Multiple Sex- and Circuit-Specific Mechanisms Underlie Exercise-Induced Stress Resistance.

Prior physical activity reduces the risk of future stress-related mental health disorders including depression, anxiety, and post-traumatic stress disorder. Rodents allowed to engage in voluntary wheel running are similarly protected from behavioral consequences of stress. The present review summarizes current knowledge on mechanisms underlying exercise-induced stress resistance. A conceptual framework involving the development (during exercise) and expression (during stress) of stress resistance from exercise is proposed. During the development of stress resistance, adaptations involving multiple exercise signals and molecular mediators occur within neural circuits orchestrating various components of the stress response, which then respond differently to stress during the expression of stress resistance. Recent data indicate that the development and expression of stress resistance from exercise involve multiple independent mechanisms that depend on sex, stressor severity, and behavioral outcome. Recent insight into the role of the prefrontal cortex in exercise-induced stress resistance illustrates these multiple mechanisms. This knowledge has important implications for the design of future experiments aimed at identifying the mechanisms underlying exercise-induced stress resistance.

Pharmacological manipulations of the dorsomedial and dorsolateral striatum during fear extinction reveal opposing roles in fear renewal.

Systemic manipulations that enhance dopamine (DA) transmission around the time of fear extinction can strengthen fear extinction and reduce conditioned fear relapse. Prior studies investigating the brain regions where DA augments fear extinction focus on targets of mesolimbic and mesocortical DA systems originating in the ventral tegmental area, given the role of these DA neurons in prediction error. The dorsal striatum (DS), a primary target of the nigrostriatal DA system originating in the substantia nigra (SN), is implicated in behaviors beyond its canonical role in movement, such as reward and punishment, goal-directed action, and stimulus-response associations, but whether DS DA contributes to fear extinction is unknown. We have observed that chemogenetic stimulation of SN DA neurons during fear extinction prevents the return of fear in contexts different from the extinction context, a form of relapse called renewal. This effect of SN DA stimulation is mimicked by a DA D1 receptor (D1R) agonist injected into the DS, thus implicating DS DA in fear extinction. Different DS subregions subserve unique functions of the DS, but it is unclear where in the DS D1R agonist acts during fear extinction to reduce renewal. Furthermore, although fear extinction increases neural activity in DS subregions, whether neural activity in DS subregions is causally involved in fear extinction is unknown. To explore the role of DS subregions in fear extinction, adult, male Long-Evans rats received microinjections of either the D1R agonist SKF38393 or a cocktail consisting of GABAA/GABAB receptor agonists muscimol/baclofen selectively into either dorsomedial (DMS) or dorsolateral (DLS) DS subregions immediately prior to fear extinction, and extinction retention and renewal were subsequently assessed drug-free. While increasing D1R signaling in the DMS during fear extinction did not impact fear extinction retention or renewal, DMS inactivation reduced later renewal. In contrast, DLS inactivation had no effect on fear extinction retention or renewal but increasing D1R signaling in the DLS during extinction reduced fear renewal. These data suggest that DMS and DLS activity during fear extinction can have opposing effects on later fear renewal, with the DMS promoting renewal and the DLS opposing renewal. Mechanisms through which the DS could influence the contextual gating of fear extinction are discussed.

Female rats are more responsive than are males to the protective effects of voluntary physical activity against the behavioral consequences of inescapable stress.

Common stress-related mental health disorders affect women more than men. Physical activity can provide protection against the development of future stress-related mental health disorders (i.e. stress resistance) in both sexes, but whether there are sex differences in exercise-induced stress resistance is unknown. We have previously observed that voluntary wheel running (VWR) protects both female and male rats against the anxiety- and exaggerated fear-like behavioral effects of inescapable stress, but the time-course and magnitude of VWR-induced stress resilience has not been compared between sexes. The goal of the current study was to determine whether there are sex differences in the time-course and magnitude of exercise-induced stress resistance. In adult female and male Sprague Dawley rats, 6 weeks of VWR produced robust protection against stress-induced social avoidance and exaggerated fear. The magnitude of stress protection was similar between the sexes and was independent of reactivity to shock, general locomotor activity, and circulating corticosterone. Interestingly, 3 weeks of VWR prevented both stress-induced social avoidance and exaggerated fear in females but only prevented stress-induced social avoidance in males. Ovariectomy altered wheel-running behavior in females such that it resembled that of males, however; 3 weeks of VWR still protected females against behavioral consequences of stress regardless of the absence of ovaries. These data indicate that female Sprague Dawley rats are more responsive to exercise-induced stress resistance than are males.

The duration of wheel running required to enable stress resistance differs between the sexes in a behavior-dependent manner.Wheel running enables rapid protection against stress-induced social avoidance in both male and female Sprague Dawley rats.Wheel running enables protection against stress-induced exaggerated fear more readily in female Sprague Dawley rats compared to males.Ovarian hormones are not necessary for stress-protection produced by 3 weeks of wheel running in female Sprague Dawley rats.

Duration- and sex-dependent neural circuit control of voluntary physical activity.

RATIONALE: Exercise participation remains low despite clear benefits. Rats engage in voluntary wheel running (VWR) that follows distinct phases of acquisition, during which VWR escalates, and maintenance, during which VWR remains stable. Understanding mechanisms driving acquisition and maintenance of VWR could lead to novel strategies to promote exercise. The two phases of VWR resemble those that occur during operant conditioning and, therefore, might involve similar neural substrates. The dorsomedial (DMS) dorsal striatum (DS) supports the acquisition of operant conditioning, whereas the dorsolateral striatum (DLS) supports its maintenance. OBJECTIVES: Here we sought to characterize the roles of DS subregions in VWR. Females escalate VWR and operant conditioning faster than males. Thus, we also assessed for sex differences. METHODS: To determine the causal role of DS subregions in VWR, we pharmacologically inactivated the DMS or DLS of adult, male and female, Long-Evans rats during the two phases of VWR. The involvement of DA receptor 1 (D1)-expressing neurons in the DS was investigated by quantifying cfos mRNA within this neuronal population. RESULTS: We observed that, in males, the DMS and DLS are critical for VWR exclusively during acquisition and maintenance, respectively. In females, the DMS is also critical only during acquisition, but the DLS contributes to VWR during both VWR phases. DLS D1 neurons could be an important driver of VWR escalation during acquisition. CONCLUSIONS: The acquisition and maintenance of VWR involve unique neural substrates in the DS that vary by sex. Results reveal targets for sex-specific strategies to promote exercise.

Acute exercise enhances fear extinction through a mechanism involving central mTOR signaling.

Impaired fear extinction, combined with the likelihood of fear relapse after exposure therapy, contributes to the persistence of many trauma-related disorders such as anxiety and post-traumatic stress disorder. Identifying mechanisms to aid fear extinction and reduce relapse could provide novel strategies for augmentation of exposure therapy. Exercise can enhance learning and memory and augment fear extinction of traumatic memories in humans and rodents. One factor that could contribute to enhanced fear extinction following exercise is the mammalian target of rapamycin (mTOR). mTOR is a translation regulator involved in synaptic plasticity and is sensitive to many exercise signals such as monoamines, growth factors, and cellular metabolism. Further, mTOR signaling is increased after chronic exercise in brain regions involved in learning and emotional behavior. Therefore, mTOR is a compelling potential facilitator of the memory-enhancing and overall beneficial effects of exercise on mental health.The goal of the current study is to test the hypothesis that mTOR signaling is necessary for the enhancement of fear extinction produced by acute, voluntary exercise. We observed that intracerebral-ventricular administration of the mTOR inhibitor rapamycin reduced immunoreactivity of phosphorylated S6, a downstream target of mTOR, in brain regions involved in fear extinction and eliminated the enhancement of fear extinction memory produced by acute exercise, without reducing voluntary exercise behavior or altering fear extinction in sedentary rats. These results suggest that mTOR signaling contributes to exercise-augmentation of fear extinction.

Sex differences in resilience: Experiential factors and their mechanisms.

Adverse life events can lead to stable changes in brain structure and function and are considered primary sources of risk for post-traumatic stress disorder, depression and other neuropsychiatric disorders. However, most individuals do not develop these conditions following exposure to traumatic experiences, and research efforts have identified a number of experiential factors associated with an individual's ability to withstand, adapt to and facilitate recovery from adversity. While multiple animal models of stress resilience exist, so that the detailed biological mechanisms can be explored, studies have been disproportionately conducted in male subjects even though the prevalence and presentation of stress-linked disorders differ between sexes. This review focuses on (a) the mechanisms by which experiential factors (behavioral control over a stressor, exercise) reduce the impact of adverse events as studied in males; (b) whether other manipulations (ketamine) that buffer against stress-induced sequelae engage the same circuit features; and (c) whether these processes operate similarly in females. We argue that investigation of experiential factors that produce resistance/resilience rather than vulnerability to adversity will generate a unique set of biological mechanisms that potentially underlie sex differences in mood disorders.

Voluntary exercise enables stress resistance in females.

Stress-related disorders are more common in females than males. This difference could arise from differential responses to behavioral interventions that enable stress resistance between sexes. In male rats, regular physical activity prevents the behavioral consequences of uncontrollable stress, such as social avoidance and exaggerated fear conditioning. However, it is unknown if these protective effects are also present in females. Here we demonstrate for the first time in female rats that six weeks of voluntary wheel running buffers against the behavioral sequelae of uncontrollable stress. This observation allows for mechanistic investigations of exercise-induced stress resistance in both sexes.

3,4-methylenedioxymethamphetamine (MDMA) impairs the extinction and reconsolidation of fear memory in rats.

Clinical trials have demonstrated that 3,4-methylenedioxymethamphetamine (MDMA) paired with psychotherapy is more effective at reducing symptoms of post-traumatic stress disorder (PTSD) than psychotherapy or pharmacotherapy, alone or in combination. The processes through which MDMA acts to enhance psychotherapy are not well understood. Given that fear memories contribute to PTSD symptomology, MDMA could augment psychotherapy by targeting fear memories. The current studies investigated the effects of a single administration of MDMA on extinction and reconsolidation of cued and contextual fear memory in adult, male Long-Evans rats. Rats were exposed to contextual or auditory fear conditioning followed by systemic administration of saline or varying doses of MDMA (between 1 and 10 mg/kg) either 30 min before fear extinction training or immediately after brief fear memory retrieval (i.e. during the reconsolidation phase). MDMA administered prior to fear extinction training failed to enhance fear extinction memory, and in fact impaired drug-free cued fear extinction recall without impacting later fear relapse. MDMA administered during the reconsolidation phase, but not outside of the reconsolidation phase, produced a delayed and persistent reduction in conditioned fear. These findings are consistent with a general memory-disrupting effect of MDMA and suggest that MDMA could augment psychotherapy by modifying fear memories during reconsolidation without necessarily enhancing their extinction.

Running from fear: Exercise modulation of fear extinction.

Extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear tends to resurface even after successful extinction. Identification of novel strategies to enhance fear extinction and reduce fear relapse is of paramount importance to mental health. Exercise can enhance cognitive function, but it is not yet well understood whether exercise can be an effective augmentation strategy for fear extinction. In the current review, we present the current state of knowledge on the effects of exercise on fear extinction. Effects of exercise duration, explanations for conflicting results, and potential mechanisms, focusing on a hypothesized role for dopamine, are all discussed. We also provide new data suggesting that the timing in which acute exercise occurs relative to fear extinction, is a crucial variable in determining whether exercise can enhance fear extinction. Clinical implications and ideas to guide future research endeavors in this area are provided.