Dopaminergic and non-dopaminergic neurons in the ventral tegmental area of the rat project, respectively, to the cerebellar cortex and deep cerebellar nuclei

doi:10.1016/0306-4522(92)90310-X

Neuroscience

Volume 51, Issue 3, December 1992, Pages 719-728

https://doi.org/10.1016/0306-4522(92)90310-X Get rights and content

Abstract

It has been suggested recently that dopamine in the cerebellum not only acts as a precursor for noradrenaline in afferent fibers supplied by locus coeruleus neurons, but also subserves an independent transmitter role in a separate neural system. The present study was initiated to investigate the possible sources for dopaminergic innervation of the cerebellum. Employing anterograde and retrograde axonal tracing with cholera toxin and a combination of fluorescent retrograde axonal tracing with Fluoro-Gold and tyrosine hydroxylase immunofluorescence histochemistry, we found in the rat that the ventral tegmental area, containing the A10 dopaminergic cell group, sends projection fibers to the cerebellum bilaterally with a slight contralateral predominance. The projections from the ventral tegmental area to the cerebellum were segregated into the dopaminergic one to the cerebellar cortex and the non-dopaminergic one to the deep cerebellar nuclei. Dopaminergic fibers projecting from the ventral tegmental area to the cerebellar cortex terminated mainly in the granular layer, additionally in the Purkinje cell layer, but not at all in the molecular layer. They were distributed predominantly in the crus I ansiform lobule and paraflocculus, and to a lesser extent in the crus II ansiform lobule. On the other hand, non-dopaminergic fibers projecting from the ventral tegmental area to the deep cerebellar nuclei were seen to terminate mainly in the lateral nucleus, to a lesser extent in the interpositus nucleus, but not at all in the medial nucleus. The ventral tegmental area was also observed to receive projection fibers from the lateral and interpositus cerebellar nuclei bilaterally with a contralateral predominance.

The projections from the ventral tegmental area to the cerebellum revealed in the present study might exert limbic influences upon the cerebro-cerebellar loops subserving the execution and co-ordination of voluntary movements.

References (49)

BecksteadR.M. et al.
Efferent connections of the substantia nigra and ventral tegmental area in the rat
Brain Res.
(1979)
BeinfeldM.C. et al.
The distribution of cholecystokinin immunoreactivity in the central nervous system of the rat as determined by radioimmunoassay
Brain Res.
(1981)
BloomF.E. et al.
Studies on norepinephrine-containing afferents to Purkinje cells of rat cerebellum. I. Localization of the fibers and their synapses
Brain Res.
(1971)
BouthenetM.-L. et al.
A detailed mapping of dopamine D-2 receptors in rat central nervous system by autoradiography with [¹²⁵I]iodosulpride
Neuroscience
(1987)
BouthenetM.-L. et al.
Localization of dopamine D₁ receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D₂ receptor mRNA
Brain Res.
(1991)
CarterD.A. et al.
Ascending projections of presumed dopamine-containing neurons in the ventral tegmentum of the rat as demonstrated by horseradish peroxidase
Neuroscience
(1977)
DawsonT.M. et al.
The D₁ dopamine receptor in the rat brain: quantitative autoradiographic localization using an iodinated ligand
Neuroscience
(1988)
DuboisA. et al.
Autoradiographic distribution of the D₁ agonist [³H]SKF 38393, in the rat brain and spinal cord. Comparison with the distribution of D₂ dopamine receptors
Neuroscience
(1986)
HökfeltT. et al.
A subpopulation of mesencephalic dopamine neurons projecting to limbic areas contains a cholecystokinin-like peptide: evidence from immunohistochemistry combined with retrograde tracing
Neuroscience
(1980)
KizerJ.S. et al.
The projections of the A8, A9 and A10 dopaminergic cell bodies: evidence for a nigral-hypothalamic-median eminence dopaminergic pathway
Brain Res.
(1976)

LoughlinS.E. et al.

Substantia nigra and vental tegmental area projections to cortex: topography and Collateralization

Neuroscience

(1984)

LuppiP.-H. et al.

Iontophoretic application of unconjugated cholera toxin B subunit (CTb) combined with immunohistochemistry of neurochemical substances: a method for transmitter identification of retrogradely labeled neurons

Brain Res.

(1990)

MansourA. et al.

A comparison of D₁ receptor binding and mRNA in rat brain using receptor autoradiographic and in situ hybridization techniques

Neuroscience

(1992)

MartresM.-P. et al.

Localisation and pharmacological characterisation of D-2 dopamine receptors in rat cerebral neocortex and cerebellum using [¹²⁵I]iodosulpride

Eur. J. Pharmac.

(1985)

OadesR.D. et al.

Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity

Brain Res. Rev.

(1987)

OlsonL. et al.

On the projections from the locus coeruleus noradrenaline neurons: the cerebellar innervation

Brain Res.

(1971)

PanagopoulosN.T. et al.

Dopaminergic innervation and binding in the rat cerebellum

Neurosci. Lett.

(1991)

PerciavalleV. et al.

Projections from the intracerebellar nuclei to the ventral midbrain tegmentum in the rat

Neuroscience

(1989)

SegalM. et al.

The projections of the nucleus locus coeruleus: an autoradiographic study

Life Sci.

(1973)

SimonH. et al.

Efferents and afferents of the ventral tegmental A10 region studied after local injection of [³H]leucine and horseradish peroxidase

Brain Res.

(1979)

SniderR.S. et al.

Cerebellar pathways to ventral midbrain and nigra

Expl Neurol.

(1976)

SwansonL.W.

The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat

Brain Res. Bull.

(1982)

TakadaM. et al.

Collateral projections from the substantia nigra to the cingulate cortex and striatum in the rat

Brain Res.

(1986)

TakadaM. et al.

Organization of ventral tegmental area cells projecting to the occipital cortex and forebrain in the rat

Brain Res.

(1987)

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