Stress-induced motivational impairment is marked by diminished frontocortical cellular communication and neuropeptide signaling.

Background: Repeated stress is a risk factor for developing motivational deficits which are common across a variety of disease states including depression and are particularly resistant to treatment with conventional pharmacotherapies. Amotivation is multifaceted and can be caused by impairments in value learning, reward anticipation, and cost-benefit decision-making. Importantly, not all individuals who experience chronic stress develop motivational symptoms, suggesting there may be neurobiological signatures of resilience. Methods: We developed a novel head-restrained effortful reinforcement task in which anticipatory and consummatory behavior can be tracked. Chronic non-discriminatory social defeat stress combined with behavioral analysis and spatially resolved RNA sequencing were used to determine the transcriptional signatures of stress in the anterior cingulate cortex of mice with varying levels of motivational impairment as well as unstressed controls. Results: While stress led to a general impairment in effortful reward seeking, animals differed in the extent of behavioral deficit, with increased 'susceptibility' marked by a unique set of differentially expressed genes within the anterior cingulate cortex (ACC). By leveraging the spatial component of our data, we were further able to identify altered interactions from inhibitory neurons and astrocytes to excitatory pyramidal cells, which correlated with intact or impaired motivated responding following stress exposure. Conclusions: Chronic psychosocial stress results in divergent effects on motivated behavior and distinct ACC transcriptional signatures that are concentrated in excitatory pyramidal neurons. Cell interaction analysis implicates enhanced inhibitory neuropeptide signaling and reduced astrocytic contact signaling as upstream markers of motivational resilience and point toward ACC hyperexcitability as a targetable feature of stress susceptibility.