Biology subjects

Lo, J. C.

Publications and source records attributed to Lo, J. C..

5 recordsLinked to original sources

bioRxiv2025

Circadian and Sleep-Wake Modulation of Functional Connectivity Across Brain Oscillations and States Linked to Cognition in Humans

Sleep and circadian rhythms both contribute to cognitive performance, but the underlying neuronal network- level changes remain unclear. We quantified the contribution of brain state, sleep-pressure dynamics across the sleep-wake cycle, and circadian rhythmicity to electroencephalographic (EEG) functional connectivity (FC) and examined how these network changes relate to cognition. Thirty-four healthy adults completed a 10-day forced-desynchrony protocol to uncouple sleep-wake and endogenous circadian rhythms. From over 1,200 hours of artifact-free EEG, we derived phase-coupling metrics to quantify FC across brain states, thirds-of-the-night (sleep pressure), and circadian phase, and related these network measures to a range of cognitive performance indices. FC differed markedly between brain states, especially in the alpha and sigma bands, and was modulated by sleep history and circadian phase. Principal component analysis revealed both a global and a topographically distributed FC component which responded differentially to sleep pressure. Dissipation of sleep pressure was accompanied by increasing global FC in NREM sleep, and especially in the delta, sigma and beta frequencies, and decreasing global FC in the alpha band. During REM sleep, global FC decreased in nearly all frequency bands with dissipation of sleep pressure. The influence of circadian phase on FC was smaller than that of sleep pressure and varied across brain states. Lower global theta-band FC in NREM and alpha-band FC during wake predicted better alertness and working memory accuracy, an effect modulated by circadian phase. These results suggest that sleep homeostasis and circadian timing interact to stabilize functional brain connectivity in wakefulness, thereby supporting optimal cognitive function. Significance StatementIdentifying how sleep restores neural networks degraded during wakefulness is of significance for understanding sleeps role in maintaining brain function. Here we used a protocol to isolate effects of sleep from effects of circadian rhythmicity on functional connectivity of neural networks and assessed associations with cognitive performance. We found that circadian rhythmicity but in particular the dissipation of sleep pressure had profound effects on global connectivity which were different for NREM sleep, REM sleep and wakefulness and varied across frequency bands. Connectivity measures in the theta, alpha and sleep spindle frequency ranges were associated with cognitive performance. These novel findings provide a new perspective on the nature of the sleep recovery process contributing to the waking performance capability of human brains.

neuroscience↗

bioRxiv2025

FGF13 regulates cardiomyocyte impulse propagation via Cx43 trafficking independent of voltage-gated sodium channels

BackgroundFibroblast growth factor homologous factor (FHF) variants associate with arrhythmias. Although FHFs are best characterized as regulators of voltage gated sodium channel (VGSC) gating, recent studies suggest broader, non-VGSC-related functions, including regulation of Cx43 gap junctions and/or hemichannels, mechanisms that have generally been understudied or disregarded. MethodsWe assessed cardiac conduction and cardiomyocyte action potentials in mice with constitutive cardiac-specific Fgf13 ablation (cFgf13KO) while targeting Cx43 gap junctions and hemichannels pharmacologically. Using immunostaining and biochemistry, we characterized FGF13 regulation of Cx43 abundance and subcellular distribution. With proximity labeling proteomics, we investigated novel candidate mechanisms underlying FGF13 regulation of Cx43. ResultsFGF13 ablation prolonged the QRS and QT intervals on the surface electrocardiogram. Carbenoxolone, a Cx43 gap junction uncoupler, markedly prolonged the QRS duration leading to conduction system block in cFgf13KO but not in WT mice. Optical mapping revealed markedly decreased conduction velocity (CV) during ventricular pacing. Microscopy revealed markedly perturbed trafficking of Cx43, reduced localization in the intercalated disc, and suggested decreased membrane Cx43 but increased Cx43 hemichannels in cardiomyocytes from cFgf13KOmice. Resting membrane potential (RMP) was depolarized and APD50 was prolonged in cFgf13KOcardiomyocytes. Both were restored towards wildtype (WT) values with Gap19 (a Cx43 hemichannel inhibitor), expression of FGF13, or expression of a mutant FGF13 incapable of binding to VGSCs, emphasizing VGSC-independent regulation by FGF13. To assess the functional impact of RMP depolarization, hearts were subjected to hypokalemia, which had no effect in WT hearts but fully rescued CV in cFgf13KO hearts. Proteomic analyses revealed candidate roles for FGF13 in the regulation of vesicular-mediated transport. Biochemistry and immunocytochemistry showed that FGF13 ablation destabilized microtubules and reduced the expression of tubulins and MAP4, the major cardiac microtubule regulator. ConclusionsFGF13 regulates microtubule-dependent trafficking and targeting of Cx43, thereby impacting cardiac impulse propagation via VGSC-independent mechanisms.

physiology↗

bioRxiv2023

Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome

The canonical G406R gain of function mutation that reduces inactivation and increases Ca2+ influx through the CACNA1C-encoded CaV1.2 voltage gated Ca2+ channel underlies the multisystem disorder Timothy syndrome (TS), characterized by invariant Long QT syndrome and consequent life-threatening arrhythmias. Severe episodic hypoglycemia, which exacerbates arrhythmia risk, is among the myriad non-cardiac TS pathologies that are poorly characterized. While hypoglycemia is thought to result from increased Ca2+ influx through CaV1.2 channels in pancreatic beta cells and consequent hyperinsulinism, this mechanism has never been demonstrated due to a lack of informative animal models, thus hampering development of preventive strategies. We generated a CaV1.2 G406R knockin mouse model that recapitulates key TS features including hypoglycemia. Unexpectedly, these mice did not show hyperactive beta cells or hyperinsulinism in the setting of normal intrinsic beta cell function, suggesting dysregulated glucose homeostasis. We discovered multiple alternative contributors to hypoglycemia, including perturbed counterregulatory hormone responses with defects in glucagon secretion and abnormal hypothalamic glucose sensing. Together, these data provide new insights into physiological contributions of the broadly expressed CaV1.2 channel and reveal integrated consequences of the mutant channel that underlie the life-threatening events in TS. Brief SummaryGain of function mutant CaV1.2 channels drive hypoglycemia through adverse effects on counterregulatory hormones and central nervous system glucose sensing

physiology↗

bioRxiv2022

Alternative Complement Pathway Regulates Thermogenic Fat Function via Adipsin and Adipocyte-derived C3aR1 in a Sex-dependent Fashion

Thermogenesis in beige/brown adipose tissues can be leveraged to combat metabolic disorders such as type 2 diabetes and obesity. The complement system plays pleiotropic roles in metabolic homeostasis and organismal energy balance with canonical effects on immune cells and non-canonical effects on non-immune cells. The adipsin/C3a/C3aR1 pathway stimulates insulin secretion and sustains pancreatic beta cell mass. However, its role in adipose thermogenesis has not been defined. Here, we show that Adipsin knockout mice exhibit increased energy expenditure and white adipose tissue (WAT) browning. C3a, a downstream product of adipsin, is generated from complement component 3 and decreases Ucp1 expression in subcutaneous adipocytes. In addition, adipocyte-specific C3aR1 knockout male mice show enhanced WAT thermogenesis and increased respiration. In stark contrast, adipocyte-specific C3aR1 knockout female mice display decreased brown fat thermogenesis and are cold intolerant. Female mice express lower levels of Adipsin in thermogenic adipocytes and adipose tissues than males. C3aR1 is also lower in female subcutaneous adipose tissue than males. Collectively, these results reveal sexual dimorphism in the adipsin/C3a/C3aR1 axis in regulating adipose thermogenesis. Our findings establish a newly discovered role of the alternative complement pathway in adipose thermogenesis and highlight sex-specific considerations in potential therapeutic targets for metabolic diseases.

cell biology↗

bioRxiv2020

A common human variant of GIPR improves systemic glucose homeostasis in a sexual dimorphic manner

Glucose-dependent insulinotropic polypeptide (GIP) has a role in controlling postprandial metabolic tone. In humans, a GIP receptor (GIPR) variant (Q354, rs1800437) is associated with a lower body mass index (BMI) and increased risk for Type 2 Diabetes. To isolate the contribution of GIPR in metabolic control, we generated a mouse model of the GIPR-Q354 variant (GIPR-Q350 mice). Female GIPR-Q350 mice are leaner than littermate controls, and male GIPR-Q350 mice are resistant to diet-induced obesity, in line with the association of the variant with reduced BMI in humans. GIPR-Q350 mice of both sexes are more glucose tolerant and exhibit an increased sensitivity to GIP. Postprandial GIP levels are reduced in GIPR-Q350 mice, revealing feedback regulation that balances the increased sensitivity of GIP target tissues to secretion of GIP from intestinal endocrine cells. The increased GIP sensitivity is recapitulated ex vivo during glucose stimulated insulin secretion assays in islets. Generation of cAMP in islets downstream of GIPR activation is not affected by the Q354 substitution. However, post-activation traffic of GIPR-Q354 variant in {beta}-cells is altered, characterized by enhanced intracellular dwell time and increased localization to the Trans-Golgi Network (TGN). Consequently, our data link altered intracellular traffic of the GIPR-Q354 variant with GIP control of metabolism. We propose that this change in spatiotemporal signaling underlies the physiologic effects of GIPR-Q350/4 and GIPR-E350/4 in mice and humans. These findings contribute to a more complete understanding of the impact of GIPR-Q354 variant on glucose homeostasis that could perhaps be leveraged to enhance pharmacologic targeting of GIPR for the treatment of metabolic disease.

physiology↗