Arshad M. Khan, M.S. (Biochemistry), Ph.D. (Neuroscience) - US grants

DESCRIPTION (provided by applicant): Corticotropin-releasing hormone (CRH)-containing neurons of the hypothalamic paraventricular nucleus (PVH) are critical for adaptive responses to stress, disruptions of which may be linked to stress-related pathologies. The long-term objective of this training proposal is to begin establishing the precise relationships among stimuli that evoke stress responses, the neural pathways conveying that information to the PVH, and the coordinated response of PVH neurons to such information. Specific aims all center around how the hindbrain-originating catecholaminergic (CA) afferents help trigger gene expression in CRH neuroendocrine neurons of the rodent PVH in response to the metabolic stressor, 2-deoxyglucose (2-DG). Proposed training includes: (1) immunohistochemistry and in situ hybridization to track cellular markers of CRH neuronal activity (e.g., MAP kinase, CREB, crh hnRNA), (2) intravenous 2-DG or PVH injection of a retrograde immunotoxin to selectively stimulate or lesion, respectively, the CA afferent system, and (3) PVH microinjections of receptor antagonists or enzyme inhibitors to probe the signaling machinery of CRH neurons. This training will further my career goal of studying cellular signaling using an in vivo approach.

DESCRIPTION (provided by applicant): This proposal, which describes a 3-4 year training program, is designed to provide the candidate with the opportunity of solving an important basic research question while simultaneously acquiring the expertise needed to become a full-time independent investigator in an academic environment. The candidate received his Ph.D. in 2002 and has since been conducting research as a postdoctoral fellow at the Neurosciences Research Institute (NRI) and the Dept. of Biological Sciences at the University of Southern California (USC). The NRI consists of about 70 faculty, of whom approximately half are located in the Hedco Neuroscience Building or in close vicinity on the main USC campus. The NRI has particular strengths in computational neuroscience, systems neuroscience (learning and memory, motivational systems, vision), and cellular and molecular neuroscience where there is a strong research presence in synaptic plasticity and release mechanisms. There are many colleagues who can be of benefit to the candidate's research. The proposed mentor, Dr. Larry W. Swanson, is an acknowledged world-class authority on neuroanatomy and an expert on the neuroanatomical tract tracing techniques which form the basis of one of two major Aims of this training proposal. The proposed co-sponsor, Dr. Michel Baudry, is similarly an acknowledged authority on neurochemistry, and an expert at cellular and molecular biochemistry related to in vitro slice preparations of brain tissue, which forms the basis of the second major Aim of this training proposal. The proposed research focuses on defining the chemical phenotypes of glucosensing neurons in the brain that respond to glycemic challenges and to define the circuits between these regions and the paraventricular hypothalamus, which helps the organism respond to these challenges by initiating glucocorticoid responses. Additionally, the plan also focuses on the regulation of PVH neurons by signals that are released by these glucosensing regions. PUBLIC HEALTH RELEVANCE: Diabetics suffering from blunted counterregulatory responses to hypoglycemia may have neural impairments in sensing/responding to hypoglycemia. The proposed research aims to define what the normal brain activation pattern to hypoglycemia is, and how neurons sensing this are connected to hypothalamic structures that contribute to glucose counterregulation.

DESCRIPTION (provided by applicant): Neuron populations in the hypothalamus and hindbrain form nodes within a larger distributed network to control multiple aspects of feeding behavior in mammals. The goal of this project is to identify and map arcade hypothalamic circuits that respond to circulating hormones that control feeding behavior. At the heart of this project lies a novel combination of functional neuroanatomical techniques: tract-tracing, wide-field and multi- fluorescence imaging, reference atlas-based mapping, and data deposition within an online neuron informatics database. These methods are being brought to bear on the arcuate hypothalamus, because it has remained a relatively uncharted and poorly defined brain structure that is otherwise critical for feeding behavior. Knowledge of the basic circuit organization of this structure, through its complete three dimensional expanse, is critical for scientists to be able to further experimentally manipulate selected sub-populations of neurons in this structure to study various aspects of feeding control. This, in turn, is expected to yield novl targets within the brain suitable for designing rationale therapeutics and treatments to help prevent or mitigate the effects of obesity, overeating, and metabolic disorders.

PROJECT ABSTRACT Neuron populations in the hypothalamus form nodes within a larger distributed network to control multiple aspects of feeding behavior in mammals. The goal of this project is to functionally interrogate newly mapped hypothalamic relay circuits that control feeding behavior. We will employ viral-based tract tracing, optogenetics, chemogenetics, behavioral analyses of feeding, wide-field and multifluorescence imaging, and reference atlas- based mapping; to determine whether these relay circuits in the hypothalamus mediate feeding triggered either by an overnight fast or by craving for rewarding foods. We will deposit all mapped and probed brain circuit locations within an online neuroinformatics database. The hypothalamus has remained a relatively uncharted and poorly defined brain structure that is otherwise critical for feeding behavior. Knowledge of the basic circuit organization of this structure, and its functional/behavioral validation, is critical for scientists to be able to further experimentally manipulate selected sub-populations of neurons in this structure to study various aspects of feeding control. This, in turn, is expected to yield novel targets within the brain suitable for designing rationale therapeutics and treatments to help prevent or mitigate the effects of obesity, overeating, and metabolic disorders.