bims-ciryme 2023-12-03 papers

Proc Natl Acad Sci U S A. 2023 Dec 05. 120(49): e2314857120

Expression of the vesicular GABA transporter within neuromedin S+ neurons sustains behavioral circadian rhythms.

Ivana L Bussi, Alexandra F Neitz, Raymond E A Sanchez, Leandro P Casiraghi, Michael Moldavan, Divya Kunda, Charles N Allen, Jennifer A Evans, Horacio O de la Iglesia.

The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of a central circadian clock that orchestrates overt rhythms of physiology and behavior. Circadian timekeeping requires intercellular communication among SCN neurons, and multiple signaling pathways contribute to SCN network coupling. Gamma-aminobutyric acid (GABA) is produced by virtually all SCN neurons, and previous work demonstrates that this transmitter regulates coupling in the adult SCN but is not essential for the nucleus to sustain overt circadian rhythms. Here, we show that the deletion of the gene that codes for the GABA vesicular transporter Vgat from neuromedin-S (NMS)+ neurons-a subset of neurons critical for SCN function-causes arrhythmia of locomotor activity and sleep. Further, NMS-Vgat deletion impairs intrinsic clock gene rhythms in SCN explants cultured ex vivo. Although vasoactive intestinal polypeptide (VIP) is critical for SCN function, Vgat deletion from VIP-expressing neurons did not lead to circadian arrhythmia in locomotor activity rhythms. Likewise, adult SCN-specific deletion of Vgat led to mild impairment of behavioral rhythms. Our results suggest that while the removal of GABA release from the adult SCN does not affect the pacemaker's ability to sustain overt circadian rhythms, its removal from a critical subset of neurons within the SCN throughout development removes the nucleus ability to sustain circadian rhythms. Our findings support a model in which SCN GABA release is critical for the developmental establishment of intercellular network properties that define the SCN as a central pacemaker.

Keywords: GABA; Vgat; sleep; suprachiasmatic

DOI: https://doi.org/10.1073/pnas.2314857120

Cell Rep Med. 2023 Nov 17. pii: S2666-3791(23)00493-7. [Epub ahead of print] 101299

Circadian organization of lipid landscape is perturbed in type 2 diabetic patients.

Flore Sinturel, Simona Chera, Marie-Claude Brulhart-Meynet, Jonathan Paz Montoya, Dirk Jan Stenvers, Peter H Bisschop, Andries Kalsbeek, Idris Guessous, François R Jornayvaz, Jacques Philippe, Steven A Brown, Giovanni D'Angelo, Howard Riezman, Charna Dibner.

Lipid homeostasis in humans follows a diurnal pattern in muscle and pancreatic islets, altered upon metabolic dysregulation. We employ tandem and liquid-chromatography mass spectrometry to investigate daily regulation of lipid metabolism in subcutaneous white adipose tissue (SAT) and serum of type 2 diabetic (T2D) and non-diabetic (ND) human volunteers (n = 12). Around 8% of ≈440 lipid metabolites exhibit diurnal rhythmicity in serum and SAT from ND and T2D subjects. The spectrum of rhythmic lipids differs between ND and T2D individuals, with the most substantial changes observed early morning, as confirmed by lipidomics in an independent cohort of ND and T2D subjects (n = 32) conducted at a single morning time point. Strikingly, metabolites identified as daily rhythmic in both serum and SAT from T2D subjects exhibit phase differences. Our study reveals massive temporal and tissue-specific alterations of human lipid homeostasis in T2D, providing essential clues for the development of lipid biomarkers in a temporal manner.

Keywords: 1-deoxyceramides; DAGs; TAGs; glycerophosphopholipids; human circadian system; lipidomics; serum; sphingolipids; subcutaneous white adipose tissue; type 2 diabetes

DOI: https://doi.org/10.1016/j.xcrm.2023.101299

JCI Insight. 2023 Nov 30. pii: e162771. [Epub ahead of print]

Neuronal deletion of the circadian clock gene Bmal1 induces cell-autonomous dopaminergic neurodegeneration.

Michael K Kanan, Patrick W Sheehan, Jessica N Haines, Pedro G Gomez, Adya Dhuler, Collin J Nadarajah, Zachary M Wargel, Brittany M Freeberg, Hemanth R Nelvagal, Mariko Izumo, Joseph S Takahashi, Jonathan D Cooper, Albert A Davis, Erik S Musiek.

Circadian rhythm dysfunction is a hallmark of Parkinson Disease (PD), and diminished expression of the core clock gene Bmal1 has been described in PD patients. BMAL1 is required for core circadian clock function, but also serves non-rhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the impact of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, post-natal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase-positive (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms, and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after alpha-synuclein fibril injection, though Bmal1 KO mice had fewer TH neurons at baseline. Transcriptomic analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson Disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival, and may have important implications for neuroprotection in PD.

Keywords: Aging; Neurodegeneration; Neuroscience; Parkinson disease

DOI: https://doi.org/10.1172/jci.insight.162771