Fig 1.
(A) Drawing of a Purkinje cell in the cat’s cerebellar cortex, by Santiago Ramón y Cajal. (B) Basic circuit in eyeblink conditioning. The Purkinje cell receives the conditioned stimulus (CS) through parallel fibers from granule cells. The unconditioned stimulus (US) arrives through the climbing fiber from the inferior olive. The Purkinje cell also receives inhibitory inputs from stellate cells. Purkinje cell output is inhibitory to the deep cerebellar nuclei (DCN), which by rebound firing activates motor neurons generating the conditioned response (CR).
Fig 2.
Basic elements of a computational system that is able to reproduce the experimental results in delay eyeblink conditioning for the Purkinje cell. A first input goes through a decoupling mechanism and activates a clock. If the clock accumulated activation coincides with another signal a coincidence detector is activated. The coincidence detector exerts a positive feedback that acts on the clock. A negative feedback activated by the clock acts on the second signal, if it gets activated quick enough it deactivates the second input.
Fig 3.
Scheme of molecular interactions in the model.
The opening of IP3 receptors (IP3r) liberates calcium (Ca2+). Both calcium (Ca2+) and G alpha stimulatory protein (Gs) stimulate adenylyl cyclase in a synergistic manner. AC generates cAMP which activates PKA. PKA creates a positive feedback opening more IP3 receptors. Calcium also activates RGS proteins wich create a negative feedback through inhibition of Gs.
Fig 4.
One pairing of CS-US with 150 ms inter-stimul us interval.
Black arrow: parallel fiber input. Red arrow: climbing fiber input. (A) Calcium released for one CS-US pairing, (B) adenylyl cyclase evolution, and (C) PKA level, during the first pairing. (D) Calcium released during a second pairing.
Fig 5.
RGS protein learns to anticipate climbing fiber signal.
Response of the model to delay eyeblink conditioning with an interstimulus interval of 150 ms. Red dashed line indicates the arrival of the climbing fiber input. Time course of RGS protein activation depends on the number of previous pairings. After training with 11 pairings protein activation anticipates climbing fiber input.
Fig 6.
RGS protein anticipates CF signal for different time intervals.
(A) Dashed line indicates the arrival of the climbing fiber input for the different inter-stimulus intervals. Continuous line shows the activation of RGS protein activity for the different inter-stimulus interval after 70 CS-US pairings. (B) Required number of pairings to learn a timed response for the different inter-stimulus intervals.