Neuroscience Letters 378 (2005) 150–155 TrkB-deficient mice show diminished phase shifts of the circadian activity rhythm in response to light Gregg C. Allen a , Xiaoyu Qu b , David J. Earnest a,b,∗ a Department of Human Anatomy and Medical Neurobiology, Texas A&M University Health Science Center, 238 Reynolds Medical Building, College Station, TX 77843-1114, USA b Center for Biological Clocks Research, Department of Biology, Texas A&M University, College Station, TX 77843-3258, USA Received 23 November 2004; received in revised form 10 December 2004; accepted 11 December 2004 Abstract Brain-derived neurotrophic factor (BDNF) has been implicated in the mechanism underlying the circadian sensitivity of the clock in the hypothalamic suprachiasmatic nucleus (SCN) to the phase-shifting effects of light. In the present study, we examined the role of the cognate receptor for BDNF, the TrkB tyrosine kinase, in the photic regulation of the SCN clock by determining whether the phase-shifting action of light is impaired in mice with targeted mutation of the TrkB gene. In comparison with wild-type littermates, heterozygous TrkB mutant mice (trkB +/- ) showed marked reductions in SCN and cortical levels of this neurotrophin receptor that were accompanied by decreases in the amplitude of light-induced phase shifts during the subjective night. These results provide further evidence indicating that BDNF-mediated signaling through the TrkB receptor is an important process in the gating of SCN responses to light and its phase-shifting effects on circadian rhythms. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Suprachiasmatic nucleus (SCN); Circadian rhythm; Neurotrophins; TrkB tyrosine kinase receptor; Brain-derived neurotrophic factor (BDNF); Photoentrainment In mammals, the hypothalamic suprachiasmatic nucleus (SCN) functions as an internal biological clock responsible for the regulation of circadian rhythms [9]. In addition to its function as a circadian pacemaker that endogenously coordi- nates the timing of physiological and behavioral processes, the SCN also mediates the entrainment or synchronization of circadian rhythms to the daily cycle of light and darkness. Entraining light signals are communicated from the retina to the SCN via the retinohypothalamic tract (RHT), a monosy- naptic projection from a subpopulation retinal ganglion cells [8,14,15]. Circadian photoentrainment occurs because the SCN pacemaker is reset by light only during discrete phases of the daily cycle. In nocturnal mammals under conditions of constant darkness (DD), the phase of mammalian circadian rhythms is largely unaltered by a brief light exposure during the subjective day (i.e., coinciding with previous light phase ∗ Corresponding author. Tel.: +1 979 862 3109; fax: +1 979 845 0790. E-mail address: dearnest@tamu.edu (D.J. Earnest). or the animal’s inactive period), but is delayed or reset to a later time when the same stimulus is administered during the early subjective night and is advanced by light during the late subjective night. The rhythmic sensitivity of the pacemaker mechanism to light presumably involves differential regula- tion of RHT synaptic input and/or SCN cellular responses to this input. Thus, identification of the signaling elements in- volved in the time-dependent regulation of these processes is necessary to further elucidate the mechanism by which light entrains circadian rhythms. Previous studies have implicated brain-derived neu- rotrophic factor (BDNF) and its high-affinity receptor, the TrkB tyrosine kinase, in the photic regulation of SCN circadian function. BDNF content in the SCN fluctuates rhythmically such that protein levels are elevated during the subjective night, coinciding with the interval of pacemaker sensitivity to the phase-shifting effects of light [13]. BDNF involvement in the modulation of SCN circadian responses to light is further supported by the finding that administration 0304-3940/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2004.12.023