Biomedical subjects

Bruce L McNaughton

Publications and source records attributed to Bruce L McNaughton.

At least 19 recordsLinked to original sources

PubMed2006

Phase precession in hippocampal interneurons showing strong functional coupling to individual pyramidal cells.

Although hippocampal interneurons typically do not show discrete regions of elevated firing in an environment, such as seen in pyramidal cell place fields, they do exhibit significant spatial modulation (McNaughton et al., 1983a). Strong monosynaptic coupling between pyramidal neurons and nearby interneurons in the CA1 stratum pyramidale has been strongly implicated on the basis of significant, short-latency peaks in cross-correlogram plots (Csicsvari et al., 1998). Furthermore, interneurons receiving a putative monosynaptic connection from a simultaneously recorded pyramidal cell appear to inherit the spatial modulation of the latter (Marshall et al., 2002). Buzsaki and colleagues hypothesize that interneurons may also adopt the firing phase dynamics of their afferent place cells, which show a phase shift relative to the hippocampal theta rhythm as a rat passes through the place field ("phase precession"). This study confirms and extends the previous reports by showing that interneurons in the dorsal and middle hippocampus with putative monosynaptic connections with place cells recorded on the same tetrode share other properties with their pyramidal cell afferents, including the spatial scale of the place field of pyramidal cell, a characteristic of the septotemporal level of the hippocampus from which the cells are recorded, and the rate of phase precession, which is slower in middle regions. Furthermore, variations in pyramidal cell place field scale within each septotemporal level attributable to task variations are similarly associated with variations in interneuron place field scale. The available data strongly suggest that spatial selectivity of CA1 stratum pyramidale interneurons is inherited from a small cluster of local pyramidal cells and is not a consequence of spatially selective synaptic input from CA3 or other sources.

Action Potentials↗

PubMed2006

Apparent encoding of sequential context in rat medial prefrontal cortex is accounted for by behavioral variability.

Simple sequences can be represented via asymmetrically linked neural assemblies, provided that the elements of the sequence are unique. When elements repeat, however (e.g., A-B-C-B-A), the same element belongs to two separate "sequential contexts," and a more complex encoding mechanism is required. To enable correct sequence performance, some neural structure must provide a disambiguating signal that differentiates the two sequential contexts (i.e., B as an element of "A-B" as opposed to "C-B"). The disambiguating signal may derive from a form of working memory, or, in some cases, a simple timing mechanism may suffice. To investigate the possible role of medial prefrontal cortex in complex sequence encoding, rats were trained on a spatial sequence containing two adjacent repeated segments (e.g., A-B-C-D-B-C-E). The double-repeat procedure minimized behavioral differences in the second leg (C) of the repeat subsequence that arise in the first leg (B) because of differences in the entry point (e.g., A-B vs D-B). Far more cells were context sensitive along the first leg than along the second (36 vs 9%), and most of the differences were accounted for by systematic variations in the rat's trajectory, which were much larger along the first leg. There is thus little evidence for sequential context-discriminative activity in the medial prefrontal cortex that cannot plausibly be accounted for by context-dependent behavior. The finding that the rodent medial prefrontal cortex is highly sensitive to sensory-behavioral variables raises doubts about previous experiments that purport to show working memory-related activity in this region.

Action Potentials↗

PubMed2006

Cannabinoids reveal importance of spike timing coordination in hippocampal function.

Cannabinoids impair hippocampus-dependent memory in both humans and animals, but the network mechanisms responsible for this effect are unknown. Here we show that the cannabinoids Delta(9)-tetrahydrocannabinol and CP55940 decreased the power of theta, gamma and ripple oscillations in the hippocampus of head-restrained and freely moving rats. These effects were blocked by a CB1 antagonist. The decrease in theta power correlated with memory impairment in a hippocampus-dependent task. By simultaneously recording from large populations of single units, we found that CP55940 severely disrupted the temporal coordination of cell assemblies in short time windows (<100 ms) yet only marginally affected population firing rates of pyramidal cells and interneurons. The decreased power of local field potential oscillations correlated with reduced temporal synchrony but not with firing rate changes. We hypothesize that reduced spike timing coordination and the associated impairment of physiological oscillations are responsible for cannabinoid-induced memory deficits.

Action Potentials↗

PubMed2006

Methodological considerations on the use of template matching to study long-lasting memory trace replay.

Replay of behaviorally induced neural activity patterns during subsequent sleep has been suggested to play an important role in memory consolidation. Many previous studies, mostly involving familiar experiences, suggest that such reactivation occurs, but decays quickly (approximately 1 h). Recently, however, long-lasting (up to approximately 48 h) "reverberation" of neural activity patterns induced by a novel experience was reported on the basis of a template-matching analysis. Because detection and quantification of memory-trace replay depends critically on analysis methods, we investigated the statistical properties of the template-matching method and analyzed rodent neural ensemble activity patterns after a novel experience. For comparison, we also analyzed the same data with an independent analysis technique, the explained variance method. Contrary to the recent report, we did not observe significant long-lasting reverberation using either the template matching or the explained variance approaches. The latter, however, did reveal short-lasting reactivation in the hippocampus and prefrontal cortex. In addition, detailed analysis of the template-matching method shows that, in the present study, coarse mean firing rate differences among neurons, but not fine temporal spike structures, dominate the results of template matching. Most importantly, it is also demonstrated that partial comparisons of template-matching correlations, such as used in the recent paper, may lead to erroneous conclusions. These investigations indicate that the outcome of template-matching analysis is very sensitive to the conditions of how it is applied, and should be interpreted cautiously, and that the existence of long-lasting reverberation after a novel experience requires additional verification.

Action Potentials↗

PubMed2006

Advanced imaging of multiple mRNAs in brain tissue using a custom hyperspectral imager and multivariate curve resolution.

Simultaneous imaging of multiple cellular components is of tremendous importance in the study of complex biological systems, but the inability to use probes with similar emission spectra and the time consuming nature of collecting images on a confocal microscope are prohibitive. Hyperspectral imaging technology, originally developed for remote sensing applications, has been adapted to measure multiple genes in complex biological tissues. A spectral imaging microscope was used to acquire overlapping fluorescence emissions from specific mRNAs in brain tissue by scanning the samples using a single fluorescence excitation wavelength. The underlying component spectra obtained from the samples are then separated into their respective spectral signatures using multivariate analyses, enabling the simultaneous quantitative measurement of multiple genes either at regional or cellular levels.

Animals↗

PubMed2006

Conjunctive representation of position, direction, and velocity in entorhinal cortex.

Grid cells in the medial entorhinal cortex (MEC) are part of an environment-independent spatial coordinate system. To determine how information about location, direction, and distance is integrated in the grid-cell network, we recorded from each principal cell layer of MEC in rats that explored two-dimensional environments. Whereas layer II was predominated by grid cells, grid cells colocalized with head-direction cells and conjunctive grid x head-direction cells in the deeper layers. All cell types were modulated by running speed. The conjunction of positional, directional, and translational information in a single MEC cell type may enable grid coordinates to be updated during self-motion-based navigation.

Animals↗

PubMed2006

Recent behavioral history modifies coupling between cell activity and Arc gene transcription in hippocampal CA1 neurons.

The ability of neurons to alter their transcriptional programs in response to synaptic input is of fundamental importance to the neuroplastic mechanisms underlying learning and memory. Because of technical limitations of conventional gene detection methods, the current view of activity-dependent neural transcription derives from experiments in which neurons are assumed quiescent until a signaling stimulus is given. The present study was designed to move beyond this static model by examining how earlier episodes of neural activity influence transcription of the immediate-early gene Arc. Using a sensitive FISH method that detects primary transcript at genomic alleles, the proportion of hippocampal CA1 neurons that activate transcription of Arc RNA was constant at approximately 40% in response to both a single novel exploration session and daily sessions repeated over 9 days. This proportion is similar to the percentage of active neurons defined electrophysiologically. However, this close correspondence was disrupted in rats exposed briefly, but repeatedly, to the same environment within a single day. Arc transcription in CA1 neurons declined dramatically after as few as four 5-min sessions, despite stable electrophysiological activity during all sessions. Additional experiments indicate that the decrement in Arc transcription occurred at the cellular, rather than synaptic level, and was not simply linked to habituation to novelty. Thus, the neural genomic response is governed by recent, but not remote, cell firing history in the behaving animal. This state-dependence of neuronal transcriptional coupling provides a mechanism of metaplasticity and may regulate capacity for synaptic modification in neural networks.

Alleles↗

PubMed2006

Organization of hippocampal cell assemblies based on theta phase precession.

The factors that control the spatial tuning of hippocampal neurons are incompletely understood, and there is no generally agreed upon definition of what constitutes a "place field". One factor that must be considered is the phenomenon of "phase precession". As a rat passes through the place field of a particular hippocampal neuron, its spikes shift to earlier phases of the theta rhythm. Except for the special cases discussed herein, the phase shift never exceeds 360 degrees. Moreover, under conditions in which place field sizes change dynamically, precession rate is tightly coupled with the place field size, suggesting that a single cycle of theta phase precession could be used to define unitary place field boundaries. Theta phase precession implies that the "cell assembly" of active hippocampal neurons changes systematically over the course of a single theta cycle. A given cell can exhibit more than one place field in a given environment, each field showing the same pattern of 360 degrees of phase precession. The existence of multiple fields implies that one cell can participate in multiple cell assemblies within the same environment. We show here that place fields, defined as a single cycle of phase precession, can overlap spatially, with the result that the cell fires with spikes clustered at two different phases over the theta cycles in which the fields overlap. Thus, the same neuron can participate in different cell assemblies within a single theta cycle.

Action Potentials↗

PubMed2006

Path integration and the neural basis of the 'cognitive map'.

The hippocampal formation can encode relative spatial location, without reference to external cues, by the integration of linear and angular self-motion (path integration). Theoretical studies, in conjunction with recent empirical discoveries, suggest that the medial entorhinal cortex (MEC) might perform some of the essential underlying computations by means of a unique, periodic synaptic matrix that could be self-organized in early development through a simple, symmetry-breaking operation. The scale at which space is represented increases systematically along the dorsoventral axis in both the hippocampus and the MEC, apparently because of systematic variation in the gain of a movement-speed signal. Convergence of spatially periodic input at multiple scales, from so-called grid cells in the entorhinal cortex, might result in non-periodic spatial firing patterns (place fields) in the hippocampus.

Animals↗

PubMed2006

Selective excitotoxic lesions of the hippocampus and basolateral amygdala have dissociable effects on appetitive cue and place conditioning based on path integration in a novel Y-maze procedure.

The hippocampus and amygdala are thought to be functionally distinct components of different learning and memory systems. This functional dissociation has been particularly apparent in pavlovian fear conditioning, where the integrity of the hippocampus is necessary for contextual conditioning, and of the amygdala for discrete cue conditioning. Their respective roles in appetitive conditioning, however, remain equivocal mainly due to the lack of agreement concerning the operational definition of a 'context'. The present study used a novel procedure to measure appetitive conditioning to spatial context or to a discrete cue. Following selective excitotoxic lesions of the hippocampus (HPC) or basolateral amygdala (BLA), rats were initially trained to acquire discrete CS-sucrose conditioning in a Y-maze apparatus with three topographically identical chambers, the chambers discriminated only on the basis of path integration. The same group of animals then underwent 'place/contextual conditioning' where the CS presented in a chamber assigned as the positive chamber was paired with sucrose, but the same CS presented in either of the other two chambers was not. Thus, spatial context was the only cue that the animal could use to retrieve the value of the CS. HPC lesions impaired the acquisition of conditioned place preference but facilitated the acquisition of cue conditioning, while BLA lesions had the opposite effect, retarding the acquisition of cue conditioning but leaving the acquisition of conditioned place preference intact. Here we provide strong support for the notion that the HPC and BLA subserve complementary and competing roles in appetitive cue and contextual conditioning.

Amygdala↗

PubMed2005

Progressive transformation of hippocampal neuronal representations in "morphed" environments.

Hippocampal neural codes for different, familiar environments are thought to reflect distinct attractor states, possibly implemented in the recurrent CA3 network. A defining property of an attractor network is its ability to undergo sharp and coherent transitions between pre-established (learned) representations when the inputs to the network are changed. To determine whether hippocampal neuronal ensembles exhibit such discontinuities, we recorded in CA3 and CA1 when a familiar square recording enclosure was morphed in quantifiable steps into a familiar circular enclosure while leaving other inputs constant. We observed a gradual noncoherent progression from the initial to the final network state. In CA3, the transformation was accompanied by significant hysteresis, resulting in more similar end states than when only square and circle were presented. These observations suggest that hippocampal cell assemblies are capable of incremental plastic deformation, with incongruous information being incorporated into pre-existing representations.

Action Potentials↗

PubMed2005

Self-motion and the hippocampal spatial metric.

Self-motion signals are sufficient for animal navigation ("path integration") and for updating hippocampal location-specific firing. The contributions of ambulatory, vestibular, and optic self-motion signals to CA1 unit activity and EEG were studied while rats either walked or drove a car between locations on a circular track (referred to as WALK and CAR, respectively) or experienced pseudomotion, in which the animal was stationary and the environment was rotated (WORLD). Fewer pyramidal cells expressed place fields during CAR and those that did exhibited substantially larger place fields. The number of theta cycles required to traverse a place field increased, whereas the slope of the theta phase of firing versus position function was reduced. The presence and/or location of place fields were not well correlated between conditions. These effects were even more accentuated during WORLD. These results are not explainable by a simple "smearing out" of place fields but, in terms of size of place fields relative to the track size, are comparable with what would be observed if the track circumference was reduced and the animal moved around it at a correspondingly slower speed. Theta (and its 14-18 Hz harmonic) power were dependent on velocity, but the gain of this function was substantially reduced during CAR and WORLD, again as if the rat were moving more slowly. The spatial scale over which the hippocampal population vector is updated appears to be derived primarily from the gain of a self-motion velocity signal with approximately equal components derived from ambulation, vestibular, and optic-flow signals.

Animals↗

PubMed2005

Independent codes for spatial and episodic memory in hippocampal neuronal ensembles.

Hippocampal neurons were recorded under conditions in which the recording chamber was varied but its location remained unchanged versus conditions in which an identical chamber was encountered in different places. Two forms of neuronal pattern separation occurred. In the variable cue-constant place condition, the firing rates of active cells varied, often over more than an order of magnitude, whereas the location of firing remained constant. In the variable place-constant cue condition, both location and rates changed, so that population vectors for a given location in the chamber were statistically independent. These independent encoding schemes may enable simultaneous representation of spatial and episodic memory information.

Animals↗

PubMed2005

Differential encoding of behavior and spatial context in deep and superficial layers of the neocortex.

Rodent hippocampal activity is correlated with spatial and behavioral context, but how context affects coding in association neocortex is not well understood. The cellular distribution of the neural activity-regulated immediate-early gene Arc was used to monitor the activity history of cells in CA1, and in deep and superficial layers of posterior parietal and gustatory cortices (which encode movement and taste, respectively), during two behavioral epochs in which spatial and behavioral context were independently manipulated while gustatory input was held constant. Under conditions in which the hippocampus strongly differentiated behavioral and spatial contexts, deep parietal and gustatory layers did not discriminate between spatial contexts, whereas superficial layers in both neocortical regions discriminated well. Deep parietal cells discriminated behavioral context, whereas deep gustatory cortex neurons encoded the two conditions identically. Increased context sensitivity of superficial neocortical layers, which receive more hippocampal outflow, may reflect a general principle of neocortical organization for memory retrieval.

Animals↗

PubMed2005

Sequential-context-dependent hippocampal activity is not necessary to learn sequences with repeated elements.

Learning sequences of events (e.g., a-b-c) is conceptually a simple problem that can be solved using asymmetrically linked cell assemblies [e.g., "phase sequences" (Hebb, 1949)], provided that the elements of the sequence are unique. When elements repeat within the sequence, however (e.g., a-b-c-d-b-e), the same element belongs to two separate "contexts," and a more complex sequence encoding mechanism is required to differentiate between the two contexts. Some neural structure must form sequential-context-dependent, or "differential," representations of the two contexts (i.e., b as an element of "a-b-c" as opposed to "d-b-e") to allow the correct choice to be made after the repeated element. To investigate the possible role of hippocampus in complex sequence encoding, rats were trained to remember repeated-location sequences under three conditions: (1) reward was given at each location; (2) during training, moveable barriers were placed at the entry and exit of the repeated segment to direct the rat and were removed once the sequence was learned; and (3) reward was withheld at the entry and exit of the repeated segment. In the first condition, hippocampal ensemble activity did not differentiate the sequential context of the repeated segment, indicating that complex sequences with repeated segments can be learned without differential encoding within the hippocampus. Differential hippocampal encoding was observed, however, under the latter two conditions, suggesting that long-term memory for discriminative cues present only during training, working memory of the most recently visited reinforcement sites, or anticipation of the subsequent reinforcement site can separate hippocampal activity patterns at the same location.

Acoustic Stimulation↗

PubMed2005

Self-motion and the origin of differential spatial scaling along the septo-temporal axis of the hippocampus.

Spatial scaling of place specific activity in the hippocampus varies systematically from the septal pole (high resolution) to the temporal pole (low resolution). Place fields get progressively larger, and the probability of observing a field in a given environment gets progressively smaller. It was previously found that decoupling movement in space from ambulation, by having the animal actively ride on a mobile platform, results in marked enlargement of the spatial scale factor in the dorsal hippocampus and a reduction in the increase in theta rhythm power with running speed, suggesting that a self-motion signal determines the spatial scale at which the hippocampal population vector updates. These results led to the hypothesis that the gain of the self-motion signal may vary systematically along the septo-temporal axis of the hippocampus. To test this hypothesis, EEG theta rhythm and ensembles of CA1 pyramidal cells and interneurons were recorded from the extreme dorsal and middle portions of the hippocampus. Pyramidal cell population vectors representing successive locations became decorrelated over substantially shorter distances in the dorsal than in the middle hippocampus. Dorsal pyramidal cells had smaller place fields, higher mean and peak firing rates, and higher intrinsic oscillation frequencies during track running than that of middle pyramidal cells. Both dorsal pyramidal cells and interneurons had more elevated mean rates during running, compared with rest, than that of the corresponding cell classes in the middle hippocampus, and both cell classes increased their rates more as a function of speed in the dorsal hippocampus.The amplitude, but not the frequency of fissure recorded theta rhythm, increased more as a function of running speed in the dorsal than in the middle hippocampus. We conclude that variation in the neuronal response to movement speed is the likely basis for the systematic variation in spatial scaling along the septo-temporal axis of the hippocampus.

Action Potentials↗

PubMed2005

Mapping behaviorally relevant neural circuits with immediate-early gene expression.

Immediate-early genes have gained widespread popularity as activity markers for mapping neuronal circuits involved in specific behaviors in many different species. In situ immediate early gene detection methods provide cellular level resolution, a major benefit for mapping neuronal networks. Recent advances using fluorescence in situ hybridization also afford temporal resolution, enabling within-animal activity maps for two distinct behaviors. Moreover, use of transgenic mice with fluorescent reporter proteins driven by immediate early gene promoters is enabling repeated measurements, over long time scales, of cortical activity within the same animal. These methodological innovations, coupled with recent advances in fluorescence imaging and probe development, will enable large scale mapping of behaviorally relevant circuits with temporal and three-dimensional spatial resolution in experimental animals.

Animals↗

PubMed2004

3D-catFISH: a system for automated quantitative three-dimensional compartmental analysis of temporal gene transcription activity imaged by fluorescence in situ hybridization.

Fluorescence in situ hybridization (FISH) of neural activity-regulated, immediate-early gene (IEG) expression provides a method of functional brain imaging with cellular resolution. This enables the identification, in one brain, of which specific principal neurons were active during each of two distinct behavioral epochs. The unprecedented potential of this differential method for large-scale analysis of functional neural circuits is limited, however, by the time-intensive nature of manual image analysis. A comprehensive software tool for processing three-dimensional, multi-spectral confocal image stacks is described which supports the automation of this analysis. Nuclei counterstained with conventional DNA dyes and FISH signals indicating the sub-cellular distribution of specific, IEG RNA species are imaged using different spectral channels. The DNA channel data are segmented into individual nuclei by a three-dimensional multi-step algorithm that corrects for depth-dependent attenuation, non-isotropic voxels, and imaging noise. Intra-nuclear and cytoplasmic FISH signals are associated spatially with the nuclear segmentation results to generate a detailed tabular/database and graphic representation. Here we present a comprehensive validation of data generated by the automated software against manual quantification by human experts on hippocampal and parietal cortical regions (96.5% concordance with multi-expert consensus). The high degree of reliability and accuracy suggests that the software will generalize well to multiple brain areas and eventually to large-scale brain analysis.

Algorithms↗