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