The brain regulates feeding behavior and metabolism however the neurocircuitry responsible for this is largely unknown. The complexity of the brain and the need to manipulate it in awake, behaving animals, represent significant technical challenges. The application of new, innovative approaches is likely to greatly accelerate progress. Recently, we and others, using pharmacogenetic and optogenetic technology, have discovered that AgRP neurons drive intense feeding behavior. With this in mind, it is now critical to determine the afferent signals (hormones and neural inputs) controlling AgRP neuron activity as well as the effectors (GABA, NPY, AgRP, and downstream neural circuits) that bring about AgRP neuron-driven feeding. Remarkably, little attention has been paid to afferent (upstream) neural inputs regulating AgRP neurons. This is unfortunate because a) defective neural control of AgRP neurons could contribute importantly to complex eating disorders (ranging from anorexia to obesity), and b) the hormonal regulation of AgRP neurons, one example being ghrelin, likely works by modulating these inputs. Recently, in Preliminary Studies, we discovered that NMDA receptors (NMDARs), key regulators of excitatory synaptic plasticity, play a critical role in regulating AgRP neuron activity and feeding;NMDARs on POMC neurons, on the other hand, play little or no role. Consistent with this, AgRP neurons have abundant dendritic spines (postsynaptic specializations where most excitatory synapses reside and within which NMDARs operate to control plasticity);POMC neurons, in contrast, lack spines. Finally, we have found that fasting-activation of AgRP neurons require NMDARs and involves dendritic spinogenesis, and very likely increased excitatory synaptogenesis. Thus, NMDAR-mediated plasticity of excitatory input to AgRP neurons plays a key, previously unknown role in regulating AgRP neuron activity and consequently feeding behavior. The present application will pursue key implications of the above-mentioned findings.
In Aim 1, using advanced 2-photon microscopy, we will mechanistically investigate """"""""regulatory"""""""" plasticity of excitatory inputs, via NMDARs/spines, to AgRP neurons.
In Aim 2, using Cre-dependent, Monosynaptic Rabies Mapping and also Channelrhodopsin-Assisted Circuit Mapping, we will identify and assess function of afferent neurons sending glutamatergic input to AgRP neurons.
In Aim 3, using pharmacogenetic activation of AgRP neurons unable to signal via GABA, NPY and/or AgRP and also anatomic-selective, optogenetic activation of AgRP nerve terminals, we will identify the downstream effectors (transmitters and circuits) of AgRP neurons.
Complex neurocircuits in the brain work in concert to regulate feeding behavior and metabolism. 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 state-of- the-art technologies: 1) neuron-specific gene manipulations to determine function, 2) cre- dependent monosynaptic rabies mapping to elucidate the wiring diagram, 3) optogenetics (light- activated neuron stimulation) to establish function of the wiring diagram, and 4) DREADD and optogenetic technology to acutely and reversibly control circuit activity in vivo.
|Fenselau, Henning; Campbell, John N; Verstegen, Anne M J et al. (2017) A rapidly acting glutamatergic ARC?PVH satiety circuit postsynaptically regulated by ?-MSH. Nat Neurosci 20:42-51|
|Cheng, Longzhen; Duan, Bo; Huang, Tianwen et al. (2017) Identification of spinal circuits involved in touch-evoked dynamic mechanical pain. Nat Neurosci 20:804-814|
|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|
|Resch, Jon M; Fenselau, Henning; Madara, Joseph C et al. (2017) Aldosterone-Sensing Neurons in the NTS Exhibit State-Dependent Pacemaker Activity and Drive Sodium Appetite via Synergy with Angiotensin II Signaling. Neuron 96:190-206.e7|
|Andermann, Mark L; Lowell, Bradford B (2017) Toward a Wiring Diagram Understanding of Appetite Control. Neuron 95:757-778|
|Mandelblat-Cerf, Yael; Kim, Angela; Burgess, Christian R et al. (2017) Bidirectional Anticipation of Future Osmotic Challenges by Vasopressin Neurons. Neuron 93:57-65|
|Livneh, Yoav; Ramesh, Rohan N; Burgess, Christian R et al. (2017) Homeostatic circuits selectively gate food cue responses in insular cortex. Nature 546:611-616|
|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|
|Burgess, Christian R; Ramesh, Rohan N; Sugden, Arthur U et al. (2016) Hunger-Dependent Enhancement of Food Cue Responses in Mouse Postrhinal Cortex and Lateral Amygdala. Neuron 91:1154-1169|
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