The VMH and Molecular Control of Energy Balance The ventral medial hypothalamus (VMH), in concert with other brain regions, regulates energy balance. A group of neurons within the VMH, marked by the expression of the transcription factor, SF1 (Nr5a1), resists the development of obesity. The adipocyte-derived, """"""""catabolic"""""""" hormone leptin excites these SF1 neurons, and deletion of leptin receptors (LEPRs) on SF1 neurons results in obesity, and also marked sensitivity to diet-induced obesity. Thus, SF1 neurons in the VMH, like POMC neurons in the actuate nucleus, are direct targets of leptin and promote negative energy balance. While much is known about how POMC neurons cause weight loss, comparatively less is known about how SF1 neurons achieve this effect. This presents the unique opportunity to identify novel mechanisms controlling energy homeostasis. In this grant, we propose to determine the following: 1) the """"""""catabolic"""""""" factor released by SF1 neurons (we propose an important role for the neuropeptide, PACAP) (Aim 1), 2) the receptor and neuron immediately downstream of SF1 neurons (we propose that the PAC1-receptor - the high affinity PACAP receptor - on POMC neurons is important) (Aim 2), and 3) on the afferent side of SF1 neurons, we propose that glutamatergic excitatory inputs, which synapse on dendritic spines of SF1 neurons, play a key role in controlling the activity of SF1 neurons, and that glutamate NMDA receptor-mediated plasticity of these inputs, and, importantly, leptin regulation of this plasticity, contributes prominently to the control of energy homeostasis. To accomplish these Aims, we will utilize the following state-of-the-art technologies: 1) neuron- specific gene manipulation to test molecular mechanisms in an in vivo context (in all three Aims), 2) optogenetics to identify functionally relevant, monosynaptic, downstream targets of SF1 neurons (in Aim 2), and 3) functional and morphologic assessments of excitatory synaptic plasticity (in Aim 3).
Complex neurocircuits in the brain work in concert to control body fat stores. In order to intelligently develop anti-obesity therapies, it is first necessary to decipher the """"""""wiring-diagrams"""""""" that underpin these circuits. To accomplish this, our group is using the following state-of-the-art technologies: 1) neuron-specific gene manipulations, 2) optogenetics (light-activated neuron stimulation), and 3) functional-morphologic assessments of synaptic organization and plasticity.
| Campbell, John N; Macosko, Evan Z; Fenselau, Henning et al. (2017) A molecular census of arcuate hypothalamus and median eminence cell types. Nat Neurosci 20:484-496 |
| Garfield, Alastair S; Shah, Bhavik P; Burgess, Christian R et al. (2016) Dynamic GABAergic afferent modulation of AgRP neurons. Nat Neurosci 19:1628-1635 |
| Crowley, Nicole A; Bloodgood, Daniel W; Hardaway, J Andrew et al. (2016) Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit. Cell Rep 14:2774-83 |
| Krashes, Michael J; Lowell, Bradford B; Garfield, Alastair S (2016) Melanocortin-4 receptor-regulated energy homeostasis. Nat Neurosci 19:206-19 |
| Vetrivelan, Ramalingam; Kong, Dong; Ferrari, Loris L et al. (2016) Melanin-concentrating hormone neurons specifically promote rapid eye movement sleep in mice. Neuroscience 336:102-113 |
| Kong, Dong; Dagon, Yossi; Campbell, John N et al. (2016) A Postsynaptic AMPK?p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons. Neuron 91:25-33 |
| Al-Hasani, Ream; McCall, Jordan G; Shin, Gunchul et al. (2015) Distinct Subpopulations of Nucleus Accumbens Dynorphin Neurons Drive Aversion and Reward. Neuron 87:1063-77 |
| Krashes, Michael J; Shah, Bhavik P; Madara, Joseph C et al. (2014) An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507:238-42 |
| Shah, Bhavik P; Vong, Linh; Olson, David P et al. (2014) MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus. Proc Natl Acad Sci U S A 111:13193-8 |
| Garfield, Alastair S; Shah, Bhavik P; Madara, Joseph C et al. (2014) A parabrachial-hypothalamic cholecystokinin neurocircuit controls counterregulatory responses to hypoglycemia. Cell Metab 20:1030-7 |
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