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Background Elevated ovarian hormones during fear extinction can enhance fear extinction memory retention and reduce fear renewal, but the mechanisms remain unknown. High levels of ovarian hormones are associated with heightened dopamine (DA) transmission, a key player in fear extinction. In males, stimulation of substantia nigra (SN) DA neurons during fear extinction reduces renewal; an effect mimicked by DA D1 receptor agonist administration into the dorsolateral striatum (DLS), a primary target of the SN. The current studies tested the role of the SN-DLS pathway in estrous cycle-modulation of fear extinction and relapse. Methods Male and female Long-Evans rats were used to investigate the effects of sex and ovarian hormone levels during fear extinction on later fear relapse and underlying mechanisms. Fear extinction-induced cFos in SN DA neurons was quantified with double-label immunohistochemistry. An intersectional chemogenetic approach was used to determine whether SN-DLS pathway activity during fear extinction is necessary and sufficient for observed effects of ovarian hormones on fear relapse. Finally, fast scan cyclic voltammetry revealed the effects of sex and ovarian hormones on electrically-evoked DA release in the DLS and verified the effectiveness of chemogenetic approaches. Results Female rats exposed to fear extinction during proestrus or estrus (Pro/Est; high hormones) had less relapse (renewal and spontaneous recovery) compared to males or females exposed to fear extinction during metestrus or diestrus (Met/Di; low hormones). Fear extinction-induced cFos within SN DA neurons and electrically-evoked DA release in the DLS was highest in female rats during Pro/Est. The behavioral and neurochemical effects of Pro/Est were mimicked by estradiol administration to ovariectomized female rats. Inhibition of the SN-DLS pathway suppressed electrically-evoked DA release in the DLS and restored fear renewal in females exposed to simultaneous fear extinction and SN-DLS inhibition during Pro/Est. Conversely, stimulation of the SN-DLS pathway during extinction reduced fear renewal in males. Conclusions Results indicate that ovarian hormones present during fear extinction reduce later fear relapse through a SN-DLS dopamine pathway. Data suggest the SN-DLS DA pathway is a novel target for the reduction of fear relapse in both sexes. Plain Language summary Women are at higher risk than men for common psychiatric disorders such as post-traumatic stress disorder. Exposure therapy is used to treat these disorders whereby subjects learn that cues previously paired with trauma no longer predict danger. However, the efficacy of exposure therapy is limited by the return of fear (relapse), even after successful fear extinction. Research is needed to better understand sex differences in the processes governing fear extinction learning and relapse. Levels of ovarian hormones present during fear extinction can influence the strength of fear extinction memory and relapse, but the mechanisms underlying the effect of ovarian hormones remain unknown. Due to an emerging role for dopamine (DA) and the substantia nigra-to-dorsolateral striatum (SN-DLS) DA pathway in relapse-resistant fear extinction, we investigated the involvement of the SN-DLS DA pathway in ovarian hormone-modulation of fear extinction and relapse. We observe that females with elevated ovarian hormones during fear extinction have less fear relapse compared to males and females with low ovarian hormones, an effect attributable to estradiol. Elevated ovarian hormones potentiated DA neural activity during fear extinction in the SN and DA release in the DLS, while inhibition of the SN-DLS pathway during fear extinction restores fear relapse in females exposed to fear extinction in the presence of high ovarian hormones. Additionally, stimulation of the SN-DLS pathway during fear extinction reduces relapse in males. The results of this study implicate the SN-DLS pathway as a novel target for the reduction of relapse in both sexes. Highlights High levels of ovarian hormones during fear extinction is associated with low levels of fear relapse in adult, female rats. Electrically-evoked dopamine release in the dorsolateral striatum is potentiated by estradiol and is highest in phases of the estrous cycle characterized by high levels of ovarian hormones. Activity of substantia nigra dopamine neurons during fear extinction is greatest in females exposed to fear extinction during estrous cycle phases associated with high levels of ovarian hormones. Inhibition of the substantia nigra-to-dorsolateral striatum pathway during fear extinction restores fear relapse in females exposed to extinction during conditions of high ovarian hormones. Stimulation of the substantia nigra-to-dorsolateral striatum pathway during fear extinction reduces fear relapse in males.

RationaleExercise 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.ObjectivesHere 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.MethodsTo 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.ResultsWe 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.ConclusionsThe 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.

Extinction that occurs during high ovarian hormone phases, proestrus or estrus (Pro/Est), or following E2 administration in ovariectomized females, enhances extinction memory retrieval compared to extinction during low ovarian hormone phases, metestrus and diestrus (Met/Di). These effects extend to fear renewal, with females extinguished during Pro/Est showing an absence of renewal, whereas females in Met/Di remain susceptible to renewal. However, it remains unclear whether these effects extend to other relapse phenomena or whether renewal is mediated by E2 levels during extinction. In males, renewal is similarly prevented by enhancing dopamine (DA) signaling within the substantia nigra (SN) and its projection target, the dorsolateral striatum (DLS) during extinction. Stimulated striatal DA release is potentiated in Est females or following E2 administration, suggesting that elevated ovarian hormones may naturally engage the SN-DLS pathway during extinction to confer resistance to renewal. However, the mechanisms underlying estrous phase modulated extinction and renewal remain unknown. To address these gaps, the present experiments examined how sex, estrous phase, and E2 during extinction influence multiple forms of fear relapse and investigated the role of the SN-DLS pathway and DLS network connectivity in relapse-resistant extinction. Undergoing extinction during Pro/Est or following E2 administration prevented renewal and reduced spontaneous recovery compared to other groups. In females extinguished during Pro/Est, this effect depended on SN-DLS pathway activity during extinction, and activation of this pathway during extinction in males was sufficient to prevent renewal. Stimulated DA release in the DLS was greater in Pro/Est females than in Met/Di females and was greater than that in the dorsomedial striatum. During extinction, Pro/Est females demonstrated decreased prefrontal activity, increased medial amygdala activity, and elevated activity within SN and VTA DA neurons compared to other groups. Network analyses in Pro/Est females during extinction revealed strong and dense functional connectivity that uniquely integrated the DLS, including as a hub. These findings identify an estrous phase-dependent shift towards SN-DLS engagement during extinction as a mechanism that may support relapse-resistant extinction in females.

Despite the well-established health benefits of exercise, adherence to physical activity remains low, highlighting the need to identify biological factors that regulate the initiation and persistence of exercise behavior. Here, we tested whether ovarian hormone state at the onset of voluntary wheel running (VWR) influences both immediate and long-term exercise behavior in female rats. Females that initiated VWR during proestrus (Pro) ran farther, spent more time running, and ran at higher speeds on the first day of wheel access than females initiating VWR outside of Pro. Remarkably, initiating VWR during Pro also produced persistent increases in running distance, duration, speed, and escalation across subsequent weeks, despite normal cycling through other estrous phases. In contrast, exogenous estradiol (E2) administered at VWR initiation did not alter day-1 behavior, but increased running distance and duration across subsequent weeks without affecting running speed or escalation. To determine whether dorsal striatal dopamine contributes to these effects, we inhibited the substantia nigra (SN) to dorsolateral striatum (DLS) pathway on the first day of VWR. This manipulation reduced the immediate and long-term effects of initiating VWR during Pro on running duration and distance but not speed or escalation. These findings identify behavioral initiation as a critical window during which hormones and nigrostriatal signaling influence future engagement in physical activity. Furthermore, analysis of individual components of VWR architecture reveals that distinct features of VWR behavior can be dissociated mechanistically and thus could be used to investigate separate motivational processes underlying physical activity.

Elevated ovarian hormones during fear extinction can enhance fear extinction memory retention and reduce renewal, but the mechanisms remain unknown. Ovarian hormones modulate dopamine (DA) transmission, a key player in fear extinction. In males, stimulation of substantia nigra (SN) DA neurons during fear extinction reduces renewal; an effect mimicked by a DA D1 receptor agonist into the dorsolateral striatum (DLS). The current studies tested the role of the SN-DLS pathway in estrous cycle-modulation of fear extinction and relapse. In cycling female, Long-Evans rats, fear extinction during proestrus or estrus (Pro/Est; high hormones) resulted in less relapse (renewal and spontaneous recovery) compared to males or females in metestrus or diestrus (Met/Di; low hormones). This effect was mimicked by estradiol (E2) administration to ovariectomized rats. Females in Pro/Est had greater fear extinction-induced cFos within SN DA neurons compared to males. Similarly, fast scan cyclic voltammetry revealed that electrically-evoked DA release in the DLS is potentiated by E2 and is greater during Pro/Est compared to Met/Di. An inhibitory intersectional chemogenetic approach targeting the SN-DLS pathway suppressed electrically-evoked DA release in the DLS and restored fear renewal in females exposed to simultaneous fear extinction and SN-DLS inhibition during Pro/Est. Conversely, chemogenetic stimulation of the SN-DLS pathway during extinction reduced fear renewal in males. These data suggest that levels of ovarian hormones present during fear extinction modulate relapse through a SN-DLS pathway, and that the SN-DLS pathway represents a novel target for the reduction of fear relapse in both sexes.

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.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Author order corrected

The impaired inhibition of learned fear is a feature of stress-related psychiatric disorders such as generalized anxiety disorder and post-traumatic stress disorder (PTSD). Extinction-based exposure therapy is the behavioral therapy of choice for these disorders, however, it has limited long term efficacy due to the vulnerability of fear memories to relapse. Women are up to 60% more likely to experience an anxiety disorder and up to twice as likely to experience PTSD compared to men. Although these sex differences exist, they are not fully considered in the field of neuroscience. Research shows that females can have enhanced extinction compared to males, and the strength of extinction in females varies depending on the phase of the estrous cycle during which extinction is learned. However, whether the phase during which extinction is learned impacts relapse has not been well characterized. The goal of this experiment was to determine whether sex and estrous phase during extinction modulates relapse. Adult male and female Long-Evans rats were exposed to conditioning in Context A, followed 24 hr later by extinction in Context B. The next day, rats were re-exposed to the conditioned stimulus in either the same context, (Context B), or a different context (Context C) to assess renewal. Spontaneous recovery of fear was assessed 1 wk later. Results indicate that males and females learned conditioning and extinction similarly. Males and females that extinguished during metestrus and diestrus phases were susceptible to renewal while females that extinguished during proestrus and estrus phases reduced renewal. Males had higher levels of spontaneous recovery compared to females. These data suggest that estrous phase during extinction modulates relapse; whereby learning extinction during proestrus and estrus phases reduces relapse. These results could have important clinical implications for the use of exposure therapy in women.