James M. Otis, Ph.D. - US grants

? DESCRIPTION (provided by applicant): Function and natural activity dynamics of thalamic inputs for reward seeking. Compulsive reward seeking and taking are hallmarks of addiction, although the precise neural circuits that orchestrate these basic motivational states remain unclear. This is in part due to a lack of experimental feasibility, as it has been difficult to conrol and monitor the activity of cell-type specific neurons in vivo. For example, the paraventricular thalamus (PVT) is a midline thalamic nucleus that interfaces with motivational circuits, is a critical regulator of feeding, and is necessary for reinstatement in several models of drug seeking. Despite this, how PVT neurons function within a broader circuit to regulate these motivational states is unknown. Thus, the objective of this project is to use contemporary tools to study the precise neurocircuitry that engages PVT for the control of reward seeking. Here I propose to identify the function and natural activity dynamics of two primary PVT inputs, particularly from the lateral hypothalamus (LH) and prelimbic cortex (PLc), for the control of reward seeking. The function of PVT inputs for reward seeking will be evaluated with inhibitory optogenetics during distinct phases of a cue-induced reward-seeking task (Aim 1). Furthermore, the natural activity dynamics of these projection-specific neurons will be visualized during reward seeking and taking through deep-brain calcium imaging in awake, freely moving mice (Aim 2). Based on my preliminary data and published work by my sponsor and others, I hypothesize that PVT-projecting LH neurons will be active and necessary for reward seeking and consumption. In contrast, based on my preliminary data and my previously published work, I hypothesize that PVT-projecting PLc neurons will be active and necessary specifically for cue-driven reward seeking, but not reward seeking and consumption in general. These data would suggest that the PVT acts to integrate distinct signals regarding motivational drive (LH) and environmental stimuli (PLc) to regulate reward-seeking behavior. Regardless of the results, these experiments will identify the function and natural activity dynamics of LH-PVT and PLc-PVT neurons for the control of reward seeking and taking.

SUMMARY/ABSTRACT Substance use disorder (SUD) is associated with abnormalities in the dorsomedial prefrontal cortex (dmPFC), a brain region that is activated by drug-predictive cues and contributes to drug seeking. Recent studies show that non-overlapping cell populations within dmPFC, defined by gene expression or projection target, display unique activity profiles during reward seeking. Interestingly, even within these defined cell populations considerable cell- to-cell variability is found suggesting that greater resolution is needed to understand the influence of unique dmPFC neuronal ensembles on behavior. Overall, the influence of unique dmPFC neuronal ensemble activity patterns on drug seeking is unclear. Activity in the dmPFC is highly suppressed following persistent drug use in rodents and humans, in part due to the reduced function of channels that control the intrinsic excitability of dmPFC output neurons. Considering this suppressed excitability, it is surprising that the presentation of drug-associated cues can evoke robust activity in dmPFC of patients with SUD, with that activity being a reliable predictor of future relapse. Thus, a rapid shift in the excitability of dmPFC neurons likely occurs during drug-associated cue exposure, a change that may be controlled by the neuromodulator noradrenaline. In support of this idea, here I show that chemogenetic inhibition of locus coeruleus noradrenergic axons in dmPFC (LC dmPFC) abolishes cue-induced reinstatement of heroin seeking. Furthermore, I confirm that downstream dmPFC excitatory output neurons display bidirectional plasticity following heroin use, becoming hypoactive following heroin self-administration but recovering normal activity during cue-induced relapse. Considering these findings, here I investigate the hypotheses that noradrenergic LC dmPFC neurons become active during the presentation of drug-predictive cues (Aim 1), that noradrenergic activity in dmPFC is critical for cue-induced drug seeking and for amplifying activity in downstream dmPFC neuronal ensembles (Aim 2), and that activity in select dmPFC neuronal ensembles modulates cue-induced drug seeking behavior (Aim 3). Overall, these experiments will characterize the activity dynamics and function of precisely defined dmPFC circuit elements during cue-induced heroin seeking. Findings from these studies are critical for the development of strategies that could normalize dmPFC activity and reduce relapse vulnerability in patients suffering from SUD.