Behavioral and neural correlates of diverse conditioned fear responses in male and female rats.

Pavlovian fear conditioning is a widely used tool that models associative learning in rodents. For decades the field has used predominantly male rodents and focused on a sole conditioned fear response: freezing. However, recent work from our lab and others has identified darting as a female-biased conditioned response, characterized by an escape-like movement across a fear conditioning chamber.

Behavioral neuroscience's inevitable SABV growing pains.

The field of rodent behavioral neuroscience is undergoing two major sea changes: an ever-growing technological revolution, and worldwide calls to consider sex as a biological variable (SABV) in experimental design. Both have enormous potential to improve the precision and rigor with which the brain can be studied, but the convergence of these shifts in scientific practice has exposed critical limitations in classic and widely used behavioral paradigms. While our tools have advanced, our behavioral metrics - mostly developed in males and often allowing for only binary outcomes - have not.

Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging.

Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections cumulatively across the life span.

CB1R blockade unmasks TRPV1-mediated contextual fear generalization in female, but not male rats.

Increasing evidence suggests that the neurobiological processes that govern learning and memory can be different in males and females, but many of the specific mechanisms underlying these sex differences have not been fully defined. Here we investigated potential sex differences in endocannabinoid (eCB) modulation of Pavlovian fear conditioning and extinction, examining multiple defensive behaviors, including shock responsivity, conditioned freezing, and conditioned darting. We found that while systemic administration of drugs acting on eCB receptors did not influence the occurrence of darting, females that were classified as Darters responded differently to the drug administration than those classified as Non-darters.

CB1R blockade unmasks TRPV1-mediated contextual fear generalization in female, but not male rats.

Increasing evidence suggests that the neurobiological processes that govern learning and memory can be different in males and females, and here we asked specifically whether the endocannabinoid (eCB) system could modulate Pavlovian fear conditioning in a sex-dependent manner. Systemic (i.p.

Mouse spontaneous behavior reflects individual variation rather than estrous state.

Behavior is shaped by both the internal state of an animal and its individual behavioral biases. Rhythmic variation in gonadal hormones during the estrous cycle is a defining feature of the female internal state, one that regulates many aspects of sociosexual behavior. However, it remains unclear whether estrous state influences spontaneous behavior and, if so, how these effects might relate to individual behavioral variation.

Sounding the Alarm: Sex Differences in Rat Ultrasonic Vocalizations during Pavlovian Fear Conditioning and Extinction.

Pavlovian fear conditioning is a prevalent tool in the study of aversive learning, which is a key component of stress-related psychiatric disorders. Adult rats can exhibit various threat-related behaviors, including freezing, motor responses, and ultrasonic vocalizations (USVs). While these responses can all signal aversion, we know little about how they relate to one another.

Automated classification of estrous stage in rodents using deep learning.

The rodent estrous cycle modulates a range of biological functions, from gene expression to behavior. The cycle is typically divided into four stages, each characterized by distinct hormone concentration profiles. Given the difficulty of repeatedly sampling plasma steroid hormones from rodents, the primary method for classifying estrous stage is by identifying vaginal epithelial cell types.

Darting across space and time: parametric modulators of sex-biased conditioned fear responses.

Pavlovian fear conditioning is a widely used behavioral paradigm for studying associative learning in rodents. Despite early recognition that subjects may engage in a variety of both conditioned and unconditioned responses, the last several decades have seen the field narrow its focus to measure freezing as the sole indicator of conditioned fear. We previously reported that female rats were more likely than males to engage in darting, an escape-like conditioned response that is associated with heightened shock reactivity.

Considering Organismal Physiology in Laboratory Studies of Rodent Behavior.

Any experiment conducted in a rodent laboratory is done so against the backdrop of each animal's physiological state at the time of the experiment. This physiological state can be the product of multiple factors, both internal (e.g.

Response and recovery of endocrine, behavioral, and neuronal morphology outcomes after different traumatic stressor exposures in male rats.

Preclinical models of organismal response to traumatic stress (threat of death or serious injury) can be monitored using neuroendocrine, behavioral, and structural metrics. While many rodent models of traumatic stress have provided a glimpse into select components of the physiological response to acute and chronic stressors, few studies have directly examined the potential differences between stressors and their potential outcomes. To address this gap, we conducted a multi-level comparison of the immediate and longer-term effects of two types of acute traumatic stressors.

Considering sex as a biological variable will require a global shift in science culture.

For over half a century, male rodents have been the default model organism in preclinical neuroscience research, a convention that has likely contributed to higher rates of misdiagnosis and adverse side effects from drug treatment in women. Studying both sexes could help to rectify these public health problems, but incentive structures in publishing and career advancement deter many researchers from doing so. Moreover, funding agency directives to include male and female animals and human participants in grant proposals lack mechanisms to hold recipients accountable.

The unique plasticity of hippocampal adult-born neurons: Contributing to a heterogeneous dentate.

The dentate gyrus (DG) of the hippocampus is evolutionarily conserved as one of the few sites of adult neurogenesis in mammals. Although there is clear evidence that neurogenesis is necessary for healthy hippocampal function, whether adult-born neurons are simply integrated into existing hippocampal networks to serve a similar purpose to that of developmentally born neurons or whether they represent a discrete cell population with unique functions remains less clear. In this review, we consider evidence for discrete cellular, synaptic, and structural features of adult-born DG neurons, suggesting that neurogenesis contributes to the formation of a heterogeneous DG.

Sex-dependent effects of endocannabinoid modulation of conditioned fear extinction in rats.

Background And Purpose: Women are twice as likely as men to develop post-traumatic stress disorder (PTSD) making the search for biological mechanisms underlying these gender disparities especially crucial. One of the hallmark symptoms of PTSD is an alteration in the ability to extinguish fear responses to trauma-associated cues. In male rodents, the endocannabinoid system can modulate fear extinction and has been suggested as a therapeutic target for PTSD.

Controllable stress elicits circuit-specific patterns of prefrontal plasticity in males, but not females.

Actual or perceived behavioral control during a traumatic event can promote resilience against future adversity, but the long-term cellular and circuit mechanisms by which this protection is conferred have not been identified. Clinical outcomes following trauma exposure differ in men and women, and, therefore, it is especially important in preclinical research to dissect these processes in both males and females. In male adult rats, an experience with behavioral control over tail shock ("escapable stress", ES) has been shown to block the neurochemical and behavioral outcomes produced by later uncontrollable tail shock ("inescapable stress", IS), a phenomenon termed "behavioral immunization".

Stress: Influence of sex, reproductive status and gender.

Emerging evidence from the preclinical and human research suggests sex differences in response to different types of stress exposure, and that developmental timing, reproductive status, and biological sex are important factors influencing the degree of HPA activation/function. Here we review data regarding: i) sex differences in behavioral and neural responses to uncontrollable and controllable stressors; ii) distinct trajectories of behavioral development and HPA-axis function in male and female rats following adolescent stress exposure; iii) normative changes in behavior and dopamine function in early postpartum rats; iv) aberrant HPA-axis function and its link to abnormal behaviors in two independent, preclinical mouse models of postpartum depression; and, v) data indicating that gender, in addition to sex, is an important determinant of stress reactivity in humans. Based on these findings, we conclude it will be important for future studies to investigate the short and long-term effects of a wide variety of stressors, how these effects may differ according to developmental timing and in relation to gonadal function, the relationship between aberrant HPA-axis activity during the postpartum and mood disorders, and influences of both sex and gender on stress reactivity in humans.

Behavioral Diversity Across Classic Rodent Models Is Sex-Dependent.

Symptoms of trauma and stressor related disorders such as post-traumatic stress disorder (PTSD) often develop well after the traumatic experience has occurred, and so identifying early predictors of risk or resilience is important for the implementation of interventional therapies. For example, passive coping strategies such as tonic immobility and peritraumatic dissociation during the trauma itself are risk factors for the developments of PTSD, especially in women. However, discrete, sex-specific coping responses that predict later outcomes in animal models have not been rigorously defined.

Sex differences in behavioral strategies: avoiding interpretational pitfalls.

Despite ample evidence for sex differences in brain structure and function, our understanding of the neurobiological basis of behavior comes almost exclusively from male animals. As neuroscientists move to comply with recent NIH mandates that biomedical researchers include both sexes in their studies, the ways we interpret outcomes in classic rodent behavioral models deserve closer scrutiny and more nuanced evaluation. In this mini-review, we highlight recent sex differences papers in learning, decision-making, and spatial navigation paradigms that underscore the distinctions between cognitive capabilities versus behavioral strategies that may confer unique benefits to males and females.

Strain-dependent sex differences in a long-term forced swim paradigm.

Women are twice as likely as men to suffer from trauma- and stressor-related disorders. The development of improved therapeutic interventions is contingent upon a more complete grasp of both the neural and behavioral dynamics of the stress response in females. The rodent forced swim test (FST) is a valuable animal model for exploring the neurobiological mechanisms responsible for selection of active and passive responses to inescapable stressors, but it is often neglected in 2-day FST studies is the dissociation of innate (Day 1) versus learned (Day 2) coping responses.

Considering Sex as a Biological Variable Will Be Valuable for Neuroscience Research.

The recently implemented National Institutes of Health policy requiring that grant applicants consider sex as a biological variable in the design of basic and preclinical animal research studies has prompted considerable discussion within the neuroscience community. Here, we present reasons to be optimistic that this new policy will be valuable for neuroscience, and we suggest some ways for neuroscientists to think about incorporating sex as a variable in their research.