Role of brain-derived neurotrophic factor in the circadian regulation of the suprachiasmatic pacemaker by light.

The central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus mediates the generation of mammalian circadian rhythms, including an oscillation in pacemaker sensitivity to photic signals conveyed by the retinohypothalamic tract. Because brain-derived neurotrophic factor (BDNF) has been implicated in the functional regulation of neural input to other targets of visual pathways, the present study examined whether changes in BDNF expression or blockade of its action in the SCN affect circadian pacemaker responses to light. In rats receiving infusion of exogenous BDNF into the SCN, the free-running rhythm of activity in constant darkness was characterized by large phase advances in response to light exposure during the midsubjective day, when the circadian pacemaker is normally insensitive to photic perturbation. In contrast, SCN infusion of BDNF did not potentiate either phase-delaying or phase-advancing effects of light on the rat activity rhythm during the subjective night. In heterozygous BDNF mutant mice, deficits and damped rhythmicity in SCN levels of this neurotrophin were accompanied by marked decreases in the amplitude of light-induced phase shifts during the subjective night. In agreement with the effects of decreased BDNF expression, SCN infusion of the tyrosine kinase inhibitor K252a blocked or strongly inhibited both the phase-delaying and -advancing effects of light during the subjective night. Collectively, these findings suggest that BDNF-mediated signaling may play an important role in the circadian regulation of SCN pacemaker sensitivity to light.