Spontaneous Dynamics of Hippocampal Place Fields in a Model of Combinatorial Competition among Stable Inputs.

We present computer simulations illustrating how the plastic integration of spatially stable inputs could contribute to the dynamic character of hippocampal spatial representations. In novel environments of slightly larger size than typical apparatus, the emergence of well-defined place fields in real place cells seems to rely on inputs from normally functioning grid cells. Theoretically, the grid-to-place transformation is possible if a place cell is able to respond selectively to a combination of suitably aligned grids. We previously identified the functional characteristics that allow a synaptic plasticity rule to accomplish this selection by synaptic competition during rat foraging behavior. Here, we show that the synaptic competition can outlast the formation of place fields, contributing to their spatial reorganization over time, when the model is run in larger environments and the topographical/modular organization of grid inputs is taken into account. Co-simulated cells that differ only by their randomly assigned grid inputs display different degrees and kinds of spatial reorganization-ranging from place-field remapping to more subtle in-field changes or lapses in firing. The model predicts a greater number of place fields and propensity for remapping in place cells recorded from more septal regions of the hippocampus and/or in larger environments, motivating future experimental standardization across studies and animal models. In sum, spontaneous remapping could arise from rapid synaptic learning involving inputs that are functionally homogeneous, spatially stable, and minimally stochastic.

Spontaneous dynamics of hippocampal place fields in a model of combinatorial competition among stable inputs.

We present computer simulations illustrating how the plastic integration of spatially stable inputs could contribute to the dynamic character of hippocampal spatial representations. In novel environments of slightly larger size than typical apparatus, the emergence of well-defined place fields in real place cells seems to rely on inputs from normally functioning grid cells. Theoretically, the grid-to-place transformation is possible if a place cell is able to respond selectively to a combination of suitably aligned grids. We previously identified the functional characteristics that allow a synaptic plasticity rule to accomplish this selection by synaptic competition during rat foraging behavior. Here, we show that the synaptic competition can outlast the formation of place fields, contributing to their spatial reorganization over time, when the model is run in larger environments and the topographical/modular organization of grid inputs is taken into account. Co-simulated cells that differ only by their randomly assigned grid inputs display different degrees and kinds of spatial reorganization-ranging from place-field remapping to more subtle in-field changes or lapses in firing. The model predicts a greater number of place fields and propensity for remapping in place cells recorded from more septal regions of the hippocampus and/or in larger environments, motivating future experimental standardization across studies and animal models. In sum, spontaneous remapping could arise from rapid synaptic learning involving inputs that are functionally homogeneous, spatially stable, and minimally stochastic. Significance Statement: In both AI and theoretical neuroscience, learning systems often rely on the asymptotic convergence of slow-acting learning rules applied to input spaces that are presumed to be sampled repeatedly, for example over developmental timescales. Place cells of the hippocampus testify to a neural system capable of rapidly encoding cognitive variables-such as the animal's position in space-from limited experience. These internal representations undergo "spontaneous" changes over time, spurring much interest in their cognitive significance and underlying mechanisms. We investigate a model suggesting that some of these changes could be a tradeoff of rapid learning.

High dose esomeprazole as an anti-inflammatory agent in sepsis: Protocol for a randomized controlled trial.

BACKGROUND: Sepsis is caused by dysregulated immune responses due to infection and still presents high mortality rate and limited efficacious therapies, apart from antibiotics. Recent evidence suggests that very high dose proton pump inhibitors might regulate major sepsis mediators' secretion by monocytes, which might attenuate excessive host reactions and improve clinical outcomes. This effect is obtained with doses which are approximately 50 times higher than prophylactic esomeprazole single daily administration and 17 times higher than the cumulative dose of a three day prophylaxis. We aim to perform a randomized trial to investigate if high dose esomeprazole reduces organ dysfunction in patients with sepsis or septic shock. METHODS: This study, called PPI-SEPSIS, is a multicenter, randomized, double blind, placebo-controlled clinical trial on critically ill septic patients admitted to the emergency department or intensive care unit. A total of 300 patients will be randomized to receive high dose esomeprazole (80 mg bolus followed by 12 mg/h for 72 h and a second 80 mg bolus 12 h after the first one) or equivolume placebo (sodium chloride 0.9%), with 1:1 allocation. The primary endpoint of the study will be mean daily Sequential Organ Failure Assessment (SOFA) score over 10 days. Secondary outcomes will include antibiotic-free days, single organ failure severity, intensive care unit-free days at day 28, and mortality. DISCUSSION: This trial aims to test the efficacy of high dose esomeprazole to reduce acute organ dysfunction in patients with septic shock. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov with the trial identification NCT03452865 in March 2018.

Superficial-layer versus deep-layer lateral entorhinal cortex: Coding of allocentric space, egocentric space, speed, boundaries, and corners.

Entorhinal cortex is the major gateway between the neocortex and the hippocampus and thus plays an essential role in subserving episodic memory and spatial navigation. It can be divided into the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), which are commonly theorized to be critical for spatial (context) and non-spatial (content) inputs, respectively. Consistent with this theory, LEC neurons are found to carry little information about allocentric self-location, even in cue-rich environments, but they exhibit egocentric spatial information about external items in the environment. The superficial and deep layers of LEC are believed to mediate the input to and output from the hippocampus, respectively. As earlier studies mainly examined the spatial firing properties of superficial-layer LEC neurons, here we characterized the deep-layer LEC neurons and made direct comparisons with their superficial counterparts in single unit recordings from behaving rats. Because deep-layer LEC cells received inputs from hippocampal regions, which have strong selectivity for self-location, we hypothesized that deep-layer LEC neurons would be more informative about allocentric position than superficial-layer LEC neurons. We found that deep-layer LEC cells showed only slightly more allocentric spatial information and higher spatial consistency than superficial-layer LEC cells. Egocentric coding properties were comparable between these two subregions. In addition, LEC neurons demonstrated preferential firing at lower speeds, as well as at the boundary or corners of the environment. These results suggest that allocentric spatial outputs from the hippocampus are transformed in deep-layer LEC into the egocentric coding dimensions of LEC, rather than maintaining the allocentric spatial tuning of the CA1 place fields.

The Dome: A virtual reality apparatus for freely locomoting rodents.

The cognitive map in the hippocampal formation of rodents and other mammals integrates multiple classes of sensory and motor information into a coherent representation of space. Here, we describe the Dome, a virtual reality apparatus for freely locomoting rats, designed to examine the relative contributions of various spatial inputs to an animal's spatial representation. The Dome was designed to preserve the range of spatial inputs typically available to an animal in free, untethered locomotion while providing the ability to perturb specific sensory cues. We present the design rationale and corresponding specifications of the Dome, along with a variety of engineering and biological analyses to validate the efficacy of the Dome as an experimental tool to examine the interaction between visual information and path integration in place cells in rodents.

Origin and role of path integration in the cognitive representations of the hippocampus: computational insights into open questions.

Path integration is a straightforward concept with varied connotations that are important to different disciplines concerned with navigation, such as ethology, cognitive science, robotics and neuroscience. In studying the hippocampal formation, it is fruitful to think of path integration as a computation that transforms a sense of motion into a sense of location, continuously integrated with landmark perception. Here, we review experimental evidence that path integration is intimately involved in fundamental properties of place cells and other spatial cells that are thought to support a cognitive abstraction of space in this brain system. We discuss hypotheses about the anatomical and computational origin of path integration in the well-characterized circuits of the rodent limbic system. We highlight how computational frameworks for map-building in robotics and cognitive science alike suggest an essential role for path integration in the creation of a new map in unfamiliar territory, and how this very role can help us make sense of differences in neurophysiological data from novel versus familiar and small versus large environments. Similar computational principles could be at work when the hippocampus builds certain non-spatial representations, such as time intervals or trajectories defined in a sensory stimulus space.

Recalibration of path integration in hippocampal place cells.

Hippocampal place cells are spatially tuned neurons that serve as elements of a 'cognitive map' in the mammalian brain1. To detect the animal's location, place cells are thought to rely upon two interacting mechanisms: sensing the position of the animal relative to familiar landmarks2,3 and measuring the distance and direction that the animal has travelled from previously occupied locations4-7. The latter mechanism-known as path integration-requires a finely tuned gain factor that relates the animal's self-movement to the updating of position on the internal cognitive map, as well as external landmarks to correct the positional error that accumulates8,9. Models of hippocampal place cells and entorhinal grid cells based on path integration treat the path-integration gain as a constant9-14, but behavioural evidence in humans suggests that the gain is modifiable15. Here we show, using physiological evidence from rat hippocampal place cells, that the path-integration gain is a highly plastic variable that can be altered by persistent conflict between self-motion cues and feedback from external landmarks. In an augmented-reality system, visual landmarks were moved in proportion to the movement of a rat on a circular track, creating continuous conflict with path integration. Sustained exposure to this cue conflict resulted in predictable and prolonged recalibration of the path-integration gain, as estimated from the place cells after the landmarks were turned off. We propose that this rapid plasticity keeps the positional update in register with the movement of the rat in the external world over behavioural timescales. These results also demonstrate that visual landmarks not only provide a signal to correct cumulative error in the path-integration system4,8,16-19, but also rapidly fine-tune the integration computation itself.

Egocentric coding of external items in the lateral entorhinal cortex.

Episodic memory, the conscious recollection of past events, is typically experienced from a first-person (egocentric) perspective. The hippocampus plays an essential role in episodic memory and spatial cognition. Although the allocentric nature of hippocampal spatial coding is well understood, little is known about whether the hippocampus receives egocentric information about external items. We recorded in rats the activity of single neurons from the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC), the two major inputs to the hippocampus. Many LEC neurons showed tuning for egocentric bearing of external items, whereas MEC cells tended to represent allocentric bearing. These results demonstrate a fundamental dissociation between the reference frames of LEC and MEC neural representations.

Framing of grid cells within and beyond navigation boundaries.

Grid cells represent an ideal candidate to investigate the allocentric determinants of the brain's cognitive map. Most studies of grid cells emphasized the roles of geometric boundaries within the navigational range of the animal. Behaviors such as novel route-taking between local environments indicate the presence of additional inputs from remote cues beyond the navigational borders. To investigate these influences, we recorded grid cells as rats explored an open-field platform in a room with salient, remote cues. The platform was rotated or translated relative to the room frame of reference. Although the local, geometric frame of reference often exerted the strongest control over the grids, the remote cues demonstrated a consistent, sometimes dominant, countervailing influence. Thus, grid cells are controlled by both local geometric boundaries and remote spatial cues, consistent with prior studies of hippocampal place cells and providing a rich representational repertoire to support complex navigational (and perhaps mnemonic) processes.

Strides toward a structure-function understanding of cortical representations of allocentric space.

Grid cells, border cells, head-directions cells, and conjunctive correlates found in the Medial Entorhinal Cortex (MEC) indicate the presence of highly specialized neural circuits that process allocentric space. New technical advancements, as described by Tang et al. (2014) in this issue, offer an integrated approach to charting the function and organization of these circuits.

The problem of conflicting reference frames when investigating three-dimensional space in surface-dwelling animals.

In a surface-dwelling animal like the rat, experimental strategies for investigating the hippocampal correlates of three-dimensional space appear inevitably complicated by the interplay of global versus local reference frames. We discuss the impact of the resulting confounds on present and future empirical analysis of the "bicoded map" hypothesis by Jeffery and colleagues.

F-18 FDG PET/CT detects muscle involvement in Erdheim-Chester disease.

A case of Erdheim-Chester disorder, a rare non-Langerhans' cell histiocytosis, was referred for restaging by F-18 FDG PET/CT more than 10 years after initial diagnosis. The patient presented diabetes insipidus, hypergondotropic hypogonadism, and osteosclerotic lesions. Previous bone scintigraphy documented pathognomonic long bones' involvement. Chronic steroid and hormone replacement therapy was administered, and the patient was asymptomatic. F-18 FDG PET/CT was useful for disease restaging at cardiac and soft tissues level.

Hebbian analysis of the transformation of medial entorhinal grid-cell inputs to hippocampal place fields.

The discovery of grid cells in the medial entorhinal cortex (MEC) permits the characterization of hippocampal computation in much greater detail than previously possible. The present study addresses how an integrate-and-fire unit driven by grid-cell spike trains may transform the multipeaked, spatial firing pattern of grid cells into the single-peaked activity that is typical of hippocampal place cells. Previous studies have shown that in the absence of network interactions, this transformation can succeed only if the place cell receives inputs from grids with overlapping vertices at the location of the place cell's firing field. In our simulations, the selection of these inputs was accomplished by fast Hebbian plasticity alone. The resulting nonlinear process was acutely sensitive to small input variations. Simulations differing only in the exact spike timing of grid cells produced different field locations for the same place cells. Place fields became concentrated in areas that correlated with the initial trajectory of the animal; the introduction of feedback inhibitory cells reduced this bias. These results suggest distinct roles for plasticity of the perforant path synapses and for competition via feedback inhibition in the formation of place fields in a novel environment. Furthermore, they imply that variability in MEC spiking patterns or in the rat's trajectory is sufficient for generating a distinct population code in a novel environment and suggest that recalling this code in a familiar environment involves additional inputs and/or a different mode of operation of the network.

Influence of boundary removal on the spatial representations of the medial entorhinal cortex.

The medial entorhinal cortex (MEC) is thought to create and update a dynamical representation of the animal's spatial location. Most suggestive of this process are grid cells, whose firing locations occur periodically in space. Prior studies in small environments were ambiguous as to whether all spatially modulated cells in MEC were variants of grid cells or whether a subset resembled classic place cells of the hippocampus. Recordings from the dorsal and ventral MEC were performed as four rats foraged in a small square box centered inside a larger one. After 6 min, without removing the rat from the enclosure, the walls of the small box were quickly removed, leaving the rat free to continue foraging in the whole area enclosed by the larger box. The rate-responses of most recorded cells (70 out of 93 cells, including 15 of 16 putative interneurons) were considered spatially modulated based on information-theoretic analysis. A number of cells that resembled classic hippocampal place cells in the small box were revealed to be grid cells in the larger box. In contrast, other cells that fired along the boundaries or corners of the small box did not show grid-cell firing in the large box, but instead fired along the corresponding locations of the large box. Remapping of the spatial response in the area corresponding to the small box after the removal of its walls was prominent in most spatially modulated cells. These results show that manipulation of local boundaries can exert a powerful influence on the spatial firing patterns of MEC cells even when the manipulations leave global cues unchanged and allow uninterrupted, self-motion-based localization. Further, they suggest the presence of landmark-related information in MEC, which might prevent cumulative drift of the spatial representation or might reset it to a previously learned configuration in a familiar environment.

Effect of chronic beta-blockade on QT interval in patients with liver cirrhosis.

BACKGROUND/AIMS: QT interval prolongation is frequent in cirrhosis, predicts a poor prognosis and may trigger severe ventricular arrhythmias. Our aim was to evaluate the effect of chronic beta-blockade on QT prolongation. METHODS: Clinical and laboratory evaluation, ECG and hepatic vein pressure gradient (HVPG) measurement were performed in 30 cirrhotic patients before and 1-3 months after prophylactic nadolol. QT was corrected for heart rate by the cirrhosis-specific formula and other formulas. RESULTS: QT(cirrhosis) was prolonged in 10 patients (33%); HVPG was increased in all cases. QT(cirrhosis) was correlated with the Child-Pugh score (r=0.40; p=0.027). Nadolol shortened QT interval only with the Bazett formula (p=0.01), remaining unchanged with the other formulas. The QT interval shortened only if prolonged at baseline (from 473.3+/-5.5 to 458.4+/-6.5 ms; p=0.007), while it lengthened when normal (from 429.8+/-3.1 to 439.3+/-2.9 ms; p=0.01). QTc changes were directly related to the baseline value (p<0.001). HVPG decreased from 19.4+/-0.8 to 15.6+/-1.3 mmHg (p=0.004). The HVPG changes did not correlate with QTc changes. CONCLUSIONS: Chronic beta-blockade shortens the QT interval only in patients with prolonged baseline values, and this is likely due to a direct cardiac effect.

QT interval in patients with non-cirrhotic portal hypertension and in cirrhotic patients treated with transjugular intrahepatic porto-systemic shunt.

BACKGROUND/AIMS: A prolonged QT interval is frequent in chronic liver disease and its aetiology remains unsettled. The study's aim was to assess the role of portal hypertension in the pathogenesis of QT prolongation. METHODS: We measured the QT interval in: (1) 10 patients with non-cirrhotic portal hypertension (NCPH) and preserved liver function; (2) 19 cirrhotic patients before, 1-3 and 6-9 months after transjugular intrahepatic porto-systemic shunt (TIPS) insertion. RESULTS: Baseline corrected maximum QT interval (QTcmax) was prolonged (>440 ms) in eight NCPH and 16 cirrhotic patients, and its value did not differ between the two groups (453+/-8 vs. 465+/-6 ms, P=NS). No patients showed an abnormal baseline QT dispersion. In cirrhotic individuals, QTcmax further increased 1-3 months after TIPS (P=0.042), thereafter remaining steadily elevated. QT dispersion only increased at the second post-TIPS determination (P=0.030). Such changes occurred despite no deterioration of liver function, plasma electrolytes and haemoglobin. CONCLUSIONS: QT interval is frequently prolonged in patient with both non-cirrhotic and cirrhotic portal hypertension and portal decompression by TIPS worsens this abnormality. These results suggest that the porto-systemic shunting is responsible for the altered ventricular repolarisation possibly through a dumping into the systemic circulation of splanchnic-derived cardioactive substances.