Evidence for Neuronal Desynchrony in the Aged Suprachiasmatic Nucleus Clock

Farajnia, Sahar; Michel, Stephan; Deboer, Tom; vanderLeest, Henk Tjebbe; Houben, Thijs; Rohling, Jos H. T.; Ramkisoensing, Ashna; Yasenkov, Roman; Meijer, Johanna H.

doi:10.1523/jneurosci.0469-12.2012

Cited by 203 publications

(237 citation statements)

References 49 publications

(66 reference statements)

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“…Hypothalamic slices containing the SCN were prepared as described previously (31). In brief, brains were quickly removed and submerged into modified ice-cold artificial cerebrospinal fluid (ACSF) containing (in mM): NaCl 116.4, KCl 5.4, NaH 2 PO 4 1.0, MgSO 4 0.8, CaCl 2 1.0, MgCl 2 4.0, NaHCO 3 23.8 , glucose 15, and 5 mg/L gentamicin (Sigma Aldrich, Munich, Germany) saturated with 95% O 2 -5% CO 2 (pH, 7.2-7.4; osmolality, 290-310 mOsm).…”

Section: Methodsmentioning

confidence: 99%

“…Whole-cell voltage-clamp recordings of sPSCs (n = 64 slices from 35 animals) were performed using a patch amplifier (EPC 10-2; HEKA, Lambrecht/Pfalz, Germany), as described previously (31). Micropipettes (with a tip resistance of 5-7 MΩ when filled with internal pipette solution) Summary of the percentages of excitatory and inhibitory responses in long-day (n = 222) versus shortday (n = 218) photoperiod-entrained neurons recorded within 1 h around midday.…”

Section: Methodsmentioning

confidence: 99%

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Seasonal induction of GABAergic excitation in the central mammalian clock

Farajnia

Westering

Meijer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

107

129

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The balance between excitation and inhibition is essential for the proper function of neuronal networks in the brain. The inhibitory neurotransmitter γ-aminobutyric acid (GABA) contributes to the network dynamics within the suprachiasmatic nucleus (SCN), which is involved in seasonal encoding. We investigated GABAergic activity and observed mainly inhibitory action in SCN neurons of mice exposed to a short-day photoperiod. Remarkably, the GABAergic activity in a long-day photoperiod shifts from inhibition toward excitation. The mechanistic basis for this appears to be a change in the equilibrium potential of GABA-evoked current. These results emphasize that environmental conditions can have substantial effects on the function of a key neurotransmitter in the central nervous system.S easonal changes in the photoperiod of the Earth's temperate zones affect the behavior and physiology of many organisms (1). The central circadian clock, located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus, can adapt to changes in day length and displays a compressed circadian pattern of electrical activity in short winter days and a decompressed pattern in long summer days (2). This pattern is based on a change in the phase distribution of the activity patterns of individual neurons, which becomes broad in the summer and narrow in the winter (3). The mechanisms that mediate and regulate photoperiod-induced phase distributions are currently not known.The neurotransmitter γ-aminobutyric acid (GABA) is believed to be involved in the phase adjustment and synchronization of the SCN neuronal network (4, 5). GABA and its receptors are expressed in most SCN neurons (6). GABAergic inhibition has been indicated to be important in normal physiological function within the brain. Alterations in this system (i.e., less inhibition) are shown to cause neurological disorders, such as epilepsy and autism (7,8). In addition to its classical inhibitory function within the SCN network, GABA has more recently been shown to also act as an excitatory transmitter, although its exact role is uncertain (4, 9-13). To understand the influence of photoperiod on GABAergic function, we studied synaptic activity, using patch clamp, and GABAergic responses, using Ca 2+ imaging techniques, in the SCN of mice adjusted to long-day and short-day photoperiods. We hypothesized that the narrow, synchronized phase distribution of active neurons during short-day photoperiods would result in increased synaptic activity during the day. Surprisingly, however, exposure to a short-day photoperiod decreased the frequency of spontaneous GABAergic synaptic events compared with the long-day photoperiod.Subsequently, we tested the effect of photoperiod on GABAinduced excitation in the SCN neuronal network. Ca 2+ transients were measured in response to GABA stimulation in long-day and short-day photoperiods. Interestingly, of all cells from the long-day photoperiod, 40% were excitatory and 36% were inhibitory. In contrast, in the short-day photoperiod, 28% of the c...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Seasonal induction of GABAergic excitation in the central mammalian clock

Farajnia

Westering

Meijer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

107

129

View full text Add to dashboard Cite

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“…Mice with targeted deletion of Bmal1 display loss of behavioral and physiologic circadian rhythms and develop increased systemic oxidative stress and signs of accelerated aging (9,10). Conversely, aging is associated with diminished expression of positive-limb clock genes in mouse brain, and impaired circadian oscillation and oxidative injury are associated with brain aging and age-related neurodegenerative conditions in humans, suggesting a possible link between circadian clock dysfunction, oxidative stress, and age-related neurodegeneration (11)(12)(13)(14)(15). However, it is unknown whether core clock genes play any role in maintaining neuronal health or if these genes influence neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration

Musiek¹,

Lim²,

Yang³

et al. 2013

J. Clin. Invest.

423

448

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Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

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“…For instance, non-photic phase-sifting induced by triazolam (Van reeth et al 1992; and novel-wheel confinement are attenuated in old hamsters. In addition, locomotor rhythm fragmentation is observed in aged human and non-human primates (Czeisler et al 1992;Zhdanova et al 2011) and mice (Valentinuzzi et al 1997;Farajnia et al 2012). Hughes and Piggins (2012) state these alterations might be due to reduction in neurochemical mediators of circadian locomotor activity, such as NPY.…”

Section: Discussionmentioning

confidence: 99%

Age-related changes in neurochemical components and retinal projections of rat intergeniculate leaflet

Fiuza

Silva

Pessoa

et al. 2015

AGE

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Aging leads to several anatomical and functional deficits in circadian timing system. In previous works, we observed morphological alterations with age in hypothalamic suprachiasmatic nuclei, one central component of this system. However, there are few data regarding aging effects on other central components of this system, such as thalamic intergeniculate leaflet (IGL). In this context, we studied possible age-related alterations in neurochemical components and retinal projections of rat IGL. For this goal, young (3 months), adult (13 months), and aged (23 months) Wistar rats were submitted to an intraocular injection of neural tracer, cholera toxin subunit b (CTb), 5 days before a tissue fixation process by paraformaldehyde perfusion. Optical density measurements and cell count were performed at digital pictures of brain tissue slices processed by immunostaining for glutamic acid decarboxylase (GAD), enkephalin (ENK), neuropeptide Y (NPY) and CTb, characteristic markers of IGL and its retinal terminals. We found a significant age-related loss in NPY immunoreactive neurons, but not in immunoreactivity to GAD and ENK. We also found a decline of retinal projections to IGL with age. We conclude aging impairs both a photic environmental clue afferent to IGL and a neurochemical expression which has an important modulatory circadian function, providing strong anatomical correlates to functional deficits of the aged biological clock.

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Evidence for Neuronal Desynchrony in the Aged Suprachiasmatic Nucleus Clock

Cited by 203 publications

References 49 publications

Seasonal induction of GABAergic excitation in the central mammalian clock

Seasonal induction of GABAergic excitation in the central mammalian clock

Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration

Age-related changes in neurochemical components and retinal projections of rat intergeniculate leaflet

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