Abstract
Major depressive disorder accounts for the most years lived with disability worldwide and cardiovascular diseases are the leading cause of death globally. These conditions are co-morbid and exhibit sexual divergence in prevalence and severity. Furthermore, stress exposure is an environmental risk factor for the onset of both mood and cardiovascular symptoms. However, the neural processes that integrate stress effects on affective and cardiovascular outcomes are unknown. Human imaging studies indicate that both sad stimuli and autonomic processes activate the ventral medial prefrontal cortex (vmPFC). In rodents, the infralimbic (IL) portion of vmPFC modulates physiological stress responses, leading us to hypothesize that IL pyramidal neurons integrate depression-relevant behaviors with cardiovascular and endocrine stress reactivity. In the current study, an optogenetic approach targeted channelrhodopsin-2 expression to IL glutamatergic neurons in male and female rats. Animals were then assessed for stimulation preference and social motivation. Additionally, radiotelemetry and echocardiography were used to examine cardiovascular stress responses and chronic stress effects on cardiac structure and function. Our results indicate that IL glutamate neurons increased place preference and social motivation in males without affecting socio-motivational behaviors in females. IL activation also reduced endocrine and cardiovascular stress responses in males, while increasing reactivity in females. Moreover, prior IL stimulation protected males from subsequent chronic stress-induced sympatho-vagal imbalance and cardiac hypertrophy. In contrast, females were resistant to stress-induced hypertrophy, yet IL stimulation increased cardiac contractility after chronic stress. Collectively, the data suggest that cortical regulation of behavior, physiological stress responses, and cardiovascular outcomes fundamentally differ between sexes.
Significance Depression and cardiovascular disease reduce health-related quality of life and increase mortality risk. These conditions commonly co-occur with sex-based differences in incidence and severity. While the biological mechanisms linking the disorders are poorly understood, the ventral medial prefrontal cortex regulates behavioral and physiological responses to stress. Therefore, activity in this region may integrate depression-related behaviors with the cardiovascular burden of chronic stress. In a rodent model, we utilized optogenetics during behavior and in vivo physiological monitoring to examine how the ventral medial prefrontal cortex regulates affect, social motivation, neuroendocrine-autonomic stress reactivity, and the cardiac consequences of chronic stress. Our findings identify a sex-specific neurobiological mechanism regulating mood and stress responding, suggesting males and females differentially integrate affective and physiological processes.
Competing Interest Statement
The authors have declared no competing interest.
