Research

Work in the lab examines how neuromodulators signal at the circuit and synaptic level and aims to identify the dysfunctions that underlies neurological and psychiatric diseases.  We use whole-cell synaptic electrophysiological recordings in combination with 2-photon microscopy, genetically encoded optical sensor, optogenetics, behavioral approaches, viral mediated gene delivery, in vivo fiber photometry and fast-scan cyclic voltammetry.  Current projects in the lab examine the cellular and synaptic regulation of reward and goal-directed action selection circuitry and changes underlying drug addiction, Parkinson’s disease, schizophrenia, and stress.

Dopamine transmission and signaling

Encoding dopamine signals: A major interest of the lab examines the mechanisms that control dopamine signaling and transmission within the basal ganglia.  We are interested in understanding the spatial and temporal dynamics governing dopamine transmission and the changes that occur in mesolimbic and nigrostriatal circuits in neurological and psychiatric diseases such at Parkinson’s disease and schizophrenia.  Our work aims to define how and where dopamine is released at synaptic sites, how the release is encoded by postsynaptic receptors and how dopamine transmission is altered in disease. Our work examining dopamine receptor signaling aims to understand the basic biology that governs dopamine synapses and define the mechanistic changes that occur in these neurological and psychiatric disorders.

Drug addiction: In addition to examining the basic biology underlying the dopamine system we also examine how dysfunctions in dopamine signaling arise following exposure to drugs of abuse such as cocaine and amphetamine. We aim to elucidate these changes and define how they drive the maladaptive behaviors that lead to subsequent drug seeking. Using the combination of behavioral approaches together with molecular and circuit tools we aim to examine how cocaine drives alterations in dopamine receptor signaling that lead to relapse and cocaine abuse.

Mechanism of Action of Antipsychotics: As a major portion of the lab is interested in dopamine D2-receptors, we have additional projects that aim to determine at the synaptic level how antipsychotic drugs that target this receptor regulate its activation and downstream signaling. By using multiple levels of analysis of D2-receptor activation and signaling we aim to elucidate how these clinically relevant therapeutics alter dopamine transmission

Parkinson’s Disease: Canonical hallmarks of Parkinson’s Disease are the degeneration of striatal dopamine inputs and the formation of Lewy Bodies. Our work, together with colleagues, aims to examine how alpha-synuclein pathologies drive parkinsonian deficits in the nigrostriatal dopamine system.

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 regulated.  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 transmission in the striatum and examine the synaptic connectivity of inputs that regulate striatal cholinergic interneurons.

Parkinson’s Disease:  Recent work has defined how the co-release of multiple transmitters from nigral dopamine neurons regulate striatal cholinergic interneurons and ACh transmission in the striatum. Our work has examined how dysfunction in synaptic transmission of these transmitters arise following degeneration of midbrain dopamine neurons in animal models of Parkinson’s disease. Our ongoing work aims to identify how these changes lead to Parkinsonian motor dysfunctions and leverage these findings to develop new therapeutic tools to rescue motor impairments that result from this disease.

Regulation of Locus Coeruleus noradrenergic excitability and alterations in stress

A third area examine the synaptic connectivity of excitatory inputs to Locus Coeruleus noradrenaline (LC-NE) neurons. Despite the importance of LC-NE signaling in the brain, the functional afferent and efferent synaptic connectivity of LC-NE neurons remains poorly understood. Our work aims to examine the properties of these inputs and identify stress-indued plasticity changes within this system

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.

Optimizing novel optical tools for probing neural circuit function

Finally, together with several groups of collaborators, we are actively engaged in devising and test new genetically encoded optical reporters and tools to measure and perturb the dynamics of neurotransmitter release.

Relationship to disease:  The goal of our research is to identify the dysfunctions in transmitter signaling and circuit function that contribute to neurological and psychiatric disorders including drug addiction and Schizophrenia and Parkinson's Disease.  Our research aims understand the circuitry that regulates neuromodulator transmission and circuit activity.  Our hope is that by elucidating the mechanisms regulating signaling we can gain new insights into the dysfunctions underlying disease.

Current Funding:

NIH-NIDA R01 DA085321                  

Encoding dopamine signals in the mesolimbic system       

NIH-NINDS R01 NS095809             

Regulation of striatal acetylcholine transmission by cholinergic interneurons   

Aligning Science Across Parkinson’s: Circuitry and Brain-Body Interactions

Dual role of neural activity in Parkinson’s disease

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 F32 DA51135 (Andrew Yee - Postdoctoral NRSA)

       Illuminating the mechanisms of dopamine neurotransmission in the striatum

Parkinson’s Foundation (Elizabeth Nielsen - Postdoctoral Fellowship)

Alterations in striatal cholinergic transmission in PD