Mechanisms of Motivation in the Nucleus Accumben

The nucleus accumbens (NAc) is a primary brain target of mesolimbic dopamine projections, and is well known to be important to motivation for rewards. Precisely how NAc neural systems generate motivation remains unclear. Here, I aimed to tease apart 1) the different roles of the two main neural populations/systems in NAc in generating reward motivation and 2) the relative roles of neuronal excitations versus neuronal inhibitions in NAc in generating intense motivation for reward. I also aimed to 3) expand understanding of the role of NAc mesolimbic dopamine projections to include motivation for social rewards, such as making a social partner potentially more attractive to interact with, beyond the motivation for physical sensory rewards (food, drugs, etc.) that has been traditionally studied.;First, I examined the role of the two main subpopulations of neurons in NAc (medium spiny neurons): NAc D1 neurons (i.e., containing D1-type dopamine receptors, and which form a 'direct pathway' for anatomical outputs to midbrain) versus D2 neurons (i.e., with D2 receptors for dopamine, and forming only 'indirect' pathways to forebrain targets). D1-direct neurons have been proposed to be reward-related or "go" neurons, whereas D2-indirect neurons have been thought to cause aversion or "stop" signals. I used newly-developed optogenetic techniques in transgenic mice, which now allow these two populations to be selectively excited in ways that were impossible before. I stimulated these two distinct subpopulations one at a time, using viral vectors targeting either D1 neurons in D1 Cre mice or D2 neurons in D2 Cre mice. In line with expectations, I found that laser-light stimulation of D1 neurons in the NAc was potently rewarding, and that mice receiving D1 stimulation would avidly work for laser depolarization and actively seek out locations paired with laser reward. Surprisingly and in contrast to standard hypotheses, I found laser-light stimulation of D2 neurons was also rewarding, and that mice would work for D2 stimulation, though at weaker levels than D1 levels.;Next, I tested the relative roles of NAc neuronal hyperpolarization vs depolarization in generating intense motivation. A major hypothesis is NAc neuronal hyperpolarization (inhibition) generates motivation by releasing targets from constant suppression (disinhibition). I directly tested whether NAc neuronal inhibition is necessary for drug microinjections (glutamate blockade) to induce intense reward motivation by reversing neuronal hyperpolarization with optogenetic laser-induced depolarization at the same NAc site. My results confirmed that NAc hyperpolarization was necessary for intense motivation to eat.;Further, to test more directly whether NAc hyperpolarization is sufficient to enhance eating, I directly used inhibitory optogenetic laser techniques to hyperpolarize neurons without drugs. I found that in direct laser inhibition of NAc neurons generated intense reward motivation to enhance food intake, confirming that NAc inhibition is sufficient to produce intense motivation.;In a final pilot dopamine experiment, I have examined how enhancement of dopamine release within the NAc can increase motivation for social exploration. I discovered that pairing laser activation of dopamine neurons to NA in TH Cre rats with encountering a social partner made that partner suddenly more attractive to pursue and interact with.;Taken together, these studies illuminate key neural mechanisms through which the NAc produces reward motivation. These findings highlight how particular neural systems and neuronal states generate intense motivations for brain stimulation, food and social rewards.