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Mace, K.

Publications and source records attributed to Mace, K..

15 recordsLinked to original sources
bioRxiv2026

Sensory-sleep dysfunction is a shared phenotype across genetically distinct neurodevelopmental disorder models

Sensory abnormalities and sleep disruption frequently co-occur in neurodevelopmental disorders (NDDs), but how sensory input interacts with sleep regulation in NDDs remains poorly understood. Here, we examined vibration-induced sleep (VIS), in which prolonged gentle vibration promotes sleep in Drosophila, in three genetically distinct NDD models: dNf1, dNrx1, and dFmr1. Despite markedly different baseline sleep phenotypes, all three mutants exhibited impaired VIS, identifying disrupted sensory-sleep integration as a shared phenotype across these NDD models. Behavioral responses to vibration, activity-associated CRTC signaling in Nanchung-positive (Nan+) mechanosensory neurons, and thermogenetic activation of Nan+ neurons revealed distinct underlying abnormalities across the three models, indicating that disruption at different points along the sensory-sleep axis can converge on the same behavioral phenotype. The effect of mechanosensory stimulation was also strongly shaped by homeostatic sleep drive: following sleep deprivation, vibration promoted sleep in dNf1 mutants, remained ineffective in dNrx1 mutants, and opposed recovery sleep in dFmr1 mutants. Together, these findings identify impaired sensory regulation of sleep as a point of convergence across genetically distinct NDD models and demonstrate that the expression of this shared phenotype depends on internal state.

neuroscience↗
bioRxiv2026

An internal scaffold supports microtubule architectural diversity in Xenopus spermatids

During spermiogenesis, early round spermatids differentiate into specialized spermatozoa through an extensive reshaping of the nucleus driven by coordinated cytoskeletal and chromatin-based mechanisms. In mammals, this process critically relies on the transient manchette, a microtubule-based structure that remodels the spermatid nucleus and serves a track to transport material required for flagellum assembly. However, the existence, organization, and molecular composition of such a structure in other vertebrates have remained poorly investigated. Here, we establish that an organized microtubule network is present in Xenopus spermatids and shares key architectural and molecular hallmarks of the mammalian manchette. We further uncover a large structural heterogeneity of spermatid microtubules, with variable protofilament numbers, skew angles, and lattice organizations. We reveal the presence of a Spaca9-Saxo2 internal scaffold in spermatid microtubules suggesting an internal reinforcement mechanism necessary for extensive nuclear reshaping and cytoplasm remodeling.

cell biology↗
bioRxiv2026

HInt: interaction-based homology discovery through accelerated genome-scale AlphaFold screening

Identifying homologous proteins across deep evolutionary distances remains a major challenge because sequence and structural similarity progressively become undetectable over time. Although protein-protein interactions (PPIs) are often constrained by function and evolution, whether conserved interaction interfaces can provide an independent signal for homology detection has remained largely unexplored owing to the computational cost of proteome-scale interaction prediction. Here we introduce HInt (Homology by Interaction), an accelerated AlphaFold-based framework that enables practical proteome-scale PPI prediction through biologically informed pre-filtering and optimised high-throughput structure modelling. Using HInt, we establish interaction-based similarity as a third axis of homology detection. We show that conserved interaction interfaces reveal homologous relationships that remain inaccessible to conventional sequence- and structure-based approaches. Application of HInt to both prokaryotic and eukaryotic systems, together with experimental validation, uncovered a previously unrecognised VirB5 pilus-tip protein in the F-plasmid type IV secretion system and a previously unannotated F-box-like protein in the Saccharomyces cerevisiae ubiquitin-proteasome system. By enabling practical proteome-scale interaction screening, HInt provides a general framework for uncovering hidden homologues and expands the conceptual landscape of protein homology inference.

molecular biology↗
bioRxiv2025

PPIFold: A Tool for Analysis of Protein-Protein Interaction from AlphaPullDown

Protein structure and protein-protein interaction (PPI) predictions based on coevolution have transformed structural biology, but managing pre-processing and post-processing can be complex and time-consuming, making these tools less accessible. Here, we introduce PPIFold, a pipeline built on the AlphaPulldown Python package, designed to automate file handling and streamline the generation of outputs, facilitating the interpretation of PPI prediction results. The pipeline was validated on the bacterial Type 4 Secretion System nanomachine, demonstrating its effectiveness in simplifying PPI analysis and enhancing accessibility for researchers.

bioinformatics↗
bioRxiv2024

Cross-species evidence for a developmental origin of adult hypersomnia with loss of synaptic adhesion molecules beat-Ia/CADM2

Idiopathic hypersomnia (IH) is a poorly-understood sleep disorder characterized by excessive daytime sleepiness despite normal nighttime sleep. Combining human genomics with behavioral and mechanistic studies in fish and flies, we uncover a role for beat-Ia/CADM2, synaptic adhesion molecules of the immunoglobulin superfamily, in excessive sleepiness. Neuronal knockdown of Drosophila beat-Ia results in sleepy flies and loss of the vertebrate ortholog of beat-Ia, CADM2, results in sleepy fish. We delineate a developmental function for beat-Ia in synaptic elaboration of neuropeptide F (NPF) neurites projecting to the suboesophageal zone (SEZ) of the fly brain. Brain connectome and experimental evidence demonstrate these NPF outputs synapse onto a subpopulation of SEZ GABAergic neurons to stabilize arousal. NPF is the Drosophila homolog of vertebrate neuropeptide Y (NPY), and an NPY receptor agonist restores sleep to normal levels in zebrafish lacking CADM2. These findings point towards NPY modulation as a treatment target for human hypersomnia.

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↗
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↗
bioRxiv2021

Learning from unexpected events in the neocortical microcircuit

Scientists have long conjectured that the neocortex learns the structure of the environment in a predictive, hierarchical manner. According to this conjecture, expected, predictable features are differentiated from unexpected ones by comparing bottom-up and top-down streams of information. It is theorized that the neocortex then changes the representation of incoming stimuli, guided by differences in the responses to expected and unexpected events. In line with this conjecture, different responses to expected and unexpected sensory features have been observed in spiking and somatic calcium events. However, it remains unknown whether these unexpected event signals occur in the distal apical dendrites where many top-down signals are received, and whether these signals govern subsequent changes in the brains stimulus representations. Here, we show that both somata and distal apical dendrites of cortical pyramidal neurons exhibit distinct unexpected event signals that systematically change over days. These findings were obtained by tracking the responses of individual somata and dendritic branches of layer 2/3 and layer 5 pyramidal neurons over multiple days in primary visual cortex of awake, behaving mice using two-photon calcium imaging. Many neurons in both layers 2/3 and 5 showed large differences between their responses to expected and unexpected events. Interestingly, these responses evolved in opposite directions in the somata and distal apical dendrites. These differences between the somata and distal apical dendrites may be important for hierarchical computation, given that these two compartments tend to receive bottom-up and top-down information, respectively.

neuroscience↗
bioRxiv2020

A standardized behavioral event equally impacts the activity of cortical visual areas and layers

Multiple recent studies have shown that motor activity greatly impacts the activity of primary sensory areas like V1. Yet, the role of this motor related activity in sensory processing is still unclear. Here we dissect how these behavior signals are broadcast to different layers and areas of the visual cortex. To do so, we leveraged a standardized and spontaneous behavioral fidget event in passively viewing mice. Importantly, this behavior event had no relevance to any ongoing task allowing us to compare its neuronal correlate with visually relevant behavior like running. A large two-photon Ca2+ imaging database of neuronal responses uncovered four neural response types during fidgets that were surprisingly consistent in their proportion and response patterns across all visual areas and layers of the visual cortex. Indeed, the layer and area identity could not be decoded above chance level based only on neuronal recordings. In contrast to running behavior, fidget evoked neural responses were independent to visual processing. The broad availability of visually orthogonal standardized behavior signals could be a key component in how the cortex selects, learns and binds local sensory information with motor outputs. Contrary to relevant motor outputs, irrelevant motor signals would use a separate neural subspaces. Significance StatementRecent studies have shown contextual and behavioral variables to dominate brain-wide activity, but yet it is unknown how this information is broadcast across cortical layers and areas. Using a large two-photon dataset collected in mice passively viewing a battery of visual stimuli, we characterized the neuronal response of neurons of the visual cortex to a standardized fidget behavior. We found that as much as 47% of excitatory neurons show significant co-activity with fidgets. Throughout all areas and layers we recorded from, those responses were distributed across surprisingly consistent three neural response types. Further analysis showed no interaction between fidget neural events and cells visual stimulus responses, contrasting with feedback neural signals induced by running. These contrasting response distribution patterns suggest that behavioral neuronal correlates are broadly available but will modulate sensory responses depending on their relevance to local sensory inputs.

neuroscience↗
bioRxiv2020

Measuring stimulus-evoked neurophysiological differentiation in distinct populations of neurons in mouse visual cortex

Despite significant progress in understanding neural coding, it remains unclear how the coordinated activity of large populations of neurons relates to what an observer actually perceives. Since neurophysiological differences must underlie differences among percepts, differentiation analysis--quantifying distinct patterns of neurophysiological activity--is an "inside out" approach that addresses this question. We used two-photon calcium imaging in mice to systematically survey stimulus-evoked neurophysiological differentiation in excitatory populations across 3 cortical layers (L2/3, L4, and L5) in each of 5 visual cortical areas (primary, lateral, anterolateral, posteromedial, and anteromedial) in response to naturalistic and phase-scrambled movie stimuli. We find that unscrambled stimuli evoke greater neurophysiological differentiation than scrambled stimuli specifically in L2/3 of the anterolateral and anteromedial areas, and that this effect is modulated by arousal state and locomotion. Contrariwise, decoding performance was far above chance and did not vary substantially across areas and layers. Differentiation also differed within the unscrambled stimulus set, suggesting that differentiation analysis may be used to probe the ethological relevance of individual stimuli.

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

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↗
bioRxiv2019

A dataset to explore kinase control of environmental stress responsive transcription

Cells respond to changes in environmental conditions by activating signal transduction pathways and gene expression programs. Here we present a dataset to explore the relationship between environmental stresses, kinases, and global gene expression in yeast. We subjected 28 drug-sensitive kinase mutants to 10 environmental conditions in the presence of inhibitor and performed mRNA deep sequencing. With these data, we reconstructed canonical stress pathways and identified examples of crosstalk among pathways. The data also implicated numerous kinases in novel environment-specific roles. However, rather than regulating dedicated sets of target genes, individual kinases tuned the magnitude of induction of the environmental stress response (ESR) - a gene expression signature shared across the set of perturbations - in environment-specific ways. This suggests that the ESR integrates inputs from multiple sensory kinases to modulate gene expression and growth control. As an example, we provide experimental evidence that the high osmolarity glycerol pathway is a constitutive negative regulator of protein kinase A, a known inhibitor of the ESR. These results elaborate the central axis of cellular stress response signaling.

systems biology↗