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Neuron Aug 2021Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There are hints that the use of psychedelics can produce neural adaptations, although the...
Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There are hints that the use of psychedelics can produce neural adaptations, although the extent and timescale of the impact in a mammalian brain are unknown. In this study, we used chronic two-photon microscopy to image longitudinally the apical dendritic spines of layer 5 pyramidal neurons in the mouse medial frontal cortex. We found that a single dose of psilocybin led to ∼10% increases in spine size and density, driven by an elevated spine formation rate. The structural remodeling occurred quickly within 24 h and was persistent 1 month later. Psilocybin also ameliorated stress-related behavioral deficit and elevated excitatory neurotransmission. Overall, the results demonstrate that psilocybin-evoked synaptic rewiring in the cortex is fast and enduring, potentially providing a structural trace for long-term integration of experiences and lasting beneficial actions.
Topics: Animals; Cerebral Cortex; Dendrites; Dendritic Spines; Female; Frontal Lobe; Male; Mice; Neuronal Plasticity; Psilocybin; Pyramidal Cells; Synaptic Transmission
PubMed: 34228959
DOI: 10.1016/j.neuron.2021.06.008 -
Frontiers in Immunology 2022Surgical pain is associated with delirium in patients, and acupuncture can treat pain. However, whether electroacupuncture can attenuate the surgical pain-associated...
Surgical pain is associated with delirium in patients, and acupuncture can treat pain. However, whether electroacupuncture can attenuate the surgical pain-associated delirium the gut-brain axis remains unknown. Leveraging a mouse model of foot incision-induced surgical pain and delirium-like behavior, we found that electroacupuncture stimulation at specific acupoints (e.g., DU20+KI1) attenuated both surgical pain and delirium-like behavior in mice. Mechanistically, mice with incision-induced surgical pain and delirium-like behavior showed gut microbiota imbalance, microglia activation in the spinal cord, somatosensory cortex, and hippocampus, as well as an enhanced dendritic spine elimination in cortex revealed by two-photon imaging. The electroacupuncture regimen that alleviated surgical pain and delirium-like behavior in mice also effectively restored the gut microbiota balance, prevented the microglia activation, and reversed the dendritic spine elimination. These data demonstrated a potentially important gut-brain interactive mechanism underlying the surgical pain-induced delirium in mice. Pending further studies, these findings revealed a possible therapeutic approach in preventing and/or treating postoperative delirium by using perioperative electroacupuncture stimulation in patients.
Topics: Animals; Delirium; Dendritic Spines; Electroacupuncture; Gastrointestinal Microbiome; Mice; Pain
PubMed: 36003380
DOI: 10.3389/fimmu.2022.955581 -
Cell Reports Oct 2021Clinical evidence suggests that rapid and sustained antidepressant action can be attained with a single exposure to psychedelics. However, the biological substrates and...
Clinical evidence suggests that rapid and sustained antidepressant action can be attained with a single exposure to psychedelics. However, the biological substrates and key mediators of psychedelics' enduring action remain unknown. Here, we show that a single administration of the psychedelic DOI produces fast-acting effects on frontal cortex dendritic spine structure and acceleration of fear extinction via the 5-HT receptor. Additionally, a single dose of DOI leads to changes in chromatin organization, particularly at enhancer regions of genes involved in synaptic assembly that stretch for days after the psychedelic exposure. These DOI-induced alterations in the neuronal epigenome overlap with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder. Together, these data support that epigenomic-driven changes in synaptic plasticity sustain psychedelics' long-lasting antidepressant action but also warn about potential substrate overlap with genetic risks for certain psychiatric conditions.
Topics: Amphetamines; Animals; Behavior, Animal; Dendritic Spines; Epigenesis, Genetic; Epigenome; Epigenomics; Extinction, Psychological; Fear; Frontal Lobe; Hallucinogens; Male; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Neuronal Plasticity; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Agonists; Synapses; Time Factors; Mice
PubMed: 34686347
DOI: 10.1016/j.celrep.2021.109836 -
Neuron Jun 2023The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is fragile X syndrome...
The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is fragile X syndrome (FXS), an NDD caused by the absence of the functional RNA-binding protein FMRP. Here, we demonstrate how the brain region-specific composition of postsynaptic density (PSD) contributes to FXS. In the striatum, the FXS mouse model shows an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, which is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.
Topics: Animals; Mice; Fragile X Syndrome; Fragile X Mental Retardation Protein; Actins; Brain; Disease Models, Animal; Mice, Knockout; Dendritic Spines; Mammals
PubMed: 36996810
DOI: 10.1016/j.neuron.2023.03.008 -
The Journal of Neuroscience : the... Oct 2023The loss of excitatory synapses is known to underlie the cognitive deficits in Alzheimer's disease (AD). Although much is known about the mechanisms underlying synaptic... (Review)
Review
The loss of excitatory synapses is known to underlie the cognitive deficits in Alzheimer's disease (AD). Although much is known about the mechanisms underlying synaptic loss in AD, how neurons compensate for this loss and whether this provides cognitive benefits remain almost completely unexplored. In this review, we describe two potential compensatory mechanisms implemented following synaptic loss: the enlargement of the surviving neighboring synapses and the regeneration of synapses. Because dendritic spines, the postsynaptic site of excitatory synapses, are easily visualized using light microscopy, we focus on a range of microscopy approaches to monitor synaptic loss and compensation. Here, we stress the importance of longitudinal dendritic spine imaging, as opposed to fixed-tissue imaging, to gain insights into the temporal dynamics of dendritic spine compensation. We believe that understanding the molecular mechanisms behind these and other forms of synaptic compensation and regeneration will be critical for the development of therapeutics aiming at delaying the onset of cognitive deficits in AD.
Topics: Humans; Alzheimer Disease; Synapses; Neuronal Plasticity; Cognition Disorders; Neurons; Dendritic Spines
PubMed: 37821232
DOI: 10.1523/JNEUROSCI.0379-23.2023 -
Advances in Neurobiology 2023Dendritic spine features in human neurons follow the up-to-date knowledge presented in the previous chapters of this book. Human dendrites are notable for their... (Review)
Review
Dendritic spine features in human neurons follow the up-to-date knowledge presented in the previous chapters of this book. Human dendrites are notable for their heterogeneity in branching patterns and spatial distribution. These data relate to circuits and specialized functions. Spines enhance neuronal connectivity, modulate and integrate synaptic inputs, and provide additional plastic functions to microcircuits and large-scale networks. Spines present a continuum of shapes and sizes, whose number and distribution along the dendritic length are diverse in neurons and different areas. Indeed, human neurons vary from aspiny or "relatively aspiny" cells to neurons covered with a high density of intermingled pleomorphic spines on very long dendrites. In this chapter, we discuss the phylogenetic and ontogenetic development of human spines and describe the heterogeneous features of human spiny neurons along the spinal cord, brainstem, cerebellum, thalamus, basal ganglia, amygdala, hippocampal regions, and neocortical areas. Three-dimensional reconstructions of Golgi-impregnated dendritic spines and data from fluorescence microscopy are reviewed with ultrastructural findings to address the complex possibilities for synaptic processing and integration in humans. Pathological changes are also presented, for example, in Alzheimer's disease and schizophrenia. Basic morphological data can be linked to current techniques, and perspectives in this research field include the characterization of spines in human neurons with specific transcriptome features, molecular classification of cellular diversity, and electrophysiological identification of coexisting subpopulations of cells. These data would enlighten how cellular attributes determine neuron type-specific connectivity and brain wiring for our diverse aptitudes and behavior.
Topics: Humans; Alzheimer Disease; Amygdala; Dendritic Spines; Neurons; Phylogeny
PubMed: 37962801
DOI: 10.1007/978-3-031-36159-3_9 -
Brain Structure & Function Sep 2021Ever since its first use in surgery, general anesthesia has been regarded as a medical miracle enabling countless life-saving diagnostic and therapeutic interventions... (Review)
Review
Ever since its first use in surgery, general anesthesia has been regarded as a medical miracle enabling countless life-saving diagnostic and therapeutic interventions without pain sensation and traumatic memories. Despite several decades of research, there is a lack of understanding of how general anesthetics induce a reversible coma-like state. Emerging evidence suggests that even brief exposure to general anesthesia may have a lasting impact on mature and especially developing brains. Commonly used anesthetics have been shown to destabilize dendritic spines and induce an enhanced plasticity state, with effects on cognition, motor functions, mood, and social behavior. Herein, we review the effects of the most widely used general anesthetics on dendritic spine dynamics and discuss functional and molecular correlates with action mechanisms. We consider the impact of neurodevelopment, anatomical location of neurons, and their neurochemical profile on neuroplasticity induction, and review the putative signaling pathways. It emerges that in addition to possible adverse effects, the stimulation of synaptic remodeling with the formation of new connections by general anesthetics may present tremendous opportunities for translational research and neurorehabilitation.
Topics: Actin Cytoskeleton; Anesthesia, General; Anesthetics, General; Dendritic Spines; Neuronal Plasticity
PubMed: 34061250
DOI: 10.1007/s00429-021-02308-6 -
Developmental Biology Aug 2022The morphogenesis and plasticity of dendritic spines are associated with synaptic strength, learning, and memory. Dendritic spines are highly compartmentalized... (Review)
Review
The morphogenesis and plasticity of dendritic spines are associated with synaptic strength, learning, and memory. Dendritic spines are highly compartmentalized structures, which makes proteins involved in cellular polarization and membrane compartmentalization likely candidates regulating their formation and maintenance. Indeed, recent studies suggest polarity proteins help form and maintain dendritic spines by compartmentalizing the spine neck and head. Here, we review emerging evidence that polarity proteins regulate dendritic spine plasticity and stability through the cytoskeleton, scaffolding molecules, and signaling molecules. We specifically analyze various polarity complexes known to contribute to different forms of cell polarization processes and examine the essential conceptual context linking these groups of polarity proteins to dendritic spine morphogenesis, plasticity, and cognitive functions.
Topics: Cytoskeleton; Dendritic Spines; Morphogenesis; Neuronal Plasticity; Signal Transduction; Synapses
PubMed: 35580729
DOI: 10.1016/j.ydbio.2022.05.007 -
Advances in Neurobiology 2023Glia comprise a heterogeneous group of cells involved in the structure and function of the central and peripheral nervous system. Glial cells are found from... (Review)
Review
Glia comprise a heterogeneous group of cells involved in the structure and function of the central and peripheral nervous system. Glial cells are found from invertebrates to humans with morphological specializations related to the neural circuits in which they are embedded. Glial cells modulate neuronal functions, brain wiring and myelination, and information processing. For example, astrocytes send processes to the synaptic cleft, actively participate in the metabolism of neurotransmitters, and release gliotransmitters, whose multiple effects depend on the targeting cells. Human astrocytes are larger and more complex than their mice and rats counterparts. Astrocytes and microglia participate in the development and plasticity of neural circuits by modulating dendritic spines. Spines enhance neuronal connectivity, integrate most postsynaptic excitatory potentials, and balance the strength of each input. Not all central synapses are engulfed by astrocytic processes. When that relationship occurs, a different pattern for thin and large spines reflects an activity-dependent remodeling of motile astrocytic processes around presynaptic and postsynaptic elements. Microglia are equally relevant for synaptic processing, and both glial cells modulate the switch of neuroendocrine secretion and behavioral display needed for reproduction. In this chapter, we provide an overview of the structure, function, and plasticity of glial cells and relate them to synaptic maturation and modulation, also involving neurotrophic factors. Together, neurons and glia coordinate synaptic transmission in both normal and abnormal conditions. Neglected over decades, this exciting research field can unravel the complexity of species-specific neural cytoarchitecture as well as the dynamic region-specific functional interactions between diverse neurons and glial subtypes.
Topics: Animals; Humans; Mice; Rats; Astrocytes; Dendritic Spines; Microglia; Neuroglia; Neurons
PubMed: 37962798
DOI: 10.1007/978-3-031-36159-3_6 -
Current Opinion in Neurobiology Dec 2019In neurons, autophagy is crucial to proper axon guidance, vesicular release, dendritic spine architecture, spine pruning and synaptic plasticity and, when dysregulated,... (Review)
Review
In neurons, autophagy is crucial to proper axon guidance, vesicular release, dendritic spine architecture, spine pruning and synaptic plasticity and, when dysregulated, is associated with brain disorders, including autism spectrum disorders, and neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Once thought to play a housekeeping function of removing misfolded proteins or compromised organelles, neuronal autophagy is now regarded as a finely tuned, real time surveillance and clearance system crucial to synaptic integrity and function. Here we review the role of autophagy in synaptic plasticity and its regulation by epigenetic mechanisms.
Topics: Autophagy; Dendritic Spines; Epigenesis, Genetic; Neuronal Plasticity; Neurons
PubMed: 31634675
DOI: 10.1016/j.conb.2019.09.010