Stress in mammals triggers physiological changes that are thought to contribute to a wide variety of human disorders and disease states. Although the hypothalamus has long been considered the neural effector """"""""command center"""""""" for these responses, the specific central mechanisms and pathways involved are largely unknown. Recently, the concept of """"""""stressor-specific"""""""" neural circuits has emerged as an organizing principal for classifying various stressors into two broad categories. Thus, distinct afferent pathways may be responsible for mobilizing the same hypothalamic effector systems in response to interoceptive (also termed physiologic or systemic) stressors and exteroceptive (emotional or psychologic) stressors. Our past studies indicate that neurons responsible for generating the integrated pattern of autonomic, neuroendocrine, and behavioral changes associated with emotional stress are found in the region of the dorsomedial hypothalamus (DMH) and not in the nearby paraventricular nucleus (PVN) as was once thought. However, to date nothing is known about the pathways that may trigger or facilitate the activation of the DMH under stressful conditions. The proposed experiments will exploit key findings from the literature and our recent preliminary data that together provide a cogent rationale for the hypothesis that: (1) neurons in a specific region of the median preoptic area (mPOA) comprise an important afferent pathway capable of recruiting the neurons in the DMH responsible for increases in heart rate, body temperature, and plasma ACTH seen in air stress, an exteroceptive stress paradigm, (2) a different pathway to the PVN - one not involving the DMH - is responsible for the increases in plasma ACTH seen in hemorrhage, a classic interoceptive stressor, and (3) activation of local ionotropic glutamate receptors as well as receptors for angiotensin II (AII) is likely to play a role in one or both mechanisms.
Our specific aims are to (1) characterize the effect of microinjection of AII and of glutamate receptor analogs into the DMH and the PVN on heart rate, blood pressure, plasma ACTH, core body temperature, and brown adipose tissue temperature, (2) assess the role of neurons in the DMH and the PVN and of local glutamate and AII AT-1 receptors in mediating the physiological response to chemical stimulation of the mPOA with PGE2, and (3) determine the effect of neuronal inhibition and of AII or glutamate receptor blockade in the DMH and the PVN on the physiological responses evoked by air stress and by hemorrhage. The experiments proposed will enhance our understanding of hypothalamic circuitry and function, particularly as it relates to the physiological responses to interoceptive and exteroceptive stress, and may provide compelling evidence for novel pathways and mechanisms playing key roles in mediating these responses. The results may also suggest new applications and therapeutic mechanisms for the growing family of drugs influencing AII and its receptors.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZRG1-IFCN-2 (01))
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Vicentic, Aleksandra
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Zaretsky, Dmitry V; Zaretskaia, Maria V; DiMicco, Joseph A (2016) Characterization of the relationship between spontaneous locomotor activity and cardiovascular parameters in conscious freely moving rats. Physiol Behav 154:60-7
Zaretsky, Dmitry V; Zaretskaia, Maria V; DiMicco, Joseph A et al. (2015) Yohimbine is a 5-HT1A agonist in rats in doses exceeding 1 mg/kg. Neurosci Lett 606:215-9
Zaretsky, Dmitry V; Zaretskaia, Maria V; Rusyniak, Daniel E et al. (2011) Stress-free microinjections in conscious rats. J Neurosci Methods 199:199-207
Hunt, Joseph L; Zaretsky, Dmitry V; Sarkar, Sumit et al. (2010) Dorsomedial hypothalamus mediates autonomic, neuroendocrine, and locomotor responses evoked from the medial preoptic area. Am J Physiol Regul Integr Comp Physiol 298:R130-40
Zaretsky, Dmitry V; Molosh, Andrei I; Zaretskaia, Maria V et al. (2010) Increase in plasma ACTH induced by urethane is not a consequence of hyperosmolality. Neurosci Lett 479:10-2
Dimicco, Joseph A; Zaretsky, Dmitry V (2007) The dorsomedial hypothalamus: a new player in thermoregulation. Am J Physiol Regul Integr Comp Physiol 292:R47-63
de Menezes, Rodrigo C A; Zaretsky, Dmitry V; Fontes, Marco A P et al. (2006) Microinjection of muscimol into caudal periaqueductal gray lowers body temperature and attenuates increases in temperature and activity evoked from the dorsomedial hypothalamus. Brain Res 1092:129-37
Shekhar, Anantha; Johnson, Philip L; Sajdyk, Tammy J et al. (2006) Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus. J Neurosci 26:9205-15
DiMicco, Joseph A; Sarkar, Sumit; Zaretskaia, Maria V et al. (2006) Stress-induced cardiac stimulation and fever: common hypothalamic origins and brainstem mechanisms. Auton Neurosci 126-127:106-19
Samuels, B C; Zaretsky, D V; DiMicco, J A (2004) Dorsomedial hypothalamic sites where disinhibition evokes tachycardia correlate with location of raphe-projecting neurons. Am J Physiol Regul Integr Comp Physiol 287:R472-8