The microbiota regulate neuronal function and fear extinction learning.

Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota1. In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases2. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders3. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.

TrkB deubiquitylation by USP8 regulates receptor levels and BDNF-dependent neuronal differentiation.

Ubiquitylation of receptor tyrosine kinases (RTKs) regulates both the levels and functions of these receptors. The neurotrophin receptor TrkB (also known as NTRK2), a RTK, is ubiquitylated upon activation by brain-derived neurotrophic factor (BDNF) binding. Although TrkB ubiquitylation has been demonstrated, there is a lack of knowledge regarding the precise repertoire of proteins that regulates TrkB ubiquitylation. Here, we provide mechanistic evidence indicating that ubiquitin carboxyl-terminal hydrolase 8 (USP8) modulates BDNF- and TrkB-dependent neuronal differentiation. USP8 binds to the C-terminus of TrkB using its microtubule-interacting domain (MIT). Immunopurified USP8 deubiquitylates TrkB in vitro, whereas knockdown of USP8 results in enhanced ubiquitylation of TrkB upon BDNF treatment in neurons. As a consequence of USP8 depletion, TrkB levels and its activation are reduced. Moreover, USP8 protein regulates the differentiation and correct BDNF-dependent dendritic formation of hippocampal neurons in vitro and in vivo We conclude that USP8 positively regulates the levels and activation of TrkB, modulating BDNF-dependent neuronal differentiation.This article has an associated First Person interview with the first author of the paper.

SorCS2 is required for social memory and trafficking of the NMDA receptor.

Social memory processing requires functional CA2 neurons, however the specific mechanisms that regulate their activity are poorly understood. Here, we document that SorCS2, a member of the family of the Vps10 family of sorting receptors, is highly expressed in pyramidal neurons of CA2, as well as ventral CA1, a circuit implicated in social memory. SorCS2 specifically localizes to the postsynaptic density and endosomes within dendritic spines of CA2 neurons. We have discovered that SorCS2 is a selective regulator of NMDA receptor surface trafficking in hippocampal neurons, without altering AMPA receptor trafficking. In addition, SorCS2 regulates dendritic spine density in CA2 neurons where SorCS2 expression is enriched, but not in dorsal CA1 neurons, which normally express very low levels of this protein. To specifically test the role of SorCS2 in behavior, we generated a novel SorCS2-deficient mouse, and identify a significant social memory deficit, with no change in sociability, olfaction, anxiety, or several hippocampal-dependent behaviors. Mutations in sorCS2 have been associated with bipolar disease, schizophrenia, and attention deficient-hyperactivity disorder, and abnormalities in social memory are core components of these neuropsychiatric conditions. Thus, our findings provide a new mechanism for social memory formation, through regulating synaptic receptor trafficking in pyramidal neurons by SorCS2.

Role of BDNF in the development of an OFC-amygdala circuit regulating sociability in mouse and human.

Social deficits are common in many psychiatric disorders. However, due to inadequate tools for manipulating circuit activity in humans and unspecific paradigms for modeling social behaviors in rodents, our understanding of the molecular and circuit mechanisms mediating social behaviors remains relatively limited. Using human functional neuroimaging and rodent fiber photometry, we identified a mOFC-BLA projection that modulates social approach behavior and influences susceptibility to social anxiety. In humans and knock-in mice with a loss of function BDNF SNP (Val66Met), the functionality of this circuit was altered, resulting in social behavioral changes in human and mice. We further showed that the development of this circuit is disrupted in BDNF Met carriers due to insufficient BDNF bioavailability, specifically during a peri-adolescent timeframe. These findings define one mechanism by which social anxiety may stem from altered maturation of orbitofronto-amygdala projections and identify a developmental window in which BDNF-based interventions may have therapeutic potential.

Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species.

Anxiety disorders peak in incidence during adolescence, a developmental window that is marked by dynamic changes in gene expression, endocannabinoid signaling, and frontolimbic circuitry. We tested whether genetic alterations in endocannabinoid signaling related to a common polymorphism in fatty acid amide hydrolase (FAAH), which alters endocannabinoid anandamide (AEA) levels, would impact the development of frontolimbic circuitry implicated in anxiety disorders. In a pediatric imaging sample of over 1,000 3- to 21-y-olds, we show effects of the FAAH genotype specific to frontolimbic connectivity that emerge by ∼12 y of age and are paralleled by changes in anxiety-related behavior. Using a knock-in mouse model of the FAAH polymorphism that controls for genetic and environmental backgrounds, we confirm phenotypic differences in frontoamygdala circuitry and anxiety-related behavior by postnatal day 45 (P45), when AEA levels begin to decrease, and also, at P75 but not before. These results, which converge across species and level of analysis, highlight the importance of underlying developmental neurobiology in the emergence of genetic effects on brain circuitry and function. Moreover, the results have important implications for the identification of risk for disease and precise targeting of treatments to the biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation.

Early-life stress has persistent effects on amygdala function and development in mice and humans.

Relatively little is known about neurobiological changes attributable to early-life stressors (e.g., orphanage rearing), even though they have been associated with a heightened risk for later psychopathology. Human neuroimaging and animal studies provide complementary insights into the neural basis of problem behaviors following stress, but too often are limited by dissimilar experimental designs. The current mouse study manipulates the type and timing of a stressor to parallel the early-life stress experience of orphanage rearing, controlling for genetic and environmental confounds inherent in human studies. The results provide evidence of both early and persistent alterations in amygdala circuitry and function following early-life stress. These effects are not reversed when the stressor is removed nor diminished with the development of prefrontal regulation regions. These neural and behavioral findings are similar to our human findings in children adopted from orphanages abroad in that even following removal from the orphanage, the ability to suppress attention toward potentially threatening information in favor of goal-directed behavior was diminished relative to never-institutionalized children. Together, these findings highlight how early-life stress can lead to altered brain circuitry and emotion dysregulation that may increase the risk for psychopathology.

An adaptive role for BDNF Val66Met polymorphism in motor recovery in chronic stroke.

Little is known about the influence of genetic diversity on stroke recovery. One exception is the polymorphism in brain derived neurotrophic factor (BDNF), a critical neurotrophin for brain repair and plasticity. Humans have a high-frequency single nucleotide polymorphism (SNP) in the prodomain of the BDNF gene. Previous studies show that the BDNF Val66Met variant negatively affects motor learning and severity of acute stroke. To investigate the impact of this common BDNF SNP on stroke recovery, we used a mouse model that contains the human BDNF Val66Met variant in both alleles (BDNF(M/M)). Male BDNF(+/+) and BDNF(M/M) littermates received sham or transient middle cerebral artery occlusion. We assessed motor function regularly for 6 months after stroke and then performed anatomical analyses. Despite reported negative association of the SNP with motor learning and acute deficits, we unexpectedly found that BDNF(M/M) mice displayed significantly enhanced motor/kinematic performance in the chronic phase of motor recovery, especially in ipsilesional hindlimb. The enhanced recovery was associated with significant increases in striatum volume, dendritic arbor, and elevated excitatory synaptic markers in the contralesional striatum. Transient inactivation of the contralateral striatum during recovery transiently abolished the enhanced function. This study showed an unexpected benefit of the BDNFVal66Met carriers for functional recovery, involving structural and molecular plasticity in the nonstroked hemisphere. Clinically, this study suggests a role for BDNF genotype in predicting stroke recovery and identifies a novel systems-level mechanism for enhanced motor recovery.

Altered fear learning across development in both mouse and human.

The only evidence-based behavioral treatment for anxiety and stress-related disorders involves desensitization techniques that rely on principles of extinction learning. However, 40% of patients do not respond to this treatment. Efforts have focused on individual differences in treatment response, but have not examined when, during development, such treatments may be most effective. We examined fear-extinction learning across development in mice and humans. Parallel behavioral studies revealed attenuated extinction learning during adolescence. Probing neural circuitry in mice revealed altered synaptic plasticity of prefrontal cortical regions implicated in suppression of fear responses across development. The results suggest a lack of synaptic plasticity in the prefrontal regions, during adolescence, is associated with blunted regulation of fear extinction. These findings provide insight into optimizing treatment outcomes for when, during development, exposure therapies may be most effective.

A small molecule TrkB ligand reduces motor impairment and neuropathology in R6/2 and BACHD mouse models of Huntington's disease.

Loss of neurotrophic support in the striatum caused by reduced brain-derived neurotrophic factor (BDNF) levels plays a critical role in Huntington's disease (HD) pathogenesis. BDNF acts via TrkB and p75 neurotrophin receptors (NTR), and restoring its signaling is a prime target for HD therapeutics. Here we sought to determine whether a small molecule ligand, LM22A-4, specific for TrkB and without effects on p75(NTR), could alleviate HD-related pathology in R6/2 and BACHD mouse models of HD. LM22A-4 was administered to R6/2 mice once daily (5-6 d/week) from 4 to 11 weeks of age via intraperitoneal and intranasal routes simultaneously to maximize brain levels. The ligand reached levels in the R6/2 forebrain greater than the maximal neuroprotective dose in vitro and corrected deficits in activation of striatal TrkB and its key signaling intermediates AKT, PLCγ, and CREB. Ligand-induced TrkB activation was associated with a reduction in HD pathologies in the striatum including decreased DARPP-32 levels, neurite degeneration of parvalbumin-containing interneurons, inflammation, and intranuclear huntingtin aggregates. Aggregates were also reduced in the cortex. Notably, LM22A-4 prevented deficits in dendritic spine density of medium spiny neurons. Moreover, R6/2 mice given LM22A-4 demonstrated improved downward climbing and grip strength compared with those given vehicle, though these groups had comparable rotarod performances and survival times. In BACHD mice, long-term LM22A-4 treatment (6 months) produced similar ameliorative effects. These results support the hypothesis that targeted activation of TrkB inhibits HD-related degenerative mechanisms, including spine loss, and may provide a disease mechanism-directed therapy for HD and other neurodegenerative conditions.

Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke.

BACKGROUND AND PURPOSE: Stroke is the leading cause of long-term disability in the United States, yet no drugs are available that are proven to improve recovery. Brain-derived neurotrophic factor stimulates neurogenesis and plasticity, processes that are implicated in stroke recovery. It binds to both the tropomyosin-related kinase B and p75 neurotrophin receptors. However, brain-derived neurotrophic factor is not a feasible therapeutic agent, and no small molecule exists that can reproduce its binding to both receptors. We tested the hypothesis that a small molecule (LM22A-4) that selectively targets tropomyosin-related kinase B would promote neurogenesis and functional recovery after stroke. METHODS: Four-month-old mice were trained on motor tasks before stroke. After stroke, functional test results were used to randomize mice into 2 equally, and severely, impaired groups. Beginning 3 days after stroke, mice received LM22A-4 or saline vehicle daily for 10 weeks. RESULTS: LM22A-4 treatment significantly improved limb swing speed and accelerated the return to normal gait accuracy after stroke. LM22A-4 treatment also doubled both the number of new mature neurons and immature neurons adjacent to the stroke. Drug-induced differences were not observed in angiogenesis, dendritic arborization, axonal sprouting, glial scar formation, or neuroinflammation. CONCLUSIONS: A small molecule agonist of tropomyosin-related kinase B improves functional recovery from stroke and increases neurogenesis when administered beginning 3 days after stroke. These findings provide proof-of-concept that targeting of tropomyosin-related kinase B alone is capable of promoting one or more mechanisms relevant to stroke recovery. LM22A-4 or its derivatives might therefore serve as "pro-recovery" therapeutic agents for stroke.

Variant BDNF Val66Met polymorphism affects extinction of conditioned aversive memory.

Brain-derived neurotrophic factor (BDNF) plays important roles in activity-dependent plasticity processes, such as long-term potentiation, learning, and memory. The recently reported human BDNF Val66Met (BDNF(Met)) polymorphism has been shown to lead to altered hippocampal volume and impaired hippocampal-dependent memory and is associated with a variety of neuropsychiatric disorders. There are few studies, however, that investigate the effect of the BDNF(Met) polymorphism on hippocampal-independent memory processes. A conditioned taste aversion (CTA) task was used for studying the mechanisms of long-term, hippocampal-independent, nondeclarative memory in the mammalian brain. Using the CTA paradigm, we found a novel impairment in extinction learning, but not acquisition or retention, of aversive memories resulting from the variant BDNF(Met). BDNF(Met) mice were slower to extinguish an aversive CTA memory compared with wild-type counterparts. Moreover, the BDNF(Met) was associated with smaller volume and decreased neuronal dendritic complexity in the ventromedial prefrontal cortex (vmPFC), which plays a significant role in extinction of CTA. Finally, this delay in extinction learning could be rescued pharmacologically with a cognitive enhancer, d-cycloserine (DCS). To our knowledge, this is the first evidence that the BDNF(Met) polymorphism contributes to abnormalities in memory extinction. This abnormality in extinction learning may be explained by alterations in neuronal morphology, as well as decreased neural activity in the vmPFC. Importantly, DCS was effective in rescuing this delay in extinction, suggesting that when coupled with behavior therapy, DCS may be an effective treatment option for anxiety disorders in humans with this genetic variant BDNF.

Endogenous truncated TrkB.T1 receptor regulates neuronal complexity and TrkB kinase receptor function in vivo.

Pathological or in vitro overexpression of the truncated TrkB (TrkB.T1) receptor inhibits signaling through the full-length TrkB (TrkB.FL) tyrosine kinase receptor. However, to date, the role of endogenous TrkB.T1 is still unknown. By studying mice lacking the truncated TrkB.T1 isoform but retaining normal spatiotemporal expression of TrkB.FL, we have analyzed TrkB.T1-specific physiological functions and its effect on endogenous TrkB kinase signaling in vivo. We found that TrkB.T1-deficient mice develop normally but show increased anxiety in association with morphological abnormalities in the length and complexity of neurites of neurons in the basolateral amygdala. However, no behavioral abnormalities were detected in hippocampal-dependent memory tasks, which correlated with lack of any obvious hippocampal morphological deficits or alterations in basal synaptic transmission and long-term potentiation. In vivo reduction of TrkB signaling by removal of one BDNF allele could be partially rescued by TrkB.T1 deletion, which was revealed by an amelioration of the enhanced aggression and weight gain associated with BDNF haploinsufficiency. Our results suggest that, at the physiological level, TrkB.T1 receptors are important regulators of TrkB.FL signaling in vivo. Moreover, TrkB.T1 selectively affects dendrite complexity of certain neuronal populations.

Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice.

Adolescence represents a developmental period with the highest risk for initiating cannabis use. Little is known about whether genetic variation in the endocannabinoid system alters mesolimbic reward circuitry to produce vulnerability to the rewarding properties of the exogenous cannabinoid Δ9-tetrahydrocannabinol (THC). Using a genetic knock-in mouse model (FAAHC/A) that biologically recapitulates the human polymorphism associated with problematic drug use, we find that in adolescent female mice, but not male mice, this FAAH polymorphism enhances the mesolimbic dopamine circuitry projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and alters cannabinoid receptor 1 (CB1R) levels at inhibitory and excitatory terminals in the VTA. These developmental changes collectively increase vulnerability of adolescent female FAAHC/A mice to THC preference that persists into adulthood. Together, these findings suggest that this endocannabinoid genetic variant is a contributing factor for increased susceptibility to cannabis dependence in adolescent females.

Variant brain-derived neurotrophic factor (Val66Met) alters adult olfactory bulb neurogenesis and spontaneous olfactory discrimination.

Neurogenesis, the division, migration, and differentiation of new neurons, occurs throughout life. Brain derived neurotrophic factor (BDNF) has been identified as a potential signaling molecule regulating neurogenesis in the subventricular zone (SVZ), but its functional consequences in vivo have not been well defined. We report marked and unexpected deficits in survival but not proliferation of newly born cells of adult knock-in mice containing a variant form of BDNF [a valine (Val) to methionine (Met) substitution at position 66 in the prodomain of BDNF (Val66Met)], a genetic mutation shown to lead to a selective impairment in activity-dependent BDNF secretion. Utilizing knock-out mouse lines, we identified BDNF and tyrosine receptor kinase B (TrkB) as the critical molecules for the observed impairments in neurogenesis, with p75 knock-out mice showing no effect on cell proliferation or survival. We then localized the activated form of TrkB to a discrete population of cells, type A migrating neuroblasts, and demonstrate a decrease in TrkB phosphorylation in the SVZ of Val66Met mutant mice. With these findings, we identify TrkB signaling, potentially through activity dependent release of BDNF, as a critical step in the survival of migrating neuroblasts. Utilizing a behavioral task shown to be sensitive to disruptions in olfactory bulb neurogenesis, we identified specific impairments in spontaneous olfactory discrimination, but not general olfactory sensitivity or habituation to olfactory stimuli in BDNF mutant mice. Through these observations, we have identified novel links between genetic variant BDNF and adult neurogenesis in vivo, which may contribute to significant impairments in olfactory function.

Opposing effects of an atypical glycinergic and substance P transmission on interpeduncular nucleus plasticity.

The medial habenula-interpeduncular nucleus (MHb-IPN) pathway has recently been implicated in the suppression of fear memory. A notable feature of this pathway is the corelease of neurotransmitters and neuropeptides from MHb neurons. Our studies in mice reveal that an activation of substance P-positive dorsomedial habenula (dMHb) neurons results in simultaneous release of glutamate and glycine in the lateral interpeduncular nucleus (LIPN). This glycine receptor activity inhibits an activity-dependent long-lasting potentiation of glutamatergic synapses in LIPN neurons, while substance P enhances this plasticity. An endocannabinoid CB1 receptor-mediated suppression of GABAB receptor activity allows substance P to induce a long-lasting increase in glutamate release in LIPN neurons. Consistent with the substance P-dependent synaptic potentiation in the LIPN, the NK1R in the IPN is involved in fear extinction but not fear conditioning. Thus, our study describes a novel plasticity mechanism in the LIPN and a region-specific role of substance P in fear extinction.

The BDNF Val66Met Prodomain Disassembles Dendritic Spines Altering Fear Extinction Circuitry and Behavior.

A human variant in the BDNF gene (Val66Met; rs6265) is associated with impaired fear extinction. Using super-resolution imaging, we demonstrate that the BDNF Met prodomain disassembles dendritic spines and eliminates synapses in hippocampal neurons. In vivo, ventral CA1 (vCA1) hippocampal neurons undergo similar morphological changes dependent on their transient co-expression of a SorCS2/p75NTR receptor complex during peri-adolescence. BDNF Met prodomain infusion into the vCA1 during this developmental time frame reduces dendritic spine density and prelimbic (PL) projections, impairing cued fear extinction. Adolescent BdnfMet/Met mice display similar spine and PL innervation deficits. Using fiber photometry, we found that, in wild-type mice, vCA1 neurons projecting to the PL encode extinction by enhancing neural activity in threat anticipation and rapidly subsiding their response. This adaptation is absent in BDNFMet/Met mice. We conclude that the BDNF Met prodomain renders vCA1-PL projection neurons underdeveloped, preventing their capacity for subsequent circuit modulation necessary for fear extinction. VIDEO ABSTRACT.

The BDNF Val66Met polymorphism enhances glutamatergic transmission but diminishes activity-dependent synaptic plasticity in the dorsolateral striatum.

The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene disrupts the activity-dependent release of BDNF, which might underlie its involvement in several neuropsychiatric disorders. Consistent with the potential role of regulated release of BDNF in synaptic functions, earlier studies have demonstrated that the BDNF Val66Met polymorphism impairs NMDA receptor-mediated synaptic transmission and plasticity in the hippocampus, the medial prefrontal cortex and the central amygdala. However, it is unknown whether the BDNF Val66Met polymorphism affects synapses in the dorsal striatum, which depends on cortical afferents for BDNF. Electrophysiological experiments revealed an enhanced glutamatergic transmission in the dorsolateral striatum (DLS) of knock-in mice containing the variant polymorphism (BDNFMet/Met) compared to the wild-type (BDNFVal/Val) mice. This increase in glutamatergic transmission is mediated by a potentiation in glutamate release and NMDA receptor transmission in the medium spiny neurons without any alterations in non-NMDA receptor-mediated transmission. We also observed an impairment of synaptic plasticity, both long-term potentiation and depression in the DLS neurons, in BDNFMet/Met mice. Thus, the BDNF Val66Met polymorphism exerts an increase in glutamatergic transmission but impairs synaptic plasticity in the dorsal striatum, which might play a role in its effect on neuropsychiatric symptoms. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.

Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice.

OBJECTIVE: Adolescence is a developmental stage in which the incidence of psychiatric disorders, such as anxiety disorders, peaks. Selective serotonin reuptake inhibitors (SSRIs) are the main class of agents used to treat anxiety disorders. However, the impact of SSRIs on the developing brain during adolescence remains unknown. The authors assessed the impact of developmentally timed SSRI administration in a genetic mouse model displaying elevated anxiety-like behaviors. METHOD: Knock-in mice containing a common human single-nucleotide polymorphism (Val66Met; rs6265) in brain-derived neurotrophic factor (BDNF), a growth factor implicated in the mechanism of action of SSRIs, were studied based on their established phenotype of increased anxiety-like behavior. Timed administration of fluoxetine was delivered during one of three developmental periods (postnatal days 21-42, 40-61, or 60-81), spanning the transition from childhood to adulthood. Neurochemical and anxiety-like behavioral analyses were performed. RESULTS: We identified a "sensitive period" during periadolescence (postnatal days 21-42) in which developmentally timed fluoxetine administration rescued anxiety-like phenotypes in BDNF Val66Met mice in adulthood. Compared with littermate controls, BDNFMet/Met mice exhibited diminished maturation of serotonergic fibers projecting particularly to the prefrontal cortex, as well as decreased expression of the serotonergic trophic factor S100B in the dorsal raphe. Interestingly, deficient serotonergic innervation, as well as S100B levels, were rescued with fluoxetine administration during periadolescence. CONCLUSIONS: These findings suggest that SSRI administration during a "sensitive period" during periadolescence leads to long-lasting anxiolytic effects in a genetic mouse model of elevated anxiety-like behaviors. These persistent effects highlight the role of BDNF in the maturation of the serotonin system and the capacity to enhance its development through a pharmacological intervention.

Dynamic changes in neural circuitry during adolescence are associated with persistent attenuation of fear memories.

Fear can be highly adaptive in promoting survival, yet it can also be detrimental when it persists long after a threat has passed. Flexibility of the fear response may be most advantageous during adolescence when animals are prone to explore novel, potentially threatening environments. Two opposing adolescent fear-related behaviours-diminished extinction of cued fear and suppressed expression of contextual fear-may serve this purpose, but the neural basis underlying these changes is unknown. Using microprisms to image prefrontal cortical spine maturation across development, we identify dynamic BLA-hippocampal-mPFC circuit reorganization associated with these behavioural shifts. Exploiting this sensitive period of neural development, we modified existing behavioural interventions in an age-specific manner to attenuate adolescent fear memories persistently into adulthood. These findings identify novel strategies that leverage dynamic neurodevelopmental changes during adolescence with the potential to extinguish pathological fears implicated in anxiety and stress-related disorders.

FAAH genetic variation enhances fronto-amygdala function in mouse and human.

Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry and behaviour. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviours. These results suggest a gain of function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human.