Abstract

Early life trauma is a risk factor for disorders characterized by altered motivation, including substance use disorder and depression. However, early adversity that is not overwhelming can promote later resilience to stress-related disorders. Our laboratory models brief early life scarcity using the Limited Bedding and Nesting (LBN) manipulation, in which rat dams and pups are reared in a low resource environment from pups PND 2-9 and compared to control rats raised in standard housing conditions. This talk will detail how LBN causes sex- and reinforcer-specific effects on motivated behavior. In male rats, prior exposure to LBN reduces self-administration and motivation for a drug reward (morphine), while increasing motivation for the natural rewards of sucrose and a social partner. In contrast, in female rats, LBN exposure impairs motivation for sucrose, consistent with an anhedonia-like phenotype. Yet, LBN does not disrupt motivation for social reward or morphine in females, perhaps because these rewards are so reinforcing a deficit is not detectable. To identify factors that mediate the effects of LBN on behavior, we are delineating molecular changes in the nucleus accumbens (NAc), a region that is a hub in reward circuitry. RNA sequencing revealed that LBN produced sex-specific changes in NAc gene transcription, including in genes related to glutamate transmission. Using a genome-wide histone posttranslational modification (PTM) screen, we identified sex-specific histone marks altered by LBN and are linking PTMs to transcriptional changes. Importantly, identifying factors that promote vulnerability/resilience to certain reinforcers may lead to novel treatment options for disorders characterized by altered motivated behavior.

Abstract

Abstract

Successful spatial navigation and orientation are critical for mammalian survival. Lesions to a brain region called the retrosplenial cortex (RSC) dramatically impair spatial orientation abilities, emphasizing the need to decipher the unique aspects of RSC circuit computations supporting its GPS-like functions. Here, using optogenetic circuit mapping, transcriptomics, in vivo recordings, and computational modeling we build towards a comprehensive cellular and circuit understanding of the RSC. We identify a uniquely small and excitable pyramidal neuron and show that it is the primary recipient of spatially-relevant inputs to the RSC. Observed synaptic dynamics enable these small neurons to compute the speed of head rotation, despite receiving head direction inputs that do not explicitly encode speed. We also show that two distinct fast brain rhythms identified in the RSC are the signatures of two very different long-range neuronal synchronization mechanisms, each precisely controlled by the speed of movement. These findings are confirmed across both rats and mice, highlighting key evolutionarily conserved circuit computations performed by the RSC in support of successful spatial navigation.