Quantitative morphological studies of developing human cerebellar cortex in various disease states.
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A quantitative morphological assessment was carried out of the cellularity and staining properties of the cells of the layers of the human cerebellar cortex, both in the normal child and in 41 children suffering from a series of disorders including mental retardation. A computerized image analyser and highly standardized procedures were used. All of the cases of mental retardation and some cases with congenital cardiac anomalies showed abnormal cell concentrations and staining properties. 3 cases of 'cot death' also showed abnormal results. These findings are presented as a new measurable aspect of brain disease, and as a indication for further study. (+info)
Novel form of spreading acidification and depression in the cerebellar cortex demonstrated by neutral red optical imaging.
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A novel form of spreading acidification and depression in the rat cerebellar cortex was imaged in vivo using the pH-sensitive dye, Neutral red. Surface stimulation evoked an initial beam of increased fluorescence (i.e., decreased pH) that spread rostrally and caudally across the folium and into neighboring folia. A transient but marked suppression in the excitability of the parallel fiber-Purkinje cell circuitry accompanied the spread. Characteristics differentiating this phenomenon from the spreading depression of Leao include: high speed of propagation on the surface (average of 450 microm/s), stable extracellular DC potential, no change in blood vessel diameter, and repeatability at short intervals. This propagating acidification constitutes a previously unknown class of neuronal processing in the cerebellar cortex. (+info)
Gating of transmission in climbing fibre paths to cerebellar cortical C1 and C3 zones in the rostral paramedian lobule during locomotion in the cat.
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1. Climbing fibre field potentials evoked by low intensity (non-noxious) electrical stimulation of the ipsilateral superficial radial nerve have been recorded in the rostral paramedian lobule (PML) in awake cats. Chronically implanted microwires were used to monitor the responses at eight different C1 and C3 zone sites during quiet rest and during steady walking on a moving belt. The latency and other characteristics of the responses identified them as mediated mainly via the dorsal funiculus-spino-olivocerebellar path (DF-SOCP). 2. At each site, mean size of response (measured as the area under the field, in mV ms) varied systematically during the step cycle without parallel fluctuations in size of the peripheral nerve volley. Largest responses occurred overwhelmingly during the stance phase of the step cycle in the ipsilateral forelimb while smallest responses occurred most frequently during swing. 3. Simultaneous recording from pairs of C1 zone sites located in the anterior lobe (lobule V) and C1 or C3 zone sites in rostral PML revealed markedly different patterns of step-related modulation. 4. The findings shed light on the extent to which the SOCPs projecting to different parts of a given zone can be regarded as functionally uniform and have implications as to their reliability as channels for conveying peripheral signals to the cerebellum during locomotion. (+info)
Electrotonic coupling interacts with intrinsic properties to generate synchronized activity in cerebellar networks of inhibitory interneurons.
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Exploring the organization and function of local inhibitory networks is an essential step on the way to understand the principles of brain operation. We show here that molecular layer inhibitory interneurons of the guinea pig cerebellar cortex are organized as local networks, generating synchronous activity. Simultaneous recording from two adjacent interneurons revealed a direct current flow between synchronized pairs of neurons. Blocking inhibitory or excitatory synaptic transmission did not alter the synchronization. The electrotonic coupling coefficient (average 0.1) depended mainly on the input resistance of the postsynaptic cell, indicating a homogenous coupling resistance between different pairs. A presynaptic action potential generated a short, attenuated spikelet in the postsynaptic cell. The passive current flow was amplified by voltage-dependent intrinsic currents to create a reciprocal interplay between the presynaptic and postsynaptic cells. This interplay results in a time window for synchronization that is wider than expected from the duration of the spikelet. Intracellular staining with biocytin revealed high incidence of dye coupling. Furthermore, the interneurons located superficially in the molecular layer tend to form larger networks compared with the inner interneurons. We propose that weakly coupled inhibitory networks can generate loosely synchronous activity, which results from the interaction of electrical coupling and intrinsic currents. (+info)
Dopamine reuptake inhibition in the rostral agranular insular cortex produces antinociception.
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We provide evidence for an antinociceptive effect of dopamine in the rat cerebral cortex that is mediated through descending nociceptive inhibition of spinal neurons. Injection of the dopamine reuptake inhibitor GBR-12935 in the rostral agranular insular cortex (RAIC), a cortical area that receives a dense dopaminergic projection and is involved in descending antinociception (Burkey et al.,1996), resulted in dose-dependent inhibition of formalin-induced nociceptive behavior, without any alteration of motor function. Injection of the dopamine reuptake inhibitor in the surrounding cortical areas had no effect on nociceptive behaviors. GBR-12935 also produced a reduction in noxious stimulus-induced c-fos expression in nociceptive areas of the spinal dorsal horn, suggesting that dopamine in the RAIC acts in part through descending antinociception. Electrophysiological recording from single wide dynamic range-type spinal dorsal horn neurons confirmed the descending nociceptive inhibitory effect. GBR-12935 in the RAIC significantly reduced neuronal responses evoked by noxious thermal stimulation of the skin, an effect that was reversed by local administration of the selective D1 receptor antagonist SCH-23390. Finally, administration of SCH-23390 alone in the RAIC decreased paw withdrawal latencies from noxious heat, suggesting that dopamine acts tonically in the cortex to inhibit nociception. (+info)
Selective disruption of "late onset" sagittal banding patterns by ectopic expression of engrailed-2 in cerebellar Purkinje cells.
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To explore the role of Engrailed proteins in development of the cerebellum, Engrailed-2 (En-2) was ectopically expressed in cerebellar Purkinje cells from the late embryonic stage into adulthood. The fundamental organization of Purkinje cell sagittal zones as revealed by the "early onset" markers L7-beta-gal and cadherin-8 was found to be virtually identical to that in wild type. In contrast, "late onset" sagittal banding patterns revealed by Purkinje cell markers zebrin I, zebrin II, and 9-O-acetyl GD3 Ganglioside (P-Path), and the granule cell marker NADPH-diaphorase, were disrupted. In general, although some evidence of banding was still detectable, boundaries defined by the latter markers were poorly defined, and the patterns overall took on a diffuse appearance. In parallel with the changes in late onset markers, anterograde tracing of spinocerebellar axons revealed a general diffusion of the mossy fiber projection pattern in lobule VIII and the anterior lobe. These observations suggest that at least two separate mediolateral boundary systems exist in the cerebellum, and these are differentially affected by ectopic En-2 expression. Alternatively, one boundary system exists that remains primarily intact in the mutant, but recognition of this system by a set of late developmental events is perturbed. (+info)
Neurotrophic activity of pituitary adenylate cyclase-activating polypeptide on rat cerebellar cortex during development.
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High concentrations of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are present in the external granule cell layer of the rat cerebellum during postnatal development. In vitro studies have shown that PACAP promotes cell survival and neurite outgrowth on immature cerebellar granule cells in primary culture. In the present study, we have investigated the effect of PACAP on the development of the cerebellar cortex of 8-day-old rats. Incubation of cultured granule cells for 12 or 18 h with PACAP provoked a significant increase in the rate of incorporation of [(3)H]thymidine in cultured granule cells, suggesting that PACAP could stimulate the proliferation of granule cells. After 96 h of treatment, in vivo administration of PACAP provoked a transient increase in the number of granule cells in the molecular layer and in the internal granule cell layer. In contrast, PACAP did not affect the number of Purkinje cells. The augmentation of the number of granule cells evoked by PACAP was significantly inhibited by the PACAP receptor antagonist PACAP(6-38). Administration of PACAP also caused a significant increase in the volume of the cerebellar cortex. The present study provides evidence that PACAP can act in vivo as a trophic factor during rat brain development. Our data indicate that PACAP increases proliferation and/or inhibits programmed cell death of granule cells, as well as stimulating neuronal migration from the external granule cell layer toward the internal granule cell layer. (+info)
Simulations of cerebellar motor learning: computational analysis of plasticity at the mossy fiber to deep nucleus synapse.
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We question the widely accepted assumption that a molecular mechanism for long-term expression of synaptic plasticity is sufficient to explain the persistence of memories. Instead, we show that learning and memory require that these cellular mechanisms be correctly integrated within the architecture of the neural circuit. To illustrate this general conclusion, our studies are based on the well characterized synaptic organization of the cerebellum and its relationship to a simple form of motor learning. Using computer simulations of cerebellar-mediated eyelid conditioning, we examine the ability of three forms of plasticity at mossy fiber synapses in the cerebellar nucleus to contribute to learning and memory storage. Results suggest that when the simulation is exposed to reasonable patterns of "background" cerebellar activity, only one of these three rules allows for the retention of memories. When plasticity at the mossy fiber synapse is controlled by nucleus or climbing fiber activity, the circuit is unable to retain memories because of interactions within the network that produce spontaneous drift of synaptic strength. In contrast, a plasticity rule controlled by the activity of the Purkinje cell allows for a memory trace that is resistant to ongoing activity in the circuit. These results suggest specific constraints for theories of cerebellar motor learning and have general implications regarding the mechanisms that may contribute to the persistence of memories. (+info)