PARASAGITTAL STRIPES: THE BASIS OF CEREBELLAR MICROCIRCUITS?
One of the greatest unknowns about the cerebellar circuit is whether the prototypical olivocerebellar loop, from olive→Purkinje cells→cerebellar nuclei→back to olive, is actually organized so that an individual olivary neuron receives inhibitory feedback from the same inhibitory nucleus neurons that it influences indirectly via Purkinje cells. In other words, does the microcircuit (at the level of individual neurons) reflect the macrocircuit (at the level of entire structures)? The most suggestive work on this question comes fromanatomical studies on the parasagittal zones of the cerebellum. Histological experiments have revealed that many proteins, including aldolase C, acetylcholinesterase, calbindin, and parvalbumin, are expressed differentially in parasagittal stripes that run the length of each longitudinal zone. These stripes, which have been given names (1+, 1−, 2+, 2−, etc.), are constant in their presence and location within a species and to some extent across species (Pakan, Graham, Gutiérrez-Ibáñez, & Wylie, 2011).
Recent work has highlighted the potential significance of these stripes in organization of microcircuits in the cerebellum. Each olivary neuron gives rise to 7 to 10 climbing fibers in the cortex; all of the Purkinje cells that receive input from one olivary neuron are located within a stripe defined by aldolase C staining. Even in cases where the olivary axon diverges to different cerebellar lobules, the climbing fibers in both lobules obey the pattern established by aldolase C stripes: either all branches are in positive stripes or all in negative stripes. Furthermore, a group of Purkinje cells that are innervated by a small cluster of olivary neurons typically exhibit converging axon arbors in the cerebellar nuclei as well, within a subregion that is also defined by aldolase C staining (Sugihara, 2011). This convergence holds true even when the Purkinje cells are located in separate lobules. The axon collaterals of olivary neurons, which extend into the cerebellar nuclei, also form small clusters of terminals suggestive of microcircuit targeting. In turn, a cluster of nuclear neurons appears to target the same olivary region from which it receives input. Even cortical interneurons may respect the boundaries defined by aldolase stripes (Sillitoe & Joyner, 2007). Together these data are strongly suggestive of a closed loop olivo-cortical-nuclear microcircuit.
These findings are exclusively anatomical, but some experiments have extended these concepts to physiology and function aswell. For example,muscle injection of a rabies virus tracer, which can travel retrogradely across many synapses, reveals one ormore longitudinal stripes of Purkinje cells bounded by aldolase C compartments. Physiologically, Purkinje cells in aldolase positive and negative stripes express different complements of glutamate transporters, some of which are more effective than others. As a result, it is easier to trigger metabotropic glutamate receptor activity, and the consequent cascade leading to long-term depression of the parallel fiber→Purkinje cell synapse, in aldolase-negative than in aldolase-positive compartments (Wadiche & Jahr, 2001). In sum, the parasagittally organized stripes of the cerebellum are highly significant for both circuit and function.
Pakan, J. M., Graham, D. J., Gutiérrez-Ibáñez, C., & Wylie, D. R. (2011). Organization of the cerebellum: correlating zebrin immunohistochemistry with optic flow zones in the pigeon flocculus. Visual Neuroscience, 28, 163–173.
Sillitoe, R. V., & Joyner, A. L. (2007). Morphology, molecular codes, and circuitry produce the three-dimensional complexity of the cerebellum. Annual Review of Cell and DevelopmentalBiology, 23, 549–577.
Sugihara, I. (2011). Compartmentalization of the deep cerebellar nuclei based on afferent projections and aldolase C expression. Cerebellum, 10, 449–463.
Wadiche, J. I., & Jahr, C. E. (2001). Multivesicular release at climbing fiber-Purkinje cell synapses. Neuron, 32, 301–313.