Excitatory Action Research Articles

Harnessing the power of natural alkaloids: the emergent role in epilepsy therapy.

The quest for effective epilepsy treatments has spotlighted natural alkaloids due to their broad neuropharmacological effects. This review provides a comprehensive analysis of the antiseizure properties of various natural compounds, with an emphasis on their mechanisms of action and potential therapeutic benefits. Our findings reveal that bioactive substances such as indole, quinoline, terpenoid, and pyridine alkaloids confer medicinal benefits by modulating synaptic interactions, restoring neuronal balance, and mitigating neuroinflammation-key factors in managing epileptic seizures. Notably, these compounds enhance GABAergic neurotransmission, diminish excitatory glutamatergic activities, particularly at NMDA receptors, and suppress proinflammatory pathways. A significant focus is placed on the strategic use of nanoparticle delivery systems to improve the solubility, stability, and bioavailability of these alkaloids, which helps overcome the challenges associated with crossing the blood-brain barrier (BBB). The review concludes with a prospective outlook on integrating these bioactive substances into epilepsy treatment regimes, advocating for extensive research to confirm their efficacy and safety. Advancing the bioavailability of alkaloids and rigorously assessing their toxicological profiles are essential to fully leverage the therapeutic potential of these compounds in clinical settings.

The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis.

A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. To understand how chronic hyperexcitability contributes to neuronal loss in MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I balance and increased vulnerability to inflammation-induced neurodegeneration. This revealed a prominent induction of the nuclear receptor NR4A2 in neurons. Mechanistically, NR4A2 increased susceptibility to excitotoxicity by stimulating continuous VGF secretion leading to glycolysis-dependent neuronal cell death. Extending these findings to people with MS (pwMS), we observed increased VGF levels in serum and brain biopsies. Notably, neuron-specific deletion of Vgf in a mouse model of MS ameliorated neurodegeneration. These findings underscore the detrimental effect of a persistent metabolic shift driven by excitatory activity as a fundamental mechanism in inflammation-induced neurodegeneration.

Analysis of the alpha activity envelope in electroencephalography in relation to the ratio of excitatory to inhibitory neural activity.

Alpha waves, one of the major components of resting and awake cortical activity in human electroencephalography (EEG), are known to show waxing and waning, but this phenomenon has rarely been analyzed. In the present study, we analyzed this phenomenon from the viewpoint of excitation and inhibition. The alpha wave envelope was subjected to secondary differentiation. This gave the positive (acceleration positive, Ap) and negative (acceleration negative, An) values of acceleration and their ratio (Ap-An ratio) at each sampling point of the envelope signals for 60 seconds. This analysis was performed on 36 participants with Alzheimer's disease (AD), 23 with frontotemporal dementia (FTD) and 29 age-matched healthy participants (NC) whose data were provided as open datasets. The mean values of the Ap-An ratio for 60 seconds at each EEG electrode were compared between the NC and AD/FTD groups. The AD (1.41 ±0.01 (SD)) and FTD (1.40 ±0.02) groups showed a larger Ap-An ratio than the NC group (1.38 ±0.02, p<0.05). A significant correlation between the envelope amplitude of alpha activity and the Ap-An ratio was observed at most electrodes in the NC group (Pearson's correlation coefficient, r = -0.92 ±0.15, mean for all electrodes), whereas the correlation was disrupted in AD (-0.09 ±0.21, p<0.05) and disrupted in the frontal region in the FTD group. The present method analyzed the envelope of alpha waves from a new perspective, that of excitation and inhibition, and it could detect properties of the EEG, Ap-An ratio, that have not been revealed by existing methods. The present study proposed a new method to analyze the alpha activity envelope in electroencephalography, which could be related to excitatory and inhibitory neural activity.

Evidence for peripheral and central actions of codeine to dysregulate swallowing in the anesthetized cat

Systemic administration of opioids has been associated with aspiration and swallow dysfunction in humans. We speculated that systemic administration of codeine would induce dysfunctional swallowing and that this effect would have a peripheral component. Experiments were conducted in spontaneously breathing, anesthetized cats. The animals were tracheotomized and electromyogram (EMG) electrodes were placed in upper airway and chest wall respiratory muscles for recording swallow related motor activity. The animals were allocated into three groups: vagal intact (VI), cervical vagotomy (CVx), and supra-nodose ganglion vagotomy (SNGx). A dose response to intravenous codeine was performed in each animal. Swallowing was elicited by injection of 3 mL of water into the oropharynx. The number of swallows after vehicle was significantly higher in the VI group than in SNGx. Codeine had no significant effect on the number of swallows induced by water in any of the groups. However, the magnitudes of water swallow-related EMGs of the thyropharyngeus muscle were significantly increased in the VI and CVx groups by 2–4 fold in a dose-related manner. In the CVx group, the geniohyoid muscle EMG during water swallows was significantly increased. There was a significant dose-related increase in spontaneous swallowing in each group from codeine. The spontaneous swallow number at the 10 mg/kg dose of codeine was significantly larger in the CVx group than that in the SNGx group. During water-evoked swallows, intravenous codeine increased upper airway motor drive in a dose-related manner, consistent with dysregulation. The data support the existence of both central and peripheral actions of codeine on spontaneous swallowing. At the highest dose of codeine, the reduced spontaneous swallow number in the SNGx group relative to CVx is consistent with a peripheral excitatory action of codeine either on pharyngeal/laryngeal receptors or in the nodose ganglion itself. The higher number of swallows in the CVx group than the VI group supports disinhibition of this behavior by elimination of inhibitory vagal sensory afferents.

Labile glutamate synaptic transmission in the adult CA1 stratum-lacunosum-moleculare region.

The excitatory monosynaptic activation of hippocampal CA1 pyramidal cells is spatially segregated such that the proximal part of the apical dendritic tree in stratum radiatum (SR) receives input from the hippocampal CA3 region while the distal part in the stratum-lacunosum-moleculare (SLM) receives input mainly from the entorhinal cortex. The AMPA receptor-mediated (AMPA) signalling of SLM synapses in slices from neonatal rats was previously found to considerably differ from that of the SR synapses. In the present study, AMPA signalling of SLM synapses in 1-month-old rats has been examined, that is, when the hippocampus is essentially functionally mature. For the SR synapses, this time is characterized by a facilitatory shift in short-term plasticity, in the disappearance of labile postsynaptic AMPA signalling, a property thought to be important for early activity-dependent organization of neural circuits, and the expression of an adult form of long-term potentiation. We found that the SLM synapses alter their short-term plasticity similarly to that of the SR synapses. However, the labile postsynaptic AMPA signalling was not only maintained but substantially enhanced in the SLM synapses. The long-term potentiation observed was not of the adult form but like that of the neonatal SR synapses based on unsilencing of AMPA labile synapses. We propose that these features of the SLM synapses in the mature hippocampus will help to produce a flexible map of the multimodal sensory input reaching the SLM required for its conjunctive operation with the SR input to generate a proper functional output from the CA1 region.

Noradrenaline and Adrenoreceptors Are Involved in the Regulation of Prostaglandin I2 Production in the Porcine Endometrium after Experimentally Induced Inflammation.

Endometritis is a common disease in animals, leading to disruption of reproductive processes and economic losses. Noradrenergic control of prostaglandin (PG)I2 formation by inflamed endometrium is unknown. We determined the involvement of α1-, α2- and β-adrenoreceptors (ARs) in noradrenaline-influenced PGI synthase (PGIS) protein abundance and PGI2 release from porcine (1) endometrial explants with Escherichia coli (E. coli)-induced inflammation in vivo, and (2) E. coli lipopolysaccharide (LPS)-treated endometrial epithelial cells. Experiment 1. E. coli suspension (E. coli group) or saline (CON group) was injected into the uterine horns. In both groups, noradrenaline increased endometrial PGIS abundance and PGI2 release versus the control values, and it was higher in the E. coli group than in the CON group. In the CON group, a noradrenaline stimulating effect on both parameters takes place through α1D-, α2C- and β2-ARs. In the E. coli group, noradrenaline increased PGIS abundance and PGI2 release via α1A-, α2(B,C)- and β(1,2)-ARs, and PGI2 release also by α2A-ARs. Experiment 2. LPS and noradrenaline augmented the examined parameters in endometrial epithelial cells versus the control value. In LPS-treated cells, β(1,2)-ARs mediate in noradrenaline excitatory action on PGIS protein abundance and PGI2 release. β3-ARs also contribute to PGI2 release. Under inflammatory conditions, noradrenaline via ARs increases PGI2 synthesis and release from the porcine endometrium, including epithelial cells. Our findings suggest that noradrenaline may indirectly affect processes regulated by PGI2 in the inflamed uterus.

Abnormal local cortical functional connectivity due to interneuron dysmaturation after neonatal intermittent hypoxia.

Premature infants often experience frequent hypoxic episodes due to immaturity of respiratory control that may result in disturbances of gray and white matter development and long-term cognitive and behavioral abnormalities. We hypothesize that neonatal intermittent hypoxia alters cortical maturation of excitatory and inhibitory circuits that can be detected early with functional MRI. C57BL/6 mouse pups were exposed to an intermittent hypoxia (IH) regimen consisting of 12 to 20 daily hypoxic episodes of 5% oxygen exposure for 2 min at 37C from P3 to P7, followed by MRI at P12 and electrophysiological recordings in cortical slices and in vivo at several time points between P7 and P13. Behavioral tests were conducted at P41-P50 to assess animal activity and motor learning. Adult mice after neonatal IH exhibited hyperactivity in open field test and impaired motor learning in complex wheel tasks. Patch clamp and evoked field potential electrophysiology revealed increased glutamatergic transmission accompanied by elevation of tonic inhibition. A decreased synaptic inhibitory drive was evidenced by miniature IPSC frequency on pyramidal cells, multi-unit activity recording in vivo in the motor cortex with selective GABA A receptor inhibitor picrotoxin injection, as well as by the decreased interneuron density at P13. There was also an increased tonic depolarizing effect of picrotoxin after IH on principal cells' membrane potential on patch clamp and direct current potential in extracellular recordings. The amplitude of low-frequency fluctuation on resting-state fMRI was larger, with a larger increase after picrotoxin injection in the IH group. Increased excitatory glutamatergic transmission, decreased numbers, and activity of inhibitory interneurons after neonatal IH may affect the maturation of connectivity in cortical networks, resulting in long-term cognitive and behavioral changes, including impaired motor learning and hyperactivity. Functional MRI reveals increased intrinsic connectivity in the sensorimotor cortex, suggesting neuronal dysfunction in cortical maturation after neonatal IH. The increased tonic inhibition, presumably due to tonic extrasynaptic GABA receptor drive, may be compensatory to the elevated excitatory glutamatergic transmission.

Epigenetic underpinnings of the autistic mind: Histone modifications and prefrontal excitation/inhibition imbalance.

Autism spectrum disorder (ASD) is complex neurobehavioral condition influenced by several cellular and molecular mechanisms that are often concerned with synaptogenesis and synaptic activity. Based on the excitation/inhibition (E/I) imbalance theory, ASD could be the result of disruption in excitatory and inhibitory synaptic transmission across the brain. The prefrontal cortex (PFC) is the chief regulator of executive function and can be affected by altered neuronal excitation and inhibition in the course of ASD. The molecular mechanisms involved in E/I imbalance are subject to epigenetic regulation. In ASD, altered enrichment and spreading of histone H3 and H4 modifications such as the activation-linked H3K4me2/3, H3K9ac, and H3K27ac, and repression-linked H3K9me2, H3K27me3, and H4K20me2 in the PFC result in dysregulation of molecules mediating synaptic excitation (ARC, EGR1, mGluR2, mGluR3, GluN2A, and GluN2B) and synaptic inhibition (BSN, EphA7, SLC6A1). Histone modifications are a dynamic component of the epigenetic regulatory elements with a pronounced effect on patterns of gene expression with regards to any biological process. The excitation/inhibition imbalance associated with ASD is based on the excitatory and inhibitory synaptic activity in different regions of the brain, including the PFC, the ultimate outcome of which is highly influenced by transcriptional activity of relevant genes.

Upregulated ECM genes and increased synaptic activity in Parkinson’s human DA neurons with PINK1/ PRKN mutations

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. Primary symptoms of PD arise with the loss of dopaminergic (DA) neurons in the Substantia Nigra Pars Compacta, but PD also affects the hippocampus and cortex, usually in its later stage. Approximately 15% of PD cases are familial with a genetic mutation. Two of the most associated genes with autosomal recessive (AR) early-onset familial PD are PINK1 and PRKN. In vitro studies of these genetic mutations are needed to understand the neurophysiological changes in patients’ neurons that may contribute to neurodegeneration. In this work, we generated and differentiated DA and hippocampal neurons from human induced pluripotent stem cells (hiPSCs) derived from two patients with a double mutation in their PINK1 and PRKN (one homozygous and one heterozygous) genes and assessed their neurophysiology compared to two healthy controls. We showed that the synaptic activity of PD neurons generated from patients with the PINK1 and PRKN mutations is impaired in the hippocampus and dopaminergic neurons. Mutant dopaminergic neurons had enhanced excitatory post-synaptic activity. In addition, DA neurons with the homozygous mutation of PINK1 exhibited more pronounced electrophysiological differences compared to the control neurons. Signaling network analysis of RNA sequencing results revealed that Focal adhesion and ECM receptor pathway were the top two upregulated pathways in the mutant PD neurons. Our findings reveal that the phenotypes linked to PINK1 and PRKN mutations differ from those from other PD mutations, suggesting a unique interplay between these two mutations that drives different PD mechanisms.

The feasibility of acupuncture on post-spinal cord injury treatment

Spinal cord injury (SCI) simultaneously causes multiple and interrelated pathophysiological disorders throughout the nervous system, hindering the development of effective treatment strategies. Mechanistically, SCI triggers excitatory signaling activation, downregulation of the inhibitory system, neuronal death, followed by the development of new synaptic circuits and reorganization, leading to chronic neurological dysfunctions and mental disorders. Therefore, a simultaneous treatment strategy, known as overlapping treatment, is needed. Over decades, both preclinical and clinical studies have established that acupuncture treatment offers neuroprotection, pain attenuation, improvement of functional recovery, and promotes reward behaviors, suggesting potential roles of acupuncture in post-SCI treatment. Recently, the importance of overlapping treatment has been recognized in developing effective treatments for post-SCI pathophysiology. However, there has been no systematic study investigating the role of acupuncture in various SCI pathophysiology. In this review, we briefly address the mechanisms of post-SCI pathophysiology and discuss the potential therapeutic effects of acupuncture, suggesting its feasibility as a treatment for post-SCI pathophysiology.

Activation and depression of neural and hemodynamic responses induced by the intracortical microstimulation and visual stimulation in the mouse visual cortex.

Objective. Intracortical microstimulation (ICMS) can be an effective method for restoring sensory perception in contemporary brain-machine interfaces. However, the mechanisms underlying better control of neuronal responses remain poorly understood, as well as the relationship between neuronal activity and other concomitant phenomena occurring around the stimulation site.Approach. Different microstimulation frequencies were investigatedin vivoon Thy1-GCaMP6s mice using widefield and two-photon imaging to evaluate the evoked excitatory neural responses across multiple spatial scales as well as the induced hemodynamic responses. Specifically, we quantified stimulation-induced neuronal activation and depression in the mouse visual cortex and measured hemodynamic oxyhemoglobin and deoxyhemoglobin signals using mesoscopic-scale widefield imaging.Main results. Our calcium imaging findings revealed a preference for lower-frequency stimulation in driving stronger neuronal activation. A depressive response following the neural activation preferred a slightly higher frequency stimulation compared to the activation. Hemodynamic signals exhibited a comparable spatial spread to neural calcium signals. Oxyhemoglobin concentration around the stimulation site remained elevated during the post-activation (depression) period. Somatic and neuropil calcium responses measured by two-photon microscopy showed similar dependence on stimulation parameters, although the magnitudes measured in soma was greater than in neuropil. Furthermore, higher-frequency stimulation induced a more pronounced activation in soma compared to neuropil, while depression was predominantly induced in soma irrespective of stimulation frequencies.Significance. These results suggest that the mechanism underlying depression differs from activation, requiring ample oxygen supply, and affecting neurons. Our findings provide a novel understanding of evoked excitatory neuronal activity induced by ICMS and offer insights into neuro-devices that utilize both activation and depression phenomena to achieve desired neural responses.

Sexual differences in neuronal and synaptic properties across subregions of the mouse insular cortex

BackgroundThe insular cortex (IC) plays a pivotal role in processing interoceptive and emotional information, offering insights into sex differences in behavior and cognition. The IC comprises two distinct subregions: the anterior insular cortex (aIC), that processes emotional and social signals, and the posterior insular cortex (pIC), specialized in interoception and perception of pain. Pyramidal projection neurons within the IC integrate multimodal sensory inputs, influencing behavior and cognition. Despite previous research focusing on neuronal connectivity and transcriptomics, there has been a gap in understanding pyramidal neurons characteristics across subregions and between sexes.MethodsAdult male and female C57Bl/6J mice were sacrificed and tissue containing the IC was collected for ex vivo slice electrophysiology recordings that examined baseline sex differences in synaptic plasticity and transmission within aIC and pIC subregions.ResultsClear differences emerged between aIC and pIC neurons in both males and females: aIC neurons exhibited distinctive features such as larger size, increased hyperpolarization, and a higher rheobase compared to their pIC counterparts. Furthermore, we observed variations in neuronal excitability linked to sex, with male pIC neurons displaying a greater level of excitability than their female counterparts. We also identified region-specific differences in excitatory and inhibitory synaptic activity and the balance between excitation and inhibition in both male and female mice. Adult females demonstrated greater synaptic strength and maximum response in the aIC compared to the pIC. Lastly, synaptic long-term potentiation occurred in both subregions in males but was specific to the aIC in females.ConclusionsWe conclude that there are sex differences in synaptic plasticity and excitatory transmission in IC subregions, and that distinct properties of IC pyramidal neurons between sexes could contribute to differences in behavior and cognition between males and females.

Transplantation of dorsal root ganglia overexpressing the NaChBac sodium channel improves locomotion after complete SCI

Spinal cord injury (SCI) is a debilitating condition currently lacking treatment. Severe SCI causes the loss of most supraspinal inputs and neuronal activity caudal to the injury, which, coupled with the limited endogenous capacity for spontaneous regeneration, can lead to complete functional loss even in anatomically incomplete lesions. We hypothesized that transplantation of mature dorsal root ganglia (DRG), genetically modified to express the NaChBac sodium channel, could serve as a therapeutic option for functionally complete SCI. We found that NaChBac expression increased the intrinsic excitability of DRG neurons, promoted cell survival and neurotrophic factor secretion in vitro. Transplantation of NaChBac-expressing dissociated DRGs improved voluntary locomotion seven weeks after injury compared to control groups. Animals transplanted with NaChBac-expressing DRGs also possessed higher tubulin-positive neuronal fiber and myelin preservation, although serotonergic descending fibers remained unaffected. We observed early preservation of the corticospinal tract fourteen days after injury and transplantation which was lost seven weeks after injury. Nevertheless, transplantation of NaChBac-expressing DRGs increased the neuronal excitatory input, by increased number of VGlut2 contacts, immediately caudal to the injuries. Our work suggests that the transplantation of NaChBac-expressing dissociated DRGs can rescue significant motor function retaining an excitatory neuronal relay activity immediately caudal to injury.

Visual Deprivation during Mouse Critical Period Reorganizes Network-Level Functional Connectivity.

A classic example of experience-dependent plasticity is ocular dominance (OD) shift, in which the responsiveness of neurons in the visual cortex is profoundly altered following monocular deprivation (MD). It has been postulated that OD shifts also modify global neural networks, but such effects have never been demonstrated. Here, we use wide-field fluorescence optical imaging (WFOI) to characterize calcium-based resting-state functional connectivity during acute (3 d) MD in female and male mice with genetically encoded calcium indicators (Thy1-GCaMP6f). We first establish the fundamental performance of WFOI by computing signal to noise properties throughout our data processing pipeline. Following MD, we found that Δ band (0.4-4 Hz) GCaMP6 activity in the deprived visual cortex decreased, suggesting that excitatory activity in this region was reduced by MD. In addition, interhemispheric visual homotopic functional connectivity decreased following MD, which was accompanied by a reduction in parietal and motor homotopic connectivity. Finally, we observed enhanced internetwork connectivity between the visual and parietal cortex that peaked 2 d after MD. Together, these findings support the hypothesis that early MD induces dynamic reorganization of disparate functional networks including the association cortices.

Mitochondrial Dysfunction as the Major Basis of Brain Aging.

The changes in the properties of three biological events that occur with cerebral aging are discussed. These adverse changes already begin to develop early in mid-life and gradually become more pronounced with senescence. Essentially, they are reflections of the progressive decline in effectiveness of key processes, resulting in the deviation of essential biochemical trajectories to ineffective and ultimately harmful variants of these programs. The emphasis of this review is the major role played by the mitochondria in the transition of these three important processes toward more deleterious variants as brain aging proceeds. The immune system: the shift away from an efficient immune response to a more unfocused, continuing inflammatory condition. Such a state is both ineffective and harmful. Reactive oxygen species are important intracellular signaling systems. Additionally, microglial phagocytic activity utilizing short lived reactive oxygen species contribute to the removal of aberrant or dead cells and bacteria. These processes are transformed into an excessive, untargeted, and persistent generation of pro-oxidant free radicals (oxidative stress). The normal efficient neural transmission is modified to a state of undirected, chronic low-level excitatory activity. Each of these changes is characterized by the occurrence of continuous activity that is inefficient and diffused. The signal/noise ratio of several critical biological events is thus reduced as beneficial responses are gradually replaced by their impaired and deleterious variants.

Impaired long-range excitatory time scale predicts abnormal neural oscillations and cognitive deficits in Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is the most common form of dementia, progressively impairing cognitive abilities. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify global abnormal biophysical mechanisms underlying the spatial and spectral electrophysiological patterns in AD, we estimated the parameters of a biophysical spectral graph model (SGM).MethodsSGM is an analytic neural mass model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. Unlike other coupled neuronal mass models, the SGM is linear, available in closed-form, and parameterized by a small set of biophysical interpretable global parameters. This facilitates their rapid and unambiguous inference which we performed here on a well-characterized clinical population of patients with AD (N = 88, age = 62.73 +/- 8.64 years) and a cohort of age-matched controls (N = 88, age = 65.07 +/- 9.92 years).ResultsPatients with AD showed significantly elevated long-range excitatory neuronal time scales, local excitatory neuronal time scales and local inhibitory neural synaptic strength. The long-range excitatory time scale had a larger effect size, compared to local excitatory time scale and inhibitory synaptic strength and contributed highest for the accurate classification of patients with AD from controls. Furthermore, increased long-range time scale was associated with greater deficits in global cognition.ConclusionsThese results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the local spectral signatures and cognition in the human brain, and how it might be a parsimonious factor underlying altered neuronal activity in AD. Our findings provide new insights into mechanistic links between abnormal local spectral signatures and global connectivity measures in AD.

Silencing CA1 pyramidal cells output reveals the role of feedback inhibition in hippocampal oscillations

The precise temporal coordination of neural activity is crucial for brain function. In the hippocampus, this precision is reflected in the oscillatory rhythms observed in CA1. While it is known that a balance between excitatory and inhibitory activity is necessary to generate and maintain these oscillations, the differential contribution of feedforward and feedback inhibition remains ambiguous. Here we use conditional genetics to chronically silence CA1 pyramidal cell transmission, ablating the ability of these neurons to recruit feedback inhibition in the local circuit, while recording physiological activity in mice. We find that this intervention leads to local pathophysiological events, with ripple amplitude and intrinsic frequency becoming significantly larger and spatially triggered local population spikes locked to the trough of the theta oscillation appearing during movement. These phenotypes demonstrate that feedback inhibition is crucial in maintaining local sparsity of activation and reveal the key role of lateral inhibition in CA1 in shaping circuit function.

Dysregulation of extracellular potassium distinguishes healthy ageing from neurodegeneration.

Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal ageing. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis is a potential mediator of neuronal injury as K+ elevations increase excitatory activity. The dysregulation of extracellular K+ and potassium channel expressions during neurodegeneration could contribute to this distinction. Here we measured the cortical extracellular K+ concentration ([K+]e) in awake wild-type mice as well as murine models of neurodegeneration using K+-sensitive microelectrodes. Unexpectedly, aged wild-type mice exhibited significantly lower cortical [K+]e than young mice. In contrast, cortical [K+]e was consistently elevated in Alzheimer's disease (APP/PS1), amyotrophic lateral sclerosis (ALS) (SOD1G93A) and Huntington's disease (R6/2) models. Cortical resting [K+]e correlated inversely with neuronal density and the [K+]e buffering rate but correlated positively with the predicted neuronal firing rate. Screening of astrocyte-selective genomic datasets revealed a number of potassium channel genes that were downregulated in these disease models but not in normal ageing. In particular, the inwardly rectifying potassium channel Kcnj10 was downregulated in ALS and Huntington's disease models but not in normal ageing, while Fxyd1 and Slc1a3, each of which acts as a negative regulator of potassium uptake, were each upregulated by astrocytes in both Alzheimer's disease and ALS models. Chronic elevation of [K+]e in response to changes in gene expression and the attendant neuronal hyperexcitability may drive the neuronal loss characteristic of these neurodegenerative diseases. These observations suggest that the dysregulation of extracellular K+ homeostasis in a number of neurodegenerative diseases could be due to aberrant astrocytic K+ buffering and as such, highlight a fundamental role for glial dysfunction in neurodegeneration.

Neuromodulator regulation and emotions: insights from the crosstalk of cell signaling.

The unraveling of the regulatory mechanisms that govern neuronal excitability is a major challenge for neuroscientists worldwide. Neurotransmitters play a critical role in maintaining the balance between excitatory and inhibitory activity in the brain. The balance controls cognitive functions and emotional responses. Glutamate and γ-aminobutyric acid (GABA) are the primary excitatory and inhibitory neurotransmitters of the brain, respectively. Disruptions in the balance between excitatory and inhibitory transmission are implicated in several psychiatric disorders, including anxiety disorders, depression, and schizophrenia. Neuromodulators such as dopamine and acetylcholine control cognition and emotion by regulating the excitatory/inhibitory balance initiated by glutamate and GABA. Dopamine is closely associated with reward-related behaviors, while acetylcholine plays a role in aversive and attentional behaviors. Although the physiological roles of neuromodulators have been extensively studied neuroanatomically and electrophysiologically, few researchers have explored the interplay between neuronal excitability and cell signaling and the resulting impact on emotion regulation. This review provides an in-depth understanding of "cell signaling crosstalk" in the context of neuronal excitability and emotion regulation. It also anticipates that the next generation of neurochemical analyses, facilitated by integrated phosphorylation studies, will shed more light on this topic.

Epigenome-wide association study on methamphetamine dependence.

Repeated abuse of methamphetamine (METH) can cause dependence, repeated relapse of psychotic symptoms, compulsive drug-seeking behaviour, and various neurological symptoms. These long-term biological changes may be associated with epigenetic mechanisms; however, the association between METH use and epigenetic mechanisms has been poorly investigated. Thus, we performed an epigenome-wide association study of METH dependence using genomic DNA extracted from the blood samples of 24 patients with METH dependence and 24 normal controls. All participants were of Japanese descent. We tested the association between METH dependence and DNA methylation using linear regression analysis. We found epigenome-wide significant associations at four CpG sites, one of which occurred in the CNOT1 gene and another in the PUM1 gene. We especially noted the CNOT1 and PUM1 genes as well as several other genes that indicated some degree of association with METH dependence. Among the relatively enriched Gene Ontology terms, we were interested in terms of mRNA metabolism, respirasome, and excitatory extracellular ligand-gated ion channel activity. Among the relatively enriched Kyoto Encyclopedia of Genes and Genome pathways, we noted pathways of several neurological diseases. Our results indicate that genetic changes akin to those in other psychiatric or neurodegenerative disorders may also occur via epigenetic mechanisms in patients with METH dependence.