Biology subjects

Halloy, N. R.

Publications and source records attributed to Halloy, N. R..

3 recordsLinked to original sources

bioRxiv2025

Cellular- and systems-level profiling of amyloid-beta effects on circadian timing

Disruption of the circadian timing system has been reported in the preclinical phase of Alzheimers disease (AD) and is a well-characterized component of mid- and late-stage AD. Given the distributed nature of the circadian timing system, with a central pacemaker in the suprachiasmatic nucleus (SCN) and peripheral clocks throughout the brain, understanding how AD affects this system has been challenging. To investigate how AD may disrupt circadian physiology, we focused on the amyloid-beta peptide, a key contributor to familial early-onset AD. Using the 5xFAD mouse model and ex vivo single-cell profiling, we examined how amyloid-beta influences clock timing in both SCN neurons and hippocampal neuronal populations. Circadian profiling of 5xFAD mice (4-and 8-months-old) showed only modest changes in key clock timing properties, including a shortening of the SCN rhythm. Interestingly, the mice showed enhanced rates of re-entrainment to changes in the light cycle, suggesting that elevated amyloid-beta levels increase the sensitivity of the SCN clock to light. Further, using both in vitro SCN slice explant and dispersed SCN culture models, the exogenous administration of oligomerized amyloid-beta had no significant effect on inherent clock timing capacity. In contrast, the timing properties of cultured hippocampal neurons showed a dose-dependent sensitivity to amyloid-beta. This included an elevated mesor and an increased rhythm amplitude. These findings reveal a divergence in amyloid-beta sensitivity between the central SCN clock and peripheral oscillators. This raises the possibility that circadian disruptions in AD may stem from both the destabilization and decoupling of peripheral oscillators from the central timing properties of the SCN.

neuroscience↗

bioRxiv2025

Circadian timing and entrainment properties of the SCN pacemaker in the PS19 mouse model of Tau pathology

Tauopathies are a group of neurodegenerative disorders caused by the misfolded microtubule-associated protein tau (MAPT), leading to its abnormal accumulation and hyperphosphorylation, and resulting in neuronal dysfunction and death. Tauopathy patients also experience disruptions to circadian rhythms of behavior and sleep. The connection between tau pathology and circadian dysfunction is not well understood, especially regarding the role of the suprachiasmatic nucleus (SCN), the brains central circadian pacemaker. Here, we conducted histological and functional analyses of the SCN in the PS19 (Prnp-huMAPT*P301S) mouse model of tauopathy. The SCN of PS19 mice had accumulation of phosphorylated tau as early as 2 months of age, and tau pathology was detected in both major neuronal subpopulations of the SCN: VIPergic (core) and AVPergic (shell) neurons. To assess SCN timing and entrainment properties, daily locomotor activity was monitored in PS19 and wild-type (WT) mice from 3 to 11 months-of-age. Activity profiles, rates of re-entrainment to changes in the light/dark cycle, and intrinsic circadian timing properties were unchanged in PS19 mice compared to age-matched WT mice. Finally, profiling circadian gene expression in tau fibril-seeded SCN explants from PS19 and WT mice did not reveal differences in network-level oscillator properties. Together, these findings suggest that tau pathology within the SCN is not sufficient to trigger marked disruptions of core circadian timing mechanisms in this tauopathy model. Further, these results raise the possibility that circadian disruptions in tauopathies arise from dysfunction in SCN-gated output pathways or downstream clock-gated circuits rather than the SCN oscillator itself.

neuroscience↗

bioRxiv2023

Formation of Müller glia-derived progenitor cells in retinas depleted of microglia

Recent studies have demonstrated the complex coordination of pro-inflammatory signaling and reactive microglia/macrophage on the formation Muller glial-derived progenitor cells (MGPCs) in the retinas of fish, birds and mice. We generated scRNA-seq libraries to identify transcriptional changes in Muller glia (MG) that result from the depletion of microglia from the chick retina. We found significant changes in different networks of genes in MG in normal and damaged retinas when the microglia are ablated. We identified a failure of MG to upregulate Wnt-ligands, Heparin binding epidermal growth factor (HBEGF), Fibroblast growth factor (FGF), retinoic acid receptors and genes related to Notch-signaling. Inhibition of GSK3{beta}, to simulate Wnt-signaling, failed to rescue the deficit in formation of proliferating MGPCs in damaged retinas missing microglia. By comparison, application of HBEGF or FGF2 completely rescued the formation of proliferating MGPCs in microglia-depleted retinas. Similarly, injection of a small molecule inhibitor to Smad3 or agonist to retinoic acid receptors partially rescued the formation of proliferating MGPCs in microglia-depleted damaged retinas. According to scRNA-seq libraries, patterns of expression of ligands, receptors, signal transducers and/or processing enzymes to cell-signaling via HBEGF, FGF, retinoic acid and TGF{beta} are rapidly and transiently upregulated by MG after neuronal damage, consistent with important roles for these cell-signaling pathways in regulating the formation of MGPCs. We conclude that quiescent and activated microglia have a significant impact upon the transcriptomic profile of MG. We conclude that signals produced by reactive microglia in damaged retinas stimulate MG to upregulate cell signaling through HBEGF, FGF and retinoic acid, and downregulate signaling through TGF{beta}/Smad3 to promote the reprogramming on MG into proliferating MGPCs.

neuroscience↗