Thomas Mrsic-Flogel

University College London | UCL

Optogenetic tools are indispensable for understanding the causal neural mechanisms underlying animal behaviour. While optogenetic actuators provide millisecond-precision control over genetically defined neural populations, successful optogenetic experiments also critically depend on associated hardware for targeted light delivery. Optic-fibres are...

The brain functions as a prediction machine, utilizing an internal model of the world to anticipate sensations and the outcomes of our actions. Discrepancies between expected and actual events, referred to as prediction errors, are leveraged to update the internal model and guide our attention towards unexpected events. Despite the importance of pr...

The neural representations of prior information about the state of the world are poorly understood. To investigate this issue, we examined brain-wide Neuropixels recordings and widefield calcium imaging collected by the International Brain Laboratory. Mice were trained to indicate the location of a visual grating stimulus, which appeared on the lef...

A key challenge in neuroscience is understanding how neurons in hundreds of interconnected brain regions integrate sensory inputs with prior expectations to initiate movements. It has proven difficult to meet this challenge when different laboratories apply different analyses to different recordings in different regions during different behaviours....

Adaptive sensory behavior is thought to depend on processing in recurrent cortical circuits, but how dynamics in these circuits shapes the integration and transmission of sensory information is not well understood. Here, we study neural coding in recurrently connected networks of neurons driven by sensory input. We show analytically how information...

Antibodies have diverse applications due to their high reaction specificities but are sensitive to denaturation when a higher working temperature is required. We have developed a simple, highly scalable and generalizable chemical approach for stabilizing off-the-shelf antibodies against thermal and chemical denaturation. We demonstrate that the sta...

Sensory processing is influenced by cognitive and behavioral states, but how these states interact to modulate responses of individual neurons is unknown. We trained mice in a visual discrimination task wherein they attended to different locations within a hemifield while running or sitting still, enabling us to examine how visual responses are mod...

Working memory—the brain’s ability to internalize information and use it flexibly to guide behaviour—is an essential component of cognition. Although activity related to working memory has been observed in several brain regions 1–3 , how neural populations actually represent working memory 4–7 and the mechanisms by which this activity is maintained...

Behavioral studies suggest that recurrence in the visual system is important for processing degraded stimuli. There are two broad anatomical forms this recurrence can take, lateral or feedback, each with different assumed functions. Here we add four different kinds of recurrence — two of each anatomical form — to a feedforward convolutional neural...

Selectivity of cortical neurons for sensory stimuli can increase across days as animals learn their behavioral relevance and across seconds when animals switch attention. While both phenomena occur in the same circuit, it is unknown whether they rely on similar mechanisms. We imaged primary visual cortex as mice learned a visual discrimination task...

Progress in science requires standardized assays whose results can be readily shared, compared, and reproduced across laboratories. Reproducibility, however, has been a concern in neuroscience, particularly for measurements of mouse behavior. Here, we show that a standardized task to probe decision-making in mice produces reproducible results acros...

How sensory evidence is transformed across multiple brain regions to influence behavior remains poorly understood. We trained mice in a visual change detection task designed to separate the covert antecedents of choices from activity associated with their execution. Wide-field calcium imaging across the dorsal cortex revealed fundamentally differen...

Selectivity of cortical neurons for sensory stimuli can increase across days as animals learn their behavioral relevance, and across seconds when animals switch attention. While both phenomena are expressed in the same cortical circuit, it is unknown whether they rely on similar mechanisms. We imaged activity of the same neuronal populations in pri...

Intentional control over external objects is informed by our sensory experience of them. To study how causal relationships are learned and effected, we devised a brain machine interface (BMI) task using wide-field calcium signals. Mice learned to entrain activity patterns in arbitrary pairs of cortical regions to guide a visual cursor to a target l...

In motor neocortex, preparatory activity predictive of specific movements is maintained by a positive feedback loop with the thalamus. Motor thalamus receives excitatory input from the cerebellum, which learns to generate predictive signals for motor control. The contribution of this pathway to neocortical preparatory signals remains poorly underst...

The interactions between neocortical areas are fluid and state-dependent, but how individual neurons couple to cortex-wide network dynamics remains poorly understood. We correlated the spiking of neurons in primary visual (V1) and retrosplenial (RSP) cortex to activity across dorsal cortex, recorded simultaneously by widefield calcium imaging. Neur...

How sensory evidence is transformed across multiple brain regions to influence behavior remains poorly understood. We trained mice in a visual change detection task designed to separate the covert antecedents of choices from activity associated with their execution. Widefield calcium imaging across dorsal cortex revealed fundamentally different dyn...

The rules by which neurons in neocortex choose their synaptic partners are not fully understood. In sensory cortex, intermingled neurons encode different attributes of sensory inputs and relay them to different long-range targets. While neurons with similar responses to sensory stimuli make connections preferentially, the relationship between synap...

This perspective describes predictive processing as a computational framework for understanding cortical function in the context of emerging evidence, with a focus on sensory processing. We discuss how the predictive processing framework may be implemented at the level of cortical circuits and how its implementation could be falsified experimentall...

How learning enhances neural representations for behaviorally relevant stimuli via activity changes of cortical cell types remains unclear. We simultaneously imaged responses of pyramidal cells (PYR) along with parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptide (VIP) inhibitory interneurons in primary visual cortex while mice l...

In motor-related areas of the neocortex, preparatory neuronal activity predictive of specific actions emerges seconds in advance of movement and is maintained by a positive feedback loop with the thalamus. A major source of excitatory drive to the motor thalamus is the cerebellum, which has been implicated in coordination and timing of learned acti...

In the cerebral cortex, the interaction of excitatory and inhibitory synaptic inputs shapes the responses of neurons to sensory stimuli, stabilizes network dynamics ¹ and improves the efficiency and robustness of the neural code 2–4 . Excitatory neurons receive inhibitory inputs that track excitation 5–8 . However, how this co-tuning of excitation...

Neocortical areas communicate through extensive axonal projections, but the logic of information transfer remains poorly understood, because the projections of individual neurons have not been systematically characterized. It is not known whether individual neurons send projections only to single cortical areas or distribute signals across multiple...

Neurons within cortical microcircuits are interconnected with recurrent excitatory synaptic connections that are thought to amplify signals (Douglas and Martin, 2007), form selective subnetworks (Ko et al., 2011), and aid feature discrimination. Strong inhibition (Haider et al., 2013) counterbalances excitation, enabling sensory features to be shar...

The rules by which neurons in neocortex choose their synaptic partners are not fully understood. In sensory cortex, intermingled neurons encode different attributes of sensory inputs and relay them to different long-range targets. While neurons with similar responses to sensory stimuli make connections preferentially, the relationship between synap...

The wiring diagram of the neocortex determines how information is processed across dozens of cortical areas. Each area communicates with multiple others via extensive long-range axonal projections 1–6 , but the logic of inter-area information transfer is unresolved. Specifically, the extent to which individual neurons send dedicated projections to...

Neurons within cortical microcircuits are interconnected with recurrent excitatory synaptic connections that are thought to amplify signals (Douglas and Martin, 2007), form selective subnetworks (Ko et al., 2011) and aid feature discrimination. Strong inhibition (Haider et al., 2013) counterbalances excitation, enabling sensory features to be sharp...

Accurate estimation of neuronal receptive fields is essential for understanding sensory processing in the early visual system. Yet a full characterization of receptive fields is still incomplete, especially with regard to natural visual stimuli and in complete populations of cortical neurons. While previous work has incorporated known structural pr...

Analysis of sensitivity of HSM to starting conditions. (A) The model performance on the training vs. validation data set across 100 HSM fits using different initial conditions. The three plots show results for each of the 3 imaged regions separately. The color coding of the regions is the same as throughout the main paper. (B) The correlations betw...

Dataset of stimuli and corresponding population responses of recorded neurons. The dataset contains the natural image stimuli used in this study, and the pre-processed population responses of mouse V1 neurons recorded in the 3 cortical regions analyzed in this study. (ZIP)

Python implementation of the HSM model. (ZIP)

Analysis of sensitivity of HSM to different re-samplings of training set. (A) The model performance on training vs. validation data set across 100 HSM fits using different sub-samples of the training set. Each sample was obtained by removing 100 random training stimuli. The three plots show results for each of the 3 imaged regions separately. The c...

We determined how learning modifies neural representations in primary visual cortex (V1) during acquisition of a visually guided behavioral task. We imaged the activity of the same layer 2/3 neuronal populations as mice learned to discriminate two visual patterns while running through a virtual corridor, where one pattern was rewarded. Improvements...

A large population of neurons can, in principle, produce an astronomical number of distinct firing patterns. In cortex, however, these patterns lie in a space of lower dimension, as if individual neurons were "obedient members of a huge orchestra". Here we use recordings from the visual cortex of mouse (Mus musculus) and monkey (Macaca mulatta) to...

The eigenvalue spectrum of the matrix of directed weights defining a neural network model is informative of several stability and dynamical properties of network activity. Existing results for eigenspectra of sparse asymmetric random matrices neglect spatial or other constraints in determining entries in these matrices, and so are of partial applic...

The strength of synaptic connections fundamentally determines how neurons influence each other’s firing. Excitatory connection amplitudes between pairs of cortical neurons vary over two orders of magnitude, comprising only very few strong connections among many weaker ones. Although this highly skewed distribution of connection strengths is observe...

At eye opening, neurons in primary visual cortex (V1) are selective for stimulus features, but circuits continue to refine in an experience-dependent manner for some weeks thereafter. How these changes contribute to the coding of visual features embedded in complex natural scenes remains unknown. Here we show that normal visual experience after eye...

In primary visual cortex (V1), connectivity between layer 2/3 (L2/3) excitatory neurons undergoes extensive reorganization after the onset of visual experience whereby neurons with similar feature selectivity form functional microcircuits (Ko et al., 2011, 2013). It remains unknown whether visual experience is required for the developmental refinem...

The sensory cortex contains a wide array of neuronal types, which are connected together into complex but partially stereotyped circuits. Sensory stimuli trigger cascades of electrical activity through these circuits, causing specific features of sensory scenes to be encoded in the firing patterns of cortical populations. Recent research is beginni...

Three studies in visual and auditory cortex show that intracortical excitatory inputs amplify incoming sensory signals, as their sensory tuning is closely matched to that arriving from the sensory thalamus.

Sensory processing occurs in neocortical microcircuits in which synaptic connectivity is highly structured and excitatory neurons form subnetworks that process related sensory information. However, the developmental mechanisms underlying the formation of functionally organized connectivity in cortical microcircuits remain unknown. Here we directly...

Two studies show how electrical coupling between sister neurons in the developing cerebral cortex might help them to link up into columnar microcircuits that process related sensory information. See Letters p.113 & p.118

Neuronal responses during sensory processing are influenced both by the organization of intracortical connections and the statistical features of sensory stimuli. How these intrinsic and extrinsic factors govern activity of excitatory and inhibitory populations is unclear. Using two-photon calcium imaging in vivo and intracellular recordings in vit...

Neuronal responses during sensory processing are influenced by both the organization of intracortical connections and the statistical features of sensory stimuli. How these intrinsic and extrinsic factors govern the activity of excitatory and inhibitory populations is unclear. Using two-photon calcium imaging in vivo and intracellular recordings in...

Neuronal connectivity is fundamental to information processing in the brain. Therefore, understanding the mechanisms of sensory processing requires uncovering how connection patterns between neurons relate to their function. On a coarse scale, long-range projections can preferentially link cortical regions with similar responses to sensory stimuli....

Recent advances in multi-electrode recording and imaging techniques have made it possible to observe the activity of large populations of neurons. However, to take full advantage of these techniques, new methods for the analysis of population responses must be developed. In this paper, we present an algorithm for optimizing population decoding with...

Sensory experiences exert a powerful influence on the function and future performance of neuronal circuits in the mammalian neocortex. Restructuring of synaptic connections is believed to be one mechanism by which cortical circuits store information about the sensory world. Excitatory synaptic structures, such as dendritic spines, are dynamic entit...

Neurons in the nervous system can change their functional properties over time. At present, there are no techniques that allow reliable monitoring of changes within identified neurons over repeated experimental sessions. We increased the signal strength of troponin C-based calcium biosensors in the low-calcium regime by mutagenesis and domain rearr...

The cerebral cortex has the ability to adapt to altered sensory inputs. In the visual cortex, a small lesion to the retina causes the deprived cortical region to become responsive to adjacent parts of the visual field. This extensive topographic remapping is assumed to be mediated by the rewiring of intracortical connections, but the dynamics of th...

Transgenic mice with mosaic, Golgi-staining-like expression of enhanced green fluorescent protein (EGFP) have been very useful in studying the dynamics of neuronal structure and function. In order to further investigate the molecular events regulating structural plasticity, it would be useful to express multiple proteins in the same sparse neurons,...

Experience-dependent plasticity is crucial for the precise formation of neuronal connections during development. It is generally thought to depend on Hebbian forms of synaptic plasticity. In addition, neurons possess other, homeostatic means of compensating for changes in sensory input, but their role in cortical plasticity is unclear. We used two-...

Ocular dominance plasticity has long served as a successful model for examining how cortical circuits are shaped by experience. In this paradigm, altered retinal activity caused by unilateral eye-lid closure leads to dramatic shifts in the binocular response properties of neurons in the visual cortex. Much of the recent progress in identifying the...

Little is known about the maturation of functional maps in the primary auditory cortex (A1) after the onset of sensory experience. We used intrinsic signal imaging to examine the development of the tonotopic organization of ferret A1 with respect to contralateral and ipsilateral tone stimulation. Sound-evoked responses were recorded as early as pos...

The brain has a remarkable capacity to adapt to alterations in its sensory environment, which is normally much more pronounced in juvenile animals. Here we show that in adult mice, the ability to adapt to changes can be improved profoundly if the mouse has already experienced a similar change in its sensory environment earlier in life. Using the st...

Neurons can transmit information about sensory stimuli via their firing rate, spike latency, or by the occurrence of complex spike patterns. Identifying which aspects of the neural responses actually encode sensory information remains a fundamental question in neuroscience. Here we compared various approaches for estimating the information transmit...

Signaling by receptor tyrosine kinases (RTKs) is mediated by their intrinsic kinase activity. Typically, kinase-activating mutations result in ligand-independent signaling and gain-of-function phenotypes. Like other RTKs, Ephs require kinase activity to signal, but signaling by Ephs in vitro also requires clustering by their membrane bound ephrin l...

During the development of the mammalian retinocollicular projection, a coarse retinotopic map is set up by the graded distribution of axon guidance molecules. Subsequent refinement of the initially diffuse projection has been shown to depend on the spatially correlated firing of retinal ganglion cells. In this scheme, the abolition of patterned ret...

Recent studies from our laboratory have indicated that the spatial response fields (SRFs) of neurons in the ferret primary auditory cortex (A1) with best frequencies > or =4 kHz may arise from a largely linear processing of binaural level and spectral localization cues. Here we extend this analysis to investigate how well the linear model can predi...

Auditory localization relies on the detection and interpretation of acoustic cues that change in value as the head and external ears grow. Here we show that the maturation of these structures is an important determinant for the development of spatial selectivity in the ferret auditory cortex. Spatial response fields (SRFs) of high-frequency cortica...

Optical imaging of intrinsic signals is widely used for high-resolution brain mapping in various animal species. A new approach using continuous data acquisition and Fourier decomposition of the signal allows for much faster mapping, opening up the possibility of applying this method to new experimental questions.

This paper describes optical imaging of the auditory cortex in the anesthetized ferret, particularly addressing optimization of narrowband stimuli. The types of sound stimuli used were tone-pip trains and sinusoidal frequency and amplitude modulated (SFM and SAM) tones. By employing short illumination wavelengths (546 nm), we have successfully char...

The response of a neuron in the visual cortex to an oriented light bar is strongly reduced by concurrent presentation of a stimulus with a different orientation. New data suggest this 'cross-orientation suppression' is caused, not by intracortical inhibition, but by rapid depression of thalamocortical synapses.

This paper describes optical imaging of the auditory cortex in the anesthetized ferret, particularly addressing optimization of narrowband stimuli. The types of sound stimuli used were tone-pip trains and sinusoidal frequency and amplitude modulated (SFM and SAM) tones. By employing short illumination wavelengths (546 nm), we have successfully char...

To determine the direction of a sound source in space, animals must process a variety of auditory spatial cues, including interaural level and time differences, as well as changes in the sound spectrum caused by the direction-dependent filtering of sound by the outer ear. Behavioural deficits observed when primary auditory cortex (A1) is damaged ha...

The localization of sounds in space is based on spatial cues that arise from the acoustical properties of the head and external ears. Individual differences in localization cue values result from variability in the shape and dimensions of these structures. We have mapped spatial response fields of high-frequency neurons in ferret primary auditory c...

The location of a sound source is derived by the auditory system from spatial cues present in the signals at the two ears. These cues include interaural timing and level differences, as well as monaural spectral cues generated by the external ear. The values of these cues vary with individual differences in the shape and dimensions of the head and...

In 1996, as an innovation for the UK, the Wellcome Trust set up two 'American style' four-year PhD programmes in neuroscience, with an initial year of broad training followed by a three-year PhD. Here, some of the first cohort of students, who are soon to graduate and the coordinators of the programmes, give their views on this experiment in neuros...

Receptor tyrosine kinases and receptor protein tyrosine phosphatases (RPTPs) appear to coordinate many aspects of neural development, including axon growth and guidance. Here, we focus on the possible roles of RPTPs in the developing avian retinotectal system. Using both in situ hybridization analysis and immunohistochemistry, we show for the first...