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.

The effect of selective nigrostriatal dopamine excess on behaviors linked to the cognitive and negative symptoms of schizophrenia.

Excess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms of schizophrenia. These observations and the fact that increasing brain-wide dopamine improves cognition have fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms. However, this idea has never been explicitly tested with DS-pathway specificity. To determine if excess DS dopamine is involved in cognitive and negative symptoms, we selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of Trpv1 knockout mice. We treated these mice with capsaicin (TRPV1 agonist) to selectively activate these neurons, validated this approach with fiber photometry, and assessed its effects on social interaction and working memory, behavioral constructs related to negative and cognitive symptoms. We combined this manipulation with antipsychotic treatment (haloperidol) and compared it to brain-wide dopamine release via amphetamine treatment. We found that selectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired social interaction and working memory. Haloperidol normalized locomotion, but only partially rescued working memory and had no effect on social interaction. By contrast, amphetamine increased locomotion but did not impair social interaction or working memory. These results suggest that excess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Future therapies should address this disregarded role for excess striatal dopamine in the treatment-resistant symptoms of psychosis.

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.