Browsing by Subject "hypothalamus"
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Item METABOLIC DYSFUNCTION IN CHRONIC INTERMITTENT HYPOXIA- ROLE OF HYPOTHALAMIC PEPTIDES(2013-04-12) Nedungadi, T.PrashantPurpose: Obstructive sleep apnea (OSA) is associated with an increase in cardiovascular risk factors that includes metabolic syndrome including hypertension. Our model of Chronic Intermittent Hypoxia (CIH) mimics the hypoxemia and the persistently elevated arterial pressure seen in OSA patients. Here we examine, if metabolic dysregulation associated with CIH is initiated through neuropeptides in central metabolic sites, arcuate nucleus (ARH) and paraventricular nucleus (PVN) of the hypothalamus. Methods: Body weight, daily food intake were measured. Biochemical assays were used for measuring hormonal levels. Metabolic studies to identify glucose tolerance, insulin tolerance and pre-disposal to diabetes were performed. Laser Capture Microdissection followed by real time RT-PCR were carried out for measurement of neuropeptide and receptor mRNA levels in the ARH and PVN along with immunohistochemical studies. Results: Body weight change was higher in the controls (CON) compared to CIH (CON: 25 ± 2.5; CIH: 16 ± 2.7). Food intake was significantly lower for CIH rats compared to controls (p < 0.03) Corticosterone (CORT) was elevated 6 fold during CIH. CIH caused reduction in fasting blood glucose levels, and improved glucose tolerance. Laser capture microdissection of ARH and PVN followed by RT-PCR showed significant increase in ΔFosB mRNA in both PVN and ARH (PVN CON: 1± 0.1 vs PVN CIH: 1.96 ± 0.14; ARH CON: 1 ± 0.18 vs ARH CIH: 2.5 ± 0.5). Neuropeptide Y mRNA levels was significantly decreased after CIH in ARH. However leptin levels were significantly higher in the PVN of CIH rats. Preliminary immunohistochemical observations suggest elevated FosB in both these regions. Conclusions: This is the first study to examine if metabolic dysfunction associated with CIH, characteristic feature of sleep apnea, is initiated through key metabolic sites in the brain. Metabolic dysregulation associated with CIH might be initiated centrally through peptides in the ARH-PVN hypothalamic circuitry.Item The Role of the MnPO in Body Fluid Balance and Blood Pressure Regulation(2019-05) Marciante, Alexandria B.; Cunningham, J. Thomas; Mifflin, Steve W.; Schreihofer, Ann M.; Goulopoulou, Styliani; Ma, Rong; Bugnariu, Nicoleta L.The median preoptic nucleus (MnPO) is situated on the anteroventral wall of the third ventricle (AV3V) between two circumventricular organs (CVOs) that lack a functional blood-brain barrier, the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT). The SFO and OVLT project to the MnPO and together these regions regulate neuroendocrine and autonomic function, arousal, and fluid balance. Early studies demonstrated that the MnPO and other regions in the AV3V contribute to regulating thirst associated with body fluid homeostasis, as well as several forms of neurogenic hypertension. The MnPO is key in relaying signals from the SFO and OVLT to downstream regions that control fluid intake and autonomic function; however, pathway-specific and stimulus-dependent mechanisms are not fully understood. These studies investigate how the MnPO differentially responds to models of physiological challenges that induce thirst, as well as pathway-specific mechanisms of blood pressure in a known model of hypertension. To study the role of the MnPO in thirst, rats were tested with models of cellular (hyperosmolality) and extracellular (angiotensin II, ANG II) dehydration associated with hypovolemia. Previous studies have shown that different populations of MnPO neurons are osmo- or ANG II-sensitive; however, both stimuli lead to a converging behavioral outcome: water consumption. This led to the hypothesis that osmotic challenges and ANG II activate MnPO neurons that project to different regions in a stimulus-dependent manner. Results show that the MnPO signals to specific thirst-driving regions of the brain and the activation of these regions is dependent on the stimulus. To study the role of the MnPO in regulating blood pressure, an experimental model of chronic intermittent hypoxia (CIH) associated with obstructive sleep apnea (OSA) is used to successfully mimic the oxygen deprivation associated with apneic breathing patterns patients with mild to moderate forms of OSA experience. Both patients with OSA and rodents in the CIH model develop diurnal hypertension, which is a sustained increase in blood pressure that persists into the waking hours. Hypertension involves multiple organ systems, including the central nervous system, and can be a heterogenous disease state that manifests from a number of factors, including CIH, ANG II from renin-angiotensin system (RAS), and changes in body fluid osmolality. This led to the hypothesis that pathway-specific inhibition of MnPO neurons that project to pre-autonomic neurons in the paraventricular nucleus (PVN) of the hypothalamus would block persistent hypertension. Results indicate that lesioning PVN-projecting MnPO neurons can block CIH-induced hypertension, resulting in decreases in oxidative stress and improved cardiovascular health. These findings provide new information about how the MnPO differentially regulates behavioral and physiological outcomes in a stimulus-dependent manner. These outcomes also have broad clinical implications relating to the role of the central nervous system in disease states affecting body fluid balance and blood pressure regulation.