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Casal, L.

Publications and source records attributed to Casal, L..

12 recordsLinked to original sources
bioRxiv2025

Map of spiking activity underlying change detection in the mouse visual system

Visual behavior requires coordinated activity across hierarchically organized brain circuits. Understanding this complexity demands datasets that are both large-scale (sampling many areas) and dense (recording many neurons in each area). Here we present a database of spiking activity across the mouse visual system--including thalamus, cortex, and midbrain--while mice perform an image change detection task. Using Neuropixels probes, we record from >75,000 high-quality units in 54 mice, mapping area-, cortical layer-, and cell type-specific coding of sensory and motor information. Modulation by task-engagement increased across the thalamocortical hierarchy but was strongest in the midbrain. Novel images modulated cortical (but not thalamic) responses through delayed recurrent activity. Population decoding and optogenetics identified a critical decision window for change detection and revealed that mice use an adaptation-based rather than image-comparison strategy. This comprehensive resource provides a valuable substrate for understanding sensorimotor computations in neural networks.

neuroscience↗
bioRxiv2023

Differential encoding of temporal context and expectation under representational drift across hierarchically connected areas

The classic view that neural populations in sensory cortices preferentially encode responses to incoming stimuli has been strongly challenged by recent experimental studies. Despite the fact that a large fraction of variance of visual responses in rodents can be attributed to behavioral state and movements, trial-history, and salience, the effects of contextual modulations and expectations on sensory-evoked responses in visual and association areas remain elusive. Here, we present a comprehensive experimental and theoretical study showing that hierarchically connected visual and association areas differentially encode the temporal context and expectation of naturalistic visual stimuli, consistent with the theory of hierarchical predictive coding. We measured neural responses to expected and unexpected sequences of natural scenes in the primary visual cortex (V1), the posterior medial higher order visual area (PM), and retrosplenial cortex (RSP) using 2-photon imaging in behaving mice collected through the Allen Institute Mindscopes OpenScope program. We found that information about image identity in neural population activity depended on the temporal context of transitions preceding each scene, and decreased along the hierarchy. Furthermore, our analyses revealed that the conjunctive encoding of temporal context and image identity was modulated by expectations of sequential events. In V1 and PM, we found enhanced and specific responses to unexpected oddball images, signaling stimulus-specific expectation violation. In contrast, in RSP the population response to oddball presentation recapitulated the missing expected image rather than the oddball image. These differential responses along the hierarchy are consistent with classic theories of hierarchical predictive coding whereby higher areas encode predictions and lower areas encode deviations from expectation. We further found evidence for drift in visual responses on the timescale of minutes. Although activity drift was present in all areas, population responses in V1 and PM, but not in RSP, maintained stable encoding of visual information and representational geometry. Instead we found that RSP drift was independent of stimulus information, suggesting a role in generating an internal model of the environment in the temporal domain. Overall, our results establish temporal context and expectation as substantial encoding dimensions in the visual cortex subject to fast representational drift and suggest that hierarchically connected areas instantiate a predictive coding mechanism.

neuroscience↗
bioRxiv2023

Stimulus novelty uncovers coding diversity in visual cortical circuits

Detecting novel stimuli in the environment is critical for learning and survival, yet the neural basis of novelty processing is not understood. To characterize cell type-specific novelty processing, we surveyed the activity of [~]15,000 excitatory and inhibitory neurons in mice performing a visual task with novel and familiar stimuli. Clustering revealed a dozen functional neuron types defined by experience-dependent encoding. Vasoactive-intestinal-peptide (Vip) expressing inhibitory neurons were diverse, encoding novel stimuli, omissions of familiar stimuli, or behavioral features. Distinct Somatostatin (Sst) expressing inhibitory neurons encoded either familiar or novel stimuli. Subsets of excitatory neurons co-clustered with specific Vip or Sst subpopulations, while Sst and Vip inhibitory clusters were non-overlapping. This study establishes that novelty processing is mediated by diverse functional neuron types in the visual cortex.

neuroscience↗
bioRxiv2021

A whole-brain monosynaptic input connectome to neuron classes in mouse visual cortex

Identification of the structural connections between neurons is a prerequisite to understanding brain function. We developed a pipeline to systematically map brain-wide monosynaptic inputs to specific neuronal populations using Cre-driver mouse lines and the recombinant rabies tracing system. We first improved the rabies virus tracing strategy to accurately identify starter cells and to efficiently quantify presynaptic inputs. We then mapped brain-wide presynaptic inputs to different excitatory and inhibitory neuron subclasses in the primary visual cortex and seven higher visual areas. Our results reveal quantitative target-, layer- and cell-class-specific differences in the retrograde connectomes, despite similar global input patterns to different neuronal populations in the same anatomical area. The retrograde connectivity we define is consistent with the presence of the ventral and dorsal visual information processing streams and reveals further subnetworks within the dorsal stream. The hierarchical organization of the entire visual cortex can be derived from intracortical feedforward and feedback pathways mediated by upper- and lower-layer input neurons, respectively. This study expands our knowledge of the brain-wide inputs regulating visual areas and demonstrates that our improved rabies virus tracing strategy can be used to scale up the effort in dissecting connectivity of genetically defined cell populations in the whole mouse brain.

neuroscience↗
bioRxiv2020

Reconciling functional differences in populations of neurons recorded with two-photon imaging and electrophysiology

Extracellular electrophysiology and two-photon calcium imaging are widely used methods for measuring physiological activity with single-cell resolution across large populations of neurons in the brain. While these two modalities have distinct advantages and disadvantages, neither provides complete, unbiased information about the underlying neural population. Here, we compare evoked responses in visual cortex recorded in awake mice under highly standardized conditions using either imaging or electrophysiology. Across all stimulus conditions tested, we observe a larger fraction of responsive neurons in electrophysiology and higher stimulus selectivity in calcium imaging. This work explores which data transformations are most useful for explaining these modality-specific discrepancies. We show that the higher selectivity in imaging can be partially reconciled by applying a spikes-to-calcium forward model to the electrophysiology data. However, the forward model could not reconcile differences in responsiveness without sub-selecting neurons based on event rate or level of signal contamination. This suggests that differences in responsiveness more likely reflect neuronal sampling bias or cluster-merging artifacts during spike sorting of electrophysiological recordings, rather than flaws in event detection from fluorescence time series. This work establishes the dominant impacts of the two modalities respective biases on a set of functional metrics that are fundamental for characterizing sensory-evoked responses.

neuroscience↗
bioRxiv2020

Similar visual perception in GCaMP6 transgenic mice despite differences in learning and motivation

To study mechanisms of perception and cognition, neural measurements must be made during behavior. A goal of the Allen Brain Observatory is to map activity in distinct cortical cell classes during visual processing and behavior. Here we characterize learning and performance of five GCaMP6-expressing transgenic lines trained on a visual change detection task. We used automated training procedures to facilitate comparisons across mice. Training times varied, but most transgenic mice learned the task. Motivation levels also varied across mice. To compare mice in similar motivational states we subdivided sessions into over-, under-, and optimally motivated periods. When motivated, the pattern of perceptual decisions were highly correlated across transgenic lines, although overall d-prime was lower in one line labeling somatostatin inhibitory cells. These results provide important context for using these mice to map neural activity underlying perception and behavior.

neuroscience↗
bioRxiv2019

A survey of spiking activity reveals a functional hierarchy of mouse corticothalamic visual areas

The mammalian visual system, from retina to neocortex, has been extensively studied at both anatomical and functional levels. Anatomy indicates the cortico-thalamic system is hierarchical, but characterization of cellular-level functional interactions across multiple levels of this hierarchy is lacking, partially due to the challenge of simultaneously recording activity across numerous regions. Here, we describe a large, open dataset (part of the Allen Brain Observatory) that surveys spiking from units in six cortical and two thalamic regions responding to a battery of visual stimuli. Using spike cross-correlation analysis, we find that inter-area functional connectivity mirrors the anatomical hierarchy from the Allen Mouse Brain Connectivity Atlas. Classical functional measures of hierarchy, including visual response latency, receptive field size, phase-locking to a drifting grating stimulus, and autocorrelation timescale are all correlated with the anatomical hierarchy. Moreover, recordings during a visual task support the behavioral relevance of hierarchical processing. Overall, this dataset and the hierarchy we describe provide a foundation for understanding coding and dynamics in the mouse cortico-thalamic visual system.

neuroscience↗
bioRxiv2019

Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease

Huntington disease (HD) is a neurodegenerative disorder that is caused by a CAG repeat expansion in the HTT gene. In an attempt to identify genomic modifiers that contribute towards the age of onset of HD, we performed a transcriptome wide association study assessing heritable differences in genetically determined expression in diverse tissues, employing genome wide data from over 4,000 patients. This identified genes that showed evidence for colocalization and replication, with downstream functional validation being performed in isogenic HD stem cells and patient brains. Enrichment analyses detected associations with various biologically-relevant gene sets and striatal coexpression modules that are mediated by CAG length. Further, cortical coexpression modules that are relevant for HD onset were also associated with cognitive decline and HD-related traits in a longitudinal cohort. In summary, the combination of population-scale gene expression information with HD patient genomic data identified novel modifier genes for the disorder.

genomics↗
bioRxiv2019

Experience shapes activity dynamics and stimulus coding of VIP inhibitory and excitatory cells

Cortical circuits are flexible and can change with experience and learning. However, the effects of experience on specific cell types, including distinct inhibitory types, are not well understood. Here we investigated how excitatory and VIP inhibitory cells in layer 2/3 of mouse visual cortex were impacted by visual experience in the context of a behavioral task. Mice learned to perform an image change detection task with a set of eight natural scene images, viewing these images thousands of times. Subsequently, during 2-photon imaging experiments, mice performed the task with these familiar images and three additional sets of novel images. Novel images evoked stronger overall activity in both excitatory and VIP populations, and familiar images were more sparsely coded by excitatory cells. The temporal dynamics of VIP activity differed markedly between novel and familiar images: VIP cells were stimulus-driven by novel images but displayed ramping activity during the inter-stimulus interval for familiar images. Moreover, when a familiar stimulus was omitted from an expected sequence, VIP cells showed extended ramping activity until the subsequent image presentation. This prominent shift in response dynamics suggests that VIP cells may adopt different modes of processing during familiar versus novel conditions.\n\nHIGHLIGHTSO_LIExperience with natural images in a change detection task reduces overall activity of cortical excitatory and VIP inhibitory cells\nC_LIO_LIEncoding of natural images is sharpened with experience in excitatory neurons\nC_LIO_LIVIP cells are stimulus-driven by novel images but show pre-stimulus ramping for familiar images\nC_LIO_LIVIP cells show strong ramping activity during the omission of an expected stimulus\nC_LI

neuroscience↗
bioRxiv2018

A large-scale, standardized physiological survey reveals higher order coding throughout the mouse visual cortex

To understand how the brain processes sensory information to guide behavior, we must know how stimulus representations are transformed throughout the visual cortex. Here we report an open, large-scale physiological survey of neural activity in the awake mouse visual cortex: the Allen Brain Observatory Visual Coding dataset. This publicly available dataset includes cortical activity from nearly 60,000 neurons collected from 6 visual areas, 4 layers, and 12 transgenic mouse lines from 221 adult mice, in response to a systematic set of visual stimuli. Using this dataset, we reveal functional differences across these dimensions and show that visual cortical responses are sparse but correlated. Surprisingly, responses to different stimuli are largely independent, e.g. whether a neuron responds to natural scenes provides no information about whether it responds to natural movies or to gratings. We show that these phenomena cannot be explained by standard local filter-based models, but are consistent with multi-layer hierarchical computation, as found in deeper layers of standard convolutional neural networks.

neuroscience↗
bioRxiv2018

The organization of intracortical connections by layer and cell class in the mouse brain

The mammalian cortex is a laminar structure composed of many cell types densely interconnected in complex ways. Recent systematic efforts to map the mouse mesoscale connectome provide comprehensive projection data on interareal connections, but not at the level of specific cell classes or layers within cortical areas. We present here a significant expansion of the Allen Mouse Brain Connectivity Atlas, with [~]1,000 new axonal projection mapping experiments across nearly all isocortical areas in 49 Cre driver lines. Using 13 lines selective for cortical layer-specific projection neuron classes, we identify the differential contribution of each layer/class to the overall intracortical connectivity patterns. We find layer 5 (L5) projection neurons account for essentially all intracortical outputs. L2/3, L4, and L6 neurons contact a subset of the L5 cortical targets. We also describe the most common axon lamination patterns in cortical targets. Most patterns are consistent with previous anatomical rules used to determine hierarchical position between cortical areas (feedforward, feedback), with notable exceptions. While diverse target lamination patterns arise from every source layer/class, L2/3 and L4 neurons are primarily associated with feedforward type projection patterns and L6 with feedback. L5 has both feedforward and feedback projection patterns. Finally, network analyses revealed a modular organization of the intracortical connectome. By labeling interareal and intermodule connections as feedforward or feedback, we present an integrated view of the intracortical connectome as a hierarchical network.

neuroscience↗