Functional roles of neuropeptides in cerebellar circuits

doi:10.1016/j.neuroscience.2009.01.019

Neuroscience

Volume 162, Issue 3, 1 September 2009, Pages 666-672

https://doi.org/10.1016/j.neuroscience.2009.01.019 Get rights and content

Abstract

Whereas the cerebellum contains 22 different types of neuropeptides as presently known, their expression is generally weak and diffusely dispersed in cerebellar tissues, which often makes their functional significance doubtful. Nevertheless, our knowledge about certain neuropeptides has advanced to the extent that we can figure out their unique functional roles in cerebellar circuits. Throughout the cerebellum, CRF is contained in climbing fibers and its spontaneous release is required for the induction of cerebellar long-term depression (LTD), a cellular mechanism of motor learning. Corticotropin-releasing factor (CRF) is also expressed in the paraventricular nucleus–pituitary system and amygdala–lower brainstem system, both of which are involved in coping responses to stress. In view that motor learning requires stressful efforts for correcting errors in repeated trials, CRF in climbing fibers may imply that the olivocerebellar system is part of a large CRF-operated functional system that acts to cope with various stressors. Orexin, on the other hand, is contained in beaded fibers, which, originating from the hypothalamus, project to various brainstem nuclei and also to the cerebellum, exclusively the flocculus. Currently available evidence suggests that, in fight-or-flight situations, orexinergic neurons switch the state of cardiovascular control systems including the flocculus to secure blood supply to working muscles. Considerable knowledge has also been accumulated about angiotensin II, galanin, and cerebellin, but there is still a gap in defining their unique functional roles in cerebellar circuits.

Section snippets

CRF (CRH)

CRF containing 41 amino acids is distributed mainly in the hypothalamus, amygdala, cerebellum, and brainstem. Two types of CRF receptor, CRFR1 and CRFR2, have been identified; CRFR2 has three splice variants α, β, and γ, but in the rodent brain, only CRFR2α is present. CRFR2α has two different isoforms, a full-length form and a truncated form, as seen in the cerebellum associated at varied ratios with the Golgi apparatus of Purkinje cells, climbing fiber terminals on somata, and mossy fiber

Orexin (hypocretin)

Orexin consists of A and B components (33 and 28 amino acids, respectively) derived from the common precursor prepro-orexin (de Lecea et al 1998, Sakurai et al 1998). Uniquely, orexin is produced only by one group of neurons located in the hypothalamus. Two types of orexin receptor, OX-R1 and OX-R2, have been identified. OX-R1 is 10-fold sensitive to orexin-A. Orexin-immunopositive axons innervate various brainstem neurons including the locus coeruleus, raphe nucleus, parabrachial nucleus, and

Angiotensin II

Angiotensin II is the effector of the renin–angiotensin system involved in blood pressure regulation and maintenance of body fluid homeostasis. In brief, the aspartyl protease renin, synthesized and released from the kidney to the blood, cleaves the precursor molecule angiotensinogen originating from the liver to the decapeptide angiotensin I. Angiotensin I is then converted to the octapeptide angiotensin II by the angiotensin-converting enzyme (ACE) produced in high amounts by endothelial

Galanin

Galanin contains 29 amino acids (30 amino acids in human). It is produced from a 123-amino-acid precursor, preprogalanin. The human preprogalanin gene is located in a 35-kb region on chromosome 11 (Crawley, 1995). Galanin is distributed broadly in the brain, spinal cord and gut, and is implicated in various biological functions such as feeding, blood pressure regulation and nociception (Vrontakis, 2002), and also as a developmental and trophic factor (Wynick and Bacon, 2002). Galanin reacts

Cerebellin

Cerebellin is a hexadecapeptide considered to arise from precerebellin, a protein having 193 amino acids. Cerebellin is a marker of Purkinje cells and is expressed only in one substantial extracerebellar structure, the dorsal cochlear nucleus (Mugnaini and Morgan, 1987). In a strain of mouse, cerebellin appears during early postnatal development and its subsequent levels parallel the cerebellar development observed in granule cell migration and parallel fiber formation, synaptogenesis, Purkinje

Functional roles of neuropeptides

Many of the neuropeptides listed in Table 1 would play the role of neuronal transmitters or modulators. Their actions are mediated by G protein–coupled metabotropic receptors, which operate relatively slowly complimentarily to amino acid transmitters that act fast via ionotropic receptors. Furthermore, peptidergic fibers are characterized by the diffuse and dispersed manner in innervating heterogenous groups of target neurons. This is often considered as a drawback for performing a specific

References (75)

T.Y. Agapova et al.
Neurotrophin gene expression in rat brain under the action of Semax, an analogue of ACTH_4–10
Neurosci Lett
(2007)
K. Akiyama et al.
Gene expression profiling of neuropeptides in mouse cerebellum, hippocampus, and retina
Nutrition
(2008)
D.L. Armstrong et al.
Angiotensin II blockade of long-term potentiation at the perforant path-granule cell synapse in vitro
Peptides
(1996)
P.W. Burnet et al.
Cerebellin-like peptide: tissue distribution in rat and guinea-pig and its release from rat cerebellum, hypothalamus and cerebellar synaptosomes in vitro
Neuroscience
(1988)
U. Coumis et al.
The effects of galanin on long-term synaptic plasticity in the CA1 area of rodent hippocampus
Neuroscience
(2002)
J.N. Crawley
Biological actions of galanin
Regul Pept
(1995)
A.J. Dunn et al.
The role of corticotropin-releasing factor and noradrenaline in stress-related responses, and the inter-relationships between the two systems
Eur J Pharmacol
(2008)
T. Furlong et al.
Neurotoxic lesions centered on the perifornical hypothalamus abolish the cardiovascular and behavioral responses of conditioned fear to context but not of restraint
Brain Res
(2007)
U. Gubler et al.
Cholecystokinin mRNA in porcine cerebellum
J Biol Chem
(1987)
T. Hökfelt
Neuropeptides in perspective: the last ten years
Neuron
(1991)

T. Hökfelt et al.

Neuropeptides—an overview

Neuropharmacology

(2000)

V. Hollt et al.

Dynorphin-related immunoreactive peptides in rat brain and pituitary

Neurosci Lett

(1980)

M. Ito

Cerebellar circuitry as a neuronal machine

Prog Neurobiol

(2006)

O. Johren et al.

Chemical lesion of the inferior olive reduces [¹²⁵I]sarcosine¹-angiotensin II binding to AT₂ receptors in the cerebellar cortex of young rats

Brain Res

(1998)

J.S. King et al.

Peptides in cerebellar circuit

Prog Neurobiol

(1992)

M. Miyata et al.

Corticotropin-releasing factor plays a permissive role in cerebellar long-term depression

Neuron

(1999)

S. Morara et al.

Ultrastructural analysis of climbing fiber–Purkinje cell synaptogenesis in the rat cerebellum

Neuroscience

(2001)

M. Mukoyama et al.

Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors

J Biol Chem

(1993)

H. Murdoch et al.

Periplakin interferes with G protein activation by the melanin-concentrating hormone receptor-1 by binding to the proximal segment of the receptor C-terminal tail

J Biol Chem

(2005)

T. Nambu et al.

Distribution of orexin neurons in the adult rat brain

Brain Res

(1999)

L.P. Reagan et al.

Immunohistochemical mapping of angiotensin type 2 (AT2) receptors in rat brain

Brain Res

(1994)

F. Rene et al.

ΑMSH stimulates cAMP-dependent gene transcription in cerebellar neurons

Regul Pept

(1994)

M.C. Ryan et al.

Localization of preprogalanin messenger RNA in rat brain identification or transcripts in a subpopulation of cerebellar Purkinje cells

Neuroscience

(1996)

T. Sakurai et al.

Orexin and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior

Cell

(1998)

P. Sarret et al.

Pharmacology and functional properties of nts2 neurotensin receptors in cerebellar granule cells

J Biol Chem

(2002)

N. Schweighofer et al.

Cerebellar aminergic neuromodulation: towards a functional understanding

Brain Res Rev

(2004)

R.M. Sherrard et al.

Localisation of insulin-like growth factor-I (IGF-I) immunoreactivity in the olivocerebellar system of developing and adult rats

Dev Brain Res

(1997)

C. Strazielle et al.

Regional brain distribution of noradrenaline uptake sites, and of α₁-, α₂- and β-adrenergic receptors in PCD mutant mice: a quantitative autoradiographic study

Neuroscience

(1999)

F. Tang et al.

The regional distribution of thyrotropin releasing hormone, leu-enkephalin, met-enkephalin, substance P, somatostatin, and cholecystokinin in the rat brain and pituitary

Neuropeptides

(1991)

P. Tongroach et al.

Angiotensin II-induced depression of Purkinje cell firing and possible modulatory action on GABA responses

Neurosci Res

(1984)

R.C. Venema et al.

Angiotensin II-induced association of phospholipase c₁ with the G protein-coupled AT₁ receptor

J Biol Chem

(1998)

D. Wynick et al.

Targeted disruption of galanin: new insights from knock-out studies

Neuropeptides

(2002)

Z.-Q.D. Xu et al.

Electrophysiological studies on galanin effect in brain—progress during the last six years

Neuropeptides

(2005)

T.A. Banchek et al.

Galanin receptor subtypes

Trends Pharmacol Sci

(2000)

D.G. Changaris et al.

Localization of angiotensin in rat brain

J Histochem Cytochem

(1978)

S.L. Cummings et al.

Distribution of corticotropin-releasing factor in the cerebellum and precerebellar nuclei of the opossum: a study utilizing immunohistochemistry, in situ hybridization histochemistry, and receptor autoradiography

J Comp Neurol

(1989)

M. de Gasparo et al.

International Union of Pharmacology. XXIIIThe angiotensin II receptors

Pharmacol Rev

(2000)

Cited by (44)

Cerebellar degeneration averts blindness-induced despaired behavior during spatial task in mice
2020, Neuroscience Letters
Citation Excerpt :
Nevertheless, the elevation of corticosterone following water-environment exposure was significantly higher in the Lurchers [12]. Although stress may promote certain compensations such as synaptic plasticity [29], the increased stress reaction to the water environment may induce behavioral disinhibition in Lurcher mice, thus reducing the chance to inhibit exploratory or escape behavior and, thereby, blocking the development of immobility responses and potentially interfering with an adequate platform searching strategy. Immobility might be considered an efficient strategy for avoiding exhaustion when escape is difficult.
Lurcher mutant mice of the C3H strain provide a model of both cerebellar and retinal degeneration. Therefore, they enable the study of the behavior of cerebellar mutants under disabled visual orientation conditions. We aimed to examine cerebellar Lurcher mutants and wild type mice with intact cerebella with and without retinal degeneration employing the rotarod and Morris water maze tests. The positions of the hidden platform and the starting point in the water maze test were stable so as to enable the use of both idiothetic navigation and visual inputs. The Lurcher mice evinced approximately 90 % shorter fall latencies on the rotarod than did the wild type mice. Retinal degeneration exerted no impact on motor performance. Only the wild type mice with normal retina were able to find the water maze platform efficiently. The wild type mice with retinal degeneration developed immobility (almost 25 % of the time) as a sign of behavioral despair. The Lurchers maintained high swimming activity as a potential manifestation of stress-induced behavioral disinhibition and their spatial performance was related to motor skills and swim speed. We demonstrated that both motor deficit and pathological behavior have the potential to contribute to abnormal performance in spatial tasks. Thus, spatial disability in cerebellar mutants is most likely a complex consequence of multiple disturbances related to cerebellar dysfunction.
Motor Control: CRF Regulates Coordination and Gait
2017, Current Biology
Citation Excerpt :
In addition, a plexus of CRF-positive varicosities localized around the soma of neurons is also found at the cortical and nuclear level. The site of origin of these neurons might be located in the hypothalamus [1] but this is still a matter of debate. Two CRF receptors have been identified: CRF-R1 and CRF-R2 [6].
Role of Corticotropin-Releasing Factor in Cerebellar Motor Control and Ataxia
2017, Current Biology
Cerebellar ataxia, characterized by motor incoordination, postural instability, and gait abnormality [1, 2, 3], greatly affects daily activities and quality of life. Although accumulating genetic and non-genetic etiological factors have been revealed [4, 5, 6, 7], effective therapies for cerebellar ataxia are still lacking. Intriguingly, corticotropin-releasing factor (CRF), a peptide hormone and neurotransmitter [8, 9], is considered a putative neurotransmitter in the olivo-cerebellar system [10, 11, 12, 13, 14]. Notably, decreased levels of CRF in the inferior olive (IO), the sole origin of cerebellar climbing fibers, have been reported in patients with spinocerebellar degeneration or olivopontocerebellar atrophy [15, 16], yet little is known about the exact role of CRF in cerebellar motor coordination and ataxia. Here we report that deficiency of CRF in the olivo-cerebellar system induces ataxia-like motor abnormalities. CRFergic neurons in the IO project directly to the cerebellar nuclei, the ultimate integration and output node of the cerebellum, and CRF selectively excites glutamatergic projection neurons rather than GABAergic neurons in the cerebellar interpositus nucleus (IN) via two CRF receptors, CRFR1 and CRFR2, and their downstream inward rectifier K⁺ channel and/or hyperpolarization-activated cyclic nucleotide-gated (HCN) channel. Furthermore, CRF promotes cerebellar motor coordination and rescues ataxic motor deficits. The findings define a previously unknown role for CRF in the olivo-cerebellar system in the control of gait, posture, and motor coordination, and provide new insight into the etiology, pathophysiology, and treatment strategy of cerebellar ataxia.
Roles of the orexin system in central motor control
2015, Neuroscience and Biobehavioral Reviews
The neuropeptides orexin-A and orexin-B are produced by one group of neurons located in the lateral hypothalamic/perifornical area. However, the orexins are widely released in entire brain including various central motor control structures. Especially, the loss of orexins has been demonstrated to associate with several motor deficits. Here, we first summarize the present knowledge that describes the anatomical and morphological connections between the orexin system and various central motor control structures. In the next section, the direct influence of orexins on related central motor control structures is reviewed at molecular, cellular, circuitry, and motor activity levels. After the summarization, the characteristic and functional relevance of the orexin system's direct influence on central motor control function are demonstrated and discussed. We also propose a hypothesis as to how the orexin system orchestrates central motor control in a homeostatic regulation manner. Besides, the importance of the orexin system's phasic modulation on related central motor control structures is highlighted in this regulation manner. Finally, a scheme combining the homeostatic regulation of orexin system on central motor control and its effects on other brain functions is presented to discuss the role of orexin system beyond the pure motor activity level, but at the complex behavioral level.
Hypothalamic orexin-A (hypocretin-1) neuronal projections to the vestibular complex and cerebellum in the rat
2014, Brain Research
Immunohistochemistry combined with retrograde tract-tracing techniques were used to investigate the distribution of orexin-A (OX-A)- and OX-A receptor-like (OX₁) immunoreactivity within the vestibular complex and cerebellum, and the location of hypothalamic OX-A neurons sending axonal projections to these regions in the Wistar rat. OX-A immunoreactive fibers and presumptive terminals were found throughout the medial (MVe) and lateral (LVe) vestibular nuclei. Light fiber labeling was also observed in the spinal and superior vestibular nuclei. Within the cerebellum, dense fiber and presumptive terminal labeling was observed in the medial cerebellar nucleus (Med; fastigial nucleus), with less dense labeling in the interposed (Int) and lateral cerebellar nuclei (Lat; dentate nucleus). A few scattered OX-A immunoreactive fibers were also observed throughout the cortex of the paraflocculus. OX₁-like immunoreactivity was found densely concentrated within LVe, moderate in MVe, and scattered within the spinal and superior vestibular nuclei. Within the cerebellum, OX₁-like immunoreactivity was also observed densely within Med and in the dorsolateral aspects of Int. Additionally, OX₁ like-labeling was found in Lat, and within the granular layer of the caudal paraflocculus cerebellar cortex. Fluorogold (FG) microinjected into these vestibular and cerebellar regions resulted in retrogradely labeled neurons throughout the ipsilateral hypothalamus. Retrogradely labeled neurons containing OX-A like immunoreactivity were observed dorsal and caudal to the anterior hypothalamic nucleus and extending laterally into the lateral hypothalamic area, with the largest number clustered around the dorsal aspects of the fornix in the perifornical area. A few FG OX-A like-immunoreactive neurons were also observed scattered throughout the dorsomedial, and posterior hypothalamic nuclei. These data indicate that axons from OX-A neurons terminate within the vestibular complex and deep cerebellar nuclei of the cerebellum and although the function of these pathways is unknown, they likely represent pathways by which hypothalamic OX-A containing neurons co-ordinate vestibulo-cerebellar motor and autonomic functions associated with ingestive behaviors.
Functional inactivation of orexin 1 receptors in the cerebellum disrupts trace eyeblink conditioning and local theta oscillations in guinea pigs
2013, Behavioural Brain Research
Citation Excerpt :
It has been demonstrated that the primary memory trace of CR is stored in the deep cerebellar nuclei (DCN) and/or the cerebellar cortex [3–8], although the forebrain regions are critically involved in the learning process when the cognitive demands are increased [9–13]. A growing body of evidence has led to the proposal that function of the cerebellum is under the influence of numerous neuropeptides [14,15]. Uniquely, orexins (orexin-A and orexin-B), the new reported neuropeptides with multiple physiological functions, are exclusively produced by one group of cells located in the lateral hypothalamus (LH) that diffusely project to various brain regions [16–20].
The cerebellum plays an essential role in motor learning. Recently, orexins, the newfound lateral hypothalamic neuropeptides, have been found to excite Purkinje cells in the cerebellar cortex and neurons in the deep cerebellar nuclei (DCN). However, little is known about their roles in cerebellum-dependent motor learning. Therefore, the present study was designed to investigate the functional significance of hypothalamic orexinergic system during trace eyeblink conditioning, a tractable behavioral model system of cerebellum-dependent motor learning. It was revealed that the orexin 1 receptors (OXR1) were specifically localized on the soma of Purkinje cells and large DCN neurons. Furthermore, interfering with the endogenous orexins’ effects on the cerebellum via the selective OXR1 antagonist SB-334867 disrupted the timing rather than the acquisition of trace conditioned eyeblink responses. In addition to the behavioral effects, the SB-334867 prevented the increase in peak amplitude of cerebellar theta oscillations with learning. These results suggest that the endogenous orexins may modulate motor learning via the activation of cerebellar OXR1.

View all citing articles on Scopus

View full text

Synaptic TransmissionFunctional roles of neuropeptides in cerebellar circuits

Abstract

Section snippets

CRF (CRH)

Orexin (hypocretin)

Angiotensin II

Galanin

Cerebellin

Functional roles of neuropeptides

Neurosci Lett

Nutrition

Peptides

Neuroscience

Neuroscience

Regul Pept

Eur J Pharmacol

Brain Res

J Biol Chem

Neuron

Neuropharmacology

Neurosci Lett

Prog Neurobiol

Brain Res

Prog Neurobiol

Neuron

Neuroscience

J Biol Chem

J Biol Chem

Brain Res

Brain Res

Regul Pept

Neuroscience

Cell

J Biol Chem

Brain Res Rev

Dev Brain Res

Neuroscience

Neuropeptides

Neurosci Res

J Biol Chem

Neuropeptides

Neuropeptides

Galanin receptor subtypes

Trends Pharmacol Sci

Localization of angiotensin in rat brain

J Histochem Cytochem

Distribution of corticotropin-releasing factor in the cerebellum and precerebellar nuclei of the opossum: a study utilizing immunohistochemistry, in situ hybridization histochemistry, and receptor autoradiography

J Comp Neurol

International Union of Pharmacology. XXIIIThe angiotensin II receptors

Pharmacol Rev

Synaptic Transmission
Functional roles of neuropeptides in cerebellar circuits