The Hebrew University of Jerusalemהאוניברסיטה העברית בירושלים
The Jerusalem Cerebellum Research Team
Cerrebellum
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Yarom's Lab

Research in the cerebellum group led by Professor Yosef Yarom focuses on the olivo-cerebellar system. Cerebellar function, which was classically thought to be restricted to motor-coordination, has recently been extended to include both sensory and cognitive functions. The simplicity and homogeneity of the circuitry of this modular structure suggest it has a rather limited repertoire of functional capabilities. More crucially, the multiplicity of functions and the simplicity of the circuit imply that this system reflects a very basic computational process that can be implemented in a variety of brain functions. One such basic process is the ability to generate precise time sequences. In fact, many cerebellar-related behaviors involve the need for precise timing to coordinate different facets of overall behavior. Recent findings on the functional organization of the cerebellar cortex, the inferior olivary nucleus, and their interconnections have prompted us to formulate a hypothetical mechanism by which the system can generate complex temporal patterns (Yarom & Cohen 2002). The working hypothesis is that temporal patterns are encoded in the complex-spike trains that are evoked in a specifically designlibsane-abatoned designed olivary network that generates propagating subthreshold oscillations (Devor & Yarom, 2002). This mechanism is presented in Figure 1. The network, which is tailored to a specific pattern, is defined by bi-stable Purkinje cell activity (Loewenstein et al., 2005) via the descending inhibitory connections from the deep cerebellar nuclei to the inferior olive. By dynamically modulating the electrical connections, this inhibitory path shapes the functional architecture of the olivary network. Once a network of olivary neurons is configured, it will generate subthreshold oscillations that propagate along the network. Olivary action potentials, which are elicited at the peaks of the propagating wave of oscillations (Lampl & Yarom, 1993; Chorev et al., 2007), converge, with various phase relations, onto the neurons of the deep cerebellar nuclei. Hence, a specific temporal pattern can be generated in the DCN, and is not bound by the fundamental frequency of the subthreshold oscillations. This hypothesis posits that input to the cerebellum, which is actually a call for a specific temporal pattern, will switch a group of Purkinje cells to an up-state of prolonged firing/spike discharge. This will form a specific functional network of olivary neurons. The resultant wave of oscillations will generate the required temporal pattern. Since the specificity of the recalled pattern is determined by a group of Purkinje cells activated by mossy fiber input via the parallel fiber system, we believe that learning of a specific pattern must occur at the granule cell – Purkinje cell synapse, in accordance with most theories of cerebellar learning. In the laboratory we use in vivo and in vitro approaches, combined with intra- and extracellular recordings as well as imaging of voltage sensitive dyes to explore various aspects of this hypothetical mechanism.
Chorev E, Yarom Y & Lampl I. (2007). Rhythmic episodes of subthreshold membrane potential oscillations in the rat inferior olive nuclei in vivo. J Neurosci 27, 5043-5052.
Devor A & Yarom Y. (2002). Generation and Propagation of Subthreshold Waves in a Network of Inferior Olivary Neurons. Journal of neurophysiology 87, 3059-3069.
Lampl I & Yarom Y. (1993). Subthreshold oscillations of the membrane potential: a functional synchronizing and timing device. Journal of neurophysiology 70, 2181-2186.
Loewenstein Y, Mahon S, Chadderton P, Kitamura K, Sompolinsky H, Yarom Y & Hausser M. (2005). Bistability of cerebellar Purkinje cells modulated by sensory stimulation. Nature neuroscience 8, 202-211.
fig1
FIG 1: The olivo-cerebellar circuits generates temporal patterns.
Fig3
FIG 3: Olivary neurons stained in green and in red immuno staining for alpha2 subunit of GABA-A receptors. Devor et al. 2001. J Neurophysiol.

fig2
FIG 2:Dye coupling between molecular layer inhibitory interneurons. Scale bar- 20 micron. Mann-Metzer & Yarom 1999; J Neurophysiol.
fig4
FIG 4: Time-frequency analysis of subthreshold oscillations recorded simultaneously from two olivary neurons. The modulation of the frequency (y-axis) and amplitude (color coded) occurred simultaneously in two olivary neurons in slice preparation. In this cell pair the frequency shifts from 5 to 10 Hz. Such an accurate synchronous modulation in frequency must be a consequence of network activity.
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