Cell-autonomous clock of astrocytes drives circadian behavior in mammals

Brancaccio, Marco; Edwards, Mathew D.; Patton, Andrew P.; Smyllie, Nicola J.; Chesham, Johanna E.; Maywood, Elizabeth S.; Hastings, Michael H.

doi:10.1126/science.aat4104

Cited by 254 publications

(275 citation statements)

References 29 publications

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“…CRE‐mediated deletion of CK1ε tau/tau specifically from SCN astrocytes is sufficient to restore the behavioural activity in these mice to a 24‐hour pattern, thus indicating that astrocytes can impact the intrinsic activity of the SCN master clock. Indeed, even in the absence of a viable circadian clock ( Cry1/2 ‐null mice), the reintroduction of Cry1 to SCN GFAP‐expressing astrocytes is sufficient to enable mice to develop an intrinsic rhythmical pattern of behaviour even when maintained in constant darkness . This is mediated, at least in part, via astrocyte‐driven glutamatergic regulation of SCN neuronal activity .…”

Section: Astrocytes and The Regulation Of Circadian Rhythmsmentioning

confidence: 99%

Astrocytes in neuroendocrine systems: An overview

Macdonald

Robb

Morrissey

et al. 2019

J Neuroendocrinology

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A class of glial cell, astrocytes, is highly abundant in the central nervous system (CNS). In addition to maintaining tissue homeostasis, astrocytes regulate neuronal communication and synaptic plasticity. There is an ever‐increasing appreciation that astrocytes are involved in the regulation of physiology and behaviour in normal and pathological states, including within neuroendocrine systems. Indeed, astrocytes are direct targets of hormone action in the CNS, via receptors expressed on their surface, and are also a source of regulatory neuropeptides, neurotransmitters and gliotransmitters. Furthermore, as part of the neurovascular unit, astrocytes can regulate hormone entry into the CNS. This review is intended to provide an overview of how astrocytes are impacted by and contribute to the regulation of a diverse range of neuroendocrine systems: energy homeostasis and metabolism, reproduction, fluid homeostasis, the stress response and circadian rhythms.

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Section: Astrocytes and The Regulation Of Circadian Rhythmsmentioning

confidence: 99%

Astrocytes in neuroendocrine systems: An overview

Macdonald

Robb

Morrissey

et al. 2019

J Neuroendocrinology

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“…Importantly, astrocyte function is regulated by the molecular clockwork (Brancaccio et al, ; Brancaccio, Patton, Chesham, Maywood, & Hastings, ; Marpegan et al, ) and the expression of astrocytic protein GFAP shows time of day‐dependent expression (Gerics, Szalay, & Hajos, ). Astrocyte‐specific deletion of Bmal1 results in memory and cognition deficits, presumably due to impaired GABA clearance (Barca‐Mayo et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…This indicates that astrocytic Bmal1 is crucial for regular brain function and homeostasis. Recently, it has been shown that astrocytic clocks can drive circadian function of SCN neurons via glutamatergic signals (Brancaccio et al, ). These data suggest that the molecular clockwork plays an important role in the interaction between astrocytes and neurons.…”

Section: Introductionmentioning

confidence: 99%

Bmal1‐deficiency affects glial synaptic coverage of the hippocampal mossy fiber synapse and the actin cytoskeleton in astrocytes

Ali

Schwarz-Herzke

Rollenhagen

et al. 2019

Glia

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Bmal1 is an essential component of the molecular clockwork, which drives circadian rhythms in cell function. In Bmal1‐deficient (Bmal1−/−) mice, chronodisruption is associated with cognitive deficits and progressive brain pathology including astrocytosis indicated by increased expression of glial fibrillary acidic protein (GFAP). However, relatively little is known about the impact of Bmal1‐deficiency on astrocyte morphology prior to astrocytosis. Therefore, in this study we analysed astrocyte morphology in young (6–8 weeks old) adult Bmal1−/− mice. At this age, overall GFAP immunoreactivity was not increased in Bmal1‐deficient mice. At the ultrastructural level, we found a decrease in the volume fraction of the fine astrocytic processes that cover the hippocampal mossy fiber synapse, suggesting an impairment of perisynaptic processes and their contribution to neurotransmission. For further analyses of actin cytoskeleton, which is essential for distal process formation, we used cultured Bmal1−/− astrocytes. Bmal1−/− astrocytes showed an impaired formation of actin stress fibers. Moreover, Bmal1−/− astrocytes showed reduced levels of the actin‐binding protein cortactin (CTTN). Cttn promoter region contains an E‐Box like element and chromatin immunoprecipitation revealed that Cttn is a potential Bmal1 target gene. In addition, the level of GTP‐bound (active) Rho‐GTPase (Rho‐GTP) was reduced in Bmal1−/− astrocytes. In summary, our data demonstrate that Bmal1‐deficiency affects morphology of the fine astrocyte processes prior to strong upregulation of GFAP, presumably because of impaired Cttn expression and reduced Rho‐GTP activation. These morphological changes might result in altered synaptic function and, thereby, relate to cognitive deficits in chronodisruption.

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“…These properties of SFO single-cell oscillators depend on the anatomical connections, as sectioning on the sagittal plane compromises their ability to maintain synchrony and lengthens their period. It is not clear why rhythms in the SFO are robust, but since this structure is enriched in the nonneuronal glia cells 32,43 and because astrocytes are important for circadian timekeeping in the SCN [44][45][46] , this network of nonneuronal cells may imbue the SFO with enhanced capability of self-sustained circadian timekeeping. 38 We extend these and are the first to demonstrate individual cell bioluminescence oscillations in the OVLT.…”

Section: Discussionmentioning

confidence: 99%

Keeping time in the lamina terminalis: Novel oscillator properties of forebrain sensory circumventricular organs

et al. 2019

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Drinking behavior and osmotic regulatory mechanisms exhibit clear daily variation which is necessary for achieving the homeostatic osmolality. In mammals, the master clock in the brain's suprachiasmatic nuclei has long been held as the main driver of circadian (24 h) rhythms in physiology and behavior. However, rhythmic clock gene expression in other brain sites raises the possibility of local circadian control of neural activity and function. The subfornical organ (SFO) and the organum vasculosum laminae terminalis (OVLT) are two sensory circumventricular organs (sCVOs) that play key roles in the central control of thirst and water homeostasis, but the extent to which they are subject to intrinsic circadian control remains undefined.Using a combination of ex vivo bioluminescence and in vivo gene expression, we report for the first time that the SFO contains an unexpectedly robust autonomous clock with unusual spatiotemporal characteristics in core and noncore clock gene expression. Furthermore, putative single-cell oscillators in the SFO and OVLT are strongly rhythmic and require action potential-dependent communication to maintain synchrony. Our results reveal that these thirst-controlling sCVOs possess intrinsic circadian timekeeping properties and raise the possibility that these contribute to daily regulation of drinking behavior. K E Y W O R D Scircadian, circumventricular organ, fluid balance, OVLT, SFO, suprachiasmatic

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Cell-autonomous clock of astrocytes drives circadian behavior in mammals

Cited by 254 publications

References 29 publications

Astrocytes in neuroendocrine systems: An overview

Astrocytes in neuroendocrine systems: An overview

Bmal1‐deficiency affects glial synaptic coverage of the hippocampal mossy fiber synapse and the actin cytoskeleton in astrocytes

Keeping time in the lamina terminalis: Novel oscillator properties of forebrain sensory circumventricular organs

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