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The suprachiasmatic nucleus (SCN) receives direct retinal input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) for circadian photoentrainment. Interestingly, the SCN is the only brain region that receives equal inputs from the left and right eyes. Despite morphological assessments showing that axonal fibers originating from ipRGCs cover the entire SCN, physiological evidence suggests that only vasoactive intestinal polypeptide (VIP)/gastrin-releasing peptide (GRP) cells located ventrally in the SCN receive retinal input. It is still unclear, therefore, which subpopulation of SCN neurons receives synaptic input from the retina and how the SCN receives equal inputs from both eyes. Here, using single ipRGC axonal tracing and a confocal microscopic analysis in mice, we show that ipRGCs have elaborate innervation patterns throughout the entire SCN. Unlike conventional retinal ganglion cells (RGCs) that innervate visual targets either ipsilaterally or contralaterally, a single ipRGC can bilaterally innervate the SCN. ipRGCs form synaptic contacts with major peptidergic cells of the SCN, including VIP, GRP, and arginine vasopressin (AVP) neurons, with each ipRGC innervating specific subdomains of the SCN. Furthermore, a single SCN-projecting ipRGC can send collateral inputs to many other brain regions. However, the size and complexity of the axonal arborizations in non-SCN regions are less elaborate than those in the SCN. Our results provide a better understanding of how retinal neurons connect to the central circadian pacemaker to synchronize endogenous circadian clocks with the solar day.

Changes in external light patterns can alter cell activities in peripheral tissues through slow entrainment of the central clock in suprachiasmatic nucleus (SCN). It remains unclear whether cells in otherwise photo-insensitive tissues can achieve rapid responses to changes in external light. Here we show that light stimulation of animals’ eyes results in rapid activation of hair follicle stem cells with prominent hair regeneration. Mechanistically, light signals are interpreted by M1-type intrinsically photosensitive retinal ganglion cells (ipRGCs), which signal to the SCN via melanopsin. Subsequently, efferent sympathetic nerves are immediately activated. Increased norepinephrine release in skin promotes hedgehog signaling to activate hair follicle stem cells. Thus, external light can directly regulate tissue stem cells via an ipRGC–SCN autonomic nervous system circuit. Since activation of sympathetic nerves is not limited to skin, this circuit can also facilitate rapid adaptive responses to external light in other homeostatic tissues.

Oxytocin, a neuropeptide and peptide hormone, is produced by neurons in the hypothalamus and released by the posterior pituitary to control breastfeeding and labor. Recent studies have revealed that oxytocin in the central nervous system is also involved in modulating social interaction. To understand the potential role and innervation pattern of oxytocin neurons before sexual interaction, here we used transgenic mice which has the Cre recombinase under the control of an endogenous oxytocin promoter and Cre dependent human placental alkaline phosphatase (hPAP) reporter to label the oxytocin neurons in the naive mouse brain. Since AP is located on the membrane of oxytocin neurons, the AP histochemistry staining enabled us to observe the fine axonal terminals and the innervation pattern of oxytocin neurons in the thick serial coronal brain slices. Here we show that the number of AP labeled cells vary with staining reaction time and range from 30% of the oxytocin immune-positive cell count to slightly higher than the oxytocin immune-positive cell count. Using AP staining with extended reaction time, which may not label all oxytocin neurons, we confirmed many innervation targets of oxytocin neurons from the anterior olfactory nucleus, some cortex regions, the limbic system, the hypothalamus, and the hindbrain, while the cell bodies were exclusively located in the hypothalamus and the bed nucleus of the stria terminalis (BST). Finally, we observe some individual variance at the olfactory area, isocortex, striatum, Paraventricular nucleus of thalamus, Locus coeruleus, and Barrington’s nucleus.

The biological clock synchronizes with the environmental light-dark cycle through circadian photoentrainment. While intracellular pathways regulating clock gene expression after light exposure in the suprachiasmatic nucleus are well studied in mammals, the neuronal circuits driving phase shifts remain unclear. Here, using a mouse model, we show that chemogenetic activation of early-night light-responsive neurons induces phase delays at any circadian time, potentially breaking the photoentrainment dead zone. In contrast, activating late-night light-responsive neurons mimics light-induced phase shifts. Using in vivo two-photon microscopy, we found that most neurons in the suprachiasmatic nucleus exhibit stochastic light responses, while a small subset is consistently activated in the early subjective night and another is inhibited in the late subjective night. Our findings suggest a dynamic bi-stable network model for circadian photoentrainment, where phase shifts arise from a functional circuit integrating signals to groups of outcome neurons, rather than a labeled-line principle seen in sensory systems. Neural mechanisms underlying circadian photoentrainment are not fully understood. Using in vivo two-photon imaging with a GRIN lens, this study reveals a dynamic bi-stable circuit in the suprachiasmatic nucleus that regulates light-driven circadian clock shifts, providing insight into mechanisms of circadian photoentrainment.

Hutchinson–Gilford progeria syndrome (HGPS) is a rare laminopathy that produces a mutant form of prelamin A, known as Progerin, resulting in premature aging. HGPS cells show morphological abnormalities of the nuclear membrane, reduced cell proliferation rates, accumulation of reactive oxygen species (ROS), and expression of senescence markers. Lysophosphatidic acid (LPA) is a growth factor‐like lipid mediator that regulates various physiological functions via activating multiple LPA G protein‐coupled receptors. Here, we study the roles of LPA and LPA receptors in premature aging. We report that the protein level of LPA3 was highly downregulated through internalization and the lysosomal degradation pathway in Progerin‐transfected HEK293 cells. By treating Progerin HEK293 cells with an LPA3 agonist (OMPT, 1‐Oleoyl‐2‐O‐methyl‐rac‐glycerophosphothionate) and performing shRNA knockdown of the Lpa3r transcript in these cells, we showed that LPA3 activation increased expression levels of antioxidant enzymes, consequently inhibiting ROS accumulation and ameliorating cell senescence. LPA3 was shown to be downregulated in HGPS patient fibroblasts through the lysosomal pathway, and it was shown to be crucial for ameliorating ROS accumulation and cell senescence in fibroblasts. Moreover, in a zebrafish model, LPA3 deficiency was sufficient to cause premature aging phenotypes in multiple organs, as well as a shorter lifespan. Taken together, these findings identify the decline of LPA3 as a key contributor to the premature aging phenotypes of HGPS cells and zebrafish. In normal cells, activation of LPA3 stabilizes Nrf2 and enhances antioxidants to prevent accumulation of reactive oxygen species (ROS) and cell senescence. In Hutchinson–Gilford progeria syndrome (HGPS) cells, LPA3 is shown to be downregulated through high internalization and subsequent lysosomal degradation. The decline of LPA3 contributes to ROS accumulation and cell senescence of HGPS cells.

RBFOX3/NeuN is a neuronal splicing regulator involved in neural circuitry balance, as well as neurogenesis and synaptogenesis. Rbfox3 is expressed in neurons; however, in the retina, expression is restricted to cells in the ganglion cell layer and some cells of the inner nuclear layer. Rbfox3 is expressed in a layer-specific manner in the retina, which implies a functional role, however, the role of RBFOX3 in the retina is unknown. Rbfox3 homozygous knockout (Rbfox3-/-) mice exhibit deficits in visual learning; therefore, understanding the role of RBFOX3 in the retina is critical for interpreting behavioral results. We found Rbfox3 expression was developmentally regulated in the retina and specifically expressed in ganglion cells, amacrine cells and horizontal cells of the retina. We demonstrate deletion of Rbfox3 resulted in a reduction in the thickness of the inner plexiform layer of the retina, where synapses are formed. Number of ganglion cells and amacrine cells is normal with loss of Rbfox3. Innervation of retinal ganglion cells into their targeted brain regions is normal in Rbfox3-/- mice. Importantly, Rbfox3-/- mice displayed normal non-image and image forming functions. Taken together, our results suggest RBFOX3 is dispensable for visual function.

Background The gut-brain axis mediates bidirectional communication between gut and central nervous activities with gut microbiota acting as a key mediator. While recent studies have mainly focused on how gut microbiota influence non-parenting social behavior in rodents, the role of gut microbiota in parenting behavior, especially in non-model species, is largely unexplored. Nest-building behavior is an early parenting behavior critical to avian survival and evolution, offering an ideal system to examine how the microbiota-gut-brain axis shapes the emergence of parental motivation. Results Using zebra finches ( Taeniopygia guttata ), which exhibit sexually dimorphic nest-construction behaviors, we showed strong association between these preparatory parenting behaviors and gut microbiota composition. High-throughput sequencing to gut contents revealed female-specific convergent composition of gut microbiota when entering nesting status, with Campylobacteraceae rising as the predominant family. The gut microbiome of nesting birds showed enriched functions for energy metabolism and biosynthesis of essential amino acids and vitamins, reflecting elevated energy and nutritional demands, especially in females. We also observed sex-specific correlations between nesting actions and gut microbial diversity and Lactobacillaceae abundance. Notably, expression of social and gonad-related hormone genes in nesting-associated brain regions correlated with both microbial diversity and Lactobacillaceae abundance, suggesting integrated relationships between the gut microbiome, brain gene expression and nesting behavior. Conclusions Our study integrates behavior experiments, microbiota profiles, and brain gene expression to investigate the role of gut microbiome in programming sex-specific nest construction behavior in birds. These findings suggest potential mechanisms through which the microbiota-gut-brain axis regulates parenting behaviors in avian systems, expanding our understanding of how gut microbiota influence complex behaviors across animal lineages.

Multiple peripheral nerves are known to degenerate after nerve compression injury but the correlation between the extent of nerve alteration and pain severity remains unclear. Here, we used intravital two-photon fluorescence microscopy to longitudinally observe changes in cutaneous fibers in the hind paw of Nav1.8-Cre-tdTomato mice after chronic constriction injury (CCI). Results showed that the CCI led to variable loss of the skin nerve plexus and intraepidermal nerve fibers. The timing of Nav1.8 nerve fiber loss correlated with the development of mechanical hypersensitivity. We compared a scoring approach that assessed whole-paw nerve degeneration with an index that quantified changes in the nerve plexus and terminals in multiple small regions of interest (ROI) from intravital images of the third and fifth toe tips. We found that the number of surviving nerve fibers was not linearly correlated with mechanical hypersensitivity. On the contrary, at 14 days after CCI, the moderately injured mice showed greater mechanical hypersensitivity than the mildly or severely injured mice. This indicates that both surviving and injured nerves are required for evoked neuropathic pain. In addition, these two methods may have the estimative effect as diagnostic and prognostic biomarkers for the assessment of neuropathic pain.

Multipotent mesenchymal stem/stromal cells (MSCs) exhibit great potential for cell-based therapy. Proper epigenomic signatures in MSCs are important for the maintenance and the subsequent differentiation potential. The DNA methyltransferase 3-like (DNMT3L) that was mainly expressed in the embryonic stem (ES) cells and the developing germ cells plays an important role in shaping the epigenetic landscape. Here, we report the reduced colony forming ability and impaired in vitro osteogenesis in Dnmt3l -knockout-mice-derived MSCs ( Dnmt3l KO MSCs). By comparing the transcriptome between undifferentiated Dnmt3l KO MSCs and the MSCs from the wild-type littermates, some of the differentially regulated genes (DEGs) were found to be associated with bone-morphology-related phenotypes. On the third day of osteogenic induction, differentiating Dnmt3l KO MSCs were enriched for genes associated with nucleosome structure, peptide binding and extracellular matrix modulation. Differentially expressed transposable elements in many subfamilies reflected the change of corresponding regional epigenomic signatures. Interestingly, DNMT3L protein is not expressed in cultured MSCs. Therefore, the observed defects in Dnmt3l KO MSCs are unlikely a direct effect from missing DNMT3L in this cell type; instead, we hypothesized them as an outcome of the pre-deposited epigenetic signatures from the DNMT3L-expressing progenitors. We observed that 24 out of the 107 upregulated DEGs in Dnmt3l KO MSCs were hypermethylated in their gene bodies of DNMT3L knock-down ES cells. Among these 24 genes, some were associated with skeletal development or homeostasis. However, we did not observe reduced bone development, or reduced bone density through aging in vivo . The stronger phenotype in vitro suggested the involvement of potential spreading and amplification of the pre-deposited epigenetic defects over passages, and the contribution of oxidative stress during in vitro culture. We demonstrated that transient deficiency of epigenetic co-factor in ES cells or progenitor cells caused compromised property in differentiating cells much later. In order to facilitate safer practice in cell-based therapy, we suggest more in-depth examination shall be implemented for cells before transplantation, even on the epigenetic level, to avoid long-term risk afterward.

Introduction A couple of studies investigated the energy balance in patients with obstructive sleep apnea (OSA) but the results were inconclusive. Moreover, OSA have been associated with visceral adiposity but the mechanism has not been fully elucidated. We hypothesized that OSA was associated with lower basal metabolic rate (BMR) and increased nutrition intake which further attributed to body adiposity. The aim of the present study is to determine the association between OSA, and BMR, nutrition intake, and body composition (BC). Methods Patients were recruited from referrals to sleep lab for suspect OSA. Measurement of the BMR with indirect calorimetry and BC with bioelectrical impedance analysis, and blood sampling were conducted in the morning next to the overnight polysomnography. Afterward, participants were evaluated with short -form IPAQ, 3-day intake dietary, 7-day sleep log, and wore Actiwatch for 7 days. The outcomes are resting energy expenditure (REE) and respiratory quotien (RQ), total fat mass (TFM), fat free mass (FFM), nutrition intake, daily total activity count, nightly sleep hour, and hormone. The association between OSA □apnea hypopnea index (AHI) >=15/h□ and REE, RQ, TFM, and FFM was analyzed with multivariable linear regression. Results 85 patients were enrolled with median age 41.7 y/o, 78.6% male, body mass index (BMI) 25.4 kg/m2, and AHI 28.8/h. Compared to no OSA, patients with OSA had higher BMI, RQ, TFM, activity count, and similar age, gender, REE, FFM, nutrition intake, sleep hour, cortisol, leptin, and Ghrelin. OSA was independently associated with RQ (coefficient 0.031; 95% CI 0.004-0.057, p=0.022) with adjustment of age, gender, BMI, and activity count but not associated with REE, TFM, and FFM. Conclusion Though OSA may be associated with metabolic dysregulation, it was not associated with energy balance and BC. Further validation of the findings in a large scale and multi-ethnicity cohort to validate the findings of the present study is warranted. Support (if any) National Science and Technology Council, Taiwan (NST 111-2314-B-002-293; MOST 109-2314-B-002-252); Ministry of Education (NTU-107L900502, 108L900502, 109L900502)”, National Taiwan University Hospital (NTHU 108-S4331, 109-42, 111-S0298, 111-X0033); MediaTek Inc. (201802034 RIPD), and LARGAN Health AI-Tec CO., Ltd (202003021 RIPB)