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Endocrine Functions of Brain Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The molecular mechanism of the endogenous circadian clock in mammals comprises feedback loops of cyclic gene products that apply negative and positive transcriptional regulation of “clock” genes and proteins. The cell-autonomous circadian clocks are generated by a feedback loop composed of the clock genes “circadian locomotor output cycles kaput” (Clock) and “brain and muscle ARNT-like 1” (Bmal1), which produce the proteins CLOCK and BMAL1, respectively. These transcription factors heterodimerize and bind to promotor elements to up-regulate the expression of period (Per1–3) and cryptochrome (Cry1–2). Subsequently, PER and CRY proteins form heterodimers that interact with the BMAL1:CLOCK complex to repress their own transcription.
The Pineal Gland Energy Transducer
Published in Len Wisneski, The Scientific Basis of Integrative Health, 2017
One possibility is cryptochrome, the vitamin B-based, light-absorbing protein pigment in the eye and SCN, which is sensitive to blue light (Ivanchenko et al., 2001). It is found both in the retinal ganglion and the inner retina (Sancar, 2000). Cryptochrome was discovered in plants and identified as the protein that allows plants to bend toward light. Other possible photoreceptors are the nonrod, noncone vitamin A-based opsin photopigments, such as melanopsin (Provencio et al., 1998). The retinal distribution of melanopsin cells bears a striking resemblance to the retinal cells known to connect to the SCN in rodents. The inner retina seems to be the only mammalian site at which melanopsin is expressed, suggesting a role in nonvisual photoreceptive tasks (Provencio et al., 2000). So, in the end, melanopsin and cryptochrome are viable, but unconfirmed, photoreceptor candidates of the mammalian clock.
Neurobiology of Mood Disorders
Published in Dr. Ather Muneer, Mood Disorders, 2018
The SCN neurons house the circadian molecular hub, while the clock itself is composed of a series of transcriptional and translational feedback loops that result in the rhythmic expression of clock genes on a timescale of just over 24 hours. In the primary feedback loop, the transcription factors, Circadian Locomotor Output Cycles Kaput (CLOCK) and Brain and Muscle Arnt-Like protein 1 (BMAL1), heterodimerize and bind to E-box containing sequences in a number of genes including the three Period (PER) genes (PER1, PER2 and PER3) and two Cryptochrome (CRY) genes (CRY1 and CRY2). Over time PER and CRY proteins dimerize in the cytosol and are shuttled back into the nucleus where CRY proteins can directly inhibit the activity of CLOCK and BMAL1. In addition to this feedback loop, the CLOCK and BMAL1 proteins regulate the expression of Rev-erbα and ROR (retinoic acid-related orphan nuclear receptors) which in turn can repress or activate BMAL1 transcription respectively, through action at the Rev-Erb/ROR response element in the promoter. There are several key proteins which regulate the timing of the molecular clock through phosphorylation, sumoylation and other mechanisms. The enzymes, casein kinases, phosphorylate the PER, CRY and BMAL1 proteins altering their stability and nuclear entry; glycogen synthase kinase 3 beta (GSK3β) also phosphorylates the PER2 protein facilitating its nuclear entry.8 As alluded to above many controlling kinases, phosphatases and secondary feedback loops act on the molecular clock, contributing to great intricacy to the circadian apparatus. Significantly, circadian transcription factors are involved in the regulation and functioning of several other clock-controlled genes, which partake in a whole range of homeostatic actions in every body system. As will become clear in the ensuing sections, these sub-cellular mechanisms regulate the key physiological functions of the body in a circadian fashion.
Can circadian rhythm predict changes in neurocognitive functioning in bipolar disorder: protocol of a 12-month longitudinal cohort study based on research domain criteria
Published in Annals of Medicine, 2023
Huirong Luo, Xueqian Wang, Yinlin Zhang, Junyao Li, Renqin Hu, Zheng Zhang, Qian Liao, Xiaoxin Zhou, Wei Deng, Jian Yang, Qinghua Luo
The importance of circadian rhythm in BD has always been emphasized as BD is somehow rhythmic by itself in clinical oscillations among depressive, hypomanic/manic, and intermittent episodes [62]. The large genome-wide association study (GWAS) has found significant changes in gene expression around circadian rhythm pathways in BD population [63]. We hypothesized that disrupted circadian rhythm also plays a role in neurocognitive functioning impairment in BD. Currently, limited evidence could be cited to support such an opinion. Mice deficient in Vipr2, which participate in internal rhythm synchronization, exhibit cognitive deficits resembling schizophrenia [64,65]. Circadian clock-deficient cryptochrome knockout mice present with cognitive dysfunction and elevated anxiety [66]. Poor sleep quality is found related to poorer neuropsychological functioning in bipolar I disorder [67]. With RDoC highlighting circadian rhythm and cognitive evaluation in arousal/modulatory system and cognitive system separately, we can’t help speculating the role of circadian rhythm in neurocognitive impairment of BD, where we seek to better understand the correlation of circadian rhythm and neurocognitive functioning [11].
Circadian gating of light-induced arousal in Drosophila sleep
Published in Journal of Neurogenetics, 2023
Since Drosophila senses light via multiple pathways (Helfrich-Forster, 2020; Mazzotta et al., 2020), we asked if the genetic deficit in any specific light-sensing pathway could modify L2 sleep suppression. Light did not suppress L2 sleep in eyeless mutant gl60j (Moses et al., 1989) and genetically blind NorpA36 flies (Bloomquist et al., 1988; Figure 5(B)). However, transgenic ablation of the photoreceptor neurons in the eye (GMR > hid) negligibly affected L2 sleep suppression (Figure 5(B)). We noted that early night sleep in GMR > hid flies was reduced in the standard LD cycle compared to control. Consequently, the 24-h sleep profiles of GMR > hid flies were very similar between LD and T12 cycles, likely indicating their insensitivity to light-induced arousal in the L2 phase. CRYPTOCHROME (CRY) is a cell-autonomous, blue-light sensor protein that is expressed in a subset of circadian pacemaker neurons and implicated in the light entrainment of circadian gene expression and behaviors (Emery et al., 2000). However, cry deletion flies displayed significant L2 sleep suppression (Figure 5(B)), indicating a redundant role of the deep brain light sensor in the light-induced arousal. Together, these results support that the visual light-sensing suppresses sleep in a circadian clock-dependent manner, allowing the misalignment of circadian time and light to arouse diurnal flies only at night.
Exploring the role of circadian clock gene and association with cancer pathophysiology
Published in Chronobiology International, 2020
Mahtab Keshvari, Mahdieh Nejadtaghi, Farnaz Hosseini-Beheshti, Ali Rastqar, Niraj Patel
Studies in animals and plants suggest that cryptochromes play a pivotal role in the generation and maintenance of circadian rhythms. Similarly, cryptochromes play a vital role in the entrainment of circadian rhythms in plants (Chaves et al. 2011). In Drosophila, cryptochrome (dCRY) acts as a blue-light photoreceptor that directly modulates light input into the circadian clock (Yoshii et al. 2016), while in mammals, cryptochromes (CRY1 and CRY2) act as transcription repressors within the circadian clockwork (Dibner et al. 2010). Some insects, including the monarch butterfly, have both a mammal-like and a Drosophila-like version of cryptochrome, providing evidence for an ancestral clock mechanism involving both light-sensing and transcriptional-repression roles for cryptochrome (Zhu et al. 2008a).