In many brain regions, glial cells substantially outnumber nerve cells, but their role in physiological and pathophysiological conditions remains poorly understood. Astrocytes are the most widely distributed glia with intimate anatomical interactions with excitatory synapses. Recent studies reveal that, in addition to providing structural and nutritional support, astrocytes dictate synapse formation and subsequent synapse refinement- elimination in the developing CNS. Our preliminary results show that, after chronic exposure to cocaine or morphine, some of these glia-based developmental mechanisms re-emerge in the adult nucleus accumbens (NAc), a forebrain region essential for addiction-related behavioral abnormalities. These drug-induced, glia- mediated synaptic remodeling processes may profoundly rewire the neurocircuits involving the NAc, and critically contribute to the pathophysiology of drug addiction. Focusing on this unique angle, the objectives of this application are: 1) To characterize the molecular and cellular mechanisms underlying glia-mediated synaptogenesis and synaptodegeneration in the NAc in mice after cocaine or morphine self-administration and withdrawal; 2) To determine the circuitry consequences of drug-induced, glia-mediated synaptic remodeling, particularly, how NAc excitatory synapses are refashioned in cocaine- and morphine-exposed mice by glia- mediated synaptogenesis or synaptodegeneration; and 3) To determine the behavioral consequences of drug- induced, glia-mediated synapse and circuitry remodeling using the mouse model of incubation of cue-induced drug craving, a drug relapse model that depends on NAc excitatory circuits. To achieve these goals, we will use a multidisciplinary approach, across the Dong and Nestler laboratories, including confocal imaging, slice electrophysiology, optogenetics, in vivo viral-mediated gene transfer, RNA interference, transgenic mouse lines, and mouse models of drug self-administration. By targeting the previously unexplored glia-mediated synapse and circuitry remodeling in drug-exposed mice, the proposed experiments promise to open new avenues toward understanding cellular and circuitry mechanisms underlying drug addiction and providing new strategies for anti-addiction treatments.

Public Health Relevance

In addition to providing structural and nutritional support, glial cells actively interact with nere cells, and many forms of glia-neuron interactions are essential for circuitry formation during development as well as circuitry remodeling in the mature brain. The current application aims to understand glia-based synapse and circuitry remodeling induced by chronic exposure to cocaine or morphine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA040620-05
Application #
9897513
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sorensen, Roger
Project Start
2016-06-01
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260
Cahill, M E; Walker, D M; Gancarz, A M et al. (2018) The dendritic spine morphogenic effects of repeated cocaine use occur through the regulation of serum response factor signaling. Mol Psychiatry 23:1474-1486
Wright, William J; Dong, Yan (2018) Intrinsic Excitability of Cocaine-Associated Memories. Neuropsychopharmacology 43:675-676
Koya, Eisuke; Dong, Yan (2018) Sound of silent synapses from the addicted hippocampus. Neuropsychopharmacology 43:1981-1982
Cahill, Michael E; Browne, Caleb J; Wang, Junshi et al. (2018) Withdrawal from repeated morphine administration augments expression of the RhoA network in the nucleus accumbens to control synaptic structure. J Neurochem 147:84-98
Wang, Junshi; Ishikawa, Masago; Yang, Yue et al. (2018) Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving. J Neurosci 38:4316-4328
Wright, William J; Schl├╝ter, Oliver M; Dong, Yan (2017) A Feedforward Inhibitory Circuit Mediated by CB1-Expressing Fast-Spiking Interneurons in the Nucleus Accumbens. Neuropsychopharmacology 42:1146-1156
Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel et al. (2017) Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles. Biol Psychiatry 81:285-295
Dong, Yan; Taylor, Jane R; Wolf, Marina E et al. (2017) Circuit and Synaptic Plasticity Mechanisms of Drug Relapse. J Neurosci 37:10867-10876
Wright, William J; Dong, Yan (2017) Tipping the Scales Toward Addiction. Biol Psychiatry 81:903-904
Liu, Yanling; Cui, Lei; Schwarz, Martin K et al. (2017) Adrenergic Gate Release for Spike Timing-Dependent Synaptic Potentiation. Neuron 93:394-408

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