Over 20 million Americans suffer from the debilitating consequences of drug abuse; and, unfortunately, even with treatment, the relapse rate for drug abuse is between 40-60%. In addition to the high relapse rate, there are limited treatment options for drug addiction. The development of efficacious treatment options depends on understanding how drugs of abuse alter neural circuitry and influence drug seeking behavior. This project will specifically examine cocaine, a major illicit drug of abuse that adversely affects multiple organ systems including the brain. Cocaine works in the brain by blocking dopamine transporters and increasing the amount of synaptic dopamine. In addition to the disruption of dopaminergic signaling, a major neural circuit disrupted by cocaine is excitatory transmission in the nucleus accumbens (NAc: a primary brain region implicated in reward and addiction behavior). Most studies on reward and cocaine addiction have focused on neurons. Little is known about astrocytes, which are emerging as important cellular elements of synaptic function regulation. Traditionally, astrocytes have been viewed as passive players in nervous system function. Classic roles of astrocytes include formation of the blood-brain barrier and maintenance of ion homeostasis. Recent research has demonstrated that although astrocytes are not electrically excitable, astrocytes respond to chemical transmitters with cytoplasmic calcium elevations. The calcium oscillations in astrocytes can trigger the release of additional chemical transmitters leading to the modulation of synaptic transmission and plasticity. The present study aims to investigate the effects of cocaine on astrocyte-neuron signaling in the NAc to reveal potential novel cellular targets for the treatment of cocaine addiction. My project aims to test the hypothesis that astrocytes are activated by dopaminergic signaling and mediate excitatory synaptic transmission in the NAc in a cocaine-dependent manner. Two-photon microscopy calcium imaging and electrophysiological recordings will be used to study astrocyte-neuron signaling in the NAc and the effects of cocaine. This project aids in elucidating the cellular mechanisms involved in the neural plasticity associated with drug addiction and provides insight into novel therapeutic cellular targets. Through this training grant, I will gain the tools necessary to investigate neuropsychiatric disorders at a cellular and circuit level to contribute to the development of efficacious treatment options for patients.

Public Health Relevance

Over 20 million Americans suffer from drug addiction, and the current proposal investigates novel cellular and circuit mechanisms associated with cocaine actions in the brain. Specifically, this project examines astrocytes, a cell type that has been traditionally overlooked as providing simple support for neurons, but is now emerging as an active key player in brain function regulation. The current proposal investigates the involvement of astrocytes in the reward signaling governing addiction and has the potential to advance treatment options for neuropsychiatric disorders, such as drug addiction, via elucidating novel cellular mechanisms implicated in brain signaling and function.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Lin, Yu
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University of Minnesota Twin Cities
Schools of Medicine
United States
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