The broad objective of the proposed research is to gain insight into a new area in mammalian circadian biology: the role of neurotrophins in SCN cicadian function. Recent findings indicate that the neurotrophin, brain- derived neurotrophic factor (BDNF0, enhances neuronal signaling in other brain regions. Our central hypothesis is that BDNF plays a comparable role in the SCN by regulating photic input and its effects on the circadian peacemaker mechanism. To address this hypothesis, the proposed studies will determine: whether retinohypothalamic tract (RHT) fibers innervating the SCN or cells receiving RHT input express TrkB tyrosine kinase receptors, the cognate receptor for BDNF, using imunochistochemical and tract tracing methods and whether alterations in BDNF and TrkB expression or inhibition of BDNF action in the rodent SCN produce predictable changes in the phase-shifting effect of light on the circadian rhythm of wheel-running behavior. Experiments will be conducted to determine whether: 1) localization of TrkB receptor immuno reactivity in the ventral SCN by electron and/or light microscopy is observed on RHT fibers or on cells receiving RHT innervation and is diminished after blinding; 2) infusion of exogenous BDNF into the SCN enables light to induce phase shifts during the subjective day when the cicadian peacemaker is normally insensitive to light; 3) transgenic deficits in BDNF and TrkB expression in heterozygous knock-out mice(bdnf+/- and trkB+/-) abate the phase-shifting effect of light during the subjective night; 4) infusion of the tyrosine kinase inhibitor, K252a, into the phase-shifting effect of light; 5) administration of TrkB-IgG fusion protein, which scavenges endogenous BDNF, similarly blocks light-induced phase shifts. These studies will purvey critical support of the role of BDNF in regulating the effects of light on the SCN peacemaker. In view of it's potential to advance our knowledge of how circadian rhythms are regulated by light in a time-dependent manner, this research has applied relevance for developing strategies in the treatment, diagnosis and understanding of disorders in human mental health and performance that result from internal desynchronization of body process, including affective disorders, dementia and physiological decline during aging.
