Interplay between limbic norepinephrine and dopamine circuits in sex differences in reward and aversion - PROJECT SUMMARY/ABSTRACT Norepinephrine (NE) and dopamine (DA), the two major catecholamines in the brain, play a key role in various psychological, physiological and behavioral processes ranging from reward and aversion to learning and motivation. As important mediators of homeostasis, the central catecholamines have been implicated in many neuropsychiatric diseases including substance use disorders. Despite a greater prevalence of such diseases today, many modern pharmacotherapies for treating catecholamine-related disorders are non-specific and lack efficacy due, in part, to a limited knowledge of the pathophysiology underlying local catecholamine circuits. Accumulating evidence suggests that NE neurons in the locus coeruleus (LC) and the nucleus of the solitary tract (NST), the main sources of brain NE, projecting to the ventral tegmental area (VTA, the primary source of mesolimbic DA), have been regarded as regulators of limbic DA functions. Thus, new insights into how the NE systems interact with mesolimbic DA are essential to understand DA-associated positive and negative affective states. However, whether LC/NST-NE inputs to the VTA (LC/NST-NEàVTA) modulate limbic VTA-DA signaling and whether there are sex differences in these pathways is still not well understood due in part to limitations of conventional techniques that lack sensitivity, selectivity, and the spatial and temporal resolution necessary to the target NE neurons. In Aim 1, we will map the anatomical and neurochemical distribution of LC-NE and NST-NE projections to the VTA and their contribution to VTA-DA regulation in the ventral striatum (nucleus accumbens (NAc) and olfactory tubercle (OT)) via NE receptors and transporters in the VTA of male and female rats. For this Aim, a novel combination of local chemogenetic manipulations of targeting the NE neurons coupled with a high- density neurochemical sensing microelectrode array will be used. In Aim 2, we will determine the functional role of LC/NST-NE signaling in the VTA on VTA-DA transmission within the ventral striatum of male and female rats in anxiety-like/aversion and reward (drug) seeking behaviors by optogenetically modulating the NE neurons in methamphetamine self-administration paradigms. These studies will (i) reveal the neurobiological mechanisms underlying the critical role of the LC/NST- NEàVTA-DA within NAc/OT circuits in limbic catecholamine systems and their crosstalk linked to various essential brain functions including reward/aversion and drug seeking as well as its distinct sex differences, and (ii) provide insight into how these catecholamine circuits may be implicated in neuropsychological and substance use disorders and may lead to novel sex specific treatment strategies.
