Selective knockdown of GABAA-α2 subunit in the dorsal dentate gyrus in adulthood induces anxiety, learning and memory deficits and impairs synaptic plasticity.

Animal studies and clinical trials suggest that maintenance of gamma-aminobutyric acid (GABA)-ergic activity may be crucial in coping with stressful conditions, anxiety and mood disorders. Drugs highly efficient in promoting anxiolysis were shown to activate this system, particularly via the α2-subunit of type A receptors (GABAA α2). Given the high expression of GABAA α2 in the dentate gyrus (DG) sub-field of the hippocampus, we sought to examine whether manipulation of the α2 subunit in this area will evoke changes in emotional behaviour, memory and learning as well as in synaptic plasticity. We found that knockdown of GABAAα2 receptor specifically in the dorsal DG of rats caused increased anxiety without affecting locomotor activity. Spatial memory and learning in the Morris water maze were also impaired in GABAAα2 receptor knocked down rats, an effect accompanied by alterations in synaptic plasticity, as assessed by long-term potentiation in the DG. Our findings provide further support to the notion that emotional information processing in the hippocampus may be controlled, at least in part, via the inhibitory GABAA α2 receptor subunit, opening a potential avenue for early interventions from pre- puberty into adulthood, as a strategy for controlling anxiety-related psychopathology.

Distinct Neural Representations and Cognitive Behaviors Attributable to Naturally Developed Active Avoidance or Reactive Escape Strategies in the Male Rat.

BACKGROUND: The high individual variability in coping with stress is often attributed to genetic background differences, sustained environmental conditions, or a combination of both. However, the neural mechanisms underlying coping style variability are still poorly understood. METHODS: Here we examined the impact of a single extended emotional challenge on coping style variability and the associated involvement of the hippocampus, medial prefrontal cortex (mPFC), and periaqueductal gray (PAG). Male Sprague-Dawley rats (n = 170) were trained in an extended 2-way shuttle avoidance (eTWSA) task for 7 days, and daily avoidance rates were measured. Forced swim test, elevated plus maze, or Morris water maze was tested before or after eTWSA exposure. Excitotoxic lesion of the hippocampal dentate gyrus (DG) was performed by Ibotenic infusion. Transient pharmacological blocking of DG, mPFC, or PAG was performed by muscimol or CNQX+TTX infusion. RESULTS: Exposing rats to eTWSA was found to lead to naturally developing dichotomous, not continuous, coping styles, which we termed active avoidance (AA) or reactive escape (RE). Prior emotional responses did not predict the developing coping style. AA was associated with beneficial outcomes, including reduced behavioral despair and improved spatial learning. RE led to impaired spatial retrieval. AA was abolished by lesioning or pharmacological blocking of the DG. RE was prevented by blocking mPFC or PAG. CONCLUSION: The results indicate that a single exposure to a significant emotional challenge can lead, in otherwise healthy individuals, to dichotomous development of an active or reactive coping style with distinctive neural correlates and subsequent behavioral significance.

Can Epigenetics Predict Drug Efficiency in Mental Disorders?

Psychiatric disorders affect millions of individuals and their families worldwide, and the costs to society are substantial and are expected to rise due to a lack of effective treatments. Personalized medicine-customized treatment tailored to the individual-offers a solution. Although most mental diseases are influenced by genetic and environmental factors, finding genetic biomarkers that predict treatment efficacy has been challenging. This review highlights the potential of epigenetics as a tool for predicting treatment efficacy and personalizing medicine for psychiatric disorders. We examine previous studies that have attempted to predict treatment efficacy through epigenetics, provide an experimental model, and note the potential challenges at each stage. While the field is still in its infancy, epigenetics holds promise as a predictive tool by examining individual patients' epigenetic profiles in conjunction with other indicators. However, further research is needed, including additional studies, replication, validation, and application beyond clinical settings.

Exposure to Juvenile Stress Induces Epigenetic Alterations in the GABAergic System in Rats.

Epigenetics is a gene-environment interaction mechanism, manifested mostly through changes in regulatory gene expression. Stress is an established environmental factor known to induce epigenetic changes. This study aimed to assess the long-term effect of stress as juveniles, or juvenile and adult stress, on alterations in glutamic acid decarboxylase genes (GAD65, GAD67). We assessed DNA methylation and RNA expression in four rat groups: (1) control group, (2) juvenile stress group sacrificed two days following stress exposure (JSe) (RNA only), (3) juvenile stress group sacrificed as adults (JS), and (4) juvenile and adult stress group (JS + AS). Three different areas of the brain were examined in each group: the dorsal dentate gyrus (dDG), the dorsal CA1 (dCA1), and the basolateral amygdala (BLA). A significantly low methylation level of GAD65 in the BLA was observed among the JS group, followed by almost complete recovery among the JS + AS group. However, in dDG, an opposite trend was captured, and higher GAD65 methylation was found in JS. In addition, RNA levels were found to be decreased in JS compared to JSe and JS + AS. These findings can point to a possible mechanism: while juvenile stress may enhance a better coping strategy with life challenges, additional stress in adulthood may trigger a contradictory response, either beneficial or harmful.

Sex-specific roles of hippocampal microRNAs in stress vulnerability and resilience.

Contrary to intuition, most individuals are resilient to psychological trauma and only a minority is vulnerable. Men and women are known to respond differently to trauma exposure, however, mechanisms underlying the relationship between sex differences and trauma resilience and vulnerability are not yet fully understood. Taking advantage of the Behavioral Profiling approach, which enables differentiating between 'affected' and 'unaffected' individuals, we examined sex-associated differences in stress exposure effects on hippocampal expression of selected stress-related GABA-A receptor targeting miRNAs. Levels of the miRNA-144 and miRNA-33 were measured in male and female affected (vulnerable, e.g., higher freezing time) and unaffected (resilient) rats. In male rats, increased levels of miRNA-144 and miRNA-33 were observed in the dorsal dentate gyrus (dDG) and ventral dentate gyrus (vDG) respectively, of stress-exposed but unaffected animals. In females, we observed an increased expression of miRNA-144 and miRNA-33 in the ventral cornu ammonis 1 (vCA1) of affected animals. Accordingly, we inhibited miRNAs expression selectively in hippocampal subregions using oligonucleotides containing locked nucleic acid bases, to examine the miRNAs' causal contribution to either vulnerability or resilience to stress in each sex. Inhibition of miRNA-144 in dDG and miRNA-33 in vDG in males resulted in an increased prevalence of vulnerable animals, while inhibition of miRNA-144 and miRNA-33 in vCA1 in females increased the proportion of resilient animals. The current findings reveal a critical sex-associated difference in the role of miRNAs in stress vulnerability and resilience. This novel understanding of sex-associated epigenetic involvement in the mechanism of stress-related psychopathologies may help improve gender-specific diagnosis and effective treatment.

The role of hippocampal CaMKII in resilience to trauma-related psychopathology.

Traumatic stress exposure can form persistent trauma-related memories. However, only a minority of individuals develop post-traumatic stress disorder (PTSD) symptoms upon exposure. We employed a rat model of PTSD, which enables differentiating between exposed-affected and exposed-unaffected individuals. Two weeks after the end of exposure, male rats were tested behaviorally, following an exposure to a trauma reminder, identifying them as trauma 'affected' or 'unaffected.' In light of the established role of hippocampal synaptic plasticity in stress and the essential role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in hippocampal based synaptic plasticity, we pharmacologically inhibited CaMKII or knocked-down (kd) αCaMKII (in two separate experiments) in the dorsal dentate gyrus of the hippocampus (dDG) following exposure to the same trauma paradigm. Both manipulations brought down the prevalence of 'affected' individuals in the trauma-exposed population. A day after the last behavioral test, long-term potentiation (LTP) was examined in the dDG as a measure of synaptic plasticity. Trauma exposure reduced the ability to induce LTP, whereas, contrary to expectation, αCaMKII-kd reversed this effect. Further examination revealed that reducing αCaMKII expression enables the formation of αCaMKII-independent LTP, which may enable increased resilience in the face of a traumatic experience. The current findings further emphasize the pivotal role dDG has in stress resilience.

Inhibitory Metaplasticity in Juvenile Stressed Rats Restores Associative Memory in Adulthood by Regulating Epigenetic Complex G9a/GLP.

BACKGROUND: Exposure to juvenile stress was found to have long-term effects on the plasticity and quality of associative memory in adulthood, but the underlying mechanisms are still poorly understood. METHODS: Three- to four week-old male Wistar rats were subjected to a 3-day juvenile stress paradigm. Their electrophysiological correlates of memory using the adult hippocampal slice were inspected to detect alterations in long-term potentiation and synaptic tagging and capture model of associativity. These cellular alterations were tied in with the behavioral outcome by subjecting the rats to a step-down inhibitory avoidance paradigm to measure strength in their memory. Given the role of epigenetic response in altering plasticity as a repercussion of juvenile stress, we aimed to chart out the possible epigenetic marker and its regulation in the long-term memory mechanisms using quantitative reverse transcription polymerase chain reaction. RESULTS: We demonstrate that even long after the elimination of actual stressors, an inhibitory metaplastic state is evident, which promotes synaptic competition over synaptic cooperation and decline in latency of associative memory in the behavioral paradigm despite the exposure to novelty. Mechanistically, juvenile stress led to a heightened expression of the epigenetic marker G9a/GLP complex, which is thus far ascribed to transcriptional silencing and goal-directed behavior. CONCLUSIONS: The blockade of the G9a/GLP complex was found to alleviate deficits in long-term plasticity and associative memory during the adulthood of animals exposed to juvenile stress. Our data provide insights on the long-term effects of juvenile stress that involve epigenetic mechanisms, which directly impact long-term plasticity, synaptic tagging and capture, and associative memory.

Individual behavioral profiling as a translational approach to assess treatment efficacy in an animal model of post-traumatic stress disorder.

A major challenge in treating post-traumatic stress disorder (PTSD) continues to be the large variability in responsiveness to pharmacotherapy. Only 20-30% of patients experience total remission to a specific treatment, while others demonstrate either partial remission or no response. However, this heterogeneity in response to pharmacotherapy has not been adequately addressed in animal models, since these analyze the averaged group effects, ignoring the individual variability to treatment response, which seriously compromises the translation power of such models. Here we examined the possibility of employing an "individual behavioral profiling" approach, originally developed to differentiate between "affected" and "exposed-unaffected" individuals in an animal model of PTSD, to also enable dissociating "responders" or "non-responders" after SSRI (fluoxetine) treatment. Importantly, this approach does not rely on a group averaged response to a single behavioral parameter, but considers a cluster of behavioral parameters, to individually characterize an animal as either "responder" or "non-responder" to the treatment. The main variable to assess drug efficacy thus being the proportion of "responders" following treatment. Alteration in excitatory/inhibitory (E/I) balance has been proposed as being associated with stress-related psychopathology. Toward a functional proof of concept for our behaviorally-based characterization approach, we examined the expression patterns of α1 and α2 subunits of GABAA receptor, and GluN1 and GluN2A subunits of the NMDAR receptor in the ventral hippocampus, as well as electrophysiologically local circuit activity in the dorsal dentate gyrus (DG). We demonstrate that with both parameters, treatment "responders" differed from treatment "non-responders," confirming the functional validity of the behavior-based categorization. The results suggest that the ability to respond to fluoxetine treatment may be linked to the ability to modulate excitation-inhibition balance in the hippocampus. We propose that employing the "individual behavioral profiling" approach, and the resultant novel variable of the proportion of "recovered" individuals following treatment, offers an effective translational tool to assess pharmacotherapy treatment efficacy in animal models of stress and trauma-related psychopathology.

Intra-amygdala metaplasticity modulation of fear extinction learning.

The amygdala is a key brain region involved in emotional memory formation. It is also responsible for memory modulation in other brain areas. Under extreme conditions, amygdala modulation may lead to the generation of abnormal plasticity and trauma-related psychopathologies. However, the amygdala itself is a dynamic brain region, which is amenable to long-term plasticity and is affected by emotional experiences. These alterations may modify the way the amygdala modulates activity and plasticity in other related brain regions, which in turn may alter the animal's response to subsequent challenges in what could be termed as "Behavioral metaplasticity."Because of the reciprocal interactions between the amygdala and other emotion processing regions, such as the medial prefrontal cortex (mPFC) or the hippocampus, experience-induced intra-amygdala metaplasticity could lead to alterations in mPFC-dependent or hippocampus-dependent behaviors. While initiated by alterations within the basolateral amygdala (BLA), such alterations in other brain regions may come to be independent of BLA modulation, thus establishing what may be termed "Trans-regional metaplasticity." In this article, we review evidence supporting the notions of intra-BLA metaplasticity and how this may develop into "Trans-regional metaplasticity." Future research is needed to understand how such dynamic metaplastic alterations contribute to developing psychopathologies, and how this knowledge may be translated into promoting novel interventions in psychopathologies associated with fear, stress, and trauma.

Machine Learning-Based Behavioral Diagnostic Tools for Depression: Advances, Challenges, and Future Directions.

The psychiatric diagnostic procedure is currently based on self-reports that are subject to personal biases. Therefore, the diagnostic process would benefit greatly from data-driven tools that can enhance accuracy and specificity. In recent years, many studies have achieved promising results in detecting and diagnosing depression based on machine learning (ML) analysis. Despite these favorable results in depression diagnosis, which are primarily based on ML analysis of neuroimaging data, most patients do not have access to neuroimaging tools. Hence, objective assessment tools are needed that can be easily integrated into the routine psychiatric diagnostic process. One solution is to use behavioral data, which can be easily collected while still maintaining objectivity. The current paper summarizes the main ML-based approaches that use behavioral data in diagnosing depression and other psychiatric disorders. We classified these studies into two main categories: (a) laboratory-based assessments and (b) data mining, the latter of which we further divided into two sub-groups: (i) social media usage and movement sensors data and (ii) demographic and clinical information. The paper discusses the advantages and challenges in this field and suggests future research directions and implementations. The paper's overarching aim is to serve as a first step in synthetizing existing knowledge about ML-based behavioral diagnosis studies in order to develop interventions and individually tailored treatments in the future.

Return of fear following extinction in youth: An event-related potential study.

The ability to learn to differentiate safety from danger matures gradually, particularly when such learning occurs over an extended time period. And yet, most research on fear learning examines the early phases of such learning and mainly in adults. The current study examined fear conditioning and extinction, as well as one form of extended learning, return of fear (ROF). Thirty-three typically developing children (age range: 7-14 years) completed fear conditioning and extinction; self-reports and psychophysiological indices were measured at this point. Two weeks later, children completed a ROF test (n = 23), and event-related potentials (ERPs) were recorded. Results indicated successful fear acquisition and extinction. Moreover, participants reported greater fear of the conditioned stimulus (CS+) than the safety stimulus (CS-) in the ROF test 2 weeks later. In electrophysiology data, ROF manifested as a larger late positive potential (LPP) response to the CS+ than the CS-. Finally, these differences in LPP responses were positively correlated with poorer extinction, as indicated by the GSR responses 2 weeks earlier. This is the first ERP study to demonstrate ROF in children. The LPP measure may index an interplay between inhibitory and excitatory brain-related processes underlying the long-term effects of fear learning.

Title: "Labels Matter: Is it stress or is it Trauma?"

In neuroscience, the term 'Stress' has a negative connotation because of its potential to trigger or exacerbate psychopathologies. Yet in the face of exposure to stress, the more common reaction to stress is resilience, indicating that resilience is the rule and stress-related pathology the exception. This is critical because neural mechanisms associated with stress-related psychopathology are expected to differ significantly from those associated with resilience.Research labels and terminology affect research directions, conclusions drawn from the results, and the way we think about a topic, while choice of labels is often influenced by biases and hidden assumptions. It is therefore important to adopt a terminology that differentiates between stress conditions, leading to different outcomes.Here, we propose to conceptually associate the term 'stress'/'stressful experience' with 'stress resilience', while restricting the use of the term 'trauma' only in reference to exposures that lead to pathology. We acknowledge that there are as yet no ideal ways for addressing the murkiness of the border between stressful and traumatic experiences. Yet ignoring these differences hampers our ability to elucidate the mechanisms of trauma-related pathologies on the one hand, and of stress resilience on the other. Accordingly, we discuss how to translate such conceptual terminology into research practice.

αCaMKII in the lateral amygdala mediates PTSD-Like behaviors and NMDAR-Dependent LTD.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals. However, its molecular and cellular mechanisms remain largely unexplored. Here, we found PTSD susceptible mice exhibited significant up-regulation of alpha-Ca2+/calmodulin-dependent kinase II (αCaMKII) in the lateral amygdala (LA). Consistently, increasing αCaMKII in the LA not only caused PTSD-like behaviors such as impaired fear extinction and anxiety-like behaviors, but also attenuated N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) at thalamo-lateral amygdala (T-LA) synapses, and reduced GluA1-Ser845/Ser831 dephosphorylation and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization. Suppressing the elevated αCaMKII to normal levels completely rescued both PTSD-like behaviors and the impairments in LTD, GluA1-Ser845/Ser831 dephosphorylation, and AMPAR internalization. Intriguingly, deficits in GluA1-Ser845/Ser831 dephosphorylation and AMPAR internalization were detected not only after impaired fear extinction, but also after attenuated LTD. Our results suggest that αCaMKII in the LA may be a potential molecular determinant of PTSD. We further demonstrate for the first time that GluA1-Ser845/Ser831 dephosphorylation and AMPAR internalization are molecular links between fear extinction and LTD.

Machine learning-based diagnosis support system for differentiating between clinical anxiety and depression disorders.

In light of the need for objective mechanism-based diagnostic tools, the current research describes a novel diagnostic support system aimed to differentiate between anxiety and depression disorders in a clinical sample. Eighty-six psychiatric patients with clinical anxiety and/or depression were recruited from a public hospital and assigned to one of the experimental groups: Depression, Anxiety, or Mixed. The control group included 25 participants with no psychiatric diagnosis. Participants performed a battery of six cognitive-behavioral tasks assessing biases of attention, expectancies, memory, interpretation and executive functions. Data were analyzed with a machine-learning (ML) random forest-based algorithm and cross-validation techniques. The model assigned participants to clinical groups based solely on their aggregated cognitive performance. By detecting each group's unique performance pattern and the specific measures contributing to the prediction, the ML algorithm predicted diagnosis classification in two models: (I) anxiety/depression/mixed vs. control (76.81% specificity, 69.66% sensitivity), and (II) anxiety group vs. depression group (80.50% and 66.46% success rates in classifying anxiety and depression, respectively). The findings demonstrate that the cognitive battery can be utilized as a support system for psychiatric diagnosis alongside the clinical interview. This implicit tool, which is not based on self-report, is expected to enable the clinician to achieve increased diagnostic specificity and precision. Further, this tool may increase the confidence of both clinician and patient in the diagnosis by equipping them with an objective assessment tool. Finally, the battery provides a profile of biased cognitions that characterizes the patient, which in turn enables more fine-tuned, individually-tailored therapy.

Reducing glutamic acid decarboxylase in the dorsal dentate gyrus attenuates juvenile stress induced emotional and cognitive deficits.

A high degree of regional, temporal and molecular specificity is evident in the regulation of GABAergic signaling in stress-responsive circuitry, hampering the use of systemic GABAergic modulators for the treatment of stress-related psychopathology. Here we investigated the effectiveness of local intervention with the GABA synthetic enzymes GAD65 and GAD67 in the dorsal dentate gyrus (dDG) vs ventral DG (vDG) to alleviate anxiety-like behavior and stress-induced symptoms in the rat. We induced shRNA-mediated knock down of either GAD65 or GAD67 with lentiviral vectors microinjected into the dDG or vDG of young adult male rats and examined anxiety behavior, learning and memory performance. Subsequently we tested whether reducing GAD65 expression in the dDG would also confer resilience against juvenile stress-induced behavioral and physiological symptoms in adulthood. While knock down of either isoform in the vDG increased anxiety levels in the open field and the elevated plus maze tests, the knock down of GAD65, but not GAD67, in the dDG conferred a significant reduction in anxiety levels. Strikingly, this manipulation also attenuated juvenile stress evoked anxiety behavior, cognitive and synaptic plasticity impairments. Local GABAergic circuitry in the DG plays an important and highly region-specific role in control of emotional behavior and stress responding. Reduction of GAD65 expression in the dDG appears to provide resilience to juvenile stress-induced emotional and cognitive deficits, opening a new direction towards addressing a significant risk factor for developing stress and trauma-related psychopathologies later in life.

Developing of Focal Ischemia in the Hippocampus or the Amygdala Reveals a Regional Compensation Rule for Fear Memory Acquisition.

Circuit compensation is often observed in patients with acute ischemic stroke, suggesting the importance of the interaction between brain regions. Also, contextual fear memory is an association between multisensory contexts and fearful stimuli, for which the interaction between the hippocampus and the amygdala is believed to be critical. To understand how focal ischemia in one region could influence the other region, we used a modified photo-thrombosis to induce focal ischemia in the hippocampus or the amygdala or both in freely-moving rats. We found that the learning curve and short-term memory (STM) were not affected in the rats although focal ischemia was induced 5 h before learning in either the hippocampus or the amygdala; these were impaired by the induction of ischemia in both the regions. Furthermore, the learning curve and STM were impaired when ischemia was induced 24 h before learning in either the hippocampus or the amygdala when the synaptic transmission was altered in one region because of ischemia in the other region. These results suggest that the circuit compensation between the hippocampus and the amygdala is critical for fear memory acquisition.

Pten is a key intrinsic factor regulating raphe 5-HT neuronal plasticity and depressive behaviors in mice.

Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to enhance serotonergic activity by blocking its reuptake. We propose PTEN as a target for an alternative approach for regulating 5-HT neuron activity in the brain and depressive behaviors. We show that PTEN is elevated in central 5-HT neurons in the raphe nucleus by chronic stress in mice, and selective deletion of Pten in the 5-HT neurons induces its structural plasticity shown by increases of dendritic branching and density of PSD95-positive puncta in the dendrites. 5-HT levels are elevated and electrical stimulation of raphe neurons evokes more 5-HT release in the brain of condition knockout (cKO) mice with Pten-deficient 5-HT neurons. In addition, the 5-HT neurons remain normal electrophysiological properties but have increased excitatory synaptic inputs. Single-cell RNA sequencing revealed gene transcript alterations that may underlay morphological and functional changes in Pten-deficient 5-HT neurons. Finally, Pten cKO mice and wild-type mice treated with systemic application of PTEN inhibitor display reduced depression-like behaviors. Thus, PTEN is an intrinsic regulator of 5-HT neuron activity, representing a novel therapeutic strategy for producing antidepressant action.

Behavioral profiling reveals an enhancement of dentate gyrus paired pulse inhibition in a rat model of PTSD.

We recently introduced behavioral profiling as a translational approach to increase the validity of animal models of posttraumatic stress disorder (PTSD). Behavioral profiling utilizes the response of a 'normal population' of control animals and compares the performance of animals with a history of traumatic stress in different behavioral tests that can capture PTSD-like symptoms. Thus, affected, PTSD-like individuals can be subdivided from resilient trauma-exposed animals. While in our recent study we focused mainly on tests for activity and anxiety, we now expand the behavioral tests battery and include also fear memory and extinction tasks as well as a spatial object recognition test in our behavioral profiling approach. Utilizing underwater trauma as the traumatic event, we found that only a small subset of animals exposed to underwater trauma showed lasting increases in anxiety-like behavior and heightened emotional memory formation. Adding juvenile stress as a model for childhood adversity increased the prevalence of such affected animals and furthermore and induced additional cognitive deficits in a subgroup of such emotionally affected individuals. In addition, multiple affected individual rats displayed increased local circuit activity in the dorsal dentate gyrus, as measured in vivo with paired pulse protocols in anesthetized animals. Together, our findings highlight behavioral profiling, refined by including multiple behavioral tests, as a valid tool to identify PTSD-like vs. resilient individual animals and further suggest that enhanced local inhibition in specific circuits of the dorsal dentate gyrus may be associated with the observed symptoms.

Hippocampal GABAergic interneurons and their co-localized neuropeptides in stress vulnerability and resilience.

Studies in humans and rodents suggest a critical role for the hippocampal formation in cognition and emotion, but also in the adaptation to stressful events. Successful stress adaptation promotes resilience, while its failure may lead to stress-induced psychopathologies such as depression and anxiety disorders. Hippocampal architecture and physiology is shaped by its strong control of activity via diverse classes of inhibitory interneurons that express typical calcium binding proteins and neuropeptides. Celltype-specific opto- and chemogenetic intervention strategies that take advantage of these biochemical markers have bolstered our understanding of the distinct role of different interneurons in anxiety, fear and stress adaptation. Moreover, some of the signature proteins of GABAergic interneurons have a potent impact on emotion and cognition on their own, making them attractive targets for interventions. In particular, neuropeptide Y is a promising endogenous agent for mediating resilience against severe stress. In this review, we evaluate the role of the major types of interneurons across hippocampal subregions in the adaptation to chronic and acute stress and to emotional memory formation.