Impaired cerebellar Purkinje cell potentiation generates unstable spatial map orientation and inaccurate navigation

Lefort, Julie; Vincent, J.D.; Tallot, Lucille; Jarlier, Frédéric; Zeeuw, Chris I. De; Rondi-Reig, Laure; Rochefort, Christelle

doi:10.1038/s41467-019-09958-5

Cited by 32 publications

(42 citation statements)

References 52 publications

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“…Congruently, our physiological data suggest that these connected cerebellar regions may dynamically interact with the hippocampus during behavior, via theta (6–12 Hz) LFP coherence. Our findings thus offer an anatomical and physiological framework for cerebello-hippocampal interactions that could support cerebellar contributions to hippocampal processes (Burguière et al, 2005), including spatial map maintenance (Rochefort et al, 2011; Rondi-Reig et al, 2014; Lefort et al, 2019).…”

Section: Discussionmentioning

confidence: 74%

“…In the hippocampus, spontaneous local field potential (LFP) activity (Iwata and Snider, 1959; Babb et al, 1974; Snider and Maiti, 1975; Krook-Magnuson et al, 2014) and place cell properties (Rochefort et al, 2011; Lefort et al, 2019) are profoundly modulated following cerebellar manipulation (Rondi-Reig et al, 2014 for review). A recent study has also described, at the single cell and blood-oxygen-level-dependent signal level, sustained activation in the dorsal hippocampus during optogenetic enhancement of cerebellar nuclei output in head-fixed mice (Choe et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Anatomical and physiological foundations of cerebello-hippocampal interaction

Watson

Obiang

Torres-Herraez

et al. 2019

eLife

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112

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Multiple lines of evidence suggest that functionally intact cerebello-hippocampal interactions are required for appropriate spatial processing. However, how the cerebellum anatomically and physiologically engages with the hippocampus to sustain such communication remains unknown. Using rabies virus as a retrograde transneuronal tracer in mice, we reveal that the dorsal hippocampus receives input from topographically restricted and disparate regions of the cerebellum. By simultaneously recording local field potential from both the dorsal hippocampus and anatomically connected cerebellar regions, we additionally suggest that the two structures interact, in a behaviorally dynamic manner, through subregion-specific synchronization of neuronal oscillations in the 6–12 Hz frequency range. Together, these results reveal a novel neural network macro-architecture through which we can understand how a brain region classically associated with motor control, the cerebellum, may influence hippocampal neuronal activity and related functions, such as spatial navigation.

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Anatomical and physiological foundations of cerebello-hippocampal interaction

Watson

Obiang

Torres-Herraez

et al. 2019

eLife

Self Cite

112

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“…Thus, we cannot exclude the possibility that the cerebellar inflammation also contributed to non-motor deficits in the SCA1 mice. Moreover, since the cerebellum modulates hippocampal functions and excitability [57][58][59] , it is possible that the hippocampus itself may be impacted by the cerebellar inflammation.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal mitochondrial dysfunction and psychiatric-relevant behavioral deficits in spinocerebellar ataxia 1 mouse model

Tichánek

Šalomová

Jedlička

et al. 2020

Sci Rep

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Spinocerebellar ataxia 1 (SCA1) is a devastating neurodegenerative disease associated with cerebellar degeneration and motor deficits. However, many patients also exhibit neuropsychiatric impairments such as depression and apathy; nevertheless, the existence of a causal link between the psychiatric symptoms and SCA1 neuropathology remains controversial. This study aimed to explore behavioral deficits in a knock-in mouse SCA1 (SCA1 154Q/2Q) model and to identify the underlying neuropathology. We found that the SCA1 mice exhibit previously undescribed behavioral impairments such as increased anxiety-and depressive-like behavior and reduced prepulse inhibition and cognitive flexibility. Surprisingly, non-motor deficits characterize the early SCA1 stage in mice better than does ataxia. Moreover, the SCA1 mice exhibit significant hippocampal atrophy with decreased plasticity-related markers and markedly impaired neurogenesis. Interestingly, the hippocampal atrophy commences earlier than the cerebellar degeneration and directly reflects the individual severity of some of the behavioral deficits. Finally, mitochondrial respirometry suggests profound mitochondrial dysfunction in the hippocampus, but not in the cerebellum of the young SCA1 mice. These findings imply the essential role of hippocampal impairments, associated with profound mitochondrial dysfunction, in SCA1 behavioral deficits. Moreover, they underline the view of SCA1 as a complex neurodegenerative disease and suggest new avenues in the search for novel SCA1 therapies. Spinocerebellar ataxia type 1 (SCA1) is a lethal dominantly-inherited neurodegenerative disease, caused by CAG repeat expansion (> 40 CAG repeats) in the ataxin-1 encoding gene (ATXN1) 1. This mutation results in ataxin-1 protein toxicity and aggregation which leads, in particular, to cerebellar and brainstem degeneration 2 , although ATXN1 is widely expressed throughout the brain 1. SCA1 symptoms usually appear in early middle-age and include motor incoordination and gait deficits followed by muscular and swallowing problems in the later stages of the disease 3. However, in a similar way to other types of spinocerebellar ataxias (SCAs), over 50% of patients also demonstrate neuropsychiatric issues 4-7 including cognitive impairments, anxiety, apathy and depression 7-9. Interestingly, in contrast to progressive ataxia, the psychiatric impairments tend to remain relatively stable over time 8. Although they are often overlooked, they profoundly impact the quality of life and health outcomes of patients with SCA1 and related diseases 9. However, the question of whether these psychiatric impairments are causally linked to SCA1 neuropathology, or if they represent an emotional response to SCA1 diagnosis and subsequent physical disability, remains controversial 9 .

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“…; Lefort et al . ), cerebellar activity can be synchronized with hippocampal oscillations (Wikgren et al . ; McAfee et al .…”

Section: Discussionmentioning

confidence: 99%

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures

Streng

Krook-Magnuson

2019

The Journal of Physiology

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Key pointsr On-demand optogenetic inhibition of glutamatergic neurons in the fastigial nucleus of the cerebellum does not alter hippocampal seizures in a mouse model of temporal lobe epilepsy.r In contrast, on-demand optogenetic excitation of glutamatergic neurons in the fastigial nucleus successfully inhibits hippocampal seizures. With this approach, even a single 50 ms pulse of light is able to significantly inhibit seizures.r On-demand optogenetic excitation of glutamatergic fastigial neurons either ipsilateral or contralateral to the seizure focus is able to inhibit seizures.r Selective excitation of glutamatergic nuclear neurons provides greater seizure inhibition than broadly exciting nuclear neurons without cell-type specificity.Abstract Temporal lobe epilepsy is the most common form of epilepsy in adults, but current treatment options provide limited efficacy, leaving as many as one-third of patients with uncontrolled seizures. Recently, attention has shifted towards more closed-loop therapies for seizure control, and on-demand optogenetic modulation of the cerebellar cortex was shown to be highly effective at attenuating hippocampal seizures. Intriguingly, both optogenetic excitation and inhibition of cerebellar cortical output neurons, Purkinje cells, attenuated seizures. The mechanisms by which the cerebellum impacts seizures, however, are unknown. In the present study, we targeted the immediate downstream projection of vermal Purkinje cells -the fastigial nucleus -in order to determine whether increases and/or decreases in fastigial output can underlie seizure cessation. Though Purkinje cell input to fastigial neurons is inhibitory, direct optogenetic inhibition of the fastigial nucleus had no effect on seizure duration. Conversely, however, fastigial excitation robustly attenuated hippocampal seizures. Seizure cessation was achieved at multiple stimulation frequencies, regardless of laterality relative to seizure focus, and even with single light pulses. Seizure inhibition was greater when selectively targeting glutamatergic fastigial neurons than when an approach that lacked cell-type specificity was used. Together, these results suggest Martha Streng received a BA in Neuroscience and Behaviour from Mount Holyoke College and a PhD in Neuroscience from the University of Minnesota, Twin Cities, where she studied the encoding of motor predictive and feedback information by Purkinje cells during online motor control tasks. Her current research focuses on the characterization of cerebellar circuitry and output channels in health and disease. that stimulating excitatory neurons in the fastigial nucleus may be a promising approach for therapeutic intervention in temporal lobe epilepsy.

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Impaired cerebellar Purkinje cell potentiation generates unstable spatial map orientation and inaccurate navigation

Cited by 32 publications

References 52 publications

Anatomical and physiological foundations of cerebello-hippocampal interaction

Anatomical and physiological foundations of cerebello-hippocampal interaction

Hippocampal mitochondrial dysfunction and psychiatric-relevant behavioral deficits in spinocerebellar ataxia 1 mouse model

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures

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