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.

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.