Cholinergic modulation of neocortical long-term potentiation in the awake, freely moving rat

Abstract

The neocortex has proven resistant to LTP induction using standard in vitro and acute, in vivo preparations. Because the neocortex is widely thought to be involved in long-term information storage, this resistance raises questions about the validity of LTP as a memory model. Recently, we have shown that the neocortex of freely moving rats reliably supports LTP, provided that the stimulation is spaced and repeated over days. The following experiments were designed to evaluate the neuromodulatory role played by cholinergic systems in the induction of LTP in this preparation. Chronically implanted rats received either low- or high-intensity LTP-inducing tetani in combination with the administration of either a cholinergic agonist or antagonist injected systemically. Potentiation was evidenced as amplitude changes in both early and late components of the evoked field potential, the former including population spikes. The cholinergic agonist facilitated LTP induction in the late component of both high- and low-intensity groups. The cholinergic antagonist blocked LTP induction in the early component of the high-intensity group. The possibility that there are component-specific modulatory effects of cholinergic agents on the induction of neocortical LTP is discussed.

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].