Explore the vast range of titles available.

The intracerebral local field potential (LFP) is a measure of brain activity that reflects the highly dynamic flow of information across neural networks. This is a composite signal that receives contributions from multiple neural sources, yet interpreting its nature and significance may be hindered by several confounding factors and technical limitations. By and large, the main factor defining the amplitude of LFPs is the geometry of the current sources, over and above the degree of synchronization or the properties of the media. As such, similar levels of activity may result in potentials that differ in several orders of magnitude in different populations. The geometry of these sources has been experimentally inaccessible until intracerebral high density recordings enabled the co-activating sources to be revealed. Without this information, it has proven difficult to interpret a century's worth of recordings that used temporal cues alone, such as event or spike related potentials and frequency bands. Meanwhile, a collection of biophysically ill-founded concepts have been considered legitimate, which can now be corrected in the light of recent advances. The relationship of LFPs to their sources is often counterintuitive. For instance, most LFP activity is not local but remote, it may be larger further from rather than close to the source, the polarity does not define its excitatory or inhibitory nature, and the amplitude may increase when source's activity is reduced. As technological developments foster the use of LFPs, the time is now ripe to raise awareness of the need to take into account spatial aspects of these signals and of the errors derived from neglecting to do so.

Hippocampal firing is organized in theta sequences controlled by internal memory processes and by external sensory cues, but how these computations are coordinated is not fully understood. Although theta activity is commonly studied as a unique coherent oscillation, it is the result of complex interactions between different rhythm generators. Here, by separating hippocampal theta activity in three different current generators, we found epochs with variable theta frequency and phase coupling, suggesting flexible interactions between theta generators. We found that epochs of highly synchronized theta rhythmicity preferentially occurred during behavioral tasks requiring coordination between internal memory representations and incoming sensory information. In addition, we found that gamma oscillations were associated with specific theta generators and the strength of theta-gamma coupling predicted the synchronization between theta generators. We propose a mechanism for segregating or integrating hippocampal computations based on the flexible coordination of different theta frameworks to accommodate the cognitive needs. In the brain, a vast number of neurons coordinate their activity to support complex cognitive processes. One of the best places to see this in action is the hippocampus, a brain structure with a key role in memory and navigation. The hippocampus shows waves of electrical activity, which represent the synchronized firing of large numbers of neurons. The hippocampus can generate multiple rhythms at once. The two main rhythms are theta and gamma. Theta waves are slow, with a frequency of about 8 Hertz. Gamma waves are faster with a frequency of up to 120 Hertz or even more. Theta waves are always present in the brains of freely moving animals, whereas gamma waves occur in brief bursts. These bursts usually correspond to a particular point on the theta wave. One burst may occur just before each peak of the theta wave, for example, whereas another burst may occur just after the peak. This separation enables individual bursts of gamma to carry different messages without them becoming mixed up. This is similar to how radio stations broadcast their signals at different carrier frequencies to avoid interference. By recording hippocampal activity in rats exploring a maze, Lopez-Madrona et al. now show that the hippocampus has not one, but three generators of theta waves. Having three sources of theta, each of which can be synchronized with gamma, provides a more versatile system for encoding and sending information. It also means that the three theta generators can vary the degree to which they coordinate their firing. This helps the brain combine or separate streams of information as required. By working together to create a single theta rhythm, for example, the three theta generators can help animals combine information stored in memory with incoming sensory input. How the coordination of theta rhythms in the hippocampus influences the activity of other brain regions involved in learning and memory remains unclear. However, uncoupling of theta and gamma waves seems to be an early sign of Alzheimer’s disease and can also be seen in the brains of people with schizophrenia and other psychiatric disorders. Understanding how this process occurs could provide clues to the origin of these disorders.

Spreading depolarizations (SDs) are classically thought to be associated with spreading depression of cortical activity. Here, we found that SDs in patients with subarachnoid hemorrhage produce variable, ranging from depression to booming, changes in electrocorticographic activity, especially in the delta frequency band. In rats, depression of activity was characteristic of high-potassium-induced full SDs, whereas partial superficial SDs caused either little change or a boom of activity at the cortical vertex, supported by volume conduction of signals from spared delta generators in the deep cortical layers. Partial SDs also caused moderate neuronal depolarization and sustained excitation, organized in gamma oscillations in a narrow sub-SD zone. Thus, our study challenges the concept of homology between spreading depolarization and spreading depression by showing that SDs produce variable, from depression to booming, changes in activity at the cortical surface and in different cortical layers depending on the depth of SD penetration. Spreading depolarizations are classically thought to be associated with depression of cortical activity. Here, authors show variable, from depression to booming, changes in cortical activity during different types of spreading depolarizations.

Santiago Ramón y Cajal’s pioneering work laid the foundations for modern neuroscience and continues to impact the development of artificial intelligence, particularly deep learning. His neuron theory, the principle of dynamic polarization, and his insights into brain plasticity and network organization have significantly influenced both our understanding of the nervous system and the design of artificial neural networks. This article reviews Cajal’s key contributions, explores their role in the evolution of AI, and emphasizes the enduring links between neuroscience and machine learning in the digital era.

Background When a patient arrives in the emergency department following a stroke, a traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug available to help protect their jeopardized neurons. One crucial reason is that we have not identified the molecular mechanisms leading to electrical failure, neuronal swelling, and blood vessel constriction in newly injured gray matter. All three result from a process termed spreading depolarization (SD). Because we only partially understand SD, we lack molecular targets and biomarkers to help neurons survive after losing their blood flow and then undergoing recurrent SD. Methods In this review, we introduce SD as a single or recurring event, generated in gray matter following lost blood flow, which compromises the Na + /K + pump. Electrical recovery from each SD event requires so much energy that neurons often die over minutes and hours following initial injury, independent of extracellular glutamate. Results We discuss how SD has been investigated with various pitfalls in numerous experimental preparations, how overtaxing the Na + /K + ATPase elicits SD. Elevated K + or glutamate are unlikely natural activators of SD. We then turn to the properties of SD itself, focusing on its initiation and propagation as well as on computer modeling. Conclusions Finally, we summarize points of consensus and contention among the authors as well as where SD research may be heading. In an accompanying review, we critique the role of the glutamate excitotoxicity theory, how it has shaped SD research, and its questionable importance to the study of early brain injury as compared with SD theory.

It is unclear whether the two hippocampal lobes convey similar or different activities and how they cooperate. Spatial discrimination of electric fields in anesthetized rats allowed us to compare the pathway-specific field potentials corresponding to the gamma-paced CA3 output (CA1 Schaffer potentials) and CA3 somatic inhibition within and between sides. Bilateral excitatory Schaffer gamma waves are generally larger and lead from the right hemisphere with only moderate covariation of amplitude, and drive CA1 pyramidal units more strongly than unilateral waves. CA3 waves lock to the ipsilateral Schaffer potentials, although bilateral coherence was weak. Notably, Schaffer activity may run laterally, as seen after the disruption of the connecting pathways. Thus, asymmetric operations promote the entrainment of CA3-autonomous gamma oscillators bilaterally, synchronizing lateralized gamma strings to converge optimally on CA1 targets. The findings support the view that interhippocampal connections integrate different aspects of information that flow through the left and right lobes. In humans and other backboned animals, the brain is divided into the left and right hemispheres, which are connected by several large bundles of nerve fibers. Thanks to these fiber tracts, sensory information from each side of the body can reach both sides of the brain. However, although many areas of the brain work with a counterpart on the opposite hemisphere to process this sensory information, they do not necessarily perform the same tasks, or perform them at the same time as their partner. The hippocampus is a brain region that helps to support navigation, to detect novelty, and to produce memories. In fact, our brains contain two hippocampi – one in each hemisphere. Previous studies of the hippocampus have tended to record from only one side of the brain. Benito, Martín-Vázquez, Makarova et al. now compare the activity of the left and right hippocampi, and consider how the two structures might work together. Recordings of the electrical activity of the hippocampi of anesthetized rats show that different groups of neurons fire in rhythmic sequence, forming waves called gamma waves. Successive waves have different amplitudes, and can be thought to form ‘strings’. The recordings made by Benito et al. show that the two hippocampi produce parallel strings of waves, although the waves that originate in the right hemisphere are generally larger than those that originate in the left. Right-hemisphere waves also tend to begin slightly earlier than their left-hemisphere counterparts. Further experiments revealed that disrupting the fiber tracts between the hemispheres uncouples the waves that no longer occur at the same time, and the strings of waves may remain constrained to one side of the brain. In healthy animals, however, the right-hand dominance acts as a master-slave device, and makes the waves from the two hemispheres pair up and merge in the neurons that receive them both. Thus the information running in both hippocampi can be integrated or compared before sending to the cortex for task execution or storage. Overall, the findings reported by Benito et al. suggest that different types of information flow through the left and right hemispheres, and that the brain integrates these two streams using asymmetric connections. The next challenge is to identify how the information in the two streams differs: whether each stream reflects different sensory stimuli, different features of a scene, or the difference between recalled and perceived information.

Field potential (FP) recording is an accessible means to capture the shifts in the activity of neuron populations. However, the spatial and composite nature of these signals has largely been ignored, at least until it became technically possible to separate activities from co-activated sources in different structures or those that overlap in a volume. The pathway-specificity of mesoscopic sources has provided an anatomical reference that facilitates transcending from theoretical analysis to the exploration of real brain structures. We review computational and experimental findings that indicate how prioritizing the spatial geometry and density of sources, as opposed to the distance to the recording site, better defines the amplitudes and spatial reach of FPs. The role of geometry is enhanced by considering that zones of the active populations that act as sources or sinks of current may arrange differently with respect to each other, and have different geometry and densities. Thus, observations that seem counterintuitive in the scheme of distance-based logic alone can now be explained. For example, geometric factors explain why some structures produce FPs and others do not, why different FP motifs generated in the same structure extend far while others remain local, why factors like the size of an active population or the strong synchronicity of its neurons may fail to affect FPs, or why the rate of FP decay varies in different directions. These considerations are exemplified in large structures like the cortex and hippocampus, in which the role of geometrical elements and regional activation in shaping well-known FP oscillations generally go unnoticed. Discovering the geometry of the sources in play will decrease the risk of population or pathway misassignments based solely on the FP amplitude or temporal pattern.

The role of interhemispheric connections along successive segments of cortico-hippocampal circuits is poorly understood. We aimed to obtain a global picture of spontaneous transfer of activity during non-theta states across several nodes of the bilateral circuit in anesthetized rats. Spatial discrimination techniques applied to bilateral laminar field potentials (FP) across the CA1/Dentate Gyrus provided simultaneous left and right readouts in five FP generators that reflect activity in specific hippocampal afferents and associative pathways. We used a battery of correlation and coherence analyses to extract complementary aspects at different time scales and frequency bands. FP generators exhibited varying bilateral correlation that was high in CA1 and low in the Dentate Gyrus. The submillisecond delays indicate coordination but not support for synaptic dependence of one side on another. The time and frequency characteristics of bilateral coupling were specific to each generator. The Schaffer generator was strongly bilaterally coherent for both sharp waves and gamma waves, although the latter maintained poor amplitude co-variation. The lacunosum-moleculare generator was composed of up to three spatially overlapping activities, and globally maintained high bilateral coherence for long but not short (gamma) waves. These two CA1 generators showed no ipsilateral relationship in any frequency band. In the Dentate Gyrus, strong bilateral coherence was observed only for input from the medial entorhinal areas, while those from the lateral entorhinal areas were largely asymmetric, for both alpha and gamma waves. Granger causality testing showed strong bidirectional relationships between all homonymous bilateral generators except the lateral entorhinal input and a local generator in the Dentate Gyrus. It also revealed few significant relationships between ipsilateral generators, most notably the anticipation of lateral entorhinal cortex toward all others. Thus, with the notable exception of the lateral entorhinal areas, there is a marked interhemispheric coherence primarily for slow envelopes of activity, but not for pulse-like gamma waves, except in the Schafer segment. The results are consistent with essentially different streams of activity entering from and returning to the cortex on each side, with slow waves reflecting times of increased activity exchange between hemispheres and fast waves generally reflecting ipsilateral processing.

Cognitive decline is one of the many characteristics of aging. Reduced long‐term potentiation (LTP) and long‐term depression (LTD) are thought to be responsible for this decline, although the precise mechanisms underlying LTP and LTD dampening in the old remain unclear. We previously showed that aging is accompanied by the loss of cholesterol from the hippocampus, which leads to PI3K/Akt phosphorylation. Given that Akt de‐phosphorylation is required for glutamate receptor internalization and LTD, we hypothesized that the decrease in cholesterol in neuronal membranes may contribute to the deficits in LTD typical of aging. Here, we show that cholesterol loss triggers p‐Akt accumulation, which in turn perturbs the normal cellular and molecular responses induced by LTD, such as impaired AMPA receptor internalization and its reduced lateral diffusion. Electrophysiology recordings in brain slices of old mice and in anesthetized elderly rats demonstrate that the reduced hippocampal LTD associated with age can be rescued by cholesterol perfusion. Accordingly, cholesterol replenishment in aging animals improves hippocampal‐dependent learning and memory in the water maze test. Synopsis It is well established that cognitive deficits go hand in hand with aging. Restoring cholesterol levels in the aged hippocampus to values found in the young can rescue learning and memory in the old, linking age‐dependent cholesterol decline with synaptic plasticity and neuronal function. A mild yet significant reduction in membrane cholesterol characterizes the aging rodent hippocampus. Low synaptic hippocampal cholesterol determines reduced Akt dephosphorylation after NMDA‐induced LTD, together with reduced glutamate (AMPA) receptor lateral diffusion and endocytosis. Low synaptic hippocampal cholesterol plays a role in the poor LTD of old mice and rats, in ex‐vivo and in vivo paradigms. Normal levels of pAkt after NMDA, proper receptor lateral diffusion, and internalization and normal (young animals‐like) LTD in the old can be rescued by membrane cholesterol replenishment. Cholesterol replenishment in living old rats improves learning and memory. Graphical Abstract It is well established that cognitive deficits go hand in hand with aging. Restoring cholesterol levels in the aged hippocampus to values found in the young can rescue learning and memory in the old, linking age‐dependent cholesterol decline with synaptic plasticity and neuronal function.

Physiological and electron microscope studies have shown that synapses are functionally and morphologically heterogeneous and that variations in size of synaptic junctions are related to characteristics such as release probability and density of postsynaptic AMPA receptors. The present article focuses on how these morphological variations impact synaptic transmission. We based our study on Monte Carlo computational simulations of simplified model synapses whose morphological features have been extracted from hundreds of actual synaptic junctions reconstructed by three-dimensional electron microscopy. We have examined the effects that parameters such as synaptic size or density of AMPA receptors have on the number of receptors that open after release of a single synaptic vesicle. Our results indicate that the maximum number of receptors that will open after the release of a single synaptic vesicle may show a ten-fold variation in the whole population of synapses. When individual synapses are considered, there is also a stochastical variability that is maximal in small synapses with low numbers of receptors. The number of postsynaptic receptors and the size of the synaptic junction are the most influential parameters, while the packing density of receptors or the concentration of extrasynaptic transporters have little or no influence on the opening of AMPA receptors.