Wang Lab Research
Our lab studies cellular and circuit mechanisms of substance use disorder, stress, and Alzheimer’s disease.
Engram, Synaptic Plasticity, and Alcohol Use Disorder
The Wang lab is interested in exploring alcohol-induced input (the mPFC versus thalamus)- and cell type (dMSNs versus iMSNs)-specific plasticity in the DMS. Using a combination of slice electrophysiology, optogenetics, viral and animal transgenics, and FosTRAP/ArcTRAP approaches, the Wang group investigates how alcohol self-administration causes synapse-specific aberrant plasticity in DMS neuronal ensembles and how these synaptic alterations are involved in pathological drinking. In addition, the few available medications for alcoholism often fail to prevent relapse to alcohol, perhaps because they do not reverse the alcohol-evoked long-term synaptic plasticity, which likely drives alcohol seeking and relapse. The Wang lab employs dual-channel optogenetics to normalize the alcohol-induced circuit-specific plasticity, thereby persistently reducing alcohol seeking and relapse in operant self-administration. They express two excitatory rhodopsins, Chrons and Chrimson, in the presynaptic terminals and postsynaptic MSNs and activate them using blue and yellow light, respectively. They then induce long-term potentiation (LTP) or depression (LTD) in vivo using optogenetic high-frequency stimulation (HFS) or spike-timing-dependent protocols (STDP) to change animal-seeking and relapsing behavior persistently.
Cognitive Flexibility, Stress (CRF), and Substance Use Disorder
The Wang lab is also interested in elucidating the mechanism of compulsive inflexible drinking. They study how pathological drinking alters thalamic PfN→CIN activity in reversal learning of instrumental action-outcome contingency and how the drinking alters CIN-mediated regulation of corticostriatal transmission in dMSNs and iMSNs. The results of the alcohol research will guide future efforts toward the development of more effective therapeutics for alcohol use disorders. * Striatal patch versus matrix compartments and opioid use disorder. The striatal patch (striosome) compartment contains extensive mu-opioid receptors (MORs). The Wang lab investigates how MOR-expressing MSNs, the non-motor outputs of the basal ganglia (i.e., EP), and their downstream circuit (i.e., the lateral habenula), contribute to opioid use disorder, with a particular interest in fentanyl abuse.
Alzheimer's disease and striatal dysfunction
Human MRI studies found Aβ deficits in the striatum of Alzheimer's patients who showed motor-related deficits. The Wang lab explores how corticostriatal transmission in MSNs, CIN activity, and cholinergic neuron activity in the basal forebrain are altered in the 5xFAD mouse model of Alzheimer's disease. They are also interested in how microglia regulates neuronal activity in AD and other disease models.