Light exerts a range of powerful biological effects beyond image vision, including mood and learning regulation. While the source of photic information affecting mood and cognitive functions is well ...established, viz. intrinsically photosensitive retinal ganglion cells (ipRGCs), the central mediators are unknown. Here, we reveal that the direct effects of light on learning and mood utilize distinct ipRGC output streams. ipRGCs that project to the suprachiasmatic nucleus (SCN) mediate the effects of light on learning, independently of the SCN’s pacemaker function. Mood regulation by light, on the other hand, requires an SCN-independent pathway linking ipRGCs to a previously unrecognized thalamic region, termed perihabenular nucleus (PHb). The PHb is integrated in a distinctive circuitry with mood-regulating centers and is both necessary and sufficient for driving the effects of light on affective behavior. Together, these results provide new insights into the neural basis required for light to influence mood and learning.
Display omitted
•Distinct ipRGC subpopulations drive the effects of light on learning and mood•SCN-projecting ipRGCs affect learning without disrupting the central pacemaker•The ipRGC-PHb pathway drives the light-mediated mood alterations•Thalamic PHb is integrated in a distinctive circuitry with mood-regulating centers
The effects of light on learning and mood via intrinsically photosensitive retinal ganglion cells involve a pacemaker-independent role for the suprachiasmatic nucleus as well as distinct circuitry in a region of the thalamus called the perihabenular nucleus.
The daily solar cycle allows organisms to synchronize their circadian rhythms and sleep-wake cycles to the correct temporal niche. Changes in day-length, shift-work, and transmeridian travel lead to ...mood alterations and cognitive function deficits. Sleep deprivation and circadian disruption underlie mood and cognitive disorders associated with irregular light schedules. Whether irregular light schedules directly affect mood and cognitive functions in the context of normal sleep and circadian rhythms remains unclear. Here we show, using an aberrant light cycle that neither changes the amount and architecture of sleep nor causes changes in the circadian timing system, that light directly regulates mood-related behaviours and cognitive functions in mice. Animals exposed to the aberrant light cycle maintain daily corticosterone rhythms, but the overall levels of corticosterone are increased. Despite normal circadian and sleep structures, these animals show increased depression-like behaviours and impaired hippocampal long-term potentiation and learning. Administration of the antidepressant drugs fluoxetine or desipramine restores learning in mice exposed to the aberrant light cycle, suggesting that the mood deficit precedes the learning impairments. To determine the retinal circuits underlying this impairment of mood and learning, we examined the behavioural consequences of this light cycle in animals that lack intrinsically photosensitive retinal ganglion cells. In these animals, the aberrant light cycle does not impair mood and learning, despite the presence of the conventional retinal ganglion cells and the ability of these animals to detect light for image formation. These findings demonstrate the ability of light to influence cognitive and mood functions directly through intrinsically photosensitive retinal ganglion cells.
For vertebrate olfactory signal transduction, a calcium-activated chloride conductance serves as a major amplification step. However, the molecular identity of the olfactory calcium-activated ...chloride channel (CaCC) is unknown. Here we report a proteomic screen for cilial membrane proteins of mouse olfactory sensory neurons (OSNs) that identified all the known olfactory transduction components as well as Anoctamin 2 (ANO2). Ano2 transcripts were expressed specifically in OSNs in the olfactory epithelium, and ANO2::EGFP fusion protein localized to the OSN cilia when expressed in vivo using an adenoviral vector. Patch-clamp analysis revealed that ANO2, when expressed in HEK-293 cells, forms a CaCC and exhibits channel properties closely resembling the native olfactory CaCC. Considering these findings together, we propose that ANO2 constitutes the olfactory calcium-activated chloride channel.
Stability of neuronal connectivity is critical for brain functions, and morphological perturbations are associated with neurodegenerative disorders. However, how neuronal morphology is maintained in ...the adult brain remains poorly understood. Here, we identify Wnt5a, a member of the Wnt family of secreted morphogens, as an essential factor in maintaining dendritic architecture in the adult hippocampus and for related cognitive functions in mice. Wnt5a expression in hippocampal neurons begins postnatally, and its deletion attenuated CaMKII and Rac1 activity, reduced GluN1 glutamate receptor expression, and impaired synaptic plasticity and spatial learning and memory in 3-mo-old mice. With increased age, Wnt5a loss caused progressive attrition of dendrite arbors and spines in Cornu Ammonis (CA)1 pyramidal neurons and exacerbated behavioral defects. Wnt5a functions cell-autonomously to maintain CA1 dendrites, and exogenous Wnt5a expression corrected structural anomalies even at late-adult stages. These findings reveal a maintenance factor in the adult brain, and highlight a trophic pathway that can be targeted to ameliorate dendrite loss in pathological conditions.
The purpose of this study was to identify an optimal surfactant-enhanced aquifer remediation (SEAR) strategy for aquifers contaminated by dense non-aqueous phase liquid (DNAPL) based on an ensemble ...of surrogates-based optimization technique. A saturated heterogeneous medium contaminated by nitrobenzene was selected as case study. A new kind of surrogate-based SEAR optimization employing an ensemble surrogate (ES) model together with a genetic algorithm (GA) is presented. Four methods, namely radial basis function artificial neural network (RBFANN), kriging (KRG), support vector regression (SVR), and kernel extreme learning machines (KELM), were used to create four individual surrogate models, which were then compared. The comparison enabled us to select the two most accurate models (KELM and KRG) to establish an ES model of the SEAR simulation model, and the developed ES model as well as these four stand-alone surrogate models was compared. The results showed that the average relative error of the average nitrobenzene removal rates between the ES model and the simulation model for 20 test samples was 0.8%, which is a high approximation accuracy, and which indicates that the ES model provides more accurate predictions than the stand-alone surrogate models. Then, a nonlinear optimization model was formulated for the minimum cost, and the developed ES model was embedded into this optimization model as a constrained condition. Besides, GA was used to solve the optimization model to provide the optimal SEAR strategy. The developed ensemble surrogate-optimization approach was effective in seeking a cost-effective SEAR strategy for heterogeneous DNAPL-contaminated sites. This research is expected to enrich and develop the theoretical and technical implications for the analysis of remediation strategy optimization of DNAPL-contaminated aquifers.
•We established a new surrogate model of SEAR simulation model employing KELM.•RBF, KRG, and SVR were employed as comparison to demonstrate effectiveness of KELM.•Ensemble model was proposed and used in groundwater remediation optimization field.•Ensemble model's accuracy is higher than the other individual surrogate models.•Ensemble surrogate-based optimization is an efficient tool for optimal strategy identification.
In vertebrate olfactory sensory neurons (OSNs), Ca
plays key roles in both mediating and regulating the olfactory response. Ca
enters OSN cilia during the response through the olfactory cyclic ...nucleotide-gated (CNG) channel and stimulates a depolarizing chloride current by opening the olfactory Ca
-activated chloride channel to amplify the response. Ca
also exerts negative regulation on the olfactory transduction cascade, through mechanisms that include reducing the CNG current by desensitizing the CNG channel via Ca
/calmodulin (CaM), to reduce the response. Ca
is removed from the cilia primarily by the K
-dependent Na
/Ca
exchanger 4 (NCKX4), and the removal of Ca
leads to closure of the chloride channel and response termination. In this study, we investigate how two mechanisms conventionally considered negative regulatory mechanisms of olfactory transduction, Ca
removal by NCKX4, and desensitization of the CNG channel by Ca
/CaM, interact to regulate the olfactory response. We performed electro-olfactogram (EOG) recordings on the double-mutant mice, NCKX4
;CNGB1
, which are simultaneously lacking NCKX4 (NCKX4
) and Ca
/CaM-mediated CNG channel desensitization (CNGB1
). Despite exhibiting alterations in various response attributes, including termination kinetics and adaption properties, OSNs in either NCKX4
mice or CNGB1
mice show normal resting sensitivity, as determined by their unchanged EOG response amplitude. We found that OSNs in NCKX4
;CNGB1
mice displayed markedly reduced EOG amplitude accompanied by alterations in other response attributes. This study suggests that what are conventionally considered negative regulatory mechanisms of olfactory transduction also play a role in setting the resting sensitivity in OSNs.
Sensory receptor cells maintain high sensitivity at rest. Although the mechanisms responsible for setting the resting sensitivity of sensory receptor cells are not well understood, it has generally been assumed that the sensitivity is set primarily by how effectively the components in the activation cascade of sensory transduction can be stimulated. Our findings in mouse olfactory sensory neurons suggest that mechanisms that are primarily responsible for terminating the olfactory response are also critical for proper resting sensitivity.
Neointimal hyperplasia characterized by abnormal accumulation of vascular smooth muscle cells (SMCs) is a hallmark of occlusive disorders such as atherosclerosis, postangioplasty restenosis, vein ...graft stenosis, and allograft vasculopathy. Cyclic nucleotides are vital in SMC proliferation and migration, which are regulated by cyclic nucleotide phosphodiesterases (PDEs).
Our goal is to understand the regulation and function of PDEs in SMC pathogenesis of vascular diseases.
We performed screening for genes differentially expressed in normal contractile versus proliferating synthetic SMCs. We observed that PDE1C expression was low in contractile SMCs but drastically elevated in synthetic SMCs in vitro and in various mouse vascular injury models in vivo. In addition, PDE1C was highly induced in neointimal SMCs of human coronary arteries. More importantly, injury-induced neointimal formation was significantly attenuated by PDE1C deficiency or PDE1 inhibition in vivo. PDE1 inhibition suppressed vascular remodeling of human saphenous vein explants ex vivo. In cultured SMCs, PDE1C deficiency or PDE1 inhibition attenuated SMC proliferation and migration. Mechanistic studies revealed that PDE1C plays a critical role in regulating the stability of growth factor receptors, such as PDGF receptor β (PDGFRβ) known to be important in pathological vascular remodeling. PDE1C interacts with low-density lipoprotein receptor-related protein-1 and PDGFRβ, thus regulating PDGFRβ endocytosis and lysosome-dependent degradation in an low-density lipoprotein receptor-related protein-1-dependent manner. A transmembrane adenylyl cyclase cAMP-dependent protein kinase cascade modulated by PDE1C is critical in regulating PDGFRβ degradation.
These findings demonstrated that PDE1C is an important regulator of SMC proliferation, migration, and neointimal hyperplasia, in part through modulating endosome/lysosome-dependent PDGFRβ protein degradation via low-density lipoprotein receptor-related protein-1.
Histone proteins are essential for the organization, expression, and inheritance of genetic material for eukaryotic cells. A centromere-specific H3 histone variant, centromere protein A (CENP-A), ...shares about 50% amino acid sequence identity with H3. CENP-A is required for packaging the centromere and for the proper separation of chromosomes during mitosis. Despite their distinct biological functions, previously reported crystal structures of the CENP-A/H4 and H3/H4 dimers reveal a high degree of similarity. In this work, we characterize the structural dynamics of CENP-A/H4 and H3/H4 dimers based on a dual-resolution approach, using both microsecond-scale explicit-solvent all-atom and coarse-grained (CG) molecular dynamics (MD) simulations. Our data show that the H4 histone is significantly more rigid compared with the H3 histone and its variant CENP-A, hence, serving as a reinforcing structural element within the histone core. We report that the CENP-A/H4 dimer is significantly more dynamic than its canonical counterpart H3/H4, and our results provide a physical explanation for this flexibility. Further, we observe that the centromere-specific chaperone Holliday Junction Recognition Protein (HJURP) stabilizes the CENP-A/H4 dimer by forming a specific electrostatic interaction network. Finally, replacing CENP-A S68 with E68 disrupts the binding interface between CENP-A and HJURP in all-atom MD simulation, and consistently, in vivo experiments demonstrate that replacing CENP-A S68 with E68 disrupts CENP-A’s localization to the centromere. Based on all our results, we propose that, during the CENP-A/H4 deposition process, the chaperone HJURP protects various substructures of the dimer, serving both as a folding and binding chaperone.
Histones compact and store DNA in both Eukarya and Archaea, forming heterodimers in Eukarya and homodimers in Archaea. Despite this, the folding mechanism of histones across species remains unclear. ...Our study addresses this gap by investigating 11 types of histone and histone-like proteins across humans, Drosophila, and Archaea through multiscale molecular dynamics (MD) simulations, complemented by NMR and circular dichroism experiments. We confirm and elaborate on the widely applied "folding upon binding" mechanism of histone dimeric proteins and report a new alternative conformation, namely, the inverted non-native dimer, which may be a thermodynamically metastable configuration. Protein sequence analysis indicated that the inverted conformation arises from the hidden ancestral head-tail sequence symmetry underlying all histone proteins, which is congruent with the previously proposed histone evolution hypotheses. Finally, to explore the potential formations of homodimers in Eukarya, we utilized MD-based AWSEM and AI-based AlphaFold-Multimer models to predict their structures and conducted extensive all-atom MD simulations to examine their respective structural stabilities. Our results suggest that eukaryotic histones may also form stable homodimers, whereas their disordered tails bring significant structural asymmetry and tip the balance towards the formation of commonly observed heterotypic dimers.
For the symmetrical mixture model and mixture test area, the lattice point set is used to partition, and then the corresponding test statistics can be constructed. In this paper, we first propose the ...partition methods under the lattice point sets and obtain several sub-simplexes without common interior points. Furthermore, we present a method for constructing a uniform design on the simplex using the center points of these sub-simplexes. The designs satisfy the uniformity of maximum distance deviation and provide good results for the mean square error deviation. Finally, the uniformity test on the mixture region is considered and illustrated by examples.
PDF
