Simulations predict differing phase responses to excitation vs. inhibition in theta-resonant pyramidal neurons.

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.

Is hippocampal remapping the physiological basis for context?

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.

"Salt and Pepper" Pontine Infarct.

A paramedian pontine stroke may herald the unique symptom of "salt and pepper" eye pain, in which patients describe the sensation of pepper rubbed into the eye. While localization of the lesion is a common thread among published cases, the mechanism for the sensation of eye pain is still a matter of conjecture. It is important for clinicians to be aware of this unique symptom because strokes rarely present with eye pain and failure to establish this diagnosis might lead to a poor clinical outcome.

What is optimized in an optimal path?

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.

Heading-vector navigation based on head-direction cells and path integration.

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.

Recurrent seizures induce a reversible impairment in a spatial hidden goal task.

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.

Changes in goal selection induced by cue conflicts are in register with predictions from changes in place cell field locations.

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.

Seizure-induced changes in place cell physiology: relationship to spatial memory.

Status epilepticus (SE) is a frequent neurological emergency associated with a significant risk of morbidity in survivors. Impairment of hippocampal-specific memory is a common and serious deficit occurring in many of the survivors. However, the pathophysiological basis of cognitive deficits after SE is not clear. To directly address the cellular concomitants of spatial memory impairment, we recorded the activity of place cells from CA1 in freely moving rats subjected to SE during early development and compared this activity to that in control rats. Place cells discharge rapidly only when the rat's head is in a cell-specific part of the environment called the "firing field." This firing field remains stable over time. Normal place cell function seems to be essential for stable spatial memory for the environment. We, therefore, compared place cell firing patterns with visual-spatial memory in the water maze in SE and control rats. Compared with controls, place cells from the SE rats were less precise and less stable. Concordantly, the water maze performance was also impaired. There was a close relationship between precision and stability of place cells and water maze performance. In contrast, a single, acute, chemically induced seizure produced cessation of place cell activity and spatial memory impairment in water maze performance that reversed within 24 hr. These results strongly bolster the idea that there is a relationship between abnormal place cells and spatial memory. Our findings also suggest that the defects in place cell and spatial memory after SE and acute chemically induced seizures result from different processes.

Conditioned discrimination of airborne odorants by garter snakes (Thamnophis radix and T. sirtalis sirtalis).

For snakes, the nasal chemical senses are critical in intraspecific communication and prey recognition. Although it is known that garter snakes can respond differentially to airborne odorants, no previous study has demonstrated that snakes can learn a task with airborne odors as discriminative stimuli. In Experiment 1, 7 plains garter snakes (Thamnophis radix) were trained in a two-choice apparatus to move into a compartment containing lemon-scented chips for a food reward. All 7 snakes improved performance when the first 10 and last 10 trials of the 100 trials of conditioning were compared. Four of the snakes were subsequently trained to move away from the scented compartment into the unscented compartment. The 4 snakes rapidly learned this reversal. In Experiment 2, 7 common garter snakes (T. sirtalis sirtalis) were trained to traverse a two-choice maze with the presence or absence of amyl acetate odor as the conditioned stimulus. The snakes were pretested for odor versus nonodor preference and were trained to go to the initially nonpreferred stimulus. Of the 7 snakes, 5 achieved a predetermined criterion (two training sessions with cumulative correct responding above the .05 confidence level) within 85 trials.

Grid cells require excitatory drive from the hippocampus.

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.

Linear look-ahead in conjunctive cells: an entorhinal mechanism for vector-based navigation.

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.

NEURO.TV: Neuroscience Education on the Internet

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.

Telemetry system for reliable recording of action potentials from freely moving rats.

Recording single cells from alert rats currently requires a cable to connect brain electrodes to the acquisition system. If no cable were necessary, a variety of interesting experiments would become possible, and the design of other experiments would be simplified. To eliminate the need for a cable we have developed a one-channel radiotelemetry system that is easily carried by a rat. This system transmits a signal that is reliable, highly accurate and can be detected over distances of > or = 20 m. The mobile part of the system has three components: (1) a headstage with built-in amplifiers that plugs into the connector for the electrode array on the rat's head; the headstage also incorporates a light-emitting diode (LED) used to track the rat's position; (2) a backpack that contains the transmitter and batteries (2 N cells); the backpack also provides additional amplification of the single cell signals; and (3) a short cable that connects the headstage to the backpack; the cable supplies power to the headstage amplifiers and the LED, and carries the physiological signals from the headstage to the backpack. By using a differential amplifier and recording between two brain microelectrodes the system can transmit action potential activity from two nearly independent sources. In a future improvement, two transmitters with different frequencies would be used telemeter signals from four microelectrodes simultaneously.