Novelty and anxiolytic drugs dissociate two components of hippocampal theta in behaving rats

Hippocampal processing is strongly implicated in both spatial cognition and anxiety and is temporally organized by the theta rhythm. However, there has been little attempt to understand how each type of processing relates to the other in behaving animals, despite their common substrate. In freely moving rats, there is a broadly linear relationship between hippocampal theta frequency and running speed over the normal range of speeds used during foraging. A recent model predicts that spatial-translation-related and arousal/anxiety-related mechanisms of hippocampal theta generation underlie dissociable aspects of the theta frequency–running speed relationship (the slope and intercept, respectively). Here we provide the first confirmatory evidence: environmental novelty decreases slope, whereas anxiolytic drugs reduce intercept. Variation in slope predicted changes in spatial representation by CA1 place cells and novelty-responsive behavior. Variation in intercept predicted anxiety-like behavior. Our findings isolate and doubly dissociate two components of theta generation that operate in parallel in behaving animals and link them to anxiolytic drug action, novelty, and the metric for self-motion

Evaluation of the Oscillatory Interference Model of Grid Cell Firing through Analysis and Measured Period Variance of Some Biological Oscillators

Models of the hexagonally arrayed spatial activity pattern of grid cell firing in the literature generally fall into two main categories: continuous attractor models or oscillatory interference models. Burak and Fiete (2009, PLoS Comput Biol) recently examined noise in two continuous attractor models, but did not consider oscillatory interference models in detail. Here we analyze an oscillatory interference model to examine the effects of noise on its stability and spatial firing properties. We show analytically that the square of the drift in encoded position due to noise is proportional to time and inversely proportional to the number of oscillators. We also show there is a relatively fixed breakdown point, independent of many parameters of the model, past which noise overwhelms the spatial signal. Based on this result, we show that a pair of oscillators are expected to maintain a stable grid for approximately t = 5µ3/(4πσ)2 seconds where µ is the mean period of an oscillator in seconds and σ2 its variance in seconds2. We apply this criterion to recordings of individual persistent spiking neurons in postsubiculum (dorsal presubiculum) and layers III and V of entorhinal cortex, to subthreshold membrane potential oscillation recordings in layer II stellate cells of medial entorhinal cortex and to values from the literature regarding medial septum theta bursting cells. All oscillators examined have expected stability times far below those seen in experimental recordings of grid cells, suggesting the examined biological oscillators are unfit as a substrate for current implementations of oscillatory interference models. However, oscillatory interference models can tolerate small amounts of noise, suggesting the utility of circuit level effects which might reduce oscillator variability. Further implications for grid cell models are discussed

Environmental novelty is signaled by reduction of the hippocampal theta frequency

The hippocampal formation (HF) plays a key role in novelty detection, but the mechanisms remain unknown. Novelty detection aids the encoding of new information into memory—a process thought to depend on the HF and to be modulated by the theta rhythm of EEG. We examined EEG recorded in the HF of rats foraging for food within a novel environment, as it became familiar over the next five days, and in two more novel environments unexpectedly experienced in trials interspersed with familiar trials over three further days. We found that environmental novelty produces a sharp reduction in the theta frequency of foraging rats, that this reduction is greater for an unexpected environment than for a completely novel one, and that it slowly disappears with increasing familiarity. These results do not reflect changes in running speed and suggest that the septo-hippocampal system signals unexpected environmental change via a reduction in theta frequency. In addition, they provide evidence in support of a cholinergically mediated mechanism for novelty detection, have important implications for our understanding of oscillatory coding within memory and for the interpretation of event-related potentials, and provide indirect support for the oscillatory interference model of grid cell firing in medial entorhinal cortex

Evidence for encoding versus retrieval scheduling in the hippocampus by theta phase and acetylcholine

The formation of new memories requires new information to be encoded in the face of proactive interference from the past. Two solutions have been proposed for hippocampal region CA1: (1) acetylcholine, released in novelty, selectively suppresses excitatory projections to CA1 from CA3 (mediating the products of retrieval), while sparing entorhinal inputs (mediating novel sensory information) and (2) encoding preferentially occurs at the pyramidal-layer theta peak, coincident with input from entorhinal cortex, and retrieval occurs at the trough, coincident with input from CA3, consistent with theta phase-dependent synaptic plasticity. We examined three predictions of these models: (1) in novel environments, the preferred theta phase of CA1 place cell firing should shift closer to the CA1 pyramidal-layer theta peak, shifting the encoding-retrieval balance toward encoding; (2) the encoding-related shift in novel environments should be disrupted by cholinergic antagonism; and (3) in familiar environments, cholinergic antagonism should shift the preferred theta firing phase closer to the theta trough, shifting the encoding-retrieval balance even further toward retrieval. We tested these predictions by recording from CA1 pyramidal cells in freely moving rats as they foraged in open field environments under the influence of scopolamine (an amnestic cholinergic antagonist) or vehicle (saline). Results confirmed all three predictions, supporting both the theta phase and cholinergic models of encoding versus retrieval dynamics. Also consistent with cholinergic enhancement of encoding, scopolamine attenuated the formation of distinct spatial representations in a new environment, reducing the extent of place cell “remapping.

Boundary vector cells in the subiculum of the hippocampal formation

“Boundary vector cells” were predicted to exist by computational models of the environmental inputs underlying the spatial firing patterns of hippocampal place cells (O'Keefe and Burgess, 1996; Burgess et al., 2000; Hartley et al., 2000). Here, we report the existence of cells fulfilling this description in recordings from the subiculum of freely moving rats. These cells may contribute environmental information to place cell firing, complementing path integrative information. Their relationship to other cell types, including medial entorhinal “border cells,” is discussed

Boundary coding in the rat subiculum

The spatial mapping function of the hippocampal formation is likely derived from two sets of information: one based on the external environment and the other based on self-motion. Here, we further characterize ‘boundary vector cells’ (BVCs) in the rat subiculum, which code space relative to one type of cue in the external environment: boundaries. We find that the majority of cells with fields near the perimeter of a walled environment exhibit an additional firing field when an upright barrier is inserted into the walled environment in a manner predicted by the BVC model. We use this property of field repetition as a heuristic measure to define BVCs, and characterize their spatial and temporal properties. In further tests, we find that subicular BVCs typically treat drop edges similarly to walls, including exhibiting field repetition when additional drop-type boundaries are added to the testing environment. In other words, BVCs treat both kinds of edge as environmental boundaries, despite their dissimilar sensory properties. Finally, we also report the existence of ‘boundary-off cells’, a new class of boundary-coding cells. These cells fire everywhere except where a given BVC might fire