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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.

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.

Stress, a real or perceived threat to homeostasis or well‐being, has a considerable role in the pathogenesis of mood and anxiety disorders. Moreover, prolonged stress and mood disorders are significant risk factors for numerous cardiometabolic conditions that further burden health‐related quality of life. The neurobiological mechanisms of stress‐related health detriments remain elusive; however, we have identified a specific population of glutamate neurons in the infralimbic cortex (IL) that regulate multiple aspects of stress responding. To test the hypothesis that IL glutamate neurons integrate affective processes with the cardiovascular consequences of chronic stress, we used optogenetics to stimulate these cells while investigating mood‐related behaviors and physiological stress reactivity. Additionally, we investigated whether increased IL neuronal activity mitigates chronic stress‐induced cardiac changes. These hypotheses were addressed in two experiments in which male rats received intra‐IL injections of adeno‐associated virus containing a construct coding for the light‐sensitive cation channel, channelrhodopsin‐2, or a control construct expressing yellow fluorescent protein. Both constructs were expressed under the calcium/calmodulin‐dependent protein kinase IIa promoter, permitting the activation of IL glutamate neurons via targeted blue light stimulation. Parameters of optical stimulation (power, frequency, and pulsatility) were optimized with whole‐cell recordings from prefrontal slices. In the first experiment, animals were tested in the real‐time place preference assay and three‐chambered social motivation paradigm, followed by restraint stress to measure stress‐evoked plasma glucose and corticosteroid levels. For the second experiment, after rats were instrumented for optogenetics, electrocardiography‐enabled radiotelemeters were implanted to examine cardiovascular stress reactivity and cardiac autonomic balance during novel environment exposure. Additionally, these animals underwent echocardiographic assessment of cardiac function during IL optic stimulation, both before and after chronic variable stress. Our results indicated that activation of IL glutamate neurons induced place preference and increased social motivation; further, these behavioral effects were coupled with reduced endocrine stress reactivity. IL activation also decreased novel environment stress‐induced effects on heart rate and sympathovagal balance. Moreover, chronic variable stress increased left ventricular fractional shortening, consistent with a chronic elevation of sympathetic tone driving cardiac contractility and load; however, this effect was prevented by IL optical stimulation. Collectively, these studies highlight IL cortical neurons as a critical component of the neural network(s) integrating behavioral and affective processes with physiological responses to stress. These findings also provide a neurobiological mechanism for the relationship between stress, affective disorders, and cardiovascular health outcomes.Support or Funding InformationNIH grant R00 HL122454 to B. MyersThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.