Drug addiction is a chronically relapsing disease. Relapse often occurs when addicts are re-exposed to drug-associated stimuli that trigger feelings and memories of drug use. Recent evidence from our laboratory revealed a neural circuit between the hippocampal CA3 neurons and the ventral tegmental area (VTA), via the caudal-dorsal lateral septum (cdLS). As the CA3 region is important for context and memory, and VTA in reward processing, this implicates the cdLS as an important brain region linking context and reward. It is clear from early self-stimulation studies in both humans and rodents that the lateral septum plays a role in reward- driven motivation;however, this brain region has been largely understudied in drug abuse and relapse. Using a well-established self-administration animal model of addiction, this proposal will explore the hippocampus- lateral septum circuit in both context-induced and discrete cue-induced reinstatement of cocaine seeking. [Based on the lateral septum's position between the hippocampus and VTA, as well as, preliminary data collected by the applicant, we predict that the hippocampus CA3 to cdLS circuit is necessary for context, but not cue-induced reinstatement of cocaine seeking.] This hypothesis will be tested through three specific aims. [Aim 1 will determine neuronal activation (by combining Fos and retrograde tracer immunohistochemistry) in lateral septum-projecting hippocampus CA3 neurons following context or cue-induced reinstatement of cocaine seeking.] Aim 2 will employ a DREADD-based pharmacogenetic approach to specifically and transiently inhibit neurons within the LS to determine if activity of this region is necessary for context or cue-induced reinstatement of cocaine seeking.
Aim 3 will use pharmacogenetics and cannulae microinjections to selectively inhibit the CA3 terminals in the cdLS to determine the circuit's rol in reinstatement behavior. [Together these studies will elucidate the role of an important contextual memory circuit in motivation for cocaine, help further interpret the neuropathology underlying drug addiction, and provide preclinical evidence for the use of DREADD pharmacogenetics to reduce relapse-thus supporting NIDA's mission to "improve prevention and treatment" of drug abuse. Additionally, this fellowship will train the applicant in cutting- ede techniques for analyzing behavioral functions of neural circuits in addiction, including pharmacogenetic manipulations, the self-administration paradigm, catheter and cranial virus surgeries, cannulae surgeries, microinjections, and immunohistochemistry procedures. These skills will have broad applications in the applicant's future career as an independent translationa researcher in the addiction field.]
Drug abuse remains a major public health issue;one obstacle in treating the disease is the frequency of relapse among addicts. Relapse is driven by drug-associated cues and contexts, and persists as a fundamental problem partly because important circuits linking these cues and contexts to relapse behavior have yet to be elucidated. These studies will provide greater insight into the neurocircuitry involved in drug relapse, which can facilitate the development of future therapeutics for the disease.