Darlene A. Mitrano, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Elucidating long-term neurochemical changes in the brain after chronic cocaine use is a main focus of addiction research. The neurotransmitters dopamine and glutamate and their receptors are highly affected by cocaine use and abuse. In this project we will examine the localization of metabotropic glutamate receptors (mGluRs) in the nucleus accumbens (NA), an area in the brain that is involved in experiencing reward to natural substances such as food & water, but also to drugs of abuse. Recent studies demonstrate that mGluRs are essential to mediate self-administration of cocaine in rodents. We therefore propose to use high resolution electron microscopic techniques to study the localization of these receptors in the NA of normal animals, in animals treated with cocaine and animals genetically manipulated to no longer express proteins that control the trafficking of these glutamate receptors in neurons. Findings from this project could lead to a better understanding of changes in the brain that accompany cocaine use and leads an individual vulnerable to addiction. This project will also provide valuable training for me to become a conscientious scientist and pave the way for a successful postdoctoral formation in neuroanatomy & neuropharmacology. [unreadable] [unreadable] [unreadable]

Project Summary/Abstract Sleep disorders constitute a major public health problem in the United States, and abnormalities in arousal often occur in concert with other neurological or neuropsychiatric diseases. The locus coeruleus (NE), the major source of norepinephrine (NE) in the brain, promotes arousal, attention, and wakefulness, but the neural substrates that transduce these actions of the LC have not been fully identified. One intriguing candidate is an understudied population of wake-promoting dopamine (DA) neurons in the ventral periaqueductal gray (vPAG). The LC projects to the vPAG, and our preliminary data indicate that NE provides excitatory drive onto DA neurons in this brain region via ?1-adrenergic receptors (?1ARs), suggesting that NE-DA interactions in the vPAG may promote arousal. The goal of this proposal is to delineate this LC-vPAG circuit. In Aim 1, we will use tract tracing and immunohistochemistry at the electron microscopic level to map the connections between the LC and vPAG as well as specific localization of ?1ARs. In Aim 2, we will use ex vivo slice electrophysiology to determine the cellular mechanisms underlying the ability of NE to enhance excitatory drive onto vPAG DA neurons. In Aim 3, we will use DREADD chemogenetics to assess the behavioral consequences of inhibiting or stimulating various nodes of the LC-vPAG arousal circuit. These studies will define a novel arousal circuit and identify candidate neuroanatomical and molecular targets for the treatment of both primary and disease- associated deficits.