Neural circuits and neurotransmitters underlying regulation of food intake, fuel homeostasis and related behaviors.
The Lowell Lab utilizes genetic engineering techniques in mice - in conjunction with electrophysiology - and a number of other techniques, such as optogenetics and expression of "designer receptors," to study central neurocircuits controlling behavior, body weight homeostasis and fuel metabolism.
Specifically, our research group uses transgenic, gene knockout, and cre-dependent AAV viral approaches to manipulate neuronal function in discrete populations of neurons. The ultimate goal of our studies is to link the function of a protein, within defined sets of neurons, with specific behaviors and physiologic processes. Genes being manipulated, in a neuron-specific fashion, include the leptin receptor, the melanocortin-4 receptor (MC4R), the ATP-regulated K channel (KATP channel, Kir6.2 subunit), uncoupling protein-2 (controls mitochondrial ATP production), the vesicular glutamate transporter-2 (VGLUT2 - packages glutamate into synaptic vesicles), the vesicular GABA transporter (VGAT - packages GABA into synaptic vesicles), glutamate NMDA receptors, the neuropeptide - PACAP, the PACAP receptor - PAC1, channelrhodopsin-2, and "designer receptors" (DREADDs). These genes are being manipulated in a number of different groups of neurons throughout the brain. A partial listing of questions being addressed is listed below.
Leptin: Which leptin-responsive, "first order" neurons mediate the anti-obesity actions of leptin? What is the role of leptin action on POMC neurons, AgRP neurons and SF1 neurons? What is the role of leptin action on GABAergic versus glutamatergic neurons?
MC4Rs: Which neurons mediate the anti-obesity actions of MC4Rs? Through which neurons in the paraventricular nucleus do MC4Rs regulate food intake (oxytocin versus CRH versus AVP neurons)? Through which neurons do MC4Rs regulate energy expenditure (symapethic preganglionic neurons in the spinal cord versus raphe pallidus neurons in the brain stem)?
SF1 Neurons: How do SF1 neurons in the VMH regulate body weight? What effectors do they release to communicate with downstream neurons (role of glutamate versus the neuropeptides - PACAP)? How are the dendrites of SF1 neurons, and excitatory inputs passing through SF1 neurons controlled by glutamate NMDA receptors? Do NMDA receptors regulate synaptic plasticity in neural circuits controlling energy homeostasis? Does leptin-mediated regulation of NMDA receptor activity affect neuronal plasticity?
GABA and Glutamate: What are the roles of the inhibitory neurotransmitter, GABA, and the excitatory neurotransmitter, glutamate, in neurocircuits controlling energy balance and glucose homeostasis?
Glucose Sensing in the brain: What is the role of glucose sensing in POMC neurons, MCH neurons and VMH neurons in controlling whole body glucose homeostasis? Does dysregulation of these processes contribute to pathogenesis of type 2 diabetes.
UCP2 and Dopamine: Does mitochondrial function impact on the activity of dopamine neurons? Does this affect neural pathways controlling behavior, reward and addiction?
GPR101: What is the role of the orphan G-protein coupled receptor, GPR101, in controlling food intake?
For a complete listing of Dr. Lowell's publications,