Stress elicits a pattern of physiological and behavioral changes that are remarkably similar in different mammalian species. A salient feature of this response is recruitment of the hypothalamic-pituitary adrenal (HPA) axis, and alterations in HPA function are seen in a number of human psychopathologic states. Recently, neurons in the dorsomedial hypothalamus (DMH) have been implicated in the generation of a host of stress-induced physiologic and behavioral changes in rats including recruitment of the HPA axis in an experimental paradigm for emotional stress. These potential """"""""command neurons"""""""" for the stress response are under tonic GABAA receptor-mediated inhibition. Intriguingly, chronic dysfunction of GABAergic inhibition in this region in rats results in a condition bearing striking similarities to panic disorder in humans. GABAergic mechanisms in the hypothalamus - and particularly GABAA receptors - appear to be subject to a remarkable degree of plasticity; In fact, experimental evidence suggests that circulating glucocorticoids may influence the subunit composition of GABAA receptors to alter their function. These findings support the hypothesis that perinatal events that alter responsivity of the HPA axis in adult rats do so by altering GABAergic mechanisms in the DMH - perhaps through influencing the subunit composition of local GABAA receptors - and that such a mechanism may play a role in human psychopathology, including susceptibility to panic attack and anxiety disorders. This proposal is to facilitate the interaction of a group of investigators, many of whom have contributed important elements of this story, in pursuit of key preliminary data that would shed light on the regulation of the HPA axis in stress and at the same time provide potential support for this hypothesis. Included among their collective expertise are perspectives and approaches ranging from molecular biology, electrophysiology, neuroendocrinology and neuroimmunology, and behavioral paradigms to clinical experience and study of anxiety, panic disorder, and related psychopathologies in humans. Pilot studies are planned to (a) examine the regulation of HPA function in an animal model for panic disorder based on chronic dysfunction of GABAergic inhibition in the DMH, and (b) assess the effect of neonatal treatment with bacterial lipopolysaccharide (LPS), an intervention that has been shown to cause hyperresponsivity of the HPA axis to experimental stress in these rats as adults, on GABAA receptors in this region.
| Lowry, C A; Burke, K A; Renner, K J et al. (2001) Rapid changes in monoamine levels following administration of corticotropin-releasing factor or corticosterone are localized in the dorsomedial hypothalamus. Horm Behav 39:195-205 |
