Spike timing in CA3 pyramidal cells during behavior: implications for synaptic transmission.

Spike timing is thought to be an important mechanism for transmitting information in the CNS. Recent studies have emphasized millisecond precision in spike timing to allow temporal summation of rapid synaptic signals. However, spike timing over slower time scales could also be important, through mechanisms including activity-dependent synaptic plasticity or temporal summation of slow postsynaptic potentials (PSPs) such as those mediated by kainate receptors. To determine the extent to which these slower mechanisms contribute to information processing, it is first necessary to understand the properties of behaviorally relevant spike timing over this slow time scale. In this study, we examine the activity of CA3 pyramidal cells during the performance of a complex behavioral task in rats. Sustained firing rates vary over a wide range, and the firing rate of a cell is poorly correlated with the behavioral cues to which the cell responds. Nonrandom interactions between successive spikes can last for several seconds, but the nonrandom distribution of interspike intervals (ISIs) can account for the majority of nonrandom multi-spike patterns. During a stimulus, cellular responses are temporally complex, causing a shift in spike timing that favors intermediate ISIs over short and long ISIs. Response discrimination between related stimuli occurs through changes in both response time-course and response intensity. Precise synchrony between cells is limited, but loosely correlated firing between cells is common. This study indicates that spike timing is regulated over long time scales and suggests that slow synaptic mechanisms could play a substantial role in information processing in the CNS.

Recognition memory correlates of hippocampal theta cells.

Investigations of hippocampal theta cell activity have typically involved behavioral tasks with modest cognitive demands. Recordings in rats locomoting through space or engaged in simple stimulus discrimination or conditioning have revealed some place specificity and S(+)/S(-) selectivity in addition to the hippocampal EEG theta-related behavioral/motor correlates. However, little data exist regarding theta cell activity during performance of more cognitively demanding, hippocampal-dependent recognition memory tasks. Here, we examined the cognitive firing correlates of theta cells in rats that were performing an olfactory recognition memory task with distinct sample and test phases. Discriminant analysis revealed odor and match/nonmatch memory correlates in theta cell activity comparable in relative magnitude to that of the principal cells. Odor-specific theta cell responses in the sample phase were restricted primarily to CA1 and linked to task performance. In the test recognition phase, match/nonmatch theta cells were found primarily in the CA3 and CA1 fields, most of which exhibited greater activity on correct nonmatch trials in which recognition occurred than on error match trials in which recognition failed. Odor selectivity of the match/nonmatch signaling was greatest in the dentate gyrus (DG) and CA3 and least in CA1. This inverted pattern of stimulus specificity in the sample versus test phase was similar to that observed in principal cells but with a greater contrast between the CA1 and DG/CA3 fields. Together, these findings suggest that theta cells actively participate in hippocampal recognition memory processing and play a specific role in shaping the cognitive firing properties of the hippocampal principal cells.

Dynamic filtering of recognition memory codes in the hippocampus.

Principal cells of the dentate gyrus (DG), CA3, and CA1 subfields of the hippocampus were recorded in rat during performance of an odor-guided delayed nonmatch-to-sample task with distinct sample and test phases. The hippocampus was found to possess multiple encoding modes. In the sample phase, odor-selective activity was restricted primarily to CA1 and, to a lesser extent, CA3. Odor representations in half of these cells were predictive of subsequent performance (i. e., correct vs error) in the test phase. Cells in each hippocampal subfield maintained elevated or suppressed activity in the delay interval relative to pre-odor baseline, but were indiscriminate with regard to sample odor identity. In the test phase, the regional distribution of odor-selective activity was inverse to that for the sample: maximal in DG and minimal in CA1. The inverted distribution of odor selectivity was also observed for cells that discriminated match/nonmatch trial types. Most match/nonmatch cells exhibited greater activity on correct nonmatch than error match trials, indicating the presence of a hippocampal recognition memory signal on trials where recognition occurred and its absence on trials where recognition failed. These findings reveal the hippocampus as a highly dynamic encoding device, restricting perceptual stimulus information to different subfields (or none, in the delay phase) depending on memory task contingencies. Moreover, the reduction in cue-specificity of match/nonmatch comparison signals as they pass through the hippocampal trisynaptic circuit may contribute to a generalized recognition signal for use in guiding behavior.

Short-term reverberant memory model of hippocampal field CA3.

Synaptic plasticity mechanisms for associative learning require near-simultaneous pairs of inputs to target cells. Sensory cues encountered behaviorally, however, are typically staggered in time, implying the need for active short-term memory traces of antecedent cues. The dense recurrent connectivity within regions of hippocampal field CA3 is suggestive of the kind of re-entrant network that could subserve this kind of "holding" memory. Consequently, we have investigated whether an abstract model of this region incorporating its major anatomical and physiological features could function as a reverberatory memory network. The continuous-time model describes the behavior of highly connected groups of CA3 pyramidal cells, or "patches," in response to brief, rhythmic, sensory stimulation. Time constants for excitatory and inhibitory postsynaptic potentials and axonal transmission delays for local and distal connections were estimated from empirical data. When the inhibitory units in these patches were connected to an oscillator intended to model the theta wave activity of the medial septum, the network entered reverberatory states and maintained second-long memory traces of the cortical input, after which it lost its coherent behavior. Noise analysis indicated that the network's operation was moderately resistant to random fluctuations proportional to patch activity. These results suggest that field CA3 could function as a holding memory that assists the integration of disjoint stimuli found in innumerable associative tasks, and that the duration of its coherent operation might determine the temporal limits in their performance.

Distinct memory circuits composing the hippocampal region.

The very different anatomical designs of the adjacent circuitries of the cortico-hippocampal pathway, along with their somewhat different synaptic plasticity mechanisms, suggest a nearly serial pathway of distinct memory circuits each contributing its own specialized processing operation to overall hippocampal function. Modeling and formal theoretical analysis of the prominent anatomical design features of particular circuits (piriform/entorhinal cortex; hippocampal field CA3; hippocampal field CA1) are found to identify potential emergent function not readily arrived at in the absence of these formal models, and yet which once derived can be seen potentially to confer unique capabilities to an integrated hippocampal mechanism for processing memories during behavior.