Section on Neurobiology of Compulsive Behaviors

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

Early life adversity increases striatal density of dopamine D1 receptors and promotes social alcohol drinking in mice, especially males: The brain’s reward circuitry remains sensitive to experience throughout early life and into adulthood, allowing individuals to adapt to their unique environments. It is thought that adverse experiences early in life can increase vulnerability to substance use disorders, likely through alterations to this circuitry. Yet, the precise neurobiological mechanisms by which early life adversity acts are incompletely characterized. In this study, we use the limited bedding and nesting (LBN) paradigm as a translationally relevant model of fragmented maternal care in genetically identical C57BL/6J mice. After LBN-rearing, we assess the lasting behavioral and neurobiological impacts of this experience in adulthood. In robust sample sizes, our results validate previous findings of increased risk avoidance, enhanced acute response to alcohol, and greater voluntary alcohol drinking in LBN-reared mice, especially males, even when tested in social housing conditions. Further, we uncover increases in the density of dopamine D1-like receptor in the striatum, which skews the balance of D1- to D2-like receptor density in LBN-reared mice, relative to cross-fostered controls. Interestingly, after voluntary alcohol drinking, we find a downregulation in D1-like receptor density that restores the balance of dopamine receptors in the LBN-reared mice. We posit that LBN-rearing conditions upregulate striatal density of dopamine D1-receptors, via both transcriptional and post-transcriptional mechanisms, and it alters risk avoidance and acute alcohol stimulation to promote alcohol drinking among adversity-exposed mice. In all, our findings uncover specific neurobiological mechanisms that promote alcohol consumption after early life adverse events and point towards complex interactions between early life experience, dopamine receptor regulation, alcohol, and sex-related factors in the mediation of AUD vulnerability. Visual stimuli and frontal cortices, but not sensory, drive cholinergic-dependent dopamine in the mouse dorsal striatum: Everyday decisions rely on associations between sensory stimuli, actions, and outcomes. The striatum is well-positioned to facilitate these sensorimotor associations through dopamine-dependent mechanisms, including potentially through a recently identified striatal circuit in which specific cortical and thalamic inputs to the striatum can recruit striatal cholinergic interneurons to provide local control over dopamine release. While midbrain-originating dopamine signals have been extensively studied, less is known about what this local cholinergic circuit conveys, or which pathways can drive it in vivo. Here, we use in vivo methods to demonstrate that novel sensory stimuli drive striatal dopamine in a cholinergic-dependent manner. In asking which pathways may elicit these signals, we use anatomical and functional methods to demonstrate that sensory cortical areas do not form direct synaptic connections with cholinergic interneurons and cannot evoke local dopamine signals ex vivo. Instead, frontal areas, such as anterior cingulate and prelimbic cortices, form robust synaptic connections with cholinergic interneurons and can evoke striatal dopamine both ex vivo and in vivo. These results reveal significant differences between cortical areas in their ability to drive striatal cholinergic interneurons and dopamine, with implications for the circuit logic of how sensorimotor associations are formed.