Sexually divergent cortical control of affective‐autonomic integration

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. To test this hypothesis, 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. The effects of IL stimulation were also determined for corticosterone and glucose reactivity to stress. Additionally, radiotelemetry and echocardiography were used to examine cardiovascular stress responses and chronic stress effects on cardiac structure and function. Our results show that, in males, IL pyramidal neuron activity was preferred, increased social motivation, and inhibited acute physiological stress reactivity by reducing corticosterone, glucose, heart rate, and arterial pressure. Intriguingly, prior IL activation lowered net cardiac sympathetic drive and protected against subsequent myocardial remodeling after chronic stress. However, IL activity had fundamentally different regulatory effects in females. Stimulation did not have motivational valence or alter social behavior but increased glucose and heart rate reactivity to acute stress and cardiac contractility following chronic stress. Collectively, these findings identify sexual divergence in the cortical integration of affective and physiological systems, suggesting that vmPFC output signaling may differentially impact health outcomes in males and females.