Nonoscillatory Phase Coding and Synchronization in the Bat Hippocampal Formation.

Hippocampal theta oscillations were proposed to be important for multiple functions, including memory and temporal coding of position. However, previous findings from bats have questioned these proposals by reporting absence of theta rhythmicity in bat hippocampal formation. Does this mean that temporal coding is unique to rodent hippocampus and does not generalize to other species? Here, we report that, surprisingly, bat hippocampal neurons do exhibit temporal coding similar to rodents, albeit without any continuous oscillations at the 1-20 Hz range. Bat neurons exhibited very strong locking to the non-rhythmic fluctuations of the field potential, such that neurons were synchronized together despite the absence of oscillations. Further, some neurons exhibited "phase precession" and phase coding of the bat's position-with spike phases shifting earlier as the animal moved through the place field. This demonstrates an unexpected type of neural coding in the mammalian brain-nonoscillatory phase coding-and highlights the importance of synchrony and temporal coding for hippocampal function across species.

Neural Algorithms and Circuits for Motor Planning.

The brain plans and executes volitional movements. The underlying patterns of neural population activity have been explored in the context of movements of the eyes, limbs, tongue, and head in nonhuman primates and rodents. How do networks of neurons produce the slow neural dynamics that prepare specific movements and the fast dynamics that ultimately initiate these movements? Recent work exploits rapid and calibrated perturbations of neural activity to test specific dynamical systems models that are capable of producing the observed neural activity. These joint experimental and computational studies show that cortical dynamics during motor planning reflect fixed points of neural activity (attractors). Subcortical control signals reshape and move attractors over multiple timescales, causing commitment to specific actions and rapid transitions to movement execution. Experiments in rodents are beginning to reveal how these algorithms are implemented at the level of brain-wide neural circuits.

3-D Maps and Compasses in the Brain.

The world has a complex, three-dimensional (3-D) spatial structure, but until recently the neural representation of space was studied primarily in planar horizontal environments. Here we review the emerging literature on allocentric spatial representations in 3-D and discuss the relations between 3-D spatial perception and the underlying neural codes. We suggest that the statistics of movements through space determine the topology and the dimensionality of the neural representation, across species and different behavioral modes. We argue that hippocampal place-cell maps are metric in all three dimensions, and might be composed of 2-D and 3-D fragments that are stitched together into a global 3-D metric representation via the 3-D head-direction cells. Finally, we propose that the hippocampal formation might implement a neural analogue of a Kalman filter, a standard engineering algorithm used for 3-D navigation.

Three-dimensional head-direction coding in the bat brain.

Navigation requires a sense of direction ('compass'), which in mammals is thought to be provided by head-direction cells, neurons that discharge when the animal's head points to a specific azimuth. However, it remains unclear whether a three-dimensional (3D) compass exists in the brain. Here we conducted neural recordings in bats, mammals well-adapted to 3D spatial behaviours, and found head-direction cells tuned to azimuth, pitch or roll, or to conjunctive combinations of 3D angles, in both crawling and flying bats. Head-direction cells were organized along a functional-anatomical gradient in the presubiculum, transitioning from 2D to 3D representations. In inverted bats, the azimuth-tuning of neurons shifted by 180°, suggesting that 3D head direction is represented in azimuth × pitch toroidal coordinates. Consistent with our toroidal model, pitch-cell tuning was unimodal, circular, and continuous within the available 360° of pitch. Taken together, these results demonstrate a 3D head-direction mechanism in mammals, which could support navigation in 3D space.

Distributing task-related neural activity across a cortical network through task-independent connections.

Task-related neural activity is widespread across populations of neurons during goal-directed behaviors. However, little is known about the synaptic reorganization and circuit mechanisms that lead to broad activity changes. Here we trained a subset of neurons in a spiking network with strong synaptic interactions to reproduce the activity of neurons in the motor cortex during a decision-making task. Task-related activity, resembling the neural data, emerged across the network, even in the untrained neurons. Analysis of trained networks showed that strong untrained synapses, which were independent of the task and determined the dynamical state of the network, mediated the spread of task-related activity. Optogenetic perturbations suggest that the motor cortex is strongly-coupled, supporting the applicability of the mechanism to cortical networks. Our results reveal a cortical mechanism that facilitates distributed representations of task-variables by spreading the activity from a subset of plastic neurons to the entire network through task-independent strong synapses.

Immunomodulation by poly-YE reduces organophosphate-induced brain damage.

Accidental organophosphate poisoning resulting from environmental or occupational exposure, as well as the deliberate use of nerve agents on the battlefield or by terrorists, remain major threats for multi-casualty events, with no effective therapies yet available. Even transient exposure to organophosphorous compounds may lead to brain damage associated with microglial activation and to long-lasting neurological and psychological deficits. Regulation of the microglial response by adaptive immunity was previously shown to reduce the consequences of acute insult to the central nervous system (CNS). Here, we tested whether an immunization-based treatment that affects the properties of T regulatory cells (Tregs) can reduce brain damage following organophosphate intoxication, as a supplement to the standard antidotal protocol. Rats were intoxicated by acute exposure to the nerve agent soman, or the organophosphate pesticide, paraoxon, and after 24 h were treated with the immunomodulator, poly-YE. A single injection of poly-YE resulted in a significant increase in neuronal survival and tissue preservation. The beneficial effect of poly-YE treatment was associated with specific recruitment of CD4(+) T cells into the brain, reduced microglial activation, and an increase in the levels of brain derived neurotrophic factor (BDNF) in the piriform cortex. These results suggest therapeutic intervention with poly-YE as an immunomodulatory supplementary approach against consequences of organophosphate-induced brain damage.

Attractor dynamics gate cortical information flow during decision-making.

Decisions are held in memory until enacted, which makes them potentially vulnerable to distracting sensory input. Gating of information flow from sensory to motor areas could protect memory from interference during decision-making, but the underlying network mechanisms are not understood. Here, we trained mice to detect optogenetic stimulation of the somatosensory cortex, with a delay separating sensation and action. During the delay, distracting stimuli lost influence on behavior over time, even though distractor-evoked neural activity percolated through the cortex without attenuation. Instead, choice-encoding activity in the motor cortex became progressively less sensitive to the impact of distractors. Reverse engineering of neural networks trained to reproduce motor cortex activity revealed that the reduction in sensitivity to distractors was caused by a growing separation in the neural activity space between attractors that encode alternative decisions. Our results show that communication between brain regions can be gated via attractor dynamics, which control the degree of commitment to an action.

Motor Control: Three-Dimensional Metric of Head Movements in the Mouse Brain.

Many forms of human and animal behavior involve head movements. A new study reveals the neural code for three-dimensional head movements in the midbrain of freely moving mice.

Optimal dynamic coding by mixed-dimensionality neurons in the head-direction system of bats.

Ethologically relevant stimuli are often multidimensional. In many brain systems, neurons with "pure" tuning to one stimulus dimension are found along with "conjunctive" neurons that encode several dimensions, forming an apparently redundant representation. Here we show using theoretical analysis that a mixed-dimensionality code can efficiently represent a stimulus in different behavioral regimes: encoding by conjunctive cells is more robust when the stimulus changes quickly, whereas on long timescales pure cells represent the stimulus more efficiently with fewer neurons. We tested our predictions experimentally in the bat head-direction system and found that many head-direction cells switched their tuning dynamically from pure to conjunctive representation as a function of angular velocity-confirming our theoretical prediction. More broadly, our results suggest that optimal dimensionality depends on population size and on the time available for decoding-which might explain why mixed-dimensionality representations are common in sensory, motor, and higher cognitive systems across species.

A novel immune-based therapy for stroke induces neuroprotection and supports neurogenesis.

The ability of the central nervous system to cope with stressful conditions was shown to be dependent on proper T-cell-mediated immune response. Because the therapeutic window for neuroprotection after acute insults such as stroke is relatively narrow, we searched for a procedure that would allow the relevant T cells to be recruited rapidly. Permanent middle cerebral artery occlusion was induced in adult rats. To facilitate a rapid poststroke T cell activity, rats were treated with poly-YE using different regimens. Control and poly-YE-treated rats were assessed for functional recovery using neurological severity score and Morris water maze. Neuroprotection, neurogenesis, growth factor expression, and microglial phenotype were assessed using histological and immunofluorescence methods. Administration of poly-YE as late as 24 hours after middle cerebral artery occlusion yielded a beneficial effect manifested by better neurological performance, reduced neuronal loss, attenuation of behavioral deficits, and increased hippocampal and cortical neurogenesis. This compound affected the subacute phase by modulating microglial response and by increasing local production of insulin-like growth factor-I, known to be a key player in neuronal survival and neurogenesis. The relative wide therapeutic window, coupled with its efficacy in attenuating further degeneration and enhancing restoration, makes poly-YE a promising immune-based candidate for stroke therapy.

A decade after the Tokyo sarin attack: a review of neurological follow-up of the victims.

OBJECTIVE: On March 20, 1995, sarin gas was used in Tokyo by members of the Japanese "Uhm-Shinrikiu" cult, killing 12 and injuring >5,500 innocent people. Most of the casualties were mildly injured. This article reviews the neurological follow-up data for some of the victims over the past decade. METHODS: We reviewed the published literature regarding neurological follow-up of the victims, dividing the data according to the time elapsed after the attack. RESULTS: The digit span test, finger-tapping test, and computerized posturography were the only performance tests that showed statistically significant differences between the victims and the control groups in some of the surveys. The main sequela 7 years after the attack was post-traumatic stress disorder. CONCLUSIONS: The results emphasize the need for a national preparedness program for such mass casualty events, led by national health systems. This should include long-term, neurological, follow-up monitoring with performance tests and a post-traumatic stress disorder screening test.

Mobile chemical detector (AP2C+SP4E) as an aid for medical decision making in the battlefield.

The combination of the AP2C unit with the SP4E kit composes a lightweight mobile detector of chemical warfare agents (CWA), such as nerve and mustard agents, with both vapor- and liquid-sampling capabilities. This apparatus was recently introduced into our military medical units as an aid for detection of CWA on casualties. Importantly, critical information regarding the applicability in the battlefield was absent. In view of the serious consequences that might follow a proclamation of CWA recognition in battlefield, a high false-positive rate positions the utilization of this apparatus as a medical decision tool in question. We have therefore conducted a field experiment to test the false-positive rate as well as analyze possible factors leading to false-positive readings with this device. The experiment was carried out before and after a 4-day army field exercise, using a standard AP2C device, a SP4E surface sampling kit, and a specially designed medical sampling kit for casualties, intended for medical teams. Soldiers were examined at rest, after mild exercise, and after 4 days in the field. The readings with AP2C alone were compared to the combination of AP2C and SP4E and to the medical sampling kit. Various body fluids served as negative controls. Remarkably, we found a false-positive rate of 57% at rest and after mild exercise, and an even higher rate of 64% after the 4-day field exercise with the AP2C detector alone, as compared to almost no false-positive readings with the combination of AP2C and SP4E. Strikingly, the medical sampling kit has yielded numerous false-positive readings, even in normal body fluids such as blood, urine, and saliva. We therefore see no place for using the medical sampling kit due to an unaccepted high rate of false-positive readings. Finally, we have designed an algorithm that uses the entire apparatus of AP2C and SP4E as a reliable validation tool for medical triage in the setting of exposure to nerve agents in the battlefield.

[Cyanides--treatment beneath the shade of terror].

Although the use of cyanides as warfare agents has not been documented since the Iran-Iraq war in the 1980s, there are rising fears of cyanide being used by terrorists. An Al-Qaeda terror plot to use cyanide gas in the London Underground was foiled in 2002. The threat of similar events becomes more imminent in light of the terror attacks in our country and worldwide, accompanied by statements and threats by fundamentalist leaders to employ chemical weapons. Therefore, mass-intoxication with cyanides is not merely a hypothetical scenario. The treatment of cyanide poisoning is under constant evaluation and there is no international consensus on the subject. The medical treatment of victims at the scene and in hospitals should be rapid and efficient. Current treatment dictates establishing an intravenous line and a slow rate of administration of antidotes. Both demands are not feasible in this specific mass casualty event. The clinical signs of cyanide poisoning are complex, variable and not necessarily obvious for the medical team. There is great interest in reconsidering the existing treatment protocols for cyanide intoxication in light of current research. This review describes the mechanisms of cyanide toxicity, clinical signs of exposure, and current treatment protocols in use worldwide. On the basis of this evidence we suggest a medical treatment protocol for a mass casualty event caused by cyanide.

Vectorial representation of spatial goals in the hippocampus of bats.

To navigate, animals need to represent not only their own position and orientation, but also the location of their goal. Neural representations of an animal's own position and orientation have been extensively studied. However, it is unknown how navigational goals are encoded in the brain. We recorded from hippocampal CA1 neurons of bats flying in complex trajectories toward a spatial goal. We discovered a subpopulation of neurons with angular tuning to the goal direction. Many of these neurons were tuned to an occluded goal, suggesting that goal-direction representation is memory-based. We also found cells that encoded the distance to the goal, often in conjunction with goal direction. The goal-direction and goal-distance signals make up a vectorial representation of spatial goals, suggesting a previously unrecognized neuronal mechanism for goal-directed navigation.

Pharmacologic prophylaxis against nerve agent poisoning.

Nerve agent poisoning is characterized by the rapid progression of toxic signs, including hypersecretions, tremor, convulsions and profound brain damage. In the political arena of today's world, the threat of nerve agent use against military troops has prompted armies to search for prophylactic protection. The two main strategies for prophylaxis include biological scavengers that can bind or cleave nerve agents before they react with acetylcholinesterase, and antidotes as prophylactic treatment. Pyridostigmine is the current pretreatment for nerve agent poisoning and is in use by most of the armed forces in Western countries. However, since pyridostigmine barely crosses the blood-brain barrier it provides no protection against nerve agent-induced central injury. Pyridostigmine is ineffective when administered without post-exposure treatment adjuncts. Therefore, other directions for prophylactic treatment should be explored. These include combinations of carbamates (reversible AChE inhibitors) and central anticholinergics or NMDA receptor antagonists, benzodiazepines or partial agonists for benzodiazepine receptor, and other central AChE inhibitors approved for Alzheimer's disease. The transdermal route is an alternative way for delivering the prophylactic agent. Administration of prophylaxis can be extended also for civilian use during wartime.

[Political poisoning with dioxins--a weapon of chemical "disgracefulness"].

The recent attempt to poison Ukrainian President, Viktor Yuschenko with dioxins, raised public concern regarding this toxic chemical. In industrial countries, there is a constitutive exposure of humans to dioxin compounds, which are formed as by-products in manufacturing processes of various chlorinated organic chemicals and in waste incinerators. Dioxins are extremely stable in the environment and have a low turnover rate in the body--sometimes they are detected years after the original exposure. Of the dioxins, the most notoriously famous is the TCDD (2,3,7,8 tetrachlorodibenzo-p-dioxin). Dioxins exhibit high acute toxicity in various animal species. Humans, however, are considered less susceptible and so far there were no reported deaths following acute dioxin poisoning. Nevertheless, numerous adverse health effects are attributed to dioxin exposure. The most prominent is the chloracne--an acute acneiform eruption, usually appearing on facial skin. There is a solid evidence base that some dioxins are carcinogens. Other long-term deleterious effects of dioxin include: immunosuppression, effects on reproduction, impairments in developmental, neurological and cognitive functions in infants, increased risk for diabetes and cardiovascular diseases and various hormonal alterations. The action of dioxins resembles that of hormones, since their toxicity is mostly receptor-mediated. Dioxins manifest their toxicity in extremely low concentrations. Although there are compounds that exhibit their biological activity at even lower dose range (e.g. nerve gases), this potency of dioxins is considered extraordinary, since there is an every-day exposure to dioxins through environmental vectors mostly via the food chain. Until now, there is no antidotal cure for dioxins, but only symptomatic treatment combined with techniques that accelerate its excretion rate from the body.

[Laboratory methods for detection and identification of biological pathogens].

Laboratory detection and recognition methods of infectious diseases agents have developed markedly in recent years, following the proliferation of nucleic acid and immuno-based detection technologies. The present review summarizes the state of the art in current biorecognition methods: antigenic identification, genetic identification such as PCR, RFLP and FISH, protemics and mass spectrometry. For each method we have specified the technology and qualification required, time to result, specifity and sensitivity, while emphasizing the advantages and disadvantages of using each method for the detection of a given pathogen. Nucleic acid-based detection is more specific and sensitive than immunological-based detection, while the latter is simpler and expected to further development with the improvements in the affinity, specifity and mass production of new immunoglobulins. Protein-based detection methods have an advantage comparing to nucleic acid identification: the presence of the protein approves that the tested gene is functional. Mass spectrometry enables simultaneous detections of multiple proteins and thus holds a promise for new technical developments with a vast array of applications. Most physicians do not practice biodetection technologies in their every day routine, but encounter those terms in their clinical and academic work. The review aims to display basic information in this field in order to enable a common language with basic science specialists.

The role of glutamate and the immune system in organophosphate-induced CNS damage.

Organophosphate (OP) poisoning is associated with long-lasting neurological damage, which is attributed mainly to the excessive levels of glutamate caused by the intoxication. Glutamate toxicity, however, is not specific to OP poisoning, and is linked to propagation of damage in both acute and chronic neurodegenerative conditions in the central nervous system (CNS). In addition to acute excitotoxic effects of glutamate, there is now a growing amount of evidence of its intricate immunomodulatory effects in the brain, involving both the innate and the adaptive immune systems. Moreover, it was demonstrated that immunomodulatory treatments, aimed at regulating the interaction between the resident immune cells of the brain (microglia) and the peripheral immune system, can support buffering of excessive levels of glutamate and restoration of the homeostasis. In this review, we will discuss the role of glutamate as an excitotoxic agent in the acute phase of OP poisoning, and the possible functions it may have as both a neuroprotectant and an immunomodulator in the sub-acute and chronic phases of OP poisoning. In addition, we will describe the novel immune-based neuroprotective strategies aimed at counteracting the long-term neurodegenerative effects of glutamate in the CNS.

Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing fatal neurodegenerative disorder characterized by the selective death of motor neurons (MN) in the spinal cord, and is associated with local neuroinflammation. Circulating CD4(+) T cells are required for controlling the local detrimental inflammation in neurodegenerative diseases, and for supporting neuronal survival, including that of MN. T-cell deficiency increases neuronal loss, while boosting T cell levels reduces it. Here, we show that in the mutant superoxide dismutase 1 G93A (mSOD1) mouse model of ALS, the levels of natural killer T (NKT) cells increased dramatically, and T-cell distribution was altered both in lymphoid organs and in the spinal cord relative to wild-type mice. The most significant elevation of NKT cells was observed in the liver, concomitant with organ atrophy. Hepatic expression levels of insulin-like growth factor (IGF)-1 decreased, while the expression of IGF binding protein (IGFBP)-1 was augmented by more than 20-fold in mSOD1 mice relative to wild-type animals. Moreover, hepatic lymphocytes of pre-symptomatic mSOD1 mice were found to secrete significantly higher levels of cytokines when stimulated with an NKT ligand, ex-vivo. Immunomodulation of NKT cells using an analogue of α-galactosyl ceramide (α-GalCer), in a specific regimen, diminished the number of these cells in the periphery, and induced recruitment of T cells into the affected spinal cord, leading to a modest but significant prolongation of life span of mSOD1 mice. These results identify NKT cells as potential players in ALS, and the liver as an additional site of major pathology in this disease, thereby emphasizing that ALS is not only a non-cell autonomous, but a non-tissue autonomous disease, as well. Moreover, the results suggest potential new therapeutic targets such as the liver for immunomodulatory intervention for modifying the disease, in addition to MN-based neuroprotection and systemic treatments aimed at reducing oxidative stress.