Mechanisms to weigh threat and potential gain in the consideration of incipient actions are fundamental to survival and must reflect a basic function of mammalian brain. Cortico-subcortical functional- anatomical systems, alternatively called forebrain macrosystems, are cortico-subcortical information processing units thought to subserve these mechanisms. Macrosystems relay affect-labeled assessments of on-going cortical representations [1] back to the cognitive apparatus, [2] to neurons in the forebrain and brainstem that give rise to ascending modulatory (state-setting) projections (e.g., dopaminergic, cholinergic, etc.) and [3] to brainstem motor effectors. Lateral septum together with its projection area in the preoptic region (LPH) has been proposed to comprise a forebrain macrosystem by several research groups. However, whereas striatopallidum and extended amygdala have been convincingly demonstrated to exhibit the organizational framework that characterizes macrosystems, even basic septal-preoptic relationships have yet to receive much experimental attention. We do know that the main afferents of midbrain neurotensin receptors, which are powerful modulators of dopaminergic function and regulate behavioral sensitization to psychostimulant drugs, arise in LPH. The main purpose of the work proposed in this application is to bring our knowledge of septal-preoptic relationships to parity with what we know about the other macrosystems and thus improve our capacity to address how all of these systems interact to influence behavior. Research is proposed with the following specific aims: 1. Establish neuroanatomical relationships of the lateral septum and LPH. 2. Investigate behavioral correlates of stimulating and inactivating the lateral septum and LPH. 3. Determine if activation of LPH results in internalization of NTS1 nerurotensin receptors by dopaminergic neurons in the ventral tegmental area. The results of these studies results will improve our capacity to address the neurobiological bases of maladaptive decision-making, which coexists in humans with anxiety, depression, fear, panic, obsessive-compulsive behaviors and addictions. At a subclinical, social level, bad decisions pervade chronic joblessness, dysfunctional interpersonal relationships, ruinous child-rearing and addictions. Indeed, addiction is bad decision-making by definition, i.e., behavior compulsively repeated in the certain knowledge that it is self-destructive. The proposed research addresses a brain system concerned with mechanisms that underlie decision-making by investigating its neuroanatomical relationships, the behavioral correlates of stimulating and inactivating it and the mechanisms by which it influences the reward system. The results should lead to better means to address how brain mechanisms subserving decision-making are affected by stress, alcohol and drugs, and, hopefully, to improved approaches to countering maladaptive decision-making, which, to a significant extent, underlies many of the chronic problems experienced by American individuals, families and society, including various forms of addiction and the seemingly inevitable cascades of relapse.
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