Human Anxiety Disorders Research Articles

Reduced left ventricular dimension and function following early life stress: A thrifty phenotype hypothesis engendering risk for mood and anxiety disorders

BackgroundEarly life stress (ELS) in macaques in the form of insecure maternal attachment putatively induces epigenetic adaptations resulting in a “thrifty phenotype” throughout the life cycle. For instance, ELS induces persistent increases in insulin resistance, hippocampal and corpus callosum atrophy and reduced “behavioral plasticity”, which, taken together, engenders an increased risk for mood and anxiety disorders in humans but also a putative sparing of calories. Herein, we test the hypothesis whether a thrifty phenotype induced by ELS is peripherally evident as hypotrophy of cardiac structure and function, raising the possibility that certain mood disorders may represent maladaptive physiological and central thrift adaptations. Methods14 adult bonnet macaques (6 males) exposed to the maternal variable foraging demand (VFD) model of ELS were compared to 20 non-VFD adult subjects (6 males). Left ventricle end-diastolic dimension (LVEDD), Left ventricle end-systolic dimension (LVESD) and stroke volume (SV) were calculated using echocardiography. Blood pressure and heart rate were measured only in females. Previously obtained neurobehavioral correlates available only in males were analyzed in the context of cardiac parameters. ResultsReduced LVESD (p < 0.05) was observed when controlled for age, sex, body weight and crown-rump length whereas ejection fraction (EF) (p = 0.037) was greater in VFD-reared versus non-VFD subjects. Pulse pressure was lower in VFD versus non-VFD females (p < 0.05). Male timidity in response to a human intruder was associated with reduced LVEDD (p < 0.05). ConclusionsELS is associated with both structural and functional reductions of left ventricular measures, potentially implying a body-wide thrifty phenotype. Parallel “thrift” adaptations may occur in key brain areas following ELS and may play an unexplored role in mood and anxiety disorder susceptibility.

The Endocannabinoid System and Anxiety.

The medical properties of Cannabis sativa is known for centuries. Since the discovery and characterization of the endogenous cannabinoid system, several studies have evaluated how cannabinoid compounds and, particularly, how the modulation of the endocannabinoid (eCB) system influences a wide range of functions, from metabolic to mental disorders. Cannabinoids and eCB system often exert opposite effects on several functions, such as anxiety. Although the mechanisms are not completely understood, evidence points to different factors influencing those effects. In this chapter, the recent advances in research about the relationship between eCB system and anxiety disorders in humans, as well as in animal models, will be discussed. The recent data addressing modulation of the eCBs in specific brain areas, such as the medial prefrontal cortex, amygdaloid complex, bed nucleus of stria terminalis, hippocampus, and dorsal periaqueductal gray, will be summarized. Finally, data from animal models addressing the mechanisms through which the eCB system modulates anxiety-related behavior dependent on stressful situations, such as the involvement of different receptors, distinct eCBs, modulation of neurotransmitters release, HPA axis and immune system activation, and plastic mechanisms, will also be discussed.

P.1.i.030 - Effect of electroconvulsive therapy on interregional serotonin-1A receptor binding correlations in depressed patients

Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD).Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed.We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (−21.4%; p = .003). There was also a more than 20% lower 5-HT1A BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030).The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders.

Distinct state anxiety after predictable and unpredictable fear training in mice

Sustained fear paradigms in rodents have been developed to monitor states of anxious apprehension and to model situations in patients suffering from long-lasting anxiety disorders. A recent report describes a fear conditioning paradigm, allowing distinction between phasic and sustained states of conditioned fear in non-restrained mice. However, so far no prospective studies have yet been conducted to elucidate whether induction of phasic or sustained fear can affect states of anxiety. Here, we used CS (conditioned stimulus) and US (unconditioned stimulus) pairing with predictable and unpredictable timing to induce phasic and sustained fear in mice. State anxiety during various fear response components was assessed using the elevated plus-maze test. Training with unpredictable CS-US timing resulted in CS-evoked sustained components of fear (freezing), while predictable CS-US timing resulted in rapid decline. Data suggested the influence of training procedure on state anxiety which is dependent on progression of conditioned fear during fear memory retrieval. Animals trained with unpredictable CS-US timing showed an unchanged high anxiety state throughout behavioral observation. In contrast, mice trained with predictable CS-US timing showed anxiolytic-like behavior 3min after CS onset, which was accompanied by a fast decline of the fear conditioned response (freezing). Further systematic studies are needed to validate the phasic/sustained fear model in rodents as translational model for anxiety disorders in humans.

Editorial: Scents that Matter-from Olfactory Stimuli to Genes, Behaviors and Beyond.

Editorial: Scents that Matter-from Olfactory Stimuli to Genes, Behaviors and Beyond.

Assessing Fear Following Retrieval + Extinction Through Suppression of Baseline Reward Seeking vs. Freezing.

Freezing has become the predominant measure used in rodent studies of conditioned fear, but conditioned suppression of reward-seeking behavior may provide a measure that is more relevant to human anxiety disorders; that is, a measure of how fear interferes with the enjoyment of pleasurable activities. Previous work has found that an isolated presentation of a fear conditioned stimulus (CS) prior to extinction training (retrieval + extinction) results in a more robust and longer-lasting reduction in fear. The objective of this study was to assess whether the retrieval + extinction effect is evident using conditioned suppression of reward seeking, operationalized as a reduction in baseline licking (without prior water deprivation) for a 10% sucrose solution. We found that, compared to freezing, conditioned suppression of reward seeking was much more sensitive to fear conditioning and far less responsive to extinction training. As in previous work, we found that retrieval + extinction reduced post-extinction fear reinstatement when measured as freezing, but it did not reduce fear reinstatement when measured as conditioned suppression. This suggests that there is still residual fear following retrieval + extinction, or that this procedure only modifies memory traces in neural circuits relevant to the expression of freezing, but not to the suppression of reward seeking.

Anxiety-Like Behavioural Inhibition Is Normative under Environmental Threat-Reward Correlations.

Behavioural inhibition is a key anxiety-like behaviour in rodents and humans, distinct from avoidance of danger, and reduced by anxiolytic drugs. In some situations, it is not clear how behavioural inhibition minimises harm or maximises benefit for the agent, and can even appear counterproductive. Extant explanations of this phenomenon make use of descriptive models but do not provide a formal assessment of its adaptive value. This hampers a better understanding of the neural computations underlying anxiety behaviour. Here, we analyse a standard rodent anxiety model, the operant conflict test. We harvest Bayesian Decision Theory to show that behavioural inhibition normatively arises as cost-minimising strategy in temporally correlated environments. Importantly, only if behavioural inhibition is aimed at minimising cost, it depends on probability and magnitude of threat. Harnessing a virtual computer game, we test model predictions in four experiments with human participants. Humans exhibit behavioural inhibition with a strong linear dependence on threat probability and magnitude. Strikingly, inhibition occurs before motor execution and depends on the virtual environment, thus likely resulting from a neural optimisation process rather than a pre-programmed mechanism. Individual trait anxiety scores predict behavioural inhibition, underlining the validity of this anxiety model. These findings put anxiety behaviour into the context of cost-minimisation and optimal inference, and may ultimately pave the way towards a mechanistic understanding of the neural computations gone awry in human anxiety disorder.

Evidence for serotonin function as a neurochemical difference between fear and anxiety disorders in humans?

The relationships between serotonin and fear and anxiety disorders have been much studied yet many important questions remain, despite selective serotonin reuptake inhibitors having been the primary treatments for these disorders for some time. In order to explore this issue we performed a pooled analysis of six of our studies in remitted patients with a fear/anxiety disorder who were exposed to syndrome-specific aversive stimulation under acute tryptophan depletion. We based our analysis on the hypothesis that the inconsistencies observed in the studies could be predicted by Deakin and Graeff's theory about the dual role of serotonin in responses to threats, whereby serotonin is critical to prevent fear (panic) but not anxiety. In accordance with this view, our results give support to a dissociation of the disorders traditionally grouped under fear and anxiety-related disorders in terms of different roles of serotonin in modulation of responses to aversive stimulation. Implications for future studies and psychiatric nosology are discussed.

Electric foot shock stress: a useful tool in neuropsychiatric studies.

Electric foot shock is a complex stressor with both physical and emotional components. It has been employed as an important tool to develop diverse animal models in the field of psychopharmacology. The electric foot shock paradigm includes acute or chronic exposures of shocks of varying intensity and duration on an electrified grid floor in an electric foot shock apparatus. Research evidence reveals that foot shocks of varying intensity produce behavioral and neurochemical changes reflecting depression, anxiety, and post-traumatic stress disorder (PTSD) in humans. Animals generally do not habituate to foot shocks in comparison to other stressors, including loud noise, bright light, and hot and cold temperatures. Additionally, it offers an experimental advantage of control over intensity and duration; therefore, by varying its application parameters, different disorder models have been created. Electric foot shock fear conditioning-induced ultrasonic vocalization and fear-potentiated startle have been explored to develop models of anxiety and panic. Similarly, fear conditioning in the form of foot shock exposure followed by situational reminders has been used to develop a model of PTSD. Electric foot shock-induced conflict has been explored to develop operant conflict models (Geller-Seifter and Vogel tests), which in turn are pharmacologically validated to screen potential anti-anxiety agents. Inescapable electric shock-induced 'learned helplessness' mimics the symptomology of depression, and this phenomenon has been employed to develop the model of depression. The present review describes the pharmacologically validated models of anxiety, depression, and PTSD involving electric foot shock as an aversive stimulus.

Anxiogenic drug administration and elevated plus-maze exposure in rats activate populations of relaxin-3 neurons in the nucleus incertus and serotonergic neurons in the dorsal raphe nucleus

Anxiety is a complex and adaptive emotional state controlled by a distributed and interconnected network of brain regions, and disruption of these networks is thought to give rise to the behavioral symptoms associated with anxiety disorders in humans. The dorsal raphe nucleus (DR), which contains the majority of forebrain-projecting serotonergic neurons, is implicated in the control of anxiety states and anxiety-related behavior via neuromodulatory effects on these networks. Relaxin-3 is the native neuropeptide ligand for the Gi/o-protein-coupled receptor, RXFP3, and is primarily expressed in the nucleus incertus (NI), a tegmental region immediately caudal to the DR. RXFP3 activation has been shown to modulate anxiety-related behavior in rodents, and RXFP3 mRNA is expressed in the DR. In this study, we examined the response of relaxin-3-containing neurons in the NI and serotonergic neurons in the DR following pharmacologically induced anxiety and exposure to an aversive environment. We administered the anxiogenic drug FG-7142 or vehicle to adult male Wistar rats and, 30min later, exposed them to either the elevated plus-maze or home cage control conditions. Immunohistochemical detection of c-Fos was used to determine activation of serotonergic neurons in the DR and relaxin-3 neurons in the NI, measured 2h following drug injection. Analysis revealed that FG-7142 administration and exposure to the elevated plus-maze are both associated with an increase in c-Fos expression in relaxin-3-containing neurons in the NI and in serotonergic neurons in dorsal and ventrolateral regions of the DR. These data are consistent with the hypothesis that relaxin-3 systems in the NI and serotonin systems in the DR interact to form part of a network involved in the control of anxiety-related behavior.

Avoidance behavior: a free-operant lever-press avoidance task for the assessment of the effects of safety signals.

This protocol details a free-operant avoidance paradigm that has been developed to evaluate the relative contribution of different sources of reinforcement of avoidance behavior that may play an important role in the development and maintenance of human anxiety disorders. The task enables the assessment of the effects of safety cues that signal a period free from danger on lever-press avoidance behavior. Avoidance behavior trained using this protocol has been shown to be sensitive to both behavioral and pharmacological manipulations and has been optimized so that it takes approximately 1 month for rats to perform at high levels of stable avoidance responding.

Does D-cycloserine enhance exposure therapy for anxiety disorders in humans? A meta-analysis.

The treatment of anxiety is on the edge of a new era of combinations of pharmacologic and psychosocial interventions. A new wave of translational research has focused on the use of pharmacological agents as psychotherapy adjuvants using neurobiological insights into the mechanism of the action of certain psychological treatments such as exposure therapy. Recently, d-cycloserine (DCS) an antibiotic used to treat tuberculosis has been applied to enhance exposure-based treatment for anxiety and has proved to be a promising, but as yet unproven intervention. The present study aimed to evaluate the efficacy of DCS in the enhancement of exposure therapy in anxiety disorders. A systematic review/meta-analysis was conducted. Electronic searches were conducted in the databases ISI-Web of Science, Pubmed and PsycINFO. We included only randomized, double-blind, placebo-controlled trials with humans, focusing on the role of DCS in enhancing the action of exposure therapy for anxiety disorders. We identified 328 references, 13 studies were included in our final sample: 4 on obsessive-compulsive disorder, 2 on panic disorder, 2 on social anxiety disorder, 2 on posttraumatic stress disorder, one on acrophobia, and 2 on snake phobia. The results of the present meta-analysis show that DCS enhances exposure therapy in the treatment of anxiety disorders (Cohen d = −0.34; CI: −0.54 to −0.14), facilitating the specific process of extinction of fear. DCS seems to be effective when administered at a time close to the exposure therapy, at low doses and a limited number of times. DCS emerges as a potential new therapeutic approach for patients with refractory anxiety disorders that are unresponsive to the conventional treatments available. When administered correctly, DCS is a promising strategy for augmentation of CBT and could reduce health care costs, drop-out rates and bring faster relief to patients.

Escitalopram or Novel Herbal Mixture Treatments during or following Exposure to Stress Reduce Anxiety-Like Behavior through Corticosterone and BDNF Modifications

Anxiety disorders are a major public health concern worldwide. Studies indicate that repeated exposure to adverse experiences early in life can lead to anxiety disorders in adulthood. Current treatments for anxiety disorders are characterized by a low success rate and are associated with a wide variety of side effects. The aim of the present study was to evaluate the anxiolytic effects of a novel herbal treatment, in comparison to treatment with the selective serotonin reuptake inhibitor escitalopram. We recently demonstrated the anxiolytic effects of these treatments in BALB mice previously exposed to one week of stress. In the present study, ICR mice were exposed to post natal maternal separation and to 4 weeks of unpredictable chronic mild stress in adolescence, and treated during or following exposure to stress with the novel herbal treatment or with escitalopram. Anxiety-like behavior was evaluated in the elevated plus maze. Blood corticosterone levels were evaluated using radioimmunoassay. Brain derived neurotrophic factor levels in the hippocampus were evaluated using enzyme-linked immunosorbent assay. We found that (1) exposure to stress in childhood and adolescence increased anxiety-like behavior in adulthood; (2) the herbal treatment reduced anxiety-like behavior, both when treated during or following exposure to stress; (3) blood corticosterone levels were reduced following treatment with the herbal treatment or escitalopram, when treated during or following exposure to stress; (4) brain derived neurotrophic factor levels in the hippocampus of mice treated with the herbal treatment or escitalopram were increased, when treated either during or following exposure to stress. This study expands our previous findings and further points to the proposed herbal compound's potential to be highly efficacious in treating anxiety disorders in humans.

Human Hippocampus Arbitrates Approach-Avoidance Conflict

SummaryAnimal models of human anxiety often invoke a conflict between approach and avoidance [1, 2]. In these, a key behavioral assay comprises passive avoidance of potential threat and inhibition, both thought to be controlled by ventral hippocampus [2–6]. Efforts to translate these approaches to clinical contexts [7, 8] are hampered by the fact that it is not known whether humans manifest analogous approach-avoidance dispositions and, if so, whether they share a homologous neurobiological substrate [9]. Here, we developed a paradigm to investigate the role of human hippocampus in arbitrating an approach-avoidance conflict under varying levels of potential threat. Across four experiments, subjects showed analogous behavior by adapting both passive avoidance behavior and behavioral inhibition to threat level. Using functional magnetic resonance imaging (fMRI), we observe that threat level engages the anterior hippocampus, the human homolog of rodent ventral hippocampus [10]. Testing patients with selective hippocampal lesions, we demonstrate a causal role for the hippocampus with patients showing reduced passive avoidance behavior and inhibition across all threat levels. Our data provide the first human assay for approach-avoidance conflict akin to that of animal anxiety models. The findings bridge rodent and human research on passive avoidance and behavioral inhibition and furnish a framework for addressing the neuronal underpinnings of human anxiety disorders, where our data indicate a major role for the hippocampus.

Behaviourally inhibited temperament and female sex, two vulnerability factors for anxiety disorders, facilitate conditioned avoidance (also) in humans

Acquisition and maintenance of avoidance behaviour is a key feature of all human anxiety disorders. Animal models have been useful in understanding how anxiety vulnerability could translate into avoidance learning. For example, behaviourally inhibited temperament and female sex, two vulnerability factors for clinical anxiety, are associated with faster acquisition of avoidance responses in rodents. However, to date, the translation of such empirical data to human populations has been limited since many features of animal avoidance paradigms are not typically captured in human research. Here, using a computer-based task that captures many features of rodent escape-avoidance learning paradigms, we investigated whether avoidance learning would be faster in humans with inhibited temperament and/or female sex and, if so, whether this facilitation would take the same form. Results showed that, as in rats, both vulnerability factors were associated with facilitated acquisition of avoidance behaviour in humans. Specifically, inhibited temperament was associated with higher rate of avoidance responding, while female sex was associated with longer avoidance duration. These findings strengthen the direct link between animal avoidance work and human anxiety vulnerability, further motivating the study of animal models while also providing a simple testbed for a direct human testing.

Behavioral evaluation of male and female carioca high- and low-freezing rats

Recent years have seen growing interest in the development of genetic animal models to investigate the bidirectional relationship between trait anxiety and defensive reactions. The present study further analyzed behavioral correlates of two novel breeding lines of rats, Carioca high-and low-conditioned freezing (CHF and CLF), based on defensive freezing responses to contextual cues previously associated with electric footshock. Male and female rats from the 10th generation were used to assess anxiety-like reactions in the elevated plus maze (EPM), depressive-like behavior in the forced swim test (FST), and aversive memory in the contextual fear conditioning paradigm. In the EPM, female rats showed lower anxiety-like behavior than males, whereas CHF rats were more anxious than CLF rats. The same pattern of results was found in the contextual fear conditioning paradigm. No differences were found between lines or sexes in the FST. Such differences in emotionality responses in the 10th generation of selected rats further indicate a possible use of this model to study correlations between trait anxiety and defensive reactions. The face validity of the model and its use to experimentally simulate generalized anxiety disorder in humans are also discussed.

Assessing Anxiety in Nonhuman Primates

Anxiety can be broadly described as a psychological state in which normally innocuous environmental stimuli trigger negative emotional expectations. Human anxiety disorders are multidimensional and may be organic or acquired, situational or pervasive. The broad ranging nature of the anxiety phenotype speaks to the need for models that identify its various components and root causes to develop effective clinical treatments. The cross-species comparative approach to modeling anxiety disorders in animals aims to understand mechanisms that both contribute to and modulate anxiety. Nonhuman primate models provide an important bridge from nonprimate model systems because of the complexity of nonhuman primates' biobehavioral capacities and their commonalities with human emotion. The broad goal of this review is to provide an overview of various procedures available to study anxiety in the nonhuman primate, with a focus on the behavioral aspects of anxiety. Commonly used methods covered in this review include assessing animals in their home environment or in response to an ethologically relevant threat, associative conditioning and startle response tests, and cognitive bias tests. We also discuss how these procedures can help veterinarians and researchers care for captive nonhuman primates.

Fear: A Blessing and Curse

F ear : a B lessing and C urse B S J Shruti Koti Imagine a lone adventurer standing at the edge of a cliff, miles away from civilization. He looks down at the unknown below and, taking a deep breath, jumps, attached to nothing but a single bungee cord. He feels the wind in his face, his clothes billowing up above him, and something else: a hollow pit in his stomach and the terrifying feeling that he may die at any moment. It sounds extreme, but what he is feeling is something we have all experienced, and it is completely natural: fear. To jump, the bungee jumper had to overcome his fear of heights, a fairly common fear as far as phobias go. However, grappling with fear is not always this easy. The reason we feel fear is not a mystery – evolutionarily, it puts you on guard and reduces your likelihood of getting attacked. Bats have evolved echolocation to detect and catch their prey; moths in turn have evolved echolocation and evasive flight maneuvers. Noctuid moths, which are eaten by bats, respond to bat echolocation in three ways: a startle response, sonar jamming, and acoustic aposematism (Yager, 2012).This is a prime example of how in a predator-prey relationship, there is an evolutionary arms race in which prey is usually better adapted for exaggerated caution. This basic fear response forms the biological foundation for human anxiety disorders. Early learning theory hypothesized that stimuli that became associated with fears were equipotent, i.e. every stimulus had an equal chance of becoming a feared stimulus (Carey, 1990). However, in practice, the limited range of common fears – heights, enclosed spaces, and certain types of animals (snakes, spiders) – led theorists to favor the concept of prepotency or preparedness, which states that we are biologically predisposed to certain fears, or “primed” to automatically select certain evolutionary stimuli. Fear is a complicated term because it can refer to both an emotion and a physical response to a stimulus. A stimulus is an object or event that promotes a fear response (increased heartbeat, freezing, etc.). Then fear conditioning is the behavioral process that leads organisms to predict and react to adverse events or stimuli – this refers to the natural fear acquisition process, too, not just processes occurring in laboratories. Conditioning occurs if the probability of the unconditioned stimulus (US) in the presence of the conditioned stimulus (CS) is different than it its absence. One of the most famous examples of classical (Pavlovian) conditioning was an experiment in which a little boy was conditioned to fear white rats. Initially, he showed no fear of a white rat, the neutral stimulus. Then the rat was continuously presented along with loud, unpleasant sounds – here the sounds were the unconditioned stimulus. By repeatedly pairing the rat with the unconditioned stimulus, the white rat (now the conditioned stimulus) came to evoke a fear response (the conditioned response) in the child (Jones, 1924). In general, a selective associative model shows four basic characteristics shaped by evolution: selectivity with regard to input, or threatening stimuli; automaticity, the triggering of a response in the absence of conscious awareness; encapsulation, the resistance to conscious cognitive influences; and specialized neural circuitry, the module controlled by a specific neural circuit that has been shaped by evolution (Hofmann, 2008). “...we are biologically predisposed to certain fears, or “primed” to automatically select certain evolutionary stimuli.” In expressing fear, exposure to acute stress triggers the “fight or flight” response, stimulating activity in the hypothalamic-pituitary-adrenal (HPA) axis, the locus coreruleus, noradrenergic systems, and the neurocircuitry of the fear system. The fear circuitry includes the amygdala and its subnuclei, the nucleus accumbens, the hippocampus, ventro- medial hypothalamus, periaqueductal gray, several brain stem nuclei, thalamic nuclei, insular cortex, and some prefrontal regions. Some regions, however, play a more prominent role in fear circuitry. The forebrain structures that have expanded the most in evolution are the prefrontal cortex and the amygdala. It has been shown that damage to the right and left amygdala disrupts fear conditioning: the right correlates with expression of learning, and the left hemisphere is involved in tasks that require cognitive interpretation of stimuli (Delgado et al, 2008). There are extensive connections between the amygdala and the visual system, consistent with behavioral, lesion, and neuroimaging data which show that the amygdala tunes visual brain areas for effective perception of fear-related stimuli (Ohman, 2009). Sensory information reaches the amygdala by two pathways. The first involves classical sensory 16 • B erkeley S cientific J ournal • E xtremes • F all 2014 • V olume 19 • I ssue 1

Baiap3 as a genetic marker associated with anxiety and benzodiazepine abuse in mouse and man

The brain specific angiogenesis inhibitor I-associated protein 3 (Baiap3) is a member of the mammalian uncoordinated-13 (Munc13) protein family of synaptic regulators of neurotransmitter exocytosis. Baiap3 has a striking expression pattern in amygdalae, hypothalamus and periaqueductal gray. We identify Baiap3 as a first genetic risk marker for anxiety and benzodiazepine use disorder in mice and humans. Deletion of Baiap3 in mice leads to enhanced seizure propensity and increased anxiety, the latter being more pronounced in female than in male animals. We further identify human BAIAP3 risk genotypes that show a significant association with anxiety in women and, surprisingly, with benzodiazepine abuse in men. Returning to mice, we find that male, but not female Baiap3 knockout (KO) mice develop tolerance to diazepam more quickly than control animals. Analysis of cultured Baiap3 KO hypothalamus slices reveals an increase in basal network activity and an altered response to diazepam. Thus, Baiap3/BAIAP3 is the first gene shown to be gender-specifically associated with increased anxiety and benzodiazepine abuse in mice and humans. Further analysis of Baiap3/BAIAP3-related functions may therefore help elucidate mechanisms underlying the development of both disorders.

Nonlinear developmental trajectory of fear learning and memory

The transition into and out of adolescence is a unique developmental period during which neuronal circuits are particularly susceptible to modification by experience. Adolescence is associated with an increased incidence of anxiety disorders in humans, and an estimated 75% of adults with fear-related disorders met diagnostic criteria as children and adolescents. Conserved neural circuitry of rodents and humans has facilitated neurodevelopmental studies of behavioral and molecular processes associated with fear learning and memory that lie at the heart of many anxiety disorders. Here, we review the nonlinear developmental aspects of fear learning and memory during a transition period into and out of adolescence and provide a discussion of the molecular mechanisms that may underlie these alterations in behavior. We provide a model that may help to inform novel treatment strategies for children and adolescents with fear-related disorders.