Maximum-entropy-based metrics for quantifying critical dynamics in spiking neuron data.

An important working hypothesis to investigate brain activity is whether it operates in a critical regime. Recently, maximum-entropy phenomenological models have emerged as an alternative way of identifying critical behavior in neuronal data sets. In the present paper, we investigate the signatures of criticality from a firing rate-based maximum-entropy approach on data sets generated by computational models, and we compare them to experimental results. We found that the maximum entropy approach consistently identifies critical behavior around the phase transition in models and rules out criticality in models without phase transition. The maximum-entropy-model results are compatible with results for cortical data from urethane-anesthetized rats data, providing further support for criticality in the brain.

Lrig1 regulates cell fate specification of glutamatergic neurons via FGF-driven Jak2/Stat3 signaling in cortical progenitors.

The cell-intrinsic mechanisms underlying the decision of a stem/progenitor cell to either proliferate or differentiate remain incompletely understood. Here, we identify the transmembrane protein Lrig1 as a physiological homeostatic regulator of FGF2-driven proliferation and self-renewal of neural progenitors at early-to-mid embryonic stages of cortical development. We show that Lrig1 is expressed in cortical progenitors (CPs), and its ablation caused expansion and increased proliferation of radial/apical progenitors and of neurogenic transit-amplifying Tbr2+ intermediate progenitors. Notably, our findings identify a previously unreported EGF-independent mechanism through which Lrig1 negatively regulates neural progenitor proliferation by modulating the FGF2-induced IL6/Jak2/Stat3 pathway, a molecular cascade that plays a pivotal role in the generation and maintenance of CPs. Consistently, Lrig1 knockout mice showed a significant increase in the density of pyramidal glutamatergic neurons placed in superficial layers 2 and 3 of the postnatal neocortex. Together, these results support a model in which Lrig1 regulates cortical neurogenesis by influencing the cycling activity of a set of progenitors that are temporally specified to produce upper layer glutamatergic neurons.

Morphological Signatures of Neurogenesis and Neuronal Migration in Hypothalamic Vasopressinergic Magnocellular Nuclei of the Adult Rat.

The arginine vasopressin (AVP)-magnocellular neurosecretory system (AVPMNS) in the hypothalamus plays a critical role in homeostatic regulation as well as in allostatic motivational behaviors. However, it remains unclear whether adult neurogenesis exists in the AVPMNS. By using immunoreaction against AVP, neurophysin II, glial fibrillar acidic protein (GFAP), cell division marker (Ki67), migrating neuroblast markers (doublecortin, DCX), microglial marker (Ionized calcium binding adaptor molecule 1, Iba1), and 5'-bromo-2'-deoxyuridine (BrdU), we report morphological evidence that low-rate neurogenesis and migration occur in adult AVPMNS in the rat hypothalamus. Tangential AVP/GFAP migration routes and AVP/DCX neuronal chains as well as ascending AVP axonal scaffolds were observed. Chronic water deprivation significantly increased the BrdU+ nuclei within both the supraaoptic (SON) and paraventricular (PVN) nuclei. These findings raise new questions about AVPMNS's potential hormonal role for brain physiological adaptation across the lifespan, with possible involvement in coping with homeostatic adversities.

Transcriptional dynamics orchestrating the development and integration of neurons born in the adult hippocampus.

The adult hippocampus generates new granule cells (aGCs) with functional capabilities that convey unique forms of plasticity to the preexisting circuits. While early differentiation of adult radial glia-like cells (RGLs) has been studied extensively, the molecular mechanisms guiding the maturation of postmitotic neurons remain unknown. Here, we used a precise birthdating strategy to study aGC differentiation using single-nuclei RNA sequencing. Transcriptional profiling revealed a continuous trajectory from RGLs to mature aGCs, with multiple immature stages bearing increasing levels of effector genes supporting growth, excitability, and synaptogenesis. Analysis of differential gene expression, pseudo-time trajectory, and transcription factors (TFs) revealed critical transitions defining four cellular states: quiescent RGLs, proliferative progenitors, immature aGCs, and mature aGCs. Becoming mature aGCs involved a transcriptional switch that shuts down pathways promoting cell growth, such SoxC TFs, to activate programs that likely control neuronal homeostasis. aGCs overexpressing Sox4 or Sox11 remained immature. Our results unveil precise molecular mechanisms driving adult RGLs through the pathway of neuronal differentiation.

Computational Tools for Neuronal Morphometric Analysis: A Systematic Search and Review.

Morphometry is fundamental for studying and correlating neuronal morphology with brain functions. With increasing computational power, it is possible to extract morphometric characteristics automatically, including features such as length, volume, and number of neuron branches. However, to the best of our knowledge, there is no mapping of morphometric tools yet. In this context, we conducted a systematic search and review to identify and analyze tools within the scope of neuron analysis. Thus, the work followed a well-defined protocol and sought to answer the following research questions: What open-source tools are available for neuronal morphometric analysis? What morphometric characteristics are extracted by these tools? For this, aiming for greater robustness and coverage, the study was based on the paper analysis as well as the study of documentation and tests with the tools available in repositories. We analyzed 1,586 papers and mapped 23 tools, where NeuroM, L-Measure, and NeuroMorphoVis extract the most features. Furthermore, we contribute to the body of knowledge with the unprecedented presentation of 150 unique morphometric features whose terminologies were categorized and standardized. Overall, the study contributes to advancing the understanding of the complex mechanisms underlying the brain.

JNK signaling and its impact on neural cell maturation and differentiation.

C-Jun-N-terminal-kinases (JNKs), members of the mitogen-activated-protein-kinase family, are significantly linked with neurological and neurodegenerative pathologies and cancer progression. However, JNKs serve key roles under physiological conditions, particularly within the central-nervous-system (CNS), where they are critical in governing neural proliferation and differentiation during both embryogenesis and adult stages. These processes control the development of CNS, avoiding neurodevelopment disorders. JNK are key to maintain the proper activity of neural-stem-cells (NSC) and neural-progenitors (NPC) that exist in adults, which keep the convenient brain plasticity and homeostasis. This review underscores how the interaction of JNK with upstream and downstream molecules acts as a regulatory mechanism to manage the self-renewal capacity and differentiation of NSC/NPC during CNS development and in adult neurogenic niches. Evidence suggests that JNK is reliant on non-canonical Wnt components, Fbw7-ubiquitin-ligase, and WDR62-scaffold-protein, regulating substrates such as transcription factors and cytoskeletal proteins. Therefore, understanding which pathways and molecules interact with JNK will bring knowledge on how JNK activation orchestrates neuronal processes that occur in CNS development and brain disorders.

Generation of Urine-Derived Induced Pluripotent Stem Cells and Cerebral Organoids for Modeling Down Syndrome.

Down syndrome (DS, or trisomy 21, T21), is the most common genetic cause of intellectual disability. Alterations in the complex process of cerebral cortex development contribute to the neurological deficits in DS, although the underlying molecular and cellular mechanisms are not completely understood. Human cerebral organoids (COs) derived from three-dimensional (3D) cultures of induced pluripotent stem cells (iPSCs) provide a new avenue for gaining a better understanding of DS neuropathology. In this study, we aimed to generate iPSCs from individuals with DS (T21-iPSCs) and euploid controls using urine-derived cells, which can be easily and noninvasively obtained from most individuals, and examine their ability to differentiate into neurons and astrocytes grown in monolayer cultures, as well as into 3D COs. We employed nonintegrating episomal vectors to generate urine-derived iPSC lines, and a simple-to-use system to produce COs with forebrain identity. We observed that both T21 and control urine-derived iPSC lines successfully differentiate into neurons and astrocytes in monolayer, as well as into COs that recapitulate early features of human cortical development, including organization of neural progenitor zones, programmed differentiation of excitatory and inhibitory neurons, and upper-and deep-layer cortical neurons as well as astrocytes. Our findings demonstrate for the first time the suitability of using urine-derived iPSC lines to produce COs for modeling DS.

Overexpression of the dystrophins Dp40 and Dp40L170P modifies neurite outgrowth and the protein expression profile of PC12 cells.

Dp40 is ubiquitously expressed including the central nervous system. In addition to being present in the nucleus, membrane, and cytoplasm, Dp40 is detected in neurites and postsynaptic spines in hippocampal neurons. Although Dp40 is expressed from the same promoter as Dp71, its role in the cognitive impairment present in Duchenne muscular dystrophy patients is still unknown. Here, we studied the effects of overexpression of Dp40 and Dp40L170P during the neuronal differentiation of PC12 Tet-On cells. We found that Dp40 overexpression increased the percentage of PC12 cells with neurites and neurite length, while Dp40L170P overexpression decreased them compared to Dp40 overexpression. Two-dimensional gel electrophoresis analysis showed that the protein expression profile was modified in nerve growth factor-differentiated PC12-Dp40L170P cells compared to that of the control cells (PC12 Tet-On). The proteins α-internexin and S100a6, involved in cytoskeletal structure, were upregulated. The expression of vesicle-associated membrane proteins increased in differentiated PC12-Dp40 cells, in contrast to PC12-Dp40L170P cells, while neurofilament light-chain was decreased in both differentiated cells. These results suggest that Dp40 has an important role in the neuronal differentiation of PC12 cells through the regulation of proteins involved in neurofilaments and exocytosis of synaptic vesicles, functions that might be affected in PC12-Dp40L170P.

Human Sensory Neuron-like Cells and Glycated Collagen Matrix as a Model for the Screening of Analgesic Compounds.

Increased collagen-derived advanced glycation end-products (AGEs) are consistently related to painful diseases, including osteoarthritis, diabetic neuropathy, and neurodegenerative disorders. We have recently developed a model combining a two-dimensional glycated extracellular matrix (ECM-GC) and primary dorsal root ganglion (DRG) that mimicked a pro-nociceptive microenvironment. However, culturing primary cells is still a challenge for large-scale screening studies. Here, we characterized a new model using ECM-GC as a stimulus for human sensory-like neurons differentiated from SH-SY5Y cell lines to screen for analgesic compounds. First, we confirmed that the differentiation process induces the expression of neuron markers (MAP2, RBFOX3 (NeuN), and TUBB3 (ß-III tubulin), as well as sensory neuron markers critical for pain sensation (TRPV1, SCN9A (Nav1.7), SCN10A (Nav1.8), and SCN11A (Nav1.9). Next, we showed that ECM-GC increased c-Fos expression in human sensory-like neurons, which is suggestive of neuronal activation. In addition, ECM-GC upregulated the expression of critical genes involved in pain, including SCN9A and TACR1. Of interest, ECM-GC induced substance P release, a neuropeptide widely involved in neuroinflammation and pain. Finally, morphine, the prototype opiate, decreased ECM-GC-induced substance P release. Together, our results suggest that we established a functional model that can be useful as a platform for screening candidates for the management of painful conditions.

Sec3 exocyst component knockdown inhibits axonal formation and cortical neuronal migration during brain cortex development.

Neurons are the largest known cells, with complex and highly polarized morphologies and consist of a cell body (soma), several dendrites, and a single axon. The establishment of polarity necessitates initial axonal outgrowth in concomitance with the addition of new membrane to the axon's plasmalemma. Axolemmal expansion occurs by exocytosis of plasmalemmal precursor vesicles primarily at the neuronal growth cone membrane. The multiprotein exocyst complex drives spatial location and specificity of vesicle fusion at plasma membrane. However, the specific participation of its different proteins on neuronal differentiation has not been fully established. In the present work we analyzed the role of Sec3, a prominent exocyst complex protein on neuronal differentiation. Using mice hippocampal primary cultures, we determined that Sec3 is expressed in neurons at early stages prior to neuronal polarization. Furthermore, we determined that silencing of Sec3 in mice hippocampal neurons in culture precluded polarization. Moreover, using in utero electroporation experiments, we determined that Sec3 knockdown affected cortical neurons migration and morphology during neocortex formation. Our results demonstrate that the exocyst complex protein Sec3 plays an important role in axon formation in neuronal differentiation and the migration of neuronal progenitors during cortex development.

Directly Reprogrammed Human Neurons to Understand Age-Related Energy Metabolism Impairment and Mitochondrial Dysfunction in Healthy Aging and Neurodegeneration.

Brain aging is characterized by several molecular and cellular changes grouped as the hallmarks or pillars of aging, including organelle dysfunction, metabolic and nutrition-sensor changes, stem cell attrition, and macromolecular damages. Separately and collectively, these features degrade the most critical neuronal function: transmission of information in the brain. It is widely accepted that aging is the leading risk factor contributing to the onset of the most prevalent pathological conditions that affect brain functions, such as Alzheimer's, Parkinson's, and Huntington's disease. One of the limitations in understanding the molecular mechanisms involved in those diseases is the lack of an appropriate cellular model that recapitulates the "aged" context in human neurons. The advent of the cellular reprogramming of somatic cells, i.e., dermal fibroblasts, to obtain directly induced neurons (iNs) and induced pluripotent stem cell- (iPSC-) derived neurons is technical sound advances that could open the avenues to understand better the contribution of aging toward neurodegeneration. In this review, we will summarize the commonalities and singularities of these two approaches for the study of brain aging, with an emphasis on the role of mitochondrial dysfunction and redox biology. We will address the evidence showing that iNs retain age-related features in contrast to iPSC-derived neurons that lose the aging signatures during the reprogramming to pluripotency, rendering iNs a powerful strategy to deepen our knowledge of the processes driving normal cellular function decline and neurodegeneration in a human adult model. We will finally discuss the potential utilization of these novel technologies to understand the differential contribution of genetic and epigenetic factors toward neuronal aging, to identify and develop new drugs and therapeutic strategies.

The Stimulatory Effects of Intracellular α-Synuclein on Synaptic Transmission Are Attenuated by 2-Octahydroisoquinolin-2(1H)-ylethanamine.

α-Synuclein (αSyn) species can be detected in synaptic boutons, where they play a crucial role in the pathogenesis of Parkinson's Disease (PD). However, the effects of intracellular αSyn species on synaptic transmission have not been thoroughly studied. Here, using patch-clamp recordings in hippocampal neurons, we report that αSyn oligomers (αSynO), intracellularly delivered through the patch electrode, produced a fast and potent effect on synaptic transmission, causing a substantial increase in the frequency, amplitude and transferred charge of spontaneous synaptic currents. We also found an increase in the frequency of miniature synaptic currents, suggesting an effect located at the presynaptic site of the synapsis. Furthermore, our in silico approximation using docking analysis and molecular dynamics simulations showed an interaction between a previously described small anti-amyloid beta (Aß) molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine), with a central hydrophobic region of αSyn. In line with this finding, our empirical data aimed to obtain oligomerization states with thioflavin T (ThT) and Western blot (WB) indicated that M30 interfered with αSyn aggregation and decreased the formation of higher-molecular-weight species. Furthermore, the effect of αSynO on synaptic physiology was also antagonized by M30, resulting in a decrease in the frequency, amplitude, and charge transferred of synaptic currents. Overall, the present results show an excitatory effect of intracellular αSyn low molecular-weight species, not previously described, that are able to affect synaptic transmission, and the potential of a small neuroactive molecule to interfere with the aggregation process and the synaptic effect of αSyn, suggesting that M30 could be a potential therapeutic strategy for synucleinopathies.

Polycystic ovary rat model exposure to 150 kHz intermediate frequency: hypothalamic-pituitary-ovarian axis at the receptor, cellular, tissue, and hormone levels.

INTRODUCTION: The hypothalamic-pituitary-ovarian (HPO) axis is the principal regulator of the reproductive system. The neurons in the arcuate nucleus of the hypothalamus signal the basophilic cells of the anterior pituitary to release luteinizing hormone (LH) and follicle stimulating hormone (FSH), which bind to the granulosa and theca cells of a follicle in the ovary to promote healthy follicular development. Disruption of this process at any time can lead to polycystic ovaries and, if left untreated, can lead to Polycystic Ovarian Syndrome (PCOS), one of the leading causes of infertility. A novel treatment option using 150 kHz Intermediate Frequency (IF) Electromagnetic Radiation (EMR) has been proposed to monitor the effect of this frequency during cystic development. METHODS: To prove this, an experiment was conducted to study the effect of whole-body exposure to 150 kHz EMR for 8 weeks at receptor, cellular, tissue and hormonal levels on the HPO axis of 25 young cyclic female rats. RESULTS: The results showed that 150 kHz EMR did not affect the histoarchitecture of neurons of arcuate nucleus of the hypothalamus of PCO-induced rats. It was also found that the number of basophilic cells of the pituitary gland was increased and the immunoreactivity of LH and FSH secretion increased. This EMR field also decreased the development of follicular cysts in the ovary and possibly increased the immunoreactivity of the LH and FSH receptors as well on the theca and granulosa cells of follicles in the ovary. CONCLUSION: There are still many limitations to this study. If properly evaluated, the results of this experiment could help develop a new non-invasive treatment option for women with PCOS in the near future.

Adult Neurogenesis: A Story Ranging from Controversial New Neurogenic Areas and Human Adult Neurogenesis to Molecular Regulation.

The generation of new neurons in the adult brain is a currently accepted phenomenon. Over the past few decades, the subventricular zone and the hippocampal dentate gyrus have been described as the two main neurogenic niches. Neurogenic niches generate new neurons through an asymmetric division process involving several developmental steps. This process occurs throughout life in several species, including humans. These new neurons possess unique properties that contribute to the local circuitry. Despite several efforts, no other neurogenic zones have been observed in many years; the lack of observation is probably due to technical issues. However, in recent years, more brain niches have been described, once again breaking the current paradigms. Currently, a debate in the scientific community about new neurogenic areas of the brain, namely, human adult neurogenesis, is ongoing. Thus, several open questions regarding new neurogenic niches, as well as this phenomenon in adult humans, their functional relevance, and their mechanisms, remain to be answered. In this review, we discuss the literature and provide a compressive overview of the known neurogenic zones, traditional zones, and newly described zones. Additionally, we will review the regulatory roles of some molecular mechanisms, such as miRNAs, neurotrophic factors, and neurotrophins. We also join the debate on human adult neurogenesis, and we will identify similarities and differences in the literature and summarize the knowledge regarding these interesting topics.

Gossypitrin, A Naturally Occurring Flavonoid, Attenuates Iron-Induced Neuronal and Mitochondrial Damage.

The disruption of iron homeostasis is an important factor in the loss of mitochondrial function in neural cells, leading to neurodegeneration. Here, we assessed the protective action of gossypitrin (Gos), a naturally occurring flavonoid, on iron-induced neuronal cell damage using mouse hippocampal HT-22 cells and mitochondria isolated from rat brains. Gos was able to rescue HT22 cells from the damage induced by 100 µM Fe(II)-citrate (EC50 8.6 µM). This protection was linked to the prevention of both iron-induced mitochondrial membrane potential dissipation and ATP depletion. In isolated mitochondria, Gos (50 µM) elicited an almost complete protection against iron-induced mitochondrial swelling, the loss of mitochondrial transmembrane potential and ATP depletion. Gos also prevented Fe(II)-citrate-induced mitochondrial lipid peroxidation with an IC50 value (12.45 µM) that was about nine time lower than that for the tert-butylhydroperoxide-induced oxidation. Furthermore, the flavonoid was effective in inhibiting the degradation of both 15 and 1.5 mM 2-deoxyribose. It also decreased Fe(II) concentration with time, while increasing O2 consumption rate, and impairing the reduction of Fe(III) by ascorbate. Gos-Fe(II) complexes were detected by UV-VIS and IR spectroscopies, with an apparent Gos-iron stoichiometry of 2:1. Results suggest that Gos does not generally act as a classical antioxidant, but it directly affects iron, by maintaining it in its ferric form after stimulating Fe(II) oxidation. Metal ions would therefore be unable to participate in a Fenton-type reaction and the lipid peroxidation propagation phase. Hence, Gos could be used to treat neuronal diseases associated with iron-induced oxidative stress and mitochondrial damage.

zapERtrap: A light-regulated ER release system reveals unexpected neuronal trafficking pathways.

Here we introduce zapalog-mediated endoplasmic reticulum trap (zapERtrap), which allows one to use light to precisely trigger forward trafficking of diverse integral membrane proteins from internal secretory organelles to the cell surface with single cell and subcellular spatial resolution. To demonstrate its utility, we use zapERtrap in neurons to dissect where synaptic proteins emerge at the cell surface when processed through central (cell body) or remote (dendrites) secretory pathways. We reveal rapid and direct long-range trafficking of centrally processed proteins deep into the dendritic arbor to synaptic sites. Select proteins were also trafficked to the plasma membrane of the axon initial segment, revealing a novel surface trafficking hotspot. Proteins locally processed through dendritic secretory networks were widely dispersed before surface insertion, challenging assumptions for precise trafficking at remote sites. These experiments provide new insights into compartmentalized secretory trafficking and showcase the tunability and spatiotemporal control of zapERtrap, which will have broad applications for regulating cell signaling and function.

Human cultured IMR-32 neuronal-like and U87 glial-like cells have different patterns of toxicity under fluoride exposure.

BACKGROUND: Fluoride (F) is a naturally exists in nature but several studies have indicated it as an environmental toxicant to all leaving beings. Human F exposure has increased over the years since this ion has been used by industry on foods, beverages, toothpastes and on water supply. Although F is safe at optimal concentrations in water supply, human exposure to high levels could trigger neurofunctional deficits. MATERIALS AND METHODS: In this study, human glial-like (U87) and neuronal-like (IMR-32) cells lineages were used to access F toxicity and CNS cell sensibility on both cell facing the same protocol. Cells were exposed to F over 3, 5 and 10 days on two different F concentrations. Fluoride exposed cells were evaluated by standard toxicity assays to cell viability, apoptosis, necrosis and general cell metabolism. Oxidative stress parameters were evaluated by ATP and ROS levels, lipid peroxidation, GSH/GSSG ratio and comet assay. RESULTS: No changes were observed in IMR-32 at any given time while after 10 days of exposure to 0.22µg/mL, U87 glial-like cells showed signs of toxicity such as decreased cell viability by necrosis while general cell metabolism was increased. Oxidative stress parameters were next evaluated only on U87 glial-like cells after 10 days of exposure. F induced a decrease on ATP levels while no changes were observed on reactive oxygen species and lipid peroxidation. GSH/GSSG ratio was decreased followed by DNA damage both on 0.22µg/mL F. CONCLUSIONS: Our results suggest an important differential behavior of the distinct types of cells exposed to the different fluoride concentrations, pointing that the U87 glial-like cells as more susceptible to damage triggered by this ion.

Mitochondrial dysfunction in Alzheimer's disease: Therapeutic implications of lithium.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by the accumulation of abnormal tau proteins within neurons and amyloid plaques in the brain parenchyma, which leads to progressive loss of neurons in the brain. While the detailed mechanism of the pathogenesis of AD is still unknown, evidence suggests that mitochondrial dysfunction likely plays a fundamental role in the pathogenesis of this disease. Due to the relevance of mitochondrial alterations in AD, recent works have suggested the therapeutic potential of mitochondrial-targeted lithium. Lithium has been shown to possess neuroprotective and neurotrophic properties that could also be related to the upregulation of mitochondrial function. In the current work, we perform a comprehensive investigation of the significance of mitochondrial dysfunction in AD and pharmacological treatment with lithium as imperative in this pathology, through a brief review of the major findings on the effects of lithium as a therapeutic approach targeting mitochondria in the context of AD.

Tyrosine phosphorylation differentially fine-tunes ionotropic and metabotropic responses of human α7 nicotinic acetylcholine receptor.

The α7 nicotinic acetylcholine receptor is involved in neurological, neurodegenerative, and inflammatory disorders. It operates both as a ligand-gated cationic channel and as a metabotropic receptor in neuronal and non-neuronal cells. As protein phosphorylation is an important cell function regulatory mechanism, deciphering how tyrosine phosphorylation modulates α7 dual ionotropic/metabotropic molecular function is required for understanding its integral role in physiological and pathological processes. α7 single-channel activity elicited by ACh appears as brief isolated openings and less often as episodes of few openings in quick succession. The reduction of phosphorylation by tyrosine kinase inhibition increases the duration and frequency of activation episodes, whereas the inhibition of phosphatases has the opposite effect. Removal of two tyrosine residues at the α7 intracellular domain recapitulates the effects mediated by tyrosine kinase inhibition. The tyrosine-free mutant receptor shows longer duration-activation episodes, reduced desensitization rate and significantly faster recovery from desensitization, indicating that phosphorylation decreases α7 channel activity by favoring the desensitized state. However, the mutant receptor is incapable of triggering ERK1/2 phosphorylation in response to the α7-agonist. Thus, while tyrosine phosphorylation is absolutely required for α7-triggered ERK pathway, it negatively modulates α7 ionotropic activity. Overall, phosphorylation/dephosphorylation events fine-tune the integrated cell response mediated by α7 activation, thus having a broad impact on α7 cholinergic signaling.

Synaptic activity controls autophagic vacuole motility and function in dendrites.

Macroautophagy (hereafter "autophagy") is a lysosomal degradation pathway that is important for learning and memory, suggesting critical roles for autophagy at the neuronal synapse. Little is known, however, about the molecular details of how autophagy is regulated with synaptic activity. Here, we used live-cell confocal microscopy to define the autophagy pathway in primary hippocampal neurons under various paradigms of synaptic activity. We found that synaptic activity regulates the motility of autophagic vacuoles (AVs) in dendrites. Stimulation of synaptic activity dampens AV motility, whereas silencing synaptic activity induces AV motility. Activity-dependent effects on dendritic AV motility are local and reversible. Importantly, these effects are compartment specific, occurring in dendrites and not in axons. Most strikingly, synaptic activity increases the presence of degradative autolysosomes in dendrites and not in axons. On the basis of our findings, we propose a model whereby synaptic activity locally controls AV dynamics and function within dendrites that may regulate the synaptic proteome.