Project Summary/Abstract Disruptions in dopamine (DA) signaling are central to symptom presentation of several devastating neuropsychological disorders, such as schizophrenia, depression, Parkinson?s, and addiction, making normalization of DA signaling a primary concern in mental health(1-3). However, with the troubling side effects that can occur with direct dopaminergic manipulation(4; 3), and the identification of pathology within the circuits controlling DA neurons(6), the focus of much research has turned to the afferent regulation of the DA system. Through this effort, a critical pathway has been discovered from the ventral subiculum (Vsub) of the hippocampus to the ventral tegmental area (VTA), via the nucleus accumbens (NAc) and ventral pallidum (VP), that regulates population activity in the VTA(7). Population activity is important because only active DA neurons can fire in bursts(8), the behaviorally-salient output of the DA system(9-11), allowing the hippocampus to regulate the ?gain? of phasic DA release(8). A relatively unstudied regulator of hippocampal function is the medial septum (MS); a sub-region of the cholinergic basal forebrain, which, despite its known importance in psychiatric disorders, cognitive functions, and DA system interactions(13), has not been adequately evaluated in a pathway-specific manner. The MS innervates the hippocampus via primarily cholinergic and GABAergic projections(14), drives hippocampal theta rhythms(14), and affects goal-directed learning and memory(15; 16). Despite this, it has never been determined if the MS is an afferent regulator of the midbrain DA system. Additionally, no studies have drawn comparisons between Vsub-NAc-VP pathway regulation of VTA and substantia nigra (SNc), a region also implicated in psychopathology(3). Thus, it is critical to determine (1) whether the MS regulates DA activity in the VTA and SNc, (2) the mechanism and pathway by which this occurs, (3) whether this circuit is disrupted in a model of afferent-driven DA dysregulation, thereby highlighting the MS as relevant to treatment strategies, (4) the behavioral impact of this circuit, and (5) whether this circuit regulation is different in male and female rats. To test this, we will use in vivo electrophysiology to measure DA neuron firing in the VTA and SNc following MS activation with NMDA or DREADDs (hM3Dq). Pathway and neurotransmitter mechanism will be determined by inactivation of the Vsub or VP and by infusing specific antagonists into the VSub, respectively. The MAM model will be used to test this circuit in a model of afferent- driven DA dysregulation. The behavioral impact of this circuit will be tested by activating the MS with DREADDs (hM3Dq) and performing behaviors correlated to DA activity in the VTA (amphetamine-induced hyperlocomotion) and SNc (amphetamine-induced stereotypy) and a goal-direct, spatial memory task (T-maze reversal learning). These studies will lay the groundwork for the discovery of new treatment targets related to DA-driven symptoms and diseases by describing a novel regulator region of midbrain DA activity and by demonstrating differential neurotransmitter-based regional specificity in midbrain DA regulation.