Disturbances in circadian rhythms are known to contribute to a variety of diseases and to impair mental and physical performance. Within individual suprachiasmatic nucleus (SCN) neurons, circadian rhythms are generated by molecular clocks consisting of gene transcription feedback loops. Yet not all SCN neurons have rhythmic clock gene expression, a finding that raises the question of how neurons with clocks communicate with each other and with those neurons lacking clocks to generate circadian output. This lack of knowledge is a major impediment to understanding how cellular clocks govern circadian behavior. In mammals, these rhythmic and non-rhythmic neurons are organized into anatomical compartments in the SCN, which is the master circadian oscillator. These compartments differ in clock gene expression patterns, as well as in efferent and afferent neuronal connections. The long-term goal of our research is to characterize SCN compartments and their functional significance. Our current goal is to determine the synaptic signaling mechanisms of phenotypically identified neurons in a defined SCN compartment, the calbindin sub-nucleus (CBsn), which is known to be important for generating circadian locomotor behavior. Our hypothesis is that the generation of circadian outputs depends on the micro-circuitry within and between SCN compartments. To test this, we will use a unique combination of electrophysiological recording and immunohistochemical staining techniques to characterize synaptic transmission in the CBsn. Because we are using a defined cell population and a novel combination of techniques, we expect to be able to draw strong conclusions about the micro-circuitry of the CBsn.
The specific aims of the proposal are: 1) Determine the circadian phase dependence of responses of CBsn neurons to optic nerve stimulation. 2) Characterize the regulation of action potential firing and synaptic transmission by vasoactive intestinal peptide (VIP) and pituitary adenyl cyclase activating polypeptide (PACAP). 3) Examine the responses of CBsn neurons to Transforming Growth Factor alpha (TGFalpha). 4) Determine whether gastrin releasing peptide (GRP) or VIP immunoreactive neurons fire action potentials in a circadian manner. Completion of these studies will lead to a better understanding of the cellular basis of circadian rhythms as well as the potential to better treat sleep disorders and other disturbances in the circadian clock.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
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Mitler, Merrill
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Oregon Health and Science University
Schools of Medicine
United States
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Moldavan, Michael; Cravetchi, Olga; Allen, Charles N (2017) GABA transporters regulate tonic and synaptic GABAA receptor-mediated currents in the suprachiasmatic nucleus neurons. J Neurophysiol 118:3092-3106
Klett, Nathan J; Allen, Charles N (2017) Intracellular Chloride Regulation in AVP+ and VIP+ Neurons of the Suprachiasmatic Nucleus. Sci Rep 7:10226
Matus-Ortega, Maura E; Leff Gelman, Philippe; Calva-Nieves, Juan C et al. (2017) Mexneurin is a novel precursor of peptides in the central nervous system of rodents. FEBS Lett 591:1627-1636
Moldavan, Michael; Cravetchi, Olga; Williams, Melissa et al. (2015) Localization and expression of GABA transporters in the suprachiasmatic nucleus. Eur J Neurosci 42:3018-32
Moldavan, Mykhaylo G; Allen, Charles N (2013) GABAB receptor-mediated frequency-dependent and circadian changes in synaptic plasticity modulate retinal input to the suprachiasmatic nucleus. J Physiol 591:2475-90
Olsen, Reid H J; Allen, Charles N; Derkach, Victor A et al. (2013) Impaired memory and reduced sensitivity to the circadian period lengthening effects of methamphetamine in mice selected for high methamphetamine consumption. Behav Brain Res 256:197-204
Eastwood, Emily; Allen, Charles N; Raber, Jacob (2012) Effects of neonatal methamphetamine and thioperamide exposure on spatial memory retention and circadian activity later in life. Behav Brain Res 230:229-36
An, Sungwon; Irwin, Robert P; Allen, Charles N et al. (2011) Vasoactive intestinal polypeptide requires parallel changes in adenylate cyclase and phospholipase C to entrain circadian rhythms to a predictable phase. J Neurophysiol 105:2289-96
Irwin, Robert P; Allen, Charles N (2010) Neuropeptide-mediated calcium signaling in the suprachiasmatic nucleus network. Eur J Neurosci 32:1497-506
Moldavan, Mykhaylo G; Allen, Charles N (2010) Retinohypothalamic tract synapses in the rat suprachiasmatic nucleus demonstrate short-term synaptic plasticity. J Neurophysiol 103:2390-9

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