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Tamas L. Horvath"Hunger promoting hypothalamic neurons regulate higher brain functions and longevity "

Abstract :


It is not known whether motivational behaviors not related to feeding are affected by primary regulators of energy balance located in the hypothalamus.
We revealed that impairment of AgRP neuronal function by knockdown of Sirt1, a NAD+-dependent deacetylase, increases exploratory behavior of mice unrelated to feeding. Behavioral responses to cocaine, were also altered in these transgenic mice. As a neurobiological substrate of these altered behaviors, in AgRP-Sirt1 KO mice, ventral tegmental (VTA) dopamine (DA) neurons, which are targeted by AgRP efferents, exhibited enhanced spike-timing-dependent long-term potentiation (STD-LTP), decreasedamplitude of mIPSCs, and increased DA levels in basal forebrain. Early postnatal ablation of AgRP neurons led to a phenotype resembling that of AgRP-Sirt1 KO mice, with enhanced LTP in VTA-DA cells and altered response to novelty.These observations reveal a fundamental regulatory role of AgRP neurons in determining the set point of the DA reward circuitry and associated behaviors during development.

Selected publications

Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Diano S, Liu ZW, Jeong JK, Dietrich MO, Ruan HB, Kim E, Suyama S, Kelly K, Gyengesi E, Arbiser JL, Belsham DD, Sarruf DA, Schwartz MW, Bennett AM, Shanabrough M, Mobbs CV, Yang X, Gao XB, Horvath TL. Nat Med. 2011 Aug 28;17(9):1121-7. doi: 10.1038/nm.2421.

Dietrich MO, Antunes C, Geliang G, Liu Z-W, Borok E, Nie Y, Xu AW, Souza DO, Gao Q, Diano S, Gao X-B, Horvath TL (2010) AgRP neurons mediate Sirt1’s action on the melanocortin system and energy balance: roles for SirT1 in neuronal firing and synaptic plasticity. J Neurosci 2010 Sep 1;30(35):11815-25.

Horvath TL, Sarman B, García-Cáceres C, Enriori PJ, Shanabrough M, Borok E, Argente J, Chowen JA, Perez-Tilve D, Pfluger PT, Brönneke HS, Levin BE, Diano S, Cowley MA, Tschöp MH (2010) Synaptic Input Organization of the Melanocortin System Predicts Diet-Induced Hypothalamic Reactive Gliosis and Obesity. PNAS 2010 Aug 17;107(33):14875-80. Epub 2010 Aug 2.

Andrews ZB, Liu ZW, Walllingford N, Erion DM, Borok E, Friedman JM, Tschöp MH, Shanabrough M, Cline G, Shulman GI, Coppola A, Gao XB, Horvath TL, Diano S (2008) UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature. 454(7206):846-51.

Gao Q, Horvath TL (2007) Neurobiology of feeding and energy expenditure. Annu Rev Neurosci. 30:367-98

Scientific focus :

My main interest is the neuroendocrine regulation of homeostasis with particular emphasis on metabolic disorders, such as obesity and diabetes, and the effect of metabolic signals on higher brain functions and neurodegeneration. We have active research programs to pursue the role of synaptic plasticity in the mediation of peripheral hormones’ effects on the central nervous system.
We also study the role of mitochondrial membrane potential in normal and pathological brain functions with particular emphasis on the acute effect of mitochondria in neuronal transmission and neuroprotection. We combine classical neurobiological approaches, including electrophysiology and neuroanatomy, with endocrine and genetic techniques to better understand biological events at the level of the organism.
Extensive Research Description

My main interest is the neuroendocrine regulation of homeostasis with particular emphasis on metabolic disorders, such as obesity and diabetes, and the effect of metabolic signals on higher brain functions and neurodegeneration. We have active research programs to pursue the role of synaptic plasticity in the mediation of peripheral hormones’ effects on the central nervous system.

We also study the role of mitochondrial membrane potential in normal and pathological brain functions with particular emphasis on the acute effect of mitochondria in neuronal transmission and neuroprotection. We combine classical neurobiological approaches, including electrophysiology and neuroanatomy, with endocrine and genetic techniques to better understand biological events at the level of the organism.

Daniela Cota et Sophie Layé