A prominent theory argues that DA cells generate predictive signals for impending reward and/or they signal when reinforcement contingencies change. It is argued here that by taking a more dynamic and broad systems view of DA's contribution to cognition, we can better understand the significance of DA function;we need to consider not only how DA regulates plasticity in efferent structures, but also how DA neurons themselves are regulated by experience. Studies from the last grant period provide compelling evidence that DA function is context-dependent. The present proposal includes four Specific Aims that will allow us to test the hypothesis that context regulation of DA neuronal signaling of reward information is derived from a combination of inputs from existing memory and decision making systems of the prefrontal cortex (PFC) and context evaluation by hippocampus (HPC). PFC and HPC are thought to impact the timing of the DA reward signal relative to salient cues by experience-dependent gating of sensory information to DA neurons via the tegmentum. This work incorporates a combination of 1) high density single unit recording so that we can understand (relative to DA signals) the neural codes within the PFC, HPC, and two tegmental areas, the pedunculopontine nucleus (PPTg) and the lateral dorsal tegmental nucleus (LDTg), 2) reversible inactivation of brain structures to test for functional connectivity between regions of interest, and 3) behavioral genetic analysis to identify the role of the NMDA system in DA regulation.
Aim 1 will determine the nature of neural representation in structures that regulate DA activity: PPTg, LDTg, HPC and PFC.
Aim 2 will determine whether the context-sensitivity of DA neurons in the ventral tegmental area (VTA) and the substantia nigra (SNc) is due to PPTg, LDT, HPC, or PFC input.
Aim 3 will determine whether context-sensitivity of PPTg, LDTg and PFC neural representations is ultimately derived from HPC or PFC.
Aim 4 will test whether it is the glutamate (NMDA) component of the afferent input that regulates burst firing by DA cells by testing these cellular properties in freely behaving mice that are selectively missing NR1 receptors on DA cells. Broad Significance: Understanding how context information regulates signaling by DA neurons is of fundamental importance for therapeutic development in cases of drug relapse, Parkinson's disease, and normal age associated decline in learning.

Public Health Relevance

Malfunction of the dopamine system has been implicated in many disorders (e.g. Parkinson's disease) and maladaptive conditions (e.g. drug addiction and juvenile delinquency). This work proposes to delineate how memory systems of the brain modify the neural codes of dopamine neurons, allowing for new therapeutic interventions to be developed.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Neurobiology of Learning and Memory Study Section (LAM)
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Osborn, Bettina D
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University of Washington
Schools of Arts and Sciences
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Fobbs, Wambura C; Mizumori, Sheri J Y (2017) A framework for understanding and advancing intertemporal choice research using rodent models. Neurobiol Learn Mem 139:89-97
Mizumori, Sheri J Y; Baker, Phillip M (2017) The Lateral Habenula and Adaptive Behaviors. Trends Neurosci 40:481-493
Baker, Phillip M; Mizumori, Sheri J Y (2017) Control of behavioral flexibility by the lateral habenula. Pharmacol Biochem Behav 162:62-68
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Baker, Phillip M; Jhou, Thomas; Li, Bo et al. (2016) The Lateral Habenula Circuitry: Reward Processing and Cognitive Control. J Neurosci 36:11482-11488
Tryon, Valerie L; Mizumori, Sheri J Y; Morgan, Michael M (2016) Analysis of morphine-induced changes in the activity of periaqueductal gray neurons in the intact rat. Neuroscience 335:1-8
Redila, Van; Kinzel, Chantelle; Jo, Yong Sang et al. (2015) A role for the lateral dorsal tegmentum in memory and decision neural circuitry. Neurobiol Learn Mem 117:93-108
Baker, Phillip M; Oh, Sujean E; Kidder, Kevan S et al. (2015) Ongoing behavioral state information signaled in the lateral habenula guides choice flexibility in freely moving rats. Front Behav Neurosci 9:295
Fobbs, Wambura C; Mizumori, Sheri J Y (2014) Cost-benefit decision circuitry: proposed modulatory role for acetylcholine. Prog Mol Biol Transl Sci 122:233-61
Jo, Yong Sang; Lee, Jane; Mizumori, Sheri J Y (2013) Effects of prefrontal cortical inactivation on neural activity in the ventral tegmental area. J Neurosci 33:8159-71

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