Effects of inferior olive lesion on fear-conditioned bradycardia

Kotajima, Hiroko; Sakai, Kazuhisa; Hashikawa, Tsutomu; Yanagihara, Dai

doi:10.1097/wnr.0000000000000135

Cited by 9 publications

(16 citation statements)

References 23 publications

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“…Not surprisingly, with the exception of the dorsomedial cell column, a reduction in cell number in these regions was associated with reduced performance on the rotorod. These findings do not agree with the report of a 50% loss of cells in the inferior olive and a total loss of balance following the administration of 50 mg/kg 3-AP (Kotajima et al, 2014). Further, additional experiments (data not shown) assessed rotorod performance of C57BL6 mice after the administration of 100-150 mg/kg 3-AP followed 3 hours later by harmaline (15 mg/kg) to increase blood flow or followed by harmaline and nicotinamide (300 mg/kg) 90 minutes later; however, neither regimen affected rotorod performance.…”

Section: Discussioncontrasting

confidence: 98%

“…Thus, initial experiments compared the effects of 3-AP on rotorod performance of BALB/c and C57BL/6 mice. These studies used 50 mg/kg 3-AP followed by nicotinamide, which has been reported to impair rotorod performance in C57BL/6 mice (Kotajima et al, 2014), and 70-75 mg/kg followed by nicotinamide, a dose reported to impair rotorod performance in rats (Lambert et al, 2014; Wecker et al, 2013). Only animals who would remain on the rod during familiarization were used for study (8/12 BALB/c and 12/12 C57BL/6 mice).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, based on evidence that this dose of 3-AP led to total impairment of rotorod performance and a loss of cells in the inferior olive in C57BL/6 mice (Kotajima et al, 2014), we began using this strain of mice, but again, could not detect any alterations in rotorod performance. Thus, although the initial intent of these studies was not to compare mouse strains, results underscore differences in baseline rotorod behavior between C57BL/6 and BALB/c mice.…”

Section: Discussionmentioning

confidence: 99%

“…), although quantitative data were not presented and it is unclear that lesions were limited to the inferior olive. Further, Kotajima et al (2014) administered this dose of 3-AP (i.p.) followed at 3-3.5 hours with 500 mg/kg (i.p.)…”

Section: Introductionmentioning

confidence: 99%

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3-Acetylpyridine neurotoxicity in mice

et al. 2017

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3-acetylpyridine (3-AP) is a metabolic antagonist used in research to decrease levels of nicotinamide (niacinamide) in laboratory animals. The administration of 3-AP followed by nicotinamide to rats leads to the selective destruction of neurons in the medial inferior olive, resulting in a loss of climbing fibers innervating cerebellar Purkinje cells and a consequent ataxia manifest by alterations in both balance and gait. Although 3-AP has also been administered to mice to destroy neurons in the inferior olive, there are limited studies quantifying the consequent effects on balance, and no studies on gait. Further, the relationship between 3-AP-induced lesions of the inferior olive and behavior has not been elucidated. Because 3-AP continues to be used for experiments involving mice, this study characterized the effects of this toxin on both balance and gait, and on the neuronal integrity of several brain regions involved in motor coordination. Results indicate that C57BL/6 mice are less sensitive to the neurotoxic effects of 3-AP than rats, and a dose more than 6.5 times that used for rats produces deficits in both balance and gait comparable to those in rats. This dose led to a significant (p< 0.05) loss of NeuN(+) neurons in several subregions of the inferior olive including the rostral medial nucleus, dorsomedial cell column, ventrolateral protrusion, and cap of Kooy. Further, the number of NeuN(+) neurons in these subregions, with the exception of the dorsomedial cell column, was significantly (p<0.05) related to rotorod performance, implicating their involvement in this behavior.

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Section: Discussioncontrasting

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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3-Acetylpyridine neurotoxicity in mice

et al. 2017

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“…It has been suggested that parallel fibers (PFs) convey the CS and climbing fibers (CFs) transmit the US to the cerebellum during eyeblink conditioning [10]. In an earlier study, we found that a lesion in the inferior olive nuclei of mice disrupted the acquisition and/or expression of conditioned bradycardia and the attenuation of tachycardiac responses to the US [11]. These results raise the question of whether reduction in PF inputs to Purkinje cells and impairment of synaptic plasticity at the PF-Purkinje cell synapses in the cerebellar cortex affect fear-conditioned bradycardia.…”

Section: Introductionmentioning

confidence: 99%

Involvement of GluD2 in Fear-Conditioned Bradycardia in Mice

et al. 2016

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Lesions in the cerebellar vermis abolish acquisition of fear-conditioned bradycardia in animals and human patients. The δ2 glutamate receptor (GluD2) is predominantly expressed in cerebellar Purkinje cells. The mouse mutant ho15J carries a spontaneous mutation in GluD2 and these mice show a primary deficiency in parallel fiber-Purkinje cell synapses, multiple innervations of Purkinje cells by climbing fibers, and impairment of long-term depression. In the present study, we used ho15J mice to investigate the role of the cerebellum in fear-conditioned bradycardia. We recorded changes in heart rate of ho15J mice induced by repeated pairing of an acoustic (conditioned) stimulus (CS) with an aversive (unconditioned) stimulus (US). The mice acquired conditioned bradycardia on Day 1 of the CS-US phase, similarly to wild-type mice. However, the magnitude of the conditioned bradycardia was not stable in the mutant mice, but rather was exaggerated on Days 2–5 of the CS-US phase. We examined the effects of reversibly inactivating the cerebellum by injection of an antagonist against the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR). The antagonist abolished expression of conditioned responses in both wild-type and ho15J mice. We conclude that the GluD2 mutation in the ho15J mice affects stable retention of the acquired conditioned bradycardia.

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Inhibitory neurotransmission drives endocannabinoid degradation to promote memory consolidation

et al. 2020

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Endocannabinoids retrogradely regulate synaptic transmission and their abundance is controlled by the fine balance between endocannabinoid synthesis and degradation. While the common assumption is that “on-demand” release determines endocannabinoid signaling, their rapid degradation is expected to control the temporal profile of endocannabinoid action and may impact neuronal signaling. Here we show that memory formation through fear conditioning selectively accelerates the degradation of endocannabinoids in the cerebellum. Learning induced a lasting increase in GABA release and this was responsible for driving the change in endocannabinoid degradation. Conversely, Gq-DREADD activation of cerebellar Purkinje cells enhanced endocannabinoid signaling and impaired memory consolidation. Our findings identify a previously unappreciated reciprocal interaction between GABA and the endocannabinoid system in which GABA signaling accelerates endocannabinoid degradation, and triggers a form of learning-induced metaplasticity.

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Effects of inferior olive lesion on fear-conditioned bradycardia

Cited by 9 publications

References 23 publications

3-Acetylpyridine neurotoxicity in mice

3-Acetylpyridine neurotoxicity in mice

Involvement of GluD2 in Fear-Conditioned Bradycardia in Mice

Inhibitory neurotransmission drives endocannabinoid degradation to promote memory consolidation

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