Prefrontal Cortex Regulates Chronic Stress‐Induced Cardiovascular Susceptibility

Schaeuble, Derek; Packard, Amy E.B.; McKlveen, Jessica M.; Morano, Rachel; Fourman, Sarah; Smith, Brittany L.; Scheimann, Jessie R.; Packard, Benjamin A.; Wilson, Steven P.; James, J. Howard; Hui, David Y.; Ulrich‐Lai, Yvonne M.; Herman, James P.; Myers, Brent

doi:10.1161/jaha.119.014451

Cited by 37 publications

(30 citation statements)

References 73 publications

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“…The vGluT1 siRNA approach reduces vGluT1 mRNA in the IL, as well as vGluT1 protein on GFP-labeled terminals (Myers et al, 2017;Schaeuble et al, 2019). Here, the co-localization of immunolabeled vGluT1 with the GFP control construct was evident in cortico-cortical axonal processes ( Fig.1F).…”

Section: Injection Placementmentioning

confidence: 79%

“…The microsyringe was left in place for 5 min before and after injections to allow for diffusion of the virus and reduce tissue damage. Post-injection, rats recovered for 6 weeks before further experimental procedures, corresponding to timeframes from prior studies using lentivirus (Myers et al, 2017;Schaeuble et al, 2019;Wood et al, 2019).…”

Section: Stereotaxic Surgerymentioning

confidence: 99%

“…Comparative analyses indicate that the rodent mPFC contains topographically-distinct regions homologous to the human cortex (Ongür & Price, 2000;Uylings et al, 2003). The BA25 homolog in rodents, infralimbic cortex (IL), regulates neuroendocrine and cardiovascular responses to chronic stress (McKlveen et al, 2013;Myers et al, 2017;Schaeuble et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…IL glutamatergic pyramidal neurons project to multiple forebrain, hypothalamic, and brainstem nuclei involved in stressintegration (Vertes, 2004;Wood et al, 2019). Additionally, recent evidence suggests that IL glutamatergic efferents play a critical role in endocrine and autonomic responses to chronic stress (Myers et al, 2017;Schaeuble et al, 2019). However, IL cortical interactions and their regulation by chronic stress are less clear.…”

mentioning

confidence: 99%

“…Further, IL vGluT1 siRNA and CVS interact to increase cardiovascular stress reactivity, impair vascular function, and promote cardiac and arterial hypertrophy (Schaeuble et al, 2019). Thus, reduced IL output uncouples the positive association between the behavioral and physiological responses to chronic stress, leading to the de-integration of stress responses.…”

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confidence: 99%

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

Pace

Christensen

Schackmuth

et al. 2020

Preprint

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AbstractExposure 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 Brodmann’s 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 ΔFosB, which accumulates in response to repeated neural activation. Through assessment of ΔFosB-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 ΔFosB-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.

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Section: Injection Placementmentioning

confidence: 79%

Section: Stereotaxic Surgerymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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

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Christensen

Schackmuth

et al. 2020

Preprint

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Sex‐specific behavioral, neurobiological, and cardiovascular responses to chronic social stress in mice

Helman

Headrick

Vider

et al. 2022

J of Neuroscience Research

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Psychosocial stress promotes and links mood and cardiovascular disorders in a sex‐specific manner. However, findings in animal models are equivocal, in some cases opposing human dimorphisms. We examined central nervous system (CNS), behavioral, endocrine, cardiac, and hepatic outcomes in male or female C57Bl/6 mice subjected to chronic social stress (56 days of social isolation, with intermittent social confrontation encounters twice daily throughout the final 20 days). Females exhibited distinct physiological and behavioral changes, including relative weight loss, and increases in coronary resistance, hepatic inflammation, and thigmotaxic behavior in the open field. Males evidence reductions in coronary resistance and cardiac ischemic tolerance, with increased circulating and hippocampal monoamine levels and emerging anhedonia. Shared CNS gene responses include reduced hippocampal Maoa and increased Htr1b expression, while unique responses include repression of hypothalamic Ntrk1 and upregulation of cortical Nrf2 and Htr1b in females; and repression of hippocampal Drd1 and hypothalamic Gabra1 and Oprm in males. Declining cardiac stress resistance in males was associated with repression of cardiac leptin levels and metabolic, mitochondrial biogenesis, and anti‐inflammatory gene expression. These integrated data reveal distinct biological responses to social stress in males and females, and collectively evidence greater biological disruption or allostatic load in females (consistent with propensities to stress‐related mood and cardiovascular disorders in humans). Distinct stress biology, and molecular to organ responses, emphasize the importance of sex‐specific mechanisms and potential approaches to stress‐dependent disease.

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Central stress pathways in the development of cardiovascular disease

Braun,

Patel,

Kameneva

et al. 2023

Clin Auton Res

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Prefrontal Cortex Regulates Chronic Stress‐Induced Cardiovascular Susceptibility

Cited by 37 publications

References 73 publications

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

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

Sex‐specific behavioral, neurobiological, and cardiovascular responses to chronic social stress in mice

Central stress pathways in the development of cardiovascular disease

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