A specific role for septohippocampal acetylcholine in memory?

Abstract

Acetylcholine has long been implicated in memory, including hippocampal-dependent memory, but the specific role for this neurotransmitter is difficult to identify in human neuropsychology. Here, we review the evidence for a mechanistic model of acetylcholine function within the hippocampus and consider its explanatory power for interpreting effects resulting from both pharmacological anticholinergic manipulations and lesions of the cholinergic input to the hippocampus in animals. We argue that these effects indicate that acetylcholine is necessary for some, but not all, hippocampal-dependent processes. We review recent evidence from lesion, pharmacological and electrophysiological studies to support the view that a primary function of septohippocampal acetylcholine is to reduce interference in the learning process by adaptively timing and separating encoding and retrieval processes. We reinterpret cholinergic-lesion based deficits according to this view and propose that acetylcholine reduces the interference elicited by the movement of salient locations between events.

Fig. 1

Selective suppression of intrinsic hippocampal connectivity by acetylcholine. ACh has different effects upon the two main excitatory inputs to CA1: entorhinal cortex layer 3 (extrinsic input) and CA3 (intrinsic input). ACh strongly presynaptically inhibits synaptic transmission in CA1 stratum radiatum (CA3 to CA1 synapses), and CA3 recurrent collaterals (CA3–CA3 synapses), while relatively sparing transmission in CA1 lacunosum-moleculare layer (entorhinal–CA1 synapses). Thus, acetylcholine protects to-be-encoded input patterns from the proactive interference arising from read-out of CA3. Based on data reviewed in Hasselmo (2012).

Fig. 2

Separation of encoding and retrieval by the phase of theta. Left column: (a) Encoding takes place at the peak of CA1 pyramidal layer theta. (b) At this theta phase (vertical dashed line), the synaptic transmission from entorhinal cortex layer 3 (EC3) to CA1 is strong, while transmission from CA3 to CA1 is weak. (c) The thickness of the arrows indicates the strength of excitatory synaptic transmission, with thick (thin) arrows representing strong (weak) synaptic transmission. This differential strength of the EC3 and CA3 synaptic transmission to CA1 allows the EC3 input patterns to be protected against interference from previously learned associations provided by CA3 input. The entorhinal input drives encoding of novel associations in the CA3–CA1 synapses, which undergo long-term potentiation, because they are active at the peak of theta. Right column: (a) Retrieval occurs at the trough of CA1 pyramidal layer theta. (b) and (c) At this phase, synaptic transmission from EC3 is weak (but sufficient to cue retrieval), while transmission from CA3 is strong. This permits efficient retrieval of previously learned associations. No encoding involving the retrieved patterns takes place in the CA3–CA1 synapses because synapses active at the theta trough phase do not undergo long-term potentiation or undergo long-term depression. Green dashed frame indicates site of action of ACh presynaptic inhibition effects. ACh mediates transitions between encoding and retrieval on a longer timescale than theta cycle transitions by suppressing hippocampal intrinsic connectivity (see Fig. 1). High cholinergic levels in CA1 favour encoding by reducing selectively the intrinsic input from CA3, while relatively sparing the extrinsic input from EC3. In sum, encoding and retrieval dynamics are set by both theta phase and acetylcholine. Adapted from Hasselmo et al. (2012).

Fig. 3

Supporting evidence for the encoding versus retrieval scheduling by theta phase and acetylcholine. (a) Maximal firing of pyramidal cells in CA3 and EC3 occurs around the trough and the peak of CA1 pyramidal layer theta, respectively. Theta obtained from rats running in a familiar environment. The peak of CA1 pyramidal cells firing is after the trough, at a phase approximately intermediate between the CA3 and EC3 peak firing. (b) Theta–gamma coupling in CA1 is modulated by the phase of theta. The strongest theta and middle-gamma coupling (EC3–CA1 communication) is observed at the peak of CA1 pyramidal layer theta, coincident with the phase at which EC3 cell firing is maximal (see (a)) above). The coupling between theta and the low gamma is maximal in the descending phase of theta (exact value shown is provisional), potentially close to the peak firing in CA3. (c) Bidirectional modulation of CA1 pyramidal cells main theta phase of firing by novelty and scopolamine during a foraging task. In a highly familiar environment, the main theta phase of firing is slightly after the trough of CA1 pyramidal layer theta (consistent with (a)). In a novel environment, when encoding is expected to prevail, the mean phase of firing is later, closer to the pyramidal layer theta peak and to the phase of EC3–CA1 communication. In novelty, CA1 activity reflects a greater driving by its EC3 inputs, consistent with encoding novel environmental information. Scopolamine (an amnestic cholinergic antagonist), when systemically injected in the familiar environment, induces an opposite effect to that of novelty: the preferred theta phase of firing is now earlier, towards the theta trough. This shift towards the theta trough likely reflects a greater driving by CA3, and thus a bias towards retrieval and pattern completion. Scopolamine blocks the shift to a later phase normally elicited by environmental novelty (not shown), in line with the encoding impairment induced by this drug. Parts (a)–(c) based on data as follows: (a) Mizuseki et al. (2009), (b) Colgin et al. (2009), and Scheffer-Teixeira et al. (2011), (c) Douchamps et al. (2011).

Fig. 4

Outline of procedure for what-where-which and where-which tasks. Both the what-where-which (left) and where-which (right) tasks (Easton et al., 2011) involve two exposure events and a later test. The combination of two exposure events and a test comprise a trial, and objects are trial unique (though for simplicity only one set of objects is indicated in the figure). Novel combinations are indicated by ‘+’ and represent configurations of objects, locations and contexts (what-where-which; left) and locations and context (where-which; right) that have not been seen in either exposure event. The trials are counterbalanced between animals on each trial and across trials for each animal. For simplicity only one of the counterbalanced schedules is shown in the figure. Animals are always released in the centre of the arena (1 m×1 m) facing the 12 o’clock position. Each exposure event and test is 2 min long, allowing animals to explore the objects. Exploration at test is recorded and comparative exploration of the novel versus the familiar combination is used as a measure of the animal’s memory.