The role played by CRF in the dorsomedial and ventromedial hypothalamus in the modulation of different types of anxiety-related responses

• Grant number: 14/10976-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2014
• End date: June 30, 2018
• Field of knowledge: Humanities - Psychology - Physiological Psychology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Milena de Barros Viana
• Grantee: Mariana Santos Carvalho de Faria Silva
• Host Institution: Instituto de Saúde e Sociedade (ISS). Universidade Federal de São Paulo (UNIFESP). Campus Baixada Santista. Santos , SP, Brazil

Abstract

The medial hypothalamus has been implicated in a series of different behavioral and physiological functions, including feeding and metabolism, reproduction and stress/anxiety. The region is composed of a number of well-circumscribed neuronal groups - i.e., the dorsomedial hypothalamus (DMH), the anterior hypothalamus, the ventromedial hypothalamus (VMH) and the premamillary nucleus - that are highly interconnected. The medial hypothalamus seems to be particularly involved with the integration of innate stress/anxiety-related responses to environmental threats. An important neurotransmitter system that seems to be altered in stress-related disorders is the one mediated by corticotropin-releasing factor (CRF). In a previous study, male Wistar rats were bilaterally administered into the DMH with CRF (125 and 250 ng/0.2 ul, experiment 1) or with the CRFR1 antagonist antalarmin (25 ng/0.2 ul, experiment 2) and 10 min later tested in the elevated T-maze (ETM) for inhibitory avoidance and escape measurements. In clinical terms, these responses have been respectively related to generalized anxiety and panic disorder. Results showed that CRF facilitated ETM avoidance, an anxiogenic response. Antalarmin significantly decreased avoidance latencies, an anxiolytic effect, and was able to counteract the anxiogenic effects of CRF. None of the compounds administered altered escape responses or locomotor activity measurements. In the present study, we will further investigate the role played by the CRF system within the DMH and VMH in the modulation of anxiety and fear-related responses. For that, in experiment 1, male Wistar rats will be administered intra-DMH with urocortin 2 (a CRFR2 agonist), anti-sauvagine-30 and astressin-2B (CRFR2 antagonists). The effects of intra-VMH administration of CRF, antalarmin, urocortin 2, anti-sauvagine-30 and astressin-2B will also be investigated. In a second experiment, the effects of the repeated stimulation of the DMH and VMH on the behavior of animals submitted to the avoidance and escape of the ETM will be analyzed through the use of Deep Brain Stimulation (DBS). This part of the study will be performed in collaboration with the laboratory of Dr. Liana Lins Melo, from Marburg University, Germany. Aside from this behavioral analysis, this study will also investigate the effects of DBS on Fos/CRF double immunoreactivity in different brain regions related to defense. This study will contribute to a better understanding of the neurobiology of stress and anxiety. (AU)