DESCRIPTION (provided by applicant): White matter (WM) neurons are phylogenetically conserved; and in primates and other species with large gyrencephalic brains, substantial numbers of WM neurons persist beyond early development. These are neurochemically and morphologically heterogeneous. During development, these neurons are known to have essential roles in the establishment of both thalamocortical and corticocortical circuitry, and are implicated in gyral formation (Suarez-Sola et al., 2009; Kanold and Luhmann, 2010; Zilles et al., 2013; Sun and Hevner, 2014). In the adult, very little is known about these neurons, beyond the fact that at least some of these are incorporated into cortical circuitry. An important role in vascular regulation is strongly suggested for a contingent of NOS-positive WM neurons (Barbaresi et al., 2014). Further, WM neurons have attracted interest since the density of superficial WM neurons is increased in brains of some schizophrenic subjects as compared with controls (Connor et al., 2011; Yang et al., 2011). Increased density of WM neurons is also reported in the brains of autistic subjects (McFadden and Minshew, 2013). The present proposal is motivated by the hypothesis that WM neurons remain functionally important in the adult and that a nonhuman primate model will offer productive opportunities for further cellular, molecular, and circuit-level investigations. A monkey model is needed because of the greater accessibility of monkeys, as opposed to humans, to experimental manipulations, and because of the many developmental and circuitry differences between primates and rodents (Judas et al., 2010b). Key parts of the experimental design are 1) a systematic quantitative analysis of the superficial and deep WM populations in the adult rhesus monkey, sampled across different cortical regions and scored in terms of excitatory and inhibitory subpopulations, and 2) a comparable analysis in the perinatal and infant monkey (<12 months), to determine region- and cell-type differences in the numerical fall-off of WM neurons. Visualization of WM subpopulations will be by immunohistochemistry for NeuN and other standard cell type markers, in histologically sectioned brains. Success will be defined as identifying that region specific differences occur in both the adult and infant brain, as is predicted by region specific differences already reported in the human brain (Garcia-Marin et al., 2010). Anticipated next steps, in an eventual R01, would be to address network connectivity and postsynaptic targets of WM subpopulations, and to investigate anatomical differences in the WM populations across the lifespan and in monkey models of disease and other conditions.

PUBLIC HEALTH RELEVANCE: White matter (WM) neurons are a mixed population of excitatory and inhibitory neurons, that are phylogenetically conserved and have important roles in early cortical development. In primates and other species with large gyrencephalic brains, substantial numbers of WM neurons persist in the adult, where they are thought to contribute to multiple processes, including vascular regulation and hemodynamic changes, coordination of corticocortical and thalamocortical communication, and central cholinergic circuitry. The present proposal aims to acquire quantitative data about regional and cell-type distribution of WM neurons in the adult rhesus monkey and their fall-off in the infant, with the additional aim of developing a nonhuman primate model for further investigations of WM neuron function, with relevance for normal and abnormal human brain function.