Application): The long-term goal of this research is to understand how afferent, neurotransmitter identified systems impact on cortical morphogenesis and through this, behavior. Many neurological and psychiatric disorders of known or suspected developmental onset present with altered innervation by cholinergic or monoaminergic afferent transmitter systems and with concomitant abnormalities in cortical morphogenesis; often, male and female brain are affected differently. The investigators have developed a mouse model that permits them to explore causal relationships between structural, molecular, and behavioral changes in a sex-dependent fashion, and thus, to develop an understanding of what may be amiss in human developmental disorders. Previous morphometric, neurochemical, and behavioral studies in mice with neonatal lesions to basal forebrain cholinergic afferents to cortex [nBM] demonstrate quantifiable alterations of cortical cytoarchitecture that are, in part, sexually dimorphic and correlate with cognitive behavior changes. Neonatal control lesions of monoaminergic afferent to cortex support the conclusion that the morphological as well as the behavioral effects of the neonatal nBM lesion are unique to the transient cholinergic deafferentiation during neocortical development. This strongly suggests that acetylcholine [ACh] plays a role as maturational factor in cortical morphogenesis. The present proposal aims to identify the cellular and molecular mechanisms disrupted by the neonatal nBM lesions in male and female mice and to begin an exploration of potential preventative or therapeutic interventions in the processes that lead to abnormal morphogenesis and cognitive function. Specifically, the investigators will: (1) assess qualitative and qualitative changes in cortical cholinergic muscarinic and nicotinic receptors following the signal transduction pathways indicative of muscarinic cholinergic receptor activation; and (3) explore whether cholinergic enhancement during the perinatal period can ameliorate or prevent the effects of neonatal nBM lesions on cortical morphology, neurochemistry, and behavior. Correlation analysis between morphological, molecular, and behavioral consequences of the neonatal nBM lesion will aid in establishing precise structure/function relationships that can serve to pioneer diagnostic and therapeutic strategies for numerous developmental psychiatric and neurological disorders involving cholinergic hypofunction.
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