The overall aim of this project is to understand the mechanisms underlying Hypoglycemia-Associated Autonomic Failure (HAAF), a life-threatening clinical syndrome of reduced behavioral, autonomic and neuroendocrine responsiveness to hypoglycemia resulting from prior hypoglycemic bouts. Compelling evidence indicates that glucocorticoids are involved in the pathogenesis of HAAF, because they are dramatically elevated by glucoprivation and because administration of exogenous glucocorticoids can reproduce the symptoms of HAAF. This proposal will focus on hindbrain mechanisms involved in HAAF. Hindbrain glucoreceptors control two important glucoregulatory responses, increased food intake and adrenal medullary secretion. The first specific aim is to determine whether hindbrain glucoreceptors also mediate the glucoprivic control of glucocorticoid secretion. The second specific aim focuses on hindbrain NE/E neurons. These neurons are crucial for feeding, adrenal medullary and corticosterone responses to glucoprivation and impairment in their function results in symptoms similar to HAAF. This proposal will investigate the multiple pathways through which their control of corticosterone secretion may be mediated. The third specific aim will investigate the importance of NE/E neurons as a site for corticosterone feedback effects that could result in suppression of their activity during HAAF. Many of these neurons possess glucocorticoid receptors. The proposed work will attempt to relate the presence of glucocorticoid receptors on specific populations of NE/E neurons with their functions and involvement in HAAF. The last specific aim is to identify the parameters of glucocorticoid elevation that result in HAAF with particular focus on the magnitude and duration of the secretory event. Corticosterone infusions and specific stressors with differing effects on corticosterone secretion will be examined for their ability to induce HAAF.
|Li, Ai-Jun; Wang, Qing; Dinh, Thu T et al. (2009) Simultaneous silencing of Npy and Dbh expression in hindbrain A1/C1 catecholamine cells suppresses glucoprivic feeding. J Neurosci 29:280-7|
|Taylor, Kelli; Lester, Erin; Hudson, Bryan et al. (2007) Hypothalamic and hindbrain NPY, AGRP and NE increase consummatory feeding responses. Physiol Behav 90:744-50|
|Dinh, Thu T; Flynn, Francis W; Ritter, Sue (2006) Hypotensive hypovolemia and hypoglycemia activate different hindbrain catecholamine neurons with projections to the hypothalamus. Am J Physiol Regul Integr Comp Physiol 291:R870-9|
|Ritter, Sue; Dinh, Thu T; Li, Ai-Jun (2006) Hindbrain catecholamine neurons control multiple glucoregulatory responses. Physiol Behav 89:490-500|
|Li, Ai-Jun; Wang, Qing; Ritter, Sue (2006) Differential responsiveness of dopamine-beta-hydroxylase gene expression to glucoprivation in different catecholamine cell groups. Endocrinology 147:3428-34|
|Bugarith, Kishor; Dinh, Thu T; Li, Ai-Jun et al. (2005) Basomedial hypothalamic injections of neuropeptide Y conjugated to saporin selectively disrupt hypothalamic controls of food intake. Endocrinology 146:1179-91|
|I'Anson, Helen; Sundling, Lois A; Roland, Shannon M et al. (2003) Immunotoxic destruction of distinct catecholaminergic neuron populations disrupts the reproductive response to glucoprivation in female rats. Endocrinology 144:4325-31|