Neuronal Interactions Research Articles

Microglia enhance post-anesthesia neuronal activity by shielding inhibitory synapses.

Microglia are resident immune cells of the central nervous system and play key roles in brain homeostasis. During anesthesia, microglia increase their dynamic process surveillance and interact more closely with neurons. However, the functional significance of microglial process dynamics and neuronal interaction under anesthesia is largely unknown. Using in vivo two-photon imaging in mice, we show that microglia enhance neuronal activity after the cessation of isoflurane anesthesia. Hyperactive neuron somata are contacted directly by microglial processes, which specifically colocalize with GABAergic boutons. Electron-microscopy-based synaptic reconstruction after two-photon imaging reveals that, during anesthesia, microglial processes enter into the synaptic cleft to shield GABAergic inputs. Microglial ablation or loss of microglial β2-adrenergic receptors prevents post-anesthesia neuronal hyperactivity. Our study demonstrates a previously unappreciated function of microglial process dynamics, which enable microglia to transiently boost post-anesthesia neuronal activity by physically shielding inhibitory inputs.

Analysis of α-syn and parkin interaction in mediating neuronal death in Drosophila model of Parkinson's disease.

One of the hallmarks of Parkinson's Disease (PD) is aggregation of incorrectly folded α-synuclein (SNCA) protein resulting in selective death of dopaminergic neurons. Another form of PD is characterized by the loss-of-function of an E3-ubiquitin ligase, parkin. Mutations in SNCA and parkin result in impaired mitochondrial morphology, causing loss of dopaminergic neurons. Despite extensive research on the individual effects of SNCA and parkin, their interactions in dopaminergic neurons remain understudied. Here we employ Drosophila model to study the effect of collective overexpression of SNCA along with the downregulation of parkin in the dopaminergic neurons of the posterior brain. We found that overexpression of SNCA along with downregulation of parkin causes a reduction in the number of dopaminergic neuronal clusters in the posterior region of the adult brain, which is manifested as progressive locomotor dysfunction. Overexpression of SNCA and downregulation of parkin collectively results in altered mitochondrial morphology in a cluster-specific manner, only in a subset of dopaminergic neurons of the brain. Further, we found that SNCA overexpression causes transcriptional downregulation of parkin. However, this downregulation is not further enhanced upon collective SNCA overexpression and parkin downregulation. This suggests that the interactions of SNCA and parkin may not be additive. Our study thus provides insights into a potential link between α-synuclein and parkin interactions. These interactions result in altered mitochondrial morphology in a cluster-specific manner for dopaminergic neurons over a time, thus unraveling the molecular interactions involved in the etiology of Parkinson's Disease.

Fractal Resonance: Can Fractal Geometry Be Used to Optimize the Connectivity of Neurons to Artificial Implants?

In parallel to medical applications, exploring how neurons interact with the artificial interface of implants in the human body can be used to learn about their fundamental behavior. For both fundamental and applied research, it is important to determine the conditions that encourage neurons to maintain their natural behavior during these interactions. Whereas previous biocompatibility studies have focused on the material properties of the neuron-implant interface, here we discuss the concept of fractal resonance - the possibility that favorable connectivity properties might emerge by matching the fractal geometry of the implant surface to that of the neurons.To investigate fractal resonance, we first determine the degree to which neurons are fractal and the impact of this fractality on their functionality. By analyzing three-dimensional images of rat hippocampal neurons, we find that the way their dendrites fork and weave through space is important for generating their fractal-like behavior. By modeling variations in neuron connectivity along with the associated energetic and material costs, we highlight how the neurons' fractal dimension optimizes these constraints. To simulate neuron interactions with implant interfaces, we distort the neuron models away from their natural form by modifying the dendrites' fork and weaving patterns. We find that small deviations can induce large changes in fractal dimension, causing the balance between connectivity and cost to deteriorate rapidly. We propose that implant surfaces should be patterned to match the fractal dimension of the neurons, allowing them to maintain their natural functionality as they interact with the implant.

The role of astrocytes, circadian rhythms and light pollution in the pathogenesis of Alzheimer's disease

Currently, more and more importance is being attached to the interaction of brain neurons with astrocytes in order to study the pathogenesis, and in the future, to develop methods for the prevention, early diagnosis and treatment of neurodegenerative diseases of the brain. In this review article, the authors attempt to demonstrate the role of astrocytes, disturbances in circadian rhythms, sleep-wake patterns, and light pollution in the development of Alzheimer's disease. Based on the analysis of literature data, possible mechanisms of synchronization and desynchronization of these processes are presented.

NEUROMARKETING APPROACH IN TOURISM SECTOR

Neuromarketing is the field of science in which the methods of neuroscience discipline are used in marketing studies. Factors such as the inadequacy of traditional marketing methods, the development of technology and the awareness of consumers have necessitated marketers to develop new ideas. Advertising studies and marketing strategies are developed by revealing the factors that are effective in the subconscious of consumers with neuroimaging methods and analyzing the results. Neuromarketing examines the interaction of neurons in order to explain the purchasing behavior of consumers. This field, which is directly related to the human brain, can identify issues that consumers do not want to say or avoid telling the truth. This study was prepared to investigate the science of neuromarketing and to explain the structure and functions of the human brain. The study was prepared by document analysis method, which is one of the qualitative research methods. A literature review was conducted using secondary data on neuromarketing and the human brain. The study was completed by examining books, journals, articles, master's and doctoral theses, and internet resources on related topics. Neuromarketing techniques are used in many fields such as advertising and film industry, branding, pricing, brand positioning, entertainment industry and tourism. As a result of research; it is seen that the history of neuromarketing science dates back to about 50 years ago. In this case, neuromarketing is a new and developing science. In the researches conducted, it has been determined that there are insufficient studies on the subject in the tourism sector. This research aims to reveal a different area where neuromarketing can be applied in the tourism sector by examining the studies on the human brain and neuromarketing. Considering the data obtained, suggestions are made in the conclusion and evaluation section

Microstimulation reveals anesthetic state-dependent effective connectivity of neurons in cerebral cortex.

Complex neuronal interactions underlie cortical information processing that can be compromised in altered states of consciousness. Here intracortical microstimulation was applied to investigate anesthetic state-dependent effective connectivity of neurons in rat visual cortex in vivo. Extracellular activity was recorded at 32 sites in layers 5/6 while stimulating with charge-balanced discrete pulses at each electrode in random order. The same stimulation pattern was applied at three levels of anesthesia with desflurane and in wakefulness. Spikes were sorted and classified by their waveform features as putative excitatory and inhibitory neurons. Network motifs were identified in graphs of effective connectivity constructed from monosynaptic cross-correlograms. Microstimulation caused early (<10 ms) increase followed by prolonged (11-100 ms) decrease in spiking of all neurons throughout the electrode array. The early response of excitatory but not inhibitory neurons decayed rapidly with distance from the stimulation site over 1 mm. Effective connectivity of neurons with significant stimulus response was dense in wakefulness and sparse under anesthesia. The number of network motifs, especially those of higher order, increased rapidly as the anesthesia was withdrawn indicating a substantial increase in network connectivity as the animals woke up. The results illuminate the impact of anesthesia on functional integrity of local cortical circuits affecting the state of consciousness.

Quantifying morphologies of developing neuronal cells using deep learning with imperfect annotations

The functionality of human intelligence relies on the interaction and health of neurons, hence, quantifying neuronal morphologies can be crucial for investigating the functionality of the human brain. This paper proposes a deep learning (DL) based method for segmenting and quantifying neuronal structures in fluorescence microscopy images of developing neuronal cells cultured in vitro. Compared to the majority of supervised DL-based segmentation methods that heavily rely on creating exact corresponding masks of neuronal structures for the preparation of training samples, the proposed approach allows for imperfect annotation of neurons, as it only requires tracing the centrelines of the neurites. This ability accelerates the preparation of training data by several folds. Our proposed framework is built on a modified version of PSPNet with an EfficientNet backbone pre-trained on the CityScapes dataset. To handle the imperfectness of training samples, we incorporated a weighted combination of two loss functions, namely the Dice loss and Lovász loss functions, into our network. We evaluated the proposed framework and several other state-of-the-art methods on a published dataset of approximately 900 manually quantified cultured mouse neurons. Our results indicate a close correlation between the proposed method and manual quantification in terms of neuron length and the number of branches while demonstrating improved analysis speed. Furthermore, the proposed method achieved high accuracy in neuron segmentation, as evidenced by the evaluation of the neurons’ length and number of branches.

Computational model of interacting system dynamics of calcium, IP3 and β-amyloid in ischemic neuron cells

The study of single independent dynamics of calcium ([Ca2+]), IP3, and β-amyloid (Aβ) in neurons provide limited information. Some attempts are reported for the dynamics of two interacting systems of [Ca2+] and IP3, and calcium and Aβ, which gave some novel insights about the phenomena. However, the interactions of these three systems have not been analyzed till date in neurons. Therefore, a novel model is constructed to study the interactions of the spatiotemporal systems of [Ca2+], IP3, and Aβ in neurons. A two-way feedback mechanism between [Ca2+] and IP3, and [Ca2+] and Aβ has been incorporated into the model. The model is formulated by coupling three reaction-diffusion equations of [Ca2+], IP3 and Aβ, respectively. This coupling automatically takes care of the indirect two-way feedback process between IP3 and β-amyloid in neuron cells. The finite element method (FEM) with the Crank-Nicolson scheme (CNS) is utilized to study the contribution of various ER-associated processes like RyR, IP3R, SERCA pump, buffer approximation, etc on the neuronal interactions of [Ca2+], IP3, and β-amyloid during Ischemia. The numerical findings provide novel insights into alterations in ER handling during Ischemia, resulting in disturbances in the neuronal calcium, IP3, and Aβ levels, which may cause the advancement of Alzheimer’s illness and be responsible for neurotoxicity and cell death.

Co-occurring ripple oscillations facilitate neuronal interactions between cortical locations in humans.

How the human cortex integrates ("binds") information encoded by spatially distributed neurons remains largely unknown. One hypothesis suggests that synchronous bursts of high-frequency oscillations ("ripples") contribute to binding by facilitating integration of neuronal firing across different cortical locations. While studies have demonstrated that ripples modulate local activity in the cortex, it is not known whether their co-occurrence coordinates neural firing across larger distances. We tested this hypothesis using local field-potentials and single-unit firing from four 96-channel microelectrode arrays in the supragranular cortex of 3 patients. Neurons in co-rippling locations showed increased short-latency co-firing, prediction of each other's firing, and co-participation in neural assemblies. Effects were similar for putative pyramidal and interneurons, during non-rapid eye movement sleep and waking, in temporal and Rolandic cortices, and at distances up to 16 mm (the longest tested). Increased co-prediction during co-ripples was maintained when firing-rate changes were equated, indicating that it was not secondary to non-oscillatory activation. Co-rippling enhanced prediction was strongly modulated by ripple phase, supporting the most common posited mechanism for binding-by-synchrony. Co-ripple enhanced prediction is reciprocal, synergistic with local upstates, and further enhanced when multiple sites co-ripple, supporting re-entrant facilitation. Together, these results support the hypothesis that trans-cortical co-occurring ripples increase the integration of neuronal firing of neurons in different cortical locations and do so in part through phase-modulation rather than unstructured activation.

The Interplay of Common Noise and Finite Pulses on Biological Neurons

The response of neurons is highly sensitive to the stimulus. The stimulus can be associated with a direct injection in vitro experimentation (e.g., time dependent and independent inputs); or post-synaptic potentials resulting from the interaction of many neurons. A typical incoming stimulus resembles a noise which in principle can be described as a random variable. In computational neuroscience, the noise has been extensively studied for different setups. In this study, we investigate the effect of noisy inputs in a minimal network of two identical leaky integrate-and-fire (LIF) neurons interacting with finite pulses. In particular, we consider a Gaussian white noise as a standard function for stochastic modelling of neurons, while taking into account the pulse width as an elementary component for the signal transmission. By exploring the role of noise and finite pulses, the two neurons show a synchronous spiking behaviour characterized by fluctuations in the interspike intervals. Above some critical values the synchronous regime collapses onto asynchronous dynamics. The abrupt change in such dynamics is accompanied by a hysteresis, i.e., the coexistence of synchronous and asynchronous firing behaviour.

Neurophysiological markers that link genes and behavior in humans: examples from rare genetic syndromes associated with autism spectrum disorders

Rare genetic syndromes associated with autism spectrum disorders have several noninvasive neurophysiological markers that can be linked with molecular genetic characteristics and behavioral characteristics in these diseases. For the recently discovered Potocki–Lupski syndrome associated with disturbances on the 17p11.2 segment, a previously undescribed epileptiform activity was detected, characterized by a saw-like hypersynchronization at a frequency of 13 Hz, which may indicate a certain type of disturbance in the excitation/inhibition balance in neural networks. For a rare case of microduplication in SH3 and ankyrin repeat domains 3 (SHANK3), also associated with the Phelan–McDermid syndrome, we described a pathway from a violation in the functioning of the SHANK3 protein, through a distorted interaction of excitatory and inhibitory neurons, primarily associated with hypofunction of N-methyl-D-aspartate receptors on inhibitory neurons, to reduced temporal resolution in the auditory cortex, reflected in the absence of response following 40 Hz auditory stimulation (40 Hz auditory steady-state response) and underlying problems in speech development. For the Rett syndrome, which is caused by a mutation in methyl CpG binding protein 2 (MECP2), which has a very wide influence on many other genes, the neurophysiological findings were also diverse. Among the most promising are changes in sensorimotor rhythm, potentially associated with a key symptom of the disease, namely, stereotyped hand movements, as well as more delayed latency of the main components of the event-related potentials, which can have a cascading effect on information processing and affect the perception of basic information, including speech. This review focuses on the presentation of the concept of a neurophysiological profile, the construction of which can help not only to objectify the diagnosis of developmental disorders, but also in the construction of a mechanistic chain from gene to behavior.

Brain Dynamics Complexity as a Signature of Cognitive Decline in Parkinson's Disease.

Higuchi's fractal dimension (FD) captures brain dynamics complexity and may be a promising method to analyze resting-state functional magnetic resonance imaging (fMRI) data and detect the neuronal interaction complexity underlying Parkinson's disease (PD) cognitive decline. The aim was to compare FD with a more established index of spontaneous neural activity, the fractional amplitude of low-frequency fluctuations (fALFF), and identify through machine learning (ML) models which method could best distinguish across PD-cognitive states, ranging from normal cognition (PD-NC), mild cognitive impairment (PD-MCI) to dementia (PDD). Finally, the aim was to explore correlations between fALFF and FD with clinical and cognitive PD features. Among 118 PD patients age-, sex-, and education matched with 35 healthy controls, 52 were classified with PD-NC, 46 with PD-MCI, and 20 with PDD based on an extensive cognitive and clinical evaluation. fALFF and FD metrics were computed on rs-fMRI data and used to train ML models. FD outperformed fALFF metrics in differentiating between PD-cognitive states, reaching an overall accuracy of 78% (vs. 62%). PD showed increased neuronal dynamics complexity within the sensorimotor network, central executive network (CEN), and default mode network (DMN), paralleled by a reduction in spontaneous neuronal activity within the CEN and DMN, whose increased complexity was strongly linked to the presence of dementia. Further, we found that some DMN critical hubs correlated with worse cognitive performance and disease severity. Our study indicates that PD-cognitive decline is characterized by an altered spontaneous neuronal activity and increased temporal complexity, involving the CEN and DMN, possibly reflecting an increased segregation of these networks. Therefore, we propose FD as a prognostic biomarker of PD-cognitive decline. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Tau and lipid coalescence drives early lipid dysregulation in Alzheimer’s disease

AbstractBackgroundIn Alzheimer’s disease (AD), intraneuronal tau protein accumulation into neurofibrillary tangles correlates with clinical signs and neurodegeneration1. Besides neurotoxic protein aggregation, dysregulation of lipid metabolism is emerging as a common disease mechanism2. The main regulators of lipid metabolism in the brain are astrocytes and astrocyte‐neuron communication is key to provide metabolic support to neuron3. While tau has been suggested to bind to lipids4, little is known about the potential tau‐lipid interactions in the brain, it’s role in neuron‐astrocyte crosstalk and how this relates to AD pathology.MethodsWe employ a multiscale approach harnessing human 2D and 3D multicellular models combined with advanced imaging techniques, spanning from single molecule insights to ultrastructural features and functional imaging. We aim to unravel the structural and functional complexity of emerging protein‐lipid landscapes in AD and to elucidate how their misregulation triggers early lipid dyshomeostasis.ResultsTau propagates in brain organoids in highly dynamic intracellular droplet‐like structures rich in lipids. Strikingly, the molecular identity of tau droplets is cell‐type specific; tau interact with lipids in neurons but not in astrocytes (fig.1‐2). The dynamics of neuronal tau‐lipid accumulations are driven by microtubule interactions and show liquid‐like behavior. Furthermore, highly dynamic tau‐lipid droplets transition to stillness overtime giving rise to a heterogenous spectrum of conformational ensembles of tau (fig.3).ConclusionTau‐lipid interactions in vivo are neuron‐specific. Lipid colocalization correlates with dramatic changes in the structural properties of tau. In neurons, tau and lipids coalesce in highly dynamic intracellular liquid‐like droplets that undergo time‐dependent transition to potential pathological states. Our results highlight intriguing functional implications of cell‐type specific tau‐lipid interactions impacting on neuron‐astrocyte communication and overall brain lipid metabolism. Targeting tau‐lipid interactions in neurons promise exciting new avenues in AD therapeutic strategies.1. Busche, et al. Synergy between amyloid‐β and tau in Alzheimer’s disease. Nat. Neurosci. (2020).2. Yin. Lipid metabolism and Alzheimer’s disease: clinical evidence, mechanistic link and therapeutic promise. FEBS J. (2022).3. Yang, et al. Lipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases. Cell Biosci. (2022).4. Sallaberry, et al. Tau and Membranes: Interactions That Promote Folding and Condensation. Front. Cell Dev. Biol. (2021).

Widespread transposable element dysregulation in human brains with Alzheimer’s disease

AbstractBackgroundTransposable elements (TEs), known as “jumping genes” or “viral elements”, constitute approximately 45% of the human genome. However, transposable element (TE) dysregulation of quantitative trait loci (QTL) has not been well‐characterized in human disease, such as Alzheimer’s disease (AD).MethodIn this study, we present the first catalog of transposable element quantitative trait loci (teQTLs) in human brains. By leveraging large‐scale RNA‐sequencing (RNA‐seq), whole‐genome sequencing (WGS), and various QTL data (xQTL) from three brain biobanks with Alzheimer’s disease (AD), we comprehensively characterize TE dysregulation across diverse AD pathobiology, including Tau, amyloid beta, APOE genotypes, and sex differences. We further integrate different types of QTLs with GWAS loci from 278,950 AD cases and 1,780,303 controls to identify AD likely causal genes regulated by brain teQTLs through colocalization analysis. Regulatory roles of brain teQTLs are dissected via long‐range cell type‐specific enhancer‐promoter chromatin interaction maps.ResultJoint‐analysis of WGS and RNA‐seq data identified 77,335 genome‐wide significant TE expression QTLs (teQTLs) in human AD brains. Colocalization analysis of teQTLs with GWAS loci from 278,950 AD cases and 1,780,303 controls identified key AD likely causal genes regulated by brain teQTLs. This identified new AD risk genes, including complement C1q tumor necrosis factor‐related protein 4 (C1QTNF4) and farnesyl‐diphosphate farnesyltransferase 1 (FDFT1). A TE from Plat_L3 subfamily (chr11: 47605296‐47605575) suppressed expression of C1QTNF4 (its nearest gene) via long‐range enhancer‐promoter chromatin interaction in neurons. We identified that a TE from AluSz6 subfamily (chr8: 11834847‐11835127) increased expression of FDFT1 (its nearest gene) via microglia‐specific long‐range chromatin looping. Expression perturbation of FDFT1 and C1QTNF4 were significantly correlated with Braak staging score of AD patients. We further identified that individuals with AD risk allele APOE4 displayed elevated expression of AluSz6 and FDFT1 in patient induced pluripotent stem cells (iPSC)‐derived microglia and superior frontal gyrus (SFG) microglia compared to APOE3 individuals.ConclusionThese findings demonstrate widespread TE dysregulation in human brains and teQTLs offer a useful QTL analytic approach to identify AD risk genes and other complex diseases if broadly applied.

Structural networking of the developing brain: from maturation to neurosurgical implications

Modern neuroscience agrees that neurological processing emerges from the multimodal interaction among multiple cortical and subcortical neuronal hubs, connected at short and long distance by white matter, to form a largely integrated and dynamic network, called the brain “connectome.” The final architecture of these circuits results from a complex, continuous, and highly protracted development process of several axonal pathways that constitute the anatomical substrate of neuronal interactions. Awareness of the network organization of the central nervous system is crucial not only to understand the basis of children’s neurological development, but also it may be of special interest to improve the quality of neurosurgical treatments of many pediatric diseases. Although there are a flourishing number of neuroimaging studies of the connectome, a comprehensive vision linking this research to neurosurgical practice is still lacking in the current pediatric literature. The goal of this review is to contribute to bridging this gap. In the first part, we summarize the main current knowledge concerning brain network maturation and its involvement in different aspects of normal neurocognitive development as well as in the pathophysiology of specific diseases. The final section is devoted to identifying possible implications of this knowledge in the neurosurgical field, especially in epilepsy and tumor surgery, and to discuss promising perspectives for future investigations.

Brain-inspired bodily self-perception model for robot rubber hand illusion

The core of bodily self-consciousness involves perceiving ownership of one's body. A central question is how body illusions like the rubber hand illusion (RHI) occur. Existing theoretical models still lack satisfying computational explanations from connectionist perspectives, especially for how the brain encodes body perception and generates illusions from neuronal interactions. Moreover, the integration of disability experiments is also neglected. Here, we integrate biological findings of bodily self-consciousness to propose a brain-inspired bodily self-perception model by which perceptions of bodily self are autonomously constructed without any supervision signals. We successfully validated the model with six RHI experiments and a disability experiment on an iCub humanoid robot and simulated environments. The results show that our model can not only well-replicate the behavioral and neural data of monkeys in biological experiments but also reasonably explain the causes and results of RHI at the neuronal level, thus contributing to the revelation of mechanisms underlying RHI.

Progress in cancer neuroscience.

Cancer of the central nervous system (CNS) can crosstalk systemically and locally in the tumor microenvironment and has become a topic of attention for tumor initiation and advancement. Recently studied neuronal and cancer interaction fundamentally altered the knowledge about glioma and metastases, indicating how cancers invade complex neuronal networks. This review systematically discussed the interactions between neurons and cancers and elucidates new therapeutic avenues. We have overviewed the current understanding of direct or indirect communications of neuronal cells with cancer and the mechanisms associated with cancer invasion. Besides, tumor-associated neuronal dysfunction and the influence of cancer therapies on the CNS are highlighted. Furthermore, interactions between peripheral nervous system and various cancers have also been discussed separately. Intriguingly and importantly, it cannot be ignored that exosomes could mediate the "wireless communications" between nervous system and cancer. Finally, promising future strategies targeting neuronal-brain tumor interactions were reviewed. A great deal of work remains to be done to elucidate the neuroscience of cancer, and future more research should be directed toward clarifying the precise mechanisms of cancer neuroscience, which hold enormous promise to improve outcomes for a wide range of malignancies.

STIM2 regulates NMDA receptor endocytosis that is induced by short-term NMDA receptor overactivation in cortical neurons

Recent findings suggest an important role for the dysregulation of stromal interaction molecule (STIM) proteins, activators of store-operated Ca2+ channels, and the prolonged activation of N-methyl-D-aspartate receptors (NMDARs) in the development of neurodegenerative diseases. We previously demonstrated that STIM silencing increases Ca2+ influx through NMDAR and STIM–NMDAR2 complexes are present in neurons. However, the interplay between NMDAR subunits (GluN1, GluN2A, and GluN2B) and STIM1/STIM2 with regard to intracellular trafficking remains unknown. Here, we found that the activation of NMDAR endocytosis led to an increase in STIM2–GluN2A and STIM2–GluN2B interactions in primary cortical neurons. STIM1 appeared to migrate from synaptic to extrasynaptic sites. STIM2 silencing inhibited post-activation NMDAR translocation from the plasma membrane and synaptic spines and increased NMDAR currents. Our findings reveal a novel molecular mechanism by which STIM2 regulates NMDAR synaptic trafficking by promoting NMDAR endocytosis after receptor overactivation, which may suggest protection against excessive uncontrolled Ca2+ influx through NMDARs.

Melatonin Relieves Paclitaxel-Induced Neuropathic Pain by Regulating pNEK2-Dependent Epigenetic Pathways in DRG Neurons.

The neurohormone melatonin (MLT) demonstrates promising potential in ameliorating neuropathic pain induced by paclitaxel (PTX) chemotherapy. However, little is known about its protective effect on dorsal root ganglion (DRG) neurons in neuropathic pain resulting from the chemotherapeutic drug PTX. Here, PTX-treated rats revealed that intrathecal administration of MLT dose-dependently elevated hind paw withdrawal thresholds and latency, indicating that MLT significantly reversed PTX-induced neuropathic pain. Mechanistically, the analgesic effects of MLT were found to be mediated via melatonin receptor 2 (MT2), as pretreatment with an MT2 receptor antagonist inhibited these effects. Moreover, intrathecal MLT injection reversed the pNEK2-dependent epigenetic program induced by PTX. All of the effects caused by MLT were blocked by pretreatment with an MT2 receptor-selective antagonist, 4P-PDOT. Remarkably, multiple MLT administered during PTX treatment (PTX+MLTs) exhibited not only rapid but also lasting reversal of allodynia/hyperalgesia compared to single-bolus MLT administered after PTX treatment (PTX+MLT). In addition, PTX+MLTs exhibited greater efficacy in reversing PTX-induced alterations in pRSK2, pNEK2, JMJD3, H3K27me3, and TRPV1 expression and interaction in DRG neurons than PTX+MLT. These results indicated that MLT administered during PTX treatment reduced the incidence and/or severity of neuropathy and had a better inhibitory effect on the pNEK2-dependent epigenetic program compared to MLT administered after PTX treatment. In conclusion, MLT/MT2 is a promising therapy for the treatment of pNEK2-dependent painful neuropathy resulting from PTX treatment. MLT administered during PTX chemotherapy may be more effective in the prevention or reduction of PTX-induced neuropathy and maintaining quality.

Investigating the Mechanisms Involved in Scopolamine-Induced Memory Degradation

In the present study, the mechanisms involved in scopolamine-induced memory impairment have been investigated. The molecular events that take place during memory mostly include mechanisms that are seen in the acquisition phase. Results show that one of the mechanisms of memory destruction caused by scopolamine, in addition to weakening the cholinergic system, is the indirect effect of scopolamine on other neurotransmitter systems, including the glutamatergic system. Scopolamine injection increases dopamine by inhibiting M2/4 muscarinic auto receptors. These auto receptors are located on dopaminergic presynaptic neurons, and their activation reduces the release of dopamine. Therefore, blocking these auto receptors by scopolamine can increase the release of dopamine. Both D1 and D2 receptors are involved in the process of learning and memory. In general, stimulation of dopamine D1 receptors follows an inverted U-shaped dose-response curve, meaning that both insufficient and excessive amounts of dopamine cause memory impairment. Therefore, one of the mechanisms of scopolamine-induced memory impairment can be an indirect effect on the dopaminergic system. Effect on cell membrane potential, effect on neuron plasticity and interaction with acetylcholine. Serotonin plays a complex role in memory and learning. Serotonin receptors (5-HT2A) also play a role in memory function through their effect on calcium transport. This action is similar to dopamine receptors and other G-protein-coupled receptors, which activate phospholipase C, enter calcium into the cell, and activate calcineurin. Activation of 5-HT2A receptors as well as 5-HT4 receptors by specific agonists of these receptors enhances LTP, which plays a very important role in memory. On the other hand, specific 5-HT3 receptor antagonist improves LTP. 5-HT6 receptor antagonist can improve memory function. Therefore, different serotonin receptors have different roles on memory function, and the interaction between scopolamine and these receptors needs further study. It has been shown that histamine increases the secretion of acetylcholine in the hippocampus and postsynaptic H1 and presynaptic H3 receptors play an important role in memory and learning, but whether scopolamine can cause memory impairment through interaction with histamine receptors, not reviewed.