Regulation Of Neuronal Activity Research Articles

The Application Progress of Optogenetics in Neuroscience and Behavioral Studies

Optogenetics, as an emerging interdisciplinary technology, has enabled the precise manipulation of neuronal activity by combining optical and genetic approaches. This paper summarizes the application of optogenetics in neuroscience and behavioral research and introduces its research background and topics. The application of optogenetics in neuronal activity regulation, neural loop resolution, exploration of learning and memory mechanisms, and treating neurological diseases were focused on. By combining a literature review and case analysis, we analyze the core principles of optogenetics and the technical points of optogenetics and demonstrate their potential applications in different research scenarios. The types and properties of photosensitive proteins and their application strategies in experiments are detailed, demonstrating the unique advantages of optogenetics in revealing the mysteries of neurobiological processes. The results show that optogenetic technology provides a powerful tool to reveal the mysteries of neurobiological processes, but it still faces challenges such as light transmission efficiency and gene delivery safety in practical applications. This paper summarizes the advantages and limitations of optogenetics and prospects for its future direction, providing an important reference for the continuous development of neuroscience and behavioral research.

Effect of calcium ions on the aggregation of highly phosphorylated tau

Tau is typically an axonal protein, but in neurons of brains affected by Alzheimer's disease (AD), aggregation of hyperphosphorylated tau in the somatodendritic compartment causes neuronal death. We have previously demonstrated that tau mRNA is transported within dendrites and undergoes immediate translation and hyperphosphorylation of AD epitopes in response to NMDA receptor stimulation. Although this explains the emergence of hyperphosphorylated tau in dendrites, the relationship between tau hyperphosphorylation and aggregation is not well understood. In this study, we found that recombinant highly phosphorylated tau purified from NG108-15 rodent neuroblastoma/glioma cells transfected with both tau and GSK3β expression vectors bound calcium ions and formed sarkosyl-insoluble aggregates. In addition, thioflavin T analysis revealed that this highly phosphorylated tau tended to aggregate on its own, further facilitated by calcium ions. When NG108-15 cells expressing the highly phosphorylated tau were treated with calcium ionophore, sarkosyl-insoluble tau was generated. Interestingly, these cells exhibited resistance to both calcium ionophore-induced cytotoxicity and glutamate-induced excitotoxicity. We further found that sarkosyl-insoluble phosphorylated tau was increased in cultured hippocampal neurons due to glutamate-induced hyperactivity. Our data suggest that hyperphosphorylated tau synthesized in response to NMDA receptor stimulation contributes to regulation of neuronal activity by binding calcium ions, but that this calcium binding may cause tau to adopt an aggregated form.

Reduction in the olfactory ability in aging Mitf mutant mice without evidence of neurodegeneration.

Age-related decline occurs in most brain structures and sensory systems. An illustrative case is olfaction. The olfactory bulb (OB) undergoes deterioration with age, resulting in reduced olfactory ability. A decline in olfaction is also associated with early symptoms of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). However, the underlying reasons are unclear. The microphthalmia-associated transcription factor (MITF) is expressed in the projection neurons (PNs) of the OB-the mitral and tufted (M/T) cells. Primary M/T cells from Mitf mutant mice show hyperactivity, potentially attributed to the reduced expression of a key potassium channel subunit, Kcnd3/Kv4.3. This influences intrinsic plasticity, an essential mechanism involving the non-synaptic regulation of neuronal activity. As neuronal hyperactivity often precedes neurodegenerative conditions, the current study aimed to determine whether the absence of Mitf causes degenerative effects during aging. Aged Mitf mutant mice showed reduced olfactory ability without inflammation. However, an increase in the expression of potassium channel subunit genes in the OBs of aged Mitf mi-vga9/mi-vga9 mice suggests that during aging, compensatory mechanisms lead to stabilization.

Increased understanding of complex neuronal circuits in the cerebellar cortex.

The prevailing belief has been that the fundamental structures of cerebellar neuronal circuits, consisting of a few major neuron types, are simple and well understood. Given that the cerebellum has long been known to be crucial for motor behaviors, these simple yet organized circuit structures seemed beneficial for theoretical studies proposing neural mechanisms underlying cerebellar motor functions and learning. On the other hand, experimental studies using advanced techniques have revealed numerous structural properties that were not traditionally defined. These include subdivided neuronal types and their circuit structures, feedback pathways from output Purkinje cells, and the multidimensional organization of neuronal interactions. With the recent recognition of the cerebellar involvement in non-motor functions, it is possible that these newly identified structural properties, which are potentially capable of generating greater complexity than previously recognized, are associated with increased information capacity. This, in turn, could contribute to the wide range of cerebellar functions. However, it remains largely unknown how such structural properties contribute to cerebellar neural computations through the regulation of neuronal activity or synaptic transmissions. To promote further research into cerebellar circuit structures and their functional significance, we aim to summarize the newly identified structural properties of the cerebellar cortex and discuss future research directions concerning cerebellar circuit structures and their potential functions.

Altered Neuronal Activity Patterns of the Prefrontal Cortex in Alzheimer's Disease After Transcranial Alternating Current Stimulation: A Resting-State fMRI Study.

Transcranial alternating current stimulation (tACS) could improve cognition in patients with Alzheimer's disease (AD). However, the effects of tACS on brain activity remain unclear. The purpose is to investigate the change in regional neuronal activity after tACS in AD patients employing resting-state functional magnetic resonance imaging (rs-fMRI). A total of 46 patients with mild AD were enrolled. Each patient received 30 one-hour sessions of real or sham tACS for three weeks (clinical trial: NCT03920826). The fractional amplitude of low-frequency fluctuations (fALFF) and the regional homogeneity (ReHo) measured by rs-fMRI were calculated to evaluate the regional brain activity. Compared to baseline, AD patients in the real group exhibited increased fALFF in the left middle frontal gyrus-orbital part and right inferior frontal gyrus-orbital part, as well as increased ReHo in the left precentral gyrus and right middle frontal gyrus at the end of intervention. At the 3-month follow-up, fALFF increased in the left superior parietal lobule and right inferior temporal gyrus, as well as ReHo, in the left middle frontal gyrus and right superior medial frontal gyrus. A higher fALFF in the right lingual gyrus and ReHo in the right parahippocampal gyrus were observed in the response group than in the nonresponse group. The findings demonstrated the beneficial effects of tACS on the neuronal activity of the prefrontal cortex and even more extensive regions and provided a neuroimaging biomarker of treatment response in AD patients.

Dimensionality reduction of neuronal degeneracy reveals two interfering physiological mechanisms.

Neuronal systems maintain stable functions despite large variability in their physiological components. Ion channel expression, in particular, is highly variable in neurons exhibiting similar electrophysiological phenotypes, which raises questions regarding how specific ion channel subsets reliably shape intrinsic properties of neurons. Here, we use detailed conductance-based modeling to explore how stable neuronal function is achieved despite variability in channel composition among neurons. Using dimensionality reduction, we uncover two principal dimensions in the channel conductance space that capture most of the variance of the observed variability. These two dimensions correspond to two sources of variability that originate from distinct physiologically relevant mechanisms underlying the regulation of neuronal activity, providing quantitative insights into how channel composition is linked to the electrophysiological activity of neurons. These insights allow us to understand and design a model-independent, reliable neuromodulation rule for variable neuronal populations.

Acute elevated dietary fat alone is not sufficient to decrease AgRP projections in the paraventricular nucleus of the hypothalamus in mice

Within the brain, the connections between neurons are constantly changing in response to environmental stimuli. A prime environmental regulator of neuronal activity is diet, and previous work has highlighted changes in hypothalamic connections in response to diets high in dietary fat and elevated sucrose. We sought to determine if the change in hypothalamic neuronal connections was driven primarily by an elevation in dietary fat alone. Analysis was performed in both male and female animals. We measured Agouti-related peptide (AgRP) neuropeptide and Synaptophysin markers in the paraventricular nucleus of the hypothalamus (PVH) in response to an acute 48 h high fat diet challenge. Using two image analysis methods described in previous studies, an effect of a high fat diet on AgRP neuronal projections in the PVH of male or female mice was not identified. These results suggest that it may not be dietary fat alone that is responsible for the previously published alterations in hypothalamic connections. Future work should focus on deciphering the role of individual macronutrients on neuroanatomical and functional changes.

Slack K+ channels confer protection against myocardial ischemia/reperfusion injury.

Na+-activated Slack potassium (K+) channels are increasingly recognized as regulators of neuronal activity, yet little is known about their role in the cardiovascular system. Slack activity increases when intracellular Na+ concentration ([Na+]i) reaches pathophysiological levels. Elevated [Na+]i is a major determinant of the ischemia and reperfusion (I/R)-induced myocardial injury, thus we hypothesized that Slack plays a role under these conditions. and results: K+ currents in cardiomyocytes (CMs) obtained from wildtype (WT) but not from global Slack knockout (KO) mice were sensitive to electrical inactivation of voltage-sensitive Na+-channels. Live-cell imaging demonstrated that K+ fluxes across the sarcolemma rely on Slack, while the depolarized resting membrane potential in Slack-deficient CMs led to excessive cytosolic Ca2+ accumulation and finally to hypoxia/reoxygenation-induced cell death. Cardiac damage in an in vivo model of I/R was exacerbated in global and CM-specific conditional Slack mutants and largely insensitive to mechanical conditioning maneuvers. Finally, the protection conferred by mitochondrial ATP-dependent K+ channels required functional Slack in CMs. Collectively, our study provides evidence for Slack's crucial involvement in the ion homeostasis of no or low O2-stressed CMs. Thereby, Slack activity opposes the I/R-induced fatal Ca2+-uptake to CMs supporting the cardioprotective signaling widely attributed to mitoKATP function.

Myelin modulates the process of isoflurane anesthesia through the regulation of neural activity.

The mechanism underlying the reversible unconsciousness induced by general anesthetics (GA) remains unclear. Recent studies revealed the critical roles of myelin and oligodendrocytes (OLs) in higher functions of the brain. However, it is unknown whether myelin actively participates in the regulation of GA. The aim of this study is to investigate the roles and possible mechanisms of myelin in the regulation of consciousness alterations induced by isoflurane anesthesia. First, demyelination models for the entire brain and specific neural nuclei were established to investigate the potential role of myelination in the regulation of GA, as well as its possible regional specificity. c-Fos staining was then performed on the demyelinated nuclei to verify the impact of myelin loss on neuronal activity. Finally, the activity of neurons during isoflurane anesthesia in demyelinated mice was recorded by optical fiber photometric calcium signal. The related behavioral indicators and EEG were recorded and analyzed. A prolonged emergence time was observed from isoflurane anesthesia in demyelinated mice, which suggested the involvement of myelin in regulating GA. The demyelination in distinct nuclei by LPC further clarified the region-specific roles of isoflurane anesthesia regulation by myelin. The effect of demyelination on isoflurane anesthesia in the certain nucleus was consistent with that in neurons towards isoflurane anesthesia. Finally, we found that the mechanism of myelin in the modulation of isoflurane anesthesia is possibly through the regulation of neuronal activity. In brief, myelin in the distinct neural nucleus plays an essential role in regulating the process of isoflurane anesthesia. The possible mechanism of myelin in the regulation of isoflurane anesthesia is neuronal activity modification by myelin integrity during GA. Our findings enhanced the comprehension of myelin function, and offered a fresh perspective for investigating the neural mechanisms of GA.

Nucleus accumbens myocyte enhancer factor 2C mediates the maintenance of peripheral nerve injury-induced physiological and behavioral maladaptations.

Preclinical and clinical work has demonstrated altered plasticity and activity in the nucleus accumbens (NAc) under chronic pain states, highlighting critical therapeutic avenues for the management of chronic pain conditions. In this study, we demonstrate that myocyte enhancer factor 2C (MEF2C), a master regulator of neuronal activity and plasticity, is repressed in NAc neurons after prolonged spared nerve injury (SNI). Viral-mediated overexpression of Mef2c in NAc neurons partially ameliorated sensory hypersensitivity and emotional behaviors in mice with SNI, while also altering transcriptional pathways associated with synaptic signaling. Mef2c overexpression also reversed SNI-induced potentiation of phasic dopamine release and neuronal hyperexcitability in the NAc. Transcriptional changes induced by Mef2c overexpression were different than those observed after desipramine treatment, suggesting a mechanism of action different from antidepressants. Overall, we show that interventions in MEF2C-regulated mechanisms in the NAc are sufficient to disrupt the maintenance of chronic pain states, providing potential new treatment avenues for neuropathic pain.

Astrocyte regulation of extracellular space parameters across the sleep-wake cycle.

Multiple subfields of neuroscience research are beginning to incorporate astrocytes into current frameworks of understanding overall brain physiology, neuronal circuitry, and disease etiology that underlie sleep and sleep-related disorders. Astrocytes have emerged as a dynamic regulator of neuronal activity through control of extracellular space (ECS) volume and composition, both of which can vary dramatically during different levels of sleep and arousal. Astrocytes are also an attractive target of sleep research due to their prominent role in the glymphatic system, a method by which toxic metabolites generated during wakefulness are cleared away. In this review we assess the literature surrounding glial influences on fluctuations in ECS volume and composition across the sleep-wake cycle. We also examine mechanisms of astrocyte volume regulation in glymphatic solute clearance and their role in sleep and wake states. Overall, findings highlight the importance of astrocytes in sleep and sleep research.

Enhanced transport of brain interstitial solutes mediated by stimulation of sensorimotor area in rats.

Solute transport in the brain is essential for maintaining cerebral homeostasis. Recent studies have shown that neuronal activity enhances the transport of cerebrospinal fluid solutes, but its impact on interstitial solute transport has not been established. In this study, we investigated whether neuronal activity affects the transport of interstitial solutes. Fluorescent Texas Red ovalbumin was injected intracortically into the unilateral sensorimotor area of the Sprague-Dawley rats. Regional neuronal activity around the injection site was elicited by transdermal electrical stimulation of a corresponding forelimb for 90 min ( n = 6). The control group of rats ( n = 6) did not receive any electrical stimulation. Subsequently, the spatial distributions of the tracer over the cortical surface and from the brain sections were imaged and compared between two groups. The ovalbumin fluorescence from the cervical lymph nodes was also compared between the groups to evaluate the effect of neuronal activity on solute clearance from the brain. Tracer distribution over the brain surface/sections revealed a significantly higher uptake of ovalbumin in the hemisphere ipsilateral to the injection among the stimulated animals compared to the unstimulated group. This difference, however, was not seen in the hemisphere contralateral to injection. A trace amount of ovalbumin in the lymph nodes was equivalent between the groups, which indicated a considerable time needed for interstitial solutes to be drained from the brain. The results suggest that neuronal activity enhances interstitial solute transport, calling for further examination of ultimate routes and mechanisms for brain solute clearance.

Soft Bioelectronics Using Nanomaterials and Nanostructures for Neuroengineering.

The identification of neural networks for large areas and the regulation of neuronal activity at the single-neuron scale have garnered considerable attention in neuroscience. In addition, detecting biochemical molecules and electrically, optically, and chemically controlling neural functions are key research issues. However, conventional rigid and bulky bioelectronics face challenges for neural applications, including mechanical mismatch, unsatisfactory signal-to-noise ratio, and poor integration of multifunctional components, thereby degrading the sensing and modulation performance, long-term stability and biocompatibility, and diagnosis and therapy efficacy. Implantable bioelectronics have been developed to be mechanically compatible with the brain environment by adopting advanced geometric designs and utilizing intrinsically stretchable materials, but such advances have not been able to address all of the aforementioned challenges.Recently, the exploration of nanomaterial synthesis and nanoscale fabrication strategies has facilitated the design of unconventional soft bioelectronics with mechanical properties similar to those of neural tissues and submicrometer-scale resolution comparable to typical neuron sizes. The introduction of nanotechnology has provided bioelectronics with improved spatial resolution, selectivity, single neuron targeting, and even multifunctionality. As a result, this state-of-the-art nanotechnology has been integrated with bioelectronics in two main types, i.e., bioelectronics integrated with synthesized nanomaterials and bioelectronics with nanoscale structures. The functional nanomaterials can be synthesized and assembled to compose bioelectronics, allowing easy customization of their functionality to meet specific requirements. The unique nanoscale structures implemented with the bioelectronics could maximize the performance in terms of sensing and stimulation. Such soft nanobioelectronics have demonstrated their applicability for neuronal recording and modulation over a long period at the intracellular level and incorporation of multiple functions, such as electrical, optical, and chemical sensing and stimulation functions.In this Account, we will discuss the technical pathways in soft bioelectronics integrated with nanomaterials and implementing nanostructures for application to neuroengineering. We traced the historical development of bioelectronics from rigid and bulky structures to soft and deformable devices to conform to neuroengineering requirements. Recent approaches that introduced nanotechnology into neural devices enhanced the spatiotemporal resolution and endowed various device functions. These soft nanobioelectronic technologies are discussed in two categories: bioelectronics with synthesized nanomaterials and bioelectronics with nanoscale structures. We describe nanomaterial-integrated soft bioelectronics exhibiting various functionalities and modalities depending on the integrated nanomaterials. Meanwhile, soft bioelectronics with nanoscale structures are explained with their superior resolution and unique administration methods. We also exemplified the neural sensing and stimulation applications of soft nanobioelectronics across various modalities, showcasing their clinical applications in the treatment of neurological diseases, such as brain tumors, epilepsy, and Parkinson's disease. Finally, we discussed the challenges and direction of next-generation technologies.

WNK-SPAK-NKCC1-KCC2 pathway in SCN: a novel regulator of neuronal activity

Background: The suprachiasmatic nucleus (SCN) plays a vital role in regulating an organism's physiological and behavioral processes by synchronizing them with the light-dark cycle. The SCN receives GABAergic inputs that may be excitatory or inhibitory, depending on the intracellular chloride concentration ([Cl−]i) that is regulated by NKCC1 and KCC2 cotransporters, determined by the WNK-SPAK/OSR1 phosphorylation pathway. Our study aimed to investigate the role of the WNK-SPAK-NKCC1-KCC pathway in regulating SCN neuronal activity.Methods: First, we perform an in silico analysis to determine the expression of the genes involved in this pathway. Furthermore, the expression of the proteins was confirmed by an immunofluorescence assay. Next, to determine if the WNK-SPAK-NKCC1-KCC2 pathway affects neuronal activity in the SCN we performed the immunohistochemical analysis of c-Fos expression in the SCN at ZT2 and ZT14 in the SPAK-KI mice. Finally, to find out if the change in SCN neuronal activity between day and night is related to pathway activity, we performed an immunofluorescence study. Results: We observed that various genes governing the pathway's regulation exhibit oscillations not only in neurons but also in other cell types. Remarkably, SPAK-KI mice displayed a significant surge in neuronal activity at ZT2 when contrasted with the control group. Additionally, we detected increased phosphorylation levels of WNK, SPAK, NKCC1, and KCC2 isoforms at ZT14 as compared to ZT2.Conclusions: Our study highlights the role of SPAK kinase in regulating SCN neuronal activity and suggests that the pathway is active during the dark period, leading to an increase in [Cl−]i during the day, as previously reported. The authors are supported by grants from CONACyT Mexico no. 87794, and from PAPIIT UNAM no IA208522 and IN223324. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Functional Analyses of Four Cryptochromes From Aquatic Organisms After Heterologous Expression in Drosophila melanogaster Circadian Clock Cells.

Cryptochromes (Crys) represent a multi-facetted class of proteins closely associated with circadian clocks. They have been shown to function as photoreceptors but also to fulfill light-independent roles as transcriptional repressors within the negative feedback loop of the circadian clock. In addition, there is evidence for Crys being involved in light-dependent magneto-sensing, and regulation of neuronal activity in insects, adding to the functional diversity of this cryptic protein class. In mammals, Crys are essential components of the circadian clock, but their role in other vertebrates is less clear. In invertebrates, Crys can function as circadian photoreceptors, or as components of the circadian clock, while in some species, both light-receptive and clock factor roles coexist. In the current study, we investigate the function of Cry proteins in zebrafish (Danio rerio), a freshwater teleost expressing 6 cry genes. Zebrafish peripheral circadian clocks are intrinsically light-sensitive, suggesting the involvement of Cry in light-resetting. Echinoderms (Strongylocentrotus purpuratus) represent the only class of deuterostomes that possess an orthologue (SpuCry) of the light-sensitive Drosophila melanogaster Cry, which is an important component of the light-resetting pathway, but also works as transcriptional repressor in peripheral clocks of fruit flies. We therefore investigated the potential of different zebrafish cry genes and SpuCry to replace the light-resetting and repressor functions of Drosophila Cry by expressing them in fruit flies lacking endogenous cry function. Using various behavioral and molecular approaches, we show that most Cry proteins analyzed are able to fulfill circadian repressor functions in flies, except for one of the zebrafish Crys, encoded by cry4a. Cry4a also shows a tendency to support light-dependent Cry functions, indicating that it might act in the light-input pathway of zebrafish.

Microglial Modulation of Synaptic Maturation, Activity, and Plasticity.

Microglia, which are the resident immune cells of the CNS, also have important functions in physiological conditions. In this chapter, we review the experimental evidence that microglia modulate neuronal and synaptic activity during normal development and in adults. We show that microglia can regulate the maturation and function of both inhibitory and excitatory synapses that can be stimulated or repressed. We further review the fact that these regulations occur in various brain regions, through soluble and membrane molecules, directly or through other cell partners. This review emphasizes the fact that microglia are genuine and highly context-dependent and thus adaptable regulators of neuronal activity.

Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons

Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment (AIS), the site of action potential generation, could impact neuronal excitability in ALS human induced pluripotent stem cell (hiPSC) motor neurons. We find that early TDP-43 and C9orf72 hiPSC motor neurons show an increase in the length of the AIS and impaired activity-dependent AIS plasticity that is linked to abnormal homeostatic regulation of neuronal activity and intrinsic hyperexcitability. In turn, these hyperactive neurons drive increased spontaneous myofiber contractions of invitro hiPSC motor units. In contrast, late hiPSC and postmortem ALS motor neurons show AIS shortening, and hiPSC motor neurons progress to hypoexcitability. At a molecular level, aberrant expression of the AIS master scaffolding protein ankyrin-G and AIS-specific voltage-gated sodium channels mirror these dynamic changes in AIS function and excitability. Our results point toward the AIS as an important site of dysfunction in ALS motor neurons.

Three‐Photon Infrared Stimulation of Endogenous Neuroreceptors in Vivo

AbstractTo interrogate neural circuits and crack their codes, in vivo brain activity imaging must be combined with spatiotemporally precise stimulation in three dimensions using genetic or pharmacological specificity. This challenge requires deep penetration and focusing as provided by infrared light and multiphoton excitation, and has promoted two‐photon photopharmacology and optogenetics. However, three‐photon brain stimulation in vivo remains to be demonstrated. We report the regulation of neuronal activity in zebrafish larvae by three‐photon excitation of a photoswitchable muscarinic agonist at 50 pM, a billion‐fold lower concentration than used for uncaging, and with mid‐infrared light of 1560 nm, the longest reported photoswitch wavelength. Robust, physiologically relevant photoresponses allow modulating brain activity in wild‐type animals with spatiotemporal and pharmacological precision. Computational calculations predict that azobenzene‐based ligands have high three‐photon absorption cross‐section and can be used directly with pulsed infrared light. The expansion of three‐photon pharmacology will deeply impact basic neurobiology and neuromodulation phototherapies.

Three-Photon Infrared Stimulation of Endogenous Neuroreceptors in Vivo.

To interrogate neural circuits and crack their codes, in vivo brain activity imaging must be combined with spatiotemporally precise stimulation in three dimensions using genetic or pharmacological specificity. This challenge requires deep penetration and focusing as provided by infrared light and multiphoton excitation, and has promoted two-photon photopharmacology and optogenetics. However, three-photon brain stimulation in vivo remains to be demonstrated. We report the regulation of neuronal activity in zebrafish larvae by three-photon excitation of a photoswitchable muscarinic agonist at 50 pM, a billion-fold lower concentration than used for uncaging, and with mid-infrared light of 1560 nm, the longest reported photoswitch wavelength. Robust, physiologically relevant photoresponses allow modulating brain activity in wild-type animals with spatiotemporal and pharmacological precision. Computational calculations predict that azobenzene-based ligands have high three-photon absorption cross-section and can be used directly with pulsed infrared light. The expansion of three-photon pharmacology will deeply impact basic neurobiology and neuromodulation phototherapies.

The Role of Perineuronal Nets in the Contralateral Hemisphere in the Electroacupuncture-Mediated Rehabilitation of Poststroke Dysphagia Mice.

Acupuncture at Lianquan (CV23) acupoint has been shown to improve swallowing function in poststroke dysphagia (PSD). This improvement is supposed to be associated with the regulation of neuronal activity in the contralateral primary motor cortex (M1), while the underlying mechanism still needs to be elucidated. Perineuronal nets (PNNs) are well-known to be involved in the regulation of neuronal activity. Thus, we here aimed to detect the role of PNNs in the contralateral M1 hemisphere in the electroacupuncture (EA)-mediated effect in male mice. The results were obtained from a combination of methods, including in vitro slice electrophysiological recording, in vivo electrophysiological recording, and immunofluorescent staining in male mice. These results showed a decrease of the excitatory postsynaptic currents (sEPSCs) and no alteration of the inhibitory postsynaptic currents (sIPSCs) in the GABAergic neurons and the tonic inhibition in the excitatory neurons in the contralateral M1 after stroke induction, and EA recovered the impaired sEPSCs in the GABAergic neurons. We further found that the effect of EA-induced increase of c-Fos expression, enhancement of spike firing, potentiation of sEPSCs in the excitatory neurons, and improvement of swallowing function were all blocked by the removal of PNNs in the contralateral M1. In conclusion, the PNNs in the contralateral M1 was suggested to be participated in stroke pathogenesis and might be associated with the EA-mediated swallowing function rehabilitation of PSD in male mice. Our study provides insight into how PNNs might be involved in the mechanism of EA treatment for stroke rehabilitation.