In this study, we investigated the effect of social environment on circadian patterns in activity by group housing either six male or six female mice together in a cage, under regular light–dark cycles. Based on the interactions among the animals, the social dominance rank of individual mice was quantitatively established by calculating Elo ratings. Our results indicated that, during our experiment, the social dominance hierarchy was rapidly established, stable yet complex, often showing more than one dominant mouse and several subordinate mice. Moreover, we found that especially dominant male mice, but not female mice, displayed a significantly higher fraction of their activity during daytime. This resulted in reduced rhythm amplitude in dominant males. After division into separate cages, male mice showed an enhancement of their 24 h rhythm, due to lower daytime activity. Recordings of several physiological parameters showed no evidence for reduced health as a potential consequence of reduced rhythm amplitude. For female mice, transfer to individual housing did not affect their daily activity pattern. We conclude that 24 h rhythms under light–dark cycles are influenced by the social environment in males but not in females, and lead to a decrement in behavioural rhythm amplitude that is larger in dominant mice.

We have recently identified a novel plasticity protein, doublecortin-like (DCL), that is specifically expressed in the shell of the mouse suprachiasmatic nucleus (SCN). DCL is implicated in neuroplastic events, such as neurogenesis, that require structural rearrangements of the microtubule cytoskeleton, enabling dynamic movements of cell bodies and dendrites. We have inspected DCL expression in the SCN by confocal microscopy and found that DCL is expressed in GABA transporter-3 (GAT3)-positive astrocytes that envelope arginine vasopressin (AVP)-expressing cells. To investigate the role of these DCL-positive astrocytes in circadian rhythmicity, we have used transgenic mice expressing doxycycline-induced short-hairpin (sh) RNA's targeting DCL mRNA (DCL knockdown mice). Compared with littermate wild type (WT) controls, DCL-knockdown mice exhibit significant shorter circadian rest-activity periods in constant darkness and adjusted significantly faster to a jet-lag protocol. As DCL-positive astrocytes are closely associated with AVP-positive cells, we analyzed AVP expression in DCL-knockdown mice and in their WT littermates by 3D reconstructions and transmission electron microscopy (TEM). We found significantly higher numbers of AVP-positive cells with increased volume and more intensity in DCL-knockdown mice. We found alterations in the numbers of dense core vesiclecontaining neurons at ZT8 and ZT20 suggesting that the peak and trough of neuropeptide biosynthesis is dampened in DCL-knockdown mice compared to WT littermates. Together, our data suggest an important role for the astrocytic plasticity in the regulation of circadian rhythms and point to the existence of a specific DCL + astrocyte-AVP + neuronal network located in the dorsal SCN implicated in AVP biosynthesis.

Our daily 24‐h rhythm is synchronized to the external light–dark cycle resulting from the Earth's daily rotation. In the mammalian brain, the suprachiasmatic nucleus (SCN) serves as the master clock and receives light‐mediated input via the retinohypothalamic tract. Abrupt changes in the timing of the light–dark cycle (e.g., due to jet lag) cause a phase shift in the circadian rhythms in the SCN. Here, we investigated the effects of a 6‐h delay in the light–dark cycle on PERIOD2::LUCIFERASE expression at the single‐cell level in mouse SCN organotypic explants. The ensemble pattern in phase shift response obtained from individual neurons in the anterior and central SCN revealed a bimodal distribution; specifically, neurons in the ventrolateral SCN responded with a rapid phase shift, while neurons in the dorsal SCN generally did not respond to the shift in the light–dark cycle. We also stimulated the hypothalamic tract in acute SCN slices to simulate light‐mediated input to the SCN; interestingly, we found similarities between the distribution and fraction of rapid shifting neurons (in response to the delay) and neurons that were excited in response to electrical stimulation. These results suggest that a subpopulation of neurons in the ventral SCN that have an excitatory response to light input, shift their clock more readily than dorsal located neurons, and initiate the SCN's entrainment to the new light–dark cycle. Thus, we propose that light‐excited neurons in the anterior and central SCN play an important role in the organism's ability to adjust to changes in the external light–dark cycle.

Cancer-related fatigue (CRF) is the most devastating long-term side effect of many cancer survivors that confounds the quality of life for months to years after treatment. However, the cause of CRF is poorly understood. As a result, cancer survivors, at best, receive psychological support. Chemotherapy has been shown to increase the risk of CRF. Here, we study therapy-induced fatigue in a non-tumor-bearing mouse model with three different topoisomerase II-poisoning cancer drugs. These drugs either induce DNA damage and/or chromatin damage. Shortly before and several weeks after treatment, running wheel activity and electroencephalographic sleep were recorded. We show that doxorubicin, combining DNA damage with chromatin damage, unlike aclarubicin or etoposide, induces sustained CRF in this model. Surprisingly, this was not related to changes in sleep. In contrast, our data indicate that the therapy-induced CRF is associated with a disrupted circadian clock. The data suggest that CRF is probably a circadian clock disorder that influences the quality of waking and that the development of CRF depends on the type of chemotherapy provided. These findings could have implications for selecting and improving chemotherapy for the treatment of cancer in order to prevent the development of CRF.