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Browsing by Author "Myers, Brent, advisor"

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    Functional organization of a cortical-medullary neural circuit mediating organismal adaptation to stress
    (Colorado State University. Libraries, 2023) Pace, Sebastian A., author; Myers, Brent, advisor; Hentges, Shane, advisor; Tobet, Stuart, committee member; Foster, Michelle, committee member
    Hindbrain regions responsible for epinephrine and norepinephrine production are critical for orchestrating stress responses, maintaining physiological equilibrium and integrating afferent information. The nuclei central to hindbrain epinephrine and norepinephrine production, create a neural network that interfaces with forebrain and spinal cord regions, facilitating the integration of neuroendocrine and autonomic functions. Despite significant strides in our comprehension of stress response systems, questions concerning the roles of sex, stress history, and circuit mechanisms endure. In this study, we unveil and characterize a prefrontal-medullary circuit crucial for the suppression of stress responses. First, anterograde and retrograde tract-tracing studies demonstrated a stress-reactive vmPFC-RVLM circuit. Activation of this vmPFC-RVLM circuit mitigates glucocorticoid stress reactivity in both males and females, by targeting non-catecholaminergic neurons. Therefore, vmPFC-RVLM circuit activation may utilize local inhibitory neurons to limit catecholaminergic activation. To better understand how chronic stress affects the medulla, we explored the impact of chronic stress on signaling machinery and revealed elevated tyrosine hydroxylase (TH) levels in both male and female rats following chronic variable stress (CVS). To understand how CVS interacts with the vmPFC-RVLM circuit, we used an intersectional TeLC (Tetanus toxin - light chain) approach to disrupt the circuit and evaluate multiple stress response systems. In males, circuit disruption and CVS largely left behavioral and cardiovascular stress reactivity unaltered, however, some neuroendocrine endpoints were affected. Conversely, females exposed to circuit disruption and chronic stress exhibited heightened stress reactivity in glycemic, corticosterone, and arterial pressure responses, coupled with avoidant-like behaviors. These findings underscore the sex-specific necessity of the vmPFC-RVLM circuit in countering chronic stress-related outcomes, emphasizing a greater protective role in females relative to males. To gain deeper insights into the role of vmPFC inputs to the RVLM in females, we once again utilized a circuit-based TeLC approach, employing in situ hybridization (ISH) coupled with immunohistochemistry (IHC) to assess TH and phenylethanolamine N-methyltransferase (PNMT) transcript density across various VLM subregions. Notably, the TeLC-induced elevation of PNMT expression in females suggests that disrupting this circuit could potentially enhance epinephrine production by RVLM neurons, potentially intensifying stress reactivity post-CVS. This comprehensive study demonstrated the critical role of the vmPFC-RVLM circuit in modulating stress responses and revealing female-specific effects in mitigating physiological, behavioral, and transcriptional outcomes after chronic stress. These findings emphasize the significance of the vmPFC-RVLM circuit in managing stress reactivity in the context of chronic stress and identify the circuit as a potential candidate for reducing stress responding.
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    Sex differences in cortical-hypothalamic control of stress reactivity and cardiovascular susceptibility
    (Colorado State University. Libraries, 2023) Schaeuble, Derek, author; Myers, Brent, advisor; Chicco, Adam, committee member; Gentile, Chris, committee member; Tobet, Stu, committee member
    Major depressive disorder (MDD) is characterized by prolonged sadness and a loss of interest, and it impacts an estimated 21 million adults in the United States. The onset of MDD is multifactorial and rates of MDD have increased due to the psychosocial and economic factors associated COVID-19 pandemic. This poses a substantial threat to population health as MDD is projected to be the leading cause of disability by 2030. Even throughout the pandemic, cardiovascular disease (CVD) is still the highest mortality rate of any disease worldwide average of 17.9 million deaths per year. More importantly, MDD and CVD have devastating comorbidity that is poorly understood. MDD doubles the risk of developing cardiovascular disease and significantly increases the chance of morbidity following cardiovascular events. Thus, we need to address mental health disabilities and cardiovascular disease susceptibility. Interestingly, both diseases are exacerbated by chronic life stressors, which increase the prevalence of mood disorders and can alter sympathetic nervous activity increasing heart rate and blood pressure. Studying how stress affects the brain may yield important information on how to treat these two diseases. In this series of experiments, I examine how the ventral medial prefrontal cortex (vmPFC) alters stress responding through its downstream connections to provide a mechanism for MDD and cardiovascular disease comorbidity. I will provide a brief background of the structure and function of the vmPFC and describe how neurons from this region can alter stress responding through synapses in the hypothalamus. Chapter 2 is the first of a series of experiments where I show decreased activity of the vmPFC interacts with chronic stress to predispose male rats to cardiovascular disease susceptibility. Because mood disorders are more common in women and cardiovascular disease is more prevalent in post-menopausal women compared to men, chapter 3 examines whether activating vmPFC projection neurons is sufficient to influence behavior, stress responding, and cardiovascular activity in both sexes of rats. This work uncovered that output of vmPFC glutamate neurons has sexually divergent outcomes on neuroendocrine and autonomic cardiovascular responses to stress. Furthermore, it became evident that altered vmPFC activity predisposes males but not females to cardiovascular disease susceptibility. The vmPFC does not directly project to autonomic or neuroendocrine effector regions, so chapter 4 investigates whether the vmPFC is sufficient to control stress autonomic and neuroendocrine responding through downstream intermediary synapses. The intermediate region of interest is the posterior hypothalamus (PH) which can regulate endocrine and cardiovascular activity and receives dense innervation from the vmPFC. In chapter 5, I am exploring the necessity of this vmPFC-PH circuit to regulate cardiovascular activity and stress reactivity following chronic stress exposure. Altogether these data identify novel neurocircuitry linking stress exposure to cardiovascular disease risk.
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    Sex-specific cardiometabolic responses to chronic stress and the impact of prefrontal-medullary regulation
    (Colorado State University. Libraries, 2024) Dearing, Carley, author; Myers, Brent, advisor; Smith, Bret, committee member; Fails, Anna, committee member; Hoke, Kim, committee member
    Globally, cardiovascular and metabolic disease are leading causes of death and years lived with disability. Chronic stress is an etiologic factor in both diseases and biologic sex plays an important role in the progression and prognosis of each. However, the neurobiological basis of how chronic stress exposure intersects with sex, cardiovascular, and metabolic function to impact systemic physiology is poorly understood. Prior studies from our group indicate that, in rats, the prefrontal infralimbic cortex (IL)-rostral ventrolateral medulla (RVLM) circuit inhibits sympathetic and endocrine responses to stress. Therefore, we aimed to address the overarching hypothesis that the IL-RVLM circuit is necessary for homeostatic function and mitigation of deleterious changes to metabolic, cardiac, and microvascular function following chronic stress. To this end, an intersectional genetic approach was used to induce Cre-dependent expression of tetanus toxin light chain and inhibit neurotransmitter release from RVLM-projecting IL neurons in male and female rats. Rats were then exposed to 2 weeks of chronic variable stress (CVS). Metabolic function was assessed with a fasted glucose tolerance test. Cardiovascular function was examined with echocardiography and non-invasive hemodynamics. Additionally, microvascular function was quantified via ex-vivo resistance arteriole pressure myography. Our results indicate that glucose tolerance, left ventricular structure, and vascular function are all impacted in a sex-dependent manner. Following chronic stress, circuit-intact females show glucodysregulation characterized by decreased glucose clearance, elevated corticosterone, and insulin insensitivity. Regardless of stress, circuit inhibition in females also impaired glucoregulation but was characterized by elevated glucagon with no compensatory insulin response. Circuit inhibition also increased relative heart size, increased endothelial-dependent vasodilation at both normotensive and hypertensive pressures, and increased myogenic tone and diastolic wall strain. These changes indicate that chronic stress in females leads to broad endocrine-autonomic dysregulation of glucose homeostasis and microvascular function that is exacerbated by IL-RVLM inhibition. While chronic stress in males resulted in an adaptive metabolic response and no changes in normotensive vasodilation, circuit inhibition in chronically-stressed males lead to glucodysregulation and increased endothelial-dependent vasodilation at hypertensive pressures. Additionally, these animals had reduced ventricular wall thickness in diastole. Broadly, these results support the hypothesis that the IL-RVLM circuit is necessary for appropriate glucose homeostasis and vascular function and that circuit inhibition and chronic stress lead to sex-specific responses that may differentially impact the progression of cardiovascular and metabolic disease.
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    Sexual divergence in prefrontal neural regulation and encoding of depression-associated behaviors
    (Colorado State University. Libraries, 2022) Wallace, Tyler, author; Myers, Brent, advisor; Hentges, Shane T., advisor; Amberg, Gregory, committee member; Conner, Bradley, committee member
    Major depressive disorder (MDD) accounts for the most years lived with disability worldwide. Yet, despite its staggering prevalence, the biological mechanisms underpinning MDD onset are not understood, further complicated by considerable sex-based differences in MDD occurrence. The ventromedial prefrontal cortex (vmPFC) is heavily associated with MDD, though how vmPFC neural populations respond to and regulate behaviors associated with MDD, including affective state, social behaviors, and stress responding is unknown. Thus, I utilized viral methods to dissect how a genetically identified neural population within the vmPFC regulates and encodes MDD-associated behaviors. In chapter 2, I utilized an optogenetic technique to increase the firing rate of a subset of glutamatergic vmPFC neurons in conjunction with behavioral testing. My results demonstrated considerable sexual divergence in vmPFC glutamatergic influence. In males, stimulation conferred positive affect, increased social motivation, and constrained aspects of the acute stress response. While in females, stimulation did not alter behavior and augmented the acute stress response. In chapter 3, I utilized a similar optogenetic technique to dissect how vmPFC projections to the posterior hypothalamus (PH), contribute to behavioral and physiological regulation. Again, my results demonstrated sexual divergence in vmPFC circuit function. In males, stimulation of the vmPFC to PH glutamatergic circuit conferred positive affect, and constrained aspects of the acute stress response, though it did not alter social behavior. The circuit similarly conferred positive affect in females, but again augmented the acute stress response. Overall, my stimulation of vmPFC glutamatergic neurons identified that they regulate affect, social behavior, and stress responding but the specific effects are sex and circuit specific. While chapters 2 and 3 identified how specific vmPFC neural populations can regulate behavioral and physiological processes, how these neural populations respond to behavior and how these responses are disrupted in pathology was unknown. Thus, in chapter 4, I utilized fluorescent calcium indicators to record the activity of genetically-identified vmPFC glutamatergic neurons during behavioral testing. To determine changes to vmPFC neural activity in pathology, animals were exposed to a preclinical model of MDD, chronic variable stress. My results showed that vmPFC glutamatergic neurons are responsive to object, social, stressful, and rewarding stimuli regardless of sex. However chronic stress exposure altered vmPFC glutamatergic activity in males more so than females, with some of these differences accounted for by female ovarian status. Overall, the work presented in this dissertation determined how a vmPFC neural population regulates MDD-disrupted behaviors, detailed how a specific vmPFC circuit contributes to this regulatory role and measured how vmPFC neurons respond to behavior in real-time with and without a history of chronic stress.