuroarchitecture and brain health research that is interested in public health.

Dysregulation in aversive contextual processing is believed to affect several forms of psychopathology, including post-traumatic stress disorder (PTSD). The dentate gyrus (DG) is an important brain region in contextual discrimination and disambiguation of new experiences from prior memories. The DG also receives dense projections from the locus coeruleus (LC), the primary source of norepinephrine (NE) in the mammalian brain, which is active during stressful events. However, how noradrenergic dynamics impact DG-dependent function during contextual discrimination and pattern separation remains unclear. Here, we report that aversive contextual processing in mice is linked to linear elevations in tonic norepinephrine release dynamics within the DG and report that this engagement of prolonged norepinephrine release is sufficient to produce contextual disambiguation, even in the absence of a salient aversive stimulus. These findings suggest that spatiotemporal ramping characteristics of LC-NE release in the DG during stress likely serve an important role in driving contextual processing.

Emotional disorders such as depression and anxiety disorders share substantial similarities in their etiology and treatment. In recent decades, these commonalities have been increasingly recognized in classification systems and treatment programs crossing diagnostic boundaries.

To examine the prospective effects of different transdiagnostic markers on relevant treatment outcomes, we plan to track a minimum of N = 200 patients with emotional disorders during their routine course of cognitive behavioral therapy at two German outpatient clinics. We will collect a wide range of transdiagnostic markers, ranging from basic perceptual processes and self-report measures to complex behavioral and neurobiological indicators, before entering therapy. Symptoms and psychopathological processes will be recorded before entering therapy, between the 20th and 24th therapy session, and at the end of therapy.

Our results could help to identify transdiagnostic markers with high predictive power, but also provide deeper insights into which patient groups with which symptom clusters are less likely to benefit from therapy, and for what reasons.

The trial was preregistered at the German Clinical Trial Register (DRKS-ID: DRKS00031206; 2023-05-09).

Early-onset epilepsy following ischemic stroke is a severe neurological condition, the pathogenesis of which remains incompletely understood. Recent studies suggest that Neural stem/progenitor cells (NSPCs) play a crucial role in the disease process, yet the precise molecular mechanisms regulating NSPCs have not been thoroughly investigated. This study utilized single-cell transcriptome sequencing and bioinformatics analysis to identify disease-related genes, which were subsequently validated in both in vitro and in vivo experiments. The findings revealed that Hsp90aa1 (heat shock protein 90 kDa alpha, class A member 1), Jun proto-oncogene (JUN), and CC Motif Ligation 2 (Ccl2) constitute an important regulatory axis influencing the migration and differentiation of NSPCs, potentially impacting the onset and progression of early-onset epilepsy post-ischemic stroke. Additionally, the expression of Hsp90aa1 was found to influence the likelihood of seizure occurrence and the severity of brain ischemia.

We investigated the effects of epigenetic modifications on post-traumatic stress disorder (PTSD) using a novel combination of herbal medicines from Panax ginseng, Astragalus membranaceus, Atractylodes macrocephala, and Glycyrrhiza uralensis. The herbal formula extract (HFE) (250 mg/kg) was administered orally once daily for 14 days to determine its effects on PTSD in mice by combining prolonged stress and foot shock. The open field and Y-maze tests determined the effect of HFE on PTSD-induced anxiety and cognition. Hippocampal neuronal plastic changes and molecular mechanism were verified. Treatment with HFE decreased anxiety-like behavior and enhanced cognition. Moreover, it reduced the number of PTSD-related hilar ectopic granule cells in the dentate gyrus (DG). PTSD mice showed reduced neuronal plasticity of doublecortin+ cells in the DG, which was restored by HFE treatment. HFE reversed PTSD-induced inhibition of the Reelin/Dab1 pathway, a critical signaling cascade involved in brain development, and regulated Reelin methylation. Furthermore, DNA methylation, methyl-CpG binding protein 2, and DNA methyltransferase 1, which were elevated in the hippocampus of PTSD mice, were restored following HFE treatment. HFE increased the expression of synaptic plasticity-related factors in the hippocampus of PTSD mice. Our findings suggest that HFE can facilitate PTSD treatment by alleviating behavioral abnormalities through the restoration of hippocampal dysfunction via regulation of the Reelin/Dab-1 pathway and DNA methylation in the hippocampus.

Contrary to humans, adult hippocampal neurogenesis in rodents is not controversial. And in the last three decades, multiple studies in rodents have deemed adult neurogenesis essential for most hippocampal functions. The functional relevance of new neurons relies on their distinct physiological properties during their maturation before they become indistinguishable from mature granule cells. Most functional studies have used very young animals with robust neurogenesis. However, this trait declines dramatically with age, questioning its functional relevance in aging animals, a caveat that has been mentioned repeatedly, but rarely analyzed quantitatively. In this meta-analysis, we use data from published studies to determine the critical functional window of new neurons and to model their numbers across age in both mice and rats. Our model shows that new neurons with distinct functional profile represent about 3% of the total granule cells in young adult 3-month-old rodents, and their number decline following a power function to reach less than 1% in middle aged animals and less than 0.5% in old mice and rats. These low ratios pose an important logical and computational caveat to the proposed essential role of new neurons in the dentate gyrus, particularly in middle aged and old animals, a factor that needs to be adequately addressed when defining the relevance of adult neurogenesis in hippocampal function.

Here, we provide an in-depth consideration of our current understanding of engrams, spanning from molecular to network levels, and hippocampal neurogenesis, in health and Alzheimer's disease (AD). This review highlights novel findings in these emerging research fields and future research directions for novel therapeutic avenues for memory failure in dementia. Engrams, memory in AD, and hippocampal neurogenesis have each been extensively studied. The integration of these topics, however, has been relatively less deliberated, and is the focus of this review. We primarily focus on the dentate gyrus (DG) of the hippocampus, which is a key area of episodic memory formation. Episodic memory is significantly impaired in AD, and is also the site of adult hippocampal neurogenesis. Advancements in technology, especially opto- and chemogenetics, have made sophisticated manipulations of engram cells possible. Furthermore, innovative methods have emerged for monitoring neurons, even specific neuronal populations, in vivo while animals engage in tasks, such as calcium imaging. In vivo calcium imaging contributes to a more comprehensive understanding of engram cells. Critically, studies of the engram in the DG using these technologies have shown the important contribution of hippocampal neurogenesis for memory in both health and AD. Together, the discussion of these topics provides a holistic perspective that motivates questions for future research.

Fear overgeneralization is a maladaptive response to traumatic stress that is associated with the inability to discriminate between threat and safety contexts, a hallmark feature of post-traumatic stress disorder (PTSD). However, the neural mechanisms underlying this deficit remain unclear. Here, we show that traumatic stress exposure impairs contextual discrimination between threat and safety contexts in the learned helplessness (LH) model. Mossy cells (MCs) in the dorsal hippocampus are suppressed in response to traumatic stress. Bidirectional manipulation of MC activity in the LH model reveals that MC inhibition is causally linked to impaired contextual discrimination. Mechanistically, MC inhibition increases the number of active granule cells in a given context, significantly overlapping context-specific ensembles. Our study demonstrates that maladaptive inhibition of MCs after traumatic stress is a substantial mechanism underlying fear overgeneralization with contextual discrimination deficit, suggesting a potential therapeutic target for cognitive symptoms of PTSD.

TSPO, translocator protein (18 kDa) ligands have demonstrated consistent antidepression and anxiolytic effects in several preclinical studies. This study aimed to examine whether YL-IPA08[N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-ichlorophenyl) -7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride], a potent and selective TSPO ligand synthesized by our institute, could alleviate anxiety-related behaviors induced by electric shock (ES) and investigate its underlying mechanism. As expected, we showed that chronic treatment with YL-IPA08 significantly reversed anxiety-related behaviors induced by electrical stimulation (0.5 mA, 12 times, duration 1s, interval 10s) exposure. Using the analysis of RNA-sequencing (RNA-seq) technology, it was found that the differential genes associated with the anxiolytic effect of YL-IPA08 were mainly related to synaptic plasticity. Furthermore, YL-IPA08 restored the decreased levels of brain-derived neurotrophic factor (BDNF), synapse-related protein (e.g. synapsin-1 and post-synaptic density95, PSD95), and the number of doublecortin (DCX) + neurons in the hippocampus of post-ES mice. In addition, YL-IPA08 also enhanced the dendritic complexity and dendritic spine density of hippocampal dentate gyrus (DG) granule neurons. Meanwhile, the induction of long-term potentiation (LTP) was significantly enhanced by YL-IPA08. In summary, the findings from the current study showed that YL-IPA08 exerted a clear anxiolytic effect, which might be partially mediated by promoting hippocampal neuroplasticity.

Stress induces a neurotransmitter switch that leads to fear in harmless situations.

Impairments in behavioral pattern separation (BPS)-the ability to distinguish between similar contexts or experiences-contribute to memory interference and overgeneralization seen in many neuropsychiatric conditions, including depression, anxiety, PTSD, dementia, and age-related cognitive decline. While BPS relies on the dentate gyrus and is sensitive to changes in adult hippocampal neurogenesis (AHN), its significance as a pharmacological target has not been tested.

In this study, we applied a human neural stem cell high-throughput screening cascade to identify compounds that increase human neurogenesis. One compound with a favorable profile, RO6871135, was then tested in BPS in mice.

Chronic treatment with RO6871135, 7.5 mg/kg increased AHN and improved BPS in a fear discrimination task in both young and aged mice. RO6871135 treatment also lowered innate anxiety-like behavior, which was more apparent in mice exposed to chronic corticosterone. Ablation of AHN by hippocampal irradiation supported a neurogenesis-dependent mechanism for RO6871135-induced improvements in BPS. To identify possible mechanisms of action, in vitro and in vivo kinase inhibition and chemical proteomics assays were performed. These tests indicated that RO6871135 inhibited CDK8, CDK11, CaMK2a, CaMK2b, MAP2K6, and GSK3b. An analog compound also demonstrated high affinity for CDK8, CaMK2a, and GSK3b.

These studies demonstrate a method for empirical identification and preclinical testing of novel neurogenic compounds that can improve BPS, and points to possible novel mechanisms that can be interrogated for the development of new therapies to improve specific endophenotypes such as impaired BPS.

Adult neurogenesis confers the hippocampus with unparalleled neural plasticity, essential for intricate cognitive functions. The specific influence of sparse newborn neurons (NBNs) in modulating neural activities and subsequently steering behavior, however, remains obscure. Using an engineered NBN-tetanus toxin mouse model (NBN-TeTX), we noninvasively silenced NBNs, elucidating their crucial role in impulse inhibition and cognitive flexibility as evidenced through Morris water maze reversal learning and Go/Nogo task in operant learning. Task-based functional MRI (tb-fMRI) paired with operant learning revealed dorsal hippocampal hyperactivation during the Nogo task in male NBN-TeTX mice, suggesting that hippocampal hyperexcitability might underlie the observed behavioral deficits. Additionally, resting-state fMRI (rs-fMRI) exhibited enhanced functional connectivity between the dorsal and ventral dentate gyrus following NBN silencing. Further investigations into the activities of PV+ interneurons and mossy cells highlighted the indispensability of NBNs in maintaining the hippocampal excitation/inhibition balance. Our findings emphasize that the neural plasticity driven by NBNs extensively modulates the hippocampus, sculpting inhibitory control and cognitive flexibility.

Numerous studies have explored the relationship between posttraumatic stress disorder (PTSD) and the hippocampus and the amygdala because both regions are implicated in the disorder's pathogenesis and pathophysiology. Nevertheless, those key limbic regions consist of functionally and cytoarchitecturally distinct substructures that may play different roles in the etiology of PTSD. Spurred by the availability of automatic segmentation software, structural neuroimaging studies of human hippocampal and amygdala subregions have proliferated in recent years. Here, we present a preregistered scoping review of the existing structural neuroimaging studies of the hippocampus and amygdala subregions in adults diagnosed with PTSD. A total of 3513 studies assessing subregion volumes were identified, 1689 of which were screened, and 21 studies were eligible for this review (total N = 2876 individuals). Most studies examined hippocampal subregions and reported decreased CA1, CA3, dentate gyrus, and subiculum volumes in PTSD. Fewer studies investigated amygdala subregions and reported altered lateral, basal, and central nuclei volumes in PTSD. This review further highlights the conceptual and methodological limitations of the current literature and identifies future directions to increase understanding of the distinct roles of hippocampal and amygdalar subregions in posttraumatic psychopathology.

In mammals, the subgranular zone of the dentate gyrus is one of two brain regions (with the subventricular zone of the olfactory bulb) that continues to generate new neurons throughout adulthood, a phenomenon known as adult hippocampal neurogenesis (AHN) (Eriksson et al., Nat Med 4:1313-1317, 1998; García-Verdugo et al., J Neurobiol 36:234-248, 1998). The integration of these new neurons into the dentate gyrus (DG) has implications for memory encoding, with unique firing and wiring properties of immature neurons that affect how the hippocampal network encodes and stores attributes of memory. In this chapter, we will describe the process of AHN and properties of adult-born cells as they integrate into the hippocampal circuit and mature. Then, we will discuss some methodological considerations before we review evidence for the role of AHN in two major processes supporting memory that are performed by the DG. First, we will discuss encoding of contextual information for episodic memories and how this is facilitated by AHN. Second, will discuss pattern separation, a major role of the DG that reduces interference for the formation of new memories. Finally, we will review clinical and translational considerations, suggesting that stimulation of AHN may help decrease overgeneralization-a common endophenotype of mood, anxiety, trauma-related, and age-related disorders.

Adult-born granule cells (abGCs) have been implicated in memory discrimination through a neural computation known as pattern separation. Here, using in vivo Ca2+ imaging, we examined how chronic ablation or acute chemogenetic silencing of abGCs affects the activity of mature granule cells (mGCs). In both cases, we observed altered remapping of mGCs. Rather than broadly modulating the activity of all mGCs, abGCs promote the remapping of place cells' firing fields while increasing rate remapping of mGCs that represent sensory cues. In turn, these remapping deficits are associated with behavioral impairments in animals' ability to correctly identify new goal locations. Thus, abGCs facilitate pattern separation through the formation of non-overlapping representations for identical sensory cues encountered in different locations. In the absence of abGCs, the dentate gyrus shifts to a state that is dominated by cue information, a situation that is consistent with the overgeneralization often observed in anxiety or age-related disorders.

Adult neurogenesis, comprising the generation, differentiation and integration of new neurons in the mature brain, has emerged as a dynamic area of research over decades. The discovery of adult neurogenesis was a paradigm shift to comprehend mechanisms underlying brain plasticity, cognitive function, and neurological disorders. This review deliberates significant findings from articles published over four decades on adult neurogenesis, highlighting key milestones, methodological advances, and controversies that have shaped our comprehension of the phenomenon of adult neurogenesis. Early skepticism gave way to a rich body of evidence via various reliable approaches. Studies on neurogenic niches, microenvironmental factors, molecular regulators, and functional implications have uncovered the involvement of adult neurogenesis in learning, memory, mood, and even neurological and neurodegenerative conditions. Despite significant progress, several questions still need to be answered, including the exact contributions of new neurons to brain function, their integration into existing circuits, and the impact of enhancing adult neurogenesis in the human hippocampus. While the existence of robust neurogenesis in the adult and aged human hippocampus is yet to be confirmed, this review highlights evidence from a significant number of studies supporting the persistence of hippocampal neurogenesis during adulthood and aging in humans, including in some neurological conditions, such as epilepsy and Alzheimer's disease. Nonetheless, additional large-scale studies using single cell-RNA-seq, single nucleus-RNA-seq, and spatial transcriptomics are critical to validate the presence and contribution of hippocampal neurogenesis in the pathophysiology of various neurological and neurodegenerative conditions at different stages of the disease. There is also a need to develop standardized protocols for analyzing postmortem hippocampal tissues for cellular and molecular analyses.

Organophosphate flame retardant (OPFR) contamination is ubiquitous and bio-monitoring studies have shown that human exposure is widespread and may be unavoidable. OPFRs bear structural similarities to known neurotoxicants such as organophosphate insecticides and have been shown to have both endocrine disrupting and developmental neurotoxic effects. The perinatal period in rodents represents a critical period in the organization of the developing nervous system and insults during this time can impart profound changes on the trajectory of neural development and function, lasting into adulthood. Adult hippocampal neurogenesis (AHN) facilitates dentate gyrus function and broader hippocampal circuit activity in adults; however, the neurogenic potential of this process in adulthood is vulnerable to disruption by exogenous factors during early life. We sought to assess the impact of OPFRs on AHN in offspring of dams exposed during gestation and lactation. Results indicate that developmental OPFR exposure has significant, sex specific impacts on multiple markers of AHN in the dentate gyrus of rats. In males, OPFR exposure significantly reduced the number of neural progenitors the number of new/immature neurons and reduced dentate gyrus volume. In females, exposure increased the number of neural progenitors, decreased the number of new/immature neurons, but had no significant effect on dentate gyrus volume. These results further elucidate the developmental neurotoxic properties of OPFRs, emphasize the long-term impact of early life OPFR exposure on neural processes, and highlight the importance of including sex as a biological variable in neurotoxicology research.

Emotions are characterized not only by their valence but also by whether they are stable or labile. Yet, we do not understand the molecular or circuit mechanisms that control the dynamic nature of emotional responses. We have shown that glucocorticoid receptor overexpression in the forebrain (GRov) leads to a highly reactive mouse with increased anxiety behavior coupled with greater swings in emotional responses. This phenotype is established early in development and persists into adulthood. However, the neural circuitry mediating this lifelong emotional lability remains unknown. In the present study, optogenetic stimulation in ventral dentate gyrus (vDG) of GRov mice led to a greater range and a prolonged duration of anxiety behavior. cFos expression analysis showed that the amplified behavioral response to vDG activation in GRov mice is coupled to increased neuronal activity in specific brain regions. Relative to wild type mice, GRov mice displayed glutamatergic/GABAergic activation imbalance in ventral CA1 (vCA1) and selectively increased glutamatergic activation in the basal posterior amygdaloid complex. Moreover, forebrain GR overexpression led to increased activation of molecularly distinct subpopulations of neurons within the hippocampus and the posterior basolateral amygdala (pBLA) as evident from the increased cFos co-labeling in the calbindin1+ glutamatergic neurons in vCA1 and in the DARPP-32/Ppp1r1b+ glutamatergic neurons in pBLA. We propose that a molecularly distinct hippocampal-amygdala circuit is shaped by stress early in life and tunes the dynamics of emotional responses.

Pattern separation allows us to form discrete representations of information in memory. Pattern separation can be measured in several domains including spatial and object-based discrimination. The brain area largely involved in this process is the dentate gyrus of the hippocampus, which has been shown to be particularly sensitive to the effects of sleep loss. However, methodology in rodent and human studies varies greatly making translational conclusions difficult. Therefore, the aim of the current study was to measure the effects of sleep deprivation on human hippocampal function, using well-validated spatial and object-based pattern separation tests. The effects of acute sleep loss were examined, as this method is frequently used in rodent research but not human studies. Results show that sleep loss impaired performance on the object-based version of the test, but not spatial pattern separation. The findings support the notion that these discrimination projections represent separate but complimentary hippocampal processes, and further elucidates how they may be discretely affected by acute sleep loss.

Post-traumatic stress disorder (PTSD) is an anxiety disorder caused by traumatic or frightening events, with intensified anxiety, fear memories, and cognitive impairment caused by a dysfunctional hippocampus. Owing to its complex phenotype, currently prescribed treatments for PTSD are limited. This study investigated the psychopharmacological effects of novel COMBINATION herbal medicines on the hippocampus of a PTSD murine model induced by combining single prolonged stress (SPS) and foot shock (FS). We designed a novel herbal formula extract (HFE) from Chaenomeles sinensis, Glycyrrhiza uralensis, and Atractylodes macrocephala. SPS+FS mice were administered HFE (500 and 1000 mg/kg) once daily for 14 days. The effects of HFE of HFE on the hippocampus were analyzed using behavioral tests, immunostaining, Golgi staining, and Western blotting. HFE alleviated anxiety-like behavior and fear response, improved short-term memory, and restored hippocampal dysfunction, including hippocampal neurogenesis alteration and aberrant migration and hyperactivation of dentate granule cells in SPS+FS mice. HFE increased phosphorylation of the Kv4.2 potassium channel, extracellular signal-regulated kinase, and cAMP response element-binding protein, which were reduced in the hippocampus of SPS+FS mice. Therefore, our study suggests HFE as a potential therapeutic drug for PTSD by improving behavioral impairment and hippocampal dysfunction and regulating Kv4.2 potassium channel-related pathways in the hippocampus.

Melatonin is a hormone synthesized by the pineal gland with neuroprotective and neurodevelopmental effects. Also, melatonin acts as an antidepressant by modulating the generation of new neurons in the dentate gyrus of the hippocampus. The positive effects of melatonin on behavior and neural development may suggest it is used for reverting stress but also for the alterations produced by chemotherapeutic drugs influencing behavior and brain plasticity. In this sense, temozolomide, an alkylating/anti-proliferating agent used in treating brain cancer, is associated with decreased cognitive functions and depression. We hypothesized that melatonin might prevent the effects of temozolomide on depression- and anxiety-like behavior by modulating some aspects of the neurogenic process in adult Balb/C mice. Mice were treated with temozolomide (25 mg/kg) for three days of two weeks, followed by melatonin (8 mg/kg) for fourteen days. Temozolomide produced short- and long-term decrements in cell proliferation (Ki67-positive cells: 54.89% and 53.38%, respectively) and intermediate stages of the neurogenic process (doublecortin-positive cells: 68.23% and 50.08%, respectively). However, melatonin prevented the long-term effects of temozolomide with the increased number of doublecortin-positive cells (47.21%) and the immunoreactivity of 2' 3'-Cyclic-nucleotide-3 phosphodiesterase (CNPase: 82.66%), an enzyme expressed by mature oligodendrocytes, in the hilar portion of the dentate gyrus. The effects of melatonin in the temozolomide group occurred with decreased immobility in the forced swim test (45.55%) but not anxiety-like behavior. Thus, our results suggest that melatonin prevents the harmful effects of temozolomide by modulating doublecortin cells, hilar oligodendrocytes, and depression-like behavior tested in the forced swim test. Our study could point out melatonin's beneficial effects for counteracting temozolomide's side effects.

The situation caused by the confinement due to the COVID-19 pandemic and the mobility restriction implemented by governments worldwide had a significant impact on people's routines. Stressors are known to increase emotional imbalance, uncertainty, and frustration in the general population. This study explores the factors that predispose to the risk of perceived stress from COVID-19 and determines the underlying mediating mechanisms in the Ecuadorian population.

The cross-sectional study an incidental non-probabilistic sample of n = 977 participating student volunteers from the four regions of the Republic of Ecuador (68.6% women and 31.4% men). Data on emotional regulation (ERQ), perceived stress (PSS), active procrastination (APS), diagnosis and symptoms related to COVID-19, social isolation, coexistence, and a sociodemographic questionnaire (biological sex, marital status, and age) were recruited. Statistical analysis was based on a structural equation model.

The risk of suffering perceived stress in the COVID-19 pandemic was higher for single women who have lived longer in social isolation, have lived with more people, have poor emotional regulation and high rates of procrastination. This structural model is similar in all Ecuadorian regions χ² = 21.54 (p = 0.760), RMSEA = 0.001 (95%CI, 0.00-0.02), CFI = 0.998; TLI = 0.999; SRMR = 0.020.

Although our findings are consistent and revealing for the scientific community, the lack of discrimination of the data due to strict isolation measures, taken at different periods by the Ecuadorian government against positive cases of COVID-19, is discussed. The research was applied to the university population, it would be representative to extend the study to schools and colleges.

We consider this work as a starting point for the creation of preventive models against perceived stress in the university environment in the event of health emergencies.

Anxiety and fear are dysfunctional behaviors commonly observed in domesticated dogs. Although dogs and humans share psychopathological similarities, little is known about how dysfunctional fear behaviors are represented in brain networks in dogs diagnosed with anxiety disorders. A combination of diffusion tensor imaging (DTI) and graph theory was used to investigate the underlying structural connections of dysfunctional anxiety in anxious dogs and compared with healthy dogs with normal behavior. The degree of anxiety was assessed using the Canine Behavioral Assessment & Research Questionnaire (C-BARQ), a widely used, validated questionnaire for abnormal behaviors in dogs. Anxious dogs showed significantly decreased clustering coefficient ([Formula: see text]), decreased global efficiency ([Formula: see text]), and increased small-worldness (σ) when compared with healthy dogs. The nodal parameters that differed between the anxious dogs and healthy dogs were mainly located in the posterior part of the brain, including the occipital lobe, posterior cingulate gyrus, hippocampus, mesencephalon, and cerebellum. Furthermore, the nodal degree ([Formula: see text]) of the left cerebellum was significantly negatively correlated with "excitability" in the C-BARQ of anxious dogs. These findings could contribute to the understanding of a disrupted brain structural connectome underlying the pathological mechanisms of anxiety-related disorders in dogs.

Few studies have examined the time-dependent effects of stress on fear learning. Previously, we found that stress immediately before fear conditioning enhanced fear learning. Here, we aimed to extend these findings by assessing the effects of stress 30 min prior to fear conditioning on fear learning and fear generalization. Two hundred and twenty-one healthy adults underwent stress (socially evaluated cold pressor test) or a control manipulation 30 min before completing differential fear conditioning in a fear-potentiated startle paradigm. One visual stimulus (CS+), but not another (CS-), was associated with an aversive airblast to the throat (US) during acquisition. The next day, participants were tested for their fear responses to the CS+, CS-, and several generalization stimuli. Stress impaired the acquisition of fear on Day 1 but had no significant impact on fear generalization. The stress-induced impairment of fear learning was particularly evident in participants who exhibited a robust cortisol response to the stressor. These findings are consistent with the notion that stress administered 30 min before learning impairs memory formation via corticosteroid-related mechanisms and may help us understand how fear memories are altered in stress-related psychological disorders.

An optimal intranasal (IN) dose of human mesenchymal stem cell-derived extracellular vesicles (hMSC-EVs), 90 min post-traumatic brain injury (TBI), has been reported to prevent the evolution of acute neuroinflammation into chronic neuroinflammation resulting in the alleviation of long-term cognitive and mood impairments. Since hippocampal neurogenesis decline and synapse loss contribute to TBI-induced long-term cognitive and mood dysfunction, this study investigated whether hMSC-EV treatment after TBI can prevent hippocampal neurogenesis decline and synapse loss in the chronic phase of TBI. C57BL6 mice undergoing unilateral controlled cortical impact injury (CCI) received a single IN administration of different doses of EVs or the vehicle at 90 min post-TBI. Quantifying neurogenesis in the subgranular zone-granule cell layer (SGZ-GCL) through 5'-bromodeoxyuridine and neuron-specific nuclear antigen double labeling at ~2 months post-TBI revealed decreased neurogenesis in TBI mice receiving vehicle. However, in TBI mice receiving EVs (12.8 and 25.6 × 10⁹ EVs), the extent of neurogenesis was matched to naive control levels. A similar trend of decreased neurogenesis was seen when doublecortin-positive newly generated neurons were quantified in the SGZ-GCL at ~3 months post-TBI. The above doses of EVs treatment after TBI also reduced the loss of pre-and post-synaptic marker proteins in the hippocampus and the somatosensory cortex. Moreover, at 48 h post-treatment, brain-derived neurotrophic factor (BDNF), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phosphorylated cyclic AMP response-element binding protein (p-CREB) levels were downregulated in TBI mice receiving the vehicle but were closer to naïve control levels in TBI mice receiving above doses of hMSC-EVs. Notably, improved BDNF concentration observed in TBI mice receiving hMSC-EVs in the acute phase was sustained in the chronic phase of TBI. Thus, a single IN dose of hMSC-EVs at 90 min post-TBI can ease TBI-induced declines in the BDNF-ERK-CREB signaling, hippocampal neurogenesis, and synapses.

Post-traumatic stress disorder can be viewed as a memory disorder, with trauma-related flashbacks being a core symptom. Given the central role of the hippocampus in autobiographical memory, surprisingly, there is mixed evidence concerning altered hippocampal functional connectivity in PTSD. We shed light on this discrepancy by considering the distinct roles of the anterior versus posterior hippocampus and examine how this distinction may map onto whole-brain resting-state functional connectivity patterns among those with and without PTSD.

We first assessed whole-brain between-group differences in the functional connectivity profiles of the anterior and posterior hippocampus within a publicly available data set of resting-state fMRI data from 31 male Vietnam war veterans diagnosed with PTSD (mean age = 67.6 years, sd = 2.3) and 29 age-matched combat-exposed male controls (age = 69.1 years, sd = 3.5). Next, the connectivity patterns of each subject within the PTSD group were correlated with their PTSD symptom scores. Finally, the between-group differences in whole-brain functional connectivity profiles discovered for the anterior and posterior hippocampal seeds were used to prescribe post-hoc ROIs, which were then used to perform ROI-to-ROI functional connectivity and graph-theoretic analyses.

The PTSD group showed increased functional connectivity of the anterior hippocampus with affective brain regions (anterior/posterior insula, orbitofrontal cortex, temporal pole) and decreased functional connectivity of the anterior/posterior hippocampus with regions involved in processing bodily self-consciousness (supramarginal gyrus). Notably, decreased anterior hippocampus connectivity with the posterior cingulate cortex/precuneus was associated with increased PTSD symptom severity. The left anterior hippocampus also emerged as a central locus of abnormal functional connectivity, with graph-theoretic measures suggestive of a more central hub-like role for this region in those with PTSD compared to trauma-exposed controls.

Our results highlight that the anterior hippocampus plays a critical role in the neurocircuitry underlying PTSD and underscore the importance of the differential roles of hippocampal sub-regions in serving as biomarkers of PTSD. Future studies should investigate whether the differential patterns of functional connectivity stemming from hippocampal sub-regions is observed in PTSD populations other than older war veterans.

Survivors of critical illness are at high risk of developing post-traumatic stress disorder (PTSD) but administration of glucocorticoids during the illness can lower that risk. The mechanism is not known but may involve glucocorticoid modulation of hippocampal- and amygdala-dependent memory formation. In this study, we sought to determine whether glucocorticoids given during an acute illness influence the formation and persistence of fear and non-fear memories from the time of the illness.

We performed cecal ligation and puncture in male and female mice to induce an acute infectious illness. During the illness, mice were introduced to a neutral object in their home cage and separately underwent contextual fear conditioning. We then tested the persistence of object and fear memories after recovery.

Glucocorticoid treatment enhanced object discrimination but did not alter the expression of contextual fear memory. During context re-exposure, neural activity was elevated in the dentate gyrus irrespective of fear conditioning.

Our results suggest that glucocorticoids given during illness enhance hippocampal-dependent non-fear memory processes. This indicates that PTSD outcomes in critically ill patients may be improved by enhancing non-fear memories from the time of their illness.

As a typical prescription for soothing the liver, Xiangshao granule has a good effect on the symptoms of irritability and anxiety. Clinical evidence suggests that it has significant efficacy in the treatment of Premenstrual dysphoria disorder (PMDD). However, the underlying mechanism remains unclear.

PMDD is a common disease in women of childbearing age, seriously affecting their family, society, and daily work life. The registered herbal medicine, Xiangshao granules, is used for relieving PMDD dysphoria and irritability symptoms with excellent efficacy in China. This study was focused on the deep intervention mechanism of Xiangshao granules in treating PMDD.

The vaginal smear and open field test were used to screen rats in nonreception phase of estrus cycle with similar macroscopic behaviors and regular estrus cycle. The rat model of PMDD irritability was established through social isolation and residential invasion, with which, the irritability symptoms of PMDD patients with menstrual cycle dependence was also well simulated. Elevated plus Maze Test and Social interaction activities were used to measure the anxiety-like behavior of rats. TUNEL Staining and Hematoxylin-Eosin staining were used to measure apoptosis of hippocampal neurons. RT-PCR, Western blot and immunofluorescence were used to measure the expression of GR, JIK, p-JIK, p38, P-P38, JNK, caspase 3, and caspase 12.

In this study, Xiangshao granules showed consistent therapeutic effects similar with those in clinic, significantly reducing aggressive and anxiety-like behaviors with improved social skills in PMDD rats. In mechanism, Xiangshao granules lowered the apoptosis of hippocampal neurons and weakened the morphological damage of the hippocampal brain evidenced by the decreased mRNA and protein expression of glucocorticoid receptor, caspase-3, and caspase-12. In addition, administration of Xiangshao granules led to the decreased expression of JIK in the PMDD irritability rat model which agreed well with the previous studies. The JNK/p38 mitogen-activated protein kinases (MAPKs) signaling pathway is abnormally activated in the hippocampal brain region of PMDD rats, while treated with Xiangshao granules could increase JIK expression and inhibit the abnormal activation of the JNK/p38 MAPK signaling pathway, effectively reducing the stress damage in the hippocampus.

Xiangshao Granules Reduce the Aggressive Behavior and Hippocampal Injury of Premenstrual Irritability in Rats by Regulating JIK/JNK/p38 Signal Pathway.

Hippocampus-dependent pattern separation is considered as a relevant factor for context discrimination and might therefore impact the contextual modulation of conditioned fear. However, the association between pattern separation and context-dependent fear conditioning has not been investigated so far. In the current study, 72 healthy female students completed the Mnemonic Similarity Task, a measure of behavioral pattern separation, in addition to a context-dependent fear conditioning paradigm during functional magnetic resonance imaging. The paradigm included fear acquisition in context A and extinction training in context B on a first day, as well as retrieval testing of the fear and extinction memories in the safe context B (extinction recall) and a novel context C (fear renewal) one day later. Main outcome measures comprised skin conductance responses (SCRs) and blood oxygen level-dependent responses in brain regions of the fear and extinction circuit. Regarding retrieval testing, pattern separation did not correlate with extinction recall, but with stronger dorsal anterior cingulate cortex activation and conditioned SCRs (trend) during fear renewal, indicating a stronger retrieval of the fear memory trace. Our findings suggest that behavioral pattern separation ability seems to be important for context-dependent fear modulation, which is impaired in patients with posttraumatic stress disorder.

Appropriate expression of fear in the face of threats in the environment is essential for survival. The sustained expression of fear in the absence of threat signals is a central pathological feature of trauma- and anxiety-related disorders. Our understanding of the neural circuitry that controls fear inhibition coalesces around the amygdala, hippocampus, and prefrontal cortex. By discussing thalamic and sub-thalamic influences on fear-related learning and expression in this review, we suggest a more inclusive neurobiological framework that expands our canonical view of fear. First, we visit how fear-related learning and expression is influenced by the aforementioned canonical brain regions. Next, we review emerging data that shed light on new roles for thalamic and subthalamic nuclei in fear-related learning and expression. Then, we highlight how these neuroanatomical hubs can modulate fear via integration of sensory and salient stimuli, gating information flow and calibrating behavioral responses, as well as maintaining and updating memory representations. Finally, we propose that the presence of this thalamic and sub-thalamic neuroanatomy in parallel with the tripartite prefrontal cortex-amygdala-hippocampus circuit allows for dynamic modulation of information based on interoceptive and exteroceptive signals. This article is part of the Special Issue on "Fear, Anxiety and PTSD".

Survivors of critical illness are at high risk of developing post-traumatic stress disorder (PTSD) but administration of glucocorticoids during the illness can lower that risk. The mechanism is not known but may involve glucocorticoid modulation of hippocampal- and amygdalar-dependent memory formation. In this study, we sought to determine whether glucocorticoids given during an acute illness influence the formation and persistence of fear and non-fear memories from the time of the illness. We performed cecal ligation and puncture in male and female mice to induce an acute infectious illness. During the illness, mice were introduced to a neutral object in their home cage and separately underwent contextual fear conditioning. We then tested the persistence of object and fear memories after recovery. Glucocorticoid treatment enhanced object discrimination but did not alter the expression of contextual fear memory. During context re-exposure, neural activity was elevated in the dentate gyrus irrespective of fear conditioning. Our results suggest that glucocorticoids given during illness enhance hippocampal-dependent non-fear memory processes. This indicates that PTSD outcomes in critically ill patients may be improved by enhancing non-fear memories from the time of their illness.

Reduced hippocampal and/or amygdala volumes have been reported in patients with a variety of different anxiety diagnoses, suggesting that structural alterations may vary transdiagnostically across the internalizing disorders. The current study measured hippocampal and amygdala volumes in anxiety and mood disorder patients assessing differences that vary dimensionally with transdiagnostic factors of distress, anxious arousal, and trauma, based on a principal components analysis of questionnaires relating to symptomology. High-resolution structural images were collected in a sample of 165 patients, and volumes extracted from the hippocampal formation (including CA1, CA2/3, CA4/DG, subiculum, and molecular layer) and the amygdala. Transdiagnostically, increasing distress was associated with reduced hippocampal CA1 volume, increasing anxious arousal was associated with reduced hippocampal CA4/DG volume, and increasing trauma severity was associated with reduced amygdala volume in women. Taken together, the data indicate that subcortical brain volumes decrease as the severity of transdiagnostic psychopathological symptomology increases.

Long-range synaptic connections define how information flows through neuronal networks. Here, we combined retrograde and anterograde trans-synaptic viruses to delineate areas that exert direct and indirect influence over the dorsal and ventral prefrontal cortex (PFC) of the rat (both sexes). Notably, retrograde tracing using pseudorabies virus (PRV) revealed that both dorsal and ventral areas of the PFC receive prominent disynaptic input from the dorsal CA3 (dCA3) region of the hippocampus. The PRV experiments also identified candidate anatomical relays for this disynaptic pathway, namely, the ventral hippocampus, lateral septum, thalamus, amygdala, and basal forebrain. To determine the viability of each of these relays, we performed three additional experiments. In the first, we injected the retrograde monosynaptic tracer Fluoro-Gold into the PFC and the anterograde monosynaptic tracer Fluoro-Ruby into the dCA3 to confirm the first-order connecting areas and revealed several potential relay regions between the PFC and dCA3. In the second, we combined PRV injection in the PFC with polysynaptic anterograde viral tracer (HSV-1) in the dCA3 to reveal colabeled connecting neurons, which were evident only in the ventral hippocampus. In the third, we combined retrograde adeno-associated virus (AAV) injections in the PFC with an anterograde AAV in the dCA3 to reveal anatomical relay neurons in the ventral hippocampus and dorsal lateral septum. Together, these findings reveal parallel disynaptic pathways from the dCA3 to the PFC, illuminating a new anatomical framework for understanding hippocampal-prefrontal interactions. We suggest that the representation of context and space may be a universal feature of prefrontal function.SIGNIFICANCE STATEMENT The known functions of the prefrontal cortex are shaped by input from multiple brain areas. We used transneuronal viral tracing to discover multiple prominent disynaptic pathways through which the dorsal hippocampus (specifically, the dorsal CA3) has the potential to shape the actions of the prefrontal cortex. The demonstration of neuronal relays in the ventral hippocampus and lateral septum presents a new foundation for understanding long-range influences over prefrontal interactions, including the specific contribution of the dorsal CA3 to prefrontal function.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder vulnerable individuals can develop following a traumatic event, whereas others are resilient. Enhanced insight into the mechanistic underpinnings contributing to these inter-individual differences in trauma susceptibility is key to improved treatment and prevention. Aberrant function of the hippocampal dentate gyrus (DG) may contribute to its psychopathology, with the dorsal DG potentially encoding trauma memory generalization and the ventral DG anxiety. Using a mouse model, we hypothesized that susceptibility to develop PTSD-like symptoms following trauma will be underpinned by aberrant DG structure and function. Mice were exposed to a traumatic event (unpredictable, inescapable foot shocks) and tested for PTSD-like symptomatology following recovery. In four independent experiments, DG neuronal morphology, synaptic protein gene and protein expression, and neuronal activity during trauma encoding and recall were assessed. Behaviorally, trauma-susceptible animals displayed increased anxiety-like behavior already prior to trauma, increased novelty-induced freezing, but no clear differences in remote trauma memory recall. Comparison of the ventral DG of trauma susceptible vs resilient mice revealed lower spine density, reduced expression of the postsynaptic protein homer1b/c gene and protein, a larger population of neurons active during trauma encoding, and a greater presence of somatostatin neurons. In contrast, the dorsal DG of trauma-susceptible animals did not differ in terms of spine density or gene expression but displayed more active neurons during trauma encoding and a lower amount of somatostatin neurons. Collectively, we here report on specific structural and functional changes in the ventral DG in trauma susceptible male mice.