Biology subjects

Larkum, M.

Publications and source records attributed to Larkum, M..

10 recordsLinked to original sources

bioRxiv2026

Dendritic hotspots support switching between competing rules without expanding the cortical engram

Adaptive behavior requires updating responses when contingencies change while preserving prior associations and the capacity to learn a new. How this trade-off is resolved remains unknown. Here, we combined in vivo imaging of apical tuft spines in the secondary motor cortex (M2) with biologically constrained network modeling in mice performing a cross-modal rule-switch task. M2 inactivation impaired rule-switching but not learning or maintenance, identifying it as a conflict resolution substrate. Adaptation was accompanied by elevated spine turnover concentrated within stable dendritic hotspots, in which the formation, elimination and clustering of new spines were coupled and pre-existing spines were lost early. A network model reproduces these dynamics and predicts that dendritic hotspots are critical for resource-efficient adaptation. Within these reusable domains, spines encoding the prior rule are replaced by newly-relevant ones via sharing of plasticity-related resources. Preventing reuse increases both the plasticity and the engram size requirements to encode the two rules. We propose that dendritic hotspots provide a mechanistic substrate for efficient adaptive learning.

neuroscience↗

bioRxiv2026

Cortex-wide representational drift of different layers

Representational drift, the gradual evolution of neural population codes over days, has been widely documented at the level of single neurons. However, whether drift is organized across larger cortical populations and spatial scales remains unclear. Here, we examined cortex-wide population dynamics under tightly controlled sensory input and behavior. Using widefield calcium imaging, we longitudinally recorded excitatory activity in Layers 2/3 (L2/3) or Layer 5 (L5) across 25 cortical areas while mice performed a whisker-based texture discrimination task. Sensory-evoked activity was tracked over five consecutive days during stable task performance. Population activity patterns reorganized over days, across the cortex, in both layers. This reorganization followed distinct laminar motifs: notably L5 responses exhibited a widespread, monotonic decrease in activity across most cortical areas, whereas L2/3 responses showed spatially localized and heterogeneous changes that were strongest during the sensory period. These laminar differences extended beyond the stimulus period, with L5 exhibiting more prolonged temporal engagement than L2/3. Together, these findings indicate that representational drift can unfold as a process that is coordinated across cortex with distinct laminar profiles. Thus, drift may reflect a structured feature of cortex-wide circuit dynamics.

neuroscience↗

bioRxiv2025

Cortex-wide laminar dynamics diverge during learning

Learning to link sensory information to motor actions involves dynamic coordination across cortical layers and regions. However, the involvement of a particular layer in learning, especially from a cortex-wide perspective, is relatively unknown. Using wide-field calcium imaging in mice as they learn a whisker-based go/no-go task, we tracked activity in layers 2/3 or 5 (L2/3 or L5) across 25 cortical areas. A surprising initial effect of learning was that activity in L5 but not in L2/3 was globally suppressed at auditory cue onset. As the texture comes into touch, we found that L2/3 displayed learning-related enhancements in higher order association areas rostrolateral (RL) and secondary somatosensory (S2), whereas L5 in these areas oppositely decreased. During texture touch, the barrel cortex (BC) displayed similar learning-related enhancement in both layers. As sensory information is transformed into a motor action, there was a frontal/posterior divergence that emerges after learning, in which L5 was enhanced in the frontal cortex and L2/3 was suppressed in the posterior cortex. In general, learning related correlations were often stronger between distant cortical layers than within the same column, suggesting that learning drives laminar interactions that transcend traditional columnar organization. Together, these results reveal that learning orchestrates a dynamic interplay of activity across space, time and cortical layers. Our findings emphasize the critical role of laminar architecture in shaping cortical plasticity and support the view that layer-specific circuits are fundamental to sensorimotor learning.

neuroscience↗

bioRxiv2024

The neural mechanisms of fast versus slow decision-making

Is more haste less speed? Decision time variability has been attributed to speed/accuracy trade-offs(1), internal mental architecture(2), and noisy evidence accumulation(3-5). However, exploring these possibilities is difficult in rodents that consistently behave impulsively. Here, we demonstrate a novel floating-platform system that allows head-fixed mice to voluntarily vary decision times, akin to observed human behavior, in combination with sensitive neuroimaging approaches. We track the activity flow from medial to lateral frontal cortex (MFC to LFC) and record sequences of single-neuron activity. Choice-selective neurons displayed divergent temporal codes between MFC and LFC, with remarkable MFC susceptibility to optogenetic inhibition. These results suggest that LFC acts as an integrative motor threshold, while MFC plays a broader cognitive role in strategy and choice-selection.

neuroscience↗

bioRxiv2023

A Biophysical Model of Visual Rivalry Links Cellular Mechanisms to Signatures of Conscious Perception

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 mechanistically explains, the key in vivo neural and behavioural signatures of perceptual awareness in the mouse model, as well as the response to a set of causal perturbations. We generalised the same model (with identical parameters) to a more complex task - visual rivalry - and found that the same thalamic-mediated mechanism of perceptual awareness determined perceptual dominance. This led to the generation of a set of novel, and directly testable, electrophysiological predictions. Analyses of the model based on dynamical systems theory show that perceptual awareness in simulations of both threshold detection and visual rivalry arises from the emergent systems-level dynamics of thalamocortical loops.

neuroscience↗

bioRxiv2022

A ternary neural code resolves error and sharpening signals

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 by considering a conjunctive burst code. We studied this code in vivo while animals learned to report direct electrical stimulation of the somatosensory cortex and found two acquired yet independent representations. One code, the event rate, showed a sparse and succint stiumulus representation and a small modulation upon detection errors. The other code, the burst fraction, correlated more globally with stimulation and more promptly responded to detection errors. Bursting modulation was potent and its time course evolved, even in cells that were considered unresponsive based on the firing rate. During the later stages of training, this modulation in bursting happened earlier, gradually aligning temporally with the representation in event rate. The alignment of bursting and event rate modulation sharpened the firing rate response, and was strongly associated behavioral accuracy. Thus a fine-grained separation of spike timing patterns reveals two signals that accompany stimulus representations: an error signal that can be essential to guide learning and a sharpening signal that could implement attention mechanisms.

neuroscience↗

bioRxiv2022

What moves when mice move a single whisker to touch? Individuality and stereotypy in behavior

A key function of the brain is to move the body through a rich, complex environment. When rodents engage with their environment, they move their whiskers as they extract tactile information. Even though the study of whisking has a long history, the details of individual whisker movements bilaterally, of nose movement, of stereotypy and variability in an active whisking to touch task are unknown. Here we trained head fixed mice in a simple go-cue task to move a whisker on one side of the face to touch a sensor and tracked facial movements. Our analysis shows that mice specifically control movement of the whisker they use to touch and that as they move their whiskers, they move their nose and apply forces on the head-post in a manner that reflects the behavioral epoch, i.e. whether go cue triggered movement had begun, or a whisker was touching the sensor. Importantly, mice control the setpoint, amplitude and frequency of movement of whiskers bilaterally and individually. Additionally, even though mice achieved the goal of the task -- to touch the sensor within 2 seconds -- how they coordinated movement of the nose and forces on head post with movement of individual whiskers was stereotyped and related to the distance they needed to move a whisker to touch the sensor. Our work shows how stereotyped mouse behavior can be, and it emphasizes both the level of fine motor control mice can exert over individual whiskers and the extent of facial movements in a goal-directed whisking-to-touch task. SignificanceRecent work shows that facial movements are reflected in the activity of a surprisingly large number of brain areas. But what aspects of the face do mice move when they move a whisker to actively touch an object? Our work shows that while mice control the movement of a whisker they use to touch, they also move their nose, apply forces on the head-post and move adjacent whiskers and whiskers on the other side of the face. Additionally, our analysis shows that from day-to-day, this behavior can be surprisingly stereotyped, and that small changes in how far mice move a whisker during tactile behavior fundamentally changes the relationship between the movement of a single whisker and other facial movements.

neuroscience↗

bioRxiv2021

Deep tissue scattering compensation with three-photon F-SHARP

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 present a scattering compensation technique based on three-photon (3P) excitation, which converges faster than comparable two-photon (2P) techniques and works reliably even on densely labeled samples, where 2P approaches fail. To demonstrate its usability and advantages for biomedical imaging we apply it to the imaging of dendritic spines on GFP-labeled layer 5 neurons in an anesthetized mouse.

bioengineering↗

bioRxiv2021

Predicting behavior from eye movement and whisking asymmetry

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. Here we trained head fixed mice, navigating a floating Airtrack plus maze, to overcome their directional preference and use cues indicating the direction of movement expected in each trial. Once cued, mice had to move backward out of a lane, then turn in the correct direction, and enter a new lane. In this simple paradigm, as mice begin to move backward, they position their whiskers asymmetrically: whiskers on one side of the face protract, and on the other side they retract. This asymmetry reflected the turn direction. Additionally, on each trial, mice move their eyes conjugately in the direction of the upcoming turn. Not only do they move their eyes, but saccadic eye movement is coordinated with the asymmetric positioning of the whiskers. Our analysis shows that the asymmetric positioning of the whiskers predicts the direction of turn that mice will make at an earlier stage than eye movement does. We conclude that, when mice move or plan to move in complex real-world environments, their motor plan and behavioral state can be read out in the movement of both their whiskers and eyes.

neuroscience↗

bioRxiv2019

A Bayesian decomposition of BAC firing as a mechanism for apical amplification in neocortical pyramidal neurons

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 spikes (BAC firing) that travel from the apical to the somatic site. Six key messages arise from the probabilistic information-theoretic analyses of BAC firing presented here. First, we suggest that pyramidal neurons with BAC firing could convert the odds in favour of the presence of a feature given the basal data into the odds in favour of the presence of a feature given the basal data and the apical input, by a simple Bayesian calculation. Second, the strength of the cells response to basal input can be amplified when relevant to the current context, as specified by the apical input, without corrupting the message that it sends. Third, these analyses show rigorously how this apical amplification depends upon communication between the sites. Fourth, we use data on action potentials from a very detailed multi-compartmental biophysical model to study our general model in a more realistic setting, and demonstrate that it describes the data well. Fifth, this form of BAC firing meets criteria for distinguishing modulatory from driving interactions that have been specified using recent definitions of multivariate mutual information. Sixth, our general decomposition can be extended to cases where, instead of being purely driving or purely amplifying, apical and basal inputs can be partly driving and partly amplifying to various extents. These conclusions imply that an advance beyond the assumption of a single site of integration within pyramidal cells is needed, and suggest that the evolutionary success of neocortex may depend upon the cellular mechanisms of context-sensitive selective amplification hypothesized here.\n\nAuthor summaryThe cerebral cortex has a key role in conscious perception, thought, and action, and is predominantly composed of a particular kind of neuron: the pyramidal cells. The distinct shape of the pyramidal neuron with a long dendritic shaft separating two regions of profuse dendrites allows them to integrate inputs to the two regions separately and combine the results non-linearly to produce output. Here we show how inputs to this more distant site strengthen the cells output when it is relevant to the current task and environment. By showing that such neurons have capabilities that transcend those of neurons with the single site of integration assumed by many neuroscientists, this splitting of the neuronal atom offers a radically new viewpoint from which to understand the evolution of the cortex and some of its many pathologies. This also suggests that approaches to artificial intelligence using neural networks might come closer to something analogous to real intelligence, if, instead of basing them on processing elements with a single site of integration, they were based on elements with two sites, as in cortex.

neuroscience↗