The hippocampus exhibits a variety of distinct states of activity under different conditions. For instance the rhythmic patterns of activity orchestrated by the theta oscillation during running and REM sleep are markedly different from the large irregular activity (LIA) observed during awake resting and slow wave sleep. We found that under different levels of isoflurane anesthesia activity in the hippocampus of rats displays two distinct states which have several qualities that mirror the theta and LIA states. These data provide further evidence that the two states are intrinsic modes of the hippocampus; while also characterizing a preparation that could be useful for studying the natural activity states in hippocampus. This article is protected by copyright. All rights reserved.

Analogous to learning and memory storage, long-term potentiation (LTP) is divided into induction and maintenance phases. Testing the hypothesis that the mechanism of LTP maintenance stores information requires reversing this mechanism in vivo and finding out whether long-term stored information is lost. This was not previously possible. Recently however, persistent phosphorylation by the atypical protein kinase C isoform, protein kinase Mzeta (PKMz), has been found to maintain late LTP in hippocampal slices. Here we show that a cell-permeable PKMz inhibitor, injected in the rat hippocampus, both reverses LTP maintenance in vivo and produces persistent loss of 1-day-old spatial information. Thus, the mechanism maintaining LTP sustains spatial memory.

Hippocampal place field sequences are supported by sensory cues and network internal mechanisms. In contrast, sharp-wave (SPW) sequences, theta sequences and episode-field sequences are internally generated. The relationship of these sequences to memory is unclear. SPW sequences have been shown to support learning and have been assumed to also support episodic memory. Conversely, we demonstrate these SPW sequences were present even after episodic memory in trained rats was impaired and after other internal sequences - episode-field and theta sequences - were eliminated. SPW sequences did not support memory despite continuing to 'replay' all task-related sequences - place-field and episode-field sequences. Sequence replay occurred selectively during a synchronous increase of population excitability -- SPWs. Similarly, theta sequences depended on the presence of repeated synchronized waves of excitability - theta oscillations. Thus, we suggest that either intermittent or rhythmic synchronized changes of excitability trigger sequential firing of neurons, which in turn supports learning and/or memory.

Driven either by external landmarks or by internal dynamics, hippocampal neurons form sequences of cell assemblies. The coordinated firing of these active cells is organized by the prominent "theta" oscillations in the local field potential (LFP): place cells discharge at progressively earlier theta phases as the rat crosses the respective place field ("phase precession"). The faster oscillation frequency of active neurons and the slower theta LFP, underlying phase precession, creates a paradox. How can faster oscillating neurons comprise a slower population oscillation, as reflected by the LFP? We built a mathematical model that allowed us to calculate the population activity analytically from experimentally derived parameters of the single neuron oscillation frequency, firing field size (duration), and the relationship between within-theta delays of place cell pairs and their distance representations ("compression"). The appropriate combination of these parameters generated a constant frequency population rhythm along the septo-temporal axis of the hippocampus, while allowing individual neurons to vary their oscillation frequency and field size. Our results suggest that the faster-than-theta oscillations of pyramidal cells are inherent and that phase precession is a result of the coordinated activity of temporally shifted cell assemblies, relative to the population activity, reflected by the LFP.

The hippocampus is critical for navigation in an open field. One component of this navigation requires the subject to recognize the target place using distal cues. The experiments presented in this report tested whether blocking hippocampal function would impair open field place recognition. Hungry rats were trained to press a lever on a feeder for food. In Experiment 1, they were passively transported with the feeder along a circular trajectory. Lever pressing was reinforced only if the feeder was passing through a 60 degrees -wide sector. Thus, rats preferentially lever pressed in the vicinity of the reward sector indicating that they recognized its location. Tetrodotoxin (TTX) infusions aimed at the dorsal hippocampi caused rats to substantially increase lever pressing with no preference for any region. The aim of Experiment 2 was to determine whether the TTX injections caused a loss of place recognition or a general increase of lever pressing. A separate group of rats was conditioned in a stationary apparatus to press the lever in response to a light. The TTX injections did not abolish preferential lever pressing in response to light. Lever pressing increased less than half as much as the TTX-induced increase in Experiment 1. When these animals with functional hippocampi could not determine the rewarded period because the light was always off, lever pressing increased much more and was similar to the TTX-induced increase in Experiment 1. We conclude that the TTX inactivation of the hippocampi impaired the ability to recognize the reward place.

Theta oscillations are believed to play an important role in the coordination of neuronal firing in the entorhinal (EC)-hippocampal system but the underlying mechanisms are not known. We simultaneously recorded from neurons in multiple regions of the EC-hippocampal loop and examined their temporal relationships. Theta-coordinated synchronous spiking of EC neuronal populations predicted the timing of current sinks in target layers in the hippocampus. However, the temporal delays between population activities in successive anatomical stages were longer (typically by a half theta cycle) than expected from axon conduction velocities and passive synaptic integration of feed-forward excitatory inputs. We hypothesize that the temporal windows set by the theta cycles allow for local circuit interactions and thus a considerable degree of computational independence in subdivisions of the EC-hippocampal loop.

Sensory cue inputs and memory-related internal brain activities govern the firing of hippocampal neurons, but which specific firing patterns are induced by either of the two processes remains unclear. We found that sensory cues guided the firing of neurons in rats on a timescale of seconds and supported the formation of spatial firing fields. Independently of the sensory inputs, the memory-related network activity coordinated the firing of neurons not only on a second-long timescale, but also on a millisecond-long timescale, and was dependent on medial septum inputs. We propose a network mechanism that might coordinate this internally generated firing. Overall, we suggest that two independent mechanisms support the formation of spatial firing fields in hippocampus, but only the internally organized system supports short-timescale sequential firing and episodic memory.

In rodent hippocampus, neuronal activity is organized by a 6-10 Hz theta oscillation. The spike timing of hippocampal pyramidal cells with respect to the theta rhythm correlates with an animal’s position in space. This correlation has been suggested to indicate an explicit temporal code for position. Alternatively, it may be interpreted as a byproduct of theta-dependent dynamics of spatial information flow in hippocampus. Here we show that place cell activity on different phases of theta reflects positions shifted into the future or past along the animal’s trajectory in a two-dimensional environment. The phases encoding future and past positions are consistent across recorded CA1 place cells, indicating a coherent representation at the network level. Consistent theta-dependent time offsets are not simply a consequence of phase-position correlation (phase precession), because they are no longer seen after data randomization that preserves the phase-position relationship. The scale of these time offsets, 100-300 ms, is similar to the latencies of hippocampal activity after sensory input and before motor output, suggesting that offset activity may maintain coherent brain activity in the face of information processing delays.