Date of Award

2022

Embargo Period

8-9-2022

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Carmela Reichel

Second Advisor

Antionetta Lavin

Third Advisor

Michael Scofield

Fourth Advisor

Jennifer Rinker

Abstract

Chronic use of methamphetamine (meth) disrupts cortical processing across multiple cognitive domains including impulsivity, decision making and memory. Our laboratory has consistently shown that extended access to contingent meth self-administration reliably produces memory deficits in novel object recognition (NOR) tasks designed to test the “what” component of episodic memory in a rodent model. This type of memory is dependent on an intact function of the perirhinal cortex (PRH). However, the ongoing role of the prefrontal cortex (PFC) in this task and the directionality of communication between the PRH and the PFC is not entirely understood. A set of four experiments were designed to characterize the bi-directional connection between the PFC and the PRH during the exploration of novel vs. familiar objects and whether the manipulation of the circuit will restore recognition memory following chronic meth self-administration (SA). Male and female rats were infused with retrograde GFP-tagged adeno-associated virus (AAV) in the PRH (Experiment 1) and the PFC (Experiment 2). Three weeks later rats were tested for NOR with half the animals exploring two familiar objects and half exploring a novel object. Brain tissue was processed for co-labeled cells containing both GFP and c-Fos, an indicator of neuronal activation. Rats spent more time exploring novel vs. familiar objects. During novel object exploration, animals that explored novel objects had more co-labeled cells that project from the PRH to the PFC, but not in cells that project from PFC to the PRH. A dual viral approach was utilized in the second set of experiments to activate the PRH to PFC pathway following meth SA (Experiment 3) or inhibit the PRH to PFC pathway in meth naïve animals (Experiment 4). AAV viral vectors containing CRE-dependent Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were infused into the PRH while retrograde AAV encoding CRE recombinase was infused into the PFC. A recognition memory deficit was established in meth SA rats and restored through activation of excitatory DREADDS (Experiment 3). In meth naïve animals a NOR memory deficit was also induced by activation of inhibitory DREADDS within the same circuit (Experiment 4). In conclusion, this data set suggests communication from the PRH to the PFC directs novel object recognition.

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