Activation of infralimbic cortical glutamate neurons increases motivation and sociability, reduces stress reactivity, and prevents the cardiac consequences of chronic stress
Authors: Myers Brent , Wallace Tyler , Schaeuble Derek , Pace Sebastian , Hentges Shane T , Chicco Adam J 
Published: June 2021

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.