Thalamo-hippocampal pathway regulates incidental memory capacity in mice.

Incidental memory can be challenged by increasing either the retention delay or the memory load. The dorsal hippocampus (dHP) appears to help with both consolidation from short-term (STM) to long-term memory (LTM), and higher memory loads, but the mechanism is not fully understood. Here we find that female mice, despite having the same STM capacity of 6 objects and higher resistance to distraction in our different object recognition task (DOT), when tested over 1 h or 24 h delays appear to transfer to LTM only 4 objects, whereas male mice have an STM capacity of 6 objects in this task. In male mice the dHP shows greater activation (as measured by c-Fos expression), whereas female mice show greater activation of the ventral midline thalamus (VMT). Optogenetic inhibition of the VMT-dHP pathway during off-line memory consolidation enables 6-object LTM retention in females, while chemogenetic VMT-activation impairs it in males. Thus, removing or enhancing sub-cortical inhibitory control over the hippocampus leads to differences in incidental memory.

Modulation of perception and brain activity by predictable trajectories of facial expressions.

People track facial expression dynamics with ease to accurately perceive distinct emotions. Although the superior temporal sulcus (STS) appears to possess mechanisms for perceiving changeable facial attributes such as expressions, the nature of the underlying neural computations is not known. Motivated by novel theoretical accounts, we hypothesized that visual and motor areas represent expressions as anticipated motion trajectories. Using magnetoencephalography, we show predictable transitions between fearful and neutral expressions (compared with scrambled and static presentations) heighten activity in visual cortex as quickly as 165 ms poststimulus onset and later (237 ms) engage fusiform gyrus, STS and premotor areas. Consistent with proposed models of biological motion representation, we suggest that visual areas predictively represent coherent facial trajectories. We show that such representations bias emotion perception of subsequent static faces, suggesting that facial movements elicit predictions that bias perception. Our findings reveal critical processes evoked in the perception of dynamic stimuli such as facial expressions, which can endow perception with temporal continuity.

Modifying interleukin-2 concentrations during culture improves function of T cells for adoptive immunotherapy.

BACKGROUND: Adoptive immunotherapy with cytotoxic T cells has shown promising clinical results in patients with metastatic melanoma and post-transplant-associated viral infections. Cell transfer therapies often require the ex vivo expansion of large numbers of reactive lymphocytes. Therefore interleukin-2 (IL-2), a potent T-cell mitogenic cytokine that critically affects the features and effectiveness of T cells, is frequently added to cell culture media. METHODS: We examined the influence of various IL-2 concentrations on cell growth, cytotoxicity, cytokine release and surface marker expression of tumor-infiltrating lymphocytes (TIL) during a standard 14-day rapid expansion phase. The study was conducted under good manufacturing practice (GMP) conditions, using approved reagents in a class 10000 laboratory. RESULTS: T-cell cultures grown in very high IL-2 concentrations (600-6000 IU/mL) expanded massively and maximally secreted interferon (IFN)-gamma in response to antigenic stimulation, but exhibited only low direct cytotoxicity. On the other hand, TIL cultures grown in low concentrations of IL-2 throughout the rapid expansion phase expanded to a lower extent and barely secreted IFN-gamma but displayed high cytotoxic activity. A combined approach of starting with 10-120 IU/mL IL-2 during the first week, followed by increasing the IL-2 concentration to 6000 IU/mL during the second week, results in T cells that expand well, maximally produce IFN-gamma and are highly cytotoxic against tumor cells. DISCUSSION: Fine tuning of the IL-2 concentration during ex vivo expansion of T cells can yield high numbers of T cells with optimal features for clinical use.

What is the mammalian dentate gyrus good for?

In the mammalian hippocampus, the dentate gyrus (DG) is characterized by sparse and powerful unidirectional projections to CA3 pyramidal cells, the so-called mossy fibers (MF). The MF form a distinct type of synapses, rich in zinc, that appear to duplicate, in terms of the information they convey, what CA3 cells already receive from entorhinal cortex layer II cells, which project both to the DG and to CA3. Computational models have hypothesized that the function of the MF is to enforce a new, well-separated pattern of activity onto CA3 cells, to represent a new memory, prevailing over the interference produced by the traces of older memories already stored on CA3 recurrent collateral connections. Although behavioral observations support the notion that the MF are crucial for decorrelating new memory representations from previous ones, a number of findings require that this view be reassessed and articulated more precisely in the spatial and temporal domains. First, neurophysiological recordings indicate that the very sparse dentate activity is concentrated on cells that display multiple but disorderly place fields, unlike both the single fields typical of CA3 and the multiple regular grid-aligned fields of medial entorhinal cortex. Second, neurogenesis is found to occur in the adult DG, leading to new cells that are functionally added to the existing circuitry, and may account for much of its ongoing activity. Third, a comparative analysis suggests that only mammals have evolved a DG, despite some of its features being present also in reptiles, whereas the avian hippocampus seems to have taken a different evolutionary path. Thus, we need to understand both how the mammalian dentate operates, in space and time, and whether evolution, in other vertebrate lineages, has offered alternative solutions to the same computational problems.

Hippocampal shape differences in dementia with Lewy bodies.

To assess the morphological changes of the hippocampus in Lewy body dementia (LBD) patients we used radial atrophy mapping, a mathematical modeling method sensitive to subtle differences in hippocampal shape. T1-weighted high resolution magnetic resonance (MR) scans were acquired from 14 LBD and 28 controls of similar age and gender, and were compared to those of 28 patients with Alzheimer's disease (AD) described previously. MR images were normalized by linear (12 parameter) transformation to a customized template. The hippocampal formation was isolated by manual tracing. Group differences were assessed with algorithms that average hippocampal shapes across subjects, using three-dimensional parametric surface mesh models. In LBD patients, significant tissue loss amounting to 10-20% was found in the hippocampal subregions corresponding to the anterior portion of the CA1 field on both sides, along the longitudinal midline in the dorsal aspect within the CA2-3 field, and in the subiculum and presubiculum. The direct comparisons between LBD and AD patients showed that this pattern of local atrophy is different from that characteristic of AD. LBD pattern of hippocampal atrophy might be related to the peculiar neuropathology of the disease.

Face adaptation aftereffects reveal anterior medial temporal cortex role in high level category representation.

Previous studies have shown reductions of the functional magnetic resonance imaging (fMRI) signal in response to repetition of specific visual stimuli. We examined how adaptation affects the neural responses associated with categorization behavior, using face adaptation aftereffects. Adaptation to a given facial category biases categorization towards non-adapted facial categories in response to presentation of ambiguous morphs. We explored a hypothesis, posed by recent psychophysical studies, that these adaptation-induced categorizations are mediated by activity in relatively advanced stages within the occipitotemporal visual processing stream. Replicating these studies, we find that adaptation to a facial expression heightens perception of non-adapted expressions. Using comparable behavioral methods, we also show that adaptation to a specific identity heightens perception of a second identity in morph faces. We show both expression and identity effects to be associated with heightened anterior medial temporal lobe activity, specifically when perceiving the non-adapted category. These regions, incorporating bilateral anterior ventral rhinal cortices, perirhinal cortex and left anterior hippocampus are regions previously implicated in high-level visual perception. These categorization effects were not evident in fusiform or occipital gyri, although activity in these regions was reduced to repeated faces. The findings suggest that adaptation-induced perception is mediated by activity in regions downstream to those showing reductions due to stimulus repetition.

Theoretical model of neuronal population coding of stimuli with both continuous and discrete dimensions.

In a recent study, the initial rise of the mutual information between the firing rates of N neurons and a set of p discrete stimuli has been analytically evaluated, under the assumption that neurons fire independently of one another to each stimulus and that each conditional distribution of firing rates is Gaussian. Yet real stimuli or behavioral correlates are high dimensional, with both discrete and continuously varying features. Moreover, the Gaussian approximation implies negative firing rates, which is biologically implausible. Here, we generalize the analysis to the case where the stimulus or behavioral correlate has both a discrete and a continuous dimension, like orientation and shape could be in a visual stimulus, or type and direction in a motor action. The functional relationship between the firing patterns and the continuous correlate is expressed through the tuning curve of the neuron, using two different parameters to modulate its width and its flatness. In the case of large noise, we evaluate the mutual information up to the quadratic approximation as a function of population size. We also show that in the limit of large N and assuming that neurons can discriminate between continuous values with a resolution Delta(theta), the mutual information grows to infinity like ln(1/Delta(theta)) when Delta(theta) goes to zero. Then we consider a more realistic distribution of firing rates, truncated at zero, and we prove that the resulting correction, with respect to the Gaussian firing rates, can be expressed simply as a renormalization of the noise parameter. Finally, we demonstrate the effect of averaging the distribution across the discrete dimension, evaluating the mutual information only with respect to the continuously varying correlate.

Characterization of the variability of glutamatergic synaptic responses to presynaptic trains in rat hippocampal pyramidal neurons.

Excitatory postsynaptic currents from CA3 hippocampal neurons, elicited by trains of presynaptic action potentials either in mossy fibres or associative commissural fibres, have been analysed, by using a quantal analysis approach, in order to characterize their variability and the correlation among successive responses. As quantal parameters may change during the train according to the previous release events, correlation within consecutive EPSCs is expected. We tested simple hypotheses on how quantal parameters p and N may change on the basis of correlation detection in EPSCs. The statistical significance of these tests has been evaluated. The tests showed that, although simple binomial distributions can give a good description of synaptic responses at the level of single spikes, only stochastic chains can always account for correlations observed within the train. A systematic model fitting procedure has been developed and applied to extract information on the dynamics of synaptic transmission. As an application of this novel type of analysis, a measure of transmitted information to be associated with synaptic variability, a quantity that allows an estimate of the capability of the synapse to transmit reliable information in time, is proposed. We showed that this transmitted information depends on short-term plasticity and that the change in the type of short-term plasticity from facilitating to depressing obtained by increasing the extracellular calcium concentration results in a change of the related transmitted information.

Representational capacity of a set of independent neurons.

The capacity with which a system of independent neuron-like units represents a given set of stimuli is studied by calculating the mutual information between the stimuli and the neural responses. Both discrete noiseless and continuous noisy neurons are analyzed. In both cases, the information grows monotonically with the number of neurons considered. Under the assumption that neurons are independent, the mutual information rises linearly from zero, and approaches exponentially its maximum value. We find the dependence of the initial slope on the number of stimuli and on the sparseness of the representation.

Theory and method in studies of vigilance and aggregation.

Predation is considered one of the most important selective pressures on free-ranging animals. Our understanding of it derives mainly from studies of individual vigilance (visual scanning of the surroundings beyond the immediate vicinity) and aggregation in prey. Vigilance bears a direct relationship to aggregation, because animals in groups may rely on associates for early warning of danger. This review addresses the relationship between vigilance and aggregation with particular attention to the prediction that individual vigilance declines with increasing group size. Contrary to most other animals studied, primates do not support the prediction. Exploring this, I examined the assumptions underlying vigilance theory in the light of primate behaviour. First I tested whether manual harvesting and upright processing of food as seen among primates might permit them to feed and scan simultaneously. I found no support for this idea. Next I examined the targets of primate vigilance and found that one component (within-group vigilance) might explain the differences between primates and other animals. Finally, I evaluated whether individual primates in large groups face a lower risk of predation than those in small groups. A conclusion was impossible, but by separating group-level from individual-level risk, I was able to identify several common circumstances in which group size would not predict individual risk or vigilance. These circumstances arose for primates and nonprimates alike. I concluded that the relationship of vigilance to aggregation is not straightforward. The absence of a group-size effect on vigilance among primates is probably due to functional differences in vigilance behaviour or safety in groups, not to methodological differences. Furthermore, future work on animal vigilance and aggregation must fully consider both the targets of glances, and the assumption that larger groups are safer from predators. I predict that animals will not relax vigilance in larger groups if conspecific threat increases with group size. Group size will not predict individual risk of predation nor individual vigilance rates when predators do not rely on surprise, or when predators select a small subset of highly vulnerable group members. Copyright 2000 The Association for the Study of Animal Behaviour.

Analytical model for the effects of learning on spike count distributions.

The spike count distribution observed when recording from a variety of neurons in many different conditions has a fairly stereotypical shape, with a single mode at zero or close to a low average count, and a long, quasi-exponential tail to high counts. Such a distribution has been suggested to be the direct result of three simple facts: the firing frequency of a typical cortical neuron is close to linear in the summed input current entering the soma, above a threshold; the input current varies on several timescales, both faster and slower than the window used to count spikes; and the input distribution at any timescale can be taken to be approximately normal. The third assumption is violated by associative learning, which generates correlations between the synaptic weight vector on the dendritic tree of a neuron, and the input activity vectors it is repeatedly subject to. We show analytically that for a simple feed-forward model, the normal distribution of the slow components of the input current becomes the sum of two quasi-normal terms. The term important below threshold shifts with learning, while the term important above threshold does not shift but grows in width. These deviations from the standard distribution may be observable in appropriate recording experiments.

Correlations and the encoding of information in the nervous system.

Is the information transmitted by an ensemble of neurons determined solely by the number of spikes fired by each cell, or do correlations in the emission of action potentials also play a significant role? We derive a simple formula which enables this question to be answered rigorously for short time-scales. The formula quantifies the corrections to the instantaneous information rate which result from correlations in spike emission between pairs of neurons. The mutual information that the ensemble of neurons conveys about external stimuli can thus be broken down into firing rate and correlation components. This analysis provides fundamental constraints upon the nature of information coding, showing that over short time-scales correlations cannot dominate information representation, that stimulus-independent correlations may lead to synergy (where the neurons together convey more information than they would if they were considered independently), but that only certain combinations of the different sources of correlation result in significant synergy rather than in redundancy or in negligible effects. This analysis leads to a new quantification procedure which is directly applicable to simultaneous multiple neuron recordings.

Simultaneous X-Ray and TeV Observations of a Rapid Flare from Markarian 421.

Mrk 421 was observed for about 2 days with BeppoSAX in 1998 April as part of a worldwide multiwavelength campaign. A large, well-defined flare was observed in X-rays. The same flare was observed simultaneously at TeV energies by the Whipple Observatory gamma-ray telescope. These data provide (1) the first evidence that the X-ray and TeV intensities are well correlated on timescales of hours and (2) the first exactly simultaneous X-ray and TeV spectra. The results imply that the X-ray and TeV photons derive from the same region and from the same population of relativistic electrons. The physical parameters deduced from a homogeneous synchrotron self-Compton model for the spectral energy distribution yield electron cooling times close to the observed variability timescales.

On decoding the responses of a population of neurons from short time windows.

The effectiveness of various stimulus identification (decoding) procedures for extracting the information carried by the responses of a population of neurons to a set of repeatedly presented stimuli is studied analytically, in the limit of short time windows. It is shown that in this limit, the entire information content of the responses can sometimes be decoded, and when this is not the case, the lost information is quantified. In particular, the mutual information extracted by taking into account only the most likely stimulus in each trial turns out to be, if not equal, much closer to the true value than that calculated from all the probabilities that each of the possible stimuli in the set was the actual one. The relation between the mutual information extracted by decoding and the percentage of correct stimulus decodings is also derived analytically in the same limit, showing that the metric content index can be estimated reliably from a few cells recorded from brief periods. Computer simulations as well as the activity of real neurons recorded in the primate hippocampus serve to confirm these results and illustrate the utility and limitations of the approach.

Within-group vigilance in red colobus and redtail monkeys.

In theory, animals are expected to relax vigilance in the safety of large groups. Four controlled studies of primates have failed to detect relaxed vigilance as group size increases. The counter-intuitive behavior of primates might arise if another component of vigilance increases with group size, masking any decrease in outward, anti-predator vigilance. Surveillance of associates is a major component of primate vigilance and might be expected to increase with group size due to an increase in competitive interactions. The present analysis uses data on glances toward associates to determine if within-group surveillance is related to group size in wild red colobus and redtail monkeys of Uganda. Although males glance at associates more frequently during mating periods and females glance at associates more often when infants are young or out of contact, there was no evidence of a group-size effect on within-group surveillance. As with previous studies, primate vigilance patterns reflect reproductive strategies such as infant protection and mate defense. This study joins several others that indicate that primate vigilance is unresponsive to group size. New models that take into account association patterns below the level of the group may be needed.

Firing rate distributions and efficiency of information transmission of inferior temporal cortex neurons to natural visual stimuli.

The distribution of responses of sensory neurons to ecological stimulation has been proposed to be designed to maximize information transmission, which according to a simple model would imply an exponential distribution of spike counts in a given time window. We have used recordings from inferior temporal cortex neurons responding to quasi-natural visual stimulation (presented using a video of everyday lab scenes and a large number of static images of faces and natural scenes) to assess the validity of this exponential model and to develop an alternative simple model of spike count distributions. We find that the exponential model has to be rejected in 84% of cases (at the p < 0.01 level). A new model, which accounts for the firing rate distribution found in terms of slow and fast variability in the inputs that produce neuronal activation, is rejected statistically in only 16% of cases. Finally, we show that the neurons are moderately efficient at transmitting information but not optimally efficient.

Risk and opportunity for humans coexisting with large carnivores.

Models of Plio-Pleistocene hominid behavioral ecology often emphasize competition with large carnivores. This paper describes competition between modern humans and large carnivores in rural Uganda, including active, confrontational scavenging of carnivore kills by humans and carnivore attacks on humans. Information gathered from Ugandan Game Department archives (1923-1994) reveals that twentieth-century agropastoralists regularly tried to scavenge from leopard (Panthera pardus) and lion (Panthera leo) kills, and that these large carnivores have preyed on hundreds of humans in Uganda over the past several decades. Men were most often targets of carnivore attack, particularly while engaged in hunting-related activities. However attacks on men were less often lethal than attacks on women and children. Analyses show that lion attacks were more dangerous than leopard attacks. These data support recent contentions that hominids armed with even simple weapons can succeed in active, confrontational scavenging by chasing carnivores from kills. Hominids sharing East African habitats with large carnivores may have been regularly subject to attack.