Biology subjects

McKlveen, J. M.

Publications and source records attributed to McKlveen, J. M..

2 recordsLinked to original sources

bioRxiv2020

Infralimbic cortical glutamate output is necessary for the neural and behavioral consequences of chronic stress

Exposure to prolonged stress is a major risk-factor for psychiatric disorders such as generalized anxiety and major depressive disorder (MDD). Human imaging studies have identified structural and functional abnormalities in the prefrontal cortex of MDD patients, particularly Brodmanns area 25 (BA25). Further, deep brain stimulation of BA25 reduces symptoms of treatment-resistant depression. The rat homolog of BA25 is the infralimbic cortex (IL), which is critical for cognitive appraisal, executive function, and physiological stress reactivity. Previous studies indicate that the IL undergoes stress-induced changes in excitatory/inhibitory balance culminating in reduced activity of glutamate output neurons. However, the regulatory role of IL glutamate output in mood-related behaviors after chronic variable stress (CVS) is unknown. Here, we utilized a lentiviral-packaged small-interfering RNA to reduce translation of vesicular glutamate transporter 1 (vGluT1 siRNA), thereby constraining IL glutamate output. This viral-mediated gene transfer was used in conjunction with a quantitative anatomical analysis of cells expressing the stable immediate-early gene product {Delta}FosB, which accumulates in response to repeated neural activation. Through assessment of {Delta}FosB-expressing neurons across the frontal lobe in adult male rats, we mapped regions altered by chronic stress and determined the coordinating role of the IL in frontal cortical plasticity. Specifically, CVS-exposed rats had increased density of {Delta}FosB-expressing cells in the IL and decreased density in the anterior insula. The later effect was dependent on IL glutamate output. Next, we examined the interaction of CVS and reduced IL glutamate output in behavioral assays examining coping, anxiety-like behavior, associative learning, and nociception. IL glutamate knockdown decreased immobility during the forced swim test compared to GFP controls, both in rats exposed to CVS as well as rats without previous stress exposure. Further, vGluT1 siRNA prevented CVS-induced avoidance behaviors, while also reducing risk aversion and passive coping. Ultimately, this study identifies the necessity of IL glutamatergic output for regulating frontal cortical neural activity and behavior following chronic stress. These findings also highlight how disruption of excitatory/inhibitory balance within specific frontal cortical cell populations may impact neurobehavioral adaptation and lead to stress-related disorders.

neuroscience↗

bioRxiv2019

Prefrontal Cortex Regulates Chronic Stress-Induced Cardiovascular Susceptibility

The medial prefrontal cortex (mPFC) is necessary for appropriate appraisal of stressful information, as well as coordinating visceral and behavioral processes. However, prolonged stress impairs mPFC function and prefrontal-dependent behaviors. Additionally, chronic stress induces sympathetic predominance, contributing to health detriments associated with autonomic imbalance. Previous studies identified a subregion of rodent prefrontal cortex, infralimbic cortex (IL), as a key regulator of neuroendocrine-autonomic integration after chronic stress, suggesting that IL output may prevent chronic stress-induced autonomic imbalance. In the current study, we tested the hypothesis that the IL regulates hemodynamic, vascular, and cardiac responses to chronic stress. To address this hypothesis, a viral-packaged siRNA construct was used to knockdown vesicular glutamate transporter 1 (vGluT1) and reduce glutamate packaging and release from IL projection neurons. Male rats were injected with a vGluT1 siRNA-expressing construct or GFP control into the IL and then remained as unstressed controls or were exposed to chronic variable stress (CVS). IL vGluT1 knockdown increased heart rate and mean arterial pressure (MAP) reactivity, while CVS increased chronic MAP only in siRNA-treated rats. In a separate cohort, CVS and vGluT1 knockdown interacted to impair both endothelial-dependent and endothelial-independent vasoreactivity ex vivo. Furthermore, vGluT1 knockdown and CVS increased histological markers of fibrosis and hypertrophy. Thus, knockdown of glutamate release from IL projection neurons indicates that these cells are necessary to prevent the enhanced physiological responses to stress that promote susceptibility to cardiovascular pathophysiology. Ultimately, these findings provide evidence for a neurobiological mechanism mediating the relationship between stress and poor cardiovascular health outcomes.\n\nClinical perspectiveWhat is new? O_LIKnockdown of glutamate release from infralimbic cortex increases heart rate and arterial pressure reactivity\nC_LIO_LIDecreased infralimbic glutamate output leads to vascular dysfunction after chronic stress\nC_LIO_LIThese functional changes associate with histological indicators of cardiac hypertrophy, as well as vascular hypertrophy and fibrosis\nC_LI\n\nWhat are the clinical implications? O_LIThese studies provide a neurobiological mechanism that may account for the link between long-term stress and increased cardiovascular disease risk\nC_LI

neuroscience↗