Epigenetic Regulation of Neural Transmission after Cerebellar Fastigial Nucleus Lesions in Juvenile Rats

Abstract

Structural and functional abnormalities in the cerebellar midline region, including the fastigial nucleus, have been reported in neuropsychiatric disorders, also comprising the cerebellar cognitive affecting syndrome. In rats, early fastigial lesions reduce social interaction during development and lead to cognitive and emotional deficits in adults, accompanied by compromised neuronal network activity. Since epigenetic mechanisms are implicated in the etiology of neuropsychiatric disorders, we investigated whether fastigial nucleus lesions in juvenile rats would impact epigenetic regulation of neural transmission. The fastigial nucleus was lesioned bilaterally in 23-day-old male rats. Sham-lesion and naïve rats served as controls. DNA methylation was investigated for target genes of the GABAergic, dopaminergic, glutamatergic and oxytocinergic systems in brain regions with anatomic connections to the fastigial nucleus, i.e., medial prefrontal cortex, nucleus accumbens, striatum, thalamus, and sensorimotor cortex. Protein expression was examined for the respective target genes in case of altered DNA methylation between lesion and control groups. Lesioning of the fastigial nucleus led to significant differences in the epigenetic regulation of glutamate decarboxylase 1 and the oxytocin receptor in the nucleus accumbens and the prefrontal cortex. No differences were found for the other target genes and brain regions. Our findings indicate that epigenetic dysregulation after lesioning of the fastigial nucleus may influence long-term recovery and the emergence of behavioral changes. Together with previous behavioral and electrophysiological investigations of this rat model, these observations can play a role in the cerebellar cognitive affective syndrome and other neuropsychiatric disorders.

Involvement of the cerebellum in migraine

“…One study using a mutant mouse line with Purkinje cell death reported that mutants spent more time in the open arms of the elevated plus maze, suggesting an anti-anxiety phenotype (Hilber et al, 2004 ). Bilateral lesion of the MN in juvenile rats was shown to alter anxiety in adulthood although it was not clear whether the anxiety was enhanced or decreased (Helgers et al, 2020 ), accompanied by enhancement of local field coherence between the medial prefrontal cortex and the sensorimotor cortex (Helgers et al, 2020 ) and epigenetic dysregulation of the GABAergic system in the nucleus accumbens and the oxytocin system in the prefrontal cortex (Helgers et al, 2021 ). Cerebellar manipulation can also change fear responses, an affective component of pain.…”

Targeting DBS to the centrolateral thalamic nucleus improves movement in a lesion-based model of acquired cerebellar dystonia in mice

“…Knowing that a variety of manipulations of afferent signaling to the cerebellar cortex, and disruption of cerebellar cortical function both lead to dystonia, we sought to devise a paradigm that would allow for the reliable induction of highly focal lesions to test whether disruption of cerebellar efferent signaling would also produce dystonia. Previous groups have used monopolar electrodes to induce lesions of the fastigial (medial) nucleus in rats[1, 33, 34]. Therefore, using tungsten electrodes, we sought to deliver a charge of 1600 mA at 50 Hz using a pulse generator attached to the electrode.…”

“…In humans, acute lesioning of the cerebellar outflow tract leads to a constellation of symptoms termed the cerebellar cognitive affective syndrome, the severity of which occurs in direct proportion to the percent damage to the tract bilaterally[3, 35]. In rats, lesioning of the medial (fastigial) cerebellar nuclei has also been associated with a constellation of behavioral deficits[1, 33, 34]. In mice, the sequelae of lesioning of the cerebellar outflow tracts have not been examined.…”

“…Previously, excitotoxic lesions of the cerebellar hemispheres or vermis, using kainic acid, have shown that injury to cerebellar components of the dystonia network can lead to dystonia[27, 59, 63, 79], while pharmacologic manipulations of the cerebellum in mouse models predisposed to dystonia also elicit dystonia[14]. Non-pharmacological lesioning of the cerebellar outflow tracts has not, to our knowledge, been reported in mice in the context of dystonia, although models of injury to the medial cerebellar nuclei and vermis have been reported in rats, using electrolytic charge delivery and mechanical suction, respectively[1, 8, 33, 34]. These studies do not report on dystonia, although the study on medial cerebellar nuclei lesions reported difficulty with ambulation in the early post-operative days[1].…”

“…The SCP itself is a key tract involved in motor adaptation [6]. Previously, studies involving lesions of the SCP or cerebellar nuclei (fastigial) have been performed, reporting degenerative changes in connected structures [15], and abnormalities in motor, cognitive, and social behavior [1,33,34]. Given the crucial position of the SCP in connecting two key loci required for sensorimotor integration, the cerebellum and thalamus, in the dystonia network, we posit that structural manipulation of this link may yield important insights into dystonia pathogenesis and treatment [56,64,73].…”