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An increasing body of evidence confirms the effectiveness of physical exercise (PE) in promoting brain health by preventing age-related cognitive decline and reducing the risk of neurodegenerative diseases. The benefits of PE are attributed to neuroplasticity processes which have been reported to enhance cerebral health. However, moderate to high-intensity PE is necessary to induce these responses and these intensities cannot always be achieved especially by people with physical limitations. As a countermeasure, electrical stimulation (ES) offers several benefits, particularly for improving physical functions, for various neurological diseases. This review aims to provide an overview of key mechanisms that could contribute to the enhancement in brain health in response to ES-induced exercise, including increases in cerebral blood flow, neuronal activity, and humoral pathways. This narrative review also focuses on the effects of ES protocols, applied to both humans and animals, on cognition. Despite a certain paucity of research when compared to the more classical aerobic exercise, it seems that ES could be of interest for improving cerebral health, particularly in people who have difficulty engaging in voluntary exercise. [ABSTRACT FROM AUTHOR]

• PANS IgG drawn at flare shows elevated binding to CINs in both mouse and human brain. • PANS IgG binding to CINs reduces their activity using p-rpS6 as a marker. • Elevated IgG binding to CINs is resolved in the same subject during symptom recovery. • Reduction of PANS IgG binding to CINs parallels symptom improvement during recovery. • Striatal CINs may be a locus of interest to investigate the pathophysiology in PANS. Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by the abrupt onset of significant obsessive–compulsive symptoms (OCS) and/or severe food restriction, together with other neuropsychiatric manifestations. An autoimmune pathogenesis triggered by infection has been proposed for at least a subset of PANS. The older diagnosis of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS) describes rapid onset of OCD and/or tics associated with infection with Group A Streptococcus. The pathophysiology of PANS and PANDAS remains incompletely understood. We recently found serum antibodies from children with rigorously defined PANDAS to selectively bind to cholinergic interneurons (CINs) in the striatum. Here we examine this binding in children with relapsing and remitting PANS, a more heterogeneous condition, collected in a distinct clinical context from those examined in our previous work, from children with a clinical history of Streptococcus infection. IgG from PANS cases showed elevated binding to striatal CINs in both mouse and human brain. Patient plasma collected during symptom flare decreased a molecular marker of CIN activity, phospho-riboprotein S6, in ex vivo brain slices; control plasma did not. Neither elevated antibody binding to CINs nor diminished CIN activity was seen with plasma collected from the same children during remission. These findings replicate what we have seen previously in PANDAS and support the hypothesis that at least a subset of PANS cases have a neuroimmune pathogenesis. Given the critical role of CINs in modulating basal ganglia function, these findings confirm striatal CINs as a locus of interest in the pathophysiology of both PANS and PANDAS. [ABSTRACT FROM AUTHOR]

Thermogenetics is a promising neuromodulation technique based on the use of heat-sensitive ion channels. However, on the way to its clinical application, a number of questions have to be addressed. First, to avoid immune response in future human applications, human ion channels should be studied as thermogenetic actuators. Second, heating levels necessary to activate these channels in vivo in brain tissue should be studied and cytotoxicity of these temperatures addressed. Third, the possibility and safety of chronic neuromodulation has to be demonstrated. In this study, we present a comprehensive framework for thermogenetic neuromodulation in vivo using the thermosensitive human ion channel hTRPV1. By targeting hTRPV1 expression to excitatory neurons of the mouse brain and activating them within a non-harmful temperature range with a fiber-coupled infrared laser, we not only induced neuronal firing and stimulated locomotion in mice, but also demonstrated that thermogenetics can be employed for repeated neuromodulation without causing evident brain tissue injury. Our results lay the foundation for the use of thermogenetic neuromodulation in brain research and therapy of neuropathologies. [ABSTRACT FROM AUTHOR]

Improved genetically encoded calcium indicators (GECIs) are essential for capturing intracellular dynamics of both muscle and neurons. A novel set of GECIs with ultrafast kinetics and high sensitivity was recently reported by Zhang et al. (2023). While these indicators, called jGCaMP8, were demonstrated to work in Drosophila and mice, data for Caenorhabditis elegans were not reported. Here, we present an optimized construct for C. elegans and use this to generate several strains expressing GCaMP8f (fast variant of the indicator). Utilizing the myo-2 promoter, we compare pharyngeal muscle activity measured with GCaMP7f and GCaMP8f and find that GCaMP8f is brighter upon binding to calcium, shows faster kinetics, and is not disruptive to the intrinsic contraction dynamics of the pharynx. Additionally, we validate its application for detecting neuronal activity in touch receptor neurons which reveals robust calcium transients even at small stimulus amplitudes. As such, we establish GCaMP8f as a potent tool for C. elegans research which is capable of extracting fast calcium dynamics at very low magnifications across multiple cell types. [ABSTRACT FROM AUTHOR]

Neuronal activity-regulated gene expression plays a crucial role in sculpting neural circuits that underpin adaptive brain function. Transcriptional enhancers are now recognized as key components of gene regulation that orchestrate spatiotemporally precise patterns of gene transcription. We propose that the dynamics of enhancer activation uniquely position these genomic elements to finely tune activity-dependent cellular plasticity. Enhancer specificity and modularity can be exploited to gain selective genetic access to specific cell states, and the precise modulation of target gene expression within restricted cellular contexts enabled by targeted enhancer manipulation allows for fine-grained evaluation of gene function. Mounting evidence also suggests that enduring stimulus-induced changes in enhancer states can modify target gene activation upon restimulation, thereby contributing to a form of cell-wide metaplasticity. We advocate for focused exploration of activity-dependent enhancer function to gain new insight into the mechanisms underlying brain plasticity and cognitive dysfunction. Neuronal activity-responsive gene expression regulates neural circuit plasticity. Griffith et al. review the critical role of cis -regulatory enhancer elements in orchestrating gene expression programs and highlight the promise of enhancer-focused studies to advance understanding of neural plasticity mechanisms. [ABSTRACT FROM AUTHOR]

Synaptic communication is an important process in the central nervous system that allows for the rapid and spatially specified transfer of signals. Neurons receive various synaptic inputs and generate action potentials required for information transfer, and these inputs can be excitatory or inhibitory, which collectively determines the output. Non-neuronal cells (glial cells) have been identified as crucial participants in influencing neuronal activity and synaptic transmission, with astrocytes forming tripartite synapses and microglia pruning synapses. While it has been known that oligodendrocyte precursor cells (OPCs) receive neuronal inputs, whether they also influence neuronal activity and synaptic transmission has remained unknown for two decades. Recent findings indicate that OPCs, too, modulate neuronal synapses. In this review, we discuss the roles of different glial cell types at synapses, including the recently discovered involvement of OPCs in synaptic transmission and synapse refinement, and discuss overlapping roles played by multiple glial cell types. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a common cause of mortality and severe disability in human and currently lacks effective treatment. Neuronal activation and neuroinflammation are the major two causes of neuronal damage. However, little is known about the connection of these two phenomena. This study uses middle cerebral artery occlusion mouse model and chemogenetic techniques to study the underlying mechanisms of neuronal excitotoxicity and severe neuroinflammation after ischemic stroke. Chemogenetic inhibition of neuronal activity in ipsilesional M1 alleviates infarct area and neuroinflammation, and improves motor recovery in ischemia mice. This study identifies that ischemic challenge triggers neuron to produce unique small extracellular vesicles (EVs) to aberrantly activate adjacent neurons which enlarge the neuron damage range. Importantly, these EVs also drive microglia activation to exacerbate neuroinflammation. Mechanistically, EVs from ischemia-evoked neuronal activity induce neuronal apoptosis and innate immune responses by transferring higher miR-100-5p to adjacent neuron and microglia. MiR-100-5p can bind to and activate TLR7 through U18U19G20-motif, thereby activating NF-κB pathway. Furthermore, knock-down of miR-100-5p expression improves poststroke outcomes in mice. Taken together, this study suggests that the combination of inhibiting aberrant neuronal activity and the secretion of specific EVs-miRNAs may serve as novel methods for stroke treatment. [ABSTRACT FROM AUTHOR]

Abstract Ischemic stroke is a common cause of mortality and severe disability in human and currently lacks effective treatment. Neuronal activation and neuroinflammation are the major two causes of neuronal damage. However, little is known about the connection of these two phenomena. This study uses middle cerebral artery occlusion mouse model and chemogenetic techniques to study the underlying mechanisms of neuronal excitotoxicity and severe neuroinflammation after ischemic stroke. Chemogenetic inhibition of neuronal activity in ipsilesional M1 alleviates infarct area and neuroinflammation, and improves motor recovery in ischemia mice. This study identifies that ischemic challenge triggers neuron to produce unique small extracellular vesicles (EVs) to aberrantly activate adjacent neurons which enlarge the neuron damage range. Importantly, these EVs also drive microglia activation to exacerbate neuroinflammation. Mechanistically, EVs from ischemia-evoked neuronal activity induce neuronal apoptosis and innate immune responses by transferring higher miR-100-5p to adjacent neuron and microglia. MiR-100-5p can bind to and activate TLR7 through U18U19G20-motif, thereby activating NF-κB pathway. Furthermore, knock-down of miR-100-5p expression improves poststroke outcomes in mice. Taken together, this study suggests that the combination of inhibiting aberrant neuronal activity and the secretion of specific EVs-miRNAs may serve as novel methods for stroke treatment. Graphical Abstract

Abstract Radiation therapy and stereotactic radiosurgery are common treatments for brain malignancies. However, the impact of radiation on underlying neuronal circuits is poorly understood. In the prefrontal cortex (PFC), neurons communicate via action potentials that control cognitive processes, thus it is important to understand the impact of radiation on these circuits. Here we present a novel protocol to investigate the effect of radiation on the activity and survival of PFC networks in vitro. Escalating doses of radiation were applied to PFC slices using a robotic radiosurgery platform at a standard dose rate of 10 Gy/min. High-density multielectrode array recordings of radiated slices were collected to capture extracellular activity across 4,096 channels. Radiated slices showed an increase in firing rate, functional connectivity, and complexity. Graph-theoretic measures of functional connectivity were altered following radiation. These results were compared to pharmacologically induced epileptic slices where neural complexity was markedly elevated, and functional connections were strong but remained spatially focused. Finally, propidium iodide staining revealed a dose-dependent effect of radiation on apoptosis. These findings provide a novel assay to investigate the impacts of clinically relevant doses of radiation on brain circuits and highlight the acute effects of escalating radiation doses on PFC neurons.

Abstract Several human diseases, including cancer and neurodegeneration, are associated with excessive mitochondrial fragmentation. In this context, mitochondrial division inhibitor (Mdivi-1) has been tested as a therapeutic to block the fission-related protein dynamin-like protein-1 (Drp1). Recent studies suggest that Mdivi-1 interferes with mitochondrial bioenergetics and complex I function. Here we show that the molecular mechanism of Mdivi-1 is based on inhibition of complex I at the IQ site. This leads to the destabilization of complex I, impairs the assembly of N- and Q-respirasomes, and is associated with increased ROS production and reduced efficiency of ATP generation. Second, the calcium homeostasis of cells is impaired, which for example affects the electrical activity of neurons. Given the results presented here, a potential therapeutic application of Mdivi-1 is challenging because of its potential impact on synaptic activity. Similar to the Complex I inhibitor rotenone, Mdivi-1 may lead to neurodegenerative effects in the long term.

Abstract Background Mainly known as a transcription factor patterning the rostral brain and governing its histogenesis, FOXG1 has been also detected outside the nucleus; however, biological meaning of that has been only partially clarified. Results Prompted by FOXG1 expression in cytoplasm of pallial neurons, we investigated its implication in translational control. We documented the impact of FOXG1 on ribosomal recruitment of Grin1-mRNA, encoding for the main subunit of NMDA receptor. Next, we showed that FOXG1 increases GRIN1 protein level by enhancing the translation of its mRNA, while not increasing its stability. Molecular mechanisms underlying this activity included FOXG1 interaction with EIF4E and, possibly, Grin1-mRNA. Besides, we found that, within murine neocortical cultures, de novo synthesis of GRIN1 undergoes a prominent and reversible, homeostatic regulation and FOXG1 is instrumental to that. Finally, by integrated analysis of multiple omic data, we inferred that FOXG1 is implicated in translational control of hundreds of neuronal genes, modulating ribosome engagement and progression. In a few selected cases, we experimentally verified such inference. Conclusions These findings point to FOXG1 as a key effector, potentially crucial to multi-scale temporal tuning of neocortical pyramid activity, an issue with profound physiological and neuropathological implications.

Radiation therapy and stereotactic radiosurgery are common treatments for brain malignancies. However, the impact of radiation on underlying neuronal circuits is poorly understood. In the prefrontal cortex (PFC), neurons communicate via action potentials that control cognitive processes, thus it is important to understand the impact of radiation on these circuits. Here we present a novel protocol to investigate the effect of radiation on the activity and survival of PFC networks in vitro. Escalating doses of radiation were applied to PFC slices using a robotic radiosurgery platform at a standard dose rate of 10 Gy/min. High-density multielectrode array recordings of radiated slices were collected to capture extracellular activity across 4,096 channels. Radiated slices showed an increase in firing rate, functional connectivity, and complexity. Graph-theoretic measures of functional connectivity were altered following radiation. These results were compared to pharmacologically induced epileptic slices where neural complexity was markedly elevated, and functional connections were strong but remained spatially focused. Finally, propidium iodide staining revealed a dose-dependent effect of radiation on apoptosis. These findings provide a novel assay to investigate the impacts of clinically relevant doses of radiation on brain circuits and highlight the acute effects of escalating radiation doses on PFC neurons. [ABSTRACT FROM AUTHOR]

Background: Mainly known as a transcription factor patterning the rostral brain and governing its histogenesis, FOXG1 has been also detected outside the nucleus; however, biological meaning of that has been only partially clarified. Results: Prompted by FOXG1 expression in cytoplasm of pallial neurons, we investigated its implication in translational control. We documented the impact of FOXG1 on ribosomal recruitment of Grin1-mRNA, encoding for the main subunit of NMDA receptor. Next, we showed that FOXG1 increases GRIN1 protein level by enhancing the translation of its mRNA, while not increasing its stability. Molecular mechanisms underlying this activity included FOXG1 interaction with EIF4E and, possibly, Grin1-mRNA. Besides, we found that, within murine neocortical cultures, de novo synthesis of GRIN1 undergoes a prominent and reversible, homeostatic regulation and FOXG1 is instrumental to that. Finally, by integrated analysis of multiple omic data, we inferred that FOXG1 is implicated in translational control of hundreds of neuronal genes, modulating ribosome engagement and progression. In a few selected cases, we experimentally verified such inference. Conclusions: These findings point to FOXG1 as a key effector, potentially crucial to multi-scale temporal tuning of neocortical pyramid activity, an issue with profound physiological and neuropathological implications. [ABSTRACT FROM AUTHOR]

The intracerebral spread of tau is a critical mechanism associated with functional decline in Alzheimer's disease (AD) and other tauopathies. Recently, a hypothesis has emerged suggesting that tau propagation is linked to functional neuronal connections, specifically driven by neuronal hyperactivity. However, experimental validation of this hypothesis remains limited. In this study, we investigated how tau propagation from the entorhinal cortex to the hippocampus, the neuronal circuit most susceptible to tau pathology in AD, is affected by the selective stimulation of neuronal activity along this circuit. Using a mouse model of seed-induced propagation combined with optogenetics, we found that the chronic stimulation of this neuronal connection over a 4-week period resulted in a significant increase in insoluble tau accumulation in both the entorhinal cortex and hippocampus. Importantly, the ratio of tau accumulation in the hippocampus relative to that in the entorhinal cortex, serving as an indicator of transcellular spreading, was significantly higher in mice subjected to chronic stimulation. These results support the notion that abnormal neuronal activity promotes tau propagation, thereby implicating it in the progression of tauopathy. [ABSTRACT FROM AUTHOR]

Methylphenidate (MPD) remains a cornerstone pharmacological intervention for managing ADHD, yet its increasing usage among ordinary youth and adults outside clinical contexts necessitates a thorough investigation into its developmental effects. This study seeks to simultaneously investigate the behavioral and neuronal changes within the dorsal raphe (DR) nucleus, a center of serotonergic neurons in the mammalian brain, before and after the administration of varying doses of acute and chronic MPD in freely behaving young and adult rats implanted with DR recording electrodes. Wireless neuronal and behavioral recording systems were used over 10 consecutive experimental days. Eight groups were examined: saline, 0.6, 2.5, and 10.0 mg/kg MPD for both young and adult rats. Six daily MPD injections were administered on experimental days 1 to 6, followed by a three-day washout period and MPD re-administration on experimental day 10 (ED10). The analysis of neuronal activity recorded from 504 DR neurons (DRNs) in young rats and 356 DRNs in adult rats reveals significant age-dependent differences in acute and chronic MPD responses. This study emphasizes the importance of aligning electrophysiological evaluations with behavioral outcomes following extended MPD exposure, elucidating the critical role of DRNs and serotonin signaling in modulating MPD responses and delineating age-specific variations in young versus adult rat models. [ABSTRACT FROM AUTHOR]

To understand how neurons and neural circuits function during behaviors, it is essential to record neuronal activity in the brain in vivo. Among the various technologies developed for recording neuronal activity, molecular tools that induce gene expression in an activity-dependent manner have attracted particular attention for their ability to clarify the causal relationships between neuronal activity and behavior. In this review, we summarize recently developed activity-dependent gene expression tools and their potential contributions to the study of neural circuits. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH) in rodents mimics the hypoxia‐induced elevation of blood pressure seen in individuals experiencing episodic breathing. The brainstem nucleus tractus solitarii (nTS) is the first site of visceral sensory afferent integration, and thus is critical for cardiorespiratory homeostasis and its adaptation during a variety of stressors. In addition, the paraventricular nucleus of the hypothalamus (PVN), in part through its nTS projections that contain oxytocin (OT) and/or corticotropin‐releasing hormone (CRH), contributes to cardiorespiratory regulation. Within the nTS, these PVN‐derived neuropeptides alter nTS activity and the cardiorespiratory response to hypoxia. Nevertheless, their contribution to nTS activity after CIH is not fully understood. We hypothesized that OT and CRH would increase nTS activity to a greater extent following CIH, and co‐activation of OT+CRH receptors would further magnify nTS activity. Our data show that compared to their normoxic controls, 10 days' CIH exaggerated nTS discharge, excitatory synaptic currents and Ca2+ influx in response to CRH, which were further enhanced by the addition of OT. CIH increased the tonic functional contribution of CRH receptors, which occurred with elevation of mRNA and protein. Together, our data demonstrate that intermittent hypoxia exaggerates the expression and function of neuropeptides on nTS activity. Key points: Episodic breathing and chronic intermittent hypoxia (CIH) are associated with autonomic dysregulation, including elevated sympathetic nervous system activity. Altered nucleus tractus solitarii (nTS) activity contributes to this response.Neurons originating in the paraventricular nucleus (PVN), including those containing oxytocin (OT) and corticotropin‐releasing hormone (CRH), project to the nTS, and modulate the cardiorespiratory system. Their role in CIH is unknown.In this study, we focused on OT and CRH individually and together on nTS activity from rats exposed to either CIH or normoxia control.We show that after CIH, CRH alone and with OT increased to a greater extent overall nTS discharge, neuronal calcium influx, synaptic transmission to second‐order nTS neurons, and OT and CRH receptor expression.These results provide insights into the underlying circuits and mechanisms contributing to autonomic dysfunction during periods of episodic breathing. [ABSTRACT FROM AUTHOR]

The circular RNA (circRNA) Cdr1as is conserved across mammals and highly expressed in neurons, where it directly interacts with microRNA miR-7. However, the biological function of this interaction is unknown. Here, using primary cortical murine neurons, we demonstrate that stimulating neurons by sustained depolarization rapidly induces two-fold transcriptional upregulation of Cdr1as and strong post-transcriptional stabilization of miR-7. Cdr1as loss causes doubling of glutamate release from stimulated synapses and increased frequency and duration of local neuronal bursts. Moreover, the periodicity of neuronal networks increases, and synchronicity is impaired. Strikingly, these effects are reverted by sustained expression of miR-7, which also clears Cdr1as molecules from neuronal projections. Consistently, without Cdr1as, transcriptomic changes caused by miR-7 overexpression are stronger (including miR-7-targets downregulation) and enriched in secretion/synaptic plasticity pathways. Altogether, our results suggest that in cortical neurons Cdr1as buffers miR-7 activity to control glutamatergic excitatory transmission and neuronal connectivity important for long-lasting synaptic adaptations. Synopsis: In mouse cortical neurons, miR-7 regulates glutamate release, controlled by the buffering action of Cdr1as. These molecules together govern glutamatergic transmission and neuronal connectivity, influencing synaptic adaptations at transcriptional and neuronal activity levels. Neuronal depolarization transcriptionally induces Cdr1as and post-transcriptionally stabilizes miR-7 Cdr1as-KO neurons show chronically elevated neuronal activity, higher asynchrony and oscillation, increased pre-synaptic glutamate release, and inhibition of synaptic adaptation. Cdr1as:miR-7 interaction exerts a synergetic gene regulation of the neuronal transcriptome, compared to their individual mutations. Additionally, miR-7 up-regulation is sufficient to restore local and network neural activity and glutamate secretion, but it depends on Cdr1as expression. In mouse cortical neurons, miR-7 regulates glutamate release, controlled by the buffering action of Cdr1as. These molecules together govern glutamatergic transmission and neuronal connectivity, influencing synaptic adaptations at transcriptional and neuronal activity levels. [ABSTRACT FROM AUTHOR]

The nucleus raphe magnus (RMg) is a key structure of the endogenous antinociceptive system, the activity of which is regulated by serotonin 5-HT1A receptors. A recipient of the RMg descending projections is the caudal ventrolateral medulla (cVLM)—the first supraspinal center for processing visceral and somatic pain signals. Intestinal pathology is known to cause persistent functional alterations in the RMg, which are associated with the development of visceral and somatic hyperalgesia. Presumably, a consequence of the alterations may be changes in the RMg modulating effects on cVLM nociceptive activity. However, the specific neuronal and molecular mechanisms underlying such influence in normal conditions, as well as their changes in pathology remain unexplored. The aim of our neurophysiological experiments performed in anesthetized adult male Wistar rats was to compare the effects of RMg electrical stimulation on the activity of cVLM neurons evoked by visceral (colorectal distension, CRD) and somatic (tail squeezing) pain stimulations that occur in normal conditions and after intestinal inflammation (colitis), with an assessment of the contribution to these processes of the supraspinal 5-HT1A receptor activation with intracerebroventricular buspirone. It has been shown that RMg can exert an inhibitory effect on both non-selective and differential responses of the cVLM neurons to diverse pain stimuli, causing a weakening of excitatory neuronal reactions and an increase in inhibitory responses to CRD while inhibiting both types of reactions to tail squeezing. The RMg-evoked suppression of nociceptive excitation in the caudal medullary neurons is enhanced under activation of supraspinal 5-HT1A receptors by buspirone. It has been established that in postcolitis period the RMg inhibitory action on different populations of cVLM neurons are significantly diminished, indicating an impairment of the nucleus' antinociceptive function. In these conditions, the RMg descending influence loses its 5-HT1A receptor-dependent component. The changes described may contribute to the supraspinal mechanisms underlying pathogenesis of post-inflammatory abdominal pain and comorbid somatic hyperalgesia. [ABSTRACT FROM AUTHOR]

Given the pivotal role of neuronal populations in various biological processes, assessing their collective output is crucial for understanding the nervous system’s complex functions. Building on our prior development of a spiral scanning mechanism for the rapid acquisition of Raman spectra from single cells and incorporating machine learning for label-free evaluation of cell states, we investigated whether the Paint Raman Express Spectroscopy System (PRESS) can assess neuronal activities. We tested this hypothesis by examining the chemical responses of glutamatergic neurons as individual neurons and autonomic neuron ganglia as neuronal populations derived from human-induced pluripotent stem cells. The PRESS successfully acquired Raman spectra from both individual neurons and ganglia within a few seconds, achieving a signal-to-noise ratio sufficient for detailed analysis. To evaluate the ligand responsiveness of the induced neurons and ganglia, the Raman spectra were subjected to principal component and partial least squares discriminant analyses. The PRESS detected neuronal activity in response to glutamate and nicotine, which were absent in the absence of calcium. Additionally, the PRESS induced dose-dependent neuronal activity changes. These findings underscore the capability of the PRESS to assess individual neuronal activity and elucidate neuronal population dynamics and pharmacological responses, heralding new opportunities for drug discovery and regenerative medicine advancement. [ABSTRACT FROM AUTHOR]

The advent of artificial lighting, particularly during the evening and night, has significantly altered the predictable daily light and dark cycles in recent times. Altered light environments disrupt the biological clock and negatively impact mood and cognition. Although adolescents commonly experience chronic changes in light/dark cycles, our understanding of how the adolescents’ brain adapts to altered light environments remains limited. Here, we investigated the impact of chronic light cycle disruption (LCD) during adolescence, exposing adolescent mice to 19  h of light and 5  h of darkness for 5  days and 12  L:12D for 2  days per week (LCD group) for 4  weeks. We showed that LCD exposure did not affect circadian locomotor activity but impaired memory and increased avoidance response in adolescent mice. Clock gene expression and neuronal activity rhythms analysis revealed that LCD disrupted local molecular clock and neuronal activity in the dentate gyrus (DG) and in the medial amygdala (MeA) but not in the circadian pacemaker (SCN). In addition, we characterized the photoresponsiveness of the MeA and showed that somatostatin neurons are affected by acute and chronic aberrant light exposure during adolescence. Our research provides new evidence highlighting the potential consequences of altered light environments during pubertal development on neuronal physiology and behaviors. [ABSTRACT FROM AUTHOR]

Neurons in the central nervous system communicate with each other by activating billions of tiny synaptic boutons distributed along their fine axons. These presynaptic varicosities are very crowded environments, comprising hundreds of synaptic vesicles. Only a fraction of these vesicles can be recruited in a single release episode, either spontaneous or evoked by action potentials. Since the seminal work by Fatt and Katz, spontaneous release has been modelled as a memoryless process. Nevertheless, at central synapses, experimental evidence indicates more complex features, including non‐exponential distributions of release intervals and power‐law behaviour in their rate. To describe these features, we developed a probabilistic model of spontaneous release based on Brownian motion of synaptic vesicles in the presynaptic environment. To account for different diffusion regimes, we based our simulations on fractional Brownian motion. We show that this model can predict both deviation from the Poisson hypothesis and power‐law features in experimental quantal release series, thus suggesting that the vesicular motion by diffusion could per se explain the emergence of these properties. We demonstrate the efficacy of our modelling approach using electrophysiological recordings at single synaptic boutons and ultrastructural data. When this approach was used to simulate evoked responses, we found that the replenishment of the readily releasable pool driven by Brownian motion of vesicles can reproduce the characteristic binomial release distributions seen experimentally. We believe that our modelling approach supports the idea that vesicle diffusion and readily releasable pool dynamics are crucial factors for the physiological functioning of neuronal communication. Key points: We developed a new probabilistic model of spontaneous and evoked vesicle fusion based on simple biophysical assumptions, including the motion of vesicles before they dock to the release site.We provide closed‐form equations for the interval distribution of spontaneous releases in the special case of Brownian diffusion of vesicles, showing that a power‐law heavy tail is generated.Fractional Brownian motion (fBm) was exploited to simulate anomalous vesicle diffusion, including directed and non‐directed motion, by varying the Hurst exponent.We show that our model predicts non‐linear features observed in experimental spontaneous quantal release series as well as ultrastructural data of synaptic vesicles spatial distribution.Evoked exocytosis based on a diffusion‐replenished readily releasable pool might explain the emergence of power‐law behaviour in neuronal activity. [ABSTRACT FROM AUTHOR]

Pain management in neonates continues to be a challenge. Diverse therapies are available that cause loss of pain sensitivity. However, because of side effects, the search for better options remains open. Dexmedetomidine is a promising drug; it has shown high efficacy with a good safety profile in sedation and analgesia in the immature nervous system. Though dexmedetomidine is already in use for pain control in neonates (including premature neonates) and infants as an adjunct to other anesthetics, the question remains whether it affects the neuronal activity patterning that is critical for development of the immature nervous system. In this study, using the neonatal rat as a model, the pharmacodynamic effects of dexmedetomidine on the nervous and cardiorespiratory systems were studied. Our results showed that dexmedetomidine has pronounced analgesic effects in the neonatal rat pups, and also weakly modified both the immature network patterns of cortical and hippocampal activity and the physiology of sleep cycles. Though the respiration and heart rates were slightly reduced after dexmedetomidine administration, it might be considered as the preferential independent short-term therapy for pain management in the immature and developing brain. [ABSTRACT FROM AUTHOR]

The method of identifying the direction of the coupling between oscillators based on the simulation of phase dynamics of weakly coupled and weakly noisy periodic processes is used to determine the direction of the coupling between time series extracted from biological signals. Neuronal activity, arterial pressure and respiratory rate of anesthetized rats were used as initial data. Various options for the direction of the coupling between the analyzed time series were revealed. [ABSTRACT FROM AUTHOR]

The use of designer receptors exclusively activated by designer drugs (DREADDs) has led to significant advances in our understanding of the neural circuits that govern behavior. By allowing selective control over cellular activity and signaling, DREADDs have become an integral tool for defining the pathways and cellular phenotypes that regulate sleep, pain, motor activity, goal-directed behaviors, and a variety of other processes. In this review, we provide a brief overview of DREADDs and discuss notable discoveries in the neurosciences with an emphasis on circuit mechanisms. We then highlight methodological approaches to achieve pathway specific activation of DREADDs. Finally, we discuss spatial and temporal constraints of DREADDs signaling and how these features can be incorporated into experimental designs to precisely dissect circuits of interest. [ABSTRACT FROM AUTHOR]

A-to-I RNA editing, catalyzed by the ADAR protein family, significantly contributes to the diversity and adaptability of mammalian RNA signatures, aligning with developmental and physiological needs. Yet, the functions of many editing sites are still to be defined. The Unc80 gene stands out in this context due to its brain-specific expression and the evolutionary conservation of its codon-altering editing event. The precise biological functions of Unc80 and its editing, however, are still largely undefined. In this study, we first demonstrated that Unc80 editing occurs in an ADAR2-dependent manner and is exclusive to the brain. By employing the CRISPR/Cas9 system to generate Unc80 knock-in mouse models that replicate the natural editing variations, our findings revealed that mice with the "gain-of-editing" variant (Unc80G/G) exhibit heightened basal neuronal activity in critical olfactory regions, compared to the "loss-of-editing" (Unc80S/S) counterparts. Moreover, an increase in glutamate levels was observed in the olfactory bulbs of Unc80G/G mice, indicating altered neurotransmitter dynamics. Behavioral analysis of odor detection revealed distinctive responses to novel odors—both Unc80 deficient (Unc80+/−) and Unc80S/S mice demonstrated prolonged exploration times and heightened dishabituation responses. Further elucidating the olfactory connection of Unc80 editing, transcriptomic analysis of the olfactory bulb identified significant alterations in gene expression that corroborate the behavioral and physiological findings. Collectively, our research advances the understanding of Unc80's neurophysiological functions and the impact of its editing on the olfactory sensory system, shedding light on the intricate molecular underpinnings of olfactory perception and neuronal activity. [ABSTRACT FROM AUTHOR]

Multivalent binding of CTCF to variable DNA sequences is thought to underlie its ability to mediate diverse cellular functions. CTCF typically binds a 20 base-pair consensus DNA sequence, but the full diversity of CTCF binding sites (CBS) within the genome has not been interrogated. We assessed CTCF occupancy in cultured cortical neurons and observed surprisingly that ~ 22% of CBS lack the consensus CTCF motif. We report here that sequence diversity at most of these atypical CBS involves degeneracy at specific nucleotide positions within the consensus CTCF motif, which likely affect the binding of CTCF zinc fingers 6 and 7. This mode of atypical CTCF binding defines most CBS at gene promoters, as well as CBS that are dynamically altered during neural differentiation and following neuronal stimulation, revealing how atypical CTCF binding could influence gene activity. Dynamic CBS are distributed both within and outside loop anchors and TAD boundaries, suggesting both looping-dependent and independent roles for CTCF. Finally, we describe a second mode of atypical CTCF binding to DNA sequences that are completely unrelated to the consensus CTCF motif, which are enriched within the bodies of tissue-specific genes. These tissue-specific atypical CBS are also enriched in H3K27ac, which marks cis-regulatory elements within chromatin, including enhancers. Overall, these results indicate how atypical CBS could dynamically regulate gene activity patterns during differentiation, development, and in response to environmental cues. [ABSTRACT FROM AUTHOR]

An increasing body of evidence confirms the effectiveness of physical exercise (PE) in promoting brain health by preventing age-related cognitive decline and reducing the risk of neurodegenerative diseases. The benefits of PE are attributed to neuroplasticity processes which have been reported to enhance cerebral health. However, moderate to high-intensity PE is necessary to induce these responses and these intensities cannot always be achieved especially by people with physical limitations. As a countermeasure, electrical stimulation (ES) offers several benefits, particularly for improving physical functions, for various neurological diseases. This review aims to provide an overview of key mechanisms that could contribute to the enhancement in brain health in response to ES-induced exercise, including increases in cerebral blood flow, neuronal activity, and humoral pathways. This narrative review also focuses on the effects of ES protocols, applied to both humans and animals, on cognition. Despite a certain paucity of research when compared to the more classical aerobic exercise, it seems that ES could be of interest for improving cerebral health, particularly in people who have difficulty engaging in voluntary exercise.

Autophagy has two distinct pathways, degradation and secretion. Autophagic degradation plays a pivotal role in cellular homeostasis by the formation of a double-membrane autophagosome in concert with numerous ATG (autophagy-related) proteins. However, the mechanism that mediates autophagic secretion is not fully understood. To explore how autophagic secretion is physiologically triggered and regulated in neurons, we investigated whether neuronal activity affected autophagic secretion by analyzing SNCA secretion in mouse primary cortical neurons and SH-SY5Y cells. In primary neurons, rapamycin promoted SNCA secretion, while the effect was canceled in primary neurons of Becn1+/–deficient mice. Stimulating neuronal activity by glutamate promoted SNCA secretion, autophagic flux, and colocalization of SNCA with LC3 (microtubule-associated proteins 1 light chain 3). These effects were inhibited by the intracellular Ca2+ chelator BAPTA-AM. Additionally, glutamate-induced SNCA secretion was suppressed by Atg5 or Rab8a knockdown in SH-SY5Y cells, and mainly occurred in the fashion associated with extracellular vesicles in primary neurons. These results suggest that neuronal activity triggers autophagic secretion for releasing SNCA via an increase in intracellular Ca2+ concentration.

The medial prefrontal cortex has been shown to participate in pain processing and to undergo structural and functional changes in chronic visceral pain syndromes. Its infralimbic region (IL) is directly involved in central autonomic regulation and provides extensive projections to pain-related brain centers, being most capable of modulating visceral nociception. However, the precise neuronal and molecular mechanisms underlying IL-exerted descending control of visceral pain and their probable alterations in pathology remain unknown. Considering the high levels of serotonin 5-HT3 receptors in the IL and their important role in visceral pain regulation, in this study performed in anesthetized adult male Wistar rats, we aimed to determine whether 5-HT3 receptor-dependent mechanisms are involved in the IL influence on visceral pain-responsive neurons of the caudal ventrolateral medulla (CVLM) and whether intestinal inflammation affects the process. Our results showed that electrical stimulation of the IL caused a facilitation of both excitatory and inhibitory CVLM neuron responses to noxious colorectal distension (CRD). Both effects were 5-HT3-dependent, being decreased following intracerebroventricular injection of a 5-HT3-antagonist, granisetron (20 µg in 10 µL saline). In trinitrobenzenesulfonic acid-induced colitis, the IL stimulating influence on CRD-excited CVLM neurons intensified, while the cortex-driven facilitation of CRD-inhibited cells reduced; both appeared resistant to the 5-HT3 receptor blockade. These data provide an insight to the specific mechanisms underlying cortical modulation of acute and gut pathology-associated visceral nociception, promoting the development of differentiated strategies for their treatment. [ABSTRACT FROM AUTHOR]

Microglia directly sense neurotransmitters, including norepinephrine and γ-aminobutyric acid (GABA), which act as 'brain-associated molecular patterns' to shape neuronal connectivity. Cytokines can instruct distinct microglial functional states. Microglia contact different sites on neuronal bodies, from the dendrite to the soma to the axon, using activity-dependent mechanisms, including purinergic sensing via P2Y12. Microglia can transiently alter synaptic function by interposing between pre- and post-synaptic membranes; they can also alter synapse numbers by remodeling connections. Microglia (tissue-resident macrophages of the brain) dynamically regulate healthy brain function and connectivity by directly sensing molecular patterns associated with neuronal activity, which include neurotransmitters, purines, and portions of remodeling neural circuits. Microglia are brain-resident macrophages that play key roles in brain development and experience dependent plasticity. In this review we discuss recent findings regarding the molecular mechanisms through which mammalian microglia sense the unique molecular patterns of the homeostatic brain. We propose that microglial function is acutely controlled in response to 'brain-associated molecular patterns' (BAMPs) that function as indicators of neuronal activity and neural circuit remodeling. A further layer of regulation comes from instructive cytokine cues that define unique microglial functional states. A systematic investigation of the receptors and signaling pathways that mediate these two regulatory axes may begin to define a functional code for microglia–neuron interactions. [ABSTRACT FROM AUTHOR]

Store operated Ca2+ entry (SOCE) is a ubiquitous signalling module with established roles in the immune system, secretion and muscle development. Recent evidence supports a complex role for SOCE in the nervous system. In this review we present an update of the current knowledge on SOCE function in the brain with a focus on its role as a regulator of brain activity and excitability [ABSTRACT FROM AUTHOR]

The comorbidity of chronic pain and depression poses tremendous challenges for the treatment of either one because they exacerbate each other with unknown mechanisms. As the posterior insular cortex (PIC) integrates multiple somatosensory and emotional information and is implicated in either chronic pain or depression, we hypothesize that the PIC and its projections may contribute to the pathophysiology of comorbid chronic pain and depression. We show that PIC neurons were readily activated bymechanical, thermal, aversive, and stressful and appetitive stimulation in naive and neuropathic pain male mice subjected to spared nerve injury (SNI). Optogenetic activation of PIC neurons induced hyperalgesia and conditioned place aversion in naive mice, whereas inhibition of these neurons led to analgesia, conditioned place preference (CPP), and antidepressant effect in both naive and SNI mice. Combining neuronal tracing, optogenetics, and electrophysiological techniques, we found that the monosynaptic glutamatergic projections from the PIC to the basolateral amygdala (BLA) and the ventromedial nucleus (VM) of the thalamus mimicked PIC neurons in pain modulation in naive mice; in SNI mice, both projections were enhanced accompanied by hyperactivity of PIC, BLA, and VM neurons and inhibition of these projections led to analgesia, CPP, and antidepressant-like effect. The present study suggests that potentiation of the PIC→BLA and PIC→VM projections may be important pathophysiological bases for hyperalgesia and depression-like behavior in neuropathic pain and reversing the potentiation may be a promising therapeutic strategy for comorbid chronic pain and depression. [ABSTRACT FROM AUTHOR]

Introduction: Cognitive dysfunction due to reduced neuronal transmission in the brain is a major emerging complication in diabetes. However, recent neuroimaging studies have demonstrated non-linear changes including hyperactivity in the hippocampus during the early stage of diabetes. This study aimed to determine the changes in neuronal activity at a single-cell level in hippocampal CA1 pyramidal neurons in the early stage of streptozotocin-induced type 1 diabetes in mice. Methods: Whole-cell patch-clamp recordings from acute brain slices were performed in mice over 4 consecutive weeks following the induction of hyperglycaemia using streptozotocin. In addition, microdialysate was collected from CA1 area while the mice were in an arousal state. The concentrations of glutamate and GABA in the microdialysate were then measured using ultra-performance liquid chromatography with mass spectrometry. Results: CA1 neurons in streptozotocin-induced diabetic mice exhibited higher membrane potentials (p = 0.0052), higher frequency of action potentials (p = 0.0052), and higher frequency of spontaneous excitatory post-synaptic currents (p = 0.037) compared with controls during the second week after hyperglycaemia was established. No changes in electrophysiological parameters were observed during the first, the third, and the fourth week. Moreover, the diabetic mice had higher extracellular glutamate concentration in CA1 area compared with controls (p = 0.021) during the second week after the initiation of diabetes. No change in the extracellular GABA concentration was observed. Conclusion: Our study demonstrated a temporary state of neuronal hyperactivity at the single-cell level in the hippocampal CA1 region during the early stage of diabetes. This neuronal hyperactivity might be related to altered glutamate metabolism and provide clues for future brain-target intervention. [ABSTRACT FROM AUTHOR]

Rodent studies have shown that alternative splicing in neurons plays important roles in development and maturity, and is regulatable by signals such as electrical activity. However, rodent-human similarities are less well explored. We compared basal and activity-dependent exon splicing in cortical-patterned human ESC-derived neurons with that in cortical mouse ESC-derived neurons, primary mouse cortical neurons at two developmental stages, and mouse hippocampal neurons, focussing on conserved orthologous exons. Both basal exon inclusion levels and activity-dependent changes in splicing showed human-mouse correlation. Conserved activity regulated exons are enriched in RBFOX, SAM68, NOVA and PTBP targets, and centered on cytoskeletal organization, mRNA processing, and synaptic signaling genes. However, human-mouse correlations were weaker than inter-mouse comparisons of neurons from different brain regions, developmental stages and origin (ESC vs. primary), suggestive of some inter-species divergence. The set of genes where activity-dependent splicing was observed only in human neurons were dominated by those involved in lipid biosynthesis, signaling and trafficking. Study of human exon splicing in mouse Tc1 neurons carrying human chromosome-21 showed that neuronal basal exon inclusion was influenced by cis-acting sequences, although may not be sufficient to confer activity-responsiveness in an allospecific environment. Overall, these comparisons suggest that neuronal alternative splicing should be confirmed in a human-relevant system even when exon structure is evolutionarily conserved.

We used light-sensitive drugs to identify the brain region-specific role of mGlu5 metabotropic glutamate receptors in the control of pain. Optical activation of systemic JF-NP-26, a caged, normally inactive, negative allosteric modulator (NAM) of mGlu5 receptors, in cingulate, prelimbic, and infralimbic cortices and thalamus inhibited neuropathic pain hypersensitivity. Systemic treatment of alloswitch-1, an intrinsically active mGlu5 receptor NAM, caused analgesia, and the effect was reversed by light-induced drug inactivation in the prelimbic and infralimbic cortices, and thalamus. This demonstrates that mGlu5 receptor blockade in the medial prefrontal cortex and thalamus is both sufficient and necessary for the analgesic activity of mGlu5 receptor antagonists. Surprisingly, when the light was delivered in the basolateral amygdala, local activation of systemic JF-NP-26 reduced pain thresholds, whereas inactivation of alloswitch-1 enhanced analgesia. Electrophysiological analysis showed that alloswitch-1 increased excitatory synaptic responses in prelimbic pyramidal neurons evoked by stimulation of presumed BLA input, and decreased BLA-driven feedforward inhibition of amygdala output neurons. Both effects were reversed by optical silencing and reinstated by optical reactivation of alloswitch-1. These findings demonstrate for the first time that the action of mGlu5 receptors in the pain neuraxis is not homogenous, and suggest that blockade of mGlu5 receptors in the BLA may limit the overall analgesic activity of mGlu5 receptor antagonists. This could explain the suboptimal effect of mGlu5 NAMs on pain in human studies and validate photopharmacology as an important tool to determine ideal target sites for systemic drugs.

Synaptic changes are early manifestations of neuronal dysfunction in Huntington's disease (HD). However, the mechanisms by which mutant HTT protein impacts synaptogenesis and function are not well understood. Herein we explored HD pathogenesis in the BACHD mouse model by examining synaptogenesis and function in long term primary cortical cultures. At DIV14 (days in vitro), BACHD cortical neurons showed no difference from WT neurons in synaptogenesis as revealed by colocalization of a pre-synaptic (Synapsin I) and a post-synaptic (PSD95) marker. From DIV21 to DIV35, BACHD neurons showed progressively reduced colocalization of Synapsin I and PSD95 relative to WT neurons. The deficits were effectively rescued by treatment of BACHD neurons with BDNF. The recombinant apical domain of CCT1 (ApiCCT1) yielded a partial rescuing effect. BACHD neurons also showed culture age-related significant functional deficits as revealed by multielectrode arrays (MEAs). These deficits were prevented by BDNF, whereas ApiCCT1 showed a less potent effect. These findings are evidence that deficits in BACHD synapse and function can be replicated in vitro and that BDNF or a TRiC-inspired reagent can potentially be protective against these changes in BACHD neurons. Our findings support the use of cellular models to further explicate HD pathogenesis and potential treatments.

Immediate early genes (IEGs) are transcribed in response to neuronal activity from sensory stimulation during multiple adaptive processes in the brain. The transcriptional profile of IEGs is indicative of the duration of neuronal activity, but its sensitivity to the strength of depolarization remains unknown. Also unknown is whether activity history of graded potential changes influence future neuronal activity. In this work with dissociated rat cortical neurons, we found that mild depolarization-mediated by elevated extracellular potassium (K+)-induces a wide array of rapid IEGs and transiently depresses transcriptional and signaling responses to a successive stimulus. This latter effect was independent of de novo transcription, translation, and signaling via calcineurin or mitogen-activated protein kinase. Furthermore, as measured by multiple electrode arrays and calcium imaging, mild depolarization acutely subdues subsequent spontaneous and bicuculline-evoked activity via calcium- and N-methyl-d-aspartate receptor-dependent mechanisms. Collectively, this work suggests that a recent history of graded potential changes acutely depress neuronal intrinsic properties and subsequent responses. Such effects may have several potential downstream implications, including reducing signal-to-noise ratio during synaptic plasticity processes.

Symptomatic dermographism (SD) is a common form of urticaria, which is triggered by stroking the skin. Brain involvement in its aetiology was investigated by means of magnetoencephalography (MEG) after provocation with histamine and dermography. Wheals were induced by histamine skin prick test and dermography in twelve SD patients and fourteen controls. Itch severity was scored on a Visual Analogue Scale (VAS). Relative power and functional connectivity (FC) were measured using a 306‐channel whole‐head MEG system at baseline and 10 min after histamine and dermography, and contrasted between groups and conditions. Furthermore, wheal diameter and itch scores after these procedures were correlated with the MEG values. SD patients had higher itch scores after histamine and dermography. No significant group‐differences were observed in relative power or FC for any condition. In both groups, power decreases were mostly observed in the beta band, and power increases in the alpha bands, after provocation, with more regions involved in patients compared to controls. Increased FC was seen after histamine in patients, and after dermography in controls. In patients only, dermography and histamine wheal size correlated with the alpha2 power in the regions of interest that showed significant condition effects after these procedures. Our findings may be cautiously interpreted as aberrant itch processing, and suggest involvement of the central nervous system in the aetiology of SD. [ABSTRACT FROM AUTHOR]

Background: Olfactory dysfunction is known to be an early manifestation of Alzheimer's disease (AD). However, the underlying mechanism, particularly the specific molecular events that occur during the early stages of olfactory disorders, remains unclear. Methods: In this study, we utilized transcriptomic sequencing, bioinformatics analysis, and biochemical detection to investigate the specific pathological and molecular characteristics of the olfactory bulb (OB) in 4‐month‐old male triple transgenic 3xTg‐AD mice (PS1M146V/APPSwe/TauP301L). Results: Initially, during the early stages of olfactory impairment, no significant learning and memory deficits were observed. Correspondingly, we observed significant accumulation of amyloid‐beta (Aβ) and Tau pathology specifically in the OB, but not in the hippocampus. In addition, significant axonal morphological defects were detected in the olfactory bulb, cortex, and hippocampal brain regions of 3xTg‐AD mice. Transcriptomic analysis revealed a significant increase in the expression of neuroinflammation‐related genes, accompanied by a significant decrease in neuronal activity‐related genes in the OB. Moreover, immunofluorescence and immunoblotting demonstrated an activation of glial cell biomarkers Iba1 and GFAP, along with a reduction in the expression levels of neuronal activity‐related molecules Nr4a2 and FosB, as well as olfaction‐related marker OMP. Conclusion: In sum, the early accumulation of Aβ and Tau pathology induces neuroinflammation, which subsequently leads to a decrease in neuronal activity within the OB, causing axonal transport deficits that contribute to olfactory disorders. Nr4a2 and FosB appear to be promising targets for intervention aimed at improving early olfactory impairment in AD. [ABSTRACT FROM AUTHOR]

Objective: First implementation of dynamic oxygen-17 (17O) MRI at 7 Tesla (T) during neuronal stimulation in the human brain. Methods: Five healthy volunteers underwent a three-phase 17O gas (17O2) inhalation experiment. Combined right-side visual stimulus and right-hand finger tapping were used to achieve neuronal stimulation in the left cerebral hemisphere. Data analysis included the evaluation of the relative partial volume (PV)-corrected time evolution of absolute 17O water (H217O) concentration and of the relative signal evolution without PV correction. Statistical analysis was performed using a one-tailed paired t test. Blood oxygen level-dependent (BOLD) experiments were performed to validate the stimulation paradigm. Results: The BOLD maps showed significant activity in the stimulated left visual and sensorimotor cortex compared to the non-stimulated right side. PV correction of 17O MR data resulted in high signal fluctuations with a noise level of 10% due to small regions of interest (ROI), impeding further quantitative analysis. Statistical evaluation of the relative H217O signal with PV correction (p = 0.168) and without (p = 0.382) did not show significant difference between the stimulated left and non-stimulated right sensorimotor ROI. Discussion: The change of cerebral oxygen metabolism induced by sensorimotor and visual stimulation is not large enough to be reliably detected with the current setup and methodology of dynamic 17O MRI at 7 T. [ABSTRACT FROM AUTHOR]

The theory of engrams, proposed several years ago, is highly crucial to understanding the progress of memory. Although it significantly contributes to identifying new treatments for cognitive disorders, it is limited by a lack of technology. Several scientists have attempted to validate this theory but failed. With the increasing availability of activity-dependent tools, several researchers have found traces of engram cells. Activity-dependent tools are based on the mechanisms underlying neuronal activity and use a combination of emerging molecular biological and genetic technology. Scientists have used these tools to tag and manipulate engram neurons and identified numerous internal connections between engram neurons and memory. In this review, we provide the background, principles, and selected examples of applications of existing activity-dependent tools. Using a combination of traditional definitions and concepts of engram cells, we discuss the applications and limitations of these tools and propose certain developmental directions to further explore the functions of engram cells. [ABSTRACT FROM AUTHOR]

Activity-regulated cytoskeleton-associated protein (Arc) plays essential roles in diverse forms of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), and homeostatic plasticity. In addition, it assembles into virus-like particles that may deliver mRNAs and/or other cargo between neurons and neighboring cells. Considering this broad range of activities, it is not surprising that Arc is subject to regulation by multiple types of post-translational modification, including phosphorylation, palmitoylation, SUMOylation, ubiquitylation, and acetylation. Here we explore the potential regulatory role of Arc phosphorylation by protein kinase C (PKC), which occurs on serines 84 and 90 within an α-helical segment in the N-terminal domain. To mimic the effect of PKC phosphorylation, we mutated the two serines to negatively charged glutamic acid. A consequence of introducing these phosphomimetic mutations is the almost complete inhibition of Arc palmitoylation, which occurs on nearby cysteines and contributes to synaptic weakening. The mutations also inhibit the binding of nucleic acids and destabilize high-order Arc oligomers. Thus, PKC phosphorylation of Arc may limit the full expression of LTD and may suppress the interneuronal transport of mRNAs. [ABSTRACT FROM AUTHOR]

Astrocytes, alongside oligodendrocytes and microglia, constitutes the glia tissues that accompany neurons. Given the significance and advancements in this field, this bibliographic review aims to in compile the information related to the structure and function of astrocytes. The review was conducted by searching for "astrocytes" in neurosciences journals at the cellular and molecular levels, such as "Glia", "Cells", and "Neuron", published within the last five years (2018-2023). The review encompasses the evolution of glia, types of astrocytes, and the structure and function of these cells. Additionally, it explores how astrocytes interact with other cells, as well as circulatory, immune, and neuroendocrine systems, highlighting their essential roles in metabolism, synaptogenesis, neuroplasticity, and neuroprotection. [ABSTRACT FROM AUTHOR]

BACKGROUND: Both sevoflurane and propofol have analgesic effects and exert neuroprotective effects by inhibiting neuronal apoptosis, but the specific mechanisms are not fully understood. OBJECTIVE: To study the effects of sevoflurane combined with propofol on pain mediators, nerve cell activity and mitogen activated protein kinase (MAPK)/ cAMP response element binding peotein (CREB) in rats with spinal cord fracture. METHODS: Of 80 SPF male Sprague-Dawley rats, 15 rats were randomly selected as healthy group and the remaining rats were used to make animal models of spinal cord fracture. During the modeling, five rats were dead unexpectedly. After successful modeling, 60 model rats were randomized into model group, sevoflurane group, propofol group, and combined group (sevoflurane+propofol), with 15 rats in each group. The rats in the sevoflurane group were placed in a closed experimental box, given an oxygen flow of 2 L/min, and inhaled 2% sevoflurane for 0.5 hours; the rats in the propofol group were injected with 2 mL/kg/h propofol through the tail vein for 4 hours; the rats in the combined group were given both propofol and sevoflurane interventions; and the rats in the healthy group and model group inhaled pure oxygen for 0.5 hours. Von Frey filament method was used to measure mechanical withdrawal threshold values. Hematoxylin-eosin staining was used to observe the pathological morphology of spinal cord tissue of rats. TUNEL was used to detect the apoptosis of neurons in spinal cord tissue of rats. Real-time PCR was used to detect the expression of p38MAPK and CREB mRNA. Western blot assay was used to detect the expression of p38MAPK, CREB, p-p38MAPK, and p75NTR proteins in spinal cord tissue of rats. RESULTS AND CONCLUSION: (1) Compared with the healthy group, the mechanical withdrawal threshold value was decreased in the other four groups at different time points (P < 0.05). Compared with the model group, the mechanical withdrawal threshold value was significantly increased in the sevoflurane, propofol, and combined groups at different time points (P < 0.05), especially in the combined group (P < 0.05). (2) In the model group, the white matter and central gray matter fused into a large cavity, and the white matter had a large number of vacuoles. In the sevoflurane and propofol groups, there were many cracks in the white matter and central gray matter and massive small vacuoles in the white matter. In the combined group, there were a few cracks in the white matter and central gray matter and a few vacuoles in the white matter. (3) The apoptosis rate of neurons in the model group was significantly higher than that in the sevoflurane, propofol, and combined groups (P < 0.05). The apoptosis rate of neurons was lowest in the combined group (P < 0.05). (4) Compared with the healthy group, the mRNA and protein levels of p38MAPK and CREB were significantly increased in the other four groups (P < 0.05), while the expression of p75NTR was significantly decreased (P < 0.05). Compared with the model group, the expression of p38MAPK mRNA and protein as well as the expression of p-p38MAPK protein decreased in the sevoflurane, propofol, and combined groups, while the expression of CREB mRNA and protein and the expression of p75NTR protein increased (P < 0.05). Changes in the expression of above mRNAs and proteins were most significant in the combined group (P < 0.05). (5) To conclude, sevoflurane combined with propofol can effectively improve neuropathic pain and inhibit neuronal apoptosis in rats with spinal cord fracture, which may be related to inhibiting the expression of p38MAPK and promoting the expression of CREB [ABSTRACT FROM AUTHOR]

The task is to determine the indices of phase synchronization between biological data extracted from neuronal activity and fluctuations in blood pressure and respiration, based on the calculation of instantaneous frequencies and phases using the synchrosqueezed wavelet analysis. Differences in synchronization indices between the analyzed data in two groups of rats (the control group and the group with experimentally induced colitis) were revealed. Pain exposure was found to be associated with frequency adjustment of the variability of the neuronal activity or the blood pressure, followed by the onset of phase synchronization. [ABSTRACT FROM AUTHOR]

Using a method based on averaging the conditional probabilities of recurrence intervals, a comparative analysis was performed to estimate the direction of coupling between different physiological rhythms (fluctuations in blood pressure, respiration, and neuronal activity in the reticular formation of the medulla oblongata) in two groups of anesthetized rats with or without painful stimulation. Different variants were observed for the directions of coupling between the rhythms. A statistically significant unidirectionality of coupling was detected with most of the data obtained from rats of the control group and rats with experimentally induced colitis. Painful stimulation did not affect the direction of coupling, but slightly reduced the amount of data with unidirectional coupling. Rhythms associated with the cardiovascular system (blood pressure variability) were controlled by rhythms of the respiratory system, and the respiratory rhythm controlled the variability of neuronal activity in the reticular formation of the medulla oblongata. [ABSTRACT FROM AUTHOR]