Cerebellar Lobulus Simplex and Crus I Differentially Represent Phase and Phase Difference of Prefrontal Cortical and Hippocampal Oscillations

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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“…; McAfee et al . ) and inhibition of Purkinje cells leads to functional activation of the hippocampus (Choe 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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“…It stands to reason that powerful cerebellar computations are necessary to drive such critical behaviors. One possibility is that the cerebellum promotes coherent activity between cortical brain regions; an example could be an adjustment in hippocampal-prefrontal cortex coherence upon Purkinje cell activation (McAfee et al, 2019). Interestingly, the hippocampus (Hoogland et al, 2019;Krasowska et al, 2014;Miranda et al, 2015Miranda et al, , 2016 and prefrontal cortex (Suzuki et al, 2017) exhibit abnormalities in human DMD and mdx mice.…”

Section: Discussionmentioning

confidence: 99%

“…The cerebellum controls a variety of motor behaviors, including coordination, learning, balance and posture (Reeber et al, 2013;Thach, 2014). It may also play a pivotal role in non-motor functions such as cognition, language, emotion, reward, social interactions and spatial working memory (Buckner, 2013;Carta et al, 2019;D'Angelo and Casali, 2013;McAfee et al, 2019;Stoodley, 2012). The execution of all these behaviors requires proper Purkinje cell function (Heiney et al, 2014;Tsai et al, 2012;White et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

In vivo cerebellar circuit function is disrupted in an mdx mouse model of Duchenne muscular dystrophy

Stay

Miterko

Arancillo

et al. 2019

Disease Models &Amp; Mechanisms

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Duchenne muscular dystrophy (DMD) is a debilitating and ultimately lethal disease involving progressive muscle degeneration and neurological dysfunction. DMD is caused by mutations in the dystrophin gene, which result in extremely low or total loss of dystrophin protein expression. In the brain, dystrophin is heavily localized to cerebellar Purkinje cells, which control motor and nonmotor functions. In vitro experiments in mouse Purkinje cells revealed that loss of dystrophin leads to low firing rates and high spiking variability. However, it is still unclear how the loss of dystrophin affects cerebellar function in the intact brain. Here, we used in vivo electrophysiology to record Purkinje cells and cerebellar nuclear neurons in awake and anesthetized female mdx (also known as Dmd) mice. Purkinje cell simple spike firing rate is significantly lower in mdx mice compared to controls. Although simple spike firing regularity is not affected, complex spike regularity is increased in mdx mutants. Mean firing rate in cerebellar nuclear neurons is not altered in mdx mice, but their local firing pattern is irregular. Based on the relatively wellpreserved cytoarchitecture in the mdx cerebellum, our data suggest that faulty signals across the circuit between Purkinje cells and cerebellar nuclei drive the abnormal firing activity. The in vivo requirements of dystrophin during cerebellar circuit communication could help explain the motor and cognitive anomalies seen in individuals with DMD. This article has an associated First Person interview with the first author of the paper.

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“…In addition to the interpositus nucleus, EBC requires cerebellar cortex near the base of the primary fissure. Cerebellar cortex is critical for other cognitive functions, creating closed-loop circuits with prefrontal cortex and other cerebral areas that may allow for cerebellum to modulate higher-order functions 50,51 . For example, Crus I has been linked to cognitive flexibility 52 , perceptual decision-making 53 , and social behaviors 54 .…”

Section: Neural Vulnerability To Stressmentioning

confidence: 99%

Long-term aberrations to cerebellar endocannabinoids induced by early-life stress

Moussa-Tooks

Larson

Gimeno

et al. 2019

Preprint

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AbstractStudies of early-life stress traditionally focus on glucocorticoid signaling as a modulator of neurodevelopmental risk, but emerging evidence points to the role of the endocannabinoid system in long-term stress-induced neural remodeling. Existing studies on stress-induced endocannabinoid dysregulation have focused on changes to cerebrum that are temporally proximal to stressors, but little is known about temporally distal effects, especially in cerebellum, which is vulnerable to early developmental stress and is dense with cannabinoid receptors. Further, sex-specific effects of stress on cerebellar endocannabinoid tone are understudied. Following a naturalistic rodent model of early-life stress, limited bedding at postnatal days 2-9, adult (postnatal day 70) cerebellar and hippocampal endocannabinoids and related lipids and mRNA were assessed, and behavioral performance was evaluated. Regional and sex-specific effects were present at baseline and following early-life stress. Limited bedding impaired peripherally-measured basal corticosterone in adult males only. In the CNS, early-life stress (1) decreased 2-arachidonoyl glycerol and arachidonic acid in the cerebellar deep nuclei in males only; (2) decreased 2-arachidonoyl glycerol in females only in cerebellar Crus I; and (3) increased dorsal hippocampus prostaglandins in males only. Transcriptomics for cerebellar interpositus nucleus revealed substantial sex effects, with minimal effects of stress. Stress did impair novel object recognition in both sexes and social preference in females. Taken together, the cerebellar endocannabinoids system exhibits robust sex-specific differences, malleable through early-life stress and perhaps also contributing to sexual differentiation of the brain. The current study may foster future research into stress as a risk factor for cerebellar-related dysfunctions.

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Cerebellar Lobulus Simplex and Crus I Differentially Represent Phase and Phase Difference of Prefrontal Cortical and Hippocampal Oscillations

Cited by 55 publications

References 29 publications

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

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

In vivo cerebellar circuit function is disrupted in an mdx mouse model of Duchenne muscular dystrophy

Long-term aberrations to cerebellar endocannabinoids induced by early-life stress

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