CAREER: A role for axo-glial interactions between mesocortical dopamine axons and oligodendrocyte lineage cells in cortical hypomyelination caused by chronic adult social isolation

About This Grant

Today, brain plasticity is understood to include not only changes in how nerve cells communicate with each other, but also with cells responsible for producing the protective covering around nerve fibers, a substance known as myelin. When animals are isolated for long periods, it can affect regions of the brain that are involved in social behaviors. One of these changes is a reduction in myelin, and while this decrease is linked to social difficulties, it is not clear how it happens at a neuro-mechanistic level. The researcher of this project use a combination of novel gene-editing techniques, brain mapping tools, and behavioral tests to determine whether and how a brain nerve chemical called dopamine, which plays a role in a wide variety of behaviors, is involved in the reduction of myelin by social isolation. The findings will not only help advance the field’s understanding of the effects of social isolation but also of how dopamine influences brain changes seen in disorders like schizophrenia and addiction, which are linked to problems with myelin. This project also directly benefits local New York City communities by providing access to laboratory training and encouraging baccalaureate degree completion among a wide variety of students at a local college. Students’ families will be included in STEM outreach, increasing the likelihood of support and encouragement for the students’ academic and research endeavors, as well as a potential impact on younger relatives who may then be more likely to view STEM as a viable future direction. Social isolation is highly relevant across the animal kingdom due to the crucial role of social connections for all species. Across species, chronic social isolation causes experience-dependent myelination – specifically hypomyelination – in the medial prefrontal cortex (mPFC), a brain region critical for mammalian social behaviors. Evidence shows that this effect is associated with social deficits; however, the neurochemical mechanisms mediating this myelin plasticity are not known. Experiments in this proposal test the hypothesis that mesocortical dopamine mediates the effects of chronic adult social isolation on mPFC hypomyelination in mice. The investigators combine genetic and viral strategies (Cre-dependent adeno-associated virus vectors and CRISPR-Cas9 mutagenesis) with neuroanatomical approaches and behavioral experiments to test the predictions that: (1) anatomical and functional interactions occur between mesocortical dopamine terminals and local oligodendrocyte lineage cells; (2) midbrain dopamine neuron activity is necessary and/or sufficient to regulate mPFC myelination; and (3) midbrain dopamine neurons modulate mPFC myelination during chronic social isolation of adult animals. Data in support of the hypothesis that mesocortical dopamine mediates the effects of chronic adult social isolation on mPFC hypomyelination holds implications beyond social isolation because of dopamine’s wide-ranging roles in behavior. By identifying a role for dopamine in mPFC myelin plasticity, this research may guide the development of new pharmacotherapies that target myelin for the treatment of dopamine-related neuropsychiatric diseases, such as schizophrenia and addiction, which are known to be associated with altered myelin function. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.