Voluntary exercise can strengthen the circadian system in aged mice.

Consistent daily rhythms are important to healthy aging according to studies linking disrupted circadian rhythms with negative health impacts. We studied the effects of age and exercise on baseline circadian rhythms and on the circadian system's ability to respond to the perturbation induced by an 8 h advance of the light:dark (LD) cycle as a test of the system's robustness. Mice (male, mPer2(luc)/C57BL/6) were studied at one of two ages: 3.5 months (n = 39) and >18 months (n = 72). We examined activity records of these mice under entrained and shifted conditions as well as mPER2::LUC measures ex vivo to assess circadian function in the suprachiasmatic nuclei (SCN) and important target organs. Age was associated with reduced running wheel use, fragmentation of activity, and slowed resetting in both behavioral and molecular measures. Furthermore, we observed that for aged mice, the presence of a running wheel altered the amplitude of the spontaneous firing rate rhythm in the SCN in vitro. Following a shift of the LD cycle, both young and aged mice showed a change in rhythmicity properties of the mPER2::LUC oscillation of the SCN in vitro, and aged mice exhibited longer lasting internal desynchrony. Access to a running wheel alleviated some age-related changes in the circadian system. In an additional experiment, we replicated the effect of the running wheel, comparing behavioral and in vitro results from aged mice housed with or without a running wheel (>21 months, n = 8 per group, all examined 4 days after the shift). The impact of voluntary exercise on circadian rhythm properties in an aged animal is a novel finding and has implications for the health of older people living with environmentally induced circadian disruption.

Circadian entrainment and its role in depression: a mechanistic review.

The natural rotation of the earth generates an environmental day-night cycle that repeats every 24 h. This daily transition from dawn to dusk provides one of the most important time cues to which the majority of organisms synchronise their activity. Under these conditions, natural light, a photic stimulus, provides the principal entraining cue. In mammals, an endogenous circadian pacemaker located within the suprachiasmatic nucleus (SCN) of the hypothalamus acts as a coordinating centre to align physiological activity with the environmental light-dark cycle. However, the SCN also receives regulatory input from a number of behavioural, non-photic, cues such as physical activity, social interactions and feeding routines. The unique ability of the SCN to integrate both photic and non-photic cues allows it to generate a rhythm that is tailored to the individual and entrained to the environment. Here, we review the key neurotransmitter systems involved in both photic and non-photic transmission to the SCN and their interactions that assist in generating an entrained output rhythm. We also consider the impact on health of a desynchronised circadian system with a focus on depressive affective disorders and current therapies aimed at manipulating the relationship between photic and non-photic SCN regulators.

Potentiation of the resetting effects of light on circadian rhythms of hamsters using serotonin and neuropeptide Y receptor antagonists.

Circadian rhythms are entrained by light/dark cycles. In hamsters, the effects of light on circadian rhythms can be modulated by serotonergic input to the suprachiasmatic nucleus from the raphe nuclei and by neuropeptide Y containing afferents to the suprachiasmatic nucleus from the intergeniculate leaflet in the thalamus. In this study we measured effects of compounds acting on serotonergic 1A and neuropeptide Y Y5 receptors to determine if combined serotonergic-neuropeptide Y inhibition could synergistically potentiate effects of light on rhythms. We used mixed serotonergic agonist/antagonists BMY 7378 or NAN-190 as well as a neuropeptide Y Y5 antagonist CP-760,542. Both BMY 7378 and NAN-190 are thought to block serotonin release via acting as agonists at the 5-hydroxytryptamine 1A (5-HT1A) autoreceptors on cells in the raphe, and also block response of target cells by acting as antagonists at post-synaptic 5-HT1A receptors, for example, in the suprachiasmatic nuclei or the intergeniculate leaflet. Replicating prior work, we found that pretreatment with either drug alone increased the phase shift to light at circadian time 19. The combined effect of BMY 7378 and CP-760,542 given prior to light at circadian time 19 was to further potentiate the subsequent phase shift in wheel-running rhythms (the phase shift was 317% of controls; light alone: 1.35 h phase shift vs. BMY 7378, CP-760,542, and light: 4.27 h phase shift). Combined treatment with NAN-190 and CP-760,542 produced a light-induced phase shift 576% of controls (phase shift to light alone: 1.23 h vs. NAN-190, CP-760,542, and light: 7.1 h phase shift). These results suggest that the resetting effects of light on circadian rhythms can be greatly potentiated in hamsters by using pharmacological treatments that block both serotonergic and neuropeptide Y afferents to the suprachiasmatic nuclei.

Neuropeptide Y, GABA and circadian phase shifts to photic stimuli.

Circadian rhythms can be phase shifted by photic and non-photic stimuli. The circadian clock, anatomically defined as the suprachiasmatic nucleus (SCN), can be phase delayed by light during the early subjective night and phase advanced during the late subjective night. Non-photic stimuli reset the clock when presented during the subjective day. A possible pathway for the non-photic resetting of the clock is thought to originate from the intergeniculate leaflet, which conveys information to the SCN through the geniculohypothalamic tract and utilizes among others neuropeptide Y (NPY) and GABA as neurotransmitters. Photic and non-photic stimuli have been shown to interact during the early and late subjective night. Microinjections of NPY or muscimol, a GABA(A) receptor agonist, into the region of the SCN can attenuate light-induced phase shifts during the early and late subjective night. The precise mechanism for these interactions is unknown. In the current study we investigate the involvement of a GABAergic mechanism in the interaction between NPY and light during the early and late subjective night. Microinjections of NPY significantly attenuated light-induced phase delays and inhibited phase advances (P<0.05). The administration of bicuculline during light exposure, before NPY microinjection did not alter the ability of NPY to attenuate light-induced phase delays and block photic phase advances. These results indicate that NPY attenuates photic phase shifts via a mechanism independent of GABA(A) receptor activation. Furthermore it is evident that NPY influences circadian clock function via differing cellular pathways over the course of a circadian cycle.

Attenuation of circadian light induced phase advances and delays by neuropeptide Y and a neuropeptide Y Y1/Y5 receptor agonist.

Circadian rhythms can be synchronised to photic and non-photic stimuli. The circadian clock, anatomically defined as the suprachiasmatic nucleus in mammals, can be phase shifted by light during the night. Non-photic stimuli reset the circadian rhythm during the day. Photic and non-photic stimuli have been shown to interact during the day and night. Precise mechanisms for these complex interactions are unknown. A possible pathway for non-photic resetting of the clock is thought to generate from the intergeniculate leaflet, which conveys information to the suprachiasmatic nucleus (SCN) through the geniculohypothalamic tract and utilises neuropeptide Y (NPY) as its primary neurotransmitter. Interactions between light and NPY were investigated during the early (2 h after activity onset) and late (6 h after activity onset) night in male Syrian hamsters. NPY microinjections into the region of the SCN significantly attenuated light-induced phase delay, during the early subjective night. Phase advances to light were completely inhibited by the administration of NPY during the late night. The precise mechanism by which NPY attenuates or blocks photic phase shifts is unclear, but the NPY Y5 receptor has been implicated in the mediation of this inhibitory effect. The NPY Y1/Y5 receptor agonist, [Leu(31),Pro(34)]NPY, was administered via cannula microinjections following light exposure during the early and late night. [Leu(31),Pro(34)]NPY significantly attenuated phase delays to light during the early night and blocked phase advances during the late night, in a manner similar to NPY. These results show the ability of NPY to attenuate phase shifts to light during the early night and block light-induced phase advances during the late night. Furthermore, this is the first in vivo study implicating the involvement of the NPY Y1/Y5 receptors in the complex interaction of photic and non-photic stimuli during the night. The alteration of photic phase shifts by NPY may influence photic entrainment within the circadian system.

Schwannoma (neurilemmoma) of the tonsil.

Schwannoma of the tonsil is an extremely uncommon clinical entity with only one reported case in an adult in the medical literature to date. We report, to our knowledge, the first known case in a child.