Converging lines of evidence from rabbits, rats, and humans argue for the crucial involvement of the cerebellum in classical conditioning of the eyeblink/nictitating membrane response in mammals. For example, selective lesions (permanent or reversible) of the cerebellum block both acquisition and retention of eyeblink conditioning. Correspondingly, electrophysiological and brain-imaging studies indicate learning-related plasticity in the cerebellum. The involvement of the cerebellum in eyeblink conditioning is also supported by stimulation studies showing that direct stimulation of the two major afferents to the cerebellum (the mossy fibers emanating from the pontine nucleus and climbing fibers originating from the inferior olive) can substitute for the peripheral conditioned stimulus (CS) and unconditioned stimulus (US), respectively, to yield normal behavioral learning. In the present study, we examined the relative contribution of the cerebellar cortex versus deep nuclei (specifically the interpositus nucleus) in eyeblink learning by using mutant mice deficient of Purkinje cells, the exclusive output neurons of the cerebellar cortex. We report that Purkinje cell degeneration (pcd) mice exhibit a profound impairment in the acquisition of delay eyeblink conditioning in comparison with their wild-type littermates. Nevertheless, the pcd animals did acquire a subnormal level of conditioned eyeblink responses. In contrast, wild-type mice with lesions of the interpositus nucleus were completely unable to learn the conditioned eyeblink response. These results suggest that both cerebellar cortex and deep nuclei are important for normal eyeblink conditioning.
Hematopoietic cell transplantation (HCT) has become a standard treatment for many adult and pediatric conditions. Emerging evidence suggests that perturbations in the microbiota diversity increase recipients' susceptibilities to gut-mediated conditions such as diarrhea, infection and acute GvHD. Probiotics preserve the microbiota and may minimize the risk of developing a gutmediated condition; however, their safety has not been evaluated in the setting of HCT. We evaluated the safety and feasibility of the probiotic, Lactobacillus plantarum (LBP), in children and adolescents undergoing allogeneic HCT. Participants received oncedaily supplementation with LBP beginning on day − 8 or − 7 and continued until day +14. Outcomes were compliance with daily administration and incidence of LBP bacteremia. Administration of LBP was feasible with 97% (30/31, 95% confidence interval (CI) 83-100%) of children receiving at least 50% of the probiotic dose (median 97%; range 50-100%). We did not observe any case of LBP bacteremia (0% (0/30) with 95% CI 0-12%). There were not any unexpected adverse events related to LBP. Our study provides preliminary evidence that administration of LBP is safe and feasible in children and adolescents undergoing HCT. Future steps include the conduct of an approved randomized, controlled trial through Children's Oncology Group.
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