Frontiers in Cellular Neuroscience最新文献

Neurovascular unit (NVU) inflammation via activation of glial cells and neuronal damage plays a critical role in neurodegenerative diseases. Though the exact mechanism of disease pathogenesis is not understood, certain biomarkers provide valuable insight into the disease pathogenesis, severity, progression and therapeutic efficacy. These markers can be used to assess pathophysiological status of brain cells including neurons, astrocytes, microglia, oligodendrocytes, specialized microvascular endothelial cells, pericytes, NVU, and blood-brain barrier (BBB) disruption. Damage or derangements in tight junction (TJ), adherens junction (AdJ), and gap junction (GJ) components of the BBB lead to increased permeability and neuroinflammation in various brain disorders including neurodegenerative disorders. Thus, neuroinflammatory markers can be evaluated in blood, cerebrospinal fluid (CSF), or brain tissues to determine neurological disease severity, progression, and therapeutic responsiveness. Chronic inflammation is common in age-related neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia. Neurotrauma/traumatic brain injury (TBI) also leads to acute and chronic neuroinflammatory responses. The expression of some markers may also be altered many years or even decades before the onset of neurodegenerative disorders. In this review, we discuss markers of neuroinflammation, and neurodegeneration associated with acute and chronic brain disorders, especially those associated with neurovascular pathologies. These biomarkers can be evaluated in CSF, or brain tissues. Neurofilament light (NfL), ubiquitin C-terminal hydrolase-L1 (UCHL1), glial fibrillary acidic protein (GFAP), Ionized calcium-binding adaptor molecule 1 (Iba-1), transmembrane protein 119 (TMEM119), aquaporin, endothelin-1, and platelet-derived growth factor receptor beta (PDGFRβ) are some important neuroinflammatory markers. Recent BBB-on-a-chip modeling offers promising potential for providing an in-depth understanding of brain disorders and neurotherapeutics. Integration of these markers in clinical practice could potentially enhance early diagnosis, monitor disease progression, and improve therapeutic outcomes.

Alzheimer's disease (AD) is marked by the gradual and age-related deterioration of nerve cells in the central nervous system. The histopathological features observed in the brain affected by AD are the aberrant buildup of extracellular and intracellular amyloid-β and the formation of neurofibrillary tangles consisting of hyperphosphorylated tau protein. Axonal transport is a fundamental process for cargo movement along axons and relies on molecular motors like kinesins and dyneins. Kinesin's responsibility for transporting crucial cargo within neurons implicates its dysfunction in the impaired axonal transport observed in AD. Impaired axonal transport and dysfunction of molecular motor proteins, along with dysregulated signaling pathways, contribute significantly to synaptic impairment and cognitive decline in AD. Dysregulation in tau, a microtubule-associated protein, emerges as a central player, destabilizing microtubules and disrupting the transport of kinesin-1. Kinesin-1 superfamily members, including kinesin family members 5A, 5B, and 5C, and the kinesin light chain, are intricately linked to AD pathology. However, inconsistencies in the abundance of kinesin family members in AD patients underline the necessity for further exploration into the mechanistic impact of these motor proteins on neurodegeneration and axonal transport disruptions across a spectrum of neurological conditions. This review underscores the significance of kinesin-1's anterograde transport in AD. It emphasizes the need for investigations into the underlying mechanisms of the impact of motor protein across various neurological conditions. Despite current limitations in scientific literature, our study advocates for targeting kinesin and autophagy dysfunctions as promising avenues for novel therapeutic interventions and diagnostics in AD.

Several studies in both animal models and in humans have provided substantial evidence that early life stress (ELS) induces long-term changes in behavior and brain function, making it a significant risk factor in the aetiology of various mental disorders, including anxiety and depression. In this study, we tested the hypothesis that ELS in male rats (i) leads to increased anxiety and depressive-like symptoms; and (ii) that these behavioral changes are associated with functional alterations in the endocannabinoid system of the medial prefrontal cortex (mPFC). We further assessed whether the predicted changes in the gene expression of two key components of the endocannabinoid system, cannabinoid receptor 1 (CB1R) and the fatty acid amide hydrolase (FAAH), are regulated by epigenetic mechanisms. Behavioral profiling revealed that the proportion of behaviorally affected animals was increased in ELS exposed male rats compared to control animals, specifically showing symptoms of anhedonia and impaired social behavior. On the molecular level we observed a decrease in CB1R and FAAH mRNA expression in the mPFC of adult ELS exposed animals. These gene expression changes were accompanied by reduced global histone 3 acetylation in the mPFC, while no significant changes in DNA methylation and no significant changes of histone-acetylation at the promoter regions of the analyzed genes were detected. Taken together, our data provide evidence that ELS induces a long-term reduction of CB1R and FAAH expression in the mPFC of adult male rats, which may partially contribute to the ELS-induced changes in adult socio-emotional behavior.

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

Disruption of inhibitory interneurons is common in the epileptic brain and is hypothesized to play a pivotal role in epileptogenesis. Abrupt disruption and loss of interneurons is well-characterized in status epilepticus models of epilepsy, however, status epilepticus is a relatively rare cause of epilepsy in humans. How interneuron disruption evolves in other forms of epilepsy is less clear. Here, we explored how somatostatin (SST) interneuron disruption evolves in quadruple transgenic Gli1-CreER^T2, Pten^fl/fl, SST-FlpO, and frt-eGFP mice. In these animals, epilepsy develops following deletion of the mammalian target of rapamycin (mTOR) negative regulator phosphatase and tensin homolog (Pten) from a subset of dentate granule cells, while downstream Pten-expressing SST neurons are fate-mapped with green fluorescent protein (GFP). The model captures the genetic complexity of human mTORopathies, in which mutations can be restricted to excitatory neuron lineages, implying that interneuron involvement is later developing and secondary. In dentate granule cell (DGC)-Pten knockouts (KOs), the density of fate-mapped SST neurons was reduced in the hippocampus, but their molecular phenotype was unchanged, with similar percentages of GFP+ cells immunoreactive for SST and parvalbumin (PV). Surviving SST neurons in the dentate gyrus had larger somas, and the density of GFP+ processes in the dentate molecular layer was unchanged despite SST cell loss and expansion of the molecular layer, implying compensatory sprouting of surviving cells. The density of Znt3-immunolabeled puncta, a marker of granule cell presynaptic terminals, apposed to GFP+ processes in the hilus was increased, suggesting enhanced granule cell input to SST neurons. Finally, the percentage of GFP+ cells that were FosB positive was significantly increased, implying that surviving SST neurons are more active. Together, findings suggest that somatostatin-expressing interneurons exhibit a combination of pathological (cell loss) and adaptive (growth) responses to hyperexcitability and seizures driven by upstream Pten KO excitatory granule cells.

Information storage and transfer in the brain require a high computational power. Neuronal network display various local or global mechanisms to allow information storage and transfer in the brain. From synaptic to intrinsic plasticity, the rules of input-output function modulation have been well characterized in neurons. In the past years, astrocytes have been suggested to increase the computational power of the brain and we are only just starting to uncover their role in information processing. Astrocytes maintain a close bidirectional communication with neurons to modify neuronal network excitability, transmission, axonal conduction, and plasticity through various mechanisms including the release of gliotransmitters or local ion homeostasis. Astrocytes have been significantly studied in the context of long-term or short-term synaptic plasticity, but this is not the only mechanism involved in memory formation. Plasticity of intrinsic neuronal excitability also participates in memory storage through regulation of voltage-gated ion channels or axonal morphological changes. Yet, the contribution of astrocytes to these other forms of non-synaptic plasticity remains to be investigated. In this review, we summarized the recent advances on the role of astrocytes in different forms of plasticity and discuss new directions and ideas to be explored regarding astrocytes-neuronal communication and regulation of plasticity.

Recent studies indicate that astrocytes show heterogeneity in morphology and physiological function. They integrate synaptic signals and release calcium in reaction to active neurons. These calcium signals are not yet fully understood as they are highly dependent on the cell's morphology, which can vary across and within brain regions. We found structural heterogeneity among mouse hippocampal CA1 astrocytes based on geometric features, clustering 741 cells into six classes. Of those, we selected 84 cells and reconstructed their morphology based on confocal microscope images and converted them into multi-compartment models with a high detailedness. We applied a computational biophysical model simulating the intracellular ion and IP₃ signaling and diffusion in those 3D cell geometries. The cells were stimulated with three different glutamate stimuli. Calcium mainly oscillated in the stimulated and the neighboring compartment but not in the soma. Significant differences were found in the peak width, mean prominence, and mean peak amplitude of the calcium signal when comparing the signals in the stimulated and neighboring compartments. Overall, this study highlights the influence of the complex morphology of astrocytes on intracellular ionic signaling.

Astrocytes are key components of the neurovascular unit. While we have recently identified Olig2+ astrocyte progenitors (ASPs) in the developing mouse dentate gyrus (DG), their molecular signature remains incompletely characterized. Here we demonstrate that Olig2+ ASPs predominantly express brain lipid-binding protein (BLBP), while only a small population of them expresses gfap-GFP. These Olig2+/BLBP+ ASPs co-express the transcription factors Sox3, Sox9 and the proteoglycan NG2 but not Sox10, a marker for oligodendrocyte progenitors (OLPs). Olig2+ ASPs appear from embryonic day 18 (E18) onwards and decline at postnatal day 14 (P14). Consistent with the proliferation of both Olig2+ and NG2+ glial cells after brain injury, intrauterine intermittent hypoxia (IH) led to an increase in Olig2+/NG2+/BLBP+ ASPs in the postnatal DG. IH also promoted both angiogenesis and vascular coupling of Olig2+/NG2+ ASPs. Our data suggest that IH-induced expression of HIF1a increases Olig2+/NG2+/BLBP+ ASPs in a cell non-autonomous manner. Our data also revealed increased vascular coupling of GFAP+ astrocytes following IH, while the number of GFAP+ astrocytes remains unchanged. Given that BLBP, Olig2 and NG2 are expressed in reactive astrocytes, our findings suggest that Olig2+/NG2+/BLBP+ ASPs represent a subtype of reactive astrocyte progenitors. Furthermore, the enhanced vascular coupling of Olig2+/NG2+/BLBP+ ASPs appears to be an adaptive response to hypoxic brain injury. This study provides new insights into the molecular characteristics of Olig2+/NG2+/BLBP+ ASPs and their potential role in the brain's response to hypoxic injury, contributing to our understanding of neurovascular unit dynamics in both development and pathological conditions.

Auditory dysfunction affects the vast majority of people with autism spectrum disorder (ASD) and can range from deafness to hypersensitivity. In utero exposure to the antiepileptic valproic acid (VPA) is associated with significant risk of an ASD diagnosis in humans and timed in utero exposure to VPA is utilized as an animal model of ASD. VPA-exposed rats have significantly fewer neurons in their auditory brainstem, thalamus and cortex, reduced ascending projections to the midbrain and thalamus and reduced descending projections from the cortex to the auditory midbrain. Consistent with these anatomical changes, VPA-exposed animals also have abnormal auditory brainstem responses. We have recently described a significant ascending projection from calbindin-positive neurons in the medial nucleus of the trapezoid body (MNTB) to the ventral division of the medial geniculate (vMG) in rats that bypasses the central nucleus of the inferior colliculus (CNIC). Since we found that axonal projections to the vMG in VPA-exposed rats are reduced beyond what is predicted from neuron loss alone, we hypothesize that VPA exposure would result in a significant reduction in the MNTB projection to the vMG. We examined this hypothesis by quantifying the proportion of retrogradely-labeled neurons in the MNTB of control and VPA-exposed animals after injections of retrograde tracers in the CNIC and vMG in control and VPA-exposed animals. Our results indicate that in control animals, the MNTB forms the largest projection from the superior olivary complex to the MG and that this projection is nearly abolished by in utero VPA exposure.