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. 2003 Sep 10;23(23):8432-44.
doi: 10.1523/JNEUROSCI.23-23-08432.2003.

Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate

Roberta M Kelly  1 , Peter L Strick
Affiliations

Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate

Roberta M Kelly et al. J Neurosci. .

Abstract

We used transneuronal transport of neurotropic viruses to examine the topographic organization of circuits linking the cerebellar cortex with the arm area of the primary motor cortex (M1) and with area 46 in dorsolateral prefrontal cortex of monkeys. Retrograde transneuronal transport of the CVS-11 (challenge virus strain 11) strain of rabies virus in cerebello-thalamocortical pathways revealed that the arm area of M1 receives input from Purkinje cells located primarily in lobules IV-VI of the cerebellar cortex. In contrast, transneuronal transport of rabies from area 46 revealed that it receives input from Purkinje cells located primarily in Crus II of the ansiform lobule. Thus, both M1 and area 46 are the targets of output from the cerebellar cortex. However, the output to each area of the cerebral cortex originates from Purkinje cells in different regions of the cerebellar cortex. Anterograde transneuronal transport of the H129 strain of herpes simplex virus type 1 (HSV1) revealed that neurons in the arm area of M1 project via the pons to granule cells primarily in lobules IV-VI, whereas neurons in area 46 project to granule cells primarily in Crus II. Together, the findings from rabies and HSV1 experiments indicate that the regions of the cerebellar cortex that receive input from M1 are the same as those that project to M1. Similarly, the regions of the cerebellar cortex that receive input from area 46 are the same as those that project to area 46. Thus, our observations suggest that multiple closed-loop circuits represent a fundamental architectural feature of cerebrocerebellar interactions.

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Figures

Figure 1.
Figure 1.
Retrograde transneuronal transport of rabies virus in the cerebrocerebellar circuit. See Results for a complete description. CN, Cerebellar nuclei; LCI, local circuit interneurons in the cerebellar nuclei; PC, Purkinje cells; GC, granule cells; PN, pontine nuclei; RT, reticular nucleus of the thalamus; VL, ventrolateral thalamus.
Figure 3.
Figure 3.
Density maps of labeled neurons after rabies injections in M1. Top, Lateral view of the left hemisphere of the Cebus monkey. The enclosed area is enlarged at the bottom. Bottom, Density and distribution of immunolabeled neurons 2 d (left) and 4 d (right) after rabies injections into M1. The darkest pixels indicate the greatest concentration of labeled neurons (see scale). White dots indicate where the virus injection needle penetrated the cerebral cortex. Scale bars, 5 mm. ArSs, Superior limb of the arcuate sulcus; ArSi, inferior limb of the arcuate sulcus; CS, central sulcus; PS, principal sulcus.
Figure 8.
Figure 8.
Effective regions of virus uptake after rabies (solid lines) and H129 (broken lines) injections into M1 and area 46 in four representative animals (see Table 1 for details). Scale bar, 3 mm. ArSs, Superior limb of the arcuate sulcus; ArSi, inferior limb of the arcuate sulcus; CS, central sulcus.
Figure 2.
Figure 2.
Purkinje cells infected with rabies. Top, A cluster of injected Purkinje cells found on a sagittal section through the cerebellar hemisphere. Bottom, An isolated infected Purkinje cell in which large portions of the dendritic tree are labeled. Scale bar, 50 μm.
Figure 4.
Figure 4.
Neurons in the cerebellar nuclei infected with rabies. Top, Infected cells found on a transverse section through the cerebellar nuclei 3 d after rabies was injected in the arm area of M1. Scale bar, 200 μm. Bottom, Enlarged view of some labeled neurons in anterior interpositus (the area enclosed at the top). Scale bar, 50 μm. AIN, Anterior interpositus nucleus; PIN, posterior interpositus nucleus; DN, dentate nucleus.
Figure 5.
Figure 5.
Distribution of infected neurons in the cerebellar nuclei. The plots are transverse sections through the cerebellar nuclei. The small black dots represent labeled neurons found 3 d after rabies was injected in the arm area of M1. Scale bar, 1 mm. The graph shows the distribution of second-order neurons in the anterior-posterior extent of the dentate nucleus. Plotted sections are taken from the level indicated on the x-axis of the graph. AIN, Anterior interpositus nucleus; PIN, posterior interpositus nucleus; DN, dentate nucleus; FN, fastigial nucleus.
Figure 6.
Figure 6.
Immunolabeled neurons in the thalamus. This is a photograph of a transverse section through the thalamus 4 d after rabies was injected into the M1 arm area. At the 4 d survival time, first-, second-, and third-order neurons are labeled in subdivisions of the ventrolateral thalamus (VL), whereas labeling in the reticular nucleus of the thalamus (RT) is restricted to second- and third-order neurons. Scale bar, 200 μm.
Figure 7.
Figure 7.
Cerebellar neurons labeled by retrograde transneuronal transport of rabies 4 d after an injection of the virus into the arm area of M1. Top, Infected Purkinje cells seen on a transverse section through the lateral cerebellum. Scale bar, 500 μm. Middle, Enlarged view of the infected cells enclosed by the box at the top. Scale bar, 50 μm. M, Molecular layer; P, Purkinje cell layer; G, granule cell layer. Bottom, Infected second- and third-order neurons in the anterior interpositus nucleus 4 d after an injection of rabies into M1. The 4 d survival time is long enough to allow labeling of third-order neurons. The small labeled neurons (arrows) are typical of third-order, local circuit interneurons that were first seen in the cerebellar nuclei 4 d after cortical injections of rabies. Scale bar, 50 μm.
Figure 9.
Figure 9.
Input-output organization of the cerebellar loops with M1. Left, The distribution of Purkinje cells (small dots) that project to the arm area of M1. These neurons were labeled after retrograde transneuronal transport of rabies from injections into the arm area of M1. Right, The distribution of granule cells (fine lines) that receive input from the arm area of M1. These neurons were labeled after anterograde transneuronal transport of the H129 strain of HSV1 from injections into the arm area of M1. The shaded areas on the flattened surface maps (diagrams on the left in each panel) are unfolded on the right side of each panel to show the distribution of labeled neurons in the relevant cerebellar cortical fissures. The small icons of scissors in the diagram indicate places where the maps have been cut to facilitate the unfolding process (see Materials and Methods for details about unfolding). Scale bars, 15 mm. Nomenclature and abbreviations are according to Larsell (1970). The numbers on the scale bars indicate the location of the sections displayed in Figure 10.
Figure 10.
Figure 10.
Location of cerebellar cortical neurons that are interconnected with M1. Top, A sagittal section displaying the distribution of Purkinje cells (large dots) that project to the arm area of M1 (section 222) (Fig. 9, left). The Purkinje cells were labeled after retrograde transneuronal transport of rabies from injections into the arm area of M1. Bottom, A sagittal section displaying the distribution of granule cells (small dots) that receive input from the arm area of M1 (section 330) (Fig. 9, right). These neurons were labeled after anterograde transneuronal transport of the H129 strain of HSV1 from injections into the arm area of M1. Scale bars, 3 mm. Nomenclature and abbreviations are according to Larsell (1970).
Figure 11.
Figure 11.
Input-output organization of the cerebellar loops with area 46. Left, The distribution of Purkinje cells (small dots) that project to area 46. Right, The distribution of granule cells (fine lines) that receive input from area 46. The shaded areas on the flattened surface maps (diagrams on the left in each panel) are unfolded on the right side of each panel to show the distribution of labeled neurons in the relevant cerebellar cortical fissures. (See Materials and Methods and Figure 9 legend for additional explanation). Scale bars, 15 mm. Nomenclature and abbreviations are according to Larsell (1970). The numbers on the scale bars indicate the location of the sections displayed in Figure 12.
Figure 12.
Figure 12.
Location of cerebellar cortical neurons that are interconnected with area 46. Top, A composite of the sagittal sections displaying the distribution of Purkinje cells (large dots) that project to area 46 (sections 60-80) (Fig. 11, left). Every fourth section was used to make this composite. Bottom, A sagittal section displaying the distribution of granule cells (small dots) that receive input from area 46 (section 100) (Fig. 11, right). Nomenclature and abbreviations are according to Larsell (1970).
Figure 13.
Figure 13.
Transverse section through the cerebellar cortex showing dense clusters of granule cells labeled by anterograde transneuronal transport of H129 from an injection site into M1. Granule cell axons can be seen ascending to the molecular layer, but Purkinje cells remain free of antigen. Scale bar, 200 μm. P, Purkinje cell layer; G, granule cell layer; M, molecular layer; W, white matter.
Figure 14.
Figure 14.
Summary diagrams of the closed-loop circuits that link the cerebellum with M1 and area 46. Note that the cortical area, which is the major source of input to a circuit, is the major target of output from the circuit. See Discussion for complete details. CBM, Cerebellar cortex; DN, dentate nucleus; PN, pontine nuclei; TH, subdivisions of the thalamus.
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