The objective of the project is to develop a biomimetic, biohybrid model that can demonstrate the recovery of a learning response that is lost due to aging processes. The neuronal system chosen for this project is the cerebellar microcircuit involved in conditioning of the motor eyeblink response. Experiments are carried out with two different types of stimuli; a tone which serves a conditioned stimulus producing no naïve response and an aversive puff to the eye (unconditioned stimulus) resulting in a naïve eyeblink response. The tone always precedes the airpuff in the course of the experiment.

In order to protect their eyes young rats learn to close the eyes just before the airpuff arrives.

In old rats aging invariably compromises the acquisition and retention of this eyeblink response. To rehabilitate this learning function a biomimetic chip will be implanted in the old rat’s brain in order to interface with the cerebellum to bypass the damaged microcircuit.

The experimental environment as well as the presentation of the stimuli is controlled by the biosignal amplifier (g.USBamp) which is also used to record the neuronal activity. The presentation of the stimuli leads to an increase in activity at specific locations in the brain which can be extracted from the background neuronal activity. These signals interface with the cerebellar model on the silicon chip and initiate cerebellar learning.

The output from this biomimetic chip will then trigger the eyeblink response by way of implanted stimulation electrodes. Complete success would be achieved through real-time demonstration of functional recovery of the lost motor learning response in aged rats.

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Figure 1: Cerebellar model The picture shows a simplified model of a part of the cerebellum, responsible for conditioning of the motor eyeblink response. Conditioned Stimulus (CS) and Unconditioned Stimulus (US) groups symbolize the stimuli presented to the animal. Through the parallel fibers (pf) and climbing fibers (cf) respectively, the activity is then sent to the Inhibitory neurons and to the Purkinje SYN neurons that represent the trace of the CS (a prolonged action lasting for all the Inter Stimulus Interval (Time between the onset of the two stimuli) duration). "I" inhibits the spontaneuos activity of the Purkinje Cell (PU-SP group) so the model switches to the CS mode and the activity is driven by PU-SYN. The co-occurrence of the US (from climbing fiber cf) with the CS induces LTD (Long Term Depression, means that the weight of the synapse decreases) in the PU-SYN PU-SO synapse. LTD leads to a pause in the PU-SO that allows the Deep Nucleus (DN, output of the cerebellum) to fire. When the DN fires a CR (Conditioned Response) is created and serves as a trigger impulse for the eye blink. DN then inhibits 'cf' stopping the occurrence of the US to PU-SO and as a consequence stopping LTD. In this way CS-US does not co-occur and the system undergoes LTP (Long Term Potentiation, weight of the synapse increases again) in order to maintain an equilibrium.

Movie to download

The movie shows how the cerebellar model enables to man to learn to blink with the eyes after the signal tone. The two stimuli involved in this learning process are a conditioned stimulus (tone signal), symbolized by the left picture on the top and an unconditioned stimulus (windpuff, picture right next to the tone). Every time after playing the signal tone, the windpuff is blown in the face of the subject. The first three times he heard the signal tone and perceived the windpuff after the tone without closing the eyes because he hadn’t learned the correct response yet. During this time the onset information of the stimuli (time the stimuli appear) is sent to the model of the cerebellum where “learning” (conditioning) takes place. The model “recognizes” that the tone always precedes the windpuff and “learns” to create an response to eventually avoid the puff (because it hurts). After the fourth signal tone a trigger response is created by the cerebellar model and the man blinks with his eyes thereby avoiding the windpuff (picture disappears). The left picture below show the neuronal activity in the brain areas sensitive for the signal tone and the windpuff (top 2 channels), the onset information of the stimuli sent to the cerebellar model (3rd channel) and the cerebellar response (4th channel) (WMV 3,8 MByte).

Performed with Prof. Matti Mintz (Tel Aviv University, Israel) and Prof. Paul Verschure (Universitat Pompeu Fabra, Spanien).