Changes in the Cyto- and Fibroarchitectonics of the Cerebellar Cortex in Rats Subjected to Extreme Physical Activity.

Physical overexertion surpassing the functional capacity of the nervous system causes the hyperactivation of the neural structures of the cerebellum. In turn, it causes the depletion of intracellular resources and progressive structural changes in cerebellar cells and fibers. These degenerative changes may lead to cerebellar dysfunction, including the worsening of coordination, balance, and motor functions. In order to maintain the health and functioning of the cerebellum and the nervous system in general, one needs to avoid physical overexertion and have enough time to recover. Three major types of Purkinje cells were identified in control group animals. After the forced swimming test, animals had significant morphological changes in pyriform cells, granule cells, internuncial neurons, and neuroglial cells. In particular, the extreme degeneration of granule cells was manifested via their fusion into conglomerates. These changes demonstrate that neurodegeneration in the cerebellum takes place in response to physical overexertion.

Septo-dentate gyrus cholinergic circuits modulate function and morphogenesis of adult neural stem cells through granule cell intermediaries.

Cholinergic neurons in the basal forebrain play a crucial role in regulating adult hippocampal neurogenesis (AHN). However, the circuit and molecular mechanisms underlying cholinergic modulation of AHN, especially the initial stages of this process related to the generation of newborn progeny from quiescent radial neural stem cells (rNSCs), remain unclear. Here, we report that stimulation of the cholinergic circuits projected from the diagonal band of Broca (DB) to the dentate gyrus (DG) neurogenic niche promotes proliferation and morphological development of rNSCs, resulting in increased neural stem/progenitor pool and rNSCs with longer radial processes and larger busy heads. Interestingly, DG granule cells (GCs) are required for DB-DG cholinergic circuit-dependent modulation of proliferation and morphogenesis of rNSCs. Furthermore, single-nucleus RNA sequencing of DG reveals cell type-specific transcriptional changes in response to cholinergic circuit stimulation, with GCs (among all the DG niche cells) exhibiting the most extensive transcriptional changes. Our findings shed light on how the DB-DG cholinergic circuits orchestrate the key niche components to support neurogenic function and morphogenesis of rNSCs at the circuit and molecular levels.

Mapping the effect of the antisecretory factor on GABAA receptor α1 and α6 subunits in cerebellar granule cells in vitro.

The Antisecretory Factor (AF) is a protein that can reduce intestinal hypersecretion and various inflammation disorders in vivo. Discovered in many mammalian tissues and plasma, its mechanism of action remains unknown. Interestingly, its induction has been found to counteract vertigo in patients with Méniere's disease. This suggests an inherent ability to control body balance and posture, an activity that may play a role in cerebellar function. Therefore, it may be worthwhile to investigate whether this activity can inhibit neuronal cells involved in cerebellar circuitries and its potential action on enteric nervous system ganglia, which could explain its antisecretory effect in the intestine. Previously, we studied the role of AF on GABAA receptors in cerebellar granule cells, taking advantage of electrophysiology and evaluating the effects of the administration of AF-16, an AF peptide. Treatment with AF-16 increased GABAA receptor responses, especially those containing the α6 subunit. Here, we performed immunofluorescence experiments by staining α1 and α6 subunits before and after incubation with AF-16, analyzed super-resolved images comparing pre- and post-treatment maps and critically examined these experimental results with our previous electrophysiological data to shed light on the mechanisms of action of AF protein on GABAA receptor subpopulations, specifically the "fast" receptors of αn ß2/3 γ2 composition that contain either the α1 or the α6 subunit. The results indicate that the α6 subunit is redistributed, with a decrease in neurites and an increase in soma. Conversely, the α1 subunit shows opposite results, with an increase in neurites and a decrease in soma.

Daily oscillations of neuronal membrane capacitance.

Capacitance of biological membranes is determined by the properties of the lipid portion of the membrane as well as the morphological features of a cell. In neurons, membrane capacitance is a determining factor of synaptic integration, action potential propagation speed, and firing frequency due to its direct effect on the membrane time constant. Besides slow changes associated with increased morphological complexity during postnatal maturation, neuronal membrane capacitance is considered a stable, non-regulated, and constant magnitude. Here we report that, in two excitatory neuronal cell types, pyramidal cells of the mouse primary visual cortex and granule cells of the hippocampus, the membrane capacitance significantly changes between the start and the end of a daily light-dark cycle. The changes are large, nearly 2-fold in magnitude in pyramidal cells, but are not observed in cortical parvalbumin-expressing inhibitory interneurons. Consistent with daily capacitance fluctuations, the time window for synaptic integration also changes in pyramidal cells.

PTEN DELETION IN THE ADULT DENTATE GYRUS INDUCES EPILEPSY.

Embryonic and early postnatal promotor-driven deletion of the phosphatase and tensin homolog (PTEN) gene results in neuronal hypertrophy, hyperexcitable circuitry and development of spontaneous seizures in adulthood. We previously documented that focal, vector-mediated PTEN deletion in mature granule cells of adult dentate gyrus triggers dramatic growth of cell bodies, dendrites, and axons, similar to that seen with early postnatal PTEN deletion. Here, we assess the functional consequences of focal, adult PTEN deletion, focusing on its pro-epileptogenic potential. PTEN deletion was accomplished by injecting AAV-Cre either bilaterally or unilaterally into the dentate gyrus of double transgenic PTEN-floxed, ROSA-reporter mice. Hippocampal recording electrodes were implanted for continuous digital EEG with concurrent video recordings in the home cage. Electrographic seizures and epileptiform spikes were assessed manually by two investigators, and corelated with concurrent videos. Spontaneous electrographic and behavioral seizures appeared after focal PTEN deletion in adult dentate granule cells, commencing around 2 months post-AAV-Cre injection. Seizures occurred in the majority of mice with unilateral or bilateral PTEN deletion and led to death in several cases. PTEN-deletion provoked epilepsy was not associated with apparent hippocampal neuron death; supra-granular mossy fiber sprouting was observed in a few mice. In summary, focal, unilateral deletion of PTEN in the adult dentate gyrus suffices to provoke time-dependent emergence of a hyperexcitable circuit generating hippocampus-origin, generalizing spontaneous seizures, providing a novel model for studies of adult-onset epileptogenesis.

Effect of adult-born immature granule cells on pattern separation in the hippocampal dentate gyrus.

Young immature granule cells (imGCs) appear via adult neurogenesis in the hippocampal dentate gyrus (DG). In comparison to mature GCs (mGCs) (born during development), the imGCs exhibit two competing distinct properties such as high excitability (increasing activation degree) and low excitatory innervation (reducing activation degree). We develop a spiking neural network for the DG, incorporating both the mGCs and the imGCs. The mGCs are well known to perform "pattern separation" (i.e., a process of transforming similar input patterns into less similar output patterns) to facilitate pattern storage in the hippocampal CA3. In this paper, we investigate the effect of the young imGCs on pattern separation of the mGCs. The pattern separation efficacy (PSE) of the mGCs is found to vary through competition between high excitability and low excitatory innervation of the imGCs. Their PSE becomes enhanced (worsened) when the effect of high excitability is higher (lower) than the effect of low excitatory innervation. In contrast to the mGCs, the imGCs are found to perform "pattern integration" (i.e., making association between dissimilar patterns). Finally, we speculate that memory resolution in the hippocampal CA3 might be optimally maximized via mixed cooperative encoding through pattern separation and pattern integration.

Ablation of TrkB from Enkephalinergic Precursor-Derived Cerebellar Granule Cells Generates Ataxia.

In ataxia disorders, motor incoordination (ataxia) is primarily linked to the dysfunction and degeneration of cerebellar Purkinje cells (PCs). In spinocerebellar ataxia 6 (SCA6), for example, decreased BDNF-TrkB signalling appears to contribute to PC dysfunction and ataxia. However, abnormal BDNF-TrkB signalling in granule cells (GCs) may contribute to PC dysfunction and incoordination in ataxia disorders, as TrkB receptors are also present in GCs that provide extensive input to PCs. This study investigated whether dysfunctional BDNF-TrkB signalling restricted to a specific subset of cerebellar GCs can generate ataxia in mice. To address this question, our research focused on TrkbPenk-KO mice, in which the TrkB receptor was removed from enkephalinergic precursor-derived cerebellar GCs. We found that deleting Ntrk2, encoding the TrkB receptor, eventually interfered with PC function, leading to ataxia symptoms in the TrkbPenk-KO mice without affecting their cerebellar morphology or levels of selected synaptic markers. These findings suggest that dysfunctional BDNF-TrkB signalling in a subset of cerebellar GCs alone is sufficient to trigger ataxia symptoms and may contribute to motor incoordination in disorders like SCA6.

A human fetal cerebellar map of the late second trimester reveals developmental molecular characteristics and abnormality in trisomy 21.

Our understanding of human fetal cerebellum development during the late second trimester, a critical period for the generation of astrocytes, oligodendrocytes, and unipolar brush cells (UBCs), remains limited. Here, we performed single-cell RNA sequencing (scRNA-seq) in human fetal cerebellum samples from gestational weeks (GWs) 18-25. We find that proliferating UBC progenitors distribute in the subventricular zone of the rhombic lip (RLSVZ) near white matter (WM), forming a layer structure. We also delineate two trajectories from astrogenic radial glia (ARGs) to Bergmann glial progenitors (BGPs) and recognize oligodendrogenic radial glia (ORGs) as one source of primitive oligodendrocyte progenitor cells (PriOPCs). Additionally, our scRNA-seq analysis of the trisomy 21 fetal cerebellum at this stage reveals abnormal upregulated genes in pathways such as the cell adhesion pathway and focal adhesion pathway, which potentially promote neuronal differentiation. Overall, our research provides valuable insights into normal and abnormal development of the human fetal cerebellum.

The role of vitamin D3 in follicle development.

Vitamin D3 plays a crucial role in female reproduction. As research progresses, the mechanisms of action of vitamin D3 on follicular development have been widely discussed. Firstly, key enzymes involved in the synthesis and metabolism of vitamin D3 have been discovered in the ovary, suggesting that vitamin D3 can be synthesized and metabolized locally within the ovary. Additionally, the detection of vitamin D3 receptors (VDR) in follicles suggests that vitamin D3 may exert its effects by binding specifically to these receptors during follicular development. Further research indicates that vitamin D3 promotes follicular growth by enhancing the development of granulosa cells (GCs) and oocytes. Currently, the mechanism of action of vitamin D3 in follicular development is becoming increasingly clear. Vitamin D3 promotes oocyte development by regulating molecules involved in meiotic arrest in oocytes. It also enhances granulosa cell proliferation by stimulating steroid hormone synthesis and cell cycle regulation. Additionally, vitamin D3 exerts anti-inflammatory effects by reducing oxidative stress and advanced glycation end-products (AGEs), mitigating the detrimental effects of inflammation on follicular development. These functions of vitamin D3 have clinical applications, such as in treating polycystic ovary syndrome (PCOS), improving female fertility, and enhancing outcomes in in vitro fertilization (IVF). This review summarizes the research progress on the role and mechanisms of vitamin D3 in follicular development and briefly summarizes its clinical applications.

A specific olfactory bulb interneuron subtype Tpbg/5T4 generated at embryonic and neonatal stages.

Various mammals have shown that sensory stimulation plays a crucial role in regulating the development of diverse structures, such as the olfactory bulb (OB), cerebral cortex, hippocampus, and retina. In the OB, the dendritic development of excitatory projection neurons like mitral/tufted cells is influenced by olfactory experiences. Odor stimulation is also essential for the dendritic development of inhibitory OB interneurons, such as granule and periglomerular cells, which are continuously produced in the ventricular-subventricular zone throughout life. Based on the morphological and molecular features, OB interneurons are classified into several subtypes. The role for each interneuron subtype in the control of olfactory behavior remains poorly understood due to lack of each specific marker. Among the several OB interneuron subtypes, a specific granule cell subtype, which expresses the oncofetal trophoblast glycoprotein (Tpbg or 5T4) gene, has been reported to be required for odor detection and discrimination behavior. This review will primarily focus on elucidating the contribution of different granule cell subtypes, including the Tpbg/5T4 subtype, to olfactory processing and behavior during the embryonic and adult stages.

Understanding Cerebellar Input Stage through Computational and Plasticity Rules.

A central hypothesis concerning brain functioning is that plasticity regulates the signal transfer function by modifying the efficacy of synaptic transmission. In the cerebellum, the granular layer has been shown to control the gain of signals transmitted through the mossy fiber pathway. Until now, the impact of plasticity on incoming activity patterns has been analyzed by combining electrophysiological recordings in acute cerebellar slices and computational modeling, unraveling a broad spectrum of different forms of synaptic plasticity in the granular layer, often accompanied by forms of intrinsic excitability changes. Here, we attempt to provide a brief overview of the most prominent forms of plasticity at the excitatory synapses formed by mossy fibers onto primary neuronal components (granule cells, Golgi cells and unipolar brush cells) in the granular layer. Specifically, we highlight the current understanding of the mechanisms and their functional implications for synaptic and intrinsic plasticity, providing valuable insights into how inputs are processed and reconfigured at the cerebellar input stage.

A cerebellar granule cell-climbing fiber computation to learn to track long time intervals.

In classical cerebellar learning, Purkinje cells (PkCs) associate climbing fiber (CF) error signals with predictive granule cells (GrCs) that were active just prior (∼150 ms). The cerebellum also contributes to behaviors characterized by longer timescales. To investigate how GrC-CF-PkC circuits might learn seconds-long predictions, we imaged simultaneous GrC-CF activity over days of forelimb operant conditioning for delayed water reward. As mice learned reward timing, numerous GrCs developed anticipatory activity ramping at different rates until reward delivery, followed by widespread time-locked CF spiking. Relearning longer delays further lengthened GrC activations. We computed CF-dependent GrC→PkC plasticity rules, demonstrating that reward-evoked CF spikes sufficed to grade many GrC synapses by anticipatory timing. We predicted and confirmed that PkCs could thereby continuously ramp across seconds-long intervals from movement to reward. Learning thus leads to new GrC temporal bases linking predictors to remote CF reward signals-a strategy well suited for learning to track the long intervals common in cognitive domains.

Retinoic acid modulation of granule cell activity and spatial discrimination in the adult hippocampus.

Retinoic acid (RA), derived from vitamin A (retinol), plays a crucial role in modulating neuroplasticity within the adult brain. Perturbations in RA signaling have been associated with memory impairments, underscoring the necessity to elucidate RA's influence on neuronal activity, particularly within the hippocampus. In this study, we investigated the cell type and sub-regional distribution of RA-responsive granule cells (GCs) in the mouse hippocampus and delineated their properties. We discovered that RA-responsive GCs tend to exhibit a muted response to environmental novelty, typically remaining inactive. Interestingly, chronic dietary depletion of RA leads to an abnormal increase in GC activation evoked by a novel environment, an effect that is replicated by the localized application of an RA receptor beta (RARß) antagonist. Furthermore, our study shows that prolonged RA deficiency impairs spatial discrimination-a cognitive function reliant on the hippocampus-with such impairments being reversible with RA replenishment. In summary, our findings significantly contribute to a better understanding of RA's role in regulating adult hippocampal neuroplasticity and cognitive functions.

Maladaptation of dentate gyrus mossy cells mediates contextual discrimination deficit after traumatic stress.

Fear overgeneralization is a maladaptive response to traumatic stress that is associated with the inability to discriminate between threat and safety contexts, a hallmark feature of post-traumatic stress disorder (PTSD). However, the neural mechanisms underlying this deficit remain unclear. Here, we show that traumatic stress exposure impairs contextual discrimination between threat and safety contexts in the learned helplessness (LH) model. Mossy cells (MCs) in the dorsal hippocampus are suppressed in response to traumatic stress. Bidirectional manipulation of MC activity in the LH model reveals that MC inhibition is causally linked to impaired contextual discrimination. Mechanistically, MC inhibition increases the number of active granule cells in a given context, significantly overlapping context-specific ensembles. Our study demonstrates that maladaptive inhibition of MCs after traumatic stress is a substantial mechanism underlying fear overgeneralization with contextual discrimination deficit, suggesting a potential therapeutic target for cognitive symptoms of PTSD.

Low frequency stimulation for seizure suppression: Identification of optimal targets in the entorhinal-hippocampal circuit.

BACKGROUND: Mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) is a common form of drug-resistant focal epilepsy in adults. Treatment for pharmacoresistant patients remains a challenge, with deep brain stimulation (DBS) showing promise for alleviating intractable seizures. This study explores the efficacy of low frequency stimulation (LFS) on specific neuronal targets within the entorhinal-hippocampal circuit in a mouse model of MTLE. OBJECTIVE: Our previous research demonstrated that LFS of the medial perforant path (MPP) fibers in the sclerotic hippocampus reduced seizures in epileptic mice. Here, we aimed to identify the critical neuronal population responsible for this antiepileptic effect by optogenetically stimulating presynaptic and postsynaptic compartments of the MPP-dentate granule cell (DGC) synapse at 1 Hz. We hypothesize that specific targets for LFS can differentially influence seizure activity depending on the cellular identity and location within or outside the seizure focus. METHODS: We utilized the intrahippocampal kainate (ihKA) mouse model of MTLE and targeted specific neural populations using optogenetic stimulation. We recorded intracranial neuronal activity from freely moving chronically epileptic mice with and without optogenetic LFS up to 3 h. RESULTS: We found that LFS of MPP fibers in the sclerotic hippocampus effectively suppressed epileptiform activity while stimulating principal cells in the MEC had no impact. Targeting DGCs in the sclerotic septal or non-sclerotic temporal hippocampus with LFS did not reduce seizure numbers but shortened the epileptiform bursts. CONCLUSION: Presynaptic stimulation of the MPP-DGC synapse within the sclerotic hippocampus is critical for seizure suppression via LFS.

Intrinsic and Synaptic Contributions to Repetitive Spiking in Dentate Granule Cells.

Repetitive firing of granule cells (GCs) in the dentate gyrus (DG) facilitates synaptic transmission to the CA3 region. This facilitation can gate and amplify the flow of information through the hippocampus. High-frequency bursts in the DG are linked to behavior and plasticity, but GCs do not readily burst. Under normal conditions, a single shock to the perforant path in a hippocampal slice typically drives a GC to fire a single spike, and only occasionally more than one spike is seen. Repetitive spiking in GCs is not robust, and the mechanisms are poorly understood. Here, we used a hybrid genetically encoded voltage sensor to image voltage changes evoked by cortical inputs in many mature GCs simultaneously in hippocampal slices from male and female mice. This enabled us to study relatively infrequent double and triple spikes. We found GCs are relatively homogeneous and their double spiking behavior is cell autonomous. Blockade of GABA type A receptors increased multiple spikes and prolonged the interspike interval, indicating inhibitory interneurons limit repetitive spiking and set the time window for successive spikes. Inhibiting synaptic glutamate release showed that recurrent excitation mediated by hilar mossy cells contributes to, but is not necessary for, multiple spiking. Blockade of T-type Ca2+ channels did not reduce multiple spiking but prolonged interspike intervals. Imaging voltage changes in different GC compartments revealed that second spikes can be initiated in either dendrites or somata. Thus, pharmacological and biophysical experiments reveal roles for both synaptic circuitry and intrinsic excitability in GC repetitive spiking.

Gulf war toxicant-induced effects on the hippocampal dendritic arbor are reversed by treatment with a Withania somnifera extract.

Gulf War Illness (GWI) is a multi-symptom disorder that manifests with fatigue, sleep disturbances, mood-cognition pathologies, and musculoskeletal symptoms. GWI affects at least 25% of the military personnel that served in Operations Desert Shield and Desert Storm from 1990 to 1991. We modeled Gulf War toxicant exposure in C57BL/6J mice by combined exposure to pyridostigmine bromide (an anti-sarin drug), chlorpyrifos (an organophosphate insecticide), and DEET (an insect repellent) for 10 days followed by oral treatment with Withania somnifera root extract for 21 days beginning at 12 weeks post-exposure. W. somnifera, commonly referred to as ashwagandha, has been used in traditional Ayurvedic medicine for centuries to improve memory and reduce inflammation, and its roots contain bioactive molecules which share functional groups with modern pain, cancer, and anti-inflammatory drugs. Previously, we observed that GWI mice displayed chronic reductions in dendritic arbor and loss of spines in granule cells of the dentate gyrus of the hippocampus at 14 weeks post-exposure. Here, we examined the effects of treatment with W. somnifera root extract on chronic dendrite and spine morphology in dentate granule cells of the mouse hippocampus following Gulf War toxicant exposure. GWI mice showed approximately 25% decreases in dendritic length (p < 0.0001) and overall dendritic spine density with significant reductions in thin and mushroom spines. GWI mice treated with the Ayurvedic W. somnifera extract exhibited dendritic lengths and spine densities near normal levels. These findings demonstrate the efficacy of the Ayurvedic treatment for neuroprotection following these toxic exposures. We hope that the extract and the neuronal processes influenced will open new avenues of research regarding treatment of Gulf War Illness and neurodegenerative disorders.

Antiseizure effects of Lilii Bulbus on pentylenetetrazol kindling-induced seizures in mice: Involvement of Reelin, Netrin-1, and semaphorin.

Lilii Bulbus (Lilium lancifolium Thunberg) has a proneurogenic effect on the hippocampus. However, its effects on epilepsy and associated pathological features remain unknown. In this study, we investigated the antiseizure effects of a water extract of Lilii Bulbus (WELB) in mouse model of pentylenetetrazol (PTZ)-induced seizure. Mice were injected with PTZ once every 48 h until full kindling was achieved. WELB (100 and 500 mg/kg) was orally administered once daily before PTZ administration and during the kindling process. We found that WELB treatment protected against PTZ-induced low seizure thresholds and high seizure severity. Further, WELB-treated mice showed attenuated PTZ kindling-induced anxiety and memory impairment. Immunostaining and immunoblots showed that hyperactivation and ectopic migration of dentate granule cells (DGCs) were significantly reduced by WELB treatment in PTZ kindling-induced seizure mice. Staining for mossy fiber sprouting (MFS) using Timm staining and ZnT3 showed that WELB treatment significantly decreased PTZ kindling-induced MFS. Furthermore, the increased or decreased expression of proteins related to ectopic DGCs (Reelin and Dab-1), MFS (Netrin-1, Sema3A, and Sema3F), and their downstream effectors (ERK, AKT, and CREB) in the hippocampus of PTZ kindling mice was significantly restored by WELB treatment. Overall, our findings suggest that WELB is a potential antiseizure drug that acts by reducing ectopic DGCs and MFS and modulating epileptogenesis-related signaling in the hippocampus.

Cerebellar granule cell migration and folia development require Mllt11/Af1q/Tcf7c.

The organization of neurons into distinct layers, known as lamination, is a common feature of the nervous system. This process, which arises from the direct coupling of neurogenesis and neuronal migration, plays a crucial role in the development of the cerebellum, a structure exhibiting a distinct folding cytoarchitecture with cells arranged in discrete layers. Disruptions to neuronal migration can lead to various neurodevelopmental disorders, highlighting the significance of understanding the molecular regulation of lamination. We report a role Mllt11/Af1q/Tcf7c (myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 fused gene from chromosome 1q, also known as Mllt11 transcriptional cofactor 7; henceforth referred to Mllt11) in the migration of cerebellar granule cells (GCs). We now show that Mllt11 plays a role in both the tangential and radial migration of GCs. Loss of Mllt11 led to an accumulation of GC precursors in the rhombic lip region and a reduction in the number of GCs successfully populating developing folia. Consequently, this results in smaller folia and an overall reduction in cerebellar size. Furthermore, analysis of the anchoring centers reveals disruptions in the perinatal folia cytoarchitecture, including alterations in the Bergmann glia fiber orientation and reduced infolding of the Purkinje cell plate. Lastly, we demonstrate that Mllt11 interacts with non-muscle myosin IIB (NMIIB) and Mllt11 loss-reduced NMIIB expression. We propose that the dysregulation of NMIIB underlies altered GC migratory behavior. Taken together, the findings reported herein demonstrate a role for Mllt11 in regulating neuronal migration within the developing cerebellum, which is necessary for its proper neuroanatomical organization.

Aging, Neurodegenerative Disorders, and Cerebellum.

An important part of the central nervous system (CNS), the cerebellum is involved in motor control, learning, reflex adaptation, and cognition. Diminished cerebellar function results in the motor and cognitive impairment observed in patients with neurodegenerative disorders such as Alzheimer's disease (AD), vascular dementia (VD), Parkinson's disease (PD), Huntington's disease (HD), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Friedreich's ataxia (FRDA), and multiple sclerosis (MS), and even during the normal aging process. In most neurodegenerative disorders, impairment mainly occurs as a result of morphological changes over time, although during the early stages of some disorders such as AD, the cerebellum also serves a compensatory function. Biological aging is accompanied by changes in cerebellar circuits, which are predominantly involved in motor control. Despite decades of research, the functional contributions of the cerebellum and the underlying molecular mechanisms in aging and neurodegenerative disorders remain largely unknown. Therefore, this review will highlight the molecular and cellular events in the cerebellum that are disrupted during the process of aging and the development of neurodegenerative disorders. We believe that deeper insights into the pathophysiological mechanisms of the cerebellum during aging and the development of neurodegenerative disorders will be essential for the design of new effective strategies for neuroprotection and the alleviation of some neurodegenerative disorders.