Ventral hippocampal projections to infralimbic cortex and basolateral amygdala are differentially activated by contextual fear and extinction recall.

Fear and extinction learning are thought to generate distinct and competing memory representations in the hippocampus. How these memory representations modulate the expression of appropriate behavioral responses remains unclear. To investigate this question, we used cholera toxin B subunit to retrolabel ventral hippocampal (vHPC) neurons projecting to the infralimbic cortex (IL) and basolateral amygdala (BLA) and then quantified c-Fos immediate early gene activity within these populations following expression of either contextual fear recall or contextual fear extinction recall. Fear recall was associated with increased c-Fos expression in vHPC projections to the BLA, whereas extinction recall was associated with increased activity in vHPC projections to IL. A control experiment was performed to confirm that the apparent shift in projection neuron activity was associated with extinction learning rather than mere context exposure. Overall, results indicate that hippocampal contextual fear and extinction memory representations differentially activate vHPC projections to IL and BLA. These findings suggest that hippocampal memory representations orchestrate appropriate behavioral responses through selective activation of projection pathways.

A Window of Vascular Plasticity Coupled to Behavioral Recovery after Stroke.

Stroke causes remodeling of vasculature surrounding the infarct, but whether and how vascular remodeling contributes to recovery are unclear. We established an approach to monitor and compare changes in vascular structure and blood flow with high spatiotemporal precision after photothrombotic infarcts in motor cortex using longitudinal 2-photon and multiexposure speckle imaging in mice of both sexes. A spatially graded pattern of vascular structural remodeling in peri-infarct cortex unfolded over the first 2 weeks after stroke, characterized by vessel loss and formation, and selective stabilization of a subset of new vessels. This vascular structural plasticity was coincident with transient activation of transcriptional programs relevant for vascular remodeling, reestablishment of peri-infarct blood flow, and large improvements in motor performance. Local vascular plasticity was strongly predictive of restoration of blood flow, which was in turn predictive of behavioral recovery. These findings reveal the spatiotemporal evolution of vascular remodeling after stroke and demonstrate that a window of heightened vascular plasticity is coupled to the reestablishment of blood flow and behavioral recovery. Our findings support that neovascularization contributes to behavioral recovery after stroke by restoring blood flow to peri-infarct regions. These findings may inform strategies for enhancing recovery from stroke and other types of brain injury.SIGNIFICANCE STATEMENT An improved understanding of neural repair could inform strategies for enhancing recovery from stroke and other types of brain injury. Stroke causes remodeling of vasculature surrounding the lesion, but whether and how the process of vascular remodeling contributes to recovery of behavioral function have been unclear. Here we used longitudinal in vivo imaging to track vascular structure and blood flow in residual peri-infarct cortex after ischemic stroke in mice. We found that stroke created a restricted period of heightened vascular plasticity that was associated with restoration of blood flow, which was in turn predictive of recovery of motor function. Therefore, our findings support that vascular remodeling facilitates behavioral recovery after stroke by restoring blood flow to peri-infarct cortex.

Dentate Gyrus Contributes to Retrieval as well as Encoding: Evidence from Context Fear Conditioning, Recall, and Extinction.

Dentate gyrus (DG) is widely thought to provide a teaching signal that enables hippocampal encoding of memories, but its role during retrieval is poorly understood. Some data and models suggest that DG plays no role in retrieval; others encourage the opposite conclusion. To resolve this controversy, we evaluated the effects of optogenetic inhibition of dorsal DG during context fear conditioning, recall, generalization, and extinction in male mice. We found that (1) inhibition during training impaired context fear acquisition; (2) inhibition during recall did not impair fear expression in the training context, unless mice had to distinguish between similar feared and neutral contexts; (3) inhibition increased generalization of fear to an unfamiliar context that was similar to a feared one and impaired fear expression in the conditioned context when it was similar to a neutral one; and (4) inhibition impaired fear extinction. These effects, as well as several seemingly contradictory published findings, could be reproduced by BACON (Bayesian Context Fear Algorithm), a physiologically realistic hippocampal model positing that acquisition and retrieval both involve coordinated activity in DG and CA3. Our findings thus suggest that DG contributes to retrieval and extinction, as well as to the initial establishment of context fear.SIGNIFICANCE STATEMENT Despite abundant evidence that the hippocampal dentate gyrus (DG) plays a critical role in memory, it remains unclear whether the role of DG relates to memory acquisition or retrieval. Using contextual fear conditioning and optogenetic inhibition, we show that DG contributes to both of these processes. Using computational simulations, we identify specific mechanisms through which the suppression of DG affects memory performance. Finally, we show that DG contributes to fear extinction learning, a process in which learned fear is attenuated through exposures to a fearful context in the absence of threat. Our data resolve a long-standing question about the role of DG in memory and provide insight into how disorders affecting DG, including aging, stress, and depression, influence cognitive processes.

Behavioral mechanisms of context fear generalization in mice.

There is growing interest in generalization of learned contextual fear, driven in part by the hypothesis that mood and anxiety disorders stem from impaired hippocampal mechanisms of fear generalization and discrimination. However, there has been relatively little investigation of the behavioral and procedural mechanisms that might control generalization of contextual fear. We assessed the relative contribution of different contextual features to context fear generalization and characterized how two common conditioning protocols-foreground (uncued) and background (cued) contextual fear conditioning-affected context fear generalization. In one experiment, mice were fear conditioned in context A, and then tested for contextual fear both in A and in an alternate context created by changing a subset of A's elements. The results suggest that floor configuration and odor are more salient features than chamber shape. A second experiment compared context fear generalization in background and foreground context conditioning. Although foreground conditioning produced more context fear than background conditioning, the two procedures produced equal amounts of generalized fear. Finally, results indicated that the order of context tests (original first versus alternate first) significantly modulates context fear generalization, perhaps because the original and alternate contexts are differentially sensitive to extinction. Overall, results demonstrate that context fear generalization is sensitive to procedural variations and likely reflects the operation of multiple interacting psychological and neural mechanisms.

Adult Hippocampal Neurogenesis Modulates Fear Learning through Associative and Nonassociative Mechanisms.

Adult hippocampal neurogenesis is believed to support hippocampus-dependent learning and emotional regulation. These putative functions of adult neurogenesis have typically been studied in isolation, and little is known about how they interact to produce adaptive behavior. We used trace fear conditioning as a model system to elucidate mechanisms through which adult hippocampal neurogenesis modulates processing of aversive experience. To achieve a specific ablation of neurogenesis, we generated transgenic mice that express herpes simplex virus thymidine kinase specifically in neural progenitors and immature neurons. Intracerebroventricular injection of the prodrug ganciclovir caused a robust suppression of neurogenesis without suppressing gliogenesis. Neurogenesis ablation via this method or targeted x-irradiation caused an increase in context conditioning in trace but not delay fear conditioning. Data suggest that this phenotype represents opposing effects of neurogenesis ablation on associative and nonassociative components of fear learning. Arrest of neurogenesis sensitizes mice to nonassociative effects of fear conditioning, as evidenced by increased anxiety-like behavior in the open field after (but not in the absence of) fear conditioning. In addition, arrest of neurogenesis impairs associative trace conditioning, but this impairment can be masked by nonassociative fear. The results suggest that adult neurogenesis modulates emotional learning via two distinct but opposing mechanisms: it supports associative trace conditioning while also buffering against the generalized fear and anxiety caused by fear conditioning. SIGNIFICANCE STATEMENT: The role of adult hippocampal neurogenesis in fear learning is controversial, with some studies suggesting neurogenesis is needed for aspects of fear learning and others suggesting it is dispensable. We generated transgenic mice in which neural progenitors can be selectively and inducibly ablated. Our data suggest that adult neurogenesis supports fear learning through two distinct mechanisms: it supports the ability to learn associations between traumatic events (unconditioned stimuli) and predictors (conditioned stimuli) while also buffering against nonassociative, anxiogenic effects of a traumatic experience. As a result, arrest of neurogenesis can enhance or impair learned fear depending on intensity of the traumatic experience and the extent to which it recruits associative versus nonassociative learning.

Potent attenuation of context fear by extinction training contiguous with acquisition.

Studies on the behavioral mechanisms underlying contextual fear conditioning (CFC) have demonstrated the importance of preshock context exposure in the formation of aversive context memories. However, there has been comparatively little investigation of the effects of context exposure immediately after the shock. Some models predict that nonreinforced context exposure at the end of the acquisition session will strongly influence the strength of conditioning and/or recruit distinct neural mechanisms relative to extinction after acquisition. Here we investigate the effects of manipulating postshock context exposure on CFC in mice. Prolonging the period of context exposure immediately following the shock caused a significant and durable reduction in conditioned fear. This immediate postshock context exposure was more effective at attenuating conditioned fear than was an equivalent amount of context exposure a day or more after acquisition. The results suggest that nonreinforced exposure to the context influences conditioned fear through distinct mechanisms depending on whether it occurs during acquisition or after it. The superiority of immediate postshock context exposure was specific to single-shock CFC; in two-shock CFC, immediate and delayed postshock context exposure had similar effects. Consistent with previous reports, we hypothesize that the effectiveness of extinction is modulated by emotional state, and procedures engendering higher postshock freezing (such as two-shock CFC) are associated with weaker immediate extinction.

Characterization of the role of adult neurogenesis in touch-screen discrimination learning.

Recent theories posit that adult neurogenesis supports dentate gyrus pattern separation and hence is necessary for some types of discrimination learning. Using an inducible transgenic mouse model, we investigated the contribution of adult-born neurons to spatial and nonspatial touch-screen discriminations of varying levels of difficulty. Arresting neurogenesis caused a modest but statistically significant impairment in a position discrimination task. However, the effect was present only on trials after a learned discrimination was reversed, suggesting that neurogenesis supports cognitive flexibility rather than spatial discrimination per se. The deficit was present 4-10 weeks after the arrest of neurogenesis but not immediately after, consistent with previous evidence that the behavioral effects of arresting neurogenesis arise because of the depletion of adult-born neurons at least 1 month old. The arrest of neurogenesis failed to affect a nonspatial brightness discrimination task that was equal in difficulty to the spatial task. The data suggest that adult neurogenesis is not strictly necessary for spatial or perceptual discrimination learning and instead implicate adult neurogenesis in factors related to reversal learning, such as cognitive flexibility or proactive interference.

Extinction training suppresses activity of fear memory ensembles across the hippocampus and alters transcriptomes of fear-encoding cells.

Contextual fear conditioning has been shown to activate a set of "fear ensemble" cells in the hippocampal dentate gyrus (DG) whose reactivation is necessary and sufficient for expression of contextual fear. We previously demonstrated that extinction learning suppresses reactivation of these fear ensemble cells and activates a competing set of DG cells-the "extinction ensemble." Here, we tested whether extinction was sufficient to suppress reactivation in other regions and used single nucleus RNA sequencing (snRNA-seq) of cells in the dorsal dentate gyrus to examine how extinction affects the transcriptomic activity of fear ensemble and fear recall-activated cells. Our results confirm the suppressive effects of extinction in the dorsal and ventral dentate gyrus and demonstrate that this same effect extends to fear ensemble cells located in the dorsal CA1. Interestingly, the extinction-induced suppression of fear ensemble activity was not detected in ventral CA1. Our snRNA-seq analysis demonstrates that extinction training markedly changes transcription patterns in fear ensemble cells and that cells activated during recall of fear and recall of extinction have distinct transcriptomic profiles. Together, our results indicate that extinction training suppresses a broad portion of the fear ensemble in the hippocampus, and this suppression is accompanied by changes in the transcriptomes of fear ensemble cells and the emergence of a transcriptionally unique extinction ensemble.

Extinction Training Suppresses Activity of Fear Memory Ensembles Across the Hippocampus and Alters Transcriptomes of Fear-Encoding Cells.

Contextual fear conditioning has been shown to activate a set of "fear ensemble" cells in the hippocampal dentate gyrus (DG) whose reactivation is necessary and sufficient for expression of contextual fear. We previously demonstrated that extinction learning suppresses reactivation of these fear ensemble cells and activates a competing set of DG cells - the "extinction ensemble." Here, we tested whether extinction was sufficient to suppress reactivation in other regions and used single nucleus RNA sequencing (snRNA-seq) of cells in the dorsal dentate gyrus to examine how extinction affects the transcriptomic activity of fear ensemble and fear recall-activated cells. Our results confirm the suppressive effects of extinction in the dorsal and ventral dentate gyrus and demonstrate that this same effect extends to fear ensemble cells located in the dorsal CA1. Interestingly, the extinction-induced suppression of fear ensemble activity was not detected in ventral CA1. Our snRNA-seq analysis demonstrates that extinction training markedly changes transcription patterns in fear ensemble cells and that cells activated during recall of fear and recall of extinction have distinct transcriptomic profiles. Together, our results indicate that extinction training suppresses a broad portion of the fear ensemble in the hippocampus, and this suppression is accompanied by changes in the transcriptomes of fear ensemble cells and the emergence of a transcriptionally unique extinction ensemble.

( R,S )-ketamine's rapid-acting antidepressant effects are modulated by NR2B-containing NMDA receptors on adult-born hippocampal neurons.

Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. ( R,S )-ketamine, an N -methyl-D-aspartate (NMDA) antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the NR2B subunit of the NMDA receptor (NMDAR) on interneurons in the medial prefrontal cortex (mPFC), no study has investigated the influence of NR2B-expressing adult-born granule cells (abGCs). In this study, we examined whether ( R,S )-ketamine's efficacy depends upon these adult-born hippocampal neurons using a genetic strategy to selectively ablate the NR2B subunit of the NMDAR from Nestin + cells. To validate our findings, we also used several other transgenic lines including one in which NR2B was deleted from an interneuron (Parvalbumin (PV) + ) population. We report that in male mice, NR2B expression on 6-week-old adult-born neurons is necessary for ( R,S )-ketamine's effects on behavioral despair in the forced swim test (FST) and on hyponeophagia in the novelty suppressed feeding (NSF) paradigm, as well on fear behavior following contextual fear conditioning (CFC). In female mice, NR2B expression is necessary for effects on hyponeophagia in the NSF. We also find that ablating neurogenesis increases fear expression in CFC, which is buffered by ( R,S )-ketamine administration. In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing NR2B partially modulate ( R,S )-ketamine's rapid-acting effects. Future work targeting these 6-week-old adult-born neurons may prove beneficial for increasing the efficacy of ( R , S )-ketamine's antidepressant actions.

Subventricular zone cytogenesis provides trophic support for neural repair in a mouse model of stroke.

Stroke enhances proliferation of neural precursor cells within the subventricular zone (SVZ) and induces ectopic migration of newborn cells towards the site of injury. Here, we characterize the identity of cells arising from the SVZ after stroke and uncover a mechanism through which they facilitate neural repair and functional recovery. With genetic lineage tracing, we show that SVZ-derived cells that migrate towards cortical photothrombotic stroke in mice are predominantly undifferentiated precursors. We find that ablation of neural precursor cells or conditional knockout of VEGF impairs neuronal and vascular reparative responses and worsens recovery. Replacement of VEGF is sufficient to induce neural repair and recovery. We also provide evidence that CXCL12 from peri-infarct vasculature signals to CXCR4-expressing cells arising from the SVZ to direct their ectopic migration. These results support a model in which vasculature surrounding the site of injury attracts cells from the SVZ, and these cells subsequently provide trophic support that drives neural repair and recovery.

4- to 6-week-old adult-born hippocampal neurons influence novelty-evoked exploration and contextual fear conditioning.

To explore the role of adult hippocampal neurogenesis in novelty processing, we assessed novel object recognition (NOR) in mice after neurogenesis was arrested using focal x-irradiation of the hippocampus, or a reversible, genetic method in which glial fibrillary acidic protein-positive neural progenitor cells are ablated with ganciclovir. Arresting neurogenesis did not alter general activity or object investigation during four exposures with two constant objects. However, when a novel object replaced a constant object, mice with neurogenesis arrested by either ablation method showed increased exploration of the novel object when compared with control mice. The increased novel object exploration did not manifest until 4-6 weeks after x-irradiation or 6 weeks following a genetic ablation, indicating that exploration of the novel object is increased specifically by the elimination of 4- to 6-week-old adult born neurons. The increased novel object exploration was also observed in older mice, which exhibited a marked reduction in neurogenesis relative to young mice. Mice with neurogenesis arrested by either ablation method were also impaired in one-trial contextual fear conditioning (CFC) at 6 weeks but not at 4 weeks following ablation, further supporting the idea that 4- to 6-week-old adult born neurons are necessary for specific forms of hippocampal-dependent learning, and suggesting that the NOR and CFC effects have a common underlying mechanism. These data suggest that the transient enhancement of plasticity observed in young adult-born neurons contributes to cognitive functions.

Neural reinstatement reveals divided organization of fear and extinction memories in the human brain.

Neurobiological research in rodents has revealed that competing experiences of fear and extinction are stored as distinct memory traces in the brain. This divided organization is adaptive for mitigating overgeneralization of fear to related stimuli that are learned to be safe while also maintaining threat associations for unsafe stimuli. The mechanisms involved in organizing these competing memories in the human brain remain unclear. Here, we used a hybrid form of Pavlovian conditioning with an episodic memory component to identify overlapping multivariate patterns of fMRI activity associated with the formation and retrieval of fear versus extinction. In healthy adults, distinct regions of the medial prefrontal cortex (PFC) and hippocampus showed selective reactivation of fear versus extinction memories based on the temporal context in which these memories were encoded. This dissociation was absent in participants with posttraumatic stress disorder (PTSD) symptoms. The divided neural organization of fear and extinction may support flexible retrieval of context-appropriate emotional memories, while their disorganization may promote overgeneralization and increased fear relapse in affective disorders.

Know thy SEFL: Fear sensitization and its relevance to stressor-related disorders.

Extreme stress can cause long-lasting changes in affective behavior manifesting in conditions such as post-traumatic stress disorder (PTSD). Understanding the biological mechanisms that govern trauma-induced behavioral dysregulation requires reliable and rigorous pre-clinical models that recapitulate multiple facets of this complex disease. For decades, Pavlovian fear conditioning has been a dominant paradigm for studying the effects of trauma through an associative learning framework. However, severe stress also causes long-lasting nonassociative fear sensitization, which is often overlooked in Pavlovian fear conditioning studies. This paper synthesizes recent research on the stress-enhanced fear learning (SEFL) paradigm, a valuable rodent model that can dissociate associative and nonassociative effects of stress. We discuss evidence that the SEFL paradigm produces nonassociative fear sensitization that is distinguishable from Pavlovian fear conditioning. We also discuss key biological variables, such as age and sex, neural circuit mechanisms, and crucial gaps in knowledge. We argue that nonassociative fear sensitization deserves more attention within current PTSD models and that SEFL provides a valuable complement to Pavlovian conditioning research on trauma-related pathology.

The environmental sculpting hypothesis of juvenile and adult hippocampal neurogenesis.

We propose that a major contribution of juvenile and adult hippocampal neurogenesis is to allow behavioral experience to sculpt dentate gyrus connectivity such that sensory attributes that are relevant to the animal's environment are more strongly represented. This "specialized" dentate is then able to store a larger number of discriminable memory representations. Our hypothesis builds on accumulating evidence that neurogenesis declines to low levels prior to adulthood in many species. Rather than being necessary for ongoing hippocampal function, as several current theories posit, we argue that neurogenesis has primarily a prospective function, in that it allows experience to shape hippocampal circuits and optimize them for future learning in the particular environment in which the animal lives. Using an anatomically-based simulation of the hippocampus (BACON), we demonstrate that environmental sculpting of this kind would reduce overlap among hippocampal memory representations and provide representation cells with more information about an animal's current situation; consequently, it would allow more memories to be stored and accurately recalled without significant interference. We describe several new, testable predictions generated by the sculpting hypothesis and evaluate the hypothesis with respect to existing evidence. We argue that the sculpting hypothesis provides a strong rationale for why juvenile and adult neurogenesis occurs specifically in the dentate gyrus and why it declines significantly prior to adulthood.

Chronic social defeat stress impairs goal-directed behavior through dysregulation of ventral hippocampal activity in male mice.

Chronic stress is a risk factor for a variety of psychiatric disorders, including depression. Although impairments to motivated behavior are a major symptom of clinical depression, little is known about the circuit mechanisms through which stress impairs motivation. Furthermore, research in animal models for depression has focused on impairments to hedonic aspects of motivation, whereas patient studies suggest that impairments to appetitive, goal-directed motivation contribute significantly to motivational impairments in depression. Here, we characterized goal-directed motivation in repeated social defeat stress (R-SDS), a well-established mouse model for depression in male mice. R-SDS impaired the ability to sustain and complete goal-directed behavior in a food-seeking operant lever-press task. Furthermore, stress-exposed mice segregated into susceptible and resilient subpopulations. Interestingly, susceptibility to stress-induced motivational impairments was unrelated to stress-induced social withdrawal, another prominent effect of R-SDS in mouse models. Based on evidence that ventral hippocampus (vHP) modulates sustainment of goal-directed behavior, we monitored vHP activity during the task using fiber photometry. Successful task completion was associated with suppression of ventral hippocampal neural activity. This suppression was diminished after R-SDS in stress-susceptible but not stress-resilient mice. The serotonin selective reuptake inhibitor (SSRI) escitalopram and ketamine both normalized vHP activity during the task and restored motivated behavior. Furthermore, optogenetic vHP inhibition was sufficient to restore motivated behavior after stress. These results identify vHP hyperactivity as a circuit mechanism of stress-induced impairments to goal-directed behavior and a putative biomarker that is sensitive to antidepressant treatments and that differentiates susceptible and resilient individuals.

Reactive astrocytes facilitate vascular repair and remodeling after stroke.

Brain injury causes astrocytes to assume a reactive state that is essential for early tissue protection, but how reactive astrocytes affect later reparative processes is incompletely understood. In this study, we show that reactive astrocytes are crucial for vascular repair and remodeling after ischemic stroke in mice. Analysis of astrocytic gene expression data reveals substantial activation of transcriptional programs related to vascular remodeling after stroke. In vivo two-photon imaging provides evidence of astrocytes contacting newly formed vessels in cortex surrounding photothrombotic infarcts. Chemogenetic ablation of a subset of reactive astrocytes after stroke dramatically impairs vascular and extracellular matrix remodeling. This disruption of vascular repair is accompanied by prolonged blood flow deficits, exacerbated vascular permeability, ongoing cell death, and worsened motor recovery. In contrast, vascular structure in the non-ischemic brain is unaffected by focal astrocyte ablation. These findings position reactive astrocytes as critical cellular mediators of functionally important vascular remodeling during neural repair.

Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment.

Environmental enrichment increases adult hippocampal neurogenesis and alters hippocampal-dependent behavior in rodents. To investigate a causal link between these two observations, we analyzed the effect of enrichment on spatial learning and anxiety-like behavior while blocking adult hippocampal neurogenesis. We report that environmental enrichment alters behavior in mice regardless of their hippocampal neurogenic capability, providing evidence that the newborn cells do not mediate these effects of enrichment.

Functional neurogenesis over the years.

There has been interest in the function of adult neurogenesis since its discovery, by Joseph Altman, nearly 60 years ago. While controversy curtailed follow up studies, in the 1990s a second wave of research validated many of Altman's original claims and revealed that factors such as stress and environmental stimulation altered the production of new neurons in the hippocampus. However, only with the advent of tools for manipulating neurogenesis did it become possible to perform causal tests of the function of newborn neurons. Here, we identify approximately 100 studies in which adult neurogenesis was manipulated to study its function. A majority of these studies demonstrate functions for adult neurogenesis in classic hippocampal behaviors such as context learning and spatial memory, as well as emotional behaviors related to stress, anxiety and depression. However, a closer look reveals a number of other, arguably understudied, functions in decision making, temporal association memory, and addiction. In this special issue, we present 16 new studies and review articles that continue to address and clarify the function of adult neurogenesis in behaviors as diverse as memory formation, consolidation and forgetting, pattern separation and discrimination behaviors, addiction, and attention. Reviews of stem cell dynamics and regenerative properties provide insights into the mechanisms by which neurogenesis may be controlled to offset age- and disease-related brain injury. Finally, translation-oriented reviews identify next steps for minimizing the gap between discoveries made in animals and applications for human health. The articles in this issue synthesize and extend what we have learned in the last half century of functional neurogenesis research and identify themes that will define its future.

Know safety, no fear.

Every day we are bombarded by stimuli that must be assessed for their potential for harm or benefit. Once a stimulus is learned to predict harm, it can elicit fear responses. Such learning can last a lifetime but is not always beneficial for an organism. For an organism to thrive in its environment, it must know when to engage in defensive, avoidance behaviors and when to engage in non-defensive, approach behaviors. Fear should be suppressed in situations that are not dangerous: when a novel, innocuous stimulus resembles a feared stimulus, when a feared stimulus no longer predicts harm, or when there is an option to avoid harm. A cardinal feature of anxiety disorders is the inability to suppress fear adaptively. In PTSD, for instance, learned fear is expressed inappropriately in safe situations and is resistant to extinction. In this review, we discuss mechanisms of suppressing fear responses during stimulus discrimination, fear extinction, and active avoidance, focusing on the well-studied tripartite circuit consisting of the amygdala, medial prefrontal cortex and hippocampus.