Synaptic and Behavioral Profile of Multiple Glutamatergic Inputs to the Nucleus Accumbens

Excitatory afferents to the nucleus accumbens (NAc) are thought to facilitate reward seeking by encoding reward-associated cues. Selective activation of different glutamatergic inputs to the NAc can produce divergent physiological and behavioral responses, but mechanistic explanations for these pathway-specific effects are lacking. Here, we compared the innervation patterns and synaptic properties of ventral hippocampus, basolateral amygdala, and prefrontal cortex input to the NAc. Ventral hippocampal input was found to be uniquely localized to the medial NAc shell, where it was predominant and selectively potentiated after cocaine exposure. In vivo, bidirectional optogenetic manipulations of this pathway attenuated and enhanced cocaine-induced locomotion. Challenging the idea that any of these inputs encode motivationally neutral information, activation of each discrete pathway reinforced instrumental behaviors. Finally, direct optical activation of medium spiny neurons proved to be capable of supporting self-stimulation, demonstrating that behavioral reinforcement is an explicit consequence of strong excitatory drive to the NAc. ► Hippocampal input is predominant in the medial NAc shell and potentiated by cocaine ► Activity in hippocampal axons in the NAc drives cocaine-induced locomotion ► Irrespective of the pathway, mice work for photostimulation of glutamate axons in NAc ► Mice work to obtain direct optogenetic stimulation of NAc shell neurons Britt et al. characterize hippocampal, amygdala, and prefrontal cortex input to the nucleus accumbens. Hippocampal input is shown to be predominant in the medial accumbens shell, yet photostimulation of axons from each pathway is sufficient to reinforce instrumental behaviors.