ABSTRACT
The hypothalamic suprachiasmatic nucleus (SCN) is a circadian oscillator that receives a dense serotonergic innervation from the median raphe nucleus. Serotonin (5-HT) modulates the effects of light on circadian behavior by acting on 5-HT1B receptors on retinohypothalamic (RHT) terminals in the SCN. Activation of 5-HT1B presynaptic receptors on RHT terminals inhibits glutamate release. However, 5-HT1B receptor knockout (5-HT1B KO) mice have attenuated behavioral responses to light [P.J. Sollars, M.D. Ogilvie, A.M. Simpson, G.E. Pickard, Photic entrainment is altered in the 5-HT1B receptor knockout mouse, J. Biol. Rhythms 21 (2006) 21-32]. To assess the cellular response of the 5-HT1B KO SCN to light, light-induced Fos expression was analyzed in 5-HT1B KO and wild-type (WT) mice. In addition, the distribution of melanopsin containing retinal ganglion cells that contribute the majority of axons to the RHT was examined in 5-HT1B KO mice and compared to that of WT mice. Light-induced Fos expression in the SCN was reduced in 5-HT1B KO mice compared to WT mice at circadian time (CT) 16 and CT 23 in a manner similar to the reduction previously described in light-induced behavioral phase shifts. The number of melanopsin retinal ganglion cells was similar in WT and 5-HT1B KO mice. These data taken together with previous data suggest that functional removal of the 5-HT1B receptor results in reduced functional light input to the SCN.
Subject(s)
Circadian Rhythm/physiology , Gene Expression/physiology , Light , Oncogene Proteins v-fos/metabolism , Receptor, Serotonin, 5-HT1B/deficiency , Suprachiasmatic Nucleus/metabolism , Animals , Gene Expression/radiation effects , Immunohistochemistry/methods , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Suprachiasmatic Nucleus/radiation effectsABSTRACT
The hypothalamic suprachiasmatic nucleus (SCN) is a circadian oscillator that receives glutamatergic afferents from the retina and serotonergic afferents from the midbrain. Activation of presynaptic serotonin 1B (5-HT1B) receptors on retinal terminals in the SCN inhibits retinohypothalamic neurotransmission and light-induced behavioral phase shifts. To assess the role of 5-HT1B receptors in photic entrainment, 5-HT1B receptor knockout (5-HT1B KO) and wild-type (WT) mice were maintained in non-24 h L:D cycles (T cycles). WT mice entrained to T = 21 h and T = 22 h cycles, whereas 5-HT1B KO animals did not. 5-HT1B KO animals did entrain to T = 23 h and T = 26 h cycles, although their phase angle of entrainment was altered compared to WT animals. 5-HT1B KO mice were significantly more phase delayed under T = 23 h conditions and significantly more phase advanced under T = 26 h conditions compared to WT mice. When 5-HT1B KO mice were housed in a T = 23 h short-day photoperiod (9.5L:13.5D), the delayed phase angle of entrainment was more pronounced. Light-induced phase shifts were reduced in 5-HT1B KO mice, consistent with their behavior in T cycles, suggesting an attenuated response to light. Based on previous work, this attenuated response to light might not have been predicted but can be explained by consideration of GABAergic mechanisms within the SCN. Phase-delayed circadian rhythms during the short days of winter are characteristic of patients suffering from seasonal affective disorder, and 5-HT has been implicated in its pathophysiology. The 5-HT1B KO mouse may be useful for investigating the altered entrainment evident during this serious mood disorder.
