eNeuro最新文献

Advances in single-cell technologies have led to the discovery and characterization of new brain cell types, which in turn lead to a better understanding of the pathogenesis of Alzheimer's disease (AD). Here, we present a detailed analysis of single-nucleus (sn)RNA-seq data for three stages of AD from middle temporal gyrus and compare it with snRNA-seq data from the prefrontal cortices from individuals with alcohol use disorder (AUD). We observed a significant decrease in both inhibitory and excitatory neurons, in general agreement with previous reports. We observed several cell-type-specific gene expressions and pathway dysregulations that delineate AD stages. Endothelial and vascular leptomeningeal cells showed the greatest degree of gene expression changes. Cell-type-specific evidence of neurodegeneration was seen in multiple neuronal cell types particularly in somatostatin and Layer 5 extratelencephalic neurons, among others. Evidence of inflammatory responses was seen in non-neuronal cells, particularly in intermediate and advanced AD. We observed common perturbations in AD and AUD, particularly in pathways, like transcription, translation, apoptosis, autophagy, calcium signaling, neuroinflammation, and phosphorylation, that imply shared transcriptional pathogenic mechanisms and support the role of excessive alcohol intake in AD progression. Major AUD gene markers form and perturb a network of genes significantly associated with intermediate and advanced AD. Master regulator analysis from AUD gene markers revealed significant correlation with advanced AD of transcription factors that have implications in intellectual disability, neuroinflammation, and other neurodegenerative conditions, further suggesting a shared nexus of transcriptional changes between AD and AUD.

Selective modifications in the expression or function of dendritic ion channels regulate the propagation of synaptic inputs and determine the intrinsic excitability of a neuron. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open upon membrane hyperpolarization and conduct a depolarizing inward current (I_h). HCN channels are enriched in the dendrites of hippocampal pyramidal neurons where they regulate the integration of synaptic inputs. Synaptic plasticity can bidirectionally modify dendritic HCN channels in excitatory neurons depending on the strength of synaptic potentiation. In inhibitory neurons, however, the dendritic expression and modulation of HCN channels is largely unknown. In this study, we systematically compared the modulation of I_h by synaptic potentiation in hippocampal CA1 pyramidal neurons and stratum Radiatum (sRad) interneurons in mouse organotypic cultures. I_h properties were similar in inhibitory and excitatory neurons and contributed to resting membrane potential and action potential firing. We found that in sRad interneurons, HCN channels were downregulated after synaptic plasticity, irrespective of the strength of synaptic potentiation. This suggest differential regulation of I_h in excitatory and inhibitory neurons, possibly signifying their distinct role in network activity.Significance statement Learning reflects a change in the way information is processed in neuronal circuits. This occurs via changes in synaptic connections and via alterations of intrinsic excitability of neurons. Here we examined how synaptic changes affect properties of HCN channels, which are important ion channels for intrinsic excitability. We found that strong synaptic potentiation leads to opposite changes in HCN channels in CA1 pyramidal neurons and sRad interneurons. We speculate that this reflects their differential role in the CA1 network. An upregulation of HCN channels in pyramidal neurons results in a decrease in their excitability, which limits overall network excitation. In contrast, sRad interneurons show downregulation of I_h, and therefore an increased excitability after strong synaptic activation, which will strengthen feedforward inhibition and sharpen activity patterns.

Tetrahydroxy stilbene glucoside (TSG) from polygonum multiflorum exerts neuroprotective effects after ischemic stroke. We explored whether TSG improved ischemic stroke injury via PINK1/Parkin-mediated mitophagy. Oxygen glucose deprivation/reoxygenation (OGD/R) in vitro model and middle cerebral artery occlusion (MCAO) rat model were established. Cerebral injury was assessed by neurological score, hematoxylin and eosin staining, TTC staining and brain water content. Apoptosis, cell viability and mitochondrial membrane potential were assessed by flow cytometry, CCK-8 and JC-1 staining, respectively. Co-localization of LC3-labeled autophagosomes with LAMP2-labeled lysosomes or Tomm20-labeled mitochondria was observed with fluorescence microscopy. Ubiquitination level was determined using ubiquitination assay. The interaction between molecules was validated by co-immunoprecipitation and GST pull-down. We found that TSG promoted mitophagy and improved cerebral I/R damage in MCAO rats. In OGD/R-subjected neurons, TSG promoted mitophagy, repressed neuronal apoptosis, upregulated Y-box binding protein-1 (YBX1) and activated PINK1/Parkin signaling. TSG upregulated ubiquitin-specific peptidase 10 (USP10) to elevate YBX1 protein. Furthermore, USP10 inhibited ubiquitination-dependent YBX1 degradation. USP10 overexpression activated PINK1/Parkin signaling and promoted mitophagy, which were reversed by YBX1 knockdown. Moreover, TSG upregulated USP10 to promote mitophagy and inhibited neuronal apoptosis. Collectively, TSG facilitated PINK1/Parkin pathway mediated mitophagy by upregulating USP10/YBX1 axis to ameliorate ischemic stroke.Significance Statement: Ischemic stroke is one of leading causes of disability and death worldwide. Previous studies have demonstrated a neuroprotective role of TSG in ischemic stroke, while the underlying mechanism is still not fully understood. Here, this study confirmed that TSG relieved cerebral I/R injury in vivo and in vitro via facilitated PINK1/Parkin-mediated mitophagy. In addition, we further identified the molecular mechanism by which TSG regulates mitochondrial autophagy. Our study provided new insights into the protective role TSG in ischemic stroke via regulating mitophagy.

Deficits in social behavior are found in neurodevelopmental disorders, including autism spectrum disorders (ASDs). Since abnormalities in cerebellar morphology and function are observed in ASD patients, the cerebellum is thought to play a role in social behavior. However, it remains unknown whether the cerebellum is involved in social behavior in other animals and how cerebellar circuits control social behavior. To address this issue, we employed zebrafish stereotyped orienting behavior as a model of social behaviors, in which a pair of adult zebrafish in two separate tanks approach each other, with one swimming at synchronized angles (orienting angles) with the other. We harnessed transgenic zebrafish that express botulinum toxin, which inhibits the release of neurotransmitters, in either granule cells or Purkinje cells, and zebrafish mutants of reelin, which is involved in the positioning of cerebellar neurons, including Purkinje cells. These zebrafish, deficient in the function or formation of cerebellar neural circuits, showed a significantly shorter period of orienting behavior compared to their control siblings. We found an increase in c-fos and egr1 expression in the cerebellum after the orienting behavior. These results suggest that zebrafish cerebellar circuits play an important role in social orienting behavior.Significance Statement Abnormalities in cerebellar morphology and function are often observed in ASD patients. We describe the roles of cerebellar neural circuitry in social behavior using stereotyped orienting behavior in zebrafish, in which a pair of zebrafish in two separate tanks approach each other and show synchronous swimming. Neurotoxin-mediated inhibition of cerebellar neurons or mutations of the reelin gene, which is required for proper formation of cerebellar neural circuits, shortened the period of the orienting behavior. Furthermore, we found activation of the cerebellum in response to the orienting behavior. Our findings suggest that studies of zebrafish cerebellar neural circuits may provide a model for studying abnormalities in social behaviors, such as those seen in ASD.

Age-related brain changes affect sleep and are reflected in properties of sleep slow-waves, however the precise mechanisms behind these changes are still not completely understood. Here, we adapt a previously established whole-brain model relating structural connectivity changes to resting state dynamics, and extend it to a slow-wave sleep brain state. In particular, starting from a representative connectome at the beginning of the aging trajectory, we have gradually reduced the inter-hemispheric connections, and simulated sleep-like slow-wave activity. We show that the main empirically observed trends, namely a decrease in duration and increase in variability of the slow waves are captured by the model. Furthermore, comparing the simulated EEG activity to the source signals, we suggest that the empirically observed decrease in amplitude of the slow waves is caused by the decrease in synchrony between brain regions.Significance Statement Aging is characterized by changes in slow wave (SW) sleep features, yet the precise mechanisms driving these alterations remain elusive. Employing a connectome-based model, we implement the established age- related reductions in inter-hemispheric connectivity, successfully replicating the SW changes in the simulated activity. Our simulation of EEG activity also suggests that observed decreases in SW amplitude stems from diminished synchrony between brain regions. Our results support the notion that alterations in SW characteristics result from reductions in cortical excitatory drive-here facilitated by the inter-hemispheric connections. Our model serves as a robust foundation for extensions to population studies and interventional work in animal models of aging aimed at disentangling the contributions of network alterations, changes to local neural mass properties, and neuromodulation.

Animals, humans included, navigate their environments guided by sensory cues, responding adaptively to potential dangers and rewards. Avoidance behaviors serve as adaptive strategies in the face of signaled threats, but the neural mechanisms orchestrating these behaviors remain elusive. Current circuit models of avoidance behaviors indicate that the nucleus accumbens (NAc) in the ventral striatum plays a key role in signaled avoidance behaviors, but the nature of this engagement is unclear. Evolving perspectives propose the NAc as a pivotal hub for action selection, integrating cognitive and affective information to heighten the efficiency of both appetitive and aversive motivated behaviors. To unravel the engagement of the NAc during active and passive avoidance, we used calcium imaging fiber photometry to examine NAc GABAergic neuron activity in ad libitum moving mice performing avoidance behaviors. We then probed the functional significance of NAc neurons using optogenetics and genetically targeted or electrolytic lesions. We found that NAc neurons code contraversive orienting movements and avoidance actions. However, direct optogenetic inhibition or lesions of NAc neurons did not impair active or passive avoidance behaviors, challenging the notion of their purported pivotal role in adaptive avoidance. The findings emphasize that while the NAc encodes avoidance movements, it is not required for avoidance behaviors, highlighting the distinction between behavior encoding or representation and mediation or generation.

Autonoetic consciousness (ANC), the ability to re-experience personal past events links episodic memory and self-consciousness by bridging awareness of oneself in a past event (i.e., during its encoding) with awareness of oneself in the present (i.e., during the reliving of a past event). Recent neuroscience research revealed a bodily form of self-consciousness, including the sense of agency (SoA) and the sense of body ownership (SoO) that are based on the integration of multisensory bodily inputs and motor signals. However, the relation between SoA and/or SoO with ANC is not known. Here, we used immersive virtual reality technology and motion tracking and investigated the potential association of SoA/SoO with ANC. For this, we exposed participants to different levels of visuomotor and perspectival congruency, known to modulate SoA and SoO, during the encoding of virtual scenes and collected ANC ratings 1 week after the encoding session. In a total of 74 healthy participants, we successfully induced systematic changes in SoA and SoO during encoding and found that ANC depended on the level of SoA experienced during encoding. Moreover, ANC was positively associated with SoA, but only for the scene encoded with preserved visuomotor and perspectival congruency, and such SoA-ANC coupling was absent for SoO and control questions. Collectively, these data provide behavioral evidence in a novel paradigm that links a key subjective component of bodily self-consciousness during encoding, SoA, to the subjective reliving of those encoded events from one's past, ANC.

Successful behavior depends on attentional state and other factors related to decision-making, which may modulate neuronal activity differently. Here, we investigated whether attentional state and behavioral outcome (i.e., whether a target is detected or missed) are distinguishable using the power and phase of local field potential (LFP) recorded bilaterally from area V4 of two male rhesus monkeys performing a cued visual attention task. To link each trial's outcome to pairwise measures of attention that are typically averaged across trials, we used several methods to obtain single-trial estimates of spike count correlation and phase consistency. Surprisingly, while attentional location was best discriminated using gamma and high-gamma power, behavioral outcome was best discriminated by alpha power and steady-state visually evoked potential. Power outperformed absolute phase in attentional/behavioral discriminability, although single-trial gamma phase consistency provided reasonably high attentional discriminability. Our results suggest a dissociation between the neuronal mechanisms that regulate attentional focus and behavioral outcome.Significance statement Targets appearing at the attended location are detected more accurately than those at the unattended location. However, attention may not be the only factor regulating the behavioral outcome. We investigated whether the effects of behavioral outcome and attentional state could be differentiated using the local field potentials recorded from macaque visual area V4. We used various methods to obtain single-trial estimates of trial-wise measures like correlations and phase consistency. Remarkably, we found that while attentional location was most effectively discerned through gamma and high-gamma power, behavioral outcomes were better distinguished by alpha power and steady-state visually evoked potentials. These results suggest distinct mechanisms underlying attention and behavioral outcome, thus emphasizing the roles of additional factors in modulating the behavioral outcome.

Decision bias influences estimates of the absolute visual threshold. However, most psychophysical estimates of the murine absolute visual threshold have not taken bias into account. Here we developed a one-alternative forced choice (1AFC) assay to assess the decision bias of mice at the absolute visual threshold via the theory of signal detection and compared our approach with the more conventional high-threshold theoretic approach. In the 1AFC assay, mice of both sexes were trained to signal whether they detected a flash stimulus. We directly measured both hit and false alarm rates, which were used to estimate d' Using the theory of signal detection, we obtained absolute thresholds by interpolating the intensity where d' = 1 from d'-psychometric functions. This gave bias-independent estimates of the absolute visual threshold which ranged over sixfold, averaging ∼1 R* in 1,000 rods (n = 7 mice). To obtain high-threshold theoretic estimates of the absolute visual threshold from the same mice, we estimated threshold intensities from the frequency of seeing curves, corrected for guessing. This gave us thresholds that were strongly correlated with decision bias, ranging over 13-fold and averaged ∼1 R* in 2,500 rods. We conclude that the theory of signal detection uses false alarms to overcome decision bias and narrow the range of threshold estimates in mice, providing a powerful tool for understanding detection behavior near absolute visual threshold.

Alcohol use disorder (AUD) is a significant global health issue. Despite historically higher rates among men, AUD prevalence and negative alcohol-related outcomes in women are rising. Loneliness in humans has been associated with increased alcohol use, and traditional rodent drinking models involve single housing, presenting challenges for studying social enrichment. We developed LIQ PARTI (Lick Instance Quantifier with Poly-Animal RFID Tracking Integration), an open-source tool to examine home cage continuous access two-bottle choice drinking behavior in a group-housed setting, investigating the influence of sex and social isolation on ethanol consumption and bout microstructure in C57Bl/6J mice. LIQ PARTI, based on our previously developed single-housed LIQ HD system, accurately tracks drinking behavior using capacitive-based sensors and RFID technology. Group-housed female mice exhibited higher ethanol preference than males, while males displayed a unique undulating pattern of ethanol preference linked to cage changes, suggesting a potential stress or novelty-related response. Chronic ethanol intake distinctly altered bout microstructure between male and female mice, highlighting sex and social environmental influences on drinking behavior. Social isolation with the LIQ HD system amplified fluid intake and ethanol preference in both sexes, accompanied by sex- and fluid-dependent changes in bout microstructure. However, these effects largely reversed upon resocialization, indicating the plasticity of these behaviors in response to social context. Utilizing a novel group-housed home cage lickometer device, our findings illustrate the critical interplay of sex and housing conditions in voluntary alcohol drinking behaviors in C57Bl/6J mice, facilitating nuanced insights into the potential contributions to AUD etiology.