Biology subjects

Murphy, T. H.

Publications and source records attributed to Murphy, T. H..

14 recordsLinked to original sources

bioRxiv2025

Widespread cortical representations of innate behaviors in the mouse

Across cortex, a substantial component of observed neuronal activity can be explained by movement. Voluntary movements elicit cortical activity that contain elements related to both motor planning and sensory activity. However, automatic movements that do not require conscious processing, for example grooming or drinking, are to a large extent controlled by subcortical systems such as the brainstem. While the cortex may not be required to generate these automatic behaviors, it is unclear whether cortical activity represents the movements associated with them. In this work, we use a simple procedure to stimulate stereotyped grooming behaviors in the head-fixed mouse while measuring neuronal function across the dorsal cortex. We find specific cortical representations of grooming both at a mesoscale network-level and single-cell resolution. Mesoscale cortical activation was most prominent at the onset of grooming episodes, and declined to baseline levels despite continuous engagement in the behavior. Further stratification of grooming component movements revealed that more directed and unilateral grooming movements had greater cortical associated responses than more stereotyped bilateral movements. These findings help to frame the impact of forms of automatic movements on large scale cortical ensembles and suggest they engage specific and transient cellular and regional cortical ensembles.

neuroscience↗

bioRxiv2025

Characterization of iGABASnFR2 for in vivo mesoscale imaging of intracortical GABA dynamics

While genetically encoded sensors have advanced the study of cortical excitation, tools for large-scale imaging of inhibition remain limited. Visualizing extracellular GABA dynamics in vivo is essential for understanding how inhibitory networks shape brain activity across sensory, behavioral, and pharmacological states. To validate and apply the genetically encoded sensor iGABASnFR2 for wide-field imaging of extracellular GABA, and to characterize how cortical inhibition reorganizes across brain states, sensory modalities, and after GABA transporter blockade. We performed mesoscale imaging in head-fixed C57BL/6 mice systemically expressing iGABASnFR2. Recordings were conducted under isoflurane anesthesia, during quiet wakefulness, natural sleep (NREM and REM), and after administration of the GAT-1 inhibitor Tiagabine. We analyzed both sensory-evoked and spontaneous GABA signals using time-series, spectral, and seed-pixel correlation analyses. iGABASnFR2 demonstrated strong and modality-specific GABAergic responses to sensory stimulation, with faster and stronger activation in the contralateral cortex. Although the general spatial patterns of sensory-evoked GABA responses were consistent across anesthesia and quiet wakefulness, the amplitude, timing, and spread of these responses were significantly greater during wakefulness. During spontaneous activity, cortical GABA levels and connectivity modulated by brain state: GABA amplitude and interhemispheric synchrony were highest during quiet wakefulness but reduced during NREM sleep. Tiagabine elevated baseline GABA levels, abolished stimulus-evoked responses, and enhanced local and long-range inhibitory synchrony. iGABASnFR2 enables reliable, high-resolution imaging of cortical GABA dynamics in vivo. These results demonstrate that inhibitory signaling is dynamically structured across brain states and can be pharmacologically modulated. This tool offers new opportunities to explore the role of inhibition in health and disease at the mesoscale level.

neuroscience↗

bioRxiv2025

Mesoscale Imaging of Cortical Sensorimotor Integration in Huntington's Disease Mice During Reward-Guided Behaviour

Huntington's disease (HD) is a neurodegenerative disorder that affects numerous brain functions, yet how altered sensory processing contributes to behavioral and learning deficits remains poorly understood. Previous wide-field mesoscale imaging and electrophysiological recording from anesthetized HD mice revealed that sensory stimulation induced exaggerated, prolonged cortical activity across more brain regions compared to wildtype (WT) littermates. This suggests differences in sensory processing; as such, this study aimed to investigate the cortical activity in a cue-based sensory-guided learning task in a custom-built Raspberry Pi-controlled two-alternative forced choice (2AFC) rig. The rig reliably enabled head-fixed zQ175 knock-in HD mice and WT controls crossed with Thy1-GCaMP6s mice, to perform a cue-based visual discrimination task while mesoscale calcium imaging recorded activity across layer 2/3 of the cortex. Mice that successfully licked the reward spout displayed decreased global cortical activity before the reward presentation, with WT mice showing more spatially localized suppression than HD mice. HD mice exhibited exaggerated cortical responses to visual stimuli and prolonged motor-related activity during licking. While this is an exploratory pilot study with limited sample size, preventing definitive genotype-based comparisons, the custom behavioral system lays the groundwork for future studies into how sensory processing deficits contribute to cognitive impairments in HD. This work provides an important step toward understanding the interplay between cortical circuit dysfunction and behavioral outcomes in HD, offering a novel platform to investigate early sensorimotor integration learning impairments.

neuroscience↗

bioRxiv2023

Behavioral Classification of Sequential Neural Activity Using Time Varying Recurrent Neural Networks

Shifts in data distribution across time can strongly affect early classification of time-series data. When decoding behavior from neural activity, early detection of behavior may help in devising corrective neural stimulation before the onset of behavior. Recurrent Neural Networks (RNNs) are common models for sequence data. However, standard RNNs are not able to handle data with temporal distributional shifts to guarantee robust classification across time. To enable the network to utilize all temporal features of the neural input data, and to enhance the memory of an RNN, we propose a novel approach: RNNs with time-varying weights, here termed Time-Varying RNNs (TV-RNNs). These models are able to not only predict the class of the time-sequence correctly but also lead to accurate classification earlier in the sequence than standard RNNs. In this work, we focus on early sequential classification of brain-wide neural activity across time using TV-RNNs applied to a variety of neural data from mice and humans, as subjects perform motor tasks. Finally, we explore the contribution of different brain regions on behavior classification using SHapley Additive exPlanation (SHAP) value, and find that the somatosensory and premotor regions play a large role in behavioral classification.

neuroscience↗

bioRxiv2023

Leveraging the power of 3D brain-wide imaging and mapping tools for brain injury research in murine models

Despite the fundamental importance of understanding impaired brain activity exhibited in post-traumatic epilepsy and other neurological impairments associated with traumatic brain injury (TBI), knowledge of how brain injury affects neuronal activity remains remarkably incomplete. We describe a whole-brain imaging and analysis approach to identify alterations in neuronal activity after TBI as a complementary method to conventional two-dimensional (2D) histological approaches. Here we report an easy-to-follow experimental pipeline to quantify changes in the whole mouse brain using tissue clearing, light sheet microscopy (LSM) and an optimised open-access atlas registration workflow. We validated the outcome of the pipeline using high throughput image analysis software and a secondary atlas registration method. Using the CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration) TBI model, TRAP2 mice were subjected to repeated mild TBI or sham treatment followed by tamoxifen injection to lock c-Fos activity after TBI. Brains were SHIELD fixed and passively cleared for imaging of c-Fos+ cells throughout the rostro-caudal axis of the brain using a light sheet microscope equipped with a specialized whole-brain imaging chamber. Volumetric images were stitched and 3D rendered using Arivis Vision4D image analysis software. For quantitative analysis, 2D image stacks were exported to segment c-Fos+ cells and register them to the Allen Mouse Brain Atlas using the BrainQuant3D python package. As a result, c-Fos+ cell counts were estimated throughout the brain and heatmaps were generated. We identified a brain-wide reduction in c-Fos cell density in the TBI group compared to sham controls, indicative of TBI-induced changes in whole brain neuronal activity. Further studies using multi-dimensional imaging coupled with analysis tools will deepen our understanding of post-TBI brain-wide dynamics.

neuroscience↗

bioRxiv2023

Decoding State-Dependent Cortical-Cerebellar Cellular Functional Connectivity in the Mouse Brain

ABSTRACTThe cerebellum participates in motor tasks, but also a broad spectrum of cognitive functions. However, cerebellar connections with higher areas such as cortex are not direct and the mechanisms by which the cerebellum integrates and processes diverse information streams are not clear. We investigated the functional connectivity between single cerebellar neurons and population activity of the dorsal cortex using mesoscale imaging. Our findings revealed dynamic coupling between individual cerebellar neurons and diverse cortical networks, and such functional association can be influenced by local excitatory and inhibitory connections. While the cortical representations of individual cerebellar neurons displayed marked changes across different brain states, the overall assignments to specific cortical topographic areas at the population level remained stable. Simple spikes and complex spikes of the same Purkinje cells displayed either similar or distinct cortical functional connectivity patterns. Moreover, the spontaneous functional connectivity patterns aligned with cerebellar neurons functional responses to external stimuli in a modality-specific manner. Importantly, the tuning properties of subsets of cerebellar neurons differed between anesthesia and awake states, mirrored by state-dependent changes in their long-range functional connectivity patterns. Collectively, our results provide a comprehensive view of the state-dependent cortical-cerebellar functional connectivity landscape and demonstrate that remapping of long-range functional network association could underlie state-dependent change in sensory processing.

neuroscience↗

bioRxiv2022

Longitudinal assessment of water-reaching reveals altered cortical activity and fine motor coordination defects in a Huntington Disease model

Huntington Disease (HD), caused by dominantly inherited expansions of a CAG repeat results in characteristic motor dysfunction. Although gross motor and balance defects have been extensively characterized in multiple HD mouse models using tasks such as rotarod, beam walking and gait analysis, little is known about forelimb deficits. Here we use a high-throughput alternating reward/non-reward water-reaching task conducted daily over [~]2 months to simultaneously monitor forelimb impairment and mesoscale cortical changes in GCaMP activity, comparing female zQ175 (HD) and wildtype (WT) littermate mice, starting at [~]5.5 months of age. Behavioral analysis of the water-reaching task reveals that HD mice, despite learning the water-reaching task as proficiently as WT mice, take longer to learn the alternating event sequence. Although WT mice displayed no significant changes in cortical activity and reaching trajectory throughout the testing period, HD mice exhibited an increase in cortical activity - especially in the secondary motor and retrosplenial cortices - over time, as well as longer and more variable reaching trajectories by [~]7 months of age. HD mice also experienced a progressive reduction in successful performance rates. Tapered beam and rotarod tests before and/or after water-reaching assessment confirmed these early and manifest stages of HD characterized by the absence and presence of failed water-reaching trials, respectively. Reduced DARPP-32 (marker for striatal medium spiny neurons) expression in HD mice further confirmed disease pathology. The water-reaching task can be used to inform HD and potentially other movement disorder onset, therapeutic intervention windows and test drug efficacy. Significance statementThe movement disorder, Huntington Disease (HD), has been extensively studied in preclinical settings using mouse models of disease examining gross motor and balance defects. Little however, is known regarding forelimb deficits and underlying cortical circuit changes. Using a high-throughput alternating reward/non-reward water-reaching task, we characterized early event sequence learning defects in HD mice aged [~]5.5 months. Progressive forelimb movement defects first become apparent at [~]6.5 months of age with corresponding increases in cortical activity associated with reaching observed over time. These forelimb defects revealed in the water-reaching task are coincident with gross motor defects characterized using the tapered beam and rotarod tasks, demonstrating the suitability of the water-reaching task in phenotyping HD motor deficits.

neuroscience↗

bioRxiv2021

Scholar Metrics Scraper (SMS): automated retrieval of citation and author data

Academic departments, research clusters and evaluators analyze author and citation data to measure research impact and to support strategic planning. We created a tool, Scholar Metrics Scraper (SMS), to automate the retrieval of this bibliometric data for our research team. The project contains Jupyter notebooks (publicly-shared here) that take a list of researchers as an input to export a CSV file of citation metrics from Google Scholar and figures to visualize the groups impact. SMS is a scalable, open and publicly-accessible solution for automating the retrieval of citation data over time for a group of researchers.

scientific communication and education↗

bioRxiv2021

Mesoscale cortex-wide neural dynamics predict self-initiated actions in mice several seconds prior to movement

Volition - the sense of control or agency over ones voluntary actions - is widely recognized as the basis of both human subjective experience and natural behavior in non-human animals. Several human studies have found peaks in neural activity preceding voluntary actions, e.g. the readiness potential (RP), and some have shown upcoming actions could be decoded even before awareness. Others propose that random processes underlie and explain pre-movement neural activity. Here we seek to address these issues by evaluating whether pre-movement neural activity in mice contains structure beyond that present in random neural activity. Implementing a self-initiated water-rewarded lever pull paradigm in mice while recording widefield [Ca++] neural activity we find that cortical activity changes in variance seconds prior to movement and that upcoming lever pulls could be predicted between 3 to 5 seconds (or more in some cases) prior to movement. We found inhibition of motor cortex starting at approximately - 5sec prior to lever pulls and activation of motor cortex starting at approximately 2sec prior to a random unrewarded left limb movement. We show that mice, like humans, are biased towards commencing self-initiated actions during specific phases of neural activity but that the pre-movement neural code changes over time in some mice and is widely distributed as behavior prediction improved when using all vs single cortical areas. These findings support the presence of structured multi-second neural dynamics preceding self-initiated action beyond that expected from random processes. Our results also suggest that neural mechanisms underlying self-initiated action could be preserved between mice and humans.

neuroscience↗

bioRxiv2021

Altered cortical processing of sensory input in Huntington disease mouse models

Huntington disease (HD), a hereditary neurodegenerative disorder, manifests as progressively impaired movement and cognition. Although early abnormalities of neuronal activity in striatum are well established in HD models, there are fewer in vivo studies of the cortex. Here, we record local field potentials (LFPs) in YAC128 HD model mice versus wild-type mice. In multiple cortical areas, limb sensory stimulation evokes a greater change in LFP power in YAC128 mice. Mesoscopic imaging using voltage-sensitive dyes reveal more extensive spread of evoked sensory signals across the cortical surface in YAC128 mice. YAC128 layer 2/3 sensory cortical neurons ex vivo show increased excitatory events, which could contribute to enhanced sensory responses in vivo. Cortical LFP responses to limb stimulation, visual and auditory input are also significantly increased in zQ175 HD mice. Results presented here extend knowledge of HD beyond ex vivo studies of individual neurons to the intact cortical network.

neuroscience↗

bioRxiv2019

Stereotyped large amplitude cortical LFP events can be clustered and reveal precisely ordered phase-locking in neuronal populations

During quiet wakefulness, slow-wave sleep and anesthesia, mammalian cortex exhibits a synchronised state during which transient changes in the local field potential (LFP) accompany periods of increased single neuron firing, known as UP-states. While UP-state genesis is still debated (Crunelli and Hughes, 2010) such transitions may constitute the default activity pattern of the entire cortex (Neske, 2016). Recent findings of preserved firing order between UP-state transitions and stimulus processing in high-firing rate (>2Hz) rat auditory and barrel cortex neurons (Luczak et al., 2015) support this hypothesis. Yet it is unknown whether UP-states are homogeneous and whether neurons with firing rates <2Hz in visual cortex or other species exhibit spiking order. Using extracellular recordings during anesthetized states in cat visual cortex and mouse visual, auditory and barrel cortex, we show that UP-states can be tracked and clustered based on the shape of the LFP waveform. We show that LFP event clusters (LECs) have current-source-density profiles that are common across different recordings or animals and using simultaneous electrophysiology and widefield voltage and calcium imaging in mouse we confirm that LEC transitions are cortex-wide phenomena. Individual LEC events can be resolved in time to within 1 - 4 ms and they elicit synchronous firing of over 75% of recorded neurons with most neurons synchronizing their firing to within {+/-}5 - 15 ms relative LECs. Firing order of different neurons during LEC events was preserved over periods of ~30 minutes enabling future studies of UP-state transitions and firing order with near millisecond precision.\n\nSignificant StatementDuring sleep and anesthetic states mammalian cortex undergoes substantial changes from awake active states. Recent studies show that single neurons in some cortical areas in rats undergo increased spiking during sleep and anesthetic states (called UP-state transitions) with some neurons firing in an order similar to awake states. This suggests that sensory processing may be similar across all states and that firing order is important for stimulus processing. Yet UP-state transitions remain poorly understood and it is unclear whether firing order is present in other cortical areas or species. Here we describe multiple classes of UP-state transitions and show most neurons in visual cortex in cats and visual, barrel and auditory cortex in mice exhibit firing order during such transitions.

neuroscience↗

bioRxiv2018

Real-time markerless video tracking of body parts in mice using deep neural networks.

Markerless and accurate tracking of mouse movement is of interest to many biomedical, pharmaceutical, and behavioral science applications. The additional capability of tracking body parts in real-time with minimal latency opens up the possibility of manipulating motor feedback, allowing detailed explorations of the neural basis for behavioral control. Here we describe a system capable of tracking specific movements in mice at a frame rate of 30.3 Hz. To achieve these results, we adapt DeepLabCut - a robust movement-tracking deep neural network framework - for real-time tracking of body movements in mice. We estimate paw movements of mice in real time and demonstrate the concept of movement-triggered optogenetic stimulation by flashing a USB-CGPIO controlled LED that is triggered when real time analysis of movement exceeds a pre-set threshold. The mean time delay between movement initiation and LED flash was 93.44 ms, a latency sufficient for applying behaviorally-triggered feedback. This manuscript presents the rationale and details of the algorithms employed and shows implementation of the system using behaving mice. This system lays the groundwork for a behavior-triggered closed loop brain-machine interface with optogenetic stimulation of specific brain regions for feedback.

neuroscience↗

bioRxiv2018

Mesoscale cortical calcium imaging reveals widespread synchronized infraslow activity during social touch in mice

We employ cortical mesoscale calcium-imaging to observe brain activity in two head-fixed mice in a staged social touch-like interaction. Using a rail system, mice are brought together to a distance where macrovibrissae of each mouse make contact. Cortical signals were recorded from both mice simultaneously before, during, and after the social contact period. When the mice were together, we observed bouts of mutual whisking and cross-mouse correlated cortical activity in the vibrissae cortex. This correlated activity was specific to individual interactions as the correlations fell in trial-shuffled mouse pairs. Whisk-related global GCAMP6s signals were greater in cagemate pairs during the together period. The effects of social interaction extend outside of regions associated with mutual touch and had global synchronizing effects on cortical activity. We present an open-source platform to investigate the neurobiology of social interaction by including mechanical drawings, protocols, and software necessary for others to extend this work.

neuroscience↗

bioRxiv2017

Spontaneous activity synchronizes whisker-related sensorimotor networks prior to their maturation in the developing rat cortex

A prominent feature of the cortical systems controlling the whiskers in the adult rodent is tight coupling between sensory and motor systems. Stimulation of the whiskers evokes activation of discrete motor regions of cortex shortly after activation of the sensory cortex. To explore the factors that direct the development of sensorimotor functional connectivity, we recorded spontaneous and whisker-evoked cortical activity using voltage-sensitive imaging over a large (7X7 mm) craniotomy in postnatal rats (day 5-12) under anesthesia. We found that spontaneous bursts of activity in the barrel cortex were correlated predominantly with activity in motor (anterio-medial) cortex, at ages before whisker stimulation evoked activation in this area. Intracortical microstimulation and anatomical tracing experiments confirmed there were no functional or anatomical intracortical sensorimotor connections. We interpret these results as evidence that the spontaneous patterns of activity in the cortex synchronize functionally related regions of the brain prior to their maturation.\n\nAuthor ContributionsD.A.M, T.H.M., and M.H.M. designed the study. D.A.M, and M.H.M performed the experiments and analyzed the data and wrote the manuscript, which all authors commented on and edited. T.H.M. and M.H.M. supervised the study.

neuroscience↗