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Browsing by Author "Myers, Brent, committee member"

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    A retinal contribution to chronic opioid-induced sleep/wake dysfunction
    (Colorado State University. Libraries, 2023) Bergum, Nikolas, author; Vigh, Jozsef, advisor; Myers, Brent, committee member; Hentges, Shane, committee member; Chanda, Soham, committee member
    Light is among the most important environmental factors that regulate mammalian sleep/circadian behaviors. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) transmit environmental light information to key sleep/circadian centers in the brain through a process known as photoentrainment. Interestingly, past studies have revealed that ipRGCs express µ-opioid receptors (MORs), the primary molecular target for opioid analgesics. Furthermore, MOR agonists can directly inhibit ipRGC firing. Therefore, we hypothesize that opioid drugs acting on MORs expressed by ipRGCs could disrupt ipRGC-mediated regulation sleep/wake rhythms in response to environmental light/dark cycles. To test this idea, we need to confirm that morphine reaches the mouse retina following systemic delivery. To accomplish this, tissue (retina, brain and serum) was collected from mice following intraperitoneal morphine administration. Importantly, results from this study show that systemically administered morphine selectively accumulates in the mouse retina, but not the serum or the brain. To test the role that MORs expressed by ipRGCs play in opioid-induced dysregulation of sleep/circadian behaviors, we used mini-telemetry devices to assess how chronic morphine alters their sleep/wake behavior in mice. Importantly, we performed these experiments in wildtype mice along with mice lacking MORs exclusively in ipRGCs (McKO). Results from these studies reveal that McKO animals exhibit decreased morphine-induced locomotion compared to controls, which implicates MORs expressed by ipRGCs as a mediator of opioid-induced sleep-wake alterations. Finally, we tested whether ipRGCs developed cellular tolerance to MOR agonists following chronic exposure to morphine. The lack of cellular tolerance development at the level of solitary ipRGCs provides a potential cellular correlate for the persistent sleep/wake dysfunction commonly attributed to chronic opioid exposure. Taken together, these findings support the idea that opioid accumulation in the eye persistently activate MORs on ipRGCs, continuously altering the ability of ipRGCs to transmit light information to the brain's sleep/wake circuitry. This alteration in photic input to the brain could underlie some of the sleep/wake problems associated with long-term opioid use.
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    Anatomic plasticity and functional impacts of neural – immune and neural – epithelial signaling in the intestine
    (Colorado State University. Libraries, 2021) Schwerdtfeger, Luke A., author; Tobet, Stuart A., advisor; Chicco, Adam, committee member; Myers, Brent, committee member; Ryan, Elizabeth, committee member
    The intestinal wall is a multicompartmental barrier tissue composed of over 25 distinct cell types with integrated and complex signaling both within and between compartments. The gut wall is also a large endocrine organ comprised of cells capable of producing dozens of peptides used for hormonal and other signaling functions. However, the mechanistic roles that neural secretions play in regulating the gut epithelial barrier in health and disease are not well known. Additionally, frequently used models available for studying intestinal function outside of the body lack the complexity to investigate neural – epithelial and neural – immune signaling interactions. Using a bifurcated approach to method development, we created two culture systems for maintaining the full thickness of the intestinal wall ex vivo. One method allows for culture of mouse or human organotypic intestinal slices that maintain the gut wall for 6 or 4 days, respectively. This system does not however, maintain a true luminal – epithelial barrier as seen in the in vivo gut. The second method, a microfluidic organotypic device (MOD) enables maintenance of explanted mouse or pig intestinal tissue for up to 3 days ex vivo, with an intestinal barrier intact. These two methods allow for investigating and cross-validating of numerous biological questions now previously possible using traditional culture models. Neuronal fiber proximity to gut epithelia has been shown, with goblet, tuft and enteroendocrine cells being closely opposed by fibers. Goblet cells secrete mucopolysaccharides, a first line of defense separating luminal microbiota from host tissue. I have recently shown that vasoactive intestinal peptide (VIP) can regulate goblet cell production in organotypic slices of mouse ileum. This peptide is also in close proximity to Paneth cells in the base of the crypt, and enteric mast cells. There were sex differences in baseline mast cell neuronal proximity, quantities, and cell size in mouse ileum. Further, mast cells showed a sex difference in responses to lipopolysaccharide challenge. Further investigation of neurosecretory factor regulation of immune and epithelial function is needed, both in goblet cells and other secretory epithelia like anti-microbial producing Paneth cells, and in immune components like mast cells. Graphical illustration of the dissertation project is included below.
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    Biomarkers of allostatic load mediate stress and disease: a prospective structural equation model
    (Colorado State University. Libraries, 2019) Outland, Pearl L., author; Harman, Jennifer, advisor; Prince, Mark, committee member; Myers, Brent, committee member; Forssell, Stephen, committee member
    Minority stress theory is often cited as the explanation behind physical health disparities for sexual minority individuals, but the exact mechanism linking a stigmatizing social environment to outcomes of disease is not well understood. This study sought to bridge minority stress theory with the theory of allostatic load in physiology. A sequential mediation model was hypothesized, in which sexual orientation would predict higher rates of cancer, cardiovascular disease, and more chronic conditions, mediated via two intervening variables: everyday discrimination and allostatic load. Using data from the MIDUS, N = 495 participants (n = 45 sexual minority) were followed prospectively from 1995 -2015. No differences by sexual orientation were found for cancer or cardiovascular disease. Being a sexual minority, experiencing more everyday discrimination, and having a higher allostatic load score were all significantly associated with having a greater number of chronic conditions. Mediation and the indirect effect were not fully supported. This study was an important first step in beginning to identify the causal pathways that link sexual minority stress to disease. Further research that uses more comprehensive measures of multi-dimensional minority stress, and/ or that consider alternative operationalizations of physiological functioning are needed to better elucidate the exact process.
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    Peripheral blood flow regulation in persons with multiple sclerosis
    (Colorado State University. Libraries, 2021) Ketelhut, Nathaniel B., author; Fling, Brett W., advisor; Hickey, Matthew S., committee member; Chicco, Adam J., committee member; Myers, Brent, committee member
    Multiple sclerosis (MS) is an inflammatory, degenerative disease of the central nervous system that is believed to be autoimmune in nature. The disease affects approximately one million people in the United States and results in a wide variety of symptoms including impaired physical function, reduced exercise capacity, and increased fatigability. Although considerable effort has been invested in improving our understanding of the neuromuscular contributions to these symptoms, no studies have investigated whether cardiovascular autonomic dysfunction compromises skeletal muscle blood flow in persons with MS (PwMS). Indeed, approximately 50% of PwMS have an abnormal response to tests of cardiovascular autonomic function, and skeletal muscle blood flow is positively associated with exercise capacity. Thus, the overall goal of this dissertation was to determine whether PwMS have impaired skeletal muscle blood flow responses to exercise relative to age- and sex-matched healthy controls. The primary findings are that 1) the local control of skeletal muscle blood flow during exercise is intact in PwMS, 2) skeletal muscle blood flow is likely reduced during exercise that engages the autonomic nervous system in MS, which may be due to increased α-adrenergic mediated vascular tone, and 3) that PwMS may experience hypersensitivity to α-adrenergic signaling as evidenced by levels of systemic vascular resistance relative to plasma concentrations of norepinephrine. Together, these studies indicate that compromised skeletal muscle blood flow during exercise may contribute to reduced exercise capacity and increased fatigability in PwMS.
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    Proopiomelanocortin neuron manipulation in mouse models of energy balance disorders
    (Colorado State University. Libraries, 2021) Daimon, Caitlin Mieko, author; Hentges, Shane, advisor; Clay, Colin, committee member; Myers, Brent, committee member; Vandewoude, Susan, committee member
    Proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus are critical regulators of energy balance. Highly conserved amongst mammalian species, POMC neurons release peptide transmitters to help an organism maintain appropriate levels of food intake and bodyweight by inhibiting feeding and facilitating metabolism of consumed nutrients. Disruptions in POMC signaling are thought to underlie aspects of energy balance disorders. There are two kinds of energy balance disorders: those of positive energy balance, which includes diseases like obesity, and those of negative energy balance, which includes eating disorders like anorexia nervosa (AN). Given that POMC neurons are believed to be dysregulated in energy balance disorders, treatment strategies for these disorders have focused on POMC neurons or their targets. The goal of the studies discussed herein was to determine whether manipulation of POMC neurons could improve pathophysiological alterations in bodyweight and food intake in mouse models of energy balance disorders. Mouse models of AN and obesity were used in the current studies. AN was mimicked in the mouse via the well-validated activity-based anorexia (ABA) behavioral paradigm. The results shown in chapters 2 and 3 indicate that POMC neurons are selectively involved in generating food anticipatory activity (FAA) in mice undergoing ABA as disruption of either the POMC peptide product β-endorphin or inhibition of the entire POMC neuron resulted in decreased FAA. As FAA is the primary output of the food entrainable oscillator (FEO), the circadian clock that allows an organism to anticipate the daily arrival of meals, these results suggest that POMC neurons via the peptide product β-endorphin are possibly involved in the expression of the FEO. As the identity of the FEO has yet to be determined, future studies should further characterize the contribution of β-endorphin and POMC neurons to the FEO. To determine whether manipulation of POMC neurons is beneficial in a mouse model of obesity, mice fed an obesogenic diet were subjected to chronic POMC neuron stimulation for one month. The unexpected finding that sustained stimulation leads to weight gain as opposed to weight loss indicates that chronic stimulation of POMC neurons may not be a viable option for weight loss, at least under the dosing scheme used in the current study. How POMC neurons adapt to chronic stimulation remains unknown and should be the focus of future work.
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    Stress during pregnancy leads to long-term consequences in the offspring
    (Colorado State University. Libraries, 2024) Sheng, Julietta Angelina, author; Tobet, Stuart, advisor; Smith, Bret, advisor; Myers, Brent, committee member; Hale, Taben, committee member; Chanda, Soham, committee member
    Neuropsychiatric disorders encompass a wide range of conditions that affect neurological health and brain function and lead to disabilities worldwide. Such disorders include, but are not limited to, Major Depressive Disorder, schizophrenia, and anxiety disorders. Risk factors for developing neuropsychiatric disorders are multifaceted and can range from genetic predisposition, lifestyle, and environmental influences. Exposure to maternal stress is one type of environmental factor that can lead to changes in brain function and signaling pathways and increase susceptibility for related diseases. Maternal stress encompasses a diverse array of environmental stimuli, ranging from acute traumatic events to chronic or day-to-day life stressors. Maternal stressors, experienced by pregnant women, lead to overexposure of stress hormones in the developing fetus and impact short- and long-term neurological health the offspring. These studies evaluated developmental, neuroendocrine, and behavioral outcomes in offspring exposed to different models of maternal stress. Chapter 1 provided a brief history of stress, the development of the hypothalamic-pituitary-adrenal axis that regulates the stress response, and maternal-fetal interactions in stress regulatory systems and related behaviors. Chapter 2 evaluated several models of maternal stress, maternal high fat diet, maternal caloric restriction, maternal exposure to synthetic glucocorticoids. Although there were vast discrepancies between each type of maternal stress, one similarity was an activated immune response with elevated maternal cytokines. Therefore, Chapter 3 characterized a model of maternal immune activation using a toll-like receptor agonist, Resiquimod, that increased maternal and fetal cytokines, produced delayed developmental milestones and stress-related behavioral impairments in prepubertal (social-like) and adult (social-like, depressive-like, anxiety-like) offspring. Because these behavioral phenotypes are partially regulated by the paraventricular nucleus of the hypothalamus (PVN), Chapter 4 examined the neuroendocrine stress response and blood-brain barrier of the PVN. Data showed altered stress response accompanied by impaired blood-brain barrier integrity in the PVN of the adult offspring exposed to maternal injection of Resiquimod. Taken together, Chapters 2, 3, and 4 suggest maternal stress led to negative developmental, behavioral, and cellular pathologies indicative of neuropsychiatric-like disease. By teasing apart these specific programming mechanisms, we can better diagnose and treat progression of neuro-related disorders.
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    The autism-associated loss of δ-catenin function disrupts social behavior
    (Colorado State University. Libraries, 2023) Mendez-Vazquez, Hadassah, author; Kim, Seonil, advisor; Tamkun, Michael, committee member; Myers, Brent, committee member; Chanda, Soham, committee member
    Social impairment is a key symptom of several neuropsychiatric disorders, including autism spectrum disorder (ASD), anxiety, depression, and schizophrenia. Despite the increasing prevalence of these disorders the physiological, cellular, and molecular factors underlying social dysfunction are still poorly understood. In humans, mutations in the δ-catenin gene have been linked to severe forms of ASD. δ-catenin is a post-synaptic scaffolding protein that is expressed in excitatory synapses and functions as an anchor for N-cadherin and the AMPA receptor (AMPAR) subunit GluA2 at the postsynaptic density. A glycine 34 to serine (G34S) mutation in the δ-catenin gene was identified in ASD patients and induces a loss of δ-catenin function, which may mediate ASD pathogenesis. The mechanism by which this G34S mutation causes loss of δ-catenin function to induce ASD remains unclear. Initial findings revealed that the G34S mutation increases glycogen synthase kinase 3β (GSK3β)-dependent δ-catenin degradation to reduce δ-catenin levels. Moreover, we found that mice possessing the G34S δ-catenin mutation have significantly reduced synaptic cortical δ-catenin and GluA2 levels. The G34S mutation was also found to differentially alter glutamatergic activity in cortical excitatory and inhibitory cells. Furthermore, G34S δ-catenin mutant mice exhibit markedly impaired social behavior, which is a characteristic feature of ASD. Most significantly, we found that inhibition of GSK3β is sufficient to reverse the G34S-induced loss of δ-catenin function in cells and mice. Altogether, our study reveals that the loss of δ-catenin function arising from the ASD-associated G34S mutation induces social dysfunction via disruptions in glutamatergic activity, and that GSK3β inhibition can reverse abnormal δ-catenin G34S-induced glutamatergic activity and social deficits.