Plasticity of nonneuronal brain tissue: roles in developmental disorders

Neuronal and nonneuronal plasticity are both affected by environmental and experiential factors. Remodeling of existing neurons induced by such factors has been observed throughout the brain, and includes alterations in dendritic field dimensions, synaptogenesis, and synaptic morphology. The brain loci affected by these plastic neuronal changes are dependent on the type of experience and learning. Increased neurogenesis in the hippocampal dentate gyrus is a well-documented response to environmental complexity ("enrichment") and learning. Exposure to challenging experiences and learning opportunities also alters existing glial cells (i.e., astrocytes and oligodendrocytes), and up-regulates gliogenesis, in the cerebral cortex and cerebellum. Such glial plasticity often parallels neuronal remodeling in both time and place, and this enhanced morphological synergism may be important for optimizing the functional interaction between glial cells and neurons. Aberrant structural plasticity of nonneuronal elements is a contributing factor, as is aberrant neuron plasticity, to neurological and developmental disorders such as epilepsy, autism, and mental retardation (i.e., fragile X syndrome). Some of these nonneuronal pathologies include abnormal cerebral and cerebellar white matter and myelin-related proteins in autism; abnormal myelin basic protein in fragile X syndrome (FXS); and abnormal astrocytes in autism, FXS, and epilepsy. A number of recent studies demonstrate the possibility of using environmental and experiential intervention to reduce or ameliorate some of the neuronal and nonneuronal abnormalities, as well as behavioral deficits, present in these neurological and developmental disorders.     

Cerebellar output: motor and cognitive channels

The input to the cerebellum has long been known to originate from widespread regions of the cerebral cortex including the frontal, parietal and temporal lobes. The output of the cerebellum, however, was thought to project mainly to the primary motor cortex. Recent anatomical observations have challenged this view. It is now apparent that cerebellar output goes to multiple cortical areas, including not only the primary motor cortex, but also areas of premotor and prefrontal cortex. In fact, there is growing evidence that each of the areas of cerebral cortex that project to the cerebellum is also the target of cerebellar output. The cerebellar output to individual cortical areas originates from distinct clusters of neurons in the deep nuclei which we have termed `output channels'. The individual output channels to the cortical areas we have examined display little or no overlap. Physiological recordings in awake trained primates indicate that neurons in different output channels appear to be involved in distinct aspects of behavior, and in both motor and cognitive functions. These observations indicate that the cerebellar influence on the cerebral cortex is more extensive than previously recognized.     

Purkinje cell activity in the cerebellar anterior lobe after rabbit eyeblink conditioning

The cerebellar anterior lobe may play a critical role in the execution and proper timing of learned responses. The current study was designed to monitor Purkinje cell activity in the rabbit cerebellar anterior lobe after eyeblink conditioning, and to assess whether Purkinje cells in recording locations may project to the interpositus nucleus. Rabbits were trained in an interstimulus interval discrimination procedure in which one tone signaled a 250-msec conditioned stimulus-unconditioned stimulus (CS-US) interval and a second tone signaled a 750-msec CS-US interval. All rabbits showed conditioned responses to each CS with mean onset and peak latencies that coincided with the CS-US interval. Many anterior lobe Purkinje cells showed significant learning-related activity after eyeblink conditioning to one or both of the CSs. More Purkinje cells responded with inhibition than with excitation to CS presentation. In addition, when the firing patterns of all conditioning-related Purkinje cells were pooled, it appeared that the population showed a pattern of excitation followed by inhibition during the CS-US interval. Using cholera toxin-conjugated horseradish peroxidase, Purkinje cells in recording areas were found to project to the interpositus nucleus. These data support previous studies that have suggested a role for the anterior cerebellar cortex in eyeblink conditioning as well as models of cerebellar-mediated CR timing that postulate that Purkinje cell activity inhibits conditioned response (CR) generation during the early portion of a trial by inhibiting the deep cerebellar nuclei and permits CR generation during the later portion of a trial through disinhibition of the cerebellar nuclei.     

Cerebellar contributions to tactile perception in people with varying sensorimotor experiences: Examining the sensory acquisition hypothesis

The sensory acquisition hypothesis states that the sensory demand of a task is the most crucial factor in determining the level of cerebellar activity. The present study was conducted to examine whether the prediction of sensory demand holds when participants have different sensorimotor training experiences. Archery athletes and non-athletic control participants were asked to perform tactile discrimination tasks during fMRI scanning. In archery athletes, a pattern of reduced cerebellar activation accompanying higher sensory cortical activity was observed, whereas in non-athletic control participants the visual network was found to be in concert with extensive cerebellar activation. These findings are in accordance with the prediction that the cerebellum plays a supportive role for the cerebral cortex in sensory data acquisition.     

The bioelectrical activity of cerebellar structures in the freely-moving rat

Electrodes were implanted in the brains of 27 freelymoving rats and the bioelectrical activity of cerebellar cortical structures (lobus simplex, tuber verrais, lobus ansiformis, crus II) and the dentate nucleus was measured simultaneously with the activity of the cerebral cortex and dorsal hippocampus and respiratory rate and motor activity. Different behavioral states were produced by habituation procedures and by elaborating conditional avoidance reflexes to light-flash or click series. In addition, startle reflexes to acoustic stimuli were used to evaluate behavioral state. The following conclusions could be drawn: 1) in the awake rat the various cerebellar structures have clearly distinguishable bioelectrical activity patterns; 2) changes in these patterns depend on the actual behavioral state of the animal; 3) this dependence upon behavior is especially clear in crus II, one of the projection zones of the tactile and proprioceptive afferent nerves in the cerebellar cortex. The changes in the electrocerebellogram of the unrestrained rat may be used as an indicator of the behavioral state of the animal.     

Developmental dyslexia and widespread activation across the cerebellar hemispheres

Developmental dyslexia is the most common learning disability in school-aged children with an estimated incidence of five to ten percent. The cause and pathophysiological substrate of this developmental disorder is unclear. Recently, a possible involvement of the cerebellum in the pathogenesis of dyslexia has been postulated. In this study, 15 dyslexic children and 7 age-matched control subjects were investigated by means of functional neuroimaging (fMRI) using a noun-verb association paradigm. Comparison of activation patterns between dyslexic and control subjects revealed distinct and significant differences in cerebral and cerebellar activation. Control subjects showed bilaterally well-defined and focal activation patterns in the frontal and parietal lobes and the posterior regions of the cerebellar hemispheres. The dyslexic children, however, presented widespread and diffuse activations on the cerebral and cerebellar level. Cerebral activations were found in frontal, parietal, temporal and occipital regions. Activations in the cerebellum were found predominantly in the cerebellar cortex, including Crus I, Crus II, hemispheric lobule VI, VII and vermal lobules I, II, III, IV and VII. This preliminary study is the first to reveal a significant difference in cerebellar functioning between dyslexic children and controls during a semantic association task. As a result, we propose a new hypothesis regarding the pathophysiological mechanisms of developmental dyslexia. Given the sites of activation in the cerebellum in the dyslexic group, a defect of the intra-cerebellar distribution of activity is suspected, suggesting a disorder of the processing or transfer of information within the cerebellar cortex.     

The Cerebellum and Basal Ganglia are Interconnected

The cerebellum and the basal ganglia are major subcortical nuclei that control multiple aspects of behavior largely through their interactions with the cerebral cortex. Discrete multisynaptic loops connect both the cerebellum and the basal ganglia with multiple areas of the cerebral cortex. Interactions between these loops have traditionally been thought to occur mainly at the level of the cerebral cortex. Here, we review a series of recent anatomical studies in nonhuman primates that challenge this perspective. We show that the anatomical substrate exists for substantial interactions between the cerebellum and the basal ganglia. Furthermore, we discuss how these pathways may provide a useful framework for understanding cerebellar contributions to the manifestation of two prototypical basal ganglia disorders, Parkinson’s disease and dystonia.     

The detection and generation of sequences as a key to cerebellar function: experiments and theory

Starting from macroscopic and microscopic facts of cerebellar histology, we propose a new functional interpretation that may elucidate the role of the cerebellum in movement control. The idea is that the cerebellum is a large collection of individual lines (Eccles's "beams": Eccles et al. 1967a) that respond specifically to certain sequences of events in the input and in turn produce sequences of signals in the output. We believe that the sequence-in/sequence-out mode of operation is as typical for the cerebellar cortex as the transformation of sets into sets of active neurons is typical for the cerebral cortex, and that both the histological differences between the two and their reciprocal functional interactions become understandable in the light of this dichotomy. The response of Purkinje cells to sequences of stimuli in the mossy fiber system was shown experimentally by Heck on surviving slices of rat and guinea pig cerebellum. Sequential activation of a row of eleven stimulating electrodes in the granular layer, imitating a "movement" of the stimuli along the folium, produces a powerful volley in the parallel fibers that strongly excites Purkinje cells, as evidenced by intracellular recording. The volley, or "tidal wave," has maximal amplitude when the stimulus moves toward the recording site at the speed of conduction in parallel fibers, and much smaller amplitudes for lower or higher "velocities." The succession of stimuli has no effect when they "move" in the opposite direction. Synchronous activation of the stimulus electrodes also had hardly any effect. We believe that the sequences of mossy fiber activation that normally produce this effect in the intact cerebellum are a combination of motor planning relayed to the cerebellum by the cerebral cortex, and information about ongoing movement, reaching the cerebellum from the spinal cord. The output elicited by the specific sequence to which a "beam" is tuned may well be a succession of well timed inhibitory volleys "sculpting" the motor sequences so as to adapt them to the complicated requirements of the physics of a multijointed system.     

Using Eyeblink Classical Conditioning as a Test of the Functional Consequences of Exposure of the Developing Cerebellum to Alcohol

Exposure of the developing brain to alcohol produces profound Purkinje cell loss in the cerebellum, and deficits in tests of motor coordination. However, the precise relationship between these two sets of findings has been difficult to determine. Eyeblink classical conditioning is known to engage a discrete brainstem-cerebellar circuit, making it an ideal test of cerebellar functional integrity after developmental alcohol exposure. In eyeblink conditioning, one of the deep cerebellar nuclei, the interpositus nucleus, as well as specific Purkinje cell populations, are sites of convergence for CS and US information. A series of studies have shown that eyeblink conditioning is impaired in both weanling and adult rats given binge-like exposure to alcohol as neonates, and that these deficits can be traced, at least in part, to impaired activation of cerebellar interpositus nucleus neurons and to an overall reduction in the deep cerebellar nuclear cell population. Because particular cerebellar cell populations are utilized in well-defined ways during eyeblink conditioning, conclusions regarding specific changes in the mediation of behavior by these cell populations are greatly strengthened. Further studies will be directed towards the impact of early exposure to alcohol on the functionality of specific Purkinje cell populations, as well as towards brainstem areas that process the tone CS and the somatosensory US.     

Using eyeblink classical conditioning as a test of the functional consequences of exposure of the developing cerebellum to alcohol

Exposure of the developing brain to alcohol produces profound Purkinje cell loss in the cerebellum, and deficits in tests of motor coordination. However, the precise relationship between these two sets of findings has been difficult to determine. Eyeblink classical conditioning is known to engage a discrete brainstem-cerebellar circuit, making it an ideal test of cerebellar functional integrity after developmental alcohol exposure. In eyeblink conditioning, one of the deep cerebellar nuclei, the interpositus nucleus, as well as specific Purkinje cell populations, are sites of convergence for CS and US information. A series of studies have shown that eyeblink conditioning is impaired in both weanling and adult rats given binge-like exposure to alcohol as neonates, and that these deficits can be traced, at least in part, to impaired activation of cerebellar interpositus nucleus neurons and to an overall reduction in the deep cerebellar nuclear cell population. Because particular cerebellar cell populations are utilized in well-defined ways during eyeblink conditioning, conclusions regarding specific changes in the mediation of behavior by these cell populations are greatly strengthened. Further studies will be directed towards the impact of early exposure to alcohol on the functionality of specific Purkinje cell populations, as well as towards brainstem areas that process the tone CS and the somatosensory US.     

Glial cells for information routing?

We investigate a possible functional role of glial cells as information routing devices of the cerebral cortex. On the one hand, functionally motivated models of neural information processing were lately suggested which rely on short-term changes of connections between neural modules to dynamically route neural activity. Although successful in practice, the routing mechanisms of these models require synaptic efficacy control of large sets of synapses that is difficult to implement neurally. On the other hand, recent experiments show an active role of glial cells (astrocytes) in the interaction with large numbers of synapses. Astrocytes are sensitive to neurotransmitters released by the presynaptic terminal and in turn can influence synaptic efficacy by release of so called gliotransmitters. An analysis of the most recent literature shows that glial cells are a well-suited and natural candidate for the implementation of information routing mechanisms.     

Behavioral detection of subcortical stimuli: comparison of somatosensory and "motor" circuits

Cats were trained to press a lever for food reinforcement in response to stimulation of the ventral lateral (VL) nucleus of the thalamus and the deep cerebellar nuclei. By scaling stimulus intensities relative to the appearance of a minimal amplitude evoked response in pericruciate cortex, it was possible to measure behavioral detection thresholds and correlate behavior with electrocortical activity. With stimulus rates of 25 Hz or greater, VL was the least effective stimulus site for producing detection. At stimulus rates less than 25 Hz, stimulation of the lateral or interpositus nuclei was even less effective in eliciting behavior, but at rates of 25 Hz or more, detection thresholds decreased below those for VL stimulation; cerebellar stimulation produced detection as readily as had stimulation of the ventrobasal complex in other experiments. These findings suggest that the cerebellum may modulate sensory experiences and that some portions of cerebral cortex, the pericruciate and suprasylvian regions, do not appear to be directly involved in mediating sensory detection. It is postulated that the neural detection circuits are more likely to be found in subcortical than in cerebrocortical structures.     

Purkinje cell loss by OX7-saporin impairs acquisition and extinction of eyeblink conditioning

The current study examined the effects of globally depleting Purkinje cells in the cerebellar cortex with the immunotoxin OX7-saporin on acquisition and extinction of delay eyeblink conditioning in rats. Rats were given OX7-saporin or saline 2 wk before the start of eyeblink conditioning. The rats that reached a performance criterion of two consecutive days with 80% or greater conditioned responses were given 5 d of extinction training followed by 2 d of reacquisition training. Rats that received infusions of OX7-saporin had 77.2%-97.9% Purkinje cell loss and exhibited impaired acquisition and extinction. The amount of Purkinje cell loss was correlated with the magnitude of the acquisition and extinction impairments. The highest correlations between Purkinje cell number and the rate of acquisition were in lobule HVI and the anterior lobe. The highest negative correlation between Purkinje cell number and the percentage of conditioned responses during extinction was in the anterior lobe. The results indicate that cerebellar Purkinje cells, particularly in the anterior lobe and lobule HVI, play significant roles in acquisition and extinction of eyeblink conditioning.     

MRI-Assessed Volume of Cerebellum Correlates with Associative Learning

Richard F. Thompson's cerebellar model of classical eyeblink conditioning highlights Purkinje cells in cerebellar cortex and principal cells in the deep cerebellar nucleus as the integrating cells for acquisition of conditioned responses (CRs). CR acquisition is significantly slower in rabbits with lesions to cerebellar cortex and in Purkinje cell-deficient mice that lose all cerebellar cortical Purkinje cells. Purkinje cells are the largest neurons in the cerebellum and contribute significantly to cerebellar volume. Magnetic resonance imaging (MRI) was used to assess cerebellar volume in humans. Cerebellar volume was related to eyeblink conditioning (400-ms delay procedure) in 8 adults (21-35 years) and compared to 8 older adults (77-95 years) tested previously (Woodruff-Pak, Goldenberg, Downey-Lamb, Boyko, & Lemieux, 2000). In the young adult sample, there was a high correlation between percentage of CRs in a session and cerebellar volume (corrected for total intracranial volume [TIV], r =.58, p =.066). There were statistically significant age differences in cerebellar volume, t(14) = 8.96, p <.001, and percentage of CRs, t(14) = 3.85, p <.002, but no age difference in TIV. Combining the young and older adult sample, the correlation between percentage of CRs and cerebellar volume (corrected for TIV) was.832 (p <.001). Cerebellar volume showed age-related deficits likely due to Purkinje cell loss. Individual differences in classical eyeblink conditioning are associated with differences in cerebellar volume, supporting Thompson's model of a cerebellar cortical role in facilitating this form of associative learning.     

Inferior olive lesions impair concurrent taste aversion learning in rats.

Taste aversion learning can be established according to two different procedures, concurrent and sequential. For the concurrent task, two different taste stimuli are offered at the same time, one associated with simultaneous intragastric administration of an aversive stimulus and the other associated with physiological saline. This discrimination is learned by sham-lesioned control animals and by animals with lesions in the cerebellar cortex but not by rats lesioned in the inferior olive. At the same time, animals with lesions in the inferior olive and sham-lesioned animals achieve sequential learning when the gustatory stimuli are offered individually during each daily session. The results obtained show that electrolytic lesions in the inferior olive impair acquisition of concurrent learning and are analyzed in terms of an anatomical system consisting of the vagus nerve, inferior olive, and cerebellum, which differentiates between the two modalities of taste aversion learning, concurrent and sequential.     

Unimpaired trace classical eyeblink conditioning in Purkinje cell degeneration (pcd) mutant mice

Young adult Purkinje cell degeneration (pcd) mutant mice, with complete loss of cerebellar cortical Purkinje cells, are impaired in delay eyeblink classical conditioning. In the delay paradigm, the conditioned stimulus (CS) overlaps and coterminates with the unconditioned stimulus (US), and the cerebellar cortex supports normal acquisition. The ability of pcd mutant mice to acquire trace eyeblink conditioning in which the CS and US do not overlap has not been explored. Recent evidence suggests that cerebellar cortex may not be necessary for trace eyeblink classical conditioning. Using a 500 ms trace paradigm for which forebrain structures are essential in mice, we assessed the performance of homozygous male pcd mutant mice and their littermates in acquisition and extinction. In contrast to results with delay conditioning, acquisition of trace conditioning was unimpaired in pcd mutant mice. Extinction to the CS alone did not differ between pcd and littermate control mice, and timing of the conditioned response was not altered by the absence of Purkinje cells during acquisition or extinction. The ability of pcd mutant mice to acquire and extinguish trace eyeblink conditioning at levels comparable to controls suggests that the cerebellar cortex is not a critical component of the neural circuitry underlying trace conditioning. Results indicate that the essential neural circuitry for trace eyeblink conditioning involves connectivity that bypasses cerebellar cortex.     

情绪加工老化效应的神经机制

行为学研究发现,老年人对消极情绪的辨别、注意和记忆都有所下降,而对积极情绪并未表现出类似的现象。情绪加工老化效应的神经影像学研究发现,老年人在情绪加工过程中边缘系统（尤其杏仁核）的激活强度低于年轻人,但额叶皮层区域的激活却有所增强。研究者对该结果提出了两种假说,一种是功能代偿假说,另一种是策略改变假说。功能代偿假说认为老年人额叶皮层区域的激活增强是为了弥补边缘系统功能的下降,反映了大脑功能的代偿;策略改变假说认为老年人主动使用了不同于年轻人的策略,情绪加工方式的不同导致了两组人群大脑活动的差异。未来这方面研究可以从研究层面、研究方法、研究问题等方面逐步完善     

Stimulus generalization of conditioned eyelid responses produced without cerebellar cortex: implications for plasticity in the cerebellar nuclei

In Pavlovian eyelid conditioning and adaptation of the vestibulo-ocular reflex, cerebellar cortex lesions fail to completely abolish previously acquired learning, indicating an additional site of plasticity in the deep cerebellar or vestibular nucleus. Three forms of plasticity are known to occur in the deep cerebellar nuclei: formation of new synapses, plasticity at existing synapses, and changes in intrinsic excitability. Only a cell-wide increase in excitability predicts that learning should generalize broadly from a training stimulus to other stimuli capable of supporting learning, whereas the alternatives predict that learning should be relatively specific to the training stimulus. Here we show that deep nucleus plasticity, as assessed by conditioned eyelid responses produced without input from the cerebellar cortex, is relatively specific to the training conditioned stimulus (CS). We trained rabbits to a tone or light CS with periorbital stimulation as the unconditioned stimulus (US), and pharmacologically disconnected the cerebellar cortex during a posttraining generalization test. The short-latency conditioned responses unmasked by this treatment showed strong decrement along the dimension of auditory frequency and did not generalize across stimulus modalities. These results cannot be explained solely by a cell-wide increase in the excitability of deep nucleus neurons, and imply that an input-specific mechanism in the deep cerebellar nucleus operates as well.     

Cerebellar dentate nuclei lesions reduce motivation in appetitive operant conditioning and open field exploration

Recently identified pathways from the dentate nuclei of the cerebellum to the rostral cerebral cortex via the thalamus suggest a cerebellar role in frontal and prefrontal non-motor functioning. Disturbance of cerebellar morphology and connectivity, particularly involving these cerebellothalamocortical (CTC) projections, has been implicated in motivational and cognitive deficits. The current study explored the effects of CTC disruption on motivation in male Long Evans rats. The results of two experiments demonstrate that electrolytic lesions of the cerebellar dentate nuclei lower breaking points on an operant conditioning progressive ratio schedule and decrease open field exploration compared to sham controls. Changes occurred in the absence of motor impairment, assessed via lever pressing frequency and rotarod performance. Similar elevated plus maze performances between lesioned and sham animals indicated that anxiety did not influence task performance. Our results demonstrate hedonic and purposive motivational reduction and suggest a CTC role in global motivational processes. These implications are discussed in terms of psychiatric disorders such as schizophrenia and autism, in which cerebellar damage and motivational deficits often present concomitantly.     

A framework for local cortical oscillation patterns

Oscillations are a pervasive feature of neuronal activity in the cerebral cortex. Here, we propose a framework for understanding local cortical oscillation patterns in cognition: two classes of network interactions underlying two classes of cognitive functions produce different local oscillation patterns. Local excitatory-inhibitory interactions shape neuronal representations of sensory, motor and cognitive variables, and produce local gamma-band oscillations. By contrast, the linkage of such representations by integrative functions such as decision-making is mediated by long-range cortical interactions, which yield more diverse local oscillation patterns often involving the beta range. This framework reconciles different cortical oscillation patterns observed in recent studies and helps to understand the link between cortical oscillations and the fMRI signal. Our framework highlights the notion that cortical oscillations index the specific circuit-level mechanisms of cognition.