Influences of cerebellar interpositus nucleus and fastigial nucleus on neuronal activity of lateral hypothalamic area

Stimulation of cerebellar interpositus nucleus and (astigial nucleus could influence the neuronal activi-ty of lateral hypothalamic area in the cat, and some of the neurons which respond to the cerebellar stimulations are glucose-sensitive neurons. These results suggest that the cerebellum is involved not only in motor control, but also in the regulation of non-somatic functions through the cerebello-hypothalamic pathways.     

大鼠海马—小脑皮层—小脑深部核团投射的电生理学和HRP研究

本文用电生理学和HRP示踪法,研究了大鼠海马-小脑皮层投射的空间分布,小脑皮层的海马投射区与其深部核团间的纤维联系。 电生理学的实验结果表明,刺激背侧海马CA_1/CA_3区,均可使小脑皮层第Ⅵ小叶的浦肯野细胞产生顺行多突触的诱发简单锋电位和复杂锋电位反应。提示背侧海马CA_1/CA_3区与小脑皮层之间有经苔状纤维和攀缘纤维的多突触投射。实验证明,大鼠的这一投射的终止区域,集中在小脑皮层第Ⅵ小叶中线外侧0.8—1.4mm的范围内;并且来自CA_1区的投射以对侧性为主,CA_3区的投射以同侧性为主。HRP示踪的实验表明,背侧海马CA_1/CA_3区在小脑皮层第Ⅵ小叶的投射区是小脑纵区组构的间位区,该区皮层与间位核之间存在着交互投射关系。     

Responses of the red nucleus neurons to stimulation of the paw pads of forelimbs before and after cerebellar lesions.

Cerebellar cortex ablation releases deep cerebellar nuclei of monosynaptic inhibition from Purkinje cells. Therefore, it strengthens excitatory influence from Interpositus Nucleus (IN) upon Red Nucleus (RN), which results in much higher facilitation of the rubro-spinal neurons. This causes a big increase of spontaneous discharge rate, and eliminates brakes of discharges from responses generated by somatosensory stimuli. These two changes destroy content and timing of feedback information flowing through the spino-cerebello-rubro-spinal loop. This false bias of the feedback information, very important for fast postural adjustment and coordination of ongoing movements executed by central motor program, may at least in part be responsible for abnormal motor behavior evoked by cerebellar damage. Hemicerebellectomy resulted in dramatically reduced spontaneous activity and responses to limb stimulation because of severing a major input to the red nucleus from deep cerebellar nuclei. Due to direct somatosensory input to magnocellular Red Nucleus (mcRN) from the spinal cord that bypassed the cerebellum, the latency of response to limb stimulation was not changed and the narrower receptive fields were still present.     

The metamorphosis of the developing cerebellar microcircuit

The cerebellar cortical circuit with its organized and repetitive structure provides an excellent model system for studying how brain circuits are formed during development. The emergence of the mature brain requires that appropriate synaptic connections are formed and refined, which in the rodent cerebellum occurs primarily during the first three postnatal weeks. Developing circuits typically differ substantially from their mature counterparts, which suggests that development may not simply involve synaptic refinement, but rather involves restructuring of key synaptic components and network connections, in a manner reminiscent of metamorphosis. Here, we discuss recent evidence that, taken together, suggests that transient features of developing cerebellar synapses may act to coordinate network activity, and thereby shape the development of the cerebellar microcircuit.     

Delayed reverberation through time windows as a key to cerebellar function

We present a functional model of the cerebellum comprising cerebellar cortex, inferior olive, deep cerebellar nuclei, and brain stem nuclei. The discerning feature of the model being time coding, we consistently describe the system in terms of postsynaptic potentials, synchronous action potentials, and propagation delays. We show by means of detailed single-neuron modeling that (i) Golgi cells can fulfill a gating task in that they form short and well-defined time windows within which granule cells can reach firing threshold, thus organizing neuronal activity in discrete `time slices', and that (ii) rebound firing in cerebellar nuclei cells is a robust mechanism leading to a delayed reverberation of Purkinje cell activity through cerebellar-reticular projections back to the cerebellar cortex. Computer simulations of the whole cerebellar network consisting of several thousand neurons reveal that reverberation in conjunction with long-term plasticity at the parallel fiber-Purkinje cell synapses enables the system to learn, store, and recall spatio-temporal patterns of neuronal activity. Climbing fiber spikes act both as a synchronization and as a teacher signal, not as an error signal. They are due to intrinsic oscillatory properties of inferior olivary neurons and to delayed reverberation within the network. In addition to clear experimental predictions the present theory sheds new light on a number of experimental observation such as the synchronicity of climbing fiber spikes and provides a novel explanation of how the cerebellum solves timing tasks on a time scale of several hundreds of milliseconds. Received: 23 July 1999 / Accepted in revised form: 31 August 1999     

Influence of acute cerebellar lesions on somatosensory evoked potentials (SEPs) in cats.

We studied the effect of acute unilateral cerebellar lesions on the cerebello-thalamo-cortical projection in cats. The lesions were classified into two groups according to their extent. In group I the lesion only covered the cerebellar cortex, while in group II both the cerebellar cortex and deep cerebellar nuclei were removed. Early (short-latency) and late (long-latency) waves, evoked by an electrical stimulation of a forelimb, were collected contralateral to the stimulated leg hemisphere. Pre- and postsurgery recordings from primary and non-primary (motor and parietal) cortices were compared. Cerebellar impairment had a strong influence on discharges of all the considered cortical areas. Early non-primary and primary responses increased in group I and remained unchanged in group II. Late somatosensory evoked potentials components were suppressed in both groups. An inhibitory influence of the cerebellar cortex on the thalamo-cortical projection was confirmed. Changes within the primary sensory cortex may suggest an engagement of that area in the compensation process of cerebellar dysfunction shortly after cerebellar lesion. An alteration in the unaffected hemisphere activation indicate that the spino-cerebellar and cerebello-cortical inputs, responsible for somatosensory evoked potentials generation, are regulated through contralateral and ipsilateral pathways. These pathways are unmasked by cerebellar lesion.     

小脑顶核损毁对淋巴细胞功能的影响

目的：研究小脑顶核对淋巴细胞功能的调节作用,并初步探讨介导这种调节的中枢途径。方法：用海人酸（KA）毁损大鼠双侧小脑顶核,于术后第8d,取动物肠系膜淋巴结细胞和脾脏自然杀伤（NK）细胞进行体外培养,分别用四甲基偶氮唑（MTT）比色法检测由刀豆蛋白A（Con A）诱导的淋巴细胞的增殖反应,用流式细胞术测定NK细胞杀伤YAC-1肿瘤细胞的活性。同时用高效液相色谱法检测下丘脑中兴奋性神经递质谷氨酸的含量。结果：小脑双侧顶核注入KA后的第8d,小脑切片经Nissl染色,可见顶核内神经元胞体被有效破坏。此时,淋巴细胞对Con A诱导的增殖反应较双侧顶核注入生理盐水的对照组明显增强;而且NK细胞对YAC-1靶细胞的杀伤活性也明显高于对照组;同时下丘脑中谷氨酸含量较对照组明显减少。结论：小脑双侧顶核毁损可导致T和NK淋巴细胞功能明显增强,且下丘脑中谷氨酸含量显著下降,提示小脑顶核对淋巴细胞功能具有调节作用,小脑-下丘脑的谷氨酸能神经投射可能介导小脑顶核的免疫调节作用。     

Development and evolution of cerebellar neural circuits

The cerebellum controls smooth and skillful movements and it is also involved in higher cognitive and emotional functions. The cerebellum is derived from the dorsal part of the anterior hindbrain and contains two groups of cerebellar neurons: glutamatergic and gamma-aminobutyric acid (GABA)ergic neurons. Purkinje cells are GABAergic and granule cells are glutamatergic. Granule and Purkinje cells receive input from outside of the cerebellum from mossy and climbing fibers. Genetic analysis of mice and zebrafish has revealed genetic cascades that control the development of the cerebellum and cerebellar neural circuits. During early neurogenesis, rostrocaudal patterning by intrinsic and extrinsic factors, such as Otx2, Gbx2 and Fgf8, plays an important role in the positioning and formation of the cerebellar primordium. The cerebellar glutamatergic neurons are derived from progenitors in the cerebellar rhombic lip, which express the proneural gene Atoh1. The GABAergic neurons are derived from progenitors in the ventricular zone, which express the proneural gene Ptf1a. The mossy and climbing fiber neurons originate from progenitors in the hindbrain rhombic lip that express Atoh1 or Ptf1a. Purkinje cells exhibit mediolateral compartmentalization determined on the birthdate of Purkinje cells, and linked to the precise neural circuitry formation. Recent studies have shown that anatomy and development of the cerebellum is conserved between mammals and bony fish (teleost species). In this review, we describe the development of cerebellar neurons and neural circuitry, and discuss their evolution by comparing developmental processes of mammalian and teleost cerebellum.     

Distribution of the secondary vestibular fibers in the cerebellar cortex. An autoradiographic study in the cat

Autoradiography of tritiated leucine, injected into the vestibular nuclei in 20 cats, was used to trace the projection of the secondary vestibular fibers in the cerebellum. The distribution of these fibers in the cerebellar cortex is described and discussed in relation to the findings from other experimental works.     

Investigating cerebellar connections in the turtle using the horseradish peroxidase technique of axonal transport

Cerebellar connections were investigated in the turtle using a technique of unilateral application of horseradish peroxidase to the body and the nuclei of the cerebellum as well as the structures of the mesencephalic tegmentum. Findings showed that the origins of projections to the cerebellum in the caudal sections of the brain (vestibular nuclei, perihypoglossal complex, inferior reticular formation with the inferior olive, the spinal chord, etc.) were more numerous than in the rostral mesodiencephalic regions, such as the tegmentum and the pretectum. Extensive efferent cerebellar projections were detected both in the medulla, including the vestibular nuclei and nuclei of the dorsal columns of the spinal cord, and in the mesencephalic tegmentum, but were rare in the hypothalamus and the ventral somatic section of the thalamus. The conclusion was reached that the closest similarity between reptiles and mammals is seen in the afferent and efferent connections linking the cerebellum with the spinal cord, the caudal sections of the brain stem, and the mesencephalic brain structures, which have a common involvement in the regulation of muscle tonus and the coordination of locomotor activity.I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Academy of Sciences of the USSR, Leningrad. Translated from Neirofiziologiya, Vol. 17, No. 6, pp. 786–794, November–December, 1985.     

The Cerebellum in Feeding Control: Possible Function and Mechanism

Accumulating anatomical, functional, and behavioral studies reveal that the cerebellum is involved in the regulation of various visceral functions including feeding control. Cerebellar lesions may induce alterations in feeding behavior and decreases in body weight. Although the exact mechanisms underlying the cerebellar regulation of food intake is still unclear, a series of studies have demonstrated that there are neural pathways directly and/or indirectly connecting the cerebellum with several important centers for feeding control, such as the hypothalamus. Electrophysiological data suggest that via the direct cerebellohypothalamic projections, the cerebellar outputs may reach, converge, and be integrated with some critical feeding signals including gastric vagal afferents, CCK, leptin, and glycemia on single hypothalamic neurons. Furthermore, recent functional imaging studies provide substantial evidences that hunger, satiation, and thirst are accompanied with a cerebellar activation. Here we describe that the cerebellum may be much more than a movement coordinator and actively participate in feeding control, i.e., it may act as an essential node linking somatic and visceral systems and help to generate an integrated and coordinated somatic-visceral response in feeding behavior.     

Comparative aspects of cerebellar organization. From mormyrids to mammals.

Recent progress in the comparative analysis of the vertebrate cerebellar organization shows that the cerebella of different tetrapods have a basically similar intrinsic organization, whereas the cerebellum of fishes displays a number of fundamental differences in this respect. Clear examples of teleostean cerebellar specializations are present in the gigantocerebellum of mormyrids, including a valvula cerebelli, the absence of a parasagittal zonal organization, the presence of eurydendroid projection neurons instead of deep cerebellar nuclei, a precerebellar nucleus lateralis valvulae, olivocerebellar fibers that do not climb into the molecular layer, uni- and bilateral locations of granule cells, parallel fibers without a T-shaped bifurcation and with a coextensive distribution in the transverse plane, and different Purkinje cell arrangements including a dendritic palisade pattern. A theoretical exploration of the possible significance of these configurations suggests that they all might be involved in a single main cerebellar function, i.e. coincidence detection of parallel fiber activity by Purkinje cells.     

Uptake of oestradiol by the rabbit hypothalamus. Specificity of binding by nuclei in vitro

The binding of [6,7-(3)H]oestradiol-17beta to subcellular fractions of the hypothalamus and the cerebellum of the rabbit was studied in vitro. Uptake of steroid was higher in hypothalamic nuclei than in cerebellar nuclei. Lower binding was observed in other fractions of both tissues. After dialysis of the fractions, hypothalamic nuclei retained a high percentage of oestradiol whereas cerebellar nuclei lost most of the bound steroid. Supernatant fractions of both tissues retained a significant proportion of label after dialysis and after gel filtration on Sephadex G-200. No specific binding was observed in these fractions when subjected to sucrose-density-gradient centrifugation. Purification of nuclei followed by incubation with labelled oestradiol in the absence of the supernatant fraction resulted in loss of binding of steroid by hypothalamic nuclei. Incubation of the purified hypothalamic nuclei with supernatant fraction maintained the binding specificity of hormone retention.     

Signals from the cerebellum guide the pathfinding of inferior olivary axons

During development, inferior olivary axons cross the floor plate and project from the caudal to the rostral hindbrain, whence they grow into the cerebellar plate. We have investigated the axon guidance signals involved in the formation of this projection in vitro. When the cerebellar plate was grafted ectopically along the margin of the hindbrain in organotypic cultures, inferior olivary axons could pathfind to the ectopic cerebellum, establishing a topographically normal projection. Following rostrocaudal reversal of a region of tissue in the axon pathway between the inferior olive and the cerebellum, olivary axons still navigated towards the cerebellum. Moreover, olivary axons could cross a bridging tissue explant (spinal cord) to reach a cerebellar explant. In collagen gel cultures of inferior olive explants, olivary axon outgrowth increased significantly in the presence of cerebellar explants and axons deflected towards the cerebellar tissue. These results show that the cerebellum is a source of diffusible axon guidance signals for olivary axons. We also found that, in organotypic cultures, olivary axons which had crossed the floor plate showed an increased tendency to respond to cerebellar cues. Taken together, these results indicate that the cerebellum is the source of cues that are chemoattractant and growth-promoting for inferior olivary axons; prior exposure to the floor plate increases responsiveness to these cues.     

Distribution and characterization of the glutamate receptors in the CNS of ataxic mutant mouse

In a search for neurochemical involvement in cerebellar ataxia, Rolling Mouse Nagoya (C3Hf/Nem-rol), which shows only hypoplasia of the cerebellum but no pathological configuration of the cerebellar structure, was used to study glutamate receptors in the CNS. Kainic acid binding sites were significantly decreased in the thalamus, hypothalamus, pons, and cerebellum, and in the frontal cortex of both the ataxic mutant mouse and the non-ataxic heterozygote. Only spinal cord and midbrain of the ataxic mutant mouse showed decreased distribution of kainate binding sites in the membrane fraction.Among enzymes responsible for supplying glutamate to the receptor, GDH showed higher activity in the spinal cord of the ataxic mutanat mouse.     

Development and organization of polarity-specific segregation of primary vestibular afferent fibers in mice

A striking feature of vestibular hair cells is the polarized arrangement of their stereocilia as the basis for their directional sensitivity. In mammals, each of the vestibular end organs is characterized by a distinct distribution of these polarized cells. We utilized the technique of post-fixation transganglionic neuronal tracing with fluorescent lipid soluble dyes in embryonic and postnatal mice to investigate whether these polarity characteristics correlate with the pattern of connections between the endorgans and their central targets; the vestibular nuclei and cerebellum. We found that the cerebellar and brainstem projections develop independently from each other and have a non-overlapping distribution of neurons and afferents from E11.5 on. In addition, we show that the vestibular fibers projecting to the cerebellum originate preferentially from the lateral half of the utricular macula and the medial half of the saccular macula. In contrast, the brainstem vestibular afferents originate primarily from the medial half of the utricular macula and the lateral half of the saccular macula. This indicates that the line of hair cell polarity reversal within the striola region segregates almost mutually exclusive central projections. A possible interpretation of this feature is that this macular organization provides an inhibitory side-loop through the cerebellum to produce synergistic tuning effects in the vestibular nuclei. The canal cristae project to the brainstem vestibular nuclei and cerebellum, but the projection to the vestibulocerebellum originates preferentially from the superior half of each of the cristae. The reason for this pattern is not clear, but it may compensate for unequal activation of crista hair cells or may be an evolutionary atavism reflecting a different polarity organization in ancestral vertebrate ears.     

Developmental and Regional Studies of the Metabolism of Inositol 1,4,5-Trisphosphate in Rat Brain

Coupling of CNS receptors to phosphoinositide turnover has previously been found to vary with both age and brain region. To determine whether the metabolism of the second messenger inositol 1,4,5-trisphosphate also displays such variations, activities of inositol 1,4,5-trisphosphate 5'-phosphatase and 3'-kinase were measured in developing rat cerebral cortex and adult rat brain regions. The 5'-phosphatase activity was relatively high at birth (approximately 50% of adult values) and increased to adult levels by 2 weeks postnatal. In contrast, the 3'-kinase activity was low at birth and reached approximately 50% of adult levels by 2 weeks postnatal. In the adult rat, activities of the 3'-kinase were comparable in the cerebral cortex, hippocampus, and cerebellum, whereas much lower activities were found in hypothalamus and pons/medulla. The 5'-phosphatase activities were similar in cerebral cortex, hippocampus, hypothalamus, and pons/medulla, whereas 5- to 10-fold higher activity was present in the cerebellum. The cerebellum is estimated to contain 50-60% of the total inositol 1,4,5-trisphosphate 5'-phosphatase activity present in whole adult rat brain. The localization of the enriched 5'-phosphatase activity within the cerebellum was examined. Application of a histochemical lead-trapping technique for phosphatase indicated a concentration of inositol 1,4,5-trisphosphate 5'-phosphatase activity in the cerebellar molecular layer. Further support for this conclusion was obtained from studies of Purkinje cell-deficient mutant mice, in which a marked decrement of cerebellar 5'-phosphatase was observed. These results suggest that the metabolic fate of inositol 1,4,5-trisphosphate depends on both brain region and stage of development.     

Observations on the projection from the perihypoglossal nuclei onto the cerebellum in the macaque monkey

The occurrence and distribution of retrogradely labeled cells in the perihypoglossal nuclei of the monkey were mapped after injections of horseradish peroxidase in various cerebellar cortical regions. In general the findings are in accord with those made in the cat. The flocculus receives a heavy bilateral projection from the nucleus prepositus, particularly from its caudoventral part, and from the nucleus of Roller. There is an apparently scanty projection from the nucleus intercalatus. The uvula receives a rather similar projection, but in the prepositus the cells projecting to the uvula are on the whole situated more dorsally and rostrally than those supplying the flocculus. The projection to lobules VII-VIII is distinct. More scanty projections have been found to the paramedian lobule and the anterior lobe. The different but partially overlapping sites of origin in the prepositus of fibers to the flocculus and uvula indicate the presence of a topical pattern within the perihypoglosso-cerebellar projection, as in the cat (34). In the monkey the two regions of origin appear to coincide with two particular cell collections in the prepositus (12). Both small and middle sized cells project to the cerebellum, as they do in the cat (9, 48). The nucleus supragenualis nervi facialis in the macaque is morphologically different from the corresponding nucleus in most other mammalian species (12), but it contains labeled cells after injections in the flocculus, uvula and other cerebellar regions. A considerable number of cells in the abducent nucleus are labeled after injections in the flocculus and the posterior vermis.     

Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum

The molecular machinery governing glutamatergic-GABAergic neuronal subtype specification is unclear. Here we describe a cerebellar mutant, cerebelless, which lacks the entire cerebellar cortex in adults. The primary defect of the mutant brains was a specific inhibition of GABAergic neuron production from the cerebellar ventricular zone (VZ), resulting in secondary and complete loss of external germinal layer, pontine, and olivary nuclei during development. We identified the responsible gene, Ptf1a, whose expression was lost in the cerebellar VZ but was maintained in the pancreas in cerebelless. Lineage tracing revealed that two types of neural precursors exist in the cerebellar VZ: Ptf1a-expressing and -nonexpressing precursors, which generate GABAergic and glutamatergic neurons, respectively. Introduction of Ptf1a into glutamatergic neuron precursors in the dorsal telencephalon generated GABAergic neurons with representative morphological and migratory features. Our results suggest that Ptf1a is involved in driving neural precursors to differentiate into GABAergic neurons in the cerebellum.     

Immunohistochemical Study of Immunophilin 1–15 Fragment in Intact Frog Brain,and in the Brain and Spinal Cord of Intact and Spinal Cord Hemisectioned Rats

Previously by immunohistochemical technique the distribution of immunophilin 1–15 fragment (IphF) isolated from bovine hypothalamus was examined in various tissues (heart, lung), including immune system organs (spleen and thymus) of intact rats. IphF-like immunoreactivity (IphF-LI) was revealed in several cell types: lymphocytes, monocytes, macrophages and mast cells. In the present study the immunohistochemical localization of IphF was examined in intact rat and frog brains. In rat brain several cell groups concentrated particularly in the supraoptic nucleus (SON) of hypothalamus, medulla oblongata (reticular formation, olives, hypoglossal and facial motor nuclei) and cerebellum (lateral cerebellar nucleus) demonstrated IphF-LI. In frog hypothalamus (SON) the same working dilution (1:5000) of IphF-antiserum revealed very strong immunoreactivity. In the paraventricular nucleus (PVN) IphF-LI varicosities were scattered around the immunonegative cells. The second cell groups showing IphF-LI in the frog brain were gliocytes (mainly the astrocytes). Besides, IphF distribution was investigated in rats subjected to hemisection of spinal cord (SC) with and without administration of proline-rich polypeptide (PRP). PRP was isolated from bovine neurohypophysis neurosecretory granules, produced by magnocellular nuclei of hypothalamus. Hemisection of SC led to changes of IphF distribution in the hypothalamus. In PRP treated animals IphF showed no immunoreactivity. PRP is suggested to act as a neurotransmitter and neuroregulator.