The goal of this research is to furnish an understanding of the complex neural substrates underlying the regulation of the circadian oscillator located in the hypothalamic suprachiasmatic nucleus (SCN). Increased knowledge of the functional organization of the hypothalamus and the circadian timing system is relevant to major public health concerns such as sleep disorders, sleep disruption (as in jet lag or shift work) and serious mood disorders such as seasonal affective disorder (SAD). Photic information essential for the daily resetting of the SCN circadian clock is conveyed directly to the SCN from the retina via the retinohypothalamic tract. The SCN also receives a dense serotonergic innervation arising from the midbrain raphe. We have provided evidence that the 5HT1B receptor subtype is located in RHT terminals in the SCN and that stimulation of these receptors attenuates photic input to the SCN. We now show that animals lacking functional 5HT1B receptors synchronize to winter-like photoperiods (i.e., short days) similar to people suffering from winter-depression or SAD. Behavioral analyses of 5HT1B knockout (KO) mice will be used to describe further the behavioral phenotype of these animals. A detailed phase response curve to acute light pulses will be generated. The mechanism(s) underlying the altered entrainment to short days will be examined. We hypothesize that loss of functional 5HT1B receptors on GABA terminals in the SCN results in disinhibition of GABA release. This produces GABA """"""""spillover"""""""" and stimulation of GABAB receptors on RHT terminals. This will be investigated using electron microscopy for GABA receptors on RHT terminals, in vitro SCN electrophysiology, and behavioral pharmacology using GABAB antagonists. Altered PER2 expression in the brain in 5HT1B KO mice in short days will also be examined as a potential correlate of seasonal depression
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