Most mental health disorders have developmental etiologies and are produced by alterations in the formation and connectivity of specific forebrain regions including the medial frontal cortex and the striatum. Dopamine and other biogenic amines serve as neurotransmitters in the mature nervous system, and are also prominent drug targets in the treatment of neurological and psychiatric disorders. The dopamine system is expressed early in brain development, prior to the formation of synapses, and pleiotropically modulates decisions related to neuronal differentiation and circuit formation. Dopamine-dependent effects on dendritic morphology are receptor subtype-specific and brain region specific. We have gathered preliminary data suggesting that additional specificity is conferred by the stimulation of different signaling pathways depending on the receptor conformation(s) stabilized by distinct ligands (functional selectivity). The goals of this proposal are thus to identify the cellular functions of dopamine receptors during development of the frontal cortex and striatum, with direct reference to cellular subpopulations and functional selectivity. We propose three specific aims to probe the mechanisms by which dopamine receptor stimulation controls dendritic morphology.
In Aim 1, we will examine the effects of activating distinct dopamine receptor subpopulations on dendritic differentiation and cell signaling responses of dissociated neurons in vitro. We will test the hypothesis that D1 and D2 receptors can produce distinct effects on dendritic growth patterns depending on which G protein signaling pathway is induced by functionally distinct ligands.
In Aim 2, we will use recently created BAC reporter lines of mice (D1-tdTomato and D2-eGFP) to investigate whether spontaneous rates of process outgrowth differ as a function of dopamine receptor expression (and/or co-expression).
In Aim 3, we will move into in vivo systems, testing to what degree genetic loss of the D1 and D2 receptors alters dendritic morphology in D1- and D2 receptor- expressing neurons, respectively. Our research program will thus identify cell-specific differences in developmental responsiveness to a common biological ligand, dopamine. Alterations in dopaminergic activity during development, whether produced by genetic or pharmacological means, alters circuits mediating cognitive and emotional behaviors during critical epochs of development, and may lead to subsequent psychiatric disease later in life.
Dysfunctions in brain catecholamine systems have been linked to both the development and expression of mental illness. The studies contained in this proposal will help elucidate how ligand- specific dopamine receptor modulation contributes to the establishment of proper brain architecture.
|Ross, Emily J; Graham, Devon L; Money, Kelli M et al. (2015) Developmental consequences of fetal exposure to drugs: what we know and what we still must learn. Neuropsychopharmacology 40:61-87|