Control of drug-reward behavior and relapse vulnerability via a specialized serotonergic-septohippocampal circuit

Summary/Abstract Recovery likelihood from substance use disorders (SUD) depends, in part, on the vulnerability magnitude for relapse. A major driver of this vulnerability is the incentive motivational effect of stimuli, such as environmental or situational context, paired with the rewarding substance of abuse. If the paired contextual memory is strong and persistent during abstinence, the vulnerability for relapse can be great. Preclinical results suggest that this paired motivational effect is tunable by certain brain neurons that produce the neurochemical serotonin. Our recent work revealed that a specific subtype of brain serotonergic neuron, named genetically as r2Hoxa2-Pet1, plays a central role in determining the persistence of contextually conditioned, cocaine-seeking behavior during abstinence, likely through modulating the durability of encoded cocaine memories. We have begun delineating the circuits modulated by r2Hoxa2-Pet1 neurons. We found that r2Hoxa2-Pet1 neurons project axon fibers to the prefrontal cortex, hippocampus, and lateral septum intermediate – all brain structures implicated in contextual memory and important to valence in cocaine addiction. We found that certain r2Hoxa2-Pet1 neurons deploy a presynaptic structure called a pericellular basket comprised of numerous synaptic boutons ensheathing (basketing) the targeted neuron soma and proximal dendrites, suggesting privileged control over the output of the basketed cell. r2Hoxa2-Pet1 pericellular baskets are found most densely in the lateral septum intermediate (LSi). Work by others shows that the LSi contributes to reward reinforcement through interconnections with the lateral hypothalamus and the mesolimbic dopamine system, is causally implicated in the retrieval of relapse-inducing cocaine memories, and contains neurons that gate mobility contextually. We refer to the LSi neurons basketed by r2Hoxa2-Pet1 boutons as LSi-r2P neurons. Our preliminary findings suggest that LSi-r2P neurons are GABAergic but atypical in molecular expression, excitability, and firing properties, suggesting they are a novel cell type(s) with unique functions. We speculate that this r2Hoxa2-Pet1 and LSi-r2P circuit influences (limits or coordinates) engrams (neural representations of memory traces) encoding cocaine-use context and that this determines the strength and durability of cocaine-seeking behavior during abstinence and thus may influence vulnerability magnitude for relapse. In this exploratory, foundational R21 grant, we will, in Aim 1, delineate the intrinsic properties of the LSi-r2P neurons (excitability, firing properties, morphology, transcriptome, and output targets) and, in Aim 2, characterize the transmission interactions from r2Hoxa2-Pet1 baskets to LSi-r2P neurons. Revealed will be circuits, cells, and signaling pathways which may underlie the propensity for context-triggered drug-seeking behavior. This work may have substantial translational value because our pilot findings suggest that r2Hoxa2-Pet1 neurons also exist in the human brain.