The cerebellar-hypothalamic circuits: Potential pathways underlying cerebellar involvement in somatic-visceral integration

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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v

Review

The cerebellar-hypothalamic circuits: Potential pathways underlying cerebellar involvement in somatic-visceral integration Jing-Ning Zhu a , Wing-Ho Yung c , Billy Kwok-Chong Chow e , Ying-Shing Chan d , Jian-Jun Wang a,b,⁎ a

Department of Biological Science and Technology and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Mailbox 426, Nanjing University, 22 Hankou Road, Nanjing 210093, China b Jiangsu Key Laboratory for Bioresource Technology, School of Life Sciences, Nanjing Normal University, 122 Ninghai Road, Nanjing 210097, China c Department of Physiology, The Chinese University of Hong Kong, Hong Kong, China d Department of Physiology, The University of Hong Kong, Hong Kong, China e Department of Zoology, The University of Hong Kong, Hong Kong, China

A R T I C LE I N FO

AB S T R A C T

Article history:

The cerebellum has been considered only as a classical subcortical center for motor control.

Accepted 13 January 2006

However, accumulating experimental and clinical evidences have revealed that the

Available online 21 February 2006

cerebellum also plays an important role in cognition, for instance, in learning and memory, as well as in emotional behavior and in nonsomatic activities, such as visceral

Keywords:

and immunological responses. Although it is not yet clear through which pathways such

Cerebellum

cerebellar nonsomatic functions are mediated, the direct bidirectional connections between

Hypothalamocerebellar projection

the cerebellum and the hypothalamus, a high autonomic center, have recently been

Cerebellohypothalamic projection

demonstrated in a series of neuroanatomical investigations on a variety of mammals and

Histaminergic fiber

indicated to be potential pathways underlying the cerebellar autonomic modulation. The

Somatic-visceral integration

direct hypothalamocerebellar projections originate from the widespread hypothalamic nuclei/areas and terminate in both the cerebellar cortex as multilayered fibers and the cerebellar nuclei. Immunohistochemistry studies have offered fairly convincing evidence that some of these projecting fibers are histaminergic. It has been suggested that through their excitatory effects on cerebellar cortical and nuclear cells mediated by metabotropic histamine H2 and/or H1 receptors, the hypothalamocerebellar histaminergic fibers participate in cerebellar modulation of somatic motor as well as non-motor responses. On the other hand, the direct cerebellohypothalamic projections arise from all cerebellar nuclei (fastigial, anterior and posterior interpositus, and dentate nuclei) and reach almost all hypothalamic nuclei/areas. Neurophysiological and neuroimaging studies have demonstrated that these connections may be involved in feeding, cardiovascular, osmotic, respiratory, micturition, immune, emotion, and other nonsomatic regulation. These observations provide support for the hypothesis that the cerebellum is an essential

⁎ Corresponding author. Department of Biological Science and Technology, Mailbox 426, Nanjing University, 22 Hankou Road, Nanjing 210093, China. Fax: +86 25 8359 2714, +86 25 8359 2705. E-mail address: [email protected] (J.-J. Wang). 0165-0173/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2006.01.003

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modulator and coordinator for integrating motor, visceral and behavioral responses, and that such somatic-visceral integration through the cerebellar circuitry may be fulfilled by means of the cerebellar-hypothalamic circuits. © 2006 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypothalamocerebellar projections . . . . . . . . . . . . . . . . . . Cerebellohypothalamic projections . . . . . . . . . . . . . . . . . . Cerebellum and its nonsomatic modulation . . . . . . . . . . . . . 4.1. Cerebellar modulation of visceral activities . . . . . . . . . . 4.1.1. Gastrointestinal motor and feeding control . . . . . 4.1.2. Cardiorespiratory regulation . . . . . . . . . . . . . . 4.1.3. Micturition and defecation modulation . . . . . . . . 4.2. Cerebellar modulation of immune functions . . . . . . . . . 4.3. Cerebellar modulation of brain higher integrative functions . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.

Introduction

Our knowledge of cerebellar physiological function has long been confined to its motor control. However, the past decade has witnessed significant advances in experimental neuroanatomical, neurophysiological, behavioral and functional brain imaging studies on cerebellar nonsomatic functions, as well as in clinical observations on patients with cerebellar lesions. These intriguing findings, such as the fastigial pressor response (FPR) (Reis and Golanov, 1997), the alterations in feeding behavior and nutritional organization after lesioning rat cerebellar cortex (Scalera, 1991; Mahler, 1993), and the cerebellar cognitive affective syndrome (Schmahmann and Sherman, 1998), greatly expand the traditional understanding of cerebellar roles in central nervous system. In fact, the cerebellum is not only a subcortical center for motor control participating in the sensomotor integration, but also an essential node in the central integration of somatic and visceral activities, which contributes to generate integrated and coordinated somatic-visceral responses to adapt to the changes of internal and external environments. Therefore, naturally, a question is raised which neural pathways provide the substantial foundation for such cerebellar nonsomatic functions. It has long been well known that there are afferent and efferent connections between the cerebellum and the motor cortex as well as the motor nuclei in brainstem (Schmahmann and Pandya, 1997; Teune et al., 2000). In addition, the projections of the cerebellum to the brainstem regions relevant to visceral regulation have also been documented (Homma et al., 1995; Teune et al., 2000). Although several studies support that the FPR seems to be relative to the multi-synaptic projections of cerebellum to brainstem (Bradley et al., 1987; Homma et al., 1995; Reis and Golanov, 1997), the autonomic responses evoked by stimulating cerebellum were abolished following a precollicular decerebration (Zanchetti and Zoccolini,

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1954; Supple et al., 1988). Thus, it is imperfect that the explanation for the cerebellar modulation on various visceral activities is simply mediated the cerebello–brainstem pathways. In reality, the cerebellar influences on autonomic responses/activities are most likely to be related to higher autonomic center(s) above the mesencephalon. Recent numerous neuroanatomical studies using retrograde and anterograde tracing techniques revealed the direct bidirectional connections between the cerebellum and the hypothalamus (Dietrichs, 1984; Dietrichs and Haines, 1984; Dietrichs et al., 1992, 1994; Haines and Dietrichs, 1984; Haines et al., 1985, 1990; Çavdar et al., 2001a, b), i.e., the hypothalamocerebellar projections and the cerebellohypothalamic projections, which constitute the cerebellarhypothalamic circuits. Considering that the hypothalamus is an important high autonomic center for regulation of visceral functions, it is suggested that the cerebellar-hypothalamic circuits may be potential neuroanatomical substrates underlying the cerebellar extensive modulation of nonsomatic activities.

2.

Hypothalamocerebellar projections

The direct hypothalamocerebellar projections were first definitively presented by Dietrichs (1984) in his pioneering study on the cat that placed wheat germ agglutinin-horseradish peroxidase as retrograde tracers into the cerebellar cortex. A subsequent series of neuroanatomical investigations on various mammals including rats (Dietrichs et al., 1992), tree shrews (Haines et al., 1985), greater bushbabies (Dietrichs and Haines, 1984), squirrel monkeys (Haines and Dietrichs, 1984; Haines et al., 1986) and rhesus monkeys (Haines et al., 1990), as well as nonmammalian vertebrates (Bangma and ten Dongkelaar, 1982; Künzle, 1983), further substantiated that the

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direct hypothalamocerebellar projections extensively exist and appear to be stronger in species ascending the phylogenetic scale, and suggested that the connections may be phylogenetically old pathways (Haines et al., 1997). Haines and his colleagues reported that nuclei/areas of the hypothalamus directly projecting to the cerebellum are widespread (Fig. 1, for reviews see Dietrichs et al., 1994; Haines et al., 1997). Neurons that project directly to the cerebellum are found primarily in the lateral (LHA), posterior (PHA), and dorsal (DHA) hypothalamic areas; the supramammillary (SMN), tuberomammillary (TMN) and lateral mammillary (LMN) nuclei; the dorsomedial (DMN) and ventromedial (VMN) nuclei; and in the periventricular zone (PVZ). Available evidence suggests the projections is bilateral but with an ipsilateral preponderance (Dietrichs, 1984). There are three types of hypothalamocerebellar connections: (i) hypothalamic projections only to the cerebellar cortex; (ii) hypothalamic projections only to the cerebellar nuclei; and (iii) hypothalamic projections to the cerebellar cortex which also send collateral branches to the cerebellar nucleus. Based on the ultrastructural characteristics of hypothalamocerebellar cortical terminals are similar with those of the serotoninergic axons from raphe nuclei and the noradrenergic ones from locus ceruleus rather than the classical cerebellar mossy or climbing afferent fibers, especially considering that these fibers terminate in all three layers (molecular, Purkinje and granular layer) of the cerebellar cortex, some authors suggest that these hypothalamocerebellar cortical fibers may be classified as multilayered fibers (Dietrichs and Haines, 1985; Dietrichs et al., 1994; Haines et al., 1986, 1997). Neurophysiological studies (Bratus' and Ioltukhovskii, 1986; Supple, 1993; Wang et al., 1994) corroborate the existence of direct anatomical projections from the hypothalamic nuclei to the cerebellar cortex. Supple (1993) demonstrated unimodal excitatory, biphasic excitatory–inhibitory and complex responses of cerebellar Purkinje cells to hypothalamic stimu-

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lation. Thereafter, Wang et al. (1994) reported that stimulation of the LHA and VMN elicited inhibitory, excitatory and mixed responses of the cerebellar cortical neurons. In this study, more non-Purkinje cells responded to hypothalamic stimulation than Purkinje cells (identified by their complex spike discharges) and the majority of these cells showed a monosynaptic inhibitory response with a short latency of 10–20 ms. Furthermore, of 27 neurons responding to the LHA stimulation, only one was influenced by stimulating VMN as well, suggesting that individual hypothalamic nuclei/areas may have preferred target areas in the cerebellar cortex. The neurotransmitters in the hypothalamocerebellar projections have not been well known so far, however, a growing body of data has provided strong evidence that histamine is a potential neurotransmitter used by some pathways (Dietrichs et al., 1994; Wang et al., 1994; Haines et al., 1997; Li et al., 1999; Tian et al., 2000; Shen et al., 2002), although some other candidates, such as γ-aminobutyric acid, glycine, serotonin, noradrenaline and cerebellin were also suggested (Bratus' and Ioltukhovskii, 1986; Dietrichs et al., 1992, 1994; Haines et al., 1997) (Table 1). Histamine-releasing neurons are located exclusively in the TMN of the hypothalamus, from where they project to practically almost all brain regions including spinal cord (Brown et al., 2001; Haas and Panula, 2003). Since the primary origin of the hypothalamocerebellar projections includes the TMN, these fibers are, at least in part, histaminergic. Immunohistochemical studies have offered convincing evidence that the histamine-containing neurons project from the TMN to both cortex and nuclei of the cerebellum (Panula et al., 1989, 1993). Recent autoradiographic mapping, immunohistochemical analysis and in situ hybridization experiments have also indicated the presence of histamine H1, H2, H3, and H4 receptors in cerebellum (Traiffort et al., 1994; Arrang et al., 1995; Vizuete et al., 1997; Honrubia et al., 2000; Cogé et al., 2001; Karlstedt et al., 2001; Pillot et al., 2002). By using rat cerebellar slice preparations, Li et al. (1999) first reported that histamine

Fig. 1 – Schematic representation of the cerebellar–hypothalamic circuits in rats. Those cell groups listed under hypothalamus and out of parentheses are the prime source of direct hypothalamocerebellar fibers; those listed in parentheses are the principal targets of direct cerebellohypothalamic fibers. Cells numbered 1, 2 and 3 are indicative of (1) hypothalamic neurons that project only to the cerebellar cortex, (2) hypothalamic neurons that project to the cerebellar cortex and send collaterals into the nuclei, (3) hypothalamic neurons that project only to the cerebellar nuclei. Abbreviations: DHA, dorsal hypothalamic area; DMN, dorsomedial hypothalamic nucleus; DN, dentate nucleus; FN, fastigial nucleus; IN, interposed nucleus (including anterior and posterior parts); LHA, lateral hypothalamic area; LMN, lateral mammillary nucleus; PHA, posterior hypothalamic area; PVN, paraventricular nucleus; PVZ, periventricular zone; SMN, supramammillary nucleus; TMN, tuberomammillary nucleus; and VMN, ventromedial hypothalamic nucleus. Modified from Haines et al., Int. Rev. Neurobiol., 41, 83–107, copyright 1997, with permission from Elsevier.

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Table 1 – Neurotransmitters in the hypothalamocerebellar projections Neurotransmitters Histamine

Other potential candidates γ-aminobutyric acid (GABA) Glycine Serotonina Noradrenalinea Cerebellin

References Dietrichs et al. (1992, 1994), Haines et al. (1997), Li et al. (1999), Panula et al. (1989, 1993), Shen et al. (2002), Tian et al. (2000), Wang et al. (1994)

Takeda et al. (1984), Dietrichs et al. (1992, 1994), Haines et al. (1997) Dietrichs et al. (1994), Haines et al. (1997) Bratus' and Ioltukhovskii (1986) Bratus' and Ioltukhovskii (1986) Burnet et al. (1988), Haines et al. (1997)

a

Some authors consider that these substances are probably not present in the hypothalamocerebellar fibers (Dietrichs et al., 1994; Wang et al., 1994; Haines et al., 1997).

exerted an excitatory effect on the cerebellar cortical granule cells, the interneurons that relay information from the mossy fibers to the Purkinje cells, through histamine H1 and H2 receptors but with a predominant contribution of H1 receptors. Moreover, the direct post-synaptic excitatory effects of histamine on both of rat cerebellar cortical Purkinje cells and interpositus nuclear (IN) cells via H2 receptors were demonstrated successively in recent electrophysiological studies (Tian et al., 2000; Shen et al., 2002). These findings provide substantial physiological evidences that there are histaminergic neurotransmissions existing in the cerebellum, suggesting that the hypothalamus may influence information processes in the cerebellar neuronal network through the hypothalamocerebellar histaminergic fibers. Since both of histamine H1 and H2 receptors are metabotropic (Brown et al., 2001; Haas and Panula, 2003), the non-classical synaptic chemical transmission of histamine (Diewald et al., 1997) likely regulates the neuronal background activity and the responsiveness of the cerebellar neurons to specific mossy and climbing fiber inputs rather than transmitting discrete signals. Recent rota-rod treadmill and balance beam behavioral studies in our lab suggested that histamine might influence rat motor balance and coordination through histamine H2 receptors on the cerebellar IN neurons (Song et al., in press). In addition to the cerebellum, the histaminergic fibers from hypothalamus may also play a parallel modulating role on others subcortical motor areas, such as the medial vestibular nucleus (Wang and Dutia, 1995), red nucleus (Chen et al., 2003), and globus pallidus (Chen et al., 2005). Thus, the central histaminergic system, including the hypothalamocerebellar histaminergic fibers, may widely influence sensorimotor integration and autonomic responses.

3.

Cerebellohypothalamic projections

Following the studies used anterograde and retrograde tracing techniques (Dietrichs and Haines, 1984; Haines and Dietrichs,

1984; Haines et al., 1985, 1990; Çavdar et al., 2001a,b), the direct projections from the cerebellar nuclei to the hypothalamus have been revealed (Fig. 1). The cerebellohypothalamic projections arise from all cerebellar nuclei (fastigial, anterior and posterior interpositus, and dentate nuclei), pass through the superior cerebellar peduncle, ascendingly project to the hypothalamus, primarily including the LHA, PHA, DHA, DMN and the paraventricular nucleus of the hypothalamus (PVN). These hypothalamic nuclei/areas are just the origins of hypothalamocerebellar projections, suggesting that the connections between cerebellum and hypothalamus are reciprocal. As yet, there has been no evidence of direct projections from the cerebellar cortex Purkinje neurons to the hypothalamus (Haines and Dietrichs, 1991). A growing body of data from the electrophysiological studies corroborates the above neuroanatomical findings. By means of extracellular and intracellular recordings, Min et al. (1989) and Katafuchi and Koizumi (1990) reported that stimulating cerebellar fastigial nucleus (FN) evoked LHA and PVN neurons monosynaptic and multi-synaptic responses, predominantly monosynaptic ones. Moreover, the monosynaptic responses of LHA and PVN neurons to the cerebellar FN stimulation were mostly inhibition, while the multi-synaptic responses exhibited mainly excitation (Min et al., 1989; Katafuchi and Koizumi, 1990). Wang et al. (1997) and Zhang et al. (2003) also demonstrated monosynaptic responses in LHA neurons to the stimulation of cerebellar FN in cats and rats. Furthermore, Pu et al. (1995), Wang et al. (1997) and Zhang et al. (2005b) indicated that the mostly inhibitory monosynaptic contacts were made between the cerebellar IN (anterior or posterior not specified, the same below) neurons and the LHA cells. It was found that the responsive ratio of LHA cells to the cerebellar IN stimulation (36.2%) is higher than that to the FN stimulation (23.3%), indicating that IN-LHA fibers are much more than FN-LHA fibers in cats (Pu et al., 1995; Wang et al., 1997). Otherwise than scarce convergency of hypothalamocerebellar fibers (Wang et al., 1994), some LHA neurons received convergent inputs from the cerebellar FN and IN (Wang et al., 1997). In addition, the monosynaptic connections between the cerebellar IN neurons to the cells of VMN and PVN were recently documented in the in vivo extracellular recording studies of Zhu et al. (2004) and Wen et al. (2004). The monosynaptic contacts between the cerebellar IN and VMN were mostly inhibitory, whereas those between the cerebellar IN and PVN were mainly excitatory.

4.

Cerebellum and its nonsomatic modulation

Following the findings of (i) the direct neural circuits between the cerebellum and the hypothalamus, (ii) the indirect cerebellar-hypothalamic connections mediated by the basilar pontine nuclei, nucleus reticularis tegmenti pontis, and lateral reticular nucleus (Brodal and Walberg, 1977; Azizi et al., 1981; Dietrichs et al., 1985; Aas and Brodal, 1989; Mihailoff, 1993; Liu and Mihailoff, 1999), and (iii) other direct/indirect (e.g., through hypothalamus) connections between the cerebellum and the other autonomic nuclei/areas such as spinal visceral nuclei, dorsal motor vagal nucleus, nucleus tractus solitarii (NTS), parabrachial nucleus, raphe nuclei, nucleus ambiguus,

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amygdale, periaquaductal gray, limbic system, and neocortical association areas (Haines and Dietrichs, 1989; Haines et al., 1984, 1986, 1997; Reis and Golanov, 1997; Schmahmann and Sherman, 1998; Dietrichs and Haines, 2002), the cerebellar nonsomatic functions and their underlying mechanisms have received an increasing attention. The cerebellar regulation of nonsomatic functions has been suggested to involve gastrointestinal motor and feeding, cardiovascular, respiratory, micturition and defecation, immune, and brain higher integrative functions.

4.1.

Cerebellar modulation of visceral activities

4.1.1.

Gastrointestinal motor and feeding control

In 1947, Bard et al. reported that removal of certain parts of the cerebellum including the nodulus eliminated motion sickness (Bard et al., 1947), which brought a hypothesis that the cerebellum participates in a multitude of visceral functions beyond that of motor control. Electrical stimulation of cerebellar FN was found to influence on intestinal motility through sympathetic and vagal pathways, and to evoke both suppression and facilitation of gastric motility in a complex way in which adrenergic discharge, adrenal catecholamine release and vagal cholinergic discharge were considered to be involved (Martner, 1975). Recent behavioral studies have further revealed that the cerebellum participates in the feeding regulation. The animals with lesion of cerebellar cortex or unilateral removal of a cerebellar hemisphere showed an alteration in food intake behavior, a disturbance in nutritional utilization, and a decrease in body weight (Scalera, 1991; Mahler, 1993; Colombel et al., 2002). The mechanisms of the above cerebellar involvement in the feeding control have been suggested in a series of recent electrophysiological studies (Min et al., 1989; Pu et al., 1995; Wang et al., 1997; Zhang et al., 2003, 2005b; Zhu et al., 2004). It was found that electrical stimulation of the cerebellar FN and IN in cats and rats influenced neuronal activity of the LHA and VMN. Furthermore, the majority of those neurons in the LHA (Pu et al., 1995; Wang et al., 1997; Zhang et al., 2003, 2005b) and VMN (Zhu et al., 2004) receiving projections from the cerebellar FN and IN were sensitive to glycemia/glucose (see Fig. 2). It has been well known that the glycemia/glucose-sensitive neurons in hypothalamus are one kind of the important feedingrelated neurons (Oomura et al., 1969; Himmi et al., 1988; Orsini et al., 1991; Campfield and Smith, 2003), which may sense the blood glucose level and subsequently trigger multiple visceralsomatic responses (e.g., initiate or cease food intake) so as to maintain the blood glucose homeostasis. On the other hand, some studies also showed a strong relationship between the LHA glucose-insensitive neurons and water- or food-seeking behavior (Karadi et al., 1990; Parada et al., 1990; Aou et al., 1991). Thus, the cerebellum may be involved in the formation of feeding motivation and the regulation of feeding behavior through its influence on glycemia/glucose-sensitive and glycemia/glucose-insensitive neurons in the hypothalamus. More recently, Zhang et al. (2003, 2005b) reported a convergence of the cerebellar FN/IN and the gastric vagal inputs on single LHA glycemia-sensitive neurons. An integration of the inputs from cerebellar IN and the information from gastric vagal nerves on single glycemia-sensitive neurons in

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the VMN was also demonstrated by Zhu et al. (2004) (Fig. 2). During a meal, the gastric vagal fibers innervating the upper gastrointestinal tract, the primary neuroanatomic substrate in the gut–brain axis, are activated by the gastrointestinal mechanical, chemical and gut–peptide meal-related stimuli and subsequently transmit those negative-feedback visceral signals through the NTS to the hypothalamus, including LHA, VMN and PVN, so as to reduce the meal size (Yuan and Barber, 1992, 1996; Schwartz, 2000). Through those mechanisms including the cerebellohypothalamic projections, the cerebellum may be involved in the somatic-visceral integration. As the functional brain imaging techniques improve, the ability to observe the cerebellar participation in feeding control in human subjects has become precise. Using threedimensional high-resolution magnetic resonance imaging (MRI), Schmahmann et al. (1999) reported that hunger significantly increased regional cerebral blood flow (rCBF) in a number of brain regions of human subjects including hypothalamus, limbic structures as well as bilateral lobule V of the cerebellar cortex in the paravermian regions. In a recent functional magnetic resonance imaging (fMRI) study (Liu et al., 2000), the cerebellum, supplementary motor area, somatosensory cortex, anterior cingulate and orbitofrontal cortex were activated in a minute after glucose acquisition through a per-oral rubber tube. The activation induced by glucose ingestion was not due to any swallowing movements or other motion artifacts, thus those activated regions may be involved in the integration of sensory and visceral signals, and affective activity associated with appetite and taste or olfaction during feeding control. Using positron emission tomography (PET), Tataranni et al. (1999) and Gautier et al. (1999) observed similar cerebellar activation that correlated with hunger and satiation of appetite. On the other hand, a significant decrease of rCBF in the cerebellum following hypoglycemia was demonstrated (Teves et al., 2004). In addition, Parsons et al. (2000) noted that the cerebellum was fairly dispersedly activated, occurring bilaterally and in several different anterior and posterior cortical parts and nuclei (including vermis, FN, archicerebellum and neocerebellum) during subjects received rapid intravenous infusion of hypertonic saline to elicit thirst. That the increased cerebellar activity was not related to motor behavior suggests the cerebellum may be more directly related to not only autonomic and affective aspect of thirst experiences, but also sensory and cognitive ones.

4.1.2.

Cardiorespiratory regulation

4.1.2.1. Cardiovascular modulation. Pioneer investigations of cerebellar influences on nonsomatic functions focused on the cerebellar cardiovascular regulation, especially the FPR. In cats, electrical stimulation of the cerebellar FN potently elevates arterial pressure resulting from a sympathetically induced vasoconstriction in both renal and hindlimb beds together with a sympathetically mediated tachycardia, and the active elements responsible for FPR within the cerebellar FN is highly restricted to the rostral ventrolateral region (Miura and Reis, 1969; Reis and Golanov, 1997) (Fig. 3A). The elevations of arterial pressure elicited by a long-lasting (12 s) pulse train (0.1 ms, 200 μA, 100 Hz) stimulation appear within

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1–2 s, are graded and sustained, and recover almost immediately when stimulation is terminated (Miura and Reis, 1969). A recent study (Zhang et al., 2003) further demonstrated that stimulating the cerebellar FN with the long-lasting pulse train is necessary and sufficient for evoking FPR, but stimulating cerebellar FN with brief double pulses (0.4 ms, 200 μA, and interval 10 ms) did not elicit any change in arterial pressure (Fig. 3B). It is suggested that the FPR need a recruitment of

neural circuits. The FPR exists in a range of species, such as cats, rats, rabbits, dogs, monkeys and humans (Miura and Reis, 1969; Bradley et al., 1987; Reis and Golanov, 1997; Zhang et al., 2003). The heart rate response accompanying the FPR is, however, quite variable. In the cat, the FPR is associated usually with tachycardia, while in the rabbit a bradycardia was reported (Miura and Reis, 1969; Bradley et al., 1987). In contrast to electrical stimulation, microinjection of Lglutamate or its analog (e.g., homocysteic or kainic acids) into the cerebellar FN dose-dependently and site-specifically lower arterial pressure and heart rate (Chida et al., 1986), which is named fastigial depressor response (FDR). Moreover, after the FN cell bodies were selectively destroyed by ibotenic acid, the electrically evoked FPR even persisted while the chemically induced FDR abolished. Thus, some authors consider that the FPR and FDR are initiated by different components within the cerebellum, i.e., the FPR is a result of activation of fibers innervating and/or passing through the nucleus, whereas the FDR results from the excitation of intrinsic fastigial neurons (Bradley et al., 1987; Reis and Golanov, 1997). In addition to the cerebellar FN, the cerebellar cortex is also involved in cardiovascular modulation. For instance, stimulating the anterior lobe of the cerebellar cortex can markedly inhibit vasomotor reflexes while it hardly influences baseline blood pressure (Martner, 1975). In rabbits, the medial vermal cortex of cerebellar lobule VIIa receives the projection of the ipsilateral vagal afferent fibers, which originate from a part of the pulmonary stretch receptors and/or from receptors in the heart, pass through the NTS or other brain stem nuclei, and project to the cerebellum as climbing fiber through inferior olivary nucleus (Kondo et al., 1998). The finding indicates that the cerebellar cortex in the lobule VIIa may regulate the cardiovascular and respiratory functions. In cats, the cerebellar nodulus and uvula have also been demonstrated to modulate cardiovascular responses during postural alterations (Holmes et al., 2002), since they provide inputs to vestibular nucleus regions that are well known to affect control of blood pressure. In 1972, Doba and Reis first noted that electrical stimulation of the cerebellar FN increased blood flow in the common carotid artery and oxygenation of the cerebral cortex (Doba and Reis, 1972). The observation suggests that the cerebellar FN may also regulate the cerebral circulation through

Fig. 2 – Responses of a VMN glycemia-sensitive neurons to the simultaneous stimulation of cerebellar IN and gastric vagal nerves before and after lesion of cerebellar IN. (A–C) Simultaneous stimulation of the gastric vagal nerves and cerebellar IN elicited the cell a summation of the gastric vagal- and cerebellar IN-induced responses (P b 0.01). (D) After electrolytic lesion of cerebellar IN, simultaneous stimulation of the gastric vagal nerves and cerebellar IN only elicited the cell a gastric vagal-evoked response (P b 0.05). (E–G) The test of glucose administration (i.v.) revealed that the cell was a glycemia-sensitive neuron. The arrowheads in panels A–D indicate stimulation artifact, and the horizontal bars in panels E–G show the glucose, saline or mannitol injection that last for 30 s. Reprinted from Zhu et al., Neurosci. Res., 48, 405–417, copyright 2004, with permission from Elsevier.

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elevating rCBF besides its action on systemic circulation. However, the time course of the changes in rCBF differs from those of FPR (Reis and Golanov, 1997). The elevations in rCBF rise gradually and decline during the stimulus sustentation and recover over minutes. In fact, the stimulation of FNevoked elevation of rCBF emerges throughout the entire central nervous system including spinal cord. The maximal elevations occur in the cerebral cortex, especially in frontal areas, whereas the smallest changes appear in white matter. The pathways that mediate cerebellar regulation of systemic and cerebral circulations are still barely understood to date. Two brain stem regions, the rostral ventrolateral medulla (RVLM) and the medullary cerebrovasodilator area (MCVA), have been considered to be two crucial relays in the cerebellar cardiovascular modulation (Reis and Golanov, 1997; Golanov et al., 2000). Bilateral lesions within or adjacent to the RVLM and/or MCVA abolish all the cardiovascular effects of electrical or chemical stimulation of cerebellar FN. Besides the indirect cerebellar–brainstem pathways, there are still other neural substrates mediating the cerebellar cardiovascular modulation. Recently, Wen et al. (2004) reported that the direct cerebellohypothalamic projections might also actively mediate the cerebellar participation in cardiovascular regulation. It was found that the cerebellar IN afferent inputs impinged on the PVN neurons, including those sensitive to baroreflex and osmotic pressure (Fig. 4). Furthermore, the NTS, amygdale, preiaquaductal gray, parabrachial nucleus, and visceral thalamus regions, which send out axons to innervate cerebellum including FN (Haines et al., 1997; Reis and Golanov, 1997; Dietrichs and Haines, 2002), may also be potential relays mediating cerebellar cardiovascular regulation. As a matter of fact, these structures innervate each other in complex reciprocal interactions involving the cerebellohypothalamic pathways and eventually generate an integrated cardiovascular response.

Fig. 3 – The effects of stimulation of cerebellar FN on arterial blood pressure. (A) Localization of optimal loci for FPR in a sagittal section of cerebellum in anesthetized cat. Upper panel: the cerebellum was stimulated at dashed sites along the track. Positive sites are shown by solid circles. Small and large circles represent weak and more powerful pressor responses, respectively. Positive points were identified by stimulation at 200-μm steps with a 12-s stimulus train (0.2 mA, 50 cycles/sec). Lower panel: points along tracks identified by letters are represented by appropriate polygraph tracings below each cross section showing heart rate (HR, beats/min) and blood pressure (BP, mm Hg). Note that maximal responsive sites are localized in the rostral ventromedial portion of FN. (B) Upper panel: stimulation of the FN with the long-lasting pulse train induced a rise in arterial blood pressure, i.e., the FPR. Lower panel: stimulation of the FN and gastric vagal trunks with the brief double-negative pulses had no effect on the arterial blood pressure. (A and B) Reprinted from Reis and Golanov, Int. Rev. Neurobiol., 41, 121–149, copyright 1997, and Zhang et al., Neurosci. Res., 45, 9–16, copyright 2003, respectively, with permissions from Elsevier.

4.1.2.2. Respiratory modulation. The cerebellar FN, nodulus and uvula are capable of modulating respiratory chemo- and mechano-reflexes (Bradley et al., 1987; Xu and Frazier, 2000). Injections of the rabies virus in the respiratory muscles resulted in labeling the motoneurons and their serially connected interneurons at multiple levels of the mouse central nervous system including cerebellar FN and cortical granule cells (Gaytán et al., 2002), suggesting cerebellum might regulate the respiratory outputs via its influences on medullary respiratory neurons (Gaytán and Pásaro, 1998). Labeled cells were also found in the spinal cord, medullary reticular formation, parabrachial nucleus, periaqueductal central gray, hypothalamus, thalamus, and cerebral cortex (Gaytán et al., 2002), most of which have been also identified in the control of cardiorespiratory regulation, as well as in other autonomic functions. Also, both the cerebellum (cortex and nuclei) and hypothalamus have afferent and efferent connections with the medullary ventral respiratory group (Gaytán and Pásaro, 1998), one of the structures necessary for respiratory rhythm generation. Although it is not clear how the cerebellar– hypothalamic pathway mediates respiratory modulations, a recent PET study that assessed cerebellar responses when the urge to breathe was stimulated by inhaled CO2 provided evidence for associating the pathway with the cerebellar

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Fig. 4 – Responses of a baroreflex-sensitive and osmoresponsive PVN neuron to stimulation of cerebellar IN. (A) The cell exhibited an excitatory response (P b 0.01) to the cerebellar IN stimulation. The inset represents three consecutive oscilloscopic traces of cell's firing recordings, showing an evoked action potential following each double-pulses stimulation with a short constant responsive latency. (B–D) The neuron also responded to metaraminol injection that induced an elevation in arterial blood pressure (P b 0.05, B) with a specific inhibition (P b 0.05, C), and showed a specific response to the hypertonic saline application (P b 0.05, D), suggesting the cell was not only a baroreflex-sensitive but also an osmoresponsive neuron. The cerebellar IN stimulation (double pulses at 3 ms interval, 0.4 ms duration, 100 μA intensity) was given every 15 s. The arrows in panel A indicate stimulus artifact, and the horizontal bars in panels B–D show the duration of the metaraminol and hypertonic saline infusions. Reprinted from Wen et al., Neurosci. Lett., 370, 25–29, copyright 2004, with permission from Elsevier.

respiratory function. The conjoint physiological effects of hypercapnia and the consequent air hunger were sensed by the medullary ventral respiratory group and hypothalamus and produced strong bilateral, near-midline activations of the cerebellum (Parsons et al., 2001). In addition, electrophysiological studies have shown functional linkages between the cerebellum and vagal afferents, whose activity is well known to strongly modulate respiration. In the nembutalized cat, evoked potentials were recordable in the cerebellar anterior lobe to cervical vagus nerve stimulation (Hennemann and

Rubia, 1978). By injecting horseradish peroxidase into the cat cerebellar FN, the direct projections from vagal axons to the FN were demonstrated (Zheng et al., 1982), which may be one of the morphological foundations for cerebellar regulation of respiration. Recent evidence suggested that the cerebellum, especially the FN, contributed to respiratory timing regulation through vagal C (unmyelinated) fibers (Xu and Frazier, 1997). Electrical stimulation of neurons within the FN predominantly elevated respiratory frequency associated with a pressor response in

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both anesthetized cats and rats, and ablation of this nucleus markedly attenuated respiratory response to hypercapnia (Xu and Frazier, 2000). After blocking the FPR via pretreatment with phenoxybenzamine or use of transient electrical stimulation (less than 2 s), the evoked respiratory responses still persisted (Xu and Frazier, 2000), suggesting FN-mediated respiratory responses are independent of FPR. Elevation of the level of CO2/H+ within the rostral FN by microinjecting acetazolamider facilitated respiratory outputs (Xu et al., 2001), supporting that there is a ventilatory chemoreception existing in the FN. The medullary gigantocellular nucleus receiving monosynaptic inputs from the cerebellar FN is considered to be essential for mediating the FN participative respiratory responses (Xu et al., 2001). On the other hand, the studies related to the role of cerebellar IN and dentate nucleus in breathing is limited and the results appear controversial. Electrical or chemical stimulation of the rat cerebellar IN and dentate nucleus did not markedly modulate respiratory output (Xu and Frazier, 2000), whereas local stimulation of the cat cerebellar IN (Huang et al., 1993) or dentate nucleus (Farber, 1987) caused a facilitatory influence on expiratory activity. However, the cerebellar IN appears to be responsible for pulmonary mechanoreceptors-mediated respiratory response, since there is evidence to show that the IN contains respiratory-modulated neurons and is involved in coughing motor control (Xu et al., 1997).

4.1.2.3. Clinical observations on simultaneous somatic and cardiorespiratory dysfunctions of cerebellar patients. In addition to the experimental studies on animals and functional brain imaging observations on healthy human subjects, cardiorespiratory signs and symptoms accompanying somatomotor dysfunctions on patients with cerebellar lesions were also reported. It has been well known that cerebellar lesions may lead to an incoordination of ongoing movements and/or a deficit in terminating movements, named ataxia and dysmetria, respectively. However, recently, Haines et al. (1997) described two patients with lesions confined to the cerebellum: one with a small defect in the cerebellar FN showed bradycardia, respiratory alkalosis, and hyperventilation coexisting with a severe gait ataxia; and the other with a large area of damage involving primarily the cerebellar globose and emboliform nuclei exhibited involuntary facial grimace, flushing of face, and pupils dilation concurrent with tremor induced by voluntary movement. All these visceral signs/ symptoms may be directly or indirectly related to the function of hypothalamus. Also, it is noteworthy that the abnormal visceral manifestations were only observed during but not before and after the tremor. Thus, these two clinical cases demonstrate that lesion in the cerebellum may simultaneously induce somatic and visceral dysfunction, and support the notion that the cerebellum may be involved in the regulation of extensive visceral functions via the cerebellar–hypothalamic circuits.

4.1.3.

Micturition and defecation modulation

In addition to its regulation of adrenergically mediated gastrointestinal and cardiovascular functions, the cerebellum also influences parasympathetically conveyed autonomic patterns such as micturition and defecation reflexes. Cere-

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bellar FN stimulation reduced or totally inhibited the increase in colonic blood flow and motility as well as straining movements associated with defecation (Martner, 1975). Neurons that influence the defecation reflex are located in the rostral fastigial pole. The cerebellum may modulate defecation through its interaction of spinal, bulbar and suprabulbar centers (Martner, 1975), while its regulation of micturition may occur at one or more centers that control micturition reflex such as cerebral cortex, hypothalamus, periaquaductal grey, pons and caudal brain stem (Dietrichs and Haines, 2002). Stimulation of cerebellar FN was found to cause either facilitation or inhibition of bladder tone, which was affected by the background bladder tone as well as the stimulation site in the FN (Martner, 1975). However, it does not seem that neurons responsible for excitatory or inhibitory bladder effects have regional difference in the cerebellar FN. Recent PET (Blok et al., 1997) and fMRI (Zhang et al., 2005a) studies on human subjects also revealed that cerebellum was significantly activated in the control of the pelvic floor during micturition.

4.2.

Cerebellar modulation of immune functions

Although few works focus on the cerebellar immunomodulation, studies on strains of mutant mice with cerebellar dysfunction have suggested a close relationship between the cerebellum and functions of the immune system. In 1986, Trenkner and Hoffmann reported an impaired function of the thymus in staggerer mice whose Purkinje cells have few spines and no synapses with parallel fibers (Trenkner and Hoffmann, 1986). Green-Johnson et al. (1995) then found a suppressed T cell and macrophage function in the reeler mice. The cerebellum of the reeler mice has an abnormally high concentration of norepinephrine, which is well known to have many effects on macrophage and lymphocyte function. More directly, Ghoshal et al. (1998) reported that kainic acidinduced lesion of the vestibulocerebellum in rats caused immunosuppressive effects, including a depressed secretion of haematopoietic cytokines in tissue cultures of bone marrow and thymus, a decreased peripheral blood leukocyte concentration, a less neutrophil myeloperoxydase response, and a lower antibody titre to sheep red blood cells. Some studies also revealed an expression of chemokines (chemotactic cytokines) and their receptors in the cerebellum (Gillard et al., 2002; Ragozzino et al., 2002), indicating a novel communication between the immune and nervous system. More recently, it was found that the bilateral cerebellar IN lesions resulted in an irreversible inhibition in number and functions of T, B and natural killer (NK) lymphocytes (Peng et al., revised manuscript). Besides, Peng et al. (2005) demonstrated that the bilateral FN lesions induced a remarkably reduction in contents of glutamate and norepinephrine (NE) in the hypothalamus and concentration of NE in the spleen, following a dramatical enhancement of the T lymphocyte proliferation and the NK cell cytotoxicity (Fig. 5), suggesting that the spinocerebellum participated in the modulation of lymphocyte functions and that a pathway of cerebellum– hypothalamus–sympathetic nerves–lymphocytes instead of the functional axis of hypothalamus–pituitary–adrenal gland was involved in this spinocerebellar immunomodulation.

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Fig. 5 – The effects of lesions of cerebellar FN on lymphocyte functions. (A) Concanavalin A-induced lymphocyte proliferation. Methyl-thiazole-tetrazolium (MTT) colorimetric assay was performed on days 8, 16 and 32 following the FN lesions to evaluate T cell function. (B) NK cell cytotoxicity. Flow cytometry was performed on days 8, 16 and 32 following the FN lesions to assess NK cell cytotoxicity against YAC-1 cells, a Moloney leukemia virus induced mouse lymphoma, with noted sensitivity to NK cells. (C) Glutamate content in the hypothalamus. High-performance liquid chromatography (HPLC) assay was used to test glutamate content in the hypothalamus on the 16th day after the FN lesions. (D) Contents of monoamine neurotransmitters in the hypothalamus. The monoamine neurotransmitters in the hypothalamus, including norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT), were determined by using HPLC on the sixteenth day after the FN lesions. *P b 0.05, **P b 0.01, compared with control rats of the saline-microinjected FN; ++P b 0.01, compared with 8-day rats after injection of kainic acid (KA). Modified from Peng et al., Neurosci. Res., 51, 275–284, copyright 2005, with permission from Elsevier.

4.3. Cerebellar modulation of brain higher integrative functions Based on the cerebellar parallel processing networks (cerebellar unique longitudinal modules of similar circuits), several neuroscientists (Marr, 1969; Albus, 1971; Ito, 1984, 2001; Leiner et al., 1993; Bower, 1995; Schmahmann and Sherman, 1998) have made theoretical predictions/deductions about the involvement of the cerebellum in motor, sensory, cognitive and linguistic process. On the other hand, in fact, learning and memory, language, mood, emotion, and cognition are higher integrative functions that need whole brain coordination involving the cerebellum (Gao et al., 1996; Allen et al., 1997; Parsons et al., 2000, 2001). In particular, much effort has been devoted both theoretically and experimentally to produce a significant progress in our understanding of neural mechanisms of the cerebellum on motor learning. During the past decades, experimental studies have discovered and established long-term depression (LTD) as a unique and characteristic type of synaptic plasticity in the cerebellum, and gradually revealed the signal transduction pathways underlying LTD (Ito, 2001). In addi-

tion, theoretical studies yielded epochal Marr–Albus network models of the cerebellum around 1970 (Marr, 1969; Albus, 1971), and tried to introduce several control system principles explaining the roles of cerebellum in motor learning. Although there is still a controversy on the cerebellar contribution to motor learning (e.g., storage of the memory trace), evidences from various experimental models such as vestibulo-ocular reflex adaptation, hand/arm movement, nictitating membrane/eyeblink conditioning and locomotion have undoubtedly substantiated the cerebellar function of motor learning (Kim and Thompson, 1997; Wang et al., 1998; Ito, 2001; Bloedel, 2004). As regards emotion and cognition, Reiman et al. (1997) revealed an activation in lateral parts of both cerebellar hemispheres (lobule VI), as well as in the other central structures subserving emotional expression such as hypothalamus, amygdala, hippocampus, and occipitotemporoparietal and anterior temporal cortices, in human subjects passively viewing film clips that generated feelings of happiness, sadness, or disgust. Besides, Parsons et al. (2000, 2001), Gao et al. (1996) and Allen et al. (1997) provided solid neuroimaging evidence implicating cerebellum in support of

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sensory, emotional, attentional and cognitive process independent of motor involvement. Clinically, consistent abnormalities in the cerebellum (Purkinje cells, fastigial, globose and emboliform nuclei) have been observed among children with autism, a disorder involving severe deficits in language, attention, cognitive, and social development (Courchesne et al., 1988; Kemper and Bauman, 2002; Yung et al., in press). In addition, a growing body of data about patients with pathologies confined to the cerebellum describes that cerebellar lesions do not always manifest with ataxic motor syndromes, however, they also present impairments in executive, visual–spatial, and linguistic abilities, with affective disturbance ranging from emotional blunting and depression, to disinhibition and psychotic features, which were named the cerebellar cognitive affective syndrome (Schmahmann and Sherman, 1998). These neuropsychological and affective disorders are likely to be a consequence of disruption of the connections linking the cerebral association areas, paralimbic regions as well as hypothalamus with the cerebellum (Courchesne et al., 1988; Schmahmann and Pandya, 1997; Schmahmann and Sherman, 1998). It is also interesting to note that some hypothalamic neurons project to both cerebellum and amygdale (Dietrichs and Haines, 1986), which plays an important role in emotion and behavior. In the early period of the last century, Papez (1937) proposed the neural circuits for emotional experience and expression. In fact, hypothalamus is not only an important component of the Papez circuits (still including the anterior thalamic nuclei, the gyrus cinguli and the hippocampus), but a structure that has interconnections of both the higher cerebral cortex and the lower brainstem and spinal cord. Therefore, although the exact contribution of cerebellar–hypothalamic circuits to the higher integrative functions awaits further substantiation, the circuits may be involved, at least indirectly, in the cerebellar affective and cognitive activities.

5.

Conclusion

The hypothesis that the cerebellum participates in a multitude of brain functions considerably beyond those related to the somatomotor system has been supported by a growing body of experimental and clinical evidences. In fact, an intact motor response involves somatic, visceral, behavioral and cognitive components. The cerebellar modulation on nonsomatic functions, especially above-mentioned visceral activities such as ingestion, circulation, and respiration, is actually an element of the somatic–visceral integration mediated by neural circuits via the cerebellum. The lately discovered direct bidirectional cerebellar–hypothalamic circuits are the most likely anatomical foundations underlying the cerebellar nonsomatic functions. Furthermore, considering the cerebellum receives somatosensory (tactile and proprioceptive) inputs, information relayed through visceral nuclei, indirect inputs from areas of the cerebral cortex concerned with visual, auditory and behavioral functions and so on (Haines et al., 1997), the cerebellum may be one of the vital structures that integrate various (somatic and visceral) senses and (somatic and visceral) motion. Such cerebellar somatic–visceral integration

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and sensomotor integration permits an ultimate outcome of harmonious somatic–visceral responses during an ongoing motor behavior or motor execution for adapting to changes of internal and external environments. Further studies on the cerebellar nonsomatic functions and its mechanisms will assist us not only in understanding and reevaluating functional roles of the cerebellum, but also in comprehending entire mechanisms of the somatic–visceral integration, which redound to explaining pathogenesis of several simultaneous somatic and visceral dysfunctions.

Acknowledgments Researches from our laboratory were supported by grants 39770249, 30070250, 30370462 and the NSFC/RGC Joint Research Scheme 30318004 from the National Natural Science Foundation of China, RFDP grant 20010284021, 20050284025 from the State Educational Ministry of China and grants BK97045, BK2002083 from the Natural Science Foundation of Jiangsu Province of China. Partial works were also supported by a grant-in-aid of “985 Project” from Nanjing University.

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