Axo-glial interactions between midbrain dopamine neuron axons and oligodendrocyte lineage cells in the corpus callosum.

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Bona fide synapses between neurons and oligodendrocyte precursor cells (OPCs), a class of progenitors in the CNS that gives rise to myelinating oligodendrocytes (OLs), were first reported two decades ago. Since then, observations of neural activity- and experience- induced regulation of myelination in the adult brain have been reported. Impairments in myelin regulation contribute to social avoidance behaviors, motor learning deficits, and perturbations in the long-term retention of emotional memories, and it has been posited that myelin dysregulation contributes to neuropsychiatric disorders. Knowledge of the neuronal cell types governing myelin regulation could therefore provide new possibilities for therapeutic intervention in neuropsychiatric disorders. Evidence suggests a potential role for midbrain dopamine neurons in myelin regulation. Dopamine-related neuropsychiatric disorders, including schizophrenia, addiction, and Parkinson's disease, are associated with dysregulation of white matter tracts. Reduced white matter integrity as measured by fractional anisotropy and decreased expression of myelin-associated genes have been reported, suggesting altered function of OPCs and OLs in these clinical populations. While it is not clear from these findings whether white matter abnormalities are directly caused by altered dopamine neurotransmission, preclinical studies have demonstrated that atypical antipsychotics enhance myelin repair following cuprizone-induced demyelination by increasing the proliferation and differentiation of OPCs. Preliminary data from our group demonstrate dopamine receptor expression by forebrain-derived OPCs and OLs, consistent with previous reports. However, whether OPCs and OLs in the CC receive afferent input from midbrain dopamine neurons has never been systematically addressed. Midbrain dopamine neurons are heterogeneous, with subpopulations capable of glutamate co-transmission. This is particularly relevant in light of the fact that glutamate neurotransmission promotes myelination. Preliminary data supports a possible role for midbrain dopamine-glutamate neurons in myelin regulation, wherein proximity ligation assay (PLA)-mediated detection of neurotransmitter-specific release sites reveals contacts between dopamine-glutamate axons and OPCs and OLs in the adult CC. We propose to characterize neuro-glia interactions between dopamine-glutamate neuron axons and OPCs and OLs in the adult corpus callosum (CC) as a first step in examining the role of these neurons in myelin regulation. Experiments will adopt a multi-pronged approach that incorporates `intronic recombinase sites enabling combinatorial targeting' (INTRSECT), PLA-mediated detection of `dopamine-glutamate' neuron release sites, wide field and computational confocal microscopy, fluorescence-activated cell sorting (FACS), and complex motor learning. A promising aspect of this work is its potential contribution to the delineation of a relationship between midbrain dopamine neuron function and myelin regulation. Integral to completion of the project will be underrepresented undergraduate students at the College of Staten Island, CUNY.