The reward integrator

FINALIST Tara LeGates Tara LeGates received her B.S. in Biopsychology from Rider University and a Ph.D. from Johns Hopkins University. She completed a postdoctoral fellowship at the University of Maryland School of Medicine, where she established the importance of the strength and plasticity of hippocampus-nucleus accumbens synapses and reward behavior. LeGates is now an assistant professor at the University of Maryland, Baltimore County (UMBC). Her lab studies how neuronal circuits integrate information to regulate behavior and their alterations in psychiatric disorders. [www.sciencemag.org/content/370/6512/46.1][1] Rewards are powerful stimuli that drive and reinforce goal-directed behaviors. There are a variety of factors that contribute to this process—such as motivation, anticipation, and contextual information—that are encoded in different brain regions. As a result, normal reward-related behaviors require proper functional integration of signals from multiple brain regions, but the essential pathways and underlying mechanisms of integration remain elusive. We have found that a critical mediator of this behavior is the connection between the hippocampus and nucleus accumbens (NAc) ([ 1 ][2]). The NAc receives information from multiple brain regions and must integrate it to process rewarding stimuli and modulate hedonic responses ([ 2 ][3]–[ 4 ][4]). We were particularly interested in examining the excitatory input from the hippocampus because this region is involved in mediating contextual learning and memory, which are critical to an organism's ability to return to the location of a previous reward to obtain that reward again. Previous work provided evidence that the hippocampus and NAc are linked, implicating the potential importance of this connection in reward signaling ([ 4 ][4]–[ 8 ][5]). Hippocampal input to the NAc drives neuronal activity ([ 4 ][4], [ 9 ][6]), and rewarding stimuli such as cocaine strengthen the connectivity between these two nuclei ([ 10 ][7]). Thus, we hypothesized that plasticity of these excitatory synapses is a critical regulator of reward-related behaviors. Using whole-cell electrophysiology in mouse brain slices, we demonstrated that hippocampus-NAc synapses can be strengthened in an activity-dependent manner through long-term potentiation (LTP). We dissected the molecular mechanisms underlying this potentiation and found that it requires canonical N -methyl-d-aspartate receptor–dependent pathways in the hippocampus ([ 11 ][8]) but is independent of dopamine receptor signaling. This was surprising because activity of the dopamine-1 receptor (D1) is required for the induction of LTP at other excitatory synapses in the NAc ([ 12 ][9]–[ 15 ][10]). Although these slice experiments were informative for establishing plasticity and its underlying mechanisms, the question remained as to whether LTP can be induced at the hippocampus-NAc synapse in vivo. Using high-frequency optogenetic stimulation of these synapses, we demonstrated that they are capable of undergoing LTP in vivo. To determine the relevance of this potentiation in regulating reward-related behaviors, we combined our optogenetic approach with the conditioned place preference (CPP) paradigm. This task uses a two-chamber arena connected by a corridor, and mice are alternatively confined to each chamber—one containing a reward, one containing no reward—over multiple days. When the mice are later allowed free access to the arena, they spend more time in the chamber that had been previously paired with the reward, showing CPP. Rather than presenting a reward during conditioning, we optogenetically induced LTP while mice were confined to one of the chambers. Potentiation of these synapses in the absence of any external rewarding stimuli was sufficient to induce CPP. (The brief, highfrequency stimulation during the conditioning phase occurred at least 24 hours before testing CPP, showing that potentiation of this synapse produces long-lasting effects on reward behavior.) Our results clearly demonstrated that excitatory input from the hippocampus, which we know is important for driving NAc activity, regulates reward-related behaviors, and that potentiation of this synapse is itself rewarding. Maintaining excitatory drive in the NAc is crucial for maintaining a normal hedonic state ([ 16 ][11], [ 17 ][12]), and dysfunction of excitatory synapses in reward pathways both within and outside the NAc contributes to the genesis of depression ([ 17 ][12]). The validity of this assertion is further supported by studies showing that environmental stress, a common precipitator of depression in humans and related behaviors in animal models, weakens excitatory synapses in specific, stress-sensitive regions, including the hippocampus ([ 18 ][13], [ 19 ][14]). Antidepressants exert opposing effects to restore the normal function of these synapses ([ 20 ][15]–[ 24 ][16]). The clear bidirectional effect on these synapses occurs in parallel with many depression-related behavioral changes, such as anhedonia (loss of pleasure seeking) and social avoidance, suggesting that these changes may be causative. However, the exact nature of the stress-induced neuronal changes that promote depression in susceptible individuals remains unknown. We therefore sought to investigate how hippocampus-NAc synapses change in stress states related to depression. We used a well-validated chronic stress paradigm to induce depression-like changes in mice. The key reward-related effect of this paradigm is anhedonia, a core symptom of depression, which manifests as a loss of sucrose preference. Using whole-cell electrophysiology, we found that chronic stress weakens hippocampus-NAc synapses and impairs their plasticity. This effect was specific to the subtype of NAc neurons expressing the D1 receptor, a subpopulation of cells that has classically been associated with positive reward ([ 25 ][17]–[ 28 ][18]). This suggests that the weakening of excitatory drive at hippocampus-D1 NAc neurons contributes to stressinduced anhedonia. We also observed that chronic stress interferes with contextual reward learning, manifesting as a loss of CPP. These stress-induced changes in physiology and behavior were restored with antidepressant treatment, suggesting that restoration of excitatory synaptic strength and plasticity at the hippocampus-NAc synapse coincides with the reinstatement of normal reward behavior. Our work shows that alterations in the strength of hippocampus-NAc synapses underlie changes in reward-related behaviors, establishing this synapse as a critical regulator of reward. This finding represents a major step toward decoding the neurobiological basis for reward. Studying targeted circuits will continue to expand our understanding of the pathophysiology underlying depression and the mechanisms of antidepressant response, addressing a critical gap in our understanding of depression that currently leaves a substantial proportion of human patients inadequately treated. By moving beyond the monoamine reuptake paradigm, this field has considerable implications for the further development of antidepressant strategies. 1. [↵][19]1. T. A. LeGates et al. , Nature 564, 258 (2018). [OpenUrl][20][CrossRef][21][PubMed][22] 2. [↵][23]1. S. J. Russo, 2. E. J. Nestler , Nat. Rev. Neurosci. 14, 609 (2013). [OpenUrl][24][CrossRef][25][PubMed][26] 3. 1. G. D. Stuber, 2. J. P. Britt, 3. A. 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