In 1979, I joined Jim Ranck's group in Brooklyn and began recording hippocampal neurons. The first project was to record single neurons across three behaviors in different chambers: pellet retrieval on a radial-arm maze, bar-pressing for food reward in an operant chamber, and maternal pup-retrieval in a large home box. We found spatial firing in all three chambers, with a single-neuron's firing pattern unpredictable from one chamber to the next. We interpreted the spatial firing patterns as representing “context.” Later, in the 1980s, I began collaborating with Bob Muller (and Jim Ranck). In the first of a pair of 1987 papers, we used computerized data acquisition, recorded in simple, reduced environments to demonstrate robust, stable place cell firing and the characteristic features of firing fields. In the second paper we showed that when a rat is transferred from one environment to another, the set of place cells “remaps.” “Remapping” was defined later, in a pair of 1990 papers. “Context” was introduced in the early three-behavior experiment but was not discussed in the 1987 papers. What is the true relationship between the biological observation of “remapping” and the psychological concept of “context”? This difficult question is addressed here and in more detail in our recent paper.

Rhythmic activity is ubiquitous in neural systems, with theta-resonant pyramidal neurons integrating rhythmic inputs in many cortical structures. Impedance analysis has been widely used to examine frequency-dependent responses of neuronal membranes to rhythmic inputs, but it assumes that the neuronal membrane is a linear system, requiring the use of small signals to stay in a near-linear regime. However, postsynaptic potentials are often large and trigger nonlinear mechanisms (voltage-gated ion channels). The goals of this work were to 1) develop an analysis method to evaluate membrane responses in this nonlinear domain and 2) explore phase relationships between rhythmic stimuli and subthreshold and spiking membrane potential (Vmemb) responses in models of theta-resonant pyramidal neurons. Responses in these output regimes were asymmetrical, with different phase shifts during hyperpolarizing and depolarizing half-cycles. Suprathreshold theta-rhythmic stimuli produced nonstationary Vmemb responses. Sinusoidal inputs produced "phase retreat": action potentials occurred progressively later in cycles of the input stimulus, resulting from adaptation. Sinusoidal current with increasing amplitude over cycles produced "phase advance": action potentials occurred progressively earlier. Phase retreat, phase advance, and subthreshold phase shifts were modulated by multiple ion channel conductances. Our results suggest differential responses of cortical neurons depending on the frequency of oscillatory input, which will play a role in neuronal responses to shifts in network state. We hypothesize that intrinsic cellular properties complement network properties and contribute to in vivo phase-shift phenomena such as phase precession, seen in place and grid cells, and phase roll, also observed in hippocampal CA1 neurons.NEW & NOTEWORTHY We augmented electrical impedance analysis to characterize phase shifts between large-amplitude current stimuli and nonlinear, asymmetric membrane potential responses. We predict different frequency-dependent phase shifts in response excitation vs. inhibition, as well as shifts in spike timing over multiple input cycles, in theta-resonant pyramidal neurons. We hypothesize that these effects contribute to navigation-related phenomena such as phase precession and phase roll. Our neuron-level hypothesis complements, rather than falsifies, prior network-level explanations of these phenomena.

Rhythmic activity is ubiquitous in neural systems, and impedance analysis has been widely used to examine frequency-dependent responses of neuronal membranes to rhythmic inputs. Impedance analysis assumes the neuronal membrane is a linear system, requiring the use of small signals to stay in a near-linear regime. However, postsynaptic potentials are often large and trigger nonlinear mechanisms. We therefore augmented impedance analysis to evaluate membrane responses in this nonlinear domain, analyzing responses to injected current for subthreshold membrane voltage (V memb ), suprathreshold spike-blocked V memb , and spiking in a validated neocortical pyramidal neuron computer model. Responses in these output regimes were asymmetrical, with different phase shifts during hyperpolarizing and depolarizing half-cycles. Suprathreshold chirp stimulation gave equivocal results due to nonstationarity of response, requiring us to use fixed-frequency sinusoids. Sinusoidal inputs produced phase retreat : action potentials occurred progressively later in cycles of the input stimulus, resulting from adaptation. Conversely, sinusoidal current with increasing amplitude over cycles produced a pattern of phase advance : action potentials occurred progressively earlier. Phase retreat was dependent on I h and I AHP currents; phase advance was modulated by these currents. Our results suggest differential responses of cortical neurons depending on the frequency of oscillatory input in the delta – beta range, which will play a role in neuronal responses to shifts in network state. We hypothesize that intrinsic cellular properties complement network properties and contribute to in vivo phase-shift phenomena such as phase precession, seen in place and grid cells, and phase roll, observed in hippocampal CA1 neurons. New & Noteworthy We augmented electrical impedance analysis to characterize phase shifts between large amplitude current stimuli and nonlinear, asymmetric membrane potential responses. We predict different frequency-dependent phase shifts in response excitation versus inhibition, as well as shifts in spike timing over multiple input cycles, in resonant pyramidal neurons. We hypothesize that these effects contribute to navigation-related phenomena like phase precession and phase roll. Our neuron-level hypothesis complements, rather than falsifies, prior network-level explanations of these phenomena.

In 1980, Nadel and Wilner extended Richard Hirsh's notion that the hippocampus creates environmental representations, called "contexts," suggesting that the fundamental structure of context was the spatial representation proposed by O'Keefe and Nadel's landmark book, The Hippocampus as a Cognitive Map (1978). This book, in turn, derives from the discovery that individual hippocampal neurons act as place cells, with the complete set of place cells tiling an enclosure, forming a type of spatial map. It was found that unique environments had unique place cell representations. That is, if one takes the hippocampal map of a specific environment, this representation scrambles, or "remaps" when the animal is placed in a different environment. Several authors have speculated that "maps" and "remapping" form the physiological substrates for context and context shifting. One difficulty with this definition is that it is exclusively spatial; it can only be inferred when an animal locomotes in an enclosure. There are five aims for this article. The first is to give an historical overview of context as a variable that controls behavior. The second aim is to give an historical overview of concepts of place cell maps and remapping. The third aim is to propose an updated definition of a place cell map, based on temporal rather than spatial overlaps, which adds flexibility. The fourth aim is to address the issue of whether the biological phenomenon of hippocampal remapping, is, in fact, the substrate for shifts in the psychological phenomenon of context. The final aim is speculation of how contextual representations may contribute to effective behavior.

The medial entorhinal cortex, populated by grid cells, projects both directly and indirectly to the CA1 and CA3 cortices, the sites of hippocampal place cells. The study by Ormond and McNaughton (1) investigates a potential mechanism by which grid cells of the medial entorhinal cortex (MEC) exert their influence on the formation of firing fields of place cells. Specifically, the authors propose a “Fourier hypothesis” by which the spatial frequencies from several grid cell modules converge on the place-cell layer, molding the contours of firing fields to a composite of those several frequencies; Ormond and McNaughton tested the theory by inactivating specific input components and obtained fascinating results, largely supporting the model.

NEURO.tv is a new educational project that seeks to bring advanced concepts in neuroscience to the general public. We film one-hour discussions with leading neuroscientists, philosophers, and psychologists who have had significant impact on our current understanding of brain function, and we publish these discussions on YouTube, iTunes, and other social media outlets. Here, we explain the motivations behind this new program.

Theories of brain function have evolved through multiple stages. The first proposition was that brain networks support a set of reflex responses, with current sensory inputs producing immediate motor outputs. The behaviorist paradigm suggested that actions can always be explained as a response to immediate external cues. In response to these views, the cognitive paradigm argued that behavior cannot be understood simply as input-output functions because the hidden layers of brain generate unpredictability. The central processing was termed "cognition." Here we propose a neuroscience-based model of cognition. Our core hypothesis is that cognition depends on internal models of the animal and its world, where internally generated sequences can serve to perform "what if" scenarios and anticipate the possible consequences of alternative actions without actually testing them, and aid in the decisions of overt actions. We support our hypotheses by several examples of recent experimental findings and show how externally guided cell assembly sequences become internalized to support cognitive functions.

Bob Muller, friend, colleague, and place-cell pioneer, died following a heart attack on Sept 16, 2013. He was 71 years old. Figure 1 shows Bob at the early stages of place cell recording. FIGURE 1 Bob and John Kubie (approx. 1985) in the “large rectangle” recording chamber. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

An animal confronts numerous challenges when constructing an optimal navigational route. Spatial representations used for path optimization are likely constrained by critical environmental factors that dictate which neural systems control navigation. Multiple coding schemes depend upon their ecological relevance for a particular species, particularly when dealing with the third, or vertical, dimension of space.

To determine how hippocampal backprojections influence spatially periodic firing in grid cells, we recorded neural activity in the medial entorhinal cortex (MEC) of rats after temporary inactivation of the hippocampus. We report two major changes in entorhinal grid cells. First, hippocampal inactivation gradually and selectively extinguished the grid pattern. Second, the same grid cells that lost their grid fields acquired substantial tuning to the direction of the rat's head. This transition in firing properties was contingent on a drop in the average firing rate of the grid cells and could be replicated by the removal of an external excitatory drive in an attractor network model in which grid structure emerges by velocity-dependent translation of activity across a network with inhibitory connections. These results point to excitatory drive from the hippocampus, and possibly other regions, as one prerequisite for the formation and translocation of grid patterns in the MEC.

The crisp organization of the "firing bumps" of entorhinal grid cells and conjunctive cells leads to the notion that the entorhinal cortex may compute linear navigation routes. Specifically, we propose a process, termed "linear look-ahead," by which a stationary animal could compute a series of locations in the direction it is facing. We speculate that this computation could be achieved through learned patterns of connection strengths among entorhinal neurons. This paper has three sections. First, we describe the minimal grid cell properties that will be built into our network. Specifically, the network relies on "rigid modules" of neurons, where all members have identical grid scale and orientation, but differ in spatial phase. Additionally, these neurons must be densely interconnected with synapses that are modifiable early in the animal's life. Second, we investigate whether plasticity during short bouts of locomotion could induce patterns of connections amongst grid cells or conjunctive cells. Finally, we run a simulation to test whether the learned connection patterns can exhibit linear look-ahead. Our results are straightforward. A simulated 30-min walk produces weak strengthening of synapses between grid cells that do not support linear look-ahead. Similar training in a conjunctive cell module produces a small subset of very strong connections between cells. These strong pairs have three properties: the pre- and post-synaptic cells have similar heading direction. The cell pairs have neighboring grid bumps. Finally, the spatial offset of firing bumps of the cell pair is in the direction of the common heading preference. Such a module can produce strong and accurate linear look-ahead starting in any location and extending in any direction. We speculate that this process may: (1) compute linear paths to goals; (2) update grid cell firing during navigation; and (3) stabilize the rigid modules of grid cells and conjunctive cells.

A major question concerning the learning and memory deficits characteristic of epilepsy is the relative importance of the initial insult that leads to recurrent, unprovoked seizures versus the seizures themselves. A related issue is whether seizure-induced cognitive decline is permanent or reversible when convulsions cease. To address these problems, adult rats were extensively trained in the "spatial accuracy task," a dry-land analog of the Morris water maze. This task allows the rat's estimate of the location of a hidden goal zone to be repeatedly measured within each behavioral session. One aim was to measure, in well-trained animals, the time course of any cognitive impairment caused by a daily flurothyl-induced generalized seizure over 11 days. A second aim was to look for possible recovery during 9 subsequent days with no seizures. We saw a cumulative degradation in spatial performance during the seizure days and reversal of the deficit after seizures were stopped such that performance returned to baseline. Interestingly, the rate of learning to an asymptote, the rate of performance decline during one-per-day seizures and the rate of relearning during the recovery period were all similar. Given that the hippocampus plays an important role in spatial memory and that it is the brain structure most vulnerable to abnormal excitation the implication is that the hippocampus remains essential for precise spatial navigation even after prolonged training in locating a fixed goal zone. Clinically, this finding questions the assumption that patients who experience seizures should return to a baseline cognitive level within hours.

Insect navigation is guided by heading vectors that are computed by path integration. Mammalian navigation models, on the other hand, are typically based on map-like place representations provided by hippocampal place cells. Such models compute optimal routes as a continuous series of locations that connect the current location to a goal. We propose a "heading-vector" model in which head-direction cells or their derivatives serve both as key elements in constructing the optimal route and as the straight-line guidance during route execution. The model is based on a memory structure termed the "shortcut matrix," which is constructed during the initial exploration of an environment when a set of shortcut vectors between sequential pairs of visited waypoint locations is stored. A mechanism is proposed for calculating and storing these vectors that relies on a hypothesized cell type termed an "accumulating head-direction cell." Following exploration, shortcut vectors connecting all pairs of waypoint locations are computed by vector arithmetic and stored in the shortcut matrix. On re-entry, when local view or place representations query the shortcut matrix with a current waypoint and goal, a shortcut trajectory is retrieved. Since the trajectory direction is in head-direction compass coordinates, navigation is accomplished by tracking the firing of head-direction cells that are tuned to the heading angle. Section 1 of the manuscript describes the properties of accumulating head-direction cells. It then shows how accumulating head-direction cells can store local vectors and perform vector arithmetic to perform path-integration-based homing. Section 2 describes the construction and use of the shortcut matrix for computing direct paths between any pair of locations that have been registered in the shortcut matrix. In the discussion, we analyze the advantages of heading-based navigation over map-based navigation. Finally, we survey behavioral evidence that nonhippocampal, heading-based navigation is used in small mammals and humans.

In the cognitive mapping theory of hippocampal function, currently active place cells represent a rat's spatial location (J. O'Keefe & L. Nadel, 1978). A systematic shift of firing field locations should therefore produce a similar shift in a rat's judgment of its location. A. A. Fenton, G. Csizmadia, and R. U. Muller (2000a) recorded place cells in cylinders with 2 cue cards separated by 135 degrees. When the separation was changed, firing fields moved systematically, as described by a vector-field equation (A. A. Fenton, G. Csizmadia, & R. U. Muller, 2000b). Given this cohesive movement of firing fields, the mapping theory predicts that a rat's decisions about the location of an unmarked goal should move after card separation changes, as described by the vector-field equation. The authors tested this reasoning with a task in which the rat earned a food reward by pausing in a small, unmarked goal zone. When cues were shifted in the absence of reward, goal choice shifts were accurately predicted by the vector-field equation, providing strong support for the notion that a rat's judgment of its spatial location is intimately related to the across-cell discharge pattern of simultaneously active place cells.

Using a dry version of the Morris hidden-goal swimming task, we reexplored the retrograde and anterograde effects of hippocampal lesions on spatial performance in rats. Rats were trained to find food buried under sawdust in a 183-cm-diameter gray cylinder, the location of the buried food was constant for each rat. Either 1 week or 14 weeks after training the rats were subjected to massive hippocampal + dentate lesions by multiple injections of neurotoxic agents. Rats with a 1-week training-lesion interval could not reacquire the ability to get to the hidden food, although they performed normally when the goal location was marked with a dowel. In contrast, rats with a 14-week training-lesion interval re-learned finding the buried food at a nearly normal rate. The two groups together suggest that memory for the buried food task is susceptible to graded retrograde amnesia in a fashion similar to explicit memory in humans. Additional testing of the 14-week training-lesion group revealed, however, that the consolidated memory was not fully formed; these rats were incapable of learning to go to a new location in the same cylinder, although sham lesioned rats readily transferred. To explain this pattern of results, we propose that (1) rats with an intact hippocampus have available a neural map of the environment that permits them to learn to go from anywhere to anywhere else, and (2) hippocampally lesioned rats have no such map, but are able to show some navigational skills by using a vector field representation of the environment that permits them to get from anywhere to a single location. In a separate experiment, we provide support for the notion that the rodent hippocampus has a specialized role in spatial memory by showing that hippocampally lesioned rats performed normally in a visual object recognition task whose motor and motivational components were the same as in the buried food task.

HippocampusVolume 1, Issue 3 p. 240-242 Article Multiple representations in the hippocampus John L. Kubie, John L. Kubie Department of Anatomy and Cell Biology, SUNY Health Sciences Center at Brooklyn, 450 Clarkson Avenue, Brooklyn, NY 11203 U.S.A.Search for more papers by this authorRobert U. Muller, Robert U. Muller Department of Physiology, SUNY Health Sciences Center at Brooklyn, 450 Clarkson Avenue, Brooklyn, NY 11203 U.S.A.Search for more papers by this author John L. Kubie, John L. Kubie Department of Anatomy and Cell Biology, SUNY Health Sciences Center at Brooklyn, 450 Clarkson Avenue, Brooklyn, NY 11203 U.S.A.Search for more papers by this authorRobert U. Muller, Robert U. Muller Department of Physiology, SUNY Health Sciences Center at Brooklyn, 450 Clarkson Avenue, Brooklyn, NY 11203 U.S.A.Search for more papers by this author First published: 3 July 1991 https://doi.org/10.1002/hipo.450010305Citations: 36AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume1, Issue33 July 1991Pages 240-242 RelatedInformation