Research reportCholinergic modulation of neocortical long-term potentiation in the awake, freely moving rat
Introduction
There is considerable evidence that the cholinergic system plays an important role in learning and memory processes (for review, see [17]). The cognitive deficits associated with Alzheimer’s disease [12], [16], [34] and normal aging [15], for example, may be mediated by a reduction in cholinergic functioning. Also, it has been established in rodents that cholinergic antagonism [14], [25], [43] and agonism [18], [35], [41] attenuate and facilitate, respectively, learning in a variety of tasks. Studies using human and non-human primates have produced similar results [1], [11], [13], [21].
The model that is most widely used to study the physiology of memory is long-term synaptic potentiation (LTP) (see [4] for review). Properties such as longevity and associativity make it an attractive memory model, and it has also been shown in structures, such as the hippocampus, that are known to be involved in learning and memory.
Recently, we have successfully demonstrated an NMDA-dependent LTP in the neocortex of awake, freely moving rats using induction parameters that mimic conditions considered optimal for the construction of non-declarative memories (i.e. spaced and repeated stimulation sessions) [37], [42]. This form of LTP does not reach asymptotic levels for 7–12 days [37], [42]. These results are consistent with those from memory experiments, where the acquisition of nondeclarative information into presumed cortical stores has been found to be a slow process [31]. These properties of LTP raise questions about the suitability of the cortical slice model for studying neocortical LTP. It is not yet clear that the LTP induced in the slice (e.g. [23]) is the same phenomenon as that monitored over weeks and months in the awake animal.
LTP, like memory, has been shown to be affected by cholinergic manipulations, but these experiments were done in in vitro preparations. Cholinergic agonists, for example, enhance LTP induction in both the CAl [5] and dentate gyrus [7] regions of the hippocampus as well as in the visual cortex [6]. The facilitatory action of acetylcholine on the induction of LTP is most likely the result of enhanced postsynaptic depolarization, increasing the probability, or extent, of NMDA receptor activation [9], [32]. Even cholinergic agents by themselves have been shown to produce a long-term enhancement of responses in the hippocampus [3] or sensorimotor cortex [27]. In the hippocampus, this cholinergically-induced LTP has been shown to occlude subsequent LTP induction by electrical stimulation [3], suggesting that these two forms of LTP share a common substrate.
Previously in our hands, cholinergic stimulation has been shown to promote a long-term depression effect in the neocortex of freely moving animals following single-session stimulation protocols [37], [38]. The following experiments were undertaken to characterize the role of cholinergic neuromodulation in the induction of neocortical LTP induced by the spaced and repeated stimulation protocol. Based on the LTP slice literature and behavioural data, we predicted that the cholinergic agonist pilocarpine would enhance LTP induction, while the antagonist scopolamine would attenuate LTP induction. Portions of this research have been presented previously in abstract form [39].
Section snippets
Animals and surgery
Fifty-five male Long-Evans hooded rats from the McMaster University Breeding Colonies were used in these experiments. At the time of surgery, the animals weighed 300–400 g.They were housed individually, maintained on an ad libitum feeding schedule, and kept on a 12 h on/12 h off light cycle.
Twisted wire bipolar electrodes were prepared from Teflon-coated, stainless-steel wire (120 μm in diameter). The vertical tip separation for the recording electrode was 1.0 mm, to span the dipole. The tip
Response morphology
The responses were similar to those previously reported (Fig. 1) [8], [42]. There was a very short-latency surface positive spike-like response, which previous experiments have shown to be a mix of antidromic and orthodromic effects [8]. This is followed by an early response component with a mean latency-to-peak of 7.8 ms (range: 5.0–12.0 ms) and a mean amplitude of 1.5±0.09 mV. There is usually one strong late peak in the post-LTP record representing polysynaptic activity. At the latency at
Discussion
Previous attempts to induce neocortical long-term potentiation by pairing tetanic stimulation with cholinergic activation in freely moving rats have produced depression effects that lasted several weeks [37], [38]. These studies, however, did not use multiple, spaced stimulation sessions to induce LTP. The present data are the first to describe the modulatory influence of cholinergic agonists and antagonists on the induction parameters of neocortical LTP using our multiple-session paradigm in
Acknowledgements
We thank Mathew W. Loveless for assistance with data collection. This work was supported by a grant from the Natural Sciences and Engineering Research Council of Canada (NSERC) to RJR, an NSERC Postgraduate Scholarship to CT and a Clifton W. Sherman Graduate Scholarship for Doctoral Study in Science and Engineering to TEB.
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Current address: W.M. Keck Foundation Center for Integrative Neuroscience and Department of Physiology, Box 0444, University of California, 513 Parnassus Avenue, San Francisco, CA, 94143.