Matthew E Larkum

• PhD
• Professor (Full) at Humboldt-Universität zu Berlin

Dendrites are the main recipients of synaptic inputs and are important sites that determine neurons' input-output functions. This review focuses on thin neocortical dendrites, which receive the vast majority of synaptic inputs in cortex but also have specialized electrogenic properties. We present a simplified working-model biophysical scheme of py...

Processing of sensory information from both sides of the body requires coordination of sensory input between the two hemispheres. This coordination is achieved by transcallosal (interhemispheric) fibers that course though the upper cortical layers. In a recent study by Palmer et al. (2012), we investigated the role of this interhemispheric input on...

Interhemispheric inhibition is thought to mediate cortical rivalry between the two hemispheres through callosal input. The long-lasting form of this inhibition is believed to operate via γ-aminobutyric acid type B (GABAB) receptors, but the process is poorly understood at the cellular level. We found that the firing of layer 5 pyramidal neurons in...

Contemporary models of perceptual awareness lack tractable neurobiological constraints. Inspired by recent cellular recordings in a mouse model of tactile threshold detection, we constructed a biophysical model of perceptual awareness that incorporated essential features of thalamocortical anatomy and cellular physiology. Our model reproduced, and...

Flexible learning relies on integrating sensory and contextual information to adjust behavioral output in different environments. The anterolateral motor cortex (ALM) is a frontal area critical for action selection in rodents. Here we show that inputs critical to decision-making converge on the apical tuft dendrites of L5b pyramidal neurons in ALM....

High-speed volumetric imaging is crucial for observing fast and distributed processes such as neuronal activity. Multiphoton microscopy helps to mitigate scattering effects inside tissue, but the standard raster scanning approach limits achievable volume rates. Random access point scanning can lead to a considerable speed-up by sampling only pre-se...

The deepest layer of the cortex (layer 6b [L6b]) contains relatively few neurons, but it is the only cortical layer responsive to the potent wake-promoting neuropeptide orexin/hypocretin. Can these few neurons significantly influence brain state? Here, we show that L6b-photoactivation causes a surprisingly robust enhancement of attention-associated...

Understanding the neurobiological mechanisms underlying consciousness remains a significant challenge. Recent evidence suggests that the coupling between distal–apical and basal–somatic dendrites in thick-tufted layer 5 pyramidal neurons (L5 PN ), regulated by the nonspecific-projecting thalamus, is crucial for consciousness. Yet, it is uncertain w...

Neocortical layer 1 has been proposed to be at the center for top-down and bottom-up integration. It is a locus for interactions between long-range inputs, layer 1 interneurons, and apical tuft dendrites of pyramidal neurons. While input to layer 1 has been studied intensively, the level and effect of input to this layer has still not been complete...

Investigations into the neural basis of conscious perception span multiple scales and levels of analysis. There is, however, a theoretical and methodological gap between advances made at the microscopic scale in animal models and those made at the macroscopic scale in human cognitive neuroscience that places a fundamental limit on our understanding...

Interactions with large language models have led to the suggestion that these models may be conscious. From the perspective of neuroscience, this position is difficult to defend. For one, the architecture of large language models is missing key features of the thalamocortical system that have been linked to conscious awareness in mammals. Secondly,...

Brain research has in recent years indisputably entered a new epoch, driven by substantial methodological advances and digitally enabled data integration and modeling at multiple scales – from molecules to the whole system. Major advances are emerging at the intersection of neuroscience with technology and computing. This new science of the brain i...

This primer aims to provide a concise description of the Dendritic Integration Theory (DIT) of consciousness. We consider the motivation for DIT, the evidence for it, and how it fits with other theories of consciousness.

The use of head fixation has become routine in systems neuroscience. However, whether the behavior changes with head fixation, whether animals can learn aspects of a task while freely moving and transfer this knowledge to the head fixed condition, has not been examined in much detail. Here, we used a novel floating platform, the “Air-Track”, which...

How do new ideas come about? The central hypothesis presented here states that insights might happen during mental navigation and correspond to rapid plasticity at the cellular level. We highlight the differences between neocortical and hippocampal mechanisms of insight. We argue that the suddenness of insight can be related to the sudden emergence...

Theories of attention and learning have hypothesized a central role for high-frequency bursting in cognitive functions, but experimental reports of burst-mediated representations in vivo have been limited. Here we used a novel demultiplexing approach to separate independent streams of information from considering neurons as having three possible st...

A key function of the brain is to move the body through a rich, complex environment. When rodents engage their environment, they move their whiskers as they extract tactile information. Even though the study of whisking has a long history, the details of what mice move when they move a whisker actively to touch are still unknown. Here we trained he...

Memory consolidation is a continuous transformative process between encoding and retrieval of mental representations. Recent research has shown that neural activity immediately after encoding is particularly associated with later successful retrieval. It is currently unclear whether post-encoding neural activity makes a distinct and causal contribu...

Navigation through complex environments requires motor planning, motor preparation, and the coordination between multiple sensory-motor modalities. For example, the stepping motion when we walk is coordinated with motion of the torso, arms, head, and eyes. In rodents, movement of the animal through the environment is coordinated with whisking. Even...

In mammalian neocortex, learning triggers the formation and turnover of new postsynaptic spines on pyramidal cell dendrites. However, the biological principles of spine reorganization during learning remain elusive because the identity of their presynaptic neuronal partners is unknown. Here, we show that two presynaptic neural circuits supervise di...

Rapid advances in neuroscience have provided remarkable breakthroughs in understanding the brain on many fronts. Although promising, the role of these advancements in solving the problem of consciousness is still unclear. Based on technologies conceivably within the grasp of modern neuroscience, we discuss a thought experiment in which neural activ...

The lipid phosphatase PTEN (phosphatase and tensin homologue on chromosome 10) is a key tumour suppressor gene and an important regulator of neuronal signalling. PTEN mutations have been identified in patients with autism spectrum disorders, characterized by macrocephaly, impaired social interactions and communication, repetitive behaviour, intelle...

Rapid advances in neuroscience have provided remarkable breakthroughs in understanding the brain on many fronts. Although promising, the role of these advancements in solving the problem of consciousness is still unclear. Based on technologies conceivably within the grasp of modern neuroscience, we envision an experiment where action potentials are...

This article presents the argument that, while understanding the brain will require a multi-level approach, there is nevertheless something fundamental about understanding the components of the brain. I argue here that the standard description of neurons is not merely too simplistic, but also misses the true nature of how they operate at the comput...

Half a century since their discovery by Llinás and colleagues, dendritic spikes have been observed in various neurons in different brain regions, from the neocortex and cerebellum to the basal ganglia. Dendrites exhibit a terrifically diverse but stereotypical repertoire of spikes, sometimes specific to subregions of the dendrite. Despite their pre...

Optical imaging techniques are widely used in biological research, but their penetration depth is limited by tissue scattering. Wavefront shaping techniques are able to overcome this problem in principle, but are often slow, and their performance depends on the sample. This greatly reduces their practicability for biological applications. Here we p...

Intelligent behavior and cognitive functions in mammals depend on cortical microcircuits made up of a variety of excitatory and inhibitory cells that form a forest-like complex across six layers. Mechanistic understanding of cortical microcircuits requires both manipulation and monitoring of multiple layers and interactions between them. However, e...

Neocortical layer 1 is a locus for interactions between long-range inputs, L1 interneurons and apical tuft dendrites of pyramidal neurons. While input to this layer has a decades long history of study, the level and effect of input to this layer has still not been completely characterized. Here we assessed the input to L1 of mouse somatosensory cor...

Cortical layer 1 has a special role in long-term memory.

Synergistic interactions between independent synaptic input streams may fundamentally change the action potential (AP) output. Using partial information decomposition, we demonstrate here a substantial contribution of synergy between somatic and apical dendritic inputs to the information in the AP output of L5b pyramidal neurons. Activation of dend...

Optical imaging techniques are widely used in biological research, but their penetration depth is limited by tissue scattering. Wavefront shaping techniques are able to overcome this problem in principle, but are often slow and their performance depends on the sample. This greatly reduces their practicability for biological applications. Here we pr...

Prompt execution of planned motor action is essential for survival. The interactions between frontal cortical circuits and the basal ganglia are central to goal-oriented action selection and initiation.1, 2, 3, 4 In rodents, the ventromedial thalamic nucleus (VM) is one of the critical nodes that conveys the output of the basal ganglia to the front...

Intelligent behavior and cognitive functions in mammals depend on cortical microcircuits made up of a variety of excitatory and inhibitory cells that form a forest-like complex across six layers. Mechanistic understanding of cortical microcircuits requires both manipulation and monitoring of multiple layers and interactions between them. However, e...

Navigation through complex environments requires motor planning, motor preparation and the coordination between multiple sensory–motor modalities. For example, the stepping motion when we walk is coordinated with motion of the torso, arms, head and eyes. In rodents, movement of the animal through the environment is often coordinated with whisking....

Computer vision approaches have made significant inroads into offline tracking of behavior and estimating animal poses. In particular, because of their versatility, deep-learning approaches have been gaining attention in behavioral tracking without any markers. Here we developed an approach using DeepLabCut for real-time estimation of movement. We...

Memory consolidation in the neocortex Information transfer between brain structures located in the medial-temporal lobe and the neocortex is essential for learning. However, the neuronal underpinnings of this transfer are unknown. Doron et al. found that neurons located in the deep layers of the perirhinal cortex exhibit increased firing after micr...

The output of cortical columns is routed to different downstream targets via distinct pathways: cortico-cortical and cortico-subcortical. It is as yet unclear what roles these pathways play in perception, and which cellular and circuit mechanisms regulate their gating. We recently showed that activation of the apical dendrites of layer 5 (L5) pyram...

Recent breakthroughs in neurobiology indicate that the time is ripe to understand how cellular-level mechanisms are related to conscious experience. Here, we highlight the biophysical properties of pyramidal cells, which allow them to act as gates that control the evolution of global activation patterns. In conscious states, this cellular mechanism...

Optical microscopy is an indispensable tool in biomedical sciences, but its reach in deep tissues is limited due to aberrations and scattering. This problem can be overcome by wavefront-shaping techniques, albeit at limited fields of view (FOVs). Inspired by astronomical imaging, conjugate wavefront shaping can lead to an increased field of view in...

In this review article, we highlight several disparate ideas that are linked to changes in brain state (i.e., sleep to arousal, Down to Up, synchronized to de-synchronized). In any discussion of the brain state, we propose that the cortical pyramidal neuron has a central position. EEG recordings, which typically assess brain state, predominantly re...

In the course of a day, brain states fluctuate, from conscious awake information-acquiring states to sleep states, during which previously acquired information is further processed and stored as memories. One hypothesis is that memories are consolidated and stored during “offline” states such as sleep, a process thought to involve transfer of infor...

Layer 6b (L6b), the deepest neocortical layer, projects to cortical targets and higher-order thalamus and is the only layer responsive to the wake-promoting neuropeptide orexin/hypocretin. These characteristics suggest that L6b can strongly modulate brain state, but projections to L6b and their influence remain unknown. Here, we examine the inputs...

The mystery of general anesthesia is that it specifically suppresses consciousness by disrupting feedback signaling in the brain, even when feedforward signaling and basic neuronal function are left relatively unchanged. The mechanism for such selectiveness is unknown. Here we show that three different anesthetics have the same disruptive influence...

Human dendrites are special A special developmental program in the human brain drives the disproportionate thickening of cortical layer 2/3. This suggests that the expansion of layer 2/3, along with its numerous neurons and their large dendrites, may contribute to what makes us human. Gidon et al. thus investigated the dendritic physiology of layer...

A central function of the brain is to plan, predict, and imagine the effect of movement in a dynamically changing environment. Here we show that in mice head-fixed in a plus-maze, floating on air, and trained to pick lanes based on visual stimuli, the asymmetric movement, and position of whiskers on the two sides of the face signals whether the ani...

One of the principal functions of the brain is to control movement and rapidly adapt behavior to a changing external environment. Over the last decades our ability to monitor activity in the brain, manipulate it while also manipulating the environment the animal moves through, has been tackled with increasing sophistication. Yet, our ability to tra...

The topographic map in layer 4 of somatosensory cortex is usually specified early postnatally and stable thereafter. Genital cortex, however, undergoes a sex-hormone- and sexual-touch-dependent pubertal expansion. Here, we image pubertal development of genital cortex in Scnn1a-Tg3-Cre mice, where transgene expression has been shown to be restricted...

One fundamental feature of consciousness is that the contents of consciousness depend on the state of consciousness. Here, we propose an answer to why this is so: both the state and the contents of consciousness depend on the activity of cortical layer 5 pyramidal (L5p) neurons. These neurons affect both cortical and thalamic processing, hence coup...

Signals sent back to the neocortex from the hippocampus control the long-term storage of memories in the neocortex, but the cellular mechanisms underlying this process remain elusive. Here, we show that learning is controlled by specific medial-temporal input to neocortical layer 1. To show this we used direct cortical microstimulation detection ta...

The advent of optogenetic methods has made it possible to use endogeneously produced molecules to image and manipulate cellular, subcellular, and synaptic activity. It has also led to the development of photoactivatable calcium-dependent indicators that mark active synapses, neurons, and circuits. Furthermore, calcium-dependent photoactivation can...

Oxytocin (OT) release by axonal terminals onto the central nucleus of the amygdala exerts anxiolysis. To investigate which subpopulation of OT neurons contributes to this effect, we developed a novel method: virus-delivered genetic activity-induced tagging of cell ensembles (vGATE). With the vGATE method, we identified and permanently tagged a smal...

Pyramidal cells in layer 5 of the neocortex have two distinct integration sites. These cells integrate inputs to basal dendrites in the soma while integrating inputs to the tuft in a site at the top of the apical trunk. The two sites communicate by action potentials that backpropagate to the apical site and by backpropagation-activated calcium spik...

A central function of the brain is to plan, predict and imagine the effect of movement in a dynamically changing environment. Here we show that the position of the vibrissae, sets of mobile tactile sensors on each side of the face, reflects the behavioral state and predicts the movement of mice, head-fixed in a plus-maze floating on air. Whisker po...

Marking functionally distinct neuronal ensembles with high spatiotemporal resolution is a key challenge in systems neuroscience. We recently introduced CaMPARI, an engineered fluorescent protein whose green-to-red photoconversion depends on simultaneous light exposure and elevated calcium, which enabled marking active neuronal populations with sing...

This review addresses the function of the layers of the cerebral cortex. We develop the perspective that cortical layering needs to be understood in terms of its functional anatomy, i.e. the terminations of synaptic inputs on distinct cellular compartments and their effect on cortical activity. The cortex is a hierarchical structure in which feed f...

What can artificial intelligence learn from neuroscience, and vice versa?

Cortical surface recording techniques such as EEG and ECoG are widely used for measuring brain activity. The prevailing assumption is that surface potentials primarily reflect synaptic activity, although non-synaptic events may also contribute. Here we show that dendritic calcium spikes occurring in pyramidal neurons (that we showed previously are...

In the originally published version of this Article, incorrect references were cited on two occasions in the Results section. Under the subheading 'Ca2+ activity in single dendrites and somata of L5 neurons', the final sentence of the second paragraph incorrectly cited reference 29 instead of reference 31. Under the subheading 'Spiking of L5 cell b...

How sleep influences brain plasticity is not known. In particular, why certain electro-encephalographic (EEG) rhythms are linked to memory consolidation is poorly understood. Calcium activity in dendrites is known to be necessary for structural plasticity changes, but this has never been carefully examined during sleep. Here, we report that calcium...

Understanding the neural computations that contribute to behavior requires recording from neurons while an animal is behaving. This is not an easy task as most subcellular recording techniques require absolute head stability. The Go/No-Go sensory task is a powerful decision-driven task that enables an animal to report a binary decision during head-...

Real-time tracking of D1 and D2 whiskers. Left panel shows the real-time data transmitted from Pixy to data files. The top right panel shows the simultaneously acquired high-speed video of the two whiskers, and the bottom right shows Pixy view. The D2 whisker is painted red and shows up as the red waveform on the top left, the D1 whisker is painted...

Pixy analysis of slow-motion video data. The color high-speed video can be played back in slow motion (left panel). Pixy camera and Pixymon (middle panel) can be used to track the position of the two whiskers and the data can be extracted into a data file (right panel).

Tracking a single animal head rotation/direction and position in real time. Pixy camera tracks a multicolored piece of Styrofoam fixed on animal head-plate in regular light condition. The red traces on the top left shows the angle of head direction, while the blue traces in the middle left and green trace in bottom left shows the horizontal and ver...

Pixy in infrared illumination. A single painted whisker shown in the video on the right is tracked in real time (left panel) with infrared illumination. At 3 s into the video, the infrared light is turned off, whisker color signature disappear as well. When the light is turned on again, the whisker can be tracked again.

A traditional approach to the study of neural function is to relate activity in a circuit to a distinct behavior. While methods for measuring and manipulating neural activity have become increasingly sophisticated, the ability to monitor and manipulate behavior has not kept pace. Here we describe an automated optical method for tracking animal beha...

Now you feel it, now you don't What determines the detection of a sensory stimulus? To address this question, Takahashi et al. combined in vivo two-photon imaging, electrophysiology, optogenetics, and behavioral analysis in a study of mice. Calcium signals in apical dendrites of pyramidal neurons in the somatosensory cortex controlled the perceptua...

Key points: The genetically encoded fluorescent calcium integrator calcium-modulated photoactivatable ratiobetric integrator (CaMPARI) reports calcium influx induced by synaptic and neural activity. Its fluorescence is converted from green to red in the presence of violet light and calcium. The rate of conversion - the sensitivity to activity - is...

Neocortical pyramidal cells can integrate two classes of input separately and use one to modulate response to the other. Their tuft dendrites are electrotonically separated from basal dendrites and soma by the apical dendrite, and apical hyperpolarization-activated currents (Ih) further isolate subthreshold integration of tuft inputs. When apical d...

Natural behavior occurs in multiple sensory and motor modalities and in particular is dependent on sensory feedback that constantly adjusts behavior. To investigate the underlying neuronal correlates of natural behavior, it is useful to have access to state-of-the-art recording equipment (e.g. 2-photon imaging, patch recordings, etc.) that frequent...

Integral and amplitude of evoked calcium transient.DOI: http://dx.doi.org/10.7554/eLife.13598.004

ELife digest The brain’s billions of neurons communicate with one another using electrical signals. Applying a magnetic field to a small area of the scalp can temporarily disrupt these signals by inducing small electrical currents in the brain tissue underneath. The currents interfere with the brain’s own electrical signals and temporarily disrupt...

We summarize evidence that input to the apical tufts of neocortical pyramidal cells modulates their response to basal input. Because this apical amplification and disamplification provide intracortical mechanisms for prioritization, Mather and colleagues' arguments suggest that their effects are enhanced by noradrenergic arousal. Though that is lik...

We present a cost-effective in vivo two-photon microscope with a highly flexible frontend for in vivo research. Our design ensures fast and reproducible access to the area of interest, including rotation of imaging plane, and maximizes space for auxiliary experimental equipment in the vicinity of the animal. Mechanical flexibility is achieved with...

A fundamental issue in cortical processing of sensory information is whether top-down control circuits from higher brain areas to primary sensory areas not only modulate but actively engage in perception. Here, we report the identification of a neural circuit for top-down control in the mouse somatosensory system. The circuit consisted of a long-ra...

L5 pyramidal neurons are the only neocortical cell type with dendrites reaching all six layers of cortex, casting them as one of the main integrators in the cortical column. What is the nature and mode of computation performed in mouse primary visual cortex (V1) given the physiology of L5 pyramidal neurons? First, we experimentally establish active...

Recent evidence in vitro suggests that the tuft dendrites of pyramidal neurons are capable of evoking local NMDA receptor-dependent electrogenesis, so-called NMDA spikes. However, it has so far proved difficult to demonstrate their existence in vivo. Moreover, it is not clear whether NMDA spikes are relevant to the output of pyramidal neurons. We f...

Translating the advances seen recently in recording from neurons in vivo to dendritic recordings presents special difficulties. In vivo two-photon imaging of dendrites was achieved over a decade ago and is still the method of choice for recording from small dendritic compartments in single neurons but has proven more difficult to apply to many dend...

The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts and discuss likely technological deliverables and neuroscie...

In layer 5 neocortical pyramidal neurons, backpropagating action potentials (bAPs) firing at rates above a critical frequency (CF) induce supralinear Ca(2+) influx and regenerative potentials in apical dendrites. Paired temporally with an EPSP, this Ca(2+) influx can result in synaptic plasticity. We studied the actions of neuropeptide Y (NPY), an...

Distinct populations of layer 1 inhibitory neurons inhibit or disinhibit layer 5 pyramidal cells. A massive patch-clamp recording effort, tapping up to eight cells simultaneously, maps their influences on the cortical network.

A basic feature of intelligent systems such as the cerebral cortex is the ability to freely associate aspects of perceived experience with an internal representation of the world and make predictions about the future. Here, a hypothesis is presented that the extraordinary performance of the cortex derives from an associative mechanism built in at t...

Dendrites carry signals between synapses and the soma and play a central role in neural computation. Although they contain many nonlinear ion channels, their signal-transfer properties are linear under some experimental conditions. In experiments with continuous-time inputs, a resonant linear two-port model has been shown to provide a near-perfect...

Key points Voltage‐dependent Ca ²⁺ channels mediate a large repertoire of physiological actions, including the generation of dendritic spikes in neocortical pyramidal neurons; however, the type of Ca ²⁺ channels involved in their generation remains unknown. We found that L‐type Ca ²⁺ currents generate the sustained plateau potential of the Ca ²⁺ sp...

Dendrites are highly branched neuronal structures that form the main synaptic target of other nerve cells. They are studded with small spines that are the contact points for excitatory inputs. Dendrites integrate these excitatory inputs, along with inhibitory inputs, in the form of brief depolarising or hyperpolarizing synaptic potentials, and gene...