Search Results (3)

Cerebellar reserve compensates for and restores functions lost through cerebellar damage. This is a fundamental property of cerebellar circuitry. Clinical studies suggest (1) the involvement of synaptic plasticity in the cerebellar cortex for functional compensation and restoration, and (2) that the integrity of the cerebellar reserve requires the survival and functioning of cerebellar nuclei. On the other hand, recent physiological studies have shown that the internal forward model, embedded within the cerebellum, controls motor accuracy in a predictive fashion, and that maintaining predictive control to achieve accurate motion ultimately promotes learning and compensatory processes. Furthermore, within the proposed framework of the Kalman filter, the current status is transformed into a predictive state in the cerebellar cortex (prediction step), whereas the predictive state and sensory feedback from the periphery are integrated into a filtered state at the cerebellar nuclei (filtering step). Based on the abovementioned clinical and physiological studies, we propose that the cerebellar reserve consists of two elementary mechanisms which are critical for cerebellar functions: the first is involved in updating predictions in the residual or affected cerebellar cortex, while the second acts by adjusting its updated forecasts with the current status in the cerebellar nuclei. Cerebellar cortical lesions would impair predictive behavior, whereas cerebellar nuclear lesions would impact on adjustments of neuronal commands. We postulate that the multiple forms of distributed plasticity at the cerebellar cortex and cerebellar nuclei are the neuronal events which allow the cerebellar reserve to operate in vivo. This cortico-deep cerebellar nuclei loop model attributes two complementary functions as the underpinnings behind cerebellar reserve. Full article

Several motor, sensory, cognitive, and behavioral dysfunctions are associated with neural lesions occurring after a hypoxic injury (HI) in preterm infants. Growth hormone (GH) expression is upregulated in several brain areas when exposed to HI conditions, suggesting actions as a local neurotrophic factor. It is known that GH, either exogenous and/or locally expressed, exerts neuroprotective and regenerative actions in cerebellar neurons in response to HI. However, it is still controversial whether GH can cross the blood–brain barrier (BBB), and if its effects are exerted directly or if they are mediated by other neurotrophic factors. Here, we found that in ovo microinjection of Cy3-labeled chicken GH resulted in a wide distribution of fluorescence within several brain areas in the chicken embryo (choroid plexus, cortex, hypothalamus, periventricular areas, hippocampus, and cerebellum) in both normoxic and hypoxic conditions. In the cerebellum, Cy3-GH and GH receptor (GHR) co-localized in the granular and Purkinje layers and in deep cerebellar nuclei under hypoxic conditions, suggesting direct actions. Histological analysis showed that hypoxia provoked a significant modification in the size and organization of cerebellar layers; however, GH administration restored the width of external granular layer (EGL) and molecular layer (ML) and improved the Purkinje and granular neurons survival. Additionally, GH treatment provoked a significant reduction in apoptosis and lipoperoxidation; decreased the mRNA expression of the inflammatory mediators (TNFα, IL-6, IL-1β, and iNOS); and upregulated the expression of several neurotrophic factors (IGF-1, VEGF, and BDNF). Interestingly, we also found an upregulation of cerebellar GH and GHR mRNA expression, which suggests the existence of an endogenous protective mechanism in response to hypoxia. Overall, the results demonstrate that, in the chicken embryo exposed to hypoxia, GH crosses the BBB and reaches the cerebellum, where it exerts antiapoptotic, antioxidative, anti-inflammatory, neuroprotective, and neuroregenerative actions. Full article

Background: Ischemic stroke causes hypoexcitability in the peri-infarct motor neocortex that stems from increased tonic γ-amino-butyric acid (GABA) activity in neurons. This hypoexcitability, while neuroprotective in the acute phase, may impair neuroplasticity and functional recovery in the subacute phase of stroke. The purpose of this study is to investigate the effect of delayed and prolonged administration of S44819, which is a potent and competitive selective antagonist of GABAA receptors, on the skilled reaching function in a rodent model of stroke. Methods: Male Sprague–Dawley rats (n = 15) were subjected to permanent middle cerebral artery occlusion. Starting 3 days after stroke, a vehicle or S44819 (3 or 10 mg/kg, BID) was delivered orally twice a day for 28 days. All animals were euthanized 2 weeks later after the washout period. A single pellet reaching task (SPR) was performed before (baseline value) and after the ischemic surgery at several time points (3, 10, 17, 24, 31, 38, and 45 days) to assess the motor deficit. Infarct volume and body changes were also evaluated. Results: S44819, administered at 10 but not 3 mg/kg, significantly improves SPR results over the 45 days after the ischemic surgery. No effect was observed in the infarct size and in the body weight over time between the groups investigated. Conclusion: S44819 at 10 mg/kg significantly enhances motor recovery on a skilled reaching task after sensory-motor cortex lesion. Additionally, our study, in light of the results of the RESTORE BRAIN (Randomized Efficacy and Safety Trial of Oral GABAA α5 antagonist S44819 after Recent ischemic Event) trial, may help clinicians to design clinical studies and stratify variables and patients adequately. Full article