Pharmacological data clearly indicate that both muscarinic and nicotinic acetylcholine receptors have a role in the encoding of new memories. Localized lesions and antagonist infusions demonstrate the anatomical locus of these cholinergic effects, and computational modeling links the function of cholinergic modulation to specific cellular effects within these regions. Acetylcholine has been shown to increase the strength of afferent input relative to feedback, to contribute to theta rhythm oscillations, activate intrinsic mechanisms for persistent spiking, and increase the modification of synapses. These effects might enhance different types of encoding in different cortical structures. In particular, the effects in entorhinal and perirhinal cortex and hippocampus might be important for encoding new episodic memories.

The theta rhythm appears in the rat hippocampal electroencephalogram during exploration and shows phase locking to stimulus acquisition. Lesions that block theta rhythm impair performance in tasks requiring reversal of prior learning, including reversal in a T-maze, where associations between one arm location and food reward need to be extinguished in favor of associations between the opposite arm location and food reward. Here, a hippocampal model shows how theta rhythm could be important for reversal in this task by providing separate functional phases during each 100-300 msec cycle, consistent with physiological data. In the model, effective encoding of new associations occurs in the phase when synaptic input from entorhinal cortex is strong and long-term potentiation (LTP) of excitatory connections arising from hippocampal region CA3 is strong, but synaptic currents arising from region CA3 input are weak (to prevent interference from prior learned associations). Retrieval of old associations occurs in the phase when entorhinal input is weak and synaptic input from region CA3 is strong, but when depotentiation occurs at synapses from CA3 (to allow extinction of prior learned associations that do not match current input). These phasic changes require that LTP at synapses arising from region CA3 should be strongest at the phase when synaptic transmission at these synapses is weakest. Consistent with these requirements, our recent data show that synaptic transmission in stratum radiatum is weakest at the positive peak of local theta, which is when previous data show that induction of LTP is strongest in this layer.

Working memory represents the ability of the brain to hold externally or internally driven information for relatively short periods of time. Persistent neuronal activity is the elementary process underlying working memory but its cellular basis remains unknown. The most widely accepted hypothesis is that persistent activity is based on synaptic reverberations in recurrent circuits. The entorhinal cortex in the parahippocampal region is crucially involved in the acquisition, consolidation and retrieval of long-term memory traces for which working memory operations are essential. Here we show that individual neurons from layer V of the entorhinal cortex-which link the hippocampus to extensive cortical regions-respond to consecutive stimuli with graded changes in firing frequency that remain stable after each stimulus presentation. In addition, the sustained levels of firing frequency can be either increased or decreased in an input-specific manner. This firing behaviour displays robustness to distractors; it is linked to cholinergic muscarinic receptor activation, and relies on activity-dependent changes of a Ca2+-sensitive cationic current. Such an intrinsic neuronal ability to generate graded persistent activity constitutes an elementary mechanism for working memory.

As indicated by the profound cognitive impairments caused by cholinergic receptor antagonists, cholinergic neurotransmission plays a vital role in cognitive function, specifically attention and memory encoding. Abnormally regulated cholinergic neurotransmission has been hypothesized to contribute to the cognitive symptoms of neuropsychiatric disorders. Loss of cholinergic neurons enhances the severity of the symptoms of dementia. Cholinergic receptor agonists and acetylcholinesterase inhibitors have been investigated for the treatment of cognitive dysfunction. Evidence from experiments using new techniques for measuring rapid changes in cholinergic neurotransmission provides a novel perspective on the cholinergic regulation of cognitive processes. This evidence indicates that changes in cholinergic modulation on a timescale of seconds is triggered by sensory input cues and serves to facilitate cue detection and attentional performance. Furthermore, evidence indicates cholinergic induction of evoked intrinsic, persistent spiking mechanisms for active maintenance of sensory input and planned responses. Models have been developed to describe the neuronal mechanisms underlying the transient modulation of cortical target circuits by cholinergic activity. These models postulate specific locations and roles of nicotinic and muscarinic acetylcholine receptors and that cholinergic neurotransmission is controlled in part by (cortical) target circuits. The available evidence and these models point to new principles governing the development of the next generation of cholinergic treatments for cognitive disorders.

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SummaryIntracellular recording shows how differences in single cell subthreshold oscillation frequency could directly underlie the differences in spacing of grid cell firing locations shown previously in awake, behaving animals.Grid cells in layer II of entorhinal cortex fire to spatial locations in a repeating hexagonal grid with smaller spacing between grid fields for neurons in more dorsal anatomical locations. Data from in vitro whole-cell patch recordings show a corresponding difference in frequency of subthreshold membrane potential oscillations in entorhinal neurons at different positions along the dorsal to ventral axis, supporting a model of physiological mechanism for grid cell responses.The entorhinal cortex plays an important role in encoding of spatial information (1-3) and episodic memory (4). Many layer II neurons of rat entorhinal cortex are "grid cells," firing when the rat is in an array of spatial locations forming a hexagonal grid within the environment (5-7). The spacing of firing fields in the grid varies with anatomical position of the cell along the dorsal to ventral axis of entorhinal cortex, as measured by distance from the postrhinal border (5). Neurons closer to the dorsal border of entorhinal cortex have shorter distances between firing fields. Computational models explicitly predict that differences in grid field spacing should correspond to differences in intrinsic frequencies of neurons along the dorsal to ventral axis (3,8). This could provide systematic variation in the gain of a movement-speed signal for path integration (2,3,9).Subthreshold membrane potential oscillations in entorhinal cortical stellate cells (10) arise from a single-cell mechanism involving voltage-sensitive currents (11-13) and could contribute to network dynamics (14). We recorded subthreshold oscillations from 57 stellate cells in layer II of medial entorhinal cortex (Fig. S1) in slices from different anatomical positions along the dorsal to ventral axis, using whole-cell patch clamp techniques (15). The position of individual horizontal slices was measured relative to the dorsal surface of the brain (Fig. 1A).Stellate cells in dorsal entorhinal cortex show higher temporal frequencies of subthreshold membrane potential oscillations compared to lower frequencies in cells from more ventral entorhinal slices (Fig. 1B). Dorsal cells (n = 30) are defined as cells recorded in slices taken between 3.8 mm (the border with postrhinal cortex (16)) and 4.9 mm from the dorsal surface of the brain. Ventral cells (n = 27) are defined as cells recorded in slices between 4.9 and 7.1 mm from the dorsal surface. Fig. 1B shows the group means of the frequency of subthreshold oscillations recorded from these populations. Because frequency of subthreshold oscillations can depend upon the mean membrane potential voltage, we performed this analysis separately for data gathered at different approximate holding membrane potentials of −50 mV and −45 mV. The mean frequency in dorsal cells was significantly higher than the mean frequ...

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SUMMARY Recent studies have reported the existence of hippocampal “time cells,” neurons that fire at particular moments during periods when behavior and location are relatively constant. However, an alternative explanation of apparent time coding is that hippocampal neurons “path integrate” to encode the distance an animal has traveled. Here, we examined hippocampal neuronal firing patterns as rats ran in place on a treadmill, thus “clamping” behavior and location, while we varied the treadmill speed to distinguish time elapsed from distance traveled. Hippocampal neurons were strongly influenced by time and distance, and less so by minor variations in location. Furthermore, the activity of different neurons reflected integration over time and distance to varying extents, with most neurons strongly influenced by both factors and some significantly influenced by only time or distance. Thus, hippocampal neuronal networks captured both the organization of time and distance in a situation where these dimensions dominated an ongoing experience.