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Schizophrenia (SZ) is a complex neuropsychiatric disorder associated with severe cognitive dysfunction. Although research has mainly focused on forebrain abnormalities, emerging results support the involvement of the cerebellum in SZ physiopathology, particularly in Cognitive Impairment Associated with SZ (CIAS). Besides its role in motor learning and control, the cerebellum is implicated in cognition and emotion. Recent research suggests that structural and functional changes in the cerebellum are linked to deficits in various cognitive domains including attention, working memory, and decision-making. Moreover, cerebellar dysfunction is related to altered cerebellar circuit activities and connectivity with brain regions associated with cognitive processing. This review delves into the role of the cerebellum in CIAS. We initially consider the major forebrain alterations in CIAS, addressing impairments in neurotransmitter systems, synaptic plasticity, and connectivity. We then focus on recent findings showing that several mechanisms are also altered in the cerebellum and that cerebellar communication with the forebrain is impaired. This evidence implicates the cerebellum as a key component of circuits underpinning CIAS physiopathology. Further studies addressing cerebellar involvement in SZ and CIAS are warranted and might open new perspectives toward understanding the physiopathology and effective treatment of these disorders. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) disrupts nerve pathways and affects sensory, motor, and autonomic function. There is currently no effective treatment for SCI. SCI occurs within three temporal periods: acute, subacute, and chronic. In each period there are different alterations in the cells, inflammatory factors, and signaling pathways within the spinal cord. Many biomaterials have been investigated in the treatment of SCI, including hydrogels and fiber scaffolds, and some progress has been made in the treatment of SCI using multiple materials. However, there are limitations when using individual biomaterials in SCI treatment, and these limitations can be significantly improved by combining treatments with stem cells. In order to better understand SCI and to investigate new strategies for its treatment, several combination therapies that include materials combined with cells, drugs, cytokines, etc. are summarized in the current review. [ABSTRACT FROM AUTHOR]

Introduction: Cochlear afferent synapses connecting inner hair cells to spiral ganglion neurons are susceptible to excitotoxic trauma on exposure to loud sound, resulting in a noise-induced cochlear synaptopathy (NICS). Here we assessed the ability of cyclic AMP-dependent protein kinase (PKA) signaling to promote cochlear synapse regeneration, inferred from its ability to promote axon regeneration in axotomized CNS neurons, another system refractory to regeneration. Methods: We mimicked NICS in vitro by applying a glutamate receptor agonist, kainic acid (KA) to organotypic cochlear explant cultures and experimentally manipulated cAMP signaling to determine whether PKA could promote synapse regeneration. We then delivered the cAMP phosphodiesterase inhibitor rolipram via implanted subcutaneous minipumps in noise-exposed CBA/CaJ mice to test the hypothesis that cAMP signaling could promote cochlear synapse regeneration in vivo. Results: We showed that the application of the cell membrane-permeable cAMP agonist 8-cpt-cAMP or the cAMP phosphodiesterase inhibitor rolipram promotes significant regeneration of synapses in vitro within twelve hours after their destruction by KA. This is independent of neurotrophin-3, which also promotes synapse regeneration. Moreover, of the two independent signaling effectors activated by cAMP - the cAMP Exchange Protein Activated by cAMP and the cAMP-dependent protein kinase - it is the latter that mediates synapse regeneration. Finally, we showed that systemic delivery of rolipram promotes synapse regeneration in vivo following NICS. Discussion: In vitro experiments show that cAMP signaling promotes synapse regeneration after excitotoxic destruction of cochlear synapses and does so via PKA signaling. The cAMP phosphodiesterase inhibitor rolipram promotes synapse regeneration in vivo in noise-exposed mice. Systemic administration of rolipram or similar compounds appears to provide a minimally invasive therapeutic approach to reversing synaptopathy post-noise. [ABSTRACT FROM AUTHOR]

The increasing prevalence of neurodevelopmental disorders has highlighted the need for improved testing methods to determine developmental neurotoxicity (DNT) hazard for thousands of chemicals. This paper proposes the integration of organoid intelligence (OI); leveraging brain organoids to study neuroplasticity in vitro, into the DNT testing paradigm. OI brings a new approach to measure the impacts of xenobiotics on plasticity mechanisms – a critical biological process that is not adequately covered in current DNT in vitro assays. Finally, the integration of artificial intelligence (AI) techniques will further facilitate the analysis of complex brain organoid data to study these plasticity mechanisms.

Granule cells (GC) are the most numerous glutamatergic neurons in the cerebellar cortex and represent almost half of the neurons of the central nervous system. Despite recent advances, the mechanisms of how the glutamatergic synapses are formed in the cerebellum remain unclear. Among the TGF-β family, TGF-beta 1 (TGF-β1) has been described as a synaptogenic molecule in invertebrates and in the vertebrate peripheral nervous system. A recent paper from our group demonstrated that TGF-β1 increases the excitatory synapse formation in cortical neurons. Here, we investigated the role of TGF-β1 in glutamatergic cerebellar neurons. We showed that the expression profile of TGF-β1 and its receptor, TbRII, in the cerebellum is consistent with a role in synapse formation in vitro and in vivo. It is low in the early postnatal days (P1-P9), increases after postnatal day 12 (P12), and remains high until adulthood (P30). We also found that granule neurons express the TGF-β receptor mRNA and protein, suggesting that they may be responsive to the synaptogenic effect of TGF-β1. Treatment of granular cell cultures with TGF-β1 increased the number of glutamatergic excitatory synapses by 100%, as shown by immunocytochemistry assays for presynaptic (synaptophysin) and post-synaptic (PSD-95) proteins. This effect was dependent on TbRI activation because addition of a pharmacological inhibitor of TGF-b, SB-431542, impaired the formation of synapses between granular neurons. Together, these findings suggest that TGF-β1 has a specific key function in the cerebellum through regulation of excitatory synapse formation between granule neurons. [ABSTRACT FROM AUTHOR]

The central nervous system areas displaying the highest structural and functional complexity correspond to the so called cortices, i.e., concentric alternating neuronal and fibrous layers. Corticogenesis, i.e., the development of the cortical organization, depends on the temporal-spatial organization of several developmental events: (a) the duration of the proliferative phase of the neuroepithelium, (b) the relative duration of symmetric (expansive) versus asymmetric (neuronogenic) sub phases, (c) the spatial organization of each kind of cell division, (e) the time of determination and cell cycle exit and (f) the time of onset of the post-mitotic neuronal migration and (g) the time of onset of the neuronal structural and functional differentiation. The first five events depend on molecular mechanisms that perform a fine tuning of the proliferative activity. Changes in any of them significantly influence the cortical size or volume (tangential expansion and radial thickness), morphology, architecture and also impact on neuritogenesis and synaptogenesis affecting the cortical wiring. This paper integrates information, obtained in several species, on the developmental roles of cell proliferation in the development of the optic tectum (OT) cortex, a multilayered associative area of the dorsal (alar) midbrain. The present review (1) compiles relevant information on the temporal and spatial organization of cell proliferation in different species (fish, amphibians, birds, and mammals), (2) revises the main molecular events involved in the isthmic organizer (IsO) determination and localization, (3) describes how the patterning installed by IsO is translated into spatially organized neural stem cell proliferation (i.e., by means of growth factors, receptors, transcription factors, signaling pathways, etc.) and (4) describes the morpho- and histogenetic effect of a spatially organized cell proliferation in the above mentioned species. A brief section on the OT evolution is also included. This section considers how the differential operation of cell proliferation could explain differences among species. [ABSTRACT FROM AUTHOR]

Vascular dementia (VaD) is a pathogenetically heterogeneous neuropsychiatric syndrome, mainly characterized by cognitive impairment. Among dementias, it is second by incidence after Alzheimer's dementia (AD). VaD biomolecular bases have been poorly characterized, but vascular-linked factors affecting the CNS and its functions are generally hypothesized to perform a major role, together with cardiovascular and immunological factors. miRNAs, which perform critically important biomolecular roles within cell networks, are also found in biological fluids as circulating miRNAs (cmiRNAs). We hypothesized that differentially expressed (DE) cmiRNAs in plasma from VaD patients could be applied to diagnose VaD through liquid biopsies; these profiles also could allow to start investigating VaD molecular bases. By exploiting TaqMan Low-Density Arrays and single TaqMan assays, miR-10b*, miR29a-3p, and miR-130b-3p were discovered and validated as significantly downregulated DE cmiRNAs in VaD patients compared to unaffected controls (NCs). These miRNAs also were found to be significantly downregulated in a matched cohort of AD patients, but miR-130b-3p levels were lower in AD than in VaD. A negative correlation was detected between miR-29a and miR-130b expression and cognitive impairment in VaD and AD, respectively. Receiver operating characteristic curves demonstrated that decreased plasma levels of miR-10b*, miR29a-3p, and miR-130b-3p allow to discriminate VaD and AD patients from NCs. Furthermore, the concurrent downregulation of both miR-10b* and miR-130b-3p in VaD showed an area under the curve (AUC) of 0.789 (p < 0.0001) with 75% of sensitivity and 72% of specificity, whereas an AUC of 0.789 (p < 0.0001) with 92% of sensitivity and 81% of specificity was found for both in AD. The miRNAs profiles reported in this paper pave the way to translational applications to molecular VaD diagnosis, but they also should allow to further investigate on its molecular bases. [ABSTRACT FROM AUTHOR]

At the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered in China, causing a new coronavirus disease, termed COVID-19 by the WHO on February 11, 2020. At the time of this paper (January 31, 2021), more than 100 million cases have been recorded, which have claimed over 2 million lives worldwide. The most important clinical presentation of COVID-19 is severe pneumonia; however, many patients present various neurological symptoms, ranging from loss of olfaction, nausea, dizziness, and headache to encephalopathy and stroke, with a high prevalence of inflammatory central nervous system (CNS) syndromes. SARS-CoV-2 may also target the respiratory center in the brainstem and cause silent hypoxemia. However, the neurotropic mechanism(s) by which SARS-CoV-2 affects the CNS remain(s) unclear. In this paper, we first address the involvement of astrocytes in COVID-19 and then elucidate the present knowledge on SARS-CoV-2 as a neurotropic virus as well as several other neurotropic flaviviruses (with a particular emphasis on the West Nile virus, tick-borne encephalitis virus, and Zika virus) to highlight the neurotropic mechanisms that target astroglial cells in the CNS. These key homeostasis-providing cells in the CNS exhibit many functions that act as a favorable milieu for virus replication and possibly a favorable environment for SARS-CoV-2 as well. The role of astrocytes in COVID-19 pathology, related to aging and neurodegenerative disorders, and environmental factors, is discussed. Understanding these mechanisms is key to better understanding the pathophysiology of COVID-19 and for developing new strategies to mitigate the neurotropic manifestations of COVID-19.

Up to 15 years ago, bibliographic searches based on keywords such as "photoreceptor degeneration, inner retina" or "photoreceptor degeneration, second order neurons" returned only a handful of papers, as the field was dominated by the general assumption that retinal degeneration had direct effects on the sole populations of rods and cones. Since then, a number of studies have been dedicated to understanding the process of gradual morphological, molecular, and functional changes arising among cells located in the inner retina (comprising neurons, glia, and blood vessels), that is to say "beyond" photoreceptors. General aspects of this progression of biological rearrangements, now referred to as "remodeling", were revealed and demonstrated to accompany consistently photoreceptor loss, independently from the underlying cause of degeneration. Recurrent features of remodeling are summarized here, to provide a general frame for to the various analytical descriptions and reviews contributed by the articles in the issue (among others, see Euler and Schubert, 2015; Soto and Kerschensteiner, 2015, this issue). [ABSTRACT FROM AUTHOR]

Notch signaling plays a crucial role in adult brain function such as synaptic plasticity, memory and olfaction. Several reports suggest an involvement of this pathway in neurodegenerative dementia. Yet, to date, the mechanism underlying Notch activity in mature neurons remains unresolved. In this work, we investigate how Notch regulates synaptic potentiation and contributes to the establishment of memory in mice. We observe that Notch1 is a postsynaptic receptor with functional interactions with the Reelin receptor, apolipoprotein E receptor 2 (ApoER2) and the ionotropic receptor, N-methyl-D-aspartate receptor (NMDAR). Targeted loss of Notch1 in the hippocampal CA fields affects Reelin signaling by influencing Dab1 expression and impairs the synaptic potentiation achieved through Reelin stimulation. Further analysis indicates that loss of Notch1 affects the expression and composition of the NMDAR but not AMPAR. Glutamatergic signaling is further compromised through downregulation of CamKII and its secondary and tertiary messengers resulting in reduced cAMP response element-binding (CREB) signaling. Our results identify Notch1 as an important regulator of mechanisms involved in synaptic plasticity and memory formation. These findings emphasize the possible involvement of this signaling receptor in dementia. Highlights In this paper, we propose a mechanism for Notch1-dependent plasticity that likely underlies the function of Notch1 in memory formation: • Notch1 interacts with another important developmental pathway, the Reelin cascade. • Notch1 regulates both NMDAR expression and composition. • Notch1 influences a cascade of cellular events culminating in CREB activation. [ABSTRACT FROM AUTHOR]

The dynamics of vestibular afferent responses are thought to be strongly influenced by presynaptic properties. In this paper, by performing whole-cell perforated-patch experiments in the frog utricle, we characterized voltage-dependent currents and voltage responses to current steps and 0.3-100 Hz sinusoids. Current expression and voltage responses are strongly related to hair cell type. In particular, voltage responses of extrastriolar type eB (low pass, -3 dB corner at 52.5 ± 12.8 Hz) and striolar type F cells (resonant, tuned at 60 ± 46 Hz) agree with the dynamics (tonic and phasic, respectively) of the afferent fibers they contact. On the other hand, hair cell release (measured with single-sine membrane 1Cm measurements) was linearly related to Ca in both cell types, and therefore did not appear to contribute to dynamics differences. As a tool for quantifying the relative contribution of basolateral currents and other presynaptic factors to afferent dynamics, the recorded current, voltage and release data were used to build a NEURON model of the average extrastriolar type eB and striolar type F hair cell. The model contained all recorded conductances, a basic mechanosensitive hair bundle and a ribbon synapse sustained by stochastic voltage-dependent Ca channels, and could reproduce the recorded hair cell voltage responses. Simulated release obtained from eB-type and F-type models display significant differences in dynamics, supporting the idea that basolateral currents are able to contribute to afferent dynamics; however, release in type eB and F cell models does not reproduce tonic and phasic dynamics, mainly because of an excessive phase lag present in both cell types. This suggests the presence in vestibular hair cells of an additional, phase-advancing mechanism, in cascade with voltage modulation. [ABSTRACT FROM AUTHOR]

We have recently developed a mathematical model of axonal length sensing in which a system of delay differential equations describe a chemical signaling network. We showed that chemical oscillations emerge due to delayed negative feedback via a Hopf bifurcation, resulting in a frequency that is a monotonically decreasing function of axonal length. In this paper, we explore how frequency-encoding of axonal length can be decoded by a frequency-modulated gene network. If the protein output were thresholded, then this could provide a mechanism for axonal length control. We analyze the robustness of such a mechanism in the presence of intrinsic noise due to finite copy numbers within the gene network. [ABSTRACT FROM AUTHOR]

Damage of the brain may be caused by mechanical loads such as penetration, blunt force, shock loading from blast, and by chemical imbalances due to neurological diseases and aging that trigger not only neuronal degeneration but also changes in the mechanical properties of brain tissue. An understanding of the interconnected nature of the electro-chemo-mechanical processes that result in brain damage and ultimately loss of functionality is currently lacking. While modern mathematical models that focus on how to link brain mechanics to its biochemistry are essential in enhancing our understanding of brain science, the lack of experimental data required by these models as well as the complexity of the corresponding computations render these models hard to use in clinical applications. In this paper we propose a unified variational framework for the modeling of neuronal electromechanics. We introduce a constrained Lagrangian formulation that takes into account Newton's law of motion of a linear viscoelastic Kelvin--Voigt solid-state neuron as well as the classic Hodgkin--Huxley equations of the electronic neuron. The system of differential equations describing neuronal electromechanics is obtained by applying Hamilton's principle. Numerical simulations of possible damage dynamics in neurons will be presented. [ABSTRACT FROM AUTHOR]

Astrocytes play an essential role in supporting brain functions in physiological and pathological states. Modulation of their pathophysiological responses have beneficial actions on nerve tissue injured by brain insults and neurodegenerative diseases, therefore astrocytes are recognized as promising targets for neuroprotective drugs. Recent investigations have identified several astrocytic mechanisms for modulating synaptic transmission and neural plasticity. These include altered expression of transporters for neurotransmitters, release of gliotransmitters and neurotrophic factors, and intercellular communication through gap junctions. Investigation of patients with mental disorders shows morphological and functional alterations in astrocytes. According to these observations, manipulation of astrocytic function by gene mutation and pharmacological tools reproduce mental disorder-like behavior in experimental animals. Some drugs clinically used for mental disorders affect astrocyte function. As experimental evidence shows their role in the pathogenesis of mental disorders, astrocytes have gained much attention as drug targets for mental disorders. In this paper, I review functional alterations of astrocytes in several mental disorders including schizophrenia, mood disorder, drug dependence, and neurodevelopmental disorders. The pharmacological significance of astrocytes in mental disorders is also discussed. [ABSTRACT FROM AUTHOR]

It has long been speculated whether communication between humans and machines based on natural speech related cortical activity is possible. Over the past decade, studies have suggested that it is feasible to recognize isolated aspects of speech from neural signals, such as auditory features, phones or one of a few isolated words. However, until now it remained an unsolved challenge to decode continuously spoken speech from the neural substrate associated with speech and language processing. Here, we show for the first time that continuously spoken speech can be decoded into the expressed words from intracranial electrocorticographic (ECoG) recordings.Specifically, we implemented a system, which we call Brain-To-Text that models single phones, employs techniques from automatic speech recognition (ASR), and thereby transforms brain activity while speaking into the corresponding textual representation. Our results demonstrate that our system can achieve word error rates as low as 25% and phone error rates below 50%. Additionally, our approach contributes to the current understanding of the neural basis of continuous speech production by identifying those cortical regions that hold substantial information about individual phones. In conclusion, the Brain-To- Text system described in this paper represents an important step toward human-machine communication based on imagined speech. [ABSTRACT FROM AUTHOR]

Keywords: neurodegeneration; neuroinflammation; microglia; cognitive deficits; dementia EN neurodegeneration neuroinflammation microglia cognitive deficits dementia 1 3 3 04/21/22 20220419 NES 220419 Representing a particularly vulnerable tissue, the brain is surrounded by the blood-brain barrier (BBB), which efficiently prevents the entry of harmful blood-derived toxins, microbes, and inflammatory signals. Dark microglia appear to be much more active than the normal microglia, reaching out for synaptic clefts, and encircling axon terminals and dendritic spines with their highly ramified and thin processes. The authors suggest that microglia (and specifically dark microglia) may participate in mechanisms that control suicide resistance and susceptibility. However, the mechanism via which SARS-CoV-2 S1 protein induces neuronal injury will have to be further scrutinized, and I in vivo i studies are still needed to assess the true relevance of endolysosomal S1 spike protein accumulation for neuritic dystrophy and brain pathology. [Extracted from the article]

Neurotransmitter release at retinal ribbon-style synapses utilizes a specialized t-SNARE protein called syntaxin3B (STX3B). In contrast to other syntaxins, STX3 proteins can be phosphorylated in vitro at T14 by Ca2+/calmodulin-dependent protein kinase II (CaMKII). This modification has the potential to modulate SNARE complex formation required for neurotransmitter release in an activity-dependent manner. To determine the extent to which T14 phosphorylation occurs in vivo in the mammalian retina and characterize the pathway responsible for the in vivo phosphorylation of T14, we utilized quantitative immunofluorescence to measure the levels of STX3 and STX3 phosphorylated at T14 (pSTX3) in the synaptic terminals of mouse retinal photoreceptors and rod bipolar cells (RBCs). Results demonstrate that STX3B phosphorylation at T14 is light-regulated and dependent upon the elevation of intraterminal Ca2+. In rod photoreceptor terminals, the ratio of pSTX3 to STX3 was significantly higher in dark-adapted mice, when rods are active, than in light-exposed mice. By contrast, in RBC terminals, the ratio of pSTX3 to STX3 was higher in light-exposed mice, when these terminals are active, than in dark-adapted mice. These results were recapitulated in the isolated eyecup preparation, but only when Ca2+ was included in the external medium. In the absence of external Ca2+, pSTX3 levels remained low regardless of light/dark exposure. Using the isolated RBC preparation, we next showed that elevation of intraterminal Ca2+ alone was sufficient to increase STX3 phosphorylation at T14. Furthermore, both the non-specific kinase inhibitor staurosporine and the selective CaMKII inhibitor AIP inhibited the Ca2+-dependent increase in the pSTX3/STX3 ratio in isolated RBC terminals, while in parallel experiments, AIP suppressed RBC depolarization-evoked exocytosis, measured using membrane capacitance measurements. Our data support a novel, illumination-regulated modulation of retinal ribbon-style synapse function in which activity-dependent Ca2+ entry drives the phosphorylation of STX3B at T14 by CaMKII, which in turn, modulates the ability to form SNARE complexes required for exocytosis. [ABSTRACT FROM AUTHOR]

Introduction: The emergent coherent population activity from thousands of stochastic neurons in the brain is believed to constitute a key neuronal mechanism for salient processing of external stimuli and its link to internal states like attention and perception. In the sensory cortex, functional cell assemblies are formed by recurrent excitation and inhibitory influences. The stochastic dynamics of each cell involved is largely orchestrated by presynaptic CAV2.1 voltage-gated calcium channels (VGCCs). Cav2.1 VGCCs initiate the release of neurotransmitters from the presynaptic compartment and are therefore able to add variability into synaptic transmission which can be partly explained by their mobile organization around docked vesicles. Methods: To investigate the relevance of Cav2.1 channel surface motility for the input processing in the primary auditory cortex (A1) in vivo, we make use of a new optogenetic system which allows for acute, reversable cross-linking Cav2.1 VGCCs via a photo-cross-linkable cryptochrome mutant, CRY2olig. In order to map neuronal activity across all cortical layers of the A1, we performed laminar current-source density (CSD) recordings with varying auditory stimulus sets in transgenic mice with a citrine tag on the N-terminus of the VGCCs. Results: Clustering VGCCs suppresses overall sensory-evoked population activity, particularly when stimuli lead to a highly synchronized distribution of synaptic inputs. Discussion: Our findings reveal the importance of membrane dynamics of presynaptic calcium channels for sensory encoding by dynamically adjusting network activity across a wide range of synaptic input strength. [ABSTRACT FROM AUTHOR]

Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Revascularization of the occluded cerebral artery, either by thrombolysis or endovascular thrombectomy, is the only effective, clinically-approved stroke therapy. Several potentially neuroprotective agents, including glutamate antagonists, anti-inflammatory compounds and free radical scavenging agents were shown to be effective neuroprotectants in preclinical animal models of brain ischemia. However, these compounds did not demonstrate efficacy in clinical trials with human patients following stroke. Proposed reasons for the translational failure include an insufficient understanding on the cellular and molecular pathophysiology of ischemic stroke, lack of alignment between preclinical and clinical studies and inappropriate design of clinical trials based on the preclinical findings. Therefore, novel neuroprotective treatments must be developed based on a clearer understanding of the complex spatiotemporal mechanisms of ischemic stroke and with proper clinical trial design based on the preclinical findings from specific animal models of stroke. We and others have demonstrated the clinical potential for neuregulin-1 (NRG-1) in preclinical stroke studies. NRG-1 significantly reduced ischemia-induced neuronal death, neuroinflammation and oxidative stress in rodent stroke models with a therapeutic window of >13 h. Clinically, NRG-1 was shown to be safe in human patients and improved cardiac function in multisite phase II studies for heart failure. This review summarizes previous stroke clinical candidates and provides evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke. [ABSTRACT FROM AUTHOR]

Introduction: Repetitive transcranial magnetic stimulation (rTMS) is a widely used therapeutic tool in neurology and psychiatry, but its cellular and molecular mechanisms are not fully understood. Standardizing stimulus parameters, specifically electric field strength, is crucial in experimental and clinical settings. It enables meaningful comparisons across studies and facilitates the translation of findings into clinical practice. However, the impact of biophysical properties inherent to the stimulated neurons and networks on the outcome of rTMS protocols remains not well understood. Consequently, achieving standardization of biological effects across different brain regions and subjects poses a significant challenge. Methods: This study compared the effects of 10 Hz repetitive magnetic stimulation (rMS) in entorhino-hippocampal tissue cultures from mice and rats, providing insights into the impact of the same stimulation protocol on similar neuronal networks under standardized conditions. Results: We observed the previously described plastic changes in excitatory and inhibitory synaptic strength of CA1 pyramidal neurons in both mouse and rat tissue cultures, but a higher stimulation intensity was required for the induction of rMS-induced synaptic plasticity in rat tissue cultures. Through systematic comparison of neuronal structural and functional properties and computational modeling, we found that morphological parameters of CA1 pyramidal neurons alone are insufficient to explain the observed differences between the groups. Although morphologies of mouse and rat CA1 neurons showed no significant differences, simulations confirmed that axon morphologies significantly influence individual cell activation thresholds. Notably, differences in intrinsic cellular properties were sufficient to account for the 10% higher intensity required for the induction of synaptic plasticity in the rat tissue cultures. Conclusion: These findings demonstrate the critical importance of axon morphology and intrinsic cellular properties in predicting the plasticity effects of rTMS, carrying valuable implications for the development of computer models aimed at predicting and standardizing the biological effects of rTMS. [ABSTRACT FROM AUTHOR]

Background: Microelectronic prostheses for artificial vision stimulate neurons surviving outer retinal neurodegeneration such as retinitis pigmentosa (RP). Yet, the quality of prosthetic vision substantially varies across subjects, maybe due to different levels of retinal degeneration and/or distinct genotypes. Although the RP genotypes are remarkably diverse, prosthetic studies have primarily used retinal degeneration (rd) 1 and 10 mice, which both have Pde6b gene mutation. Here, we report the electric responses arising in retinal ganglion cells (RGCs) of the rd8 mouse model which has Crb1 mutation. Methods: We first investigated age-dependent histological changes of wild-type (wt), rd8, and rd10 mice retinas by H&E staining. Then, we used cell-attached patch clamping to record spiking responses of ON, OFF and direction selective (DS) types of RGCs to a 4-ms-long electric pulse. The electric responses of rd8 RGCs were analyzed in comparison with those of wt RGCs in terms of individual RGC spiking patterns, populational characteristics, and spiking consistency across trials. Results: In the histological examination, the rd8 mice showed partial retinal foldings, but the outer nuclear layer thicknesses remained comparable to those of the wt mice, indicating the early-stage of RP. Although spiking patterns of each RGC type seemed similar to those of the wt retinas, correlation levels between electric vs. light response features were different across the two mouse models. For example, in comparisons between light vs. electric response magnitudes, ON/OFF RGCs of the rd8 mice showed the same/opposite correlation polarity with those of wt mice, respectively. Also, the electric response spike counts of DS RGCs in the rd8 retinas showed a positive correlation with their direction selectivity indices (r = 0.40), while those of the wt retinas were negatively correlated (r = -0.90). Lastly, the spiking timing consistencies of late responses were largely decreased in both ON and OFF RGCs in the rd8 than the wt retinas, whereas no significant difference was found across DS RGCs of the two models. Conclusion: Our results indicate the electric response features are altered depending on RGC types even from the early-stage RP caused by Crb1 mutation. Given the various degeneration patterns depending on mutation genes, our study suggests the importance of both genotype- and RGC type-dependent analyses for retinal prosthetic research. [ABSTRACT FROM AUTHOR]

Animals often behave repetitively and predictably. These repetitive behaviors can have a component that is learned and ingrained as habits, which can be evolutionarily advantageous as they reduce cognitive load and the expenditure of attentional resources. Repetitive behaviors can also be conscious and deliberate, and may occur in the absence of habit formation, typically when they are a feature of normal development in children, or neuropsychiatric disorders. They can be considered pathological when they interfere with social relationships and daily activities. For instance, people affected by obsessivecompulsive disorder, autism spectrum disorder, Huntington's disease and Gilles de la Tourette syndrome can display a wide range of symptoms like compulsive, stereotyped and ritualistic behaviors. The striatum nucleus of the basal ganglia is proposed to act as a master regulator of these repetitive behaviors through its circuit connections with sensorimotor, associative, and limbic areas of the cortex. However, the precise mechanisms within the striatum, detailing its compartmental organization, cellular specificity, and the intricacies of its downstream connections, remain an area of active research. In this review, we summarize evidence across multiple scales, including circuitlevel, cellular, and molecular dimensions, to elucidate the striatal mechanisms underpinning repetitive behaviors and offer perspectives on the implicated disorders. We consider the close relationship between behavioral output and transcriptional changes, and thereby structural and circuit alterations, including those occurring through epigenetic processes. [ABSTRACT FROM AUTHOR]

Ultrasound is highly biopermeable and can non-invasively penetrate deep into the brain. Stimulation with patterned low-intensity ultrasound can induce sustained inhibition of neural activity in humans and animals, with potential implications for research and therapeutics. Although mechanosensitive channels are involved, the cellular and molecular mechanisms underlying neuromodulation by ultrasound remain unknown. To investigate the mechanism of action of ultrasound stimulation, we studied the effects of two types of patterned ultrasound on synaptic transmission and neural network activity using whole-cell recordings in primary cultured hippocampal cells. Single-shot pulsed-wave (PW) or continuous-wave (CW) ultrasound had no effect on neural activity. By contrast, although repetitive CW stimulation also had no effect, repetitive PW stimulation persistently reduced spontaneous recurrent burst firing. This inhibitory effect was dependent on extrasynaptic--but not synaptic--GABAA receptors, and the effect was abolished under astrocyte-free conditions. Pharmacological activation of astrocytic TRPA1 channels mimicked the effects of ultrasound by increasing the tonic GABAA current induced by ambient GABA. Pharmacological blockade of TRPA1 channels abolished the inhibitory effect of ultrasound. These findings suggest that the repetitive PW low-intensity ultrasound used in our study does not have a direct effect on neural function but instead exerts its sustained neuromodulatory effect through modulation of ambient GABA levels via channels with characteristics of TRPA1, which is expressed in astrocytes. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) and stroke stand as prominent causes of global disability and mortality. Treatment strategies for stroke and TBI are shifting from targeting neuroprotection toward cell-based neurorestorative strategy, aiming to augment endogenous brain remodeling, which holds considerable promise for the treatment of TBI and stroke. Compelling evidence underscores that the therapeutic effects of cell-based therapy are mediated by the active generation and release of exosomes from administered cells. Exosomes, endosomal derived and nano-sized extracellular vesicles, play a pivotal role in intercellular communication. Thus, we may independently employ exosomes to treat stroke and TBI. Systemic administration of mesenchymal stem cell (MSC) derived exosomes promotes neuroplasticity and neurological functional recovery in preclinical animal models of TBI and stroke. In this mini review, we describe the properties of exosomes and recent exosome-based therapies of TBI and stroke. It is noteworthy that the microRNA cargo within exosomes contributes to their therapeutic effects. Thus, we provide a brief introduction to microRNAs and insight into their key roles in mediating therapeutic effects. With the increasing knowledge of exosomes, researchers have "engineered" exosome microRNA content to amplify their therapeutic benefits. We therefore focus our discussion on the therapeutic benefits of recently employed microRNAenriched engineered exosomes. We also discuss the current opportunities and challenges in translating exosome-based therapy to clinical applications. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a major disease causing death and disability in the elderly and is one of the major diseases that seriously threaten human health and cause a great economic burden. In the early stage of ischemic stroke, neuronal structure is destroyed, resulting in death or damage, and the release of a variety of damage-associated pattern molecules induces an increase in neuroglial activation, peripheral immune response, and secretion of inflammatory mediators, which further exacerbates the damage to the blood-brain barrier, exacerbates cerebral edema, and microcirculatory impairment, triggering secondary brain injuries. After the acute phase of stroke, various immune cells initiate a protective effect, which is released step by step and contributes to the repair of neuronal cells through phenotypic changes. In addition, ischemic stroke induces Central Nervous System (CNS) immunosuppression, and the interaction between the two influences the outcome of stroke. Therefore, modulating the immune response of the CNS to reduce the inflammatory response and immune damage during stroke is important for the protection of brain function and long-term recovery after stroke, and modulating the immune function of the CNS is expected to be a novel therapeutic strategy. However, there are fewer studies on B-cells in brain function protection, which may play a dual role in the stroke process, and the understanding of this cell is still incomplete. We review the existing studies on the mechanisms of the role of B-cells, inflammatory response, and immune response in the development of ischemic stroke and provide a reference for the development of adjuvant therapeutic drugs for ischemic stroke targeting inflammatory injury. [ABSTRACT FROM AUTHOR]

Injuries to axons within the central nervous system (CNS) pose a substantial clinical challenge due to their limited regenerative capacity. This study investigates the therapeutic potential of Cell-free fat extract (CEFFE) in CNS injury. CEFFE was injected intravitreally after the optic nerve was crushed. Two weeks post-injury, quantification of regenerated axons and survival rates of retinal ganglion cells (RGCs) were performed. Subsequently, comprehensive gene ontology (GO) an-notation elucidated the cellular origins and functional attributes of CEFFE components. Molecular mechanisms underlying CEFFE’s therapeutic effects were explored through Western blotting (WB). Additionally, levels of inflammatory factors within CEFFE were determined using enzymelinked immunosorbent assay (ELISA), and histological staining of microglia was conducted to assess its impact on neuroinflammation. CEFFE demonstrated a significant capacity to promote axon re-generation and enhance RGCs survival. GO annotation revealed the involvement of 146 proteins within CEFFE in axonogenesis and neurogenesis. WB analysis unveiled the multifaceted pathways through which CEFFE exerts its therapeutic effects. Elevated levels of inflammatory factors were detected through ELISA, and CEFFE exhibited a modulatory effect on microglial activation in the retinal tissue following optic nerve crush (ONC). The present study highlights the therapeutic promise of CEFFE in the management of CNS injuries, exemplified by its ability to foster axon regeneration and improve RGCs survival. [ABSTRACT FROM AUTHOR]

This article discusses the role of eosinophils in olfactory dysfunction (OD) in patients with eosinophilic chronic rhinosinusitis (CRS). Eosinophilic infiltration in the olfactory mucosa is associated with severe OD and the loss of olfactory sensory neurons (OSNs). The authors suggest that further research is needed to understand the molecular mechanisms of tissue eosinophilia-induced injury of OSNs and develop new therapeutic targets for restoring olfactory function. The text also includes a list of references to various scientific articles related to chronic rhinosinusitis and olfactory dysfunction, providing valuable insights into the causes, mechanisms, and potential treatments for these conditions. [Extracted from the article]

Traumatic brain injury (TBI) is a public health burden affecting millions of people. Sustained neuroinflammation after TBI is often associated with poor outcome. As a result, increased attention has been placed on the role of immune cells in post-injury recovery. Microglia are highly dynamic after TBI and play a key role in the post-injury neuroinflammatory response. Therefore, microglia represent a malleable post-injury target that could substantially influence long-term outcome after TBI. This review highlights the cell specific role of microglia in TBI pathophysiology. Microglia have been manipulated via genetic deletion, drug inhibition, and pharmacological depletion in various preclinical TBI models. Notably, colony stimulating factor 1 (CSF1) and its receptor (CSF1R) have gained much traction in recent years as a pharmacological target on microglia. CSF1R is a transmembrane tyrosine kinase receptor that is essential for microglia proliferation, differentiation, and survival. Small molecule inhibitors targeting CSF1R result in a swift and effective depletion of microglia in rodents. Moreover, discontinuation of the inhibitors is sufficient for microglia repopulation. Attention is placed on summarizing studies that incorporate CSF1R inhibition of microglia. Indeed, microglia depletion affects multiple aspects of TBI pathophysiology, including neuroinflammation, oxidative stress, and functional recovery with measurable influence on astrocytes, peripheral immune cells, and neurons. Taken together, the data highlight an important role for microglia in sustaining neuroinflammation and increasing risk of oxidative stress, which lends to neuronal damage and behavioral deficits chronically after TBI. Ultimately, the insights gained from CSF1R depletion of microglia are critical for understanding the temporospatial role that microglia develop in mediating TBI pathophysiology and recovery. [ABSTRACT FROM AUTHOR]

Due to the increased crewed spaceflights in recent years, it is vital to understand how the space environment affects human health. A lack of gravitational force is known to risk multiple physiological functions of astronauts, particularly damage to the central nervous system (CNS). As innate immune cells of the CNS, microglia can transition from a quiescent state to a pathological state, releasing pro-inflammatory cytokines that contribute to neuroinflammation. There are reports indicating that microglia can be activated by simulating microgravity or exposure to galactic cosmic rays (GCR). Consequently, microglia may play a role in the development of neuroinflammation during spaceflight. Prolonged spaceflight sessions raise concerns about the chronic activation of microglia, which could give rise to various neurological disorders, posing concealed risks to the neural health of astronauts. This review summarizes the risks associated with neural health owing to microglial activation and explores the stressors that trigger microglial activation in the space environment. These stressors include GCR, microgravity, and exposure to isolation and stress. Of particular focus is the activation of microglia under microgravity conditions, along with the proposal of a potential mechanism. [ABSTRACT FROM AUTHOR]

Fluorescence microscopy remains one of the single most widely applied experimental approaches in neuroscience and beyond and is continuously evolving to make it easier and more versatile. The success of the approach is based on synergistic developments in imaging technologies and fluorophore labeling strategies that have allowed it to greatly diversify and be used across preparations for addressing structure as well as function. Yet, while targeted labeling strategies are a key strength of fluorescence microscopy, they reciprocally impose general limitations on the possible types of experiments and analyses. One recent development that overcomes some of these limitations is fluorescence microscopy shadow imaging, where membranebound cellular structures remain unlabeled while the surrounding extracellular space is made to fluoresce to provide a negative contrast shadow image. When based on super-resolution STED microscopy, the technique in effect provides a positive image of the extracellular space geometry and entire neuropil in the field of view. Other noteworthy advantages include the near elimination of the adverse effects of photobleaching and toxicity in live imaging, exhaustive and homogeneous labeling across the preparation, and the ability to apply and adjust the label intensity on the fly. Shadow imaging is gaining popularity and has been applied on its own or combined with conventional positive labeling to visualize cells and synaptic proteins in their parenchymal context. Here, we highlight the inherent limitations of fluorescence microscopy and conventional labeling and contrast these against the pros and cons of recent shadow imaging approaches. Our aim is to describe the brief history and current trajectory of the shadow imaging technique in the neuroscience field, and to draw attention to its ease of application and versatility. [ABSTRACT FROM AUTHOR]

Schizophrenia is a complex and severe mental disorder that affects approximately 1% of the global population. It is characterized by a wide range of symptoms, including delusions, hallucinations, disorganized speech and behavior, and cognitive impairment. Recent research has suggested that the immune system dysregulation may play a significant role in the pathogenesis of schizophrenia, and glial cells, such as astroglia and microglia known to be involved in neuroinflammation and immune regulation, have emerged as potential players in this process. The aim of this systematic review is to summarize the glial hallmarks of schizophrenia, choosing as cellular candidate the astroglia and microglia, and focusing also on disease-associated psychological (cognitive and emotional) changes. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed, Scopus, and Web of Science for articles that investigated the differences in astroglia and microglia in patients with schizophrenia, published in the last 5 years. The present systematic review indicates that changes in the density, morphology, and functioning of astroglia and microglia may be involved in the development of schizophrenia. The glial alterations may contribute to the pathogenesis of schizophrenia by dysregulating neurotransmission and immune responses, worsening cognitive capabilities. The complex interplay of astroglial and microglial activation, genetic/epigenetic variations, and cognitive assessments underscores the intricate relationship between biological mechanisms, symptomatology, and cognitive functioning in schizophrenia. [ABSTRACT FROM AUTHOR]

Introduction: Understanding the neural code has been one of the central aims of neuroscience research for decades. Spikes are commonly referred to as the units of information transfer, but multi-unit activity (MUA) recordings are routinely analyzed in aggregate forms such as binned spike counts, peristimulus time histograms, firing rates, or population codes. Various forms of averaging also occur in the brain, from the spatial averaging of spikes within dendritic trees to their temporal averaging through synaptic dynamics. However, how these forms of averaging are related to each other or to the spatial and temporal units of information representation within the neural code has remained poorly understood. Materials and methods: In this work we developed NeuroPixelHD, a symbolic hyperdimensional model of MUA, and used it to decode the spatial location and identity of static images shown to n = 9 mice in the Allen Institute Visual Coding—NeuroPixels dataset from large-scale MUA recordings. We parametrically varied the spatial and temporal resolutions of the MUA data provided to the model, and compared its resulting decoding accuracy. Results: For almost all subjects, we found 125ms temporal resolution to maximize decoding accuracy for both the spatial location of Gabor patches (81 classes for patches presented over a 9×9 grid) as well as the identity of natural images (118 classes corresponding to 118 images) across the whole brain. This optimal temporal resolution nevertheless varied greatly between dierent regions, followed a sensory-associate hierarchy, and was significantly modulated by the central frequency of theta-band oscillations across dierent regions. Spatially, the optimal resolution was at either of two mesoscale levels for almost all mice: the area level, where the spiking activity of all neurons within each brain area are combined, and the population level, where neuronal spikes within each area are combined across fast spiking (putatively inhibitory) and regular spiking (putatively excitatory) neurons, respectively. We also observed an expected interplay between optimal spatial and temporal resolutions, whereby increasing the amount of averaging across one dimension (space or time) decreases the amount of averaging that is optimal across the other dimension, and vice versa. Discussion: Our findings corroborate existing empirical practices of spatiotemporal binning and averaging in MUA data analysis, and provide a rigorous computational framework for optimizing the level of such aggregations. Our findings can also synthesize these empirical practices. [ABSTRACT FROM AUTHOR]

Introduction: Post-infection syndromes are characterised by fatigue, muscle pain, anhedonia, and cognitive impairment; mechanistic studies exploring these syndromes have focussed on pathways downstream of Toll-like receptor (TLR) 4 activation. Here, we investigated the mechanistic interplay between behaviour, metabolism, and inflammation downstream of TLR-7 activation compared to TLR-4 activation in male and female CD1 mice. Methods: Animals received either a TLR-4 (LPS; 0.83 mg/kg) or TLR-7 (R848, 5 mg/kg) agonist, or saline, and behaviour was analysed in an Open Field (OF) at 24 h (n = 20/group). Plasma, liver, and prefrontal cortex (PFC) were collected for gene expression analysis at 24 h and 1H-NMR metabolomics. Results: TLR-4 and TLR-7 activation decreased distance travelled and rearing in the OF, but activation of each receptor induced distinct cytokine responses and metabolome profiles. LPS increased IL-1b expression and CXCL1 in the PFC, but TLR7 activation did not and strongly induced PFC CXCL10 expression. Thus, TLR7 induced sickness behaviour is independent of IL-1b expression. In both cases, the behavioural response to TLR activation was sexually dimorphic: females were more resilient. However, dissociation was observed between the resilient female mice behaviour and the levels of gene cytokine expression, which was, in general, higher in the female mice. However, the metabolic shifts induced by immune activation were better correlated with the sex-dependent behavioural dimorphisms; increased levels of antioxidant potential in the female brain are intrinsic male/female metabolome differences. A common feature of both TLR4 and TLR7 activation was an increase in N-acetyl aspartate (NAA) in the PFC, which is likely be an allostatic response to the challenges as sickness behaviour is inversely correlated with NAA levels. Discussion: The results highlight how the cytokine profile induced by one PAMP cannot be extrapolated to another, but they do reveal how the manipulation of the conserved metabolome response might afford a more generic approach to the treatment of post-infection syndromes. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) is a form of retinal degeneration characterized by primary degeneration of rod photoreceptors followed by a secondary cone loss that leads to vision impairment and finally blindness. This is a rare disease with mutations in several genes and high genetic heterogeneity. A challenging effort has been the characterization of the molecular mechanisms underlying photoreceptor cell death during the progression of the disease. Some of the cell death pathways have been identified and comprise stress events found in several neurodegenerative diseases such as oxidative stress, inflammation, calcium imbalance and endoplasmic reticulum stress. Other cell death mechanisms appear more relevant to photoreceptor cells, such as high levels of cGMP and metabolic changes. Here we review some of the cell death pathways characterized in the RP mutant retina and discuss preclinical studies of therapeutic approaches targeting the molecular outcomes that lead to photoreceptor cell demise. [ABSTRACT FROM AUTHOR]

Engineered 3D neural tissues made of neurons and glial cells derived from human induced pluripotent stem cells (hiPSC) are among the most promising tools in drug discovery and neurotoxicology. They represent a cheaper, faster, and more ethical alternative to in vivo animal testing that will likely close the gap between in vitro animal models and human clinical trials. Micro-Electrode Array (MEA) technology is known to provide an assessment of compound effects on neural 2D cell cultures and acute tissue preparations by real-time, non-invasive, and long-lasting electrophysiological monitoring of spontaneous and evoked neuronal activity. Nevertheless, the use of engineered 3D neural tissues in combination with MEA biochips still involves series of constraints, such as drastically limited diffusion of oxygen and nutrients within tissues mainly due to the lack of vascularization. Therefore, 3D neural tissues are extremely sensitive to experimental conditions and require an adequately designed interface that provides optimal tissue survival conditions. A well-suited technique to overcome this issue is the combination of the Air-Liquid Interface (ALI) tissue culture method with the MEA technology. We have developed a full 3D neural tissue culture process and a data acquisition system composed of high-end electronics and novel MEA biochips based on porous, flexible, thin-film membranes integrating recording electrodes, named as “Strip-MEA,” to allow the maintenance of an ALI around the 3D neural tissues. The main motivation of the porous MEA biochips development was the possibility to monitor and to study the electrical activity of 3D neural tissues under different recording configurations, (i) the Strip-MEA can be placed below a tissue, (ii) or by taking advantage of the ALI, be directly placed on top of the tissue, or finally, (iii) it can be embedded into a larger neural tissue generated by the fusion of two (or more) tissues placed on both sides of the Strip-MEA allowing the recording from its inner part. This paper presents the recording and analyses of spontaneous activity from the three positioning configurations of the Strip-MEAs. Obtained results are discussed with the perspective of developing in vitro models of brain diseases and/or impairment of neural network functioning.

Pleiotrophin (PTN) is a secreted growth factor, and also a cytokine, associated with the extracellular matrix, which has recently starting to attract attention as a significant neuromodulator with multiple neuronal functions during development. PTN is expressed in several tissues, where its signals are generally related with cell proliferation, growth, and differentiation by acting through different receptors. In Central Nervous System (CNS), PTN exerts post-developmental neurotrophic and -protective effects, and additionally has been involved in neurodegenerative diseases and neural disorders. Studies in Drosophila shed light on some aspects of the different levels of regulatory control of PTN invertebrate homologs. Specifically in hippocampus, recent evidence from PTN Knock-out (KO) mice involves PTN functioning in learning and memory. In this paper, we summarize, discuss, and contrast the most recent advances and results that lead to proposing a PTN as a neuromodulatory molecule in the CNS, particularly in hippocampus. [ABSTRACT FROM AUTHOR]

This brief review summarizes work done in mammalian neuroscience concerning the intrinsic electrophysiological properties of four neuronal types; Cerebellar Purkinje cells, inferior olivary cells, thalamic cells, and some cortical interneurons. It is a personal perspective addressing an interesting time in neuroscience when the reflex view of brain function, as the paradigm to understand global neuroscience, began to be modified toward one in which sensory input modulates rather than dictates brain function. The perspective of the paper is not a comprehensive description of the intrinsic electrical properties of all nerve cells but rather addresses a set of cell types that provide indicative examples of mechanisms that modulate brain function. [ABSTRACT FROM AUTHOR]

Drug biotransformation is a crucial mechanism for facilitating the elimination of chemicals from the organism and for decreasing their pharmacological activity. Published evidence suggests that brain drug metabolism may play a role in the development of adverse drug reactions and in the clinical response to drugs and xenobiotics. The blood-brain barrier (BBB) has been regarded mainly as a physical barrier for drugs and xenobiotics, and little attention has been paid to the BBB as a drug-metabolizing barrier. The presence of drug-metabolizing enzymes in the BBB is likely to have functional implications because local metabolism may inactivate drugs or may modify the drug's ability to cross the BBB, thus modifying drug response and the risk of developing adverse drug reactions. In this perspective paper, we discuss the expression of relevant xenobiotic metabolizing enzymes in the brain and in the BBB, and we cover current advances and future directions on the potential role of these BBB drug-metabolizing enzymes as modifiers of drug response. [ABSTRACT FROM AUTHOR]

The neurons in layer II of the medial entorhinal cortex are part of the grid cell network involved in the representation of space. Many of these neurons are likely to be stellate cells with specific oscillatory and firing properties important for their function. A fundamental understanding of the nonlinear basis of these oscillatory properties is critical for the development of theories of grid cell firing. In order to evaluate the behavior of stellate neurons, measurements of their quadratic responses were used to estimate a second order Volterra kernel. This paper uses an operator theory, termed quadratic sinusoidal analysis (QSA), which quantitatively determines that the quadratic response accounts for a major part of the nonlinearity observed at membrane potential levels characteristic of normal synaptic events. Practically, neurons were probed with multi-sinusoidal stimulations to determine a Hermitian operator that captures the quadratic function in the frequency domain. We have shown that the frequency content of the stimulation plays an important role in the characteristics of the nonlinear response, which can distort the linear response as well. Stimulations with enhanced low frequency amplitudes evoked a different nonlinear response than broadband profiles. The nonlinear analysis was also applied to spike frequencies and it was shown that the nonlinear response of subthreshold membrane potential at resonance frequencies near the threshold is similar to the nonlinear response of spike trains. [ABSTRACT FROM AUTHOR]

Since the initial cloning of fractalkine/CX3CL1, itwas proposed that the only knownmember of the CX3C or δ subfamily of chemotactic cytokines could play some significant role in the nervous system, due to its high expression on neurons. The pivotal description of the localization of the unique CX3CL1 receptor, CX3CR1, on microglial cells, firmed up by the generation of cx3cr1GFP/GFP mice, opened the road to the hypothesis of some specific key interactions between microglia and neurons mediated by this pair. This expectation has been indeed supported by recent exciting evidence indicating that CX3CL1-mediated microglia-neuron interaction modulates basic physiological activities during development, adulthood and aging, including: synaptic pruning; promoting survival of neurons and neural precursors; modulating synaptic transmission and plasticity; enhancing synapse and network maturation; and facilitating the establishment of neuropathic pain circuits. Beyond playing such fascinating roles in physiological conditions, CX3CL1 signaling has been implicated in different neuropathologies. Early papers demonstrated that the levels of CX3CL1 may be modulated by various toxic stimuli in vitro and that CX3CL1 signaling is positively or negatively regulated in EAE and MS, in HIV infection and LPS challenge, in epilepsy, in brain tumors, and in other neuropathologies. In this review we focus on the experimental evidence of CX3CL1 involvement in neuroprotection and survey the common molecular and cellular mechanisms described in different brain diseases. [ABSTRACT FROM AUTHOR]

The pineal gland transduces photoperiodic changes to the neuroendocrine system by rhythmic secretion of melatonin. We recently provided new evidence that the pineal gland is a major neurosteroidogenic organ and actively produces a variety of neurosteroids de novo from cholesterol in birds. Notably, allopregnanolone is a major pineal neurosteroid that is far more actively produced in the pineal gland than the brain and secreted by the pineal gland in juvenile birds. Subsequently, we have demonstrated the biological action of pineal allopregnanolone on Purkinje cells in the cerebellum during development in juvenile birds. Pinealectomy (Px) induces apoptosis of Purkinje cells, whereas allopregnanolone administration to Px chicks prevents cell death. Furthermore, Px increases the number of Purkinje cells that express active caspase-3, a crucial mediator of apoptosis, and allopregnanolone administration to Px chicks decreases the number of Purkinje cells expressing active caspase-3. It thus appears that pineal allopregnanolone prevents cell death of Purkinje cells by suppressing the activity of caspase-3 during development. This paper highlights new aspects of the biosynthesis and biological action of pineal allopregnanolone. [ABSTRACT FROM AUTHOR]

The pineal gland transduces photoperiodic changes to the neuroendocrine system by rhythmic secretion of melatonin. We recently provided new evidence that the pineal gland is a major neurosteroidogenic organ and actively produces a variety of neurosteroids de novo from cholesterol in birds. Notably, allopregnanolone is a major pineal neurosteroid that is far more actively produced in the pineal gland than the brain and secreted by the pineal gland in juvenile birds. Subsequently, we have demonstrated the biological action of pineal allopregnanolone on Purkinje cells in the cerebellum during development in juvenile birds. Pinealectomy (Px) induces apoptosis of Purkinje cells, whereas allopregnanolone administration to Px chicks prevents cell death. Furthermore, Px increases the number of Purkinje cells that express active caspase-3, a crucial mediator of apoptosis, and allopregnanolone administration to Px chicks decreases the number of Purkinje cells expressing active caspase-3. It thus appears that pineal allopregnanolone prevents cell death of Purkinje cells by suppressing the activity of caspase-3 during development. This paper highlights new aspects of the biosynthesis and biological action of pineal allopregnanolone. [ABSTRACT FROM AUTHOR]

It is now widely accepted that glia cells and gamma-aminobutyric acidergic (GABA) interneurons dynamically regulate synaptic transmission and neuronal activity in time and space. This paper presents a biophysical model that captures the interaction between an astrocyte cell, a GABA interneuron and pre/postsynaptic neurons. Specifically, GABA released from a GABA interneuron triggers in astrocytes the release of calcium (Ca2+) from the endoplasmic reticulum via the inositol 1, 4, 5-trisphosphate (IP3) pathway. This results in gliotransmission which elevates the presynaptic transmission probability rate (PR) causing weight potentiation and a gradual increase in postsynaptic neuronal firing, that eventually stabilizes. However, by capturing the complex interactions between IP3, generated from both GABA and the 2-arachidonyl glycerol (2-AG) pathway, and PR, this paper shows that this interaction not only gives rise to an initial weight potentiation phase but also this phase is followed by postsynaptic bursting behavior. Moreover, the model will show that there is a presynaptic frequency range over which burst firing can occur. The proposed model offers a novel cellular level mechanism that may underpin both seizure-like activity and neuronal synchrony across different brain regions.

It has recently been proposed using a multi-compartmental mathematical model that negatively fixed charged membrane-associated sites constrain the flow of cations in perisynaptic astroglial processes. This restricted movement of ions between the perisynaptic cradle (PsC), principal astroglial processes and the astrocyte soma gives rise to potassium (K+) and sodium (Na+) microdomains at the PsC. The present paper extends the above model to demonstrate that the formation of an Na+ microdomain can reverse the Na+/Ca2+ exchanger (NCX) thus providing an additional source of calcium (Ca2+) at the PsC. Results presented clearly show that reversal of the Na+/Ca2+ exchanger is instigated by a glutamate transporter coupled increase in concentration of cytoplasmic [Na+]i at the PsC, which and instigates Ca2+ influx through the NCX. As the flow of Ca2+ along the astrocyte process and away from the PsC is also constrained by Ca2+ binding proteins, then a Ca2+ microdomain forms at the PsC. The paper also serves to demonstrate that the EAAT, NKA, and NCX represent the minimal requirement necessary and sufficient for the development of a Ca2+ microdomain and that these mechanisms directly link neuronal activity and glutamate release to the formation of localized Na+ and Ca2+ microdomains signals at the PsC. This local source of Ca2+ can provide a previously underexplored form of astroglial Ca2+ signaling.

We investigated the functional expression of nicotinic acetylcholine receptors (nAChRs) in heterogeneous populations of dissociated rat and mouse lumbar dorsal root ganglion (DRG) neurons by calcium imaging. By this experimental approach, it is possible to investigate the functional expression of multiple receptor and ion-channel subtypes across more than 100 neuronal and glial cells simultaneously. Based on nAChR expression, DRG neurons could be divided into four subclasses: (1) neurons that express predominantly α3β4 and α6β4 nAChRs; (2) neurons that express predominantly α7 nAChRs; (3) neurons that express a combination of α3β4/α6β4 and α7 nAChRs; and (4) neurons that do not express nAChRs. In this comparative study, the same four neuronal subclasses were observed in mouse and rat DRG. However, the expression frequency differed between species: substantially more rat DRG neurons were in the first three subclasses than mouse DRG neurons, at all developmental time points tested in our study. Approximately 70–80% of rat DRG neurons expressed functional nAChRs, in contrast to only ~15–30% of mouse DRG neurons. Our study also demonstrated functional coupling between nAChRs, voltagegated calcium channels, and mitochondrial Ca2+ transport in discrete subsets of DRG neurons. In contrast to the expression of nAChRs in DRG neurons, we demonstrated that a subset of non-neuronal DRG cells expressed muscarinic acetylcholine receptors and not nAChRs. The general approach to comparative cellular neurobiology outlined in this paper has the potential to better integrate molecular and systems neuroscience by uncovering the spectrum of neuronal subclasses present in a given cell population and the functionally integrated signaling components expressed in each subclass. [ABSTRACT FROM AUTHOR]

The schizophrenia brain is differentiated from the normal brain by subtle changes, with significant overlap in measures between normal and disease states. For the past 25 years, schizophrenia has increasingly been considered a neurodevelopmental disorder. This frame of reference challenges biological researchers to consider how pathological changes identified in adult brain tissue can be accounted for by aberrant developmental processes occurring during fetal, childhood, or adolescent periods. To place schizophrenia neuropathology in a neurodevelopmental context requires solid, scrutinized evidence of changes occurring during normal development of the human brain, particularly in the cortex; however, too often data on normative developmental change are selectively referenced. This paper focuses on the development of the prefrontal cortex and charts major molecular, cellular, and behavioral events on a similar time line. We first consider the time at which human cognitive abilities such as selective attention, working memory, and inhibitory control mature, emphasizing that attainment of full adult potential is a process requiring decades. We review the timing of neurogenesis, neuronal migration, white matter changes (myelination), and synapse development. We consider how molecular changes in neurotransmitter signaling pathways are altered throughout life and how they may be concomitant with cellular and cognitive changes. We end with a consideration of how the response to drugs of abuse changes with age. We conclude that the concepts around the timing of cortical neuronal migration, interneuron maturation, and synaptic regression in humans may need revision and include greater emphasis on the protracted and dynamic changes occurring in adolescence. Updating our current understanding of post-natal neurodevelopment should aid researchers in interpreting gray matter changes and derailed neurodevelopmental processes that could underlie emergence of psychosis. [ABSTRACT FROM AUTHOR]

This document is an editorial from the journal Frontiers in Cellular Neuroscience titled "Crosstalk within neurovascular unit: endothelial implications for the development and function of brain." The editorial discusses the importance of the neurovascular unit (NVU), which consists of neurons, astrocytes, pericytes, and endothelial cells, in maintaining brain homeostasis and regulating cerebral blood flow. It highlights the crucial role of endothelial cells in the communication between neurons and the vasculature, emphasizing their involvement in processes such as neurogenesis, synaptogenesis, and maintaining the blood-brain barrier (BBB) integrity. The editorial introduces a research topic that explores the concept of crosstalk within the NVU, with a specific focus on the role of endothelial cells. The research presented in this topic aims to enhance understanding of the neurovascular unit and potentially lead to therapeutic interventions for neurological disorders. The document also briefly summarizes the findings of four articles included in the research topic, which investigate the effects of prenatal alcohol exposure on placental and neurovascular development, the impact of a selective receptor agonist on endothelial cell function and mitochondrial biogenesis in a mouse model of spinal cord injury, the modulation of blood-brain barrier permeability and neuronal excitability through electroacupuncture, and the involvement of microRNA-34a in ischemic stroke and BBB permeability. The authors express their gratitude to the contributors and invite readers to explore the topic further. [Extracted from the article]

This document is an editorial titled "Women in cellular neuropathology" published in the journal Frontiers in Cellular Neuroscience. The editorial discusses the importance of understanding the cellular and molecular basis of neurological and psychiatric disorders in order to improve diagnosis and treatment. It highlights key research avenues and promising approaches in the field, including the study of myelin ultrastructural changes, cavitating leukoencephalopathy caused by COA8 cytochrome C oxidase deficiency, the role of non-coding RNA in neuronal degeneration, the crosstalk between antimicrobial peptides and the nervous system, and the aberrant responses of glial cells in psychiatric diseases. The editorial emphasizes the need for further research and collaboration to develop targeted therapies and alleviate the burden of these conditions. [Extracted from the article]

Introduction: Spatial representations in the entorhinal cortex (EC) and hippocampus (HPC) are fundamental to cognitive functions like navigation and memory. These representations, embodied in spatial field maps, dynamically remap in response to environmental changes. However, current methods, such as Pearson's correlation coefficient, struggle to capture the complexity of these remapping events, especially when fields do not overlap, or transformations are non-linear. This limitation hinders our understanding and quantification of remapping, a key aspect of spatial memory function. Methods: We propose a family of metrics based on the Earth Mover's Distance (EMD) as a versatile framework for characterizing remapping. Results: The EMD provides a granular, noise-resistant, and rate-robust description of remapping. This approach enables the identification of specific cell types and the characterization of remapping in various scenarios, including disease models. Furthermore, the EMD's properties can be manipulated to identify spatially tuned cell types and to explore remapping as it relates to alternate information forms such as spatiotemporal coding. Discussion: We present a feasible, lightweight approach that complements traditional methods. Our findings underscore the potential of the EMD as a powerful tool for enhancing our understanding of remapping in the brain and its implications for spatial navigation, memory studies and beyond. [ABSTRACT FROM AUTHOR]

Background: Apoptosis after spinal cord injury (SCI) plays a pivotal role in the secondary injury mechanisms, which cause the ultimate neurologic insults. A better understanding of the molecular and cellular basis of apoptosis in SCI allows for improved glial and neuronal survival via the administrations of anti-apoptotic biomarkers. The knowledge structure, development trends, and research hotspots of apoptosis and SCI have not yet been systematically investigated. Methods: Articles and reviews on apoptosis and SCI, published from 1st January 1994 to 1st Oct 2023, were retrieved from the Web of ScienceTM. Bibliometrix in R was used to evaluate annual publications, countries, affiliations, authors, sources, documents, key words, and hot topics. Results: A total of 3,359 publications in accordance with the criterions were obtained, which exhibited an ascending trend in annual publications. The most productive countries were the USA and China. Journal of Neurotrauma was the most impactive journal; Wenzhou Medical University was the most prolific affiliation; Cuzzocrea S was the most productive and influential author. "Apoptosis," "spinal-cord-injury," "expression," "activation," and "functional recovery" were the most frequent key words. Additionally, "transplantation," "mesenchymal stemness-cells," "therapies," "activation," "regeneration," "repair," "autophagy," "exosomes," "nlrp3 inflammasome," "neuroinflammation," and "knockdown" were the latest emerging key words, which may inform the hottest themes. Conclusions: Apoptosis after SCI may cause the ultimate neurological damages. Development of novel treatments for secondary SCI mainly depends on a better understanding of apoptosis-related mechanisms in molecular and cellular levels. Such therapeutic interventions involve the application of anti-apoptotic agents, free radical scavengers, as well as anti-inflammatory drugs, which can be targeted to inhibit core events in cellular and molecular injury cascades pathway. [ABSTRACT FROM AUTHOR]