No abstract

Synaptic plasticity contributes to behavioral adaptations. As a key node in the reward pathway, the nucleus accumbens (NAc) is important for determining motivation-to-action outcomes. Across animal models of motivation including addiction, depression, anxiety, and hedonic feeding, selective recruitment of neuromodulatory signals and plasticity mechanisms have been a focus of physiologists and behaviorists alike. Experience-dependent plasticity mechanisms within the NAc vary depending on the distinct afferents and cell-types over time. A greater understanding of molecular mechanisms determining how these changes in synaptic strength track with behavioral adaptations will provide insight into the process of learning and memory along with identifying maladaptations underlying pathological behavior. Here, we summarize recent findings detailing how changes in NAc synaptic strength and mechanisms of plasticity manifest in various models of motivational disorders.

The integrated stress response (ISR) maintains proteostasis by modulating protein synthesis and is important in synaptic plasticity, learning, and memory. We developed a reporter, SPOTlight, for brainwide imaging of ISR state with cellular resolution. Unexpectedly, we found a class of neurons in mouse brain, striatal cholinergic interneurons (CINs), in which the ISR was activated at steady state. Genetic and pharmacological manipulations revealed that ISR signaling was necessary in CINs for normal type 2 dopamine receptor (D2R) modulation. Inhibiting the ISR inverted the sign of D2R modulation of CIN firing and evoked dopamine release and altered skill learning. Thus, a noncanonical, steady-state mode of ISR activation is found in CINs, revealing a neuromodulatory role for the ISR in learning.