This study investigated the physiological, somatic and behavioral changes evoked by daily exposure to the same type of stressor (homotypic) or different aversive stressor stimuli (heterotypic) in male and female rats. For this, adult Wistar rats were subjected to a 10days regimen of repeated restraint stress (RRS, homotypic stressor) or chronic variable stress (CVS, heterotypic stressor). Effects evoked by CVS included: (i) adrenal hypertrophy and decreased body weight gain in male animals, (ii) a sympathetically-mediated increase in basal heart rate in males, and (iii) a rise in plasma corticosterone concentration and anxiogenic effects in female animals. The homotypic stressor RRS also induced an increase in plasma corticosterone and anxiogenic effects in females, decreased body weight gain in males and evoked a sympathetically-mediated increase in heart rate in both sexes. Changes in cardiovascular function and autonomic activity evoked by both stressors were followed by impairment of baroreflex activity in males, but not female animals. Both chronic stressors evoked changes in blood pressure responsiveness to vasoconstrictor and vasodilator agents in both sexes. Taken together, these results indicate that regardless of chronic stress regimen males are more vulnerable to somatic effects of chronic stressors, while females appear to be more susceptible to neuroendocrine and behavioral changes. Present findings also indicate that females are selectively vulnerable to cardiovascular and autonomic changes evoked by homotypic stressors. Nevertheless, homotypic and heterotypic stressors similarly affect cardiovascular function and autonomic activity in males.

Stress exposure is an important risk factor for psychiatric and cardiovascular disorders. Two phenotypes related to coping with stress can be observed in rodents that experience chronic social defeat stress (SDS): susceptible, showing social avoidance and behavioral changes related to depression, and resilient, showing none of these alterations. Moreover, a strong correlation exists between depression and the development of or mortality due to cardiovascular diseases. Nevertheless, little is known about cardiovascular alterations related to SDS exposure in those phenotypes or their correlation with depressive-like behaviors. Using a chronic SDS protocol followed by the social interaction test, we identified Wistar rats as resilient or susceptible to SDS. Susceptible animals showed increased depressive-like behaviors with resting tachycardia and decreased heart rate variability (HRV) due to increased sympathetic tone in the heart and a less effective baroreflex. In contrast, resilient rats were protected from these alterations by increased vagal tone, resulting in greater HRV values. To our knowledge, our study is the first to indicate that harmful cardiovascular outcomes are related to depressive-like behaviors in susceptible rats and to suggest a mechanism by which resilient rats are protected from these changes. Also, our results suggest that enhanced HRV and vagal tone may be an important trait in resilient individuals.

Altered activity of the ventral pallidum (VP) underlies disrupted motivation in stress and drug exposure. The VP is a very heterogeneous structure composed of many neuron types with distinct physiological properties and projections. Neuronal PAS 1-positive (Npas1+) VP neurons are thought to send projections to brain regions critical for motivational behavior. While Npas1+neurons have been characterized in the globus pallidus external, there is limited information on these neurons in the VP. To address this limitation, we evaluated the projection targets of the VP Npas1+neurons and performed RNA-sequencing on ribosome-associated mRNA from VP Npas1+neurons to determine their molecular identity. Finally, we used a chemogenetic approach to manipulate VP Npas1+neurons during social defeat stress (SDS) and behavioral tasks related to anxiety and motivation in Npas1-Cre mice. We used a similar approach in females using the chronic witness defeat stress (CWDS). We identified VP Npas1+projections to the nucleus accumbens, ventral tegmental area, medial and lateral habenula, lateral hypothalamus, thalamus, medial and lateral septum, and periaqueductal gray area. VP Npas1+neurons displayed distinct translatome representing distinct biological processes. Chemogenetic activation of hM3D(Gq) receptors in VP Npas1+neurons increased susceptibility to a subthreshold SDS and anxiety-like behavior in the elevated plus maze and open field while the activation of hM4D(Gi) receptors in VP Npas1+neurons enhanced resilience to chronic SDS and CWDS. Thus, the activity of VP Npas1+neurons modulates susceptibility to social stressors and anxiety-like behavior. Our studies provide new information on VP Npas1+neuron circuitry, molecular identity, and their role in stress response.SIGNIFICANCE STATEMENTThe ventral pallidum (VP) is a structure connected to both reward-related and aversive brain centers. It is a key brain area that signals the hedonic value of natural rewards. Disruption in the VP underlies altered motivation in stress and substance use disorder. However, VP is a very heterogeneous area with multiple neuron subtypes. This study characterized the projection pattern and molecular signatures of VP Neuronal PAS 1-positive (Npas1+) neurons. We further used tools to alter receptor signaling in VP Npas1+neurons in stress to demonstrate a role for these neurons in stress behavioral outcomes. Our studies have implications for understanding brain cell type identities and their role in brain disorders, such as depression, a serious disorder that is precipitated by stressful events.