Systematic screening of the transcripts and molecular and morpho-functional changes induced by metabolic dysfunctions in leptin responsive neurons in the hippocampus

• Grant number: 17/02332-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2017
• End date: December 31, 2017
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Beatriz de Carvalho Borges Del Grande
• Grantee: Adriano Gomes Silva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 14/24113-1 - Systematic screening of the transcripts and molecular and morpho-functional changes induced by metabolic dysfunctions in leptin responsive neurons in the hippocampus, AP.JP

Abstract

The comprehension of the neural systems controlling food intake and energy expenditure is crucial due to the increased prevalence of the obesity in modern societies. Leptin plays a pivotal role in the control of energy balance through its action on the leptin receptor b (LepRb) in hypothalamic nuclei. The LepRb is also expressed in the hippocampus, a brain structure involved in learning and memory processing, recently linked to the control of food intake. Leptin promotes the formation of mature spines and functional synapses in CA1 and CA3 neurons; it stimulates cognition and modulates feeding-related memory. Leptin administration to the hippocampus suppresses feeding and learned appetitive behaviors. However, the mechanisms underlying the role of leptin action in hippocampus and its control of the energy balance have not been defined. Our proposal aims: (1) to identify changes in transcript levels following metabolic challenges (i.e., diet-induced obesity) in hippocampus LepRb neurons by RNA Seq; (2) to evaluate the requirement and sufficiency of leptin action in hippocampus neurons for feeding, body weight and anxiety using conditional re-expression of LepRb in LepRb null mice (using Cre-LoxP system and adenoassociated virus vectors); (3) to define the direct monosynaptic inputs in hippocampus LepRb neurons using cre-dependent helper virus system; and finally, (4) to evaluate the role of acute activation of hippocampus LepRb neurons in feeding and appetitive behaviors using DREADD technology (Designed Receptors Exclusively Activated by Designed Drugs). Our studies will generate new insights into the role of leptin action in the hippocampus and its physiological relevance in metabolic dysfunction highly prevalent in our society. This proposal represents an outstanding opportunity to ignite and establish new scientific field and research expertise groups in the hosting institution of fundamental importance for human's health. We will also introduce cutting-edge methodologies focused on molecular, functional and neural tracking approaches, allowing future applications in multiple areas of research already established in the hosting institution. (AU)