Among the many issues surrounding the involvement of the cerebellum in motor learning, the relative roles of the cerebellar cortex and cerebellar nuclei in Pavlovian conditioning have been particularly difficult to assess. While previous studies have investigated the effects of cerebellar cortex lesions on the acquisition and retention of conditioned movements, we have examined the effects of these lesions on the timing of Pavlovian eyelid responses. The rationale for this approach arises from previous studies indicating that this timing is a component of Pavlovian eyelid responses that is learned and that involves temporal discrimination. To permit within-animal comparisons, rabbits were trained to produce differently timed responses to high- and low-frequency auditory conditioned stimuli (CSs). Before the lesion the conditioned responses to both CSs were appropriately timed--each peaked near the time at which the unconditioned stimulus was presented for that CS. However, after the lesion both CSs could elicit similarly timed conditioned responses that peaked inappropriately at very short latencies. The changes in responses timing were sensitive to the size of the lesion, particularly its rostral-caudal extent. Similar results were obtained in animals trained with one CS, indicating that the disruption of response timing is not related to impaired auditory discrimination. Because response timing is learned and therefore requires synaptic plasticity, these data suggest that there are at least two sites of plasticity involved in the motor expression of Pavlovian eyelid responses. Plasticity at one site is necessary for the learned timing of conditioned responses, while plasticity at another site is revealed by the inappropriately timed responses observed following removal of the cerebellar cortex. This lesion-induced dissociation of the expression of motor responses and their learned timing supports a synthesis of competing views by suggesting that motor learning involves both the cerebellar cortex and cerebellar nuclei. We hypothesize that motor learning involves a decrease in strength of the granule cell-Purkinje cell synapses (e.g., Ito and Kano, 1982) in the cerebellar cortex and an increase in strength of the mossy fiber-cerebellar nuclei synapses (e.g., Racine et al., 1986). Finally, these data suggest that the cerebellar cortex may mediate the temporal discriminations that are necessary for the learned timing of conditioned responses.

We test the hypothesis that the cerebellar cortex is required for the extinction of conditioned eyelid responses in rabbits trained using standard Pavlovian delay procedures. Following 10 daily training sessions during which rabbits achieved asymptotic performance, lesions of the ipsilateral hemisphere of the cerebellar cortex were made by aspiration. The target of these lesions was the anterior lobe, as suggested by previous observations that this region is necessary for the learning-dependent timing of conditioned eyelid responses (Perrett et al., 1993). We report that anterior lobe damage, as indicated by disrupted response timing and confirmed by tissue analysis, produces severe deficits in conditioned response extinction. Postlesion responses show no significant decline over ten training sessions, whereas response timing and extinction are unaffected by lesions that do not include the anterior lobe. These conditioned responses that do not extinguish display stimulus specificity, excluding the possibility that they are unlearned responses unmasked by cerebellar cortex lesions. These observations suggest that Pavlovian eyelid conditioning is mediated by synaptic plasticity in at least two sites and the anterior lobe of the cerebellar cortex influences one of these sites during extinction. Based on these and previous data, we propose the hypothesis that eyelid conditioning can involve plasticity in both the cerebellar cortex and interpositus nucleus and that plasticity in the nucleus is controlled by input from Purkinje cell activity in the cortex. This hypothesis is consistent with observations that the cerebellar cortex may not always be required for the expression of conditioned responses, but it is necessary for response timing and for extinction.

The neurotrophins (NTs) have recently been shown to elicit pronounced effects on quantal neurotransmitter release at both central and peripheral nervous system synapses. Due to their activitydependent release, as well as the subcellular localization of both protein and receptor, NTs are ideally suited to modify the strength of neuronal connections by "fine-tuning" synaptic activity through direct actions at presynaptic terminals. Here, using BDNF as a prototypical example, the authors provide an update of recent evidence demonstrating that NTs enhance quantal neurotransmitter release at synapses through presynaptic mechanisms. The authors further propose that a potential target for NT actions at presynaptic terminals is the mechanism by which terminals retrieve synaptic vesicles after exocytosis. Depending on the temporal demands placed on synapses during highfrequency synaptic transmission, synapses may use two alternative modes of synaptic vesicle retrieval, the conventional slow endosomal recycling or a faster rapid retrieval at the active zone, referred to as "kiss-and-run." By modulating Ca 2+ microdomains associated with voltage-gated Ca 2+ channels at active zones, NTs may elicit a switch from the slow to the fast mode of endocytosis of vesicles at presynaptic terminals during high-frequency synaptic transmission, allowing more reliable information transfer and neuronal signaling in the central nervous system. KeywordsBDNF; Docked vesicles; Fusion pore; Hippocampus; mEPSC; Poisson stimulation; Quantal release; SNARE proteins; Synaptic vesicles; TrkB; Voltage-gated Ca 2+ channels Experience-dependent changes in the efficacy of fast synaptic transmission are thought to be a mechanism by which an organism adapts and changes in response to interactions with its environment. How, where, and under what conditions these changes in synaptic strength occur has been under intense speculation for more than half a century. Since the development of Katz's seminal quantal theory of neurotransmitter release (Katz 1969), a host of molecules have been evaluated for their ability to modulate synaptic strength by enhancing quantal neurotransmitter release. Advances in our current knowledge and technology have permitted for more precise delineation of pre-and postsynaptic sites of action with regard to enhanced synaptic transmission, although these sites are not always mutually exclusive. Recently, neurotrophins (NT) have emerged as candidates to mediate those modulatory actions at synapses because of their pronounced effects on quantal neurotransmitter release in both the central and peripheral nervous system. The mammalian NTs, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin 4/5 (NT-4/5) have all been shown to be essential for neuronal viability and differentiation, as well as synaptic plasticity in various brain regions ). The implications of activity-dependent bidirectional release and signaling at synapses make NTs ideally suited to modify the strength...

One Hertz stimulation of afferents for 15 min with constant interstimulus intervals (regular stimulation) can induce longterm depression (LTD) of synaptic strength in the neocortex. However, it is unknown whether natural patterns of lowfrequency afferent spike activity induce LTD. Although neurons in the neocortex can fire at overall rates as low as 1 Hz, the intervals between spikes are irregular. This irregular spike activity (and thus, presumably, irregular activation of the synapses of that neuron onto postsynaptic targets) can be approximated by stimulation with Poisson-distributed interstimulus intervals (Poisson stimulation). Therefore, if low-frequency presynaptic spike activity in the intact neocortex is sufficient to induce a generalized LTD of synaptic transmission, then Poisson stimulation, which mimics this spike activity, should induce LTD in slices. We tested this hypothesis by comparing changes in the strength of synapses onto layer 2/3 pyramidal cells induced by regular and Poisson stimulation in slices from adult visual cortex. We find that regular stimulation induces LTD of excitatory synaptic transmission as assessed by field potentials and intracellular postsynaptic potentials (PSPs) with inhibition absent. However, Poisson stimulation does not induce a net LTD of excitatory synaptic transmission. When the PSP contained an inhibitory component, neither Poisson nor regular stimulation induced LTD. We propose that the short bursts of synaptic activity that occur during a Poisson train have potentiating effects that offset the induction of LTD that is favored with regular stimulation. Thus, natural (i.e., irregular) low-frequency activity in the adult neocortex in vivo should not consistently induce LTD.