Correlation dimension of high-dimensional and high-definition experimental time series.

The correlation dimension (CD) is a nonlinear measure of the complexity of invariant sets. First introduced for describing low-dimensional chaotic attractors, it has been later extended to the analysis of experimental electroencephalographic (EEG), magnetoencephalographic (MEG), and local field potential (LFP) recordings. However, its direct application to high-dimensional (dozens of signals) and high-definition (kHz sampling rate) 2HD data revealed a controversy in the results. We show that the need for an exponentially long data sample is the main difficulty in dealing with 2HD data. Then, we provide a novel method for estimating CD that enables orders of magnitude reduction of the required sample size. The approach decomposes raw data into statistically independent components and estimates the CD for each of them separately. In addition, the method allows ongoing insights into the interplay between the complexity of the contributing components, which can be related to different anatomical pathways and brain regions. The latter opens new approaches to a deeper interpretation of experimental data. Finally, we illustrate the method with synthetic data and LFPs recorded in the hippocampus of a rat.

Diversity of cortical activity changes beyond depression during Spreading Depolarizations.

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.

Uncorrelated bilateral cortical input becomes timed across hippocampal subfields for long waves whereas gamma waves are largely ipsilateral.

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.

A dietary polyphenol metabolite alters CA1 excitability ex vivo and mildly affects cortico-hippocampal field potential generators in anesthetized animals.

Dietary polyphenols have beneficial effects in situations of impaired cognition in acute models of neurodegeneration. The possibility that they may have a direct effect on the electrical activity of neuronal populations has not been tested. We explored the electrophysiological action of protocatechuic acid (PCA) on CA1 pyramidal cells ex vivo and network activity in anesthetized female rats using pathway-specific field potential (FP) generators obtained from laminar FPs in cortex and hippocampus. Whole-cell recordings from CA1 pyramidal cells revealed increased synaptic potentials, particularly in response to basal dendritic excitation, while the associated evoked firing was significantly reduced. This counterintuitive result was attributed to a marked increase of the rheobase and voltage threshold, indicating a decreased ability to generate spikes in response to depolarizing current. Systemic administration of PCA only slightly altered the ongoing activity of some FP generators, although it produced a striking disengagement of infraslow activities between the cortex and hippocampus on a scale of minutes. To our knowledge, this is the first report showing the direct action of a dietary polyphenol on electrical activity, performing neuromodulatory roles at both the cellular and network levels.

Theoretical considerations and supporting evidence for the primary role of source geometry on field potential amplitude and spatial extent.

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.

Site-dependent shaping of field potential waveforms.

The activity of neuron populations gives rise to field potentials (FPs) that extend beyond the sources. Their mixing in the volume dilutes the original temporal motifs in a site-dependent manner, a fact that has received little attention. And yet, it potentially rids of physiological significance the time-frequency parameters of individual waves (amplitude, phase, duration). This is most likely to happen when a single source or a local origin is erroneously assumed. Recent studies using spatial treatment of these signals and anatomically realistic modeling of neuron aggregates provide convincing evidence for the multisource origin and site-dependent blend of FPs. Thus, FPs generated in primary structures like the neocortex and hippocampus reach far and cross-contaminate each other but also, they add and even impose their temporal traits on distant regions. Furthermore, both structures house neurons that act as spatially distinct (but overlapped) FP sources whose activation is state, region, and time dependent, making the composition of so-called local FPs highly volatile and strongly site dependent. Since the spatial reach cannot be predicted without source geometry, it is important to assess whether waveforms and temporal motifs arise from a single source; otherwise, those from each of the co-active sources should be sought.

The Critical Role of Spreading Depolarizations in Early Brain Injury: Consensus and Contention.

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.

Questioning Glutamate Excitotoxicity in Acute Brain Damage: The Importance of Spreading Depolarization.

BACKGROUND: Within 2 min of severe ischemia, spreading depolarization (SD) propagates like a wave through compromised gray matter of the higher brain. More SDs arise over hours in adjacent tissue, expanding the neuronal damage. This period represents a therapeutic window to inhibit SD and so reduce impending tissue injury. Yet most neuroscientists assume that the course of early brain injury can be explained by glutamate excitotoxicity, the concept that immediate glutamate release promotes early and downstream brain injury. There are many problems with glutamate release being the unseen culprit, the most practical being that the concept has yielded zero therapeutics over the past 30 years. But the basic science is also flawed, arising from dubious foundational observations beginning in the 1950s METHODS: Literature pertaining to excitotoxicity and to SD over the past 60 years is critiqued. RESULTS: Excitotoxicity theory centers on the immediate and excessive release of glutamate with resulting neuronal hyperexcitation. This instigates poststroke cascades with subsequent secondary neuronal injury. By contrast, SD theory argues that although SD evokes some brief glutamate release, acute neuronal damage and the subsequent cascade of injury to neurons are elicited by the metabolic stress of SD, not by excessive glutamate release. The challenge we present here is to find new clinical targets based on more informed basic science. This is motivated by the continuing failure by neuroscientists and by industry to develop drugs that can reduce brain injury following ischemic stroke, traumatic brain injury, or sudden cardiac arrest. One important step is to recognize that SD plays a central role in promoting early neuronal damage. We argue that uncovering the molecular biology of SD initiation and propagation is essential because ischemic neurons are usually not acutely injured unless SD propagates through them. The role of glutamate excitotoxicity theory and how it has shaped SD research is then addressed, followed by a critique of its fading relevance to the study of brain injury. CONCLUSIONS: Spreading depolarizations better account for the acute neuronal injury arising from brain ischemia than does the early and excessive release of glutamate.

Different theta frameworks coexist in the rat hippocampus and are coordinated during memory-guided and novelty tasks.

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.

Mechanisms of the negative potential associated with Leão's spreading depolarization: A history of brain electrogenesis.

Spreading depolarization (SD) is a self-propagated wave that provokes transient disorder of numerous cell and tissue functions, and that may kill neurons in metabolically compromised tissue. We examined the mechanisms underlying the main hallmark of SD, a giant extracellular potential (ΔVo) for which multiple electromotive forces have been proposed. The end-point is that neurons and not glia, dendritic channels and not spatial currents, and increased sodium conductance rather than potassium gradients, appear to be the main actors in the generation of the negative ΔVo. Neuronal currents are established by two mechanisms, a voltage independent dendritic current, and the differential polarization along the neuron membranes. Notably, despite of a marked drop of ion gradients, these evolve significantly during SD, and yet the membrane potential remains clamped at zero no matter how much inward current is present. There may be substantial inward current or none in function of the evolving portion of the neuron dendrites with SD-activated channels. We propose that the ΔVo promotes swelling-induced dendritic damage. Understanding SD electrogenesis requires all elements relevant for membrane potential, action currents, field potentials and volume conduction to be jointly considered, and it has already encouraged the search for new targets to limit SD-related pathology.

Slow-Wave Activity in the S1HL Cortex Is Contributed by Different Layer-Specific Field Potential Sources during Development.

Spontaneous correlated activity in cortical columns is critical for postnatal circuit refinement. We used spatial discrimination techniques to explore the late maturation of synaptic pathways through the laminar distribution of the field potential (FP) generators underlying spontaneous and evoked activities of the S1HL cortex in juvenile (P14-P16) and adult anesthetized rats. Juveniles exhibit an intermittent FP pattern resembling Up/Down states in adults, but with much reduced power and different laminar distribution. Whereas FPs in active periods are dominated by a layer VI generator in juveniles, in adults a developing multipart generator takes over, displaying current sinks in middle layers (III-V). The blockade of excitatory transmission in upper and middle layers of adults recovered the juvenile-like FP profiles. In addition to the layer VI generator, a gamma-specific generator in supragranular layers was the same in both age groups. While searching for dynamical coupling among generators in juveniles we found significant cross-correlation in ∼one-half of the tested pairs, whereas excessive coherence hindered their efficient separation in adults. Also, potentials evoked by tactile and electrical stimuli showed different short-latency dipoles between the two age groups, and the juveniles lacked the characteristic long latency UP state currents in middle layers. In addition, the mean firing rate of neurons was lower in juveniles. Thus, cortical FPs originate from different intra-columnar segments as they become active postnatally. We suggest that although some cortical segments are active early postnatally, a functional sensory-motor control relies on a delayed maturation and network integration of synaptic connections in middle layers.SIGNIFICANCE STATEMENT Early postnatal activity in the rodent cortex is mostly endogenous, whereas it becomes driven by peripheral input at later stages. The precise schedule for the maturation of synaptic pathways is largely unknown. We explored this in the somatosensory hindlimb cortex at an age when animals begin to use their limbs by uncovering the laminar distribution of the field potential generators underlying the dominant delta waves in juveniles and adults. Our results suggest that field potentials are mostly generated by a pathway in deep layers, whereas other pathways mature later in middle layers and take over in adults. We suggest that a functional sensory-motor control relies on a delayed maturation and network integration of synaptic connections in middle layers.

Local and Volume-Conducted Contributions to Cortical Field Potentials.

Brain field potentials (FPs) can reach far from their sources, making difficult to know which waves come from where. We show that modern algorithms efficiently segregate the local and remote contributions to cortical FPs by recovering the generator-specific spatial voltage profiles. We investigated experimentally and numerically the local and remote origin of FPs in different cortical areas in anesthetized rats. All cortices examined show significant state, layer, and region dependent contribution of remote activity, while the voltage profiles help identify their subcortical or remote cortical origin. Co-activation of different cortical modules can be discriminated by the distinctive spatial features of the corresponding profiles. All frequency bands contain remote activity, thus influencing the FP time course, in cases drastically. The reach of different FP patterns is boosted by spatial coherence and curved geometry of the sources. For instance, slow cortical oscillations reached the entire brain, while hippocampal theta reached only some portions of the cortex. In anterior cortices, most alpha oscillations have a remote origin, while in the visual cortex the remote theta and gamma even surpass the local contribution. The quantitative approach to local and distant FP contributions helps to refine functional connectivity among cortical regions, and their relation to behavior.

Volume-Conducted Origin of the Field Potential at the Lateral Habenula.

Field potentials (FPs) are easily reached signals that provide information about the brain's processing. However, FP should be interpreted cautiously since their biophysical bases are complex. The lateral habenula (LHb) is a brain structure involved in the encoding of aversive motivational values. Previous work indicates that the activity of the LHb is relevant for hippocampal-dependent learning. Moreover, it has been proposed that the interaction of the LHb with the hippocampal network is evidenced by the synchronization of LHb and hippocampal FPs during theta rhythm. However, the origin of the habenular FP has not been analyzed. Hence, its validity as a measurement of LHb activity has not been proven. In this work, we used electrophysiological recordings in anesthetized rats and feed-forward modeling to investigate biophysical basis of the FP recorded in the LHb. Our results indicate that the FP in the LHb during theta rhythm is a volume-conducted signal from the hippocampus. This result highlight that FPs must be thoroughly analyzed before its biological interpretation and argues against the use of the habenular FP signal as a readout of the activity of the LHb.

Local Field Potentials: Myths and Misunderstandings.

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.

The right hippocampus leads the bilateral integration of gamma-parsed lateralized information.

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.

Diversity of LFPs Activated in Different Target Regions by a Common CA3 Input.

Identifying the pathways contributing to local field potential (LFP) events and oscillations is essential to determine whether synchronous interregional patterns indicate functional connectivity. Here, we studied experimentally and numerically how different target structures receiving input from a common population shape their LFPs. We focused on the bilateral CA3 that sends gamma-paced excitatory packages to the bilateral CA1, the lateral septum, and itself (recurrent input). The CA3-specific contribution was isolated from multisite LFPs in target regions using spatial discrimination techniques. We found strong modulation of LFPs by target-specific features, including the morphology and population arrangement of cells, the timing of CA3 inputs, volume conduction from nearby targets, and co-activated inhibition. Jointly they greatly affect the LFP amplitude, profile, and frequency characteristics. For instance, ipsilateral (Schaffer) LFPs occluded contralateral ones, and septal LFPs arise mostly from remote sources while local contribution from CA3 input was minor. In the CA3 itself, gamma waves have dual origin from local networks: in-phase excitatory and nearly antiphase inhibitory. Also, waves may have different duration and varying phase in different targets. These results indicate that to explore the cellular basis of LFPs and the functional connectivity between structures, besides identifying the origin population/s, target modifiers should be considered.

The influence of synaptic size on AMPA receptor activation: a Monte Carlo model.

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.

How spreading depolarization can be the pathophysiological correlate of both migraine aura and stroke.

The term spreading depolarization describes a mechanism of abrupt, massive ion translocation between neurons and the interstitial space, which leads to a cytotoxic edema in the gray matter of the brain. In energy-compromised tissue, spreading depolarization is preceded by a nonspreading silencing (depression of spontaneous activity) because of a neuronal hyperpolarization. By contrast, in tissue that is not energy compromised, spreading depolarization is accompanied by a spreading silencing (spreading depression) of spontaneous activity caused by a depolarization block. It is assumed that the nonspreading silencing translates into the initial clinical symptoms of ischemic stroke and the spreading silencing (spreading depression) into the symptoms of migraine aura. In energy-compromised tissue, spreading depolarization facilitates neuronal death, whereas, in healthy tissue, it is relatively innocuous. Therapies targeting spreading depolarization in metabolically compromised tissue may potentially treat conditions of acute cerebral injury such as aneurysmal subarachnoid hemorrhage.

PyramidalExplorer: A New Interactive Tool to Explore Morpho-Functional Relations of Human Pyramidal Neurons.

This work presents PyramidalExplorer, a new tool to interactively explore and reveal the detailed organization of the microanatomy of pyramidal neurons with functionally related models. It consists of a set of functionalities that allow possible regional differences in the pyramidal cell architecture to be interactively discovered by combining quantitative morphological information about the structure of the cell with implemented functional models. The key contribution of this tool is the morpho-functional oriented design that allows the user to navigate within the 3D dataset, filter and perform Content-Based Retrieval operations. As a case study, we present a human pyramidal neuron with over 9000 dendritic spines in its apical and basal dendritic trees. Using PyramidalExplorer, we were able to find unexpected differential morphological attributes of dendritic spines in particular compartments of the neuron, revealing new aspects of the morpho-functional organization of the pyramidal neuron.

Constitutive hippocampal cholesterol loss underlies poor cognition in old rodents.

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.