Biology subjects

Carlen, M.

Publications and source records attributed to Carlen, M..

10 recordsLinked to original sources

bioRxiv2026

Capturing Spatially Organized Oscillatory Cliques as Signatures of Neuronal Assemblies

State-of-the-art neural recording technologies now enable dense sampling of neuronal activity, demonstrating meaningful spiking variability from moment to moment. Yet spiking activity is sparse by nature and allows only partial access to collective neuronal dynamics. Local field potentials (LFPs) provide complementary information by capturing coordinated activity from large neuronal populations, but methods to characterize the fine-scale spatio-temporal organization of LFPs are lacking. Starting from the notion that neural oscillations are brief and burst-like, we introduce a framework to detect and analyze SPatially Organized Oscillatory Cliques (SPOOCs), oscillatory events that are cohesive in space, time, and frequency. SPOOCs displayed diverse dynamics in space and frequency and were differentially modulated during stimulus processing. Linking SPOOCs to local spiking, we demonstrate that these events index rapid reconfigurations of neuronal assemblies. With SPOOChunter, we provide an open-source toolbox that enables systematic detection and analysis of transient, spatially organized population dynamics in high-density electrophysiological recordings.

neuroscience↗

bioRxiv2026

Systematic identification of DNA methylation biomarkers for tumor-type-specific detection

DNA methylation biomarkers for cancer diagnostics often underperform when tumor and background tissues share epigenetic programs, or when complex specimens with mixed cellular composition dilute tumor-derived signals and increase variability. To address these limitations, we developed a gene-centric, browser-based discovery platform that integrates genome-wide methylomes with matched transcriptomes and reference layers spanning pan-cancer tissues and leukocytes, enabling background-aware filtering beyond binary tumor-normal contrasts. Candidate loci are prioritized using combined thresholds on methylation effect size and intra-group variability to penalize stochastic and heterogeneous variation. In colorectal cancer, methylation-sensitive restriction enzyme quantitative PCR (MSRE-qPCR) validation in independent tissue cohorts confirmed multiple candidate loci with AUCs of 0.81-1.00. Using the same framework, MSRE-qPCR validation distinguished hepatocellular carcinoma from cirrhotic liver, and analysis of public tumor methylomes identified subtype-specific markers in lung adenocarcinoma and squamous-cell carcinoma. This resource bridges genome-scale epigenomic discovery with clinically accessible PCR-based methylation assays.

bioinformatics↗

bioRxiv2025

DMC-BrainMap - an open-source, end-to-end tool for multi-feature brain mapping across species

A central goal of current neuroscience research is to understand how behavior emerges from neuronal circuit activity. For this, cellular and circuit components in intact brains need to be identified and studied using e.g. viral tracing, electrophysiology, imaging, activity perturbations, and behavior. A commonality of these approaches is the need to establish the anatomical locations of both experimental parameters (e.g. recording/injection sites) and circuit components (e.g. cell bodies/projections). The development of standardized coordinate systems, i.e. reference brain atlases, has proven essential for reproducible, cross-laboratory mapping of anatomical data. However, the process of mapping, analyzing, and visualizing anatomical data remains challenging, especially for users lacking programming expertise. Here, we introduce DMC-BrainMap, an open-source napari plugin designed as a user-friendly tool for streamlined processing and whole-brain analysis of anatomical data. The working principle and core functionalities include all steps after image acquisition, i.e., preprocessing of images, registration of images to a reference atlas, segmentation of different anatomical features, and data analysis/visualization. DMC-BrainMap can be applied to histological data obtained from a variety of model organisms at different developmental stages, including mouse, rat, and zebrafish. We demonstrate the utility of DMC-BrainMap by mapping and quantifying cell bodies, axonal densities, injection sites as well as placement of optical fibers and Neuropixels probes. Further, we show how spatial transcriptomics data can be integrated into the DMC-BrainMap workflow. By eliminating the need for programming by the user, DMC-BrainMap provides an easy-to-use tool for increased rigor, reproducibility, and data sharing in neuroscientific research involving animal models.

neuroscience↗

bioRxiv2024

A Prefrontal Cortex Map based on Single Neuron Activity

The intrinsic organization underlying the central cognitive role of the prefrontal cortex (PFC) is poorly understood. The work to date has been dominated by cytoarchitecture as a canvas for studies on the PFC, constraining concepts, analyses, results, and their interpretations to pre-configured delimitations that might not be relevant to function. We approached organization by profiling the activity and spatial location of >23,000 neurons recorded in awake mice. Regularly firing neurons were over-represented in most PFC subregions, yet a fine-grained activity map of the PFC did not align with cytoarchitecturally defined subregions. Instead, we observed a robust relationship between spontaneous activity patterns and intra-PFC hierarchy, suggesting internal organization principles transcending cytoarchitecture. Single neuron responses to sounds did not reflect intra-PFC hierarchy but were linked to spontaneous firing rate, indicating that responsiveness increases with excitability and is decoupled from the PFCs intrinsic operational structure. Our data-driven approach provides a scalable roadmap to explore functional organizations in diverse brain regions and species, opening avenues to link activity, structure, and function in the brain.

neuroscience↗

bioRxiv2024

A striosomal accumbens pathway drives compulsive seeking behaviors through an aversive Esr1+ hypothalamic-habenula circuit.

The lateral hypothalamic area (LHA) integrates external stimuli with internal states to drive the choice between competing innate or value-driven motivated behaviors. Projections from the LHA to the lateral habenula (LHb) shape internal states, with excitatory estrogen receptor 1-expressing (Esr1+) LHA-LHb neurons driving aversive responses and sustained negative states. Here, we identify and functionally characterize a specific projection from the nucleus accumbens (ACB) that targets Esr1+ LHA-LHb neurons. Using cell-type-specific tracing of monosynaptic inputs, single-nucleus RNA sequencing, and neuroanatomical mapping, we demonstrate that the Esr1+ LHA-LHb pathway receives a major input from a striosomal Tac1+/Tshz1+/Oprm1+ ACB neuron subtype. Intersectional cell-type-specific and input-output defined optogenetic manipulation of this ACB-LHA-LHb pathway revealed its role in signaling aversion after repeated activation, with the negative behavioral state being dependent on recruitment of Esr1+ LHA-LHb neurons. Importantly, we found that activation of the D1+ ACB-LHA pathway drives reward-independent compulsive-like seeking behaviors, expressed as compulsive digging or poking behaviors. We found that these complex yet stereotyped behaviors compete with highly motivated states and can override the need for natural rewards or social stimuli. Our findings reveal a discrete striosomal Tac1+ ACB projection targeting the aversive Esr1+ LHA-LHb pathway as a key circuit that promotes compulsive seeking behaviors over goal-directed actions.

neuroscience↗

bioRxiv2023

Cell type-specific representation of spatial context in the rat prefrontal cortex

The ability to represent ones own position in relation to cues, goals, or threats is crucial to successful goal-directed behavior. Using transgenic rats expressing Cre recombinase in parvalbumin (PV) neurons (PV-Cre rats) we demonstrate cell type-specific encoding of spatial and movement variables in the medial prefrontal cortex (mPFC) during reward foraging. Single neurons encoded the conjunction of the animals spatial position and the location of the reward, referred to as the spatial context. The spatial context was most prominently represented by the inhibitory PV interneurons. Movement towards the reward was signified by increased local field potential (LFP) oscillations in the gamma band but this LFP signature was not related to the spatial information in the neuronal firing. The results highlight how spatial information is incorporated into cognitive operations in the mPFC. The presented PV-Cre line opens for expanded research approaches in rats.

neuroscience↗

bioRxiv2022

Esr1+ hypothalamic-habenula neurons shape aversive states.

Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used Patch-seq guided multimodal classification to define the structural and functional heterogeneity of the LHA-LHb pathway. Our classification identified six glutamatergic neuron types with unique electrophysiological properties, molecular profiles, and projection patterns. We found that genetically-defined LHA-LHb neurons signal distinct aspects of emotional or naturalistic behaviors: Esr1+ LHA-LHb neurons induce aversion, whereas Npy+ LHA-LHb neurons control rearing behavior. Repeated optogenetic drive of Esr1+ LHA-LHb neurons induces a behaviorally persistent aversive state, and large-scale recordings showed a region-specific neural representation of the aversive state in the prelimbic region of the prefrontal cortex. We further found that exposure to unpredictable mild shocks induced a sex-specific sensitivity to develop a stress state in female mice, which was associated with a specific shift in the intrinsic properties of bursting-type Esr1+ LHA-LHb neurons. In summary, we describe the diversity of LHA-LHb neuron types, and provide evidence for the role of Esr1+ neurons in aversion and sexually dimorphic stress sensitivity.

neuroscience↗

bioRxiv2020

Network asynchrony underlying increased broadband gamma power

Synchronous activity of cortical inhibitory interneurons expressing parvalbumin (PV) underlies the expression of cortical gamma rhythms. Paradoxically, deficient PV inhibition is associated with increased broadband gamma power. Increased baseline broadband gamma is also a prominent characteristic in schizophrenia, and a hallmark of network alterations induced by N-methyl-D-aspartate receptor (NMDAR) antagonists such as ketamine. It has been questioned if enhanced broadband gamma power is a true rhythm, and if rhythmic PV inhibition is involved or not. It has been suggested that asynchronous and increased firing activities underlie broadband power increases spanning the gamma band. Using mice lacking NMDAR activity specifically in PV neurons to model deficient PV inhibition, we here show that local LFP (local field potential) oscillations and neuronal activity with decreased synchronicity generate increases in prefrontal broadband gamma power. Specifically, reduced spike time precision of both local PV interneurons and wide-spiking (WS) excitatory neurons contribute to increased firing rates, and spectral leakage of spiking activity (spike "contamination") affecting the broadband gamma band. Desynchronization was evident at multiple time scales, with reduced spike-LFP entrainment, reduced cross-frequency coupling, and fragmentation of brain states. While local application of S(+)-ketamine in wildtype mice triggered network desynchronization and increases in broadband gamma power, our investigations suggest that disparate mechanisms underlie increased power of broadband gamma caused by genetic alteration of PV interneurons, and ketamine-induced power increases in broadband gamma. Our studies, thus, confirm that broadband gamma increases can arise from asynchronous activities, and demonstrate that long-term deficiency of PV inhibition can be a contributor.

neuroscience↗

bioRxiv2020

A critical role for trkB signaling in the adult function of parvalbumin interneurons and prefrontal network dynamics

Inhibitory interneurons expressing parvalbumin (PV) in the prefrontal cortex (PFC) are central to excitatory/inhibitory (E/I) balance, generation of gamma oscillations, and cognition. Dysfunction of PV interneurons disrupts information processing and cognitive behavior. Tyrosine receptor kinase B (trkB) signaling is known to regulate the differentiation and maturation of cortical PV interneurons during development, but is also suggested to be involved in the activity and network functions of PV interneurons in the adult brain. Using a novel viral strategy for cell-type and region-specific expression of a dominant negative trkB in adult mice, we show that reduced trkB signaling in PV interneurons in the PFC leads to pronounced morphological, physiological, and behavioral changes. Our results provide evidence for a critical role of trkB signaling in the function of PV interneurons in the adult brain, local network activities central to prefrontal circuit dynamics, and cognitive behavior.

neuroscience↗

bioRxiv2020

The DMCdrive: practical 3D-printable micro-drive system for reliable chronic multi-tetrode recording and optogenetic application in freely behaving rodents

Electrophysiological recording and optogenetic control of neuronal activity in behaving animals have been integral to the elucidation of how neurons and circuits modulate network activity in the encoding and causation of behavior. However, most current electrophysiological methods require substantial economical investments and prior expertise. Further, the inclusion of optogenetics with electrophysiological recordings in freely moving animals remains a general challenge. Expansion of the technological repertoire across laboratories, research institutes, and countries, demands open access to high-quality devices that can be built with little or no prior expertise from easily accessible parts of low cost. We here present a very affordable, truly easy-to-assemble micro-drive for electrophysiology in combination with optogenetics in freely moving mice and rats. The DMCdrive is particularly suited for reliable long-term recordings of neurons and network activities, and simplify optical tagging and manipulation of neurons in the recorded brain region. The highly functional and practical drive design has been optimized for accurate tetrode movement in brain tissue, and remarkably reduced build time. We provide a complete overview of the drive design, its assembly and use, and proof-of-principle demonstration of long-term recordings paired with cell-type-specific optogenetic manipulations in the prefrontal cortex (PFC) of freely moving transgenic mice and rats.

neuroscience↗