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The inhibitory circuit of cerebellar granular layer. In the granular layer of the cerebellar cortex, granule cells receive excitatory inputs from the mossy fibers and are inhibited by Golgi cells. The synaptic contacts among granule cell (GrC) dendrites, mossy fiber (MF) terminals, and Golgi cell (GoC) axon and dendrites are enwrapped into a glial sheet, originating a peculiar anatomical structure known as cerebellar glomerulus. Each glomerulus is characterized by one mossy fiber rosette and several granule cell and Golgi cell dendrites, as well as Golgi cell axons. Each granule cell dendrite contacts different glomeruli, receiving inputs from different mossy fibers. GrC axon ascends in the molecular layer, where it originates the parallel fibers (pf), that form excitatory synapses on GoC dendrites (Palkovits et al., 1971; Palay and Chan-Palay, 1974; Hámori and Somogyi, 1983). Mossy fiber terminals contact granule cell dendrites as well as Golgi cells, that therefore inhibit granule cells in a feedforward loop. Parallel fibers originating from granule cell axons, activates Golgi cells, giving rise to a feedback inhibition on granule cells.
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Inhibitory synapses can be organized in different ways and be regulated by a multitude of mechanisms. One of the best known examples is provided by the inhibitory synapses formed by Golgi cells onto granule cells in the cerebellar glomeruli. These synapses are GABAergic and inhibit granule cells through two main mechanisms, phasic and tonic. The fo...
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... (3) Connectivity: The cerebellum shows tight bidirectional connectivity with associative areas involved in CIAS, especially the PFC (Palesi et al., 2015(Palesi et al., , 2017). (4) Microcircuit level: Cerebellar functioning relies on a delicate regulation of the internal E/I balance, which appears altered in CIAS (D' Angelo and De Zeeuw, 2009;Mapelli et al., 2014;Nieus et al., 2014;Perez-Garcia, 2015;De Schepper et al., 2022). (5) Whole brain level: The cerebellum controls the functioning and rhythms of the cerebral cortex (Popova and Naumenko, 2013;Margarint et al., 2020), which show relevant alterations in CIAS. ...
Schizophrenia (SZ) is a complex neuropsychiatric disorder associated with severe cognitive dysfunction. Although research has mainly focused on forebrain abnormalities, emerging results support the involvement of the cerebellum in SZ physiopathology, particularly in Cognitive Impairment Associated with SZ (CIAS). Besides its role in motor learning and control, the cerebellum is implicated in cognition and emotion. Recent research suggests that structural and functional changes in the cerebellum are linked to deficits in various cognitive domains including attention, working memory, and decision-making. Moreover, cerebellar dysfunction is related to altered cerebellar circuit activities and connectivity with brain regions associated with cognitive processing. This review delves into the role of the cerebellum in CIAS. We initially consider the major forebrain alterations in CIAS, addressing impairments in neurotransmitter systems, synaptic plasticity, and connectivity. We then focus on recent findings showing that several mechanisms are also altered in the cerebellum and that cerebellar communication with the forebrain is impaired. This evidence implicates the cerebellum as a key component of circuits underpinning CIAS physiopathology. Further studies addressing cerebellar involvement in SZ and CIAS are warranted and might open new perspectives toward understanding the physiopathology and effective treatment of these disorders.
... It is unknown how many Golgi cells provide fine axon filaments that enter a single glomerulus -the simulation assumes 8-12, about 1/3 of the number in range. It has been proposed that, like Golgi cell dendritic signalling, there is a sustained build-up of glomerular GABA during behaviour [16] at an adjustable concentration controlled by Golgi cell firing rates [17]. Assuming spillover from a single afferent cell is proportional to its firing rate, spillover provides the physiological equivalent of averaging afferent rates. ...
In the cerebellum, granule cells make parallel fibre contact on (and excite) Golgi cells and Golgi cells inhibit granule cells, forming an open feedback loop. Parallel fibres excite Golgi cells synaptically, each making a single contact. Golgi cells inhibit granule cells in a structure called a glomerulus almost exclusively by GABA spillover acting through extrasynaptic GABAA receptors. Golgi cells are connected dendritically by gap junctions. It has long been suspected that feedback contributes to homeostatic regulation of parallel fibre signals activity, causing the fraction of the population that are active to be maintained at a low level. We present a detailed neurophysiological and computationally-rendered model of functionally grouped Golgi cells which can infer the density of parallel fibre signals activity and convert it into proportional modulation of inhibition of granule cells. The conversion is unlearned and not actively computed; rather, output is simply the computational effect of cell morphology and network architecture. Unexpectedly, the conversion becomes more precise at low density, suggesting that self-regulation is attracted to sparse code, because it is stable. A computational function of gap junctions may not be confined to the cerebellum.
... It is unknown how many Golgi cells provide ne axon laments that enter a single glomerulus -the simulation assumes 8-12, about 1/3 of the number in range. It has been proposed that, like Golgi cell dendritic signalling, there is a sustained build-up of glomerular GABA during behaviour [16] at an adjustable concentration controlled by Golgi cell ring rates [17]. Assuming spillover from a single afferent cell is proportional to its ring rate, spillover provides the physiological equivalent of averaging afferent rates. ...
In the cerebellum, granule cells make parallel fibre contact on (and excite) Golgi cells and Golgi cells inhibit granule cells, forming an open feedback loop. Parallel fibres excite Golgi cells synaptically, each making a single contact. Golgi cells inhibit granule cells in a structure called a glomerulus almost exclusively by GABA spillover acting through extrasynaptic GABA A receptors. Golgi cells are connected dendritically by gap junctions. It has long been suspected that feedback contributes to homeostatic regulation of parallel fibre signals activity, causing the fraction of the population that are active to be maintained at a low level. We present a detailed neurophysiological and computationally-rendered model of functionally grouped Golgi cells which can infer the density of parallel fibre signals activity and convert it into proportional modulation of inhibition of granule cells. The conversion is unlearned and not actively computed; rather, output is simply the computational effect of cell morphology and network architecture. Unexpectedly, the conversion becomes more precise at low density, suggesting that self-regulation is attracted to sparse code, because it is stable. A computational function of gap junctions may not be confined to the cerebellum.
... The copyright holder for this preprint this version posted July 18, 2023. ; https://doi.org/10.1101/2023.07.14.548987 doi: bioRxiv preprint It has been suggested there may be a sustained build-up of glomerular GABA during behaviour (44) at an adjustable concentration controlled by Golgi cell firing rates (45). ...
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... During synaptic transmission, the GABA B-Rs activated by GABA release play a part in the feedback and feedforward control of the neurons in the target region [1,36,37,77]. In addition, the modulation of GABA B-Rs has been reported in several brain circuits [78][79][80]. Similarly, our results are in line with these conclusions because the GP sends axons to the rostral part of the RTn [10,11]. ...
The external globus pallidus (GP) firing rate synchronizes the basal ganglia-thalamus-cortex network controlling GABAergic output to different nuclei. In this context, two findings are significant: the activity and GABAergic transmission of the GP modulated by GABA B receptors and the presence of the GP-thalamic reticular nucleus (RTn) pathway, the functionality of which is unknown. The functional participation of GABA B receptors through this network in cortical dynamics is feasible because the RTn controls transmission between the thalamus and cortex. To analyze this hypothesis, we used single-unit recordings of RTn neurons and electroencephalograms of the motor cortex (MCx) before and after GP injection of the GABA B agonist baclofen and the antagonist saclofen in anesthetized rats. We found that GABA B agonists increase the spiking rate of the RTn and that this response decreases the spectral density of beta frequency bands in the MCx. Additionally, injections of GABA B antagonists decreased the firing activity of the RTn and reversed the effects in the power spectra of beta frequency bands in the MCx. Our results proved that the GP modulates cortical oscillation dynamics through the GP-RTn network via tonic modulation of RTn activity.
... Finally, considering the cerebellar glomerular rosette, a multisynaptic area with two different axonal (mossy and Golgi) and dendritic (granule and Golgi) terminations [48,75], the cerebella of Npc1 nmf164 mice at PN11 and PN30 showed a reduced number of synaptophysin-positive glomeruli, which were also less convoluted and smaller. In addition, from this analysis, it emerged that in Npc1 nmf164 mice there is a significant increase in the distance between GCs, probably due to the already demonstrated reduced number of these neurons [10] and a reduction in the GCglomerulus distance, present only at the stage of PN11. ...
Niemann-Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder due to mutations in the NPC1 gene resulting in the accumulation of cholesterol within the endosomal/lysosomal compartments. The prominent feature of the disorder is the progressive Purkinje cell degeneration leading to ataxia.
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We characterized the expression/localization patterns of the BDNF and its receptor, tropomyosin-related kinase B (TrkB), in the early postnatal and young adult cerebellum of the Npc1nmf164 mutant mouse strain.
In Npc1nmf164 mice, our results show: (i) a reduced expression of cerebellar BDNF and pTrkB in the first two weeks postpartum, phases in which most GCs complete the proliferative/migrative program and begin differentiation; (ii) an altered subcellular localization of the pTrkB receptor in GCs, both in vivo and in vitro; (iii) reduced chemotactic response to BDNF in GCs cultured in vitro, associated with impaired internalization of the activated TrkB receptor; (iv) an overall increase in dendritic branching in mature GCs, resulting in impaired differentiation of the cerebellar glomeruli, the major synaptic complex between GCs and mossy fibers.
... Briefly, inputs are provided by climbing fibers (from the inferior olive, directly contacting Purkinje cells) and mossy fibers (from the rest of the brain), which send collaterals to the deep cerebellar nuclei before reaching the cortex. Here, mossy fibers (MFs) contact granular layer neurons (inhibitory Golgi cells and the most abundant neurons in the entire brain, the excitatory granule cells) in anatomical structures called "glomeruli" [2]. The granular layer is therefore considered the input layer of the cerebellar cortex. ...
... In turn, PCs are excited by GrCs and inhibited by MLIs, which provide inhibitory loops in the molecular layer. It is evident that the inhibitory component is predominant both in the granular and molecular layers, to determine cerebellar cortical processing, [2,3]. The architecture of the cerebellar cortex is such that forcing a sagittal or coronal orientation to the circuit activation (by using the slicing procedure) is expected to impact cerebellar processing. ...
... loops in the molecular layer. It is evident that the inhibitory component is predominant both in the granular and molecular layers, to determine cerebellar cortical processing, [2,3]. The architecture of the cerebellar cortex is such that forcing a sagittal or coronal orientation to the circuit activation (by using the slicing procedure) is expected to impact cerebellar processing. ...
The cerebellum is one of the most connected structures of the central nervous system and receives inputs over an extended frequency range. Nevertheless, the frequency dependence of cerebellar cortical processing remains elusive. In this work, we characterized cerebellar cortex responsiveness to mossy fibers activation at different frequencies and reconstructed the spread of activity in the sagittal and coronal planes of acute mouse cerebellar slices using a high-throughput high-density multielectrode array (HD-MEA). The enhanced spatiotemporal resolution of HD-MEA revealed the frequency dependence and spatial anisotropy of cerebellar activation. Mossy fiber inputs reached the Purkinje cell layer even at the lowest frequencies, but the efficiency of transmission increased at higher frequencies. These properties, which are likely to descend from the topographic organization of local inhibition, intrinsic electroresponsiveness, and short-term synaptic plasticity, are critical elements that have to be taken into consideration to define the computational properties of the cerebellar cortex and its pathological alterations.
... This connection is characterized by a low probability of GABA release, suggesting that a robust activation of PCs is needed to activate this additional source of feedback inhibition to GrCs. These results show that, in lobules VI-X, PCs contribute to both phasic and tonic inhibition in the granular layer, therefore affecting the spatiotemporal dynamics of GrCs firing Mapelli et al., 2014). ...
The cerebellum operates exploiting a complex modular organization and a unified computational algorithm adapted to different behavioral contexts. Recent observations suggest that the cerebellum is involved not just in motor but also in emotional and cognitive processing. It is therefore critical to identify the specific regional connectivity and microcircuit properties of the emotional cerebellum. Recent studies are highlighting the differential regional localization of genes, molecules, and synaptic mechanisms and microcircuit wiring. However, the impact of these regional differences is not fully understood and will require experimental investigation and computational modeling. This review focuses on the cellular and circuit underpinnings of the cerebellar role in emotion. And since emotion involves an integration of cognitive, somatomotor, and autonomic activity, we elaborate on the tradeoff between segregation and distribution of these three main functions in the cerebellum.
... As was mentioned previously ("Electrophysiology of the Cerebellar Nuclear Neurons"), the inhibitory neurons of the CN projecting to the cerebellar cortex are not spontaneously active in vitro but show a preference for fast burst spiking upon depolarization. Activation of such a burst in type 2 glycinergic neurons could broaden the time window for synaptic integration in cerebellar granular layer [263,264]. It is possible these nucleocortical neurons with strong burst-fire behavior could be efficiently activated by the low-rate activity in olivary projections to the CN, thereby allowing modulation of the specificity of the sensory information that reaches a particular olivocerebellar module. ...
The cerebellum is a key player in many brain functions and a major topic of neuroscience research. However, the cerebellar nuclei (CN), the main output structures of the cerebellum, are often overlooked. This neglect is because research on the cerebellum typically focuses on the cortex and tends to treat the CN as relatively simple output nuclei conveying an inverted signal from the cerebellar cortex to the rest of the brain. In this review, by adopting a nucleocentric perspective we aim to rectify this impression. First, we describe CN anatomy and modularity and comprehensively integrate CN architecture with its highly organized but complex afferent and efferent connectivity. This is followed by a novel classification of the specific neuronal classes the CN comprise and speculate on the implications of CN structure and physiology for our understanding of adult cerebellar function. Based on this thorough review of the adult literature we provide a comprehensive overview of CN embryonic development and, by comparing cerebellar structures in various chordate clades, propose an interpretation of CN evolution. Despite their critical importance in cerebellar function, from a clinical perspective intriguingly few, if any, neurological disorders appear to primarily affect the CN. To highlight this curious anomaly, and encourage future nucleocentric interpretations, we build on our review to provide a brief overview of the various syndromes in which the CN are currently implicated. Finally, we summarize the specific perspectives that a nucleocentric view of the cerebellum brings, move major outstanding issues in CN biology to the limelight, and provide a roadmap to the key questions that need to be answered in order to create a comprehensive integrated model of CN structure, function, development, and evolution.
... In addition to the fast IPSC, inhibitory transmission between GoCs and GrCs involves a slower component that is mediated by high-affinity extrasynaptic GABA A Rs activated by spillover and accumulation of GABA in cerebellar glomeruli (Rossi and Hamann, 1998;Mapelli et al., 2014). This volume transmission should be ideally suited to reveal the concentration of GABA released by Golgi cells in the glomeruli. ...
Neurotransmitter content is deemed the most basic defining criterion for neuronal classes, contrasting with the intercellular heterogeneity of many other molecular and functional features. Here we show, in the adult mouse brain, that neurotransmitter content variegation within a neuronal class is a component of its functional heterogeneity. Golgi cells (GoCs), the well-defined class of cerebellar interneurons inhibiting granule cells (GrCs), contain cytosolic glycine, accumulated by the neuronal transporter GlyT2, and GABA in various proportions. By performing acute manipulations of cytosolic GABA and glycine supply, we find that competition of glycine with GABA reduces the charge of IPSC evoked in GrCs and, more specifically, the amplitude of a slow component of the IPSC decay. We then pair GrCs recordings with optogenetic stimulations of single GoCs, which preserve the intracellular transmitter mixed content. We show that the strength and decay kinetics of GrCs IPSCs, which are entirely mediated by GABA A receptors, are negatively correlated to the presynaptic expression of GlyT2 by GoCs. We isolate a slow spillover component of GrCs inhibition that is also affected by the expression of GlyT2, leading to a 56% decrease in relative charge. Our results support the hypothesis that presynaptic loading of glycine negatively impacts the GABAergic transmission in mixed interneurons, most likely through a competition for vesicular filling. We discuss how the heterogeneity of neurotransmitter supply within mixed interneurons like the GoC class may provide a presynaptic mechanism to tune the gain of microcircuits such as the granular layer, thereby expanding the realm of their possible dynamic behaviors.
