Akt Signaling at the Crossroads of Depression and Addiction

New York University School Of Medicine, New York NY

Investigators

Abstract

DESCRIPTION (provided by applicant): Our project builds on dopamine (DA) neuron-specific models of Akt1-deficiency in the mouse brain. Our goal is to determine if converging findings of pathologically altered Akt signaling in different neuropsychiatric disorders including depression and addiction are functionally related. To reveal common features of impaired Akt signaling that may impact on depression-like and addictive behaviors, we will first use the social defeat paradigm to induce depression-like behaviors in Akt1-mutant mice and congenic controls. Stressed mice will then be exposed to the psychostimulant cocaine. By combining depression- and addiction-related behavioral paradigms in Akt1-mutant mice, we will test whether impairment of Akt signaling due to genetic deficits is further enhanced by stress to augment behavioral responsiveness to cocaine. Results from our experiments will identify fundamental molecular mechanisms by which cocaine and other drugs of abuse manipulate brain circuitry, and explain how disease-related genetic variations and acquired impairments in Akt signaling due to stress increase susceptibility to their effects. The functional characterization of this pivotal signaling pathway in DA neurons holds significant potential for the development of biomarkers and approaches for risk assessment and treatment of addiction, depression and other neuropsychiatric disorders, and improves the understanding of common risk factors shared among neuropsychiatric disorders.