Cardiovascular disease is the leading cause of death worldwide. Prolonged psychosocial stress is a significant predictor of disease incidence and severity. However, the specific neural mechanisms that contribute to the cardiovascular consequences of stress are largely unknown. Therefore, the current proposal will explore how the cortical circuits responsible for cognitive appraisal of stress inhibit physiological stress responses. Recent studies in rats identified a population of cells in the infralimbic (IL) region of the medial prefrontal cortex that reduce endocrine and autonomic responses to chronic stress. Further, knockdown of glutamate release from IL neurons leads to vascular dysfunction after chronic stress. While the activity of excitatory IL projection neurons is critical for preventing the deleterious effects of chronic stress, the pathways used by these cells to limit reactivity of autonomic and endocrine effectors remain to be determined. Preliminary data indicate that the IL projects to catecholaminergic (epinephrine/norepinephrine producing) neurons in the ventrolateral medulla (VLM), the primary site of sympathetic activation. These excitatory IL projections also target inhibitory GABAergic and glycinergic neurons within the VLM, leading to the hypothesis that IL glutamatergic signaling to the VLM limits cardiovascular and endocrine stress reactivity and the consequences of chronic stress on vascular stiffness and cardiac hypertrophy. This hypothesis will be tested by optogenetic activation of IL synapses in the VLM during stress exposure in male and female rats. This approach will be employed in animals that have been previously exposed to chronic variable stress or remained as unstressed controls. Cardiovascular telemetry will be used to measure heart rate, blood pressure, and sympathetic activity. A separate aim will examine neuroendocrine stress responses of the hypothalamic- pituitary-adrenal axis. To determine how IL inputs to the VLM impact pathological responses to chronic stress, a combinatorial viral approach will be used to retrogradely silence the IL-VLM circuit with Cre-dependent tetanus toxin. Vascular stiffness, cardiac hypertrophy, and endothelial function will be assessed in male and female rats exposed to chronic stress. This circuit silencing approach will also be used to examine the importance of IL signaling for preventing chronic stress effects on the expression of cellular signaling genes in the VLM. Collectively, these experiments will determine specific circuit and cellular pathways linking cognitive appraisal and physiological stress responses. Further, this connection represents a critical biological process that could be harnessed to intervene in the cardiovascular consequences of chronic stress.

Public Health Relevance

Heart disease is the leading cause of death in the United States, and is frequently initiated or exacerbated by stress. In fact, both chronic stress exposure and heightened physiological reactivity to acute psychological stress are associated with increased cardiovascular mortality. Our preliminary data indicate that the rodent infralimbic prefrontal cortex reduces physiological stress responses and the goal of this proposal is to determine whether infralimbic projections to the brainstem prevent stress-induced cardiovascular pathology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL150559-02
Application #
10071208
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
OH, Youngsuk
Project Start
2019-12-16
Project End
2024-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Other Basic Sciences
Type
Graduate Schools
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523