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Clock timing cues that emanate from the SCN are relayed via efferents that project largely within the hypothalamus (e.g., to the paraventricular nucleus, dorso-medial nucleus, preoptic area, and the subparaventricular zone), with limited projections to extrahypothalamic targets, including the paraventricular nucleus of the thalamus, bed nuclei of the stria terminalis, the vascular organ of lamina terminalis and the lateral septal area [26,27,28,29,30] (Fig. 2). These projection pathways have been implicated in the clock regulation of diverse physiological processes, including, sleep, melatonin synthesis, feeding, reproduction, memory and even aggressive behavior [31,32,33,34].
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The SCN master clock: major efferents within the CNS, and clock-gated peripheral organ systems. Black arrows denote direct synaptic targets of the SCN. Red arrows denote cortico-limbic brain regions that are under the indirect control of the SCN, either via output from the lateral septal area (LS), or via glucocorticoid (GC) release from the adrenal gland. Blue arrows denote SCN output via the hypothalamic pituitary axis (HPA) and the autonomic nervous system (ANS) that gates the inherent oscillatory capacity of peripheral organs. The brown arrow denotes the direct, monosynaptic, input to the SCN from the retina. sPVZ: subparaventricular zone; PVNT: paraventricular nucleus of the thalamus; BNST: bed nuclei of the stria terminalis; OVLT: organ vascular of lamina terminalis; POA: preoptic area; PVN: paraventricular nucleus; DMN: dorso-medial nucleus; Hipp: hippocampus; CTX: cortex
Rhythmic regulation of ERK activity and cAMP production has been shown to play a role in the clock-gating of cognition. Along these lines Eckel-Mahan et al., [100] identified a daily rhythm in ERK activity and cAMP levels within the hippocampus, and found that the disruption of rhythmic ERK activity, via the deletion of calcium-sensitive adenylyl cyclases, constant light treatment or the pharmacological disruption of MAPK signaling, led to the disruption of clock-gated contextual memory formation and persistence. Interestingly, building off this finding, studies by Rawashdeh et al. reported that the MAPK target pP90RSK accesses the cellular nucleus by dimerization with Period1 and that this interaction is associated with the daily rhythm in hippocampal plasticity and memory [101]. Further, work by Shimizu found that SCOP (suprachiasmatic nucleus circadian oscillatory protein) underlies rhythmicity of MAPK signaling within the cortex and hippocampus, and that the daily rhythm of ERK activity in the hippocampus was disrupted in SCOP conditional KO animals. Of note, at a mechanistic level, SCOP inhibits MAPK signaling by sequestering nucleotide-free Ras [102], and the dynamic circadian regulation of RAS/MAPK signaling via SCOP has been shown to be mediated by a time-of-day accumulation of SCOP within membrane rafts, where it most effectively binds to RAS [100].
Pivoting from the SCN, a number of studies have shown that oscillator populations within cortical and limbic circuits are affected in AD. In line with this idea, Cermakian et al., (2011) examined the temporal expression patterns of circadian clock genes within the cortex and the bed nucleus of the stria terminalis in postmortem tissue from AD patients [143]. Interestingly, both the phase of clock gene oscillations and phase relationships between genes and regions were altered in AD patients, relative to aged controls, thus revealing a marked temporal desynchronization of peripheral oscillators. These findings indicate that clock timing outside of the SCN is disrupted and/or desynchronized in AD patients, and in fact, the authors of this study posited that disrupted oscillatory capacity may be an independent risk factor for AD development. In addition, in the APP/PS1 AD mouse model, daily rhythms in novel object recognition memory and LTP were disrupted, and the diurnal difference in long-term spatial memory was decreased [144]. Further, in the Tg-SwDI mouse model of AD, Fusilier et al. (2021) reported a disruption in the clock-gating of spatial memory (assessed using the spontaneous alternation assay), and this decrease in clock-gated cognitive capacity was associated with a damping of molecular clock rhythms and daytime inhibitory synaptic transmission in the hippocampus [145]. When considered within the context of the noted work indicating only modest effects of AD-like pathologies on the timing properties of the SCN, these findings support the idea that the disruption/desynchronization of oscillator populations within cortical and subcortical regions, could be a key event that underlies early and mid-stage learning and memory deficits in AD. Interestingly, Kress et al. (2018) reported that the disruption of peripheral clock timing in the CNS led to an increase in ApoE expression and fibrillar Aβ plaque formation (of note however, several other measures of Aβ load did not appear to be markedly affected by the disruption of peripheral clock timing) [146].
Canonical and non-canonical regulation of HIF signaling. a Oxygen- dependent regulation of HIF-α. Under normoxic condition, the ODD module within HIF-1α will be degraded via binding to VHL E3 ubiquitin ligase complex which consisting of pVHL, Cullin 2 (Cul-2) and Elongin B. This process is mediated by ubiquitin-proteasome pathway, which α-ketoglutarate-dependent PHDs catalyze the hydroxylation of ODD domain which is recognized by VHL, eventually leading to proteasomal degradation of HIF-α. More, factor inhibiting HIF (FIH) inhibits the binding of p300 to HIF-α by hydroxylating asparagine residue within C terminal domain, which play a role of inhibition on HIF-α activity. b Regulation of the HIF pathway at mRNA and protein level. In hypoxic conditions, inhibition of PHDs promote the heterodimer formation consisting of HIF-α and ARNT. Extracellular signaling TNF-α stimulates I-κB kinase (IKK) complex which is comprised of IKKα and IKKβ, and other normal TNF signaling (NIK), which contribute to p65/50 complex and p52/RelB complex formation. Many other components NF-κB together activate target genes, including HIF-α, and further induce inflammation. More, PI3K, PDK and PKB activation induced by growth factors (GFs) activates mTOR pathway results in elevated HIF-α transcriptional activity. And phosphorylation of FoxO1 PI3K/PKB, which is transferred from the nucleus to the cytoplasm, prevents FoxO1 from acting on HIF-α. G9a/GLP methylates HIF-1α protein and inhibits HIF-1α activity within solid tumors, making it unable to bind to the hypoxic response element (HRE) of its target genes, resulting in inhibition of the downstream HIF pathway. More, HIF-1α acts on TIP60, which leads to chromatin histone acetylation and then to the activation of polymerase II, which ultimately activates HIF-1α target genes transcription. IκB, nuclear factor of κB inhibitor, alpha; IKK, IκB kinase; 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; eIF-4E, eukaryotic translation initiation factor; GβL: G protein beta subunit-like; Grb2: growth factor receptor-bound protein 2; EPO: erythropoietin; PAI: plasminogen activator inhibitor; iNOS: nitric oxide synthase; REDD1: regulated in development and DNA damage response 1; PGK: phosphoglycerate kinase
In the past few years, numerous studies have shown that metabolism is passive, subordinate to the metabolic needs of the tumor, driven by the activation of oncogenes and the inactivation of tumor suppressor factors [158]. HIF-driven tumor metabolic remodeling activates multiple metabolic pathways, including pyruvate dehydrogenase kinase 1 (PDK1), BHLH Transcription Factor (MYC), pyruvate kinase M2 (PKM2), tumor protein P53 (TP53) [159, 160]. Many HIF target genes encode special enzymes, in turn, metabolites, including succinate, fumarate, pyruvate, lactate and oxaloacetate etc. affect HIF proteins stability due to loss-of-function of PHD (Fig. 2) [161,162,163]. For example, three succinate dehydrogenase (SDHB, SDHC and SDHD) and fumarate hydratase are reported to response to hypoxia, and aberrant function of these enzymes inhibit the process of mitochondrial respiratory [164]. Their mutation lead to increased ROS, and altered intracellular metabolites of TCA cycle as messengers to induce HIF stability [165]. In detail, inhibition of SDH genes coding aberrant enzymes lead to the loss-of-function PHDs with increased amount of succinate. As we discussed above, PHDs are responsible for the ubiquitylation leading to degradation of HIF-α, therefore the inhibition of PHDs leads to the accumulation PHDs substrates, above all HIF-α subunits [164]. Interestingly, among the accumulated substrates, succinate and fumarate could also contribute to HIF stability [165]. The recent study confirms this opinion that the FIH in concert with PHD/VHL in rapidly response to hypoxia, in turn, altered metabolites lead to HIF stability [56]. And authentic study speculated that lipopolysaccharide produced by gram-negative bacteria potently enhance the TCA-cycle intermediate metabolites succinate, performing a role of stabilizing HIF-1α accompanied with increased interleukin-1β, which finally mediating inflammation [161]. Isocitrate dehydrogenase isoform-1 (IDH1) and 2 (IDH2) mutations are considered to be associated with HIF-α stability in solid tumors, notably glioblastoma and acute myeloid leukemia (AML) [166, 167]. Mutant IDH proteins obtain neomorphic enzymatic activity that catalyze the transformation of α-ketoglutarate (α-KG) to R-2-hydroxyglutarate (R-2HG), which activates prolyl hydroxylase domain-2 that further leads to the degradation of HIF-α [168]. Moreover, non-catalytic enzymes associated with metabolic plasticity could also interact with HIF-α, such as fructose-1,6-bisphosphatase (FBP1) and PKM2. In ccRCC, the loss of FBP1 has been identified, and it may function as repressor of HIF-α via binding to the degradation domain of HIF in the nucleus, and further inhibit ccRCC progression. In human pancreatic adenocarcinoma, high level PKM2 expression interacts with NF-κB and HIF-1α to induce the activation of HIF target gene VEGF. In contrast to FBP1, PKM2 could function as a coactivator to directly bind with HIF-1α by facilitating the recruitment of p300 [16, 37, 169]. 041b061a72
