1. Classical Conditioning

2. Associative Learning Nonassociative HabituationSensitization A single type of stimulus The relationship between two stimuli Classical conditioning Operant conditioning Extinction Blocking

3. Definitions An Unconditioned stimulus (US) is a stimulus which “naturally” elicits an (unconditioned) response (UR). For example: An airpuff to the eye is an unconditioned stimulus which elicits an eyeblink (nictitating membrane response). A conditioned stimulus (CS) is a “neutral” stimulus (e.g. a tone), which, by being associated with the US, leads after learning to a conditioned response (CR).

4. Basic paradigm Before learning,US -> UR CS -> nothing Training:CS+US -> UR CS -> increasing CR(=UR) Post-training:CS-> CR (=UR). Temporal relationship of CS,US: Simultaneous, delayed (partial overlap in time) or trace (separated in time). Usually strongest conditioning effects for ISI of 200ms-2s.

5. Circuitry for eyelid conditioning / nictitating membrane response

6. Single unit recording of complex spike responses of cerebellar Purkinje cells over the course of the behavioral training. The inferior olive’s ability to convey US to the cerebellum becomes functionally suppressed, as eyeblink conditioning occurs.

7. Blocking neuronal activity in cerebellar output Superior cerebellar peduncle blocked using perfusion of TTX Expression of eyeblink conditioning blocked, but not acquisition Krupa and Thompson, PNAS 1995

8. Cerebellar LTD and Learning-Dependent Timing of Conditioned Eyelid Responses S.K.E.Koekkoek,H.C.Hulscher,B.R.Dortland,R.A.Hensbroek, Y.Elgersma,T.J.H.Ruigrok,C.I.De Zeeuw* Science 2003 Inhibition of climbing fibers is a signal for the extinction of conditioned eyelid responses Medina, Nores and Mauk Nature 2002 Inhibitory Cerebello-olivary projections and blocking effect in classical conditioning. Kim, Krupa and Thompson Science 1998

9. CR-induced inhibition of the inferior olive activity is GABA-mediated US only CS-US With PTX

10. phase 1 : seven daily sessions of tone-airpuff conditioning. phase 2 : five sessions of tone-light-airpuff compound conditioning while either PTX or ACSF was infused. phase 3 : all animals were presented with light-airpuff pairing tests. controls experienced only the second phase of the blocking procedure. Blocking of conditioned eyelid responses

11. Both control and PTX animals exhibited significant learning to the light CS compared with the ACSF animals - blocking did not occur in the PTX group. PTX had no effect on the performance of CRs and URs during the compound conditioning, indicating that PTX selectively affected blocking. ACSF PTX CONTROL Phase 1 phase 2 phase 3

12. Infusion of picrotoxin into the inferior olive prevented extinction of conditioned responses Training: five daily sessions Extinction protocol with: no infusion ACSF PTX

13. Infusion of NBQX into the inferior olive caused extinction of conditioned responses Retraining: five daily sessions Tone plus unconditioned stimulus test sessions with: ACSF NBQX (AMPA receptor antagonist) Trial or time dependent influence?

14. olivepons PFCF PC’s LTD DCN CR Blocking: US inhibition USCS PTX: blocks inhibition prevents blocking prevents extinction Extinction: without US or with NBQX

15. The daily training consisted of 10 blocks of 10 trials. The trials were separated by a random intervals (20to 40 ms). The trials were separated by a random intervals (20 to 40 ms). Response of wild-type (wt) after 2 days and after 4 days. CR- conditioned response UR- unconditioned response

16. Wild-type: Conditioned responses (%)- 80 Average peak amplitude- 0.68 Average peak velocity- 32.6 mm/s LTD-deficient mice: Conditioned responses (%)- 30 Average peak amplitude- 0.44 Average peak velocity- 19.6 mm/s

17. Average CS-alone responses of a wild-type animal and a L7-PKCi mutant At T-4 (but not at T-2) the wt shows well-timed responses around the US onset time. The response peak of the mutant doesn’t change. At T-4 (but not at T-2) there are changes between wt and the mutant. Blue- wild type Red- mutants

18. Average CS-alone responses when the ISI is extended to 500 ms If the timing is LTD- dependent, the amplitude and velocity in the L7-PKCi mutant should not be influenced by the length of the ISI. indeed, the mutants ’ peak amplitude and peak velocity weren ’ t changed. In contrast, those wt values were changed. Blue- wild type Red- mutants

19. Red - pre-lesion Blue – post-lesion Green - post-sham lesion Mutants wt (After T-4) Conditioned responses still occur after lesions of the cerebellum in both mutants and wt, but the amplitudes were significantly reduced.