Neural mechanism underlying depressive-like state associated with social status loss.

Downward social mobility is a well-known mental risk factor for depression, but its neural mechanism remains elusive. Here, by forcing mice to lose against their subordinates in a non-violent social contest, we lower their social ranks stably and induce depressive-like behaviors. These rank-decline-associated depressive-like behaviors can be reversed by regaining social status. In vivo fiber photometry and single-unit electrophysiological recording show that forced loss, but not natural loss, generates negative reward prediction error (RPE). Through the lateral hypothalamus, the RPE strongly activates the brain's anti-reward center, the lateral habenula (LHb). LHb activation inhibits the medial prefrontal cortex (mPFC) that controls social competitiveness and reinforces retreats in contests. These results reveal the core neural mechanisms mutually promoting social status loss and depressive behaviors. The intertwined neuronal signaling controlling mPFC and LHb activities provides a mechanistic foundation for the crosstalk between social mobility and psychological disorder, unveiling a promising target for intervention.

A Phase Separation Model for Transcriptional Control.

Phase-separated multi-molecular assemblies provide a general regulatory mechanism to compartmentalize biochemical reactions within cells. We propose that a phase separation model explains established and recently described features of transcriptional control. These features include the formation of super-enhancers, the sensitivity of super-enhancers to perturbation, the transcriptional bursting patterns of enhancers, and the ability of an enhancer to produce simultaneous activation at multiple genes. This model provides a conceptual framework to further explore principles of gene control in mammals.

Functional coordination between transcription factor clustering and gene activity.

The prevailing view of metazoan gene regulation is that transcription is facilitated through the formation of static activator complexes at distal regulatory regions. Here, we employed quantitative single-cell live-imaging and computational analysis to provide evidence that the dynamic assembly and disassembly process of transcription factor (TF) clusters at enhancers is a major source of transcriptional bursting in developing Drosophila embryos. We further show that the regulatory connectivity between TF clustering and burst induction is highly regulated through intrinsically disordered regions (IDRs). Addition of a poly-glutamine tract to the maternal morphogen Bicoid demonstrated that extended IDR length leads to ectopic TF clustering and burst induction from its endogenous target genes, resulting in defects in body segmentation during embryogenesis. Moreover, we successfully visualized the presence of "shared" TF clusters during the co-activation of two distant genes, which provides a concrete molecular explanation for the newly proposed "topological operon" hypothesis in metazoan gene regulation.

How auditory neurons count temporal intervals and decode information.

The numerical sense of animals includes identifying the numerosity of a sequence of events that occur with specific intervals, e.g., notes in a call or bar of music. Across nervous systems, the temporal patterning of spikes can code these events, but how this information is decoded (counted) remains elusive. In the anuran auditory system, temporal information of this type is decoded in the midbrain, where "interval-counting" neurons spike only after at least a threshold number of sound pulses have occurred with specific timing. We show that this decoding process, i.e., interval counting, arises from integrating phasic, onset-type and offset inhibition with excitation that augments across successive intervals, possibly due to a progressive decrease in "shunting" effects of inhibition. Because these physiological properties are ubiquitous within and across central nervous systems, interval counting may be a general mechanism for decoding diverse information coded/encoded in temporal patterns of spikes, including "bursts," and estimating elapsed time.

Modulatory dynamics mark the transition between anesthetic states of unconsciousness.

Unconsciousness maintained by GABAergic anesthetics, such as propofol and sevoflurane, is characterized by slow-delta oscillations (0.3 to 4 Hz) and alpha oscillations (8 to 14 Hz) that are readily visible in the electroencephalogram. At higher doses, these slow-delta-alpha (SDA) oscillations transition into burst suppression. This is a marker of a state of profound brain inactivation during which isoelectric (flatline) periods alternate with periods of the SDA patterns present at lower doses. While the SDA and burst suppression patterns have been analyzed separately, the transition from one to the other has not. Using state-space methods, we characterize the dynamic evolution of brain activity from SDA to burst suppression and back during unconsciousness maintained with propofol or sevoflurane in volunteer subjects and surgical patients. We uncover two dynamical processes that continuously modulate the SDA oscillations: alpha-wave amplitude and slow-wave frequency modulation. We present an alpha modulation index and a slow modulation index which characterize how these processes track the transition from SDA oscillations to burst suppression and back to SDA oscillations as a function of increasing and decreasing anesthetic doses, respectively. Our biophysical model reveals that these dynamics track the combined evolution of the neurophysiological and metabolic effects of a GABAergic anesthetic on brain circuits. Our characterization of the modulatory dynamics mediated by GABAergic anesthetics offers insights into the mechanisms of these agents and strategies for monitoring and precisely controlling the level of unconsciousness in patients under general anesthesia.

Brainstem Neural Circuits Triggering Vertical Saccades and Fixation.

Neurons in the nucleus raphe interpositus have tonic activity that suppresses saccadic burst neurons (BNs) during eye fixations, and that is inhibited before and during saccades in all directions (omnipause neurons, OPNs). We have previously demonstrated via intracellular recording and anatomical staining in anesthetized cats of both sexes that OPNs are inhibited by BNs in the medullary reticular formation (horizontal inhibitory BNs, IBNs). These horizontal IBNs receive monosynaptic input from the caudal horizontal saccade area of the superior colliculus (SC), and then produce monosynaptic inhibition in OPNs, providing a mechanism to trigger saccades. However, it is well known that the neural circuits driving horizontal components of saccades are independent from the circuits driving vertical components. Thus, our previous results are unable to explain how purely vertical saccades are triggered. Here, we again apply intracellular recording to show that a disynaptic vertical IBN circuit exists, analogous to the horizontal circuit. Specifically, we show that stimulation of the SC rostral vertical saccade area produces disynaptic inhibition in OPNs, which is not abolished by midline section between the horizontal IBNs. This excludes the possibility that horizontal IBNs could be responsible for the OPN inhibition during vertical saccades. We then show that vertical IBNs in the interstitial nucleus of Cajal, which receive monosynaptic input from rostral SC, are responsible for the disynaptic inhibition of OPNs. These results indicate that a similarly functioning SC-IBN-OPN circuit exists for both the horizontal and vertical oculomotor pathways. These two IBN-mediated circuits are capable of triggering saccades in any direction.Significance Statement Saccades shift gaze to objects of interest, moving their image to the central retina, where it is maintained for detailed examination (fixation). During fixation, high gain saccade burst neurons (BNs) are tonically inhibited by omnipause neurons (OPNs). Our previous study showed that medullary horizontal inhibitory BNs (IBNs) activated from the caudal superior colliculus (SC) inhibit tonically active OPNs in order to initiate horizontal saccades. The present study addresses the source of OPN inhibition for vertical saccades. We find that OPNs monosynaptically inhibit vertical IBNs in the interstitial nucleus of Cajal during fixation. Those same vertical IBNs are activated by the rostral SC, and inhibit OPN activity to initiate vertical saccades.

The CsAP2-09-CsWRKY25-CsRBOH2 cascade confers resistance against citrus bacterial canker by regulating ROS homeostasis.

Citrus bacterial canker (CBC) is a serious bacterial disease caused by Xanthomonas citri subsp. citri (Xcc) that adversely impacts the global citrus industry. In a previous study, we demonstrated that overexpression of an Xcc-inducible apetala 2/ethylene response factor encoded by Citrus sinensis, CsAP2-09, enhances CBC resistance. The mechanism responsible for this effect, however, is not known. In the present study, we showed that CsAP2-09 targeted the promoter of the Xcc-inducible WRKY transcription factor coding gene CsWRKY25 directly, activating its transcription. CsWRKY25 was found to localize to the nucleus and to activate transcriptional activity. Plants overexpressing CsWRKY25 were more resistant to CBC and showed higher expression of the respiratory burst oxidase homolog (RBOH) CsRBOH2, in addition to exhibiting increased RBOH activity. Transient overexpression assays in citrus confirmed that CsWRKY25 and CsRBOH2 participated in the generation of reactive oxygen species (ROS) bursts, which were able to restore the ROS degradation caused by CsAP2-09 knockdown. Moreover, CsWRKY25 was found to bind directly to W-box elements within the CsRBOH2 promoter. Notably, CsRBOH2 knockdown had been reported previously to reduce the CBC resistance, while demonstrated in this study, CsRBOH2 transient overexpression can enhance the CBC resistance. Overall, our results outline a pathway through which CsAP2-09-CsWRKY25 transcriptionally reprograms CsRBOH2-mediated ROS homeostasis in a manner conducive to CBC resistance. These data offer new insight into the mechanisms and regulatory pathways through which CsAP2-09 regulates CBC resistance, highlighting its potential utility as a target for the breeding of CBC-resistant citrus varieties.

Inferring the Evolutionary Model of Community-Structuring Traits with Convolutional Kitchen Sinks.

When communities are assembled through processes such as filtering or limiting similarity acting on phylogenetically conserved traits, the evolutionary signature of those traits may be reflected in patterns of community membership. We show how the model of trait evolution underlying community-structuring traits can be inferred from community membership data using both a variation of a traditional eco-phylogenetic metric-the mean pairwise phylogenetic distance (MPD) between taxa-and a recent machine learning tool, Convolutional Kitchen Sinks (CKS). Both methods perform well across a range of phylogenetically informative evolutionary models, but CKS outperforms MPD as tree size increases. We demonstrate CKS by inferring the evolutionary history of freeze tolerance in angiosperms. Our analysis is consistent with a late burst model, suggesting freeze tolerance evolved recently. We suggest that multiple data types that are ordered on phylogenies, such as trait values, species interactions, or community presence/absence, are good candidates for CKS modeling because the generative models produce structured differences between neighboring points that CKS is well-suited for. We introduce the R package kitchen to perform CKS for generic application of the technique.

Switching off: disruptive TMS reveals distinct contributions of the posterior middle temporal gyrus and angular gyrus to bilingual speech production.

The role of the left temporoparietal cortex in speech production has been extensively studied during native language processing, proving crucial in controlled lexico-semantic retrieval under varying cognitive demands. Yet, its role in bilinguals, fluent in both native and second languages, remains poorly understood. Here, we employed continuous theta burst stimulation to disrupt neural activity in the left posterior middle-temporal gyrus (pMTG) and angular gyrus (AG) while Italian-Friulian bilinguals performed a cued picture-naming task. The task involved between-language (naming objects in Italian or Friulian) and within-language blocks (naming objects ["knife"] or associated actions ["cut"] in a single language) in which participants could either maintain (non-switch) or change (switch) instructions based on cues. During within-language blocks, cTBS over the pMTG entailed faster naming for high-demanding switch trials, while cTBS to the AG elicited slower latencies in low-demanding non-switch trials. No cTBS effects were observed in the between-language block. Our findings suggest a causal involvement of the left pMTG and AG in lexico-semantic processing across languages, with distinct contributions to controlled vs. "automatic" retrieval, respectively. However, they do not support the existence of shared control mechanisms within and between language(s) production. Altogether, these results inform neurobiological models of semantic control in bilinguals.

Effects of accelerated intermittent theta-burst stimulation in modulating brain of Alzheimer's disease.

Intermittent theta-burst stimulation (iTBS) is emerging as a noninvasive therapeutic strategy for Alzheimer's disease (AD). Recent advances highlighted a new accelerated iTBS (aiTBS) protocol, consisting of multiple sessions per day and higher overall pulse doses, in brain modulation. To examine the possibility of applying the aiTBS in treating AD patients, we enrolled 45 patients in AD at early clinical stages, and they were randomly assigned to either receive real or sham aiTBS. Neuropsychological scores were evaluated before and after treatment. Moreover, we detected cortical excitability and oscillatory activity changes in AD, by the single-pulse TMS in combination with EEG (TMS-EEG). Real stimulation showed markedly better performances in the group average of Auditory Verbal Learning Test scores compared to baseline. TMS-EEG revealed that aiTBS has reinforced this memory-related cortical mechanism by increasing cortical excitability and beta oscillatory activity underlying TMS target. We also found an enhancement of local natural frequency after aiTBS treatment. The novel findings implicated that high-dose aiTBS targeting left DLPFC is rapid-acting, safe, and tolerable in AD patients. Furthermore, TMS-related increase of specific neural oscillation elucidates the mechanisms of the AD cognitive impairment ameliorated by aiTBS.

Diffusion MRI-guided theta burst stimulation enhances memory and functional connectivity along the inferior longitudinal fasciculus in mild cognitive impairment.

Mild cognitive impairment (MCI) during aging is often a harbinger of Alzheimer's disease, and, therefore, early intervention to preserve cognitive abilities before the MCI symptoms become medically refractory is particularly critical. Functional MRI­guided transcranial magnetic stimulation is a promising approach for modulating hippocampal functional connectivity and enhancing memory in healthy adults. Here, we extend these previous findings to individuals with MCI and leverage theta burst stimulation (TBS) and white matter tractography derived from diffusion-weighted MRI to target the hippocampus. Our preliminary findings suggested that TBS could be used to improve associative memory performance and increase resting-state functional connectivity of the hippocampus and other brain regions, including the occipital fusiform, frontal orbital cortex, putamen, posterior parahippocampal gyrus, and temporal pole, along the inferior longitudinal fasciculus in MCI. Although the sample size is small, these results shed light on how TBS propagates from the superficial cortex around the parietal lobe to the hippocampus.

Protective down-regulated states in the human brain: A possible lesson from COVID-19.

The COVID-19 pandemic has created a large population of patients who are slow to recover consciousness following mechanical ventilation and sedation in the intensive care unit. Few clinical scenarios are comparable. Possible exceptions are the rare patients in post-cardiac arrest coma with minimal to no structural brain injuries who recovered cognitive and motor functions after prolonged delays. A common electroencephalogram (EEG) signature seen in these patients is burst suppression [8]. Biophysical modeling has shown that burst suppression is likely a signature of a neurometabolic state that preserves basic cellular function "during states of lowered energy availability." These states likely act as a brain protective mechanism [9]. Similar EEG patterns are observed in the anoxia resistant painted turtle [24]. We present a conceptual analysis to interpret the brain state of COVID-19 patients suffering prolonged recovery of consciousness. We begin with the Ching model and integrate findings from other clinical scenarios and studies of the anoxia-tolerant physiology of the painted turtle. We postulate that prolonged recovery of consciousness in COVID-19 patients could reflect the effects of modest hypoxic injury to neurons and the unmasking of latent neuroprotective mechanisms in the human brain. This putative protective down-regulated state appears similar to that observed in the painted turtle and suggests new approaches to enhancing coma recovery [12].

E-cigarette vapor renders neutrophils dysfunctional due to filamentous actin accumulation.

BACKGROUND: Electronic cigarette (e-cigarette) use continues to rise despite concerns of long-term effects, especially the risk of developing lung diseases such as chronic obstructive pulmonary disease. Neutrophils are central to the pathogenesis of chronic obstructive pulmonary disease, with changes in phenotype and function implicated in tissue damage. OBJECTIVE: We sought to measure the impact of direct exposure to nicotine-containing and nicotine-free e-cigarette vapor on human neutrophil function and phenotype. METHODS: Neutrophils were isolated from the whole blood of self-reported nonsmoking, nonvaping healthy volunteers. Neutrophils were exposed to 40 puffs of e-cigarette vapor generated from e-cigarette devices using flavorless e-cigarette liquids with and without nicotine before functions, deformability, and phenotype were assessed. RESULTS: Neutrophil surface marker expression was altered, with CD62L and CXCR2 expression significantly reduced in neutrophils treated with e-cigarette vapor containing nicotine. Neutrophil migration to IL-8, phagocytosis of Escherichia coli and Staphylococcus aureus pHrodo bioparticles, oxidative burst response, and phorbol 12-myristate 13-acetate-stimulated neutrophil extracellular trap formation were all significantly reduced by e-cigarette vapor treatments, independent of nicotine content. E-cigarette vapor induced increased levels of baseline polymerized filamentous actin levels in the cytoplasm, compared with untreated controls. CONCLUSIONS: The significant reduction in effector neutrophil functions after exposure to high-power e-cigarette devices, even in the absence of nicotine, is associated with excessive filamentous actin polymerization. This highlights the potentially damaging impact of vaping on respiratory health and reinforces the urgency of research to uncover the long-term health implications of e-cigarettes.

Spontaneous α Brain Dynamics Track the Episodic "When".

Across species, neurons track time over the course of seconds to minutes, which may feed the sense of time passing. Here, we asked whether neural signatures of time-tracking could be found in humans. Participants stayed quietly awake for a few minutes while being recorded with magnetoencephalography (MEG). They were unaware they would be asked how long the recording lasted (retrospective time) or instructed beforehand to estimate how long it will last (prospective timing). At rest, rhythmic brain activity is nonstationary and displays bursts of activity in the alpha range (α: 7-14 Hz). When participants were not instructed to attend to time, the relative duration of α bursts linearly predicted individuals' retrospective estimates of how long their quiet wakefulness lasted. The relative duration of α bursts was a better predictor than α power or burst amplitude. No other rhythmic or arrhythmic activity predicted retrospective duration. However, when participants timed prospectively, the relative duration of α bursts failed to predict their duration estimates. Consistent with this, the amount of α bursts was discriminant between prospective and retrospective timing. Last, with a control experiment, we demonstrate that the relation between α bursts and retrospective time is preserved even when participants are engaged in a visual counting task. Thus, at the time scale of minutes, we report that the relative time of spontaneous α burstiness predicts conscious retrospective time. We conclude that in the absence of overt attention to time, α bursts embody discrete states of awareness constitutive of episodic timing.SIGNIFICANCE STATEMENT The feeling that time passes is a core component of consciousness and episodic memory. A century ago, brain rhythms called "α" were hypothesized to embody an internal clock. However, rhythmic brain activity is nonstationary and displays on-and-off oscillatory bursts, which would serve irregular ticks to the hypothetical clock. Here, we discovered that in a given lapse of time, the relative bursting time of α rhythms is a good indicator of how much time an individual will report to have elapsed. Remarkably, this relation only holds true when the individual does not attend to time and vanishes when attending to it. Our observations suggest that at the scale of minutes, α brain activity tracks episodic time.

Bursting with Potential: How Sensorimotor Beta Bursts Develop from Infancy to Adulthood.

Beta activity is thought to play a critical role in sensorimotor processes. However, little is known about how activity in this frequency band develops. Here, we investigated the developmental trajectory of sensorimotor beta activity from infancy to adulthood. We recorded EEG from 9-month-old, 12-month-old, and adult humans (male and female) while they observed and executed grasping movements. We analyzed "beta burst" activity using a novel method that combines time-frequency decomposition and principal component analysis. We then examined the changes in burst rate and waveform motifs along the selected principal components. Our results reveal systematic changes in beta activity during action execution across development. We found a decrease in beta burst rate during movement execution in all age groups, with the greatest decrease observed in adults. Additionally, we identified three principal components that defined waveform motifs that systematically changed throughout the trial. We found that bursts with waveform shapes closer to the median waveform were not rate-modulated, whereas those with waveform shapes further from the median were differentially rate-modulated. Interestingly, the decrease in the rate of certain burst motifs occurred earlier during movement and was more lateralized in adults than in infants, suggesting that the rate modulation of specific types of beta bursts becomes increasingly refined with age.SIGNIFICANCE STATEMENT We demonstrate that, like in adults, sensorimotor beta activity in infants during reaching and grasping movements occurs in bursts, not oscillations like thought traditionally. Furthermore, different beta waveform shapes were differentially modulated with age, including more lateralization in adults. Aberrant beta activity characterizes various developmental disorders and motor difficulties linked to early brain injury, so looking at burst waveform shape could provide more sensitivity for early identification and treatment of affected individuals before any behavioral symptoms emerge. More generally, comparison of beta burst activity in typical versus atypical motor development will also be instrumental in teasing apart the mechanistic functional roles of different types of beta bursts.

Effects of the motor cortical theta-burst transcranial-focused ultrasound stimulation on the contralateral motor cortex.

Theta-burst transcranial ultrasound stimulation (tbTUS) increases primary motor cortex (M1) excitability for at least 30 min. However, the remote effects of focal M1 tbTUS on the excitability of other cortical areas are unknown. Here, we examined the effects of left M1 tbTUS on right M1 excitability. An 80 s train of active or sham tbTUS was delivered to the left M1 in 20 healthy subjects. Before and after the tbTUS, we measured: (1) corticospinal excitability using motor-evoked potential (MEP) amplitudes from single-pulse transcranial magnetic stimulation (TMS) of left and right M1; (2) interhemispheric inhibition (IHI) from left to right M1 and from right to left M1 using a dual-site paired-pulse TMS paradigm; and (3) intracortical circuits of the right M1 with short-interval intracortical inhibition and intracortical facilitation (ICF) using paired-pulse TMS. Left M1 tbTUS decreased right M1 excitability as shown by decreased MEP amplitudes, increased right M1 ICF and decreased short-interval IHI from left to right hemisphere at interstimulus interval (ISI) of 10 ms but not long-interval IHI at interstimulus interval of 40 ms. The study showed that left M1 tbTUS can change the excitability of remote cortical areas with decreased right M1 excitability and interhemispheric inhibition. The remote effects of tbTUS should be considered when it is used in neuroscience research and as a potential neuromodulation treatment for brain disorders. KEY POINTS: Transcranial ultrasound stimulation (TUS) is a novel non-invasive brain stimulation technique for neuromodulation with the advantages of being able to achieve high spatial resolution and target deep brain structures. A repetitive TUS protocol, with an 80 s train of theta burst patterned TUS (tbTUS), has been shown to increase primary motor cortex (M1) excitability, as well as increase alpha and beta movement-related spectral power in distinct brain regions. In this study, we examined on the effects of the motor cortical tbTUS on the excitability of contralateral M1 measured with MEPs elicited by transcranial magnetic stimulation. We showed that left M1 tbTUS decreased right M1 excitability and left-to-right M1 interhemispheric inhibition, and increased intracortical facilitation of right M1. These results lead to better understand the effects of tbTUS and can help the development of tbTUS for the treatment of neurological and psychiatric disorders and in neuroscience research.

Personalized depth-specific neuromodulation of the human primary motor cortex via ultrasound.

Non-invasive brain stimulation has the potential to boost neuronal plasticity in the primary motor cortex (M1), but it remains unclear whether the stimulation of both superficial and deep layers of the human motor cortex can effectively promote M1 plasticity. Here, we leveraged transcranial ultrasound stimulation (TUS) to precisely target M1 circuits at depths of approximately 5 mm and 16 mm from the cortical surface. Initially, we generated computed tomography images from each participant's individual anatomical magnetic resonance images (MRI), which allowed for the generation of accurate acoustic simulations. This process ensured that personalized TUS was administered exactly to the targeted depths within M1 for each participant. Using long-term depression and long-term potentiation (LTD/LTP) theta-burst stimulation paradigms, we examined whether TUS over distinct depths of M1 could induce LTD/LTP plasticity. Our findings indicated that continuous theta-burst TUS-induced LTD-like plasticity with both superficial and deep M1 stimulation, persisting for at least 30 min. In comparison, sham TUS did not significantly alter M1 excitability. Moreover, intermittent theta-burst TUS did not result in the induction of LTP- or LTD-like plasticity with either superficial or deep M1 stimulation. These findings suggest that the induction of M1 plasticity can be achieved with ultrasound stimulation targeting distinct depths of M1, which is contingent on the characteristics of TUS. KEY POINTS: The study integrated personalized transcranial ultrasound stimulation (TUS) with electrophysiology to determine whether TUS targeting superficial and deep layers of the human motor cortex (M1) could elicit long-term depression (LTD) or long-term potentiation (LTP) plastic changes. Utilizing acoustic simulations derived from individualized pseudo-computed tomography scans, we ensured the precision of TUS delivery to the intended M1 depths for each participant. Continuous theta-burst TUS targeting both the superficial and deep layers of M1 resulted in the emergence of LTD-like plasticity, lasting for at least 30 min. Administering intermittent theta-burst TUS to both the superficial and deep layers of M1 did not lead to the induction of LTP- or LTD-like plastic changes. We suggest that theta-burst TUS targeting distinct depths of M1 can induce plasticity, but this effect is dependent on specific TUS parameters.

Hippocampal neurodegeneration induces transient endogenous regeneration and long-term exhaustion of the neurogenic niche.

The hippocampal dentate gyrus, responds to diverse pathological stimuli through neurogenesis. This phenomenon, observed following brain injury or neurodegeneration, is postulated to contribute to neuronal repair and functional recovery, thereby presenting an avenue for endogenous neuronal restoration. This study investigated the extent of regenerative response in hippocampal neurogenesis by leveraging the well-established kainic acid-induced status epilepticus model in vivo. In our study, we observed the activation and proliferation of neuronal progenitors or neural stem cell (NSC) and their subsequent migration to the injury sites following the seizure. At the injury sites, new neurons (Tuj1+BrdU+ and NeuN+BrdU+) have been generated indicating regenerative and reparative roles of the progenitor cells. We further detected whether this transient neurogenic burst, which might be a response towards an attempt to repair the brain, is associated with persistent long-term exhaustion of the dentate progenitor cells and impairment of adult neurogenesis marked by downregulation of Ki67, HoPX, and Sox2 with BrdU+ cell in the later part of life. Our studies suggest that the adult brain has the constitutive endogenous regenerative potential for brain repair to restore the damaged neurons, meanwhile, in the long term, it accelerates the depletion of the finite NSC pool in the hippocampal neurogenic niche by changing its proliferative and neurogenic capacity. A thorough understanding of the impact of modulating adult neurogenesis will eventually be required to design novel therapeutics to stimulate or assist brain repair while simultaneously preventing the adverse effects of early robust neurogenesis on the proliferative potential of endogenous neuronal progenitors.

Signatures of local adaptation to current and future climate in phenology-related genes in natural populations of Quercus robur.

BACKGROUND: Local adaptation is a key evolutionary process that enhances the growth of plants in their native habitat compared to non-native habitats, resulting in patterns of adaptive genetic variation across the entire geographic range of the species. The study of population adaptation to local environments and predicting their response to future climate change is important because of climate change. RESULTS: Here, we explored the genetic diversity of candidate genes associated with bud burst in pedunculate oak individuals sampled from 6 populations in Poland. Single nucleotide polymorphism (SNP) diversity was assessed in 720 candidate genes using the sequence capture technique, yielding 18,799 SNPs. Using landscape genomic approaches, we identified 8 FST outliers and 781 unique SNPs in 389 genes associated with geography, climate, and phenotypic variables (individual/family spring and autumn phenology, family diameter at breast height (DBH), height, and survival) that are potentially involved in local adaptation. Then, using a nonlinear multivariate model, Gradient Forests, we identified vulnerable areas of the pedunculate oak distribution in Poland that are at risk from climate change. CONCLUSIONS: The model revealed that pedunculate oak populations in the eastern part of the analyzed geographical region are the most sensitive to climate change. Our results might offer an initial evaluation of a potential management strategy for preserving the genetic diversity of pedunculate oak.

Flexible multi-step hypothesis testing of human ECoG data using cluster-based permutation tests with GLMEs.

BACKGROUND: Time series analysis is critical for understanding brain signals and their relationship to behavior and cognition. Cluster-based permutation tests (CBPT) are commonly used to analyze a variety of electrophysiological signals including EEG, MEG, ECoG, and sEEG data without a priori assumptions about specific temporal effects. However, two major limitations of CBPT include the inability to directly analyze experiments with multiple fixed effects and the inability to account for random effects (e.g. variability across subjects). Here, we propose a flexible multi-step hypothesis testing strategy using CBPT with Linear Mixed Effects Models (LMEs) and Generalized Linear Mixed Effects Models (GLMEs) that can be applied to a wide range of experimental designs and data types. METHODS: We first evaluate the statistical robustness of LMEs and GLMEs using simulated data distributions. Second, we apply a multi-step hypothesis testing strategy to analyze ERPs and broadband power signals extracted from human ECoG recordings collected during a simple image viewing experiment with image category and novelty as fixed effects. Third, we assess the statistical power differences between analyzing signals with CBPT using LMEs compared to CBPT using separate t-tests run on each fixed effect through simulations that emulate broadband power signals. Finally, we apply CBPT using GLMEs to high-gamma burst data to demonstrate the extension of the proposed method to the analysis of nonlinear data. RESULTS: First, we found that LMEs and GLMEs are robust statistical models. In simple simulations LMEs produced highly congruent results with other appropriately applied linear statistical models, but LMEs outperformed many linear statistical models in the analysis of "suboptimal" data and maintained power better than analyzing individual fixed effects with separate t-tests. GLMEs also performed similarly to other nonlinear statistical models. Second, in real world human ECoG data, LMEs performed at least as well as separate t-tests when applied to predefined time windows or when used in conjunction with CBPT. Additionally, fixed effects time courses extracted with CBPT using LMEs from group-level models of pseudo-populations replicated latency effects found in individual category-selective channels. Third, analysis of simulated broadband power signals demonstrated that CBPT using LMEs was superior to CBPT using separate t-tests in identifying time windows with significant fixed effects especially for small effect sizes. Lastly, the analysis of high-gamma burst data using CBPT with GLMEs produced results consistent with CBPT using LMEs applied to broadband power data. CONCLUSIONS: We propose a general approach for statistical analysis of electrophysiological data using CBPT in conjunction with LMEs and GLMEs. We demonstrate that this method is robust for experiments with multiple fixed effects and applicable to the analysis of linear and nonlinear data. Our methodology maximizes the statistical power available in a dataset across multiple experimental variables while accounting for hierarchical random effects and controlling FWER across fixed effects. This approach substantially improves power leading to better reproducibility. Additionally, CBPT using LMEs and GLMEs can be used to analyze individual channels or pseudo-population data for the comparison of functional or anatomical groups of data.