Social memory deficit gated by dysregulation of the cerebellar vermis

Chao, Owen Y; Pathak, Salil Saurav; Zhang, Hao; Augustine, George J; Christie, Jason M.; Taniguchi, Hiroki; Yang, Yi

doi:10.21203/rs.3.rs-1393639/v1

Cited by 4 publications

(4 citation statements)

References 80 publications

(179 reference statements)

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“…Recent studies show that vermal and hemispheric regions project via the deep cerebellar nuclei to distinctive patterns of forebrain structures (Chao et al, 2022;De Zeeuw, 2021;De Zeeuw et al, 2021;Fujita et al, 2020;Leiner et al, 1993Leiner et al, , 1986, influencing thalamocortical nonmotor processing. Chemogenetic inhibition of lobule VI Purkinje cells led to broad decreases in thalamic activity as measured using c-Fos.…”

Section: Discussionmentioning

confidence: 99%

Cerebellar contributions to a brainwide network for reversal learning

Verpeut

Bergeler

Kislin

et al. 2021

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The cerebellum regulates nonmotor behavior, but the routes by which it exerts its influence are not well characterized. Here we report a necessary role for posterior cerebellum in guiding flexible behavior, acting through a network of diencephalic and neocortical structures. After chemogenetic inhibition of Purkinje cells in lobule VI or crus I, high-throughput automated analysis of complex whole-body movement revealed deficiencies in adaptation across days to an open field environment. Neither perturbation affected gait, within-day open-field adaptation, or location preference. In a Y-maze task, mice could learn but were impaired in their ability to reverse their initial choice. To map targets of perturbation, we imaged c-Fos activation in cleared whole brains using light-sheet microscopy. Reversal learning activated diencephalic regions and associative neocortical regions. Distinctive subsets of structures were altered by perturbation of lobule VI (thalamus and habenula) and crus I (hypothalamus and prelimbic/orbital cortex), and both perturbations influenced anterior cingulate and infralimbic cortex. Taken together, these experiments reveal parts of a brainwide system for cerebellar influence to guide flexible learning.

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Section: Discussionmentioning

confidence: 99%

Cerebellar contributions to a brainwide network for reversal learning

Verpeut

Bergeler

Kislin

et al. 2021

Preprint

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“…Next, we quantified neuronal activity in the PFC using a molecular marker, c-Fos 33 . By counting the number of c-Fos-positive cells in the PFC, we found a significant effect on c-Fos levels in the PFC (Figure 1B).…”

Section: Cerebellar Expression Of Mutant Atxn1 Is Sufficient To Impac...mentioning

confidence: 99%

Cerebellar contribution to cognitive deficits and prefrontal cortex dysfunction in Spinocerebellar Ataxia Type 1 (SCA1)

Sbrocco,

Borgenheimer,

Zhang

et al. 2024

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The cerebellum role in cognition and its functional bi-directional connectivity with prefrontal cortex (PFC) is well recognized. However, how chronic cerebellar dysfunction affects PFC function and cognition remains less understood. Spinocerebellar ataxia type 1 (SCA1), is an inherited, fatal neurodegenerative disease caused by an abnormal expansion of glutamine (Q) encoding CAG repeats in the gene Ataxin-1 (ATXN1) and characterized by severe loss of Purkinje cells (PCs) in the cerebellum. Patients with SCA1 suffer from movement and balance deficits, cognitive decline and premature lethality. Cognitive deficits significantly impact patients quality of life, yet how exactly cerebellar degeneration contributes to cognitive deficits and PFC dysfunction in SCA1 is unknown. We have previously demonstrated that expression of mutant ATXN1 only in cerebellar Purkinje cells (PCs) is sufficient to cause cognitive deficits in a transgenic ATXN1[82Q] mouse line. To understand how cerebellar dysfunction impacts the PFC, we examined neuronal activity, synaptic density, and gene expression changes in the PFC of ATXN1[82Q] mice. Remarkably, we found decreased neuronal activity, reduced synaptic density, and altered expression of immediate early genes and pathways involved in glucose metabolism, inflammation and amphetamine in the PFC of ATXN1[82Q] mice. Furthermore, we characterized cellular and molecular PFC dysfunction in a novel conditional knock-in SCA1 line, f-ATXN1146Q mice, expressing floxed human expanded ATXN1 throughout the brain. Intriguingly, we found an increased number of neurons, increased synaptic density and large gene expression alterations in the PFC of f-ATXN1146Q mice. Finally, to precisely determine the role of cerebellar dysfunction in cognitive deficits and PFC dysfunction in SCA1, we crossed f-ATXN1146Q mice with Pcp2-Cre mice expressing Cre recombinase in PCs to delete expanded ATXN1 only in PCs. Surprisingly, we have found that deleting expanded ATXN1 in PCs exacerbated cognitive deficits and PFC dysfunction in these mice. Our findings demonstrate that circumscribed cerebellar dysfunction is sufficient to impact PFC activity and synaptic connectivity impairing cognition. However, when multiple brain regions are impacted in disease, cerebellar dysfunction may ameliorate PFC pathology and cognitive performance.

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“…Although Purkinje cells spontaneously discharge action potentials, their firing rate is modulated by excitatory and inhibitory synaptic inputs. Inhibitory inputs are provided by interneurons in the cerebellar molecular layer (MLI), and chemogenetic excitation and inhibition of MLI both lead to impaired social behavior in mice (Badura et al, 2018;Chao et al, 2023).…”

Section: Hemizygous Deletion Of Tsc1 In Purkinje Cellsmentioning

confidence: 99%

“…The link between the cerebellum and cognitive impairments in these disorders previously seemed perplexing because the cerebellum was traditionally considered a part of the motor system. However, recent studies show that the cerebellum is also involved in various non-motor functions, such as cognitive processing, social behavior, fear, and emotion, through its interaction with other brain regions (Koziol et al, 2014;Palesi et al, 2015;Badura et al, 2018;Vaaga et al, 2020;Fastenrath et al, 2022;Chao et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Loss of Purkinje cells in the developing cerebellum strengthens the cerebellothalamic synapses

Nishiyama,

Zemelman

2023

Preprint

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Cerebellar damage early in life often causes long-lasting motor, social, and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviors. This recent finding has promoted research on how cerebellar damage affects the development of the cerebral cortex, the brain region responsible for higher-order control of all behaviors. However, the cerebral cortex is not directly connected to the cerebellum. The thalamus is the direct postsynaptic target of the cerebellum, sending cerebellar outputs to the cerebral cortex. Despite its crucial position in cerebello-cerebral interaction, thalamic susceptibility to cerebellar damage remains largely unclear. Here, we studied the consequences of early cerebellar perturbation on thalamic development. Whole-cell patch-clamp recordings showed that the synaptic organization of the cerebellothlamic circuit is similar to that of the primary sensory thalamus, in which aberrant sensory activity alters synaptic circuit formation. The hemizygous deletion of the tuberous sclerosis complex-1 (Tsc1) gene in the Purkinje cell—known to cause Purkinje cell hypoactivity and autistic behaviors—did not alter cerebellothalamic synapses or intrinsic membrane properties of thalamic neurons. However, the ablation of Purkinje cells in the developing cerebellum strengthened the cerebellothalamic synapses and enhanced thalamic suprathreshold activities. These results suggest that the cerebellothalamic circuit is resistant to moderate perturbation in the developing cerebellum, such as the reduced firing rate of Purkinje cells, and that autistic behaviors are not necessarily linked to thalamic abnormality. Still, Purkinje cell loss alters the thalamic circuit, suggesting the vulnerability of the thalamus to substantial disturbance in the developing cerebellum.

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Social memory deficit gated by dysregulation of the cerebellar vermis

Cited by 4 publications

References 80 publications

Cerebellar contributions to a brainwide network for reversal learning

Cerebellar contributions to a brainwide network for reversal learning

Cerebellar contribution to cognitive deficits and prefrontal cortex dysfunction in Spinocerebellar Ataxia Type 1 (SCA1)

Loss of Purkinje cells in the developing cerebellum strengthens the cerebellothalamic synapses

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