We have used aspiration and electrolytic lesions to investigate the contributions of cerebellar cortex to the acquisition and expression of conditioned eyelid responses. We show that lesions of the anterior lobe of rabbit cerebellar cortex disrupt the timing of previously learned conditioned eyelid responses. These short-latency responses were used as an indication that the cerebellar cortex was sufficiently damaged and that the underlying pathways necessary for the expression of responses were sufficiently intact to support responses. Rabbits were subsequently trained for 15 daily sessions using a new conditioned stimulus. Whereas rabbits in which lesions had no significant effect on response timing showed rapid acquisition of appropriately timed eyelid responses to the new conditioned stimulus, animals with lesions that disrupt timing showed no significant increases in either amplitude or probability of responses. Histological analysis suggests that damage to the anterior lobe of the cerebellar cortex is necessary and sufficient to abolish timing and prevent acquisition. These data indicate that the cerebellar cortex is necessary for the acquisition of conditioned eyelid responses and are consistent with the hypotheses that (1) eyelid conditioning results in plasticity in both the anterior lobe of the cerebellar cortex and in the anterior interpositus nucleus and (2) induction of plasticity in the interpositus requires intact input from the cerebellar cortex.

Although much is known about the induction of synaptic plasticity, the persistence of memories suggests the importance of understanding factors that maintain synaptic strength and prevent unwanted synaptic changes. Here we present evidence that recurrent inhibitory connections in the CA1 region of hippocampus may contribute to this task by modulating the relative ability to induce long-term potentiation and depression (LTP and LTD). Bath application of the gamma-aminobutyric acid (GABA) type A agonist muscimol to hippocampal slices increased the range of frequencies that produce LTD, whereas in the presence of the GABA type A antagonist picrotoxin LTD was induced only at very low stimulation frequencies (0.25-0.5 Hz). Because one source of GABAergic input to CA1 pyramidal cells is via recurrent inhibition, we tested the prediction that elevated postsynaptic spike activity would increase feedback GABA inhibition and favor the induction of LTD. By using an induction stimulation of 8 Hz, which alone produced no net change in synaptic strength, we found that stimulation presented during antidromic activation of pyramidal cell spikes induced LTD. This effect was blocked by picrotoxin. The influence of recurrent inhibition on LTP and LTD displays properties that may decrease the potential for self-reinforcing, runaway changes in synapse strength. A mechanism of this sort may help maintain patterns of synaptic strengths despite the ongoing opportunities for plasticity produced by synapse activation.

No abstract

No abstract

and Anatomy and behavioral analyses that can effectively exclude alterna-Keck Center for the Neurobiology tives. Attempts to demonstrate component specificity of Learning and Memory via histological analysis are less satisfying. While such University of Texas Medical School strategies can provide assurance about missing or dam-Houston, Texas 77030 aged tissue, they can less assuredly verify the physiological health of remaining tissue. As all slice physiologists know, healthy looking slices can display a complete Progress in neurobiology is often driven by advances absence of synaptic transmission. in technology, and it is hard to imagine an advance Targeted mutations appear to offer great promise for that has captured more attention than targeted genetic component specificity, but they suffer from the same mutations in mice (Chen and Tonegawa, 1997; Silva et difficulties. On the plus side, there is generally only one al., 1997). In principle the concept is simple: study the gene that differs between wild-type and mutant mice. contributions of a molecule to behavior by eliminating its Moreover, the growing list of known cell-specific progene, or by introducing a gene whose product interferes moters means that the primary effects of mutations can with the molecule in some way (see Capecchi, 1989, increasingly be limited to a single cell type. However, 1994; Zimmer, 1992). But systems-level neuroscientists mutations are not only subject to criticisms related to know that using molecular or anatomical lesions of the possible compensatory changes, but also to concerns brain is a tricky business. It is, after all, studying the brain regarding developmental abnormalities. Thus, as with by breaking its parts. Now that the dust from the initial conventional lesions, it may be tempting to conclude stampede may be settling somewhat, it seems useful that the absence of a molecule is directly responsible to take a close look at gene targeting as a tool for studyfor observed behavioral deficits, but such conclusions ing the neural basis of behavior, particularly the mechaare almost always relatively unsatisfying. nisms of learning and memory. We will consider the Mutations Versus a Mutation Approach strengths and weaknesses of genetic mutations relativeIn sum, component specificity is fundamentally importo older and less exotic methods, and we will suggest tant, but a number of factors conspire to make it exfeatures that could make the use of mutations even tremely difficult to achieve and to verify. Yet there are more effective for the study of neural system function.many examples in which neural components mediating Behaviors are generated by collections of neural comparticular behaviors have been identified using brain ponents (cells, synapses, etc.) interacting in ways that lesions. The resolution of this apparent contradiction constitute a system with certain input/output properties.stems from the distinction between the limitations of As such, identifying the list of essential components is each single lesion experiment...