5HT and circadian gene and protein networks of the brain have extensive, reciprocal interactions thatdemonstrably impact human mental health. The master circadian pacemaker of the brain, thesuprachiasmatic nucleus (SCN), receives direct serotonergic innervation and, in turn, makes polysynapticoutput to the mid-brain serotonergic nuclei. At the gene network level, 5HT signaling genes such as SERTand SHTRs are expressed in the SCN, whereas circadian clock genes are expressed in serotonergicneurons of the raphe nuclei. In Project 6: Interactions of 5HT and Circadian Signaling Networks, DougMcMahon combines his lab's expertise with that of multiple Conte Center investigators to examine theeffects of genetic variation in, and environmental manipulation of, the serotonergic system on the cellular andmolecular properties of serotonergic neurons, SCN circuitry and a readily quantified behavior, circadianocomotor rhythms. McMahon's overall hypothesis is that the serotonergic and circadian networks of thebrain are interlocked through genetic, physiological and developmental mechanisms, and that perturbation inone system affects the function of the other, resulting in behavioral alterations associated with humanaffective disorders. He will test this hypothesis using mouse models with genetic alterations in specificsignaling molecules of the serotonergic and circadian systems as well as epigenetic manipulations.Specifically, he will use electrophysiological, molecular, behavioral and real-time gene expression imagingendpoints to define the impact on: (/) 5HT neuron function of genetic manipulation of circadian and 5HT genenetworks; (//) circadian function of genetic manipulation/variation in 5HT gene networks; (Hi) 5HT andcircadian function of environmental manipulation of circadian and 5HT network development. The long-termgoal of the proposed project is to gain an understanding of the specific mechanistic links between theserotonergic and circadian networks of the brain. Such an understanding will provide an expanded basis founderstanding the etiology, pathophysiology and therapeutic intervention into human mood disorders, inwhich dysregulation of circadian and serotonergic function are co-mingled. The experiments proposed inProject 6 will determine the functional consequences for 5HT neurons of altering the 5HT molecular signalingnetwork, characterizing the impact of circadian gene network on 5HT function and defining the changes inthe neural substrate for a defined 5HT-modulated behavior. Through these efforts, Project 6 will identifynovel gene interactions to be further explored in the collaborating projects of the Conte Center, generatingnovel hypotheses regarding the molecular, cellular and behavioral outcomes of alterations in 5HT receptoand transporter genes and further elucidating the mechanisms involved in defining the 5HT neuron network and the influence of the 5HT network on its neural targets.
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