Alcohol and NMDARs

This work is focused on understanding the interactions of ethanol with NMDA receptors-ionotropic glutamate receptors involved in excitatory synaptic transmission. We use mutagenesis, electrophysiology and behavior to study how altering the ethanol sensitivity of NMDA receptors changes the brain's response to alcohol.

Representative figures from some of our work are shown below.

Glutamate Synapse

Structural model of GluN1/2A NMDAR

TM3/4 Domains of NMDAR

Reduced ethanol sensitivity of NMDAR EPSCS in mPFC neurons from GluN1(F639A) mice

Reduced sensitivity of GluN1(F639A) mice to locomotor impairing effects of ethanol

Reduced ethanol inhibition of NMDAR EPSCs in Purkinje neurons from GluN1(F639A) mice

Reduced ethanol inhibition of NMDA EPSCs in mPFC and Cerebellum of male and female Grin2A(A825W) mice

Grin2A(A825W) male but not female mice show less ethanol-induced motor incoordination than their wild-type littermates

Abused Inhalants and Addiction Neurocircuitry

This research is focused on understanding the actions of abused inhalants such as toluene on the addiction neurocircuitry of the brain. Inhalants are an under-studied drug of abuse and have a relatively high incidence of use among children and adolescents. This works uses in vitro and in vivo techniques to determine how toluene and other inhalants affect cortical and sub-cortical areas involved in cognition and reward.

Representative figures from some of our work are shown below.

Effects of Toluene on Different Ion Channels

Effects of Toluene Vapor on Addiction Neurocircuitry

Toluene Vapor Enhances the AMPA/NMDA ratio of VTA DA Neurons that Project to the Nucleus Accumbens

Toluene vapor increases spine density in nucleus accubens medium spiny neurons

Toluene vapor exposure decreases firing of NAc-core projecting layer 5/6 mPFC neurons but not those projecting to NAc-shell.

Toluene self-administration in rats. Mean (±SEM) number of infusions per session for air and toluene rats over the training period (Ai) and last week of self-administration (Aii). Rate of infusions for air and toluene rats during the final toluene self-administration test (Aiii).

Classes of Abused Inhalants

GCamP6f Fiber Photometry of mPFC activity during probabilistic risk task

Alcohol and the Frontal Cortex

This project is a component of our NIAAA P50 Alcohol Center. A combination of in vivo ethanol exposure, slice electrophysiology, imaging and behavioral approaches are used to define the actions of ethanol on neurons located in the orbitofrontal cortex, basolateral amygdala and dorsal striatum.

Representative figures from some of our work are shown below.

Spontaneous up-state activity in slice cultures of medial prefrontal cortex, VTA and hippocampus

Vapor protocol for producing ethanol dependence in mice

CIE enhances OFC neuron excitability and reduces the AHP

CIE exposure impairs reversal learning in mice

In vivo fiber photometery of calcium transients in mouse OFC neurons before and after i.p. injection of ethanol

Rabies labeling of spines in striatal projecting OFC neuron

Alcohol and the Cerebellum

These studies are focused on defining how non-motor areas of the posterior cerebellum are involved in voluntary ethanol drinking. We use chemogenetics, homecage and operant ethanol administration and FosTrap2 mice to determine the role of cerebellar circuitry in drinking.

Representative figures from some of our work are shown below.

CNO reduces drinking in mice with inhibitory DREADDs in posterior but not anterior cerebellum

CNO enhances Purkinje neuron firing rate in DREADD expressing mice

Examples of Fos+ neurons in FosTrap2 mice following i.p. injection of ethanol

Summary of effects of CNO on locomotor activity in male and female mice expressing the inhibitory DREADD in posterior or anterior cerebellum

Collaborative Neuroscience Research

We collaborate with Dr. Patrick Mulholland and Dr. Jennifer Rinker on one of eight projects organized within the Integrated Neuroscience Initiative on Alcoholism consortium (INIA-Stress). In this study, we examine the effects of stress and long-term drinking on neuronal gene and protein expression and function in mice and non-human primates.

Representative figures from some of our work are shown below.

Ethanol inhibition of spike firing in OFC neurons is blunted in long-term drinking cynomolgus males

Enhanced spontaneous EPSCs in OFC neurons from long-term drinking cynomolgus males

Proteomic changes in OFC from long-term drinking cynomolgus males

Exploratory analysis of the OFC synaptome identifies differences between low and high drinking cynomolgus males

Research Training Opportunities

Laboratory Research Positions

Please contact me if you are a pre-doctoral or post-doctoral fellow interested in studying the actions of alcohol and abused inhalants on brain ion channels.

Some of the techniques currently in use in the lab include:

Patch-clamp electrophysiology combined with mutagenesis to study wild-type and recombinant ion channels expressed in transfected HEK cells

Patch-clamp recording of neuronal activity in brain slices, slice cultures and dissociated neurons

In vivo imaging techniques such as Fiber Photometry using Cre-mediated expression of calcium and glutamate sensors including GCaMPs and iGluSnFr

Expression of optogenetic and DREADD constructs via viral vectors for input specific control of neuronal activity combined with operant based behaviors to assess circuit-level control of alcohol and abused inhalant use

If you are interested in applying for a position, send me an email (woodward@musc.edu) containing your CV and the names of three references and a brief description of your research experience and interests.

NIH Funded Training Fellowship Positions
MUSC holds NIH sponsored training grants from both NIDA (drug abuse) and NIAAA (alcohol) that offer advanced training in research related to addiction. Dr. Woodward (woodward@musc.edu) serves as Director of the NIAAA Training Grant and Dr. McGinty (mcginty@musc.edu) is Training Director for the NIDA Training Grant. Contact either one of us for more information on how to apply for a Research Fellowship in Addiction Research.

Note: NIH funded training grant positions are open to US citizens or permanent residents only. NIH funded research grant do not have a citizenship eligibility rule but do require the appropriate visa.

Lab Personnel

Neuroscience Graduate Students

Abby Kastner
kastnera@musc.edu

Research Techs, Post-docs and Faculty

Seth Hester, Research Specialist I
hesterse@musc.edu

Sudarat Roberts (Nimitvilai), Ph.D.; Post-doctoral fellow nimitvil@musc.edu

Paula Zamudio, Ph.D.; Research Asst. Professor
zamudiob@musc.edu

John J. Woodward, Ph.D.; Professor
woodward@musc.edu

Lab Alumni and Former Trainees
Dominic Gioia, PhD
Kevin Braunscheidel, PhD
Wes Wayman, PhD
Carolina den Hartog, PhD
Ben Hughes, PhD
Jacob Beckley, PhD
Corigan Smothers, PhD
Matthew Pava, PhD
Minfu Xu, PhD
Carl Weitlauf, PhD
Patrick Mulholland, PhD
Katherine Chike-Harris, D.N.P
Chun Jin, MD
Yali Tu, MD
Ambuja Bale, PhD
Doug Anders, PhD
Kim Ronald, PhD
Tooraj Mirshahi, PhD
Amy Stout, PhD
Angelo del Ray, MS, MD
Ahmed Khaldi, MS, MD
Rick Tillar, MS

Address

30 Courtenay Drive
Thurmond-Gazes 627B
Charleston, SC 29425

Contacts

Email: woodward@musc.edu
Phone: (843) 792-5225
Fax: (843) 792-7353

MUSC Links

Department of Neuroscience
CHS Alcohol Research Center

Woodward Neuroscience Lab