Work in the lab examines how neuromodulators signal at the synaptic level. We use whole-cell synaptic electrophysiological recordings in combination with 2-photon microscopy, optogenetics, viral mediated gene delivery, fast-scan cyclic voltammetry and the rapid application of agonists to excised patches. There are several ongoing projects in the lab examining the cellular and synaptic regulation of reward circuitry.
Dopamine transmission and signaling through D2-receptors
A major interest of the lab examines the mechanisms that control dopamine signaling and the synaptic activation of D2-receptors. We are interested in understanding the spatial and temporal dynamics governing dopamine transmission. Our work examines how transporters gate the spillover of dopamine to determine how drugs of abuse like cocaine block reuptake to alter transmission at synapses within the striatum, nucleus accumbens and ventral tegmental area. By studying synaptic potentials mediated by D2-receptors we have the opportunity to understand the basic biology that governs dopamine synapses and mechanisms by which drugs of abuse alter the synaptic actions of dopamine.
Regulation of cholinergic transmission in the dorsal striatum
A second area of interest examines how the release of acetylcholine from cholinergic interneurons in the dorsal striatum is encoded through muscarinic receptors. Like dopamine, cholinergic transmission is involved in multiple basal ganglia based functions and dysfunctions in acetylcholine signaling are associated with a variety of neurological movement disorders including Parkinson’s disease, Huntington’s disease, and dystonia. We examine the dynamics and modulation of acetylcholine release at muscarinic synapses onto direct pathway medium spiny neurons using the combination of viral-mediated gene delivery, optogenetics and electrophysiology to understand how cholinergic signals regulate striatal circuit activity.
Regulation of dopamine neuron excitability
Other projects examine how synaptic inputs regulate the excitability of dopamine neurons in the VTA. Inhibitory and excitatory synaptic inputs are important regulators of dopamine cell excitability. These inputs control the baseline firing of dopamine cells and drive bursting activity. All known drugs of abuse (ranging from cocaine and morphine to alcohol and nicotine) stimulate the release of dopamine. The strength of these synaptic inputs becomes potentiated following administration of drugs of abuse. This is thought to be one of the initial triggers that may initiate and/or underlie addiction. Our work aims to understand the basic physiology by which these synaptic inputs regulate dopamine cell firing with the long-term goal being to understand the underlying alterations that result from drug abuse.
Relationship to disease: The goal of our research is to identify the dysfunctions in dopamine signaling that contribute to neurological and psychiatric disorders including drug addiction and Schizophrenia and Parkinson's Disease. The release of dopamine is necessary for mediating neural aspects of reward, motivation and sequence learning. However, addictive drugs usurp these learning processes within the brain so as to dissociate themselves from normal behavior control. This leads to the reinforcing of drug taking. Our research aims understand the circuitry that regulates dopamine transmission. Our hope is that by elucidating the basic aspects of dopamine transmission and signaling we can gain new insights into how drugs of abuse alter normal processes during disease. In addition, other projects in the lab using models of Parkinson's Disease examine how loss of dopamine inputs drives plasticity and alters the excitability of striatal circuits.
NIH-NIDA R01 DA085321
Encoding dopamine signals in the mesolimbic system
NIH-NINDS R01 NS095809
Regulation of striatal acetylcholine transmission by cholinergic interneurons
NIH-NINDS UF1 NS107710 (BRAIN Initiative)
Validating and extending optical tools for extended neural silencing
NIH-NIDA F30 DA048543 (Sarah Zych - Predoctoral NRSA)
Mapping somatodendritic circuits of midbrain dopamine neurons
NIH-NIDA F32 DA043924 (Kelsey Barcomb - Postdoctoral NRSA)
Circuit Specific Effects of Morphine on VTA Inhibitory Neuroplasticity
NIH-NIDA F30 DA040996 (Pamela Marcott - Predoctoral NRSA)
Functional properties of dopamine and glutamate cotransmission in the nucleus accumbens