Biology subjects

Wotjak, C. T.

Publications and source records attributed to Wotjak, C. T..

5 recordsLinked to original sources

bioRxiv2026

Comparison of multiple video tracking-based behavioral summary approaches for compound discrimination

The rapidly increasing number of video tracking-based behavioral summary tools and methods raises the question as to the most suitable approaches for pharmacological fingerprinting in pre-clinical research. We have recently shown that social context has a strong effect on behavioral syntax in mice, further suggesting that treatment effects can be context dependent. Here, we aim to answer the question whether there is an optimal combination of context and behavioral summary method for effect detection and discrimination of different psychoactive substances in a controlled environment. To this end, we applied eight different treatment-dosage pairs (amphetamine 1.5,3,6 mg/kg; modafinil 5,10,50 mg/kg; seltorexant 3,10 mg/kg) and evaluated five different approaches to behavioral summary: parametric aggregation, unsupervised segmentation in Keypoint-MoSeq (KPMS) & Variational Animal Motion Encoding (VAME), and supervised segmentation in Simple Behavioral Analysis (SimBA) & A-SOiD, across two different contexts (Solitary & Social) in 314 recordings of freely moving mice in an open-field arena. Surprisingly, our results show no significant differences in performance across models and context. Across treatment effect detection to treatment-dose discrimination, all models showed performance significantly above chance that was insensitive to various data limitations and extensions. Overall, our study shows that under the tested conditions and treatments, the choice of a behavioral summary model does not meaningfully affect the description of treatment effects. Simple aggregate measures from tracking data and machine learning based behavioral summary approaches that are expensive, in terms of training data and computational resources, performed equally well. Our findings taken together with literature suggest that the fuller decomposition of complex behavior through unsupervised machine learning might be necessary for the description of large-scale datasets but does not necessarily align with the goals present in smaller-scale treatment discrimination tasks common in pre-clinical research.

animal behavior and cognition↗

bioRxiv2025

Social Context Restructures Behavioral Syntax in Mice

The study of social behavior in mice has grown increasingly relevant for unraveling associated brain circuits and advancing the development of treatments for psychiatric symptoms involving social withdrawal or social anxiety. However, a data-driven understanding of behavior and its modulation in solitary and social contexts is lacking. In this study, we employed motion sequencing ("MoSeq") to decompose mouse behaviors into discrete units ("Syllables") and investigate whether--and how--the behavioral repertoire differs between solitary and dyadic (social) settings. Our results reveal that social context significantly modulates a minority (25%) of syllables, containing predominantly stationary and undirected behaviors. Notably, these changes are associated with spatial proximity to another mouse rather than active social contact. Interestingly, a network analysis of syllable transitions shows that context-sensitive syllables exhibit altered network influence, independent of the number of connected syllables, suggesting a regulatory role. Furthermore, syllable composition changes significantly during social contact events with two distinct sequence families governing approach and withdrawal behaviors. However, no unique syllable sequences mapped to specific social interactions. Overall, our findings suggest that a subset of syllables drives contextual behavioral adaptation in mice, potentially facilitating transitions within the broader behavioral repertoire. This highlights the utility of MoSeq in dissecting nuanced, context-dependent behavioral dynamics.

animal behavior and cognition↗

bioRxiv2024

Long-term adaptation of prefrontal circuits in a mouse model of NMDAR hypofunction

Pharmacological approaches to induce N-methyl-D-aspartate receptor (NMDAR) hypofunction have been intensively used to understand the aetiology and pathophysiology of schizophrenia. Yet, the precise cellular and molecular mechanisms that relate to brain network dysfunction remain largely unknown. Here, we used a set of complementary approaches to assess the functional network abnormalities present in mice that underwent a 7-day subchronic phencyclidine (PCP 10mg/kg, subcutaneously, once daily) treatment. Our data revealed that pharmacological intervention with PCP affected cognitive performance and auditory evoked gamma oscillations in the prefrontal cortex (PFC) mimicking endophenotypes of some schizophrenia patients. We further assessed PFC cellular function and identified altered neuronal intrinsic membrane properties, reduced parvalbumin (PV) immunostaining and diminished inhibition onto L5 PFC pyramidal cells. A decrease in the strength of optogenetically-evoked glutamatergic current at the ventral hippocampus (HPC) to PFC synapse was also demonstrated, along with a weaker shunt of excitatory transmission by local PFC interneurons. On a macrocircuit level, functional ultrasound measurements indicated compromised functional connectivity within several brain regions particularly involving PFC and frontostriatal circuits. Herein, we reproduced a panel of schizophrenia endophenotypes induced by subchronic PCP application in mice. We further recapitulated electrophysiological signatures associated with schizophrenia and provided an anatomical reference to critical elements in the brain circuitry. Together, our findings contribute to a better understanding of the physiological underpinnings of deficits induced by subchronic NMDAR antagonist regimes and provide a test system for characterization of pharmacological compounds. HighlightsO_LISubchronic PCP treatment alters cognitive performance and evoked gamma synchronization in the prefrontal cortex. C_LIO_LISubchronic PCP reduces number of parvalbumin-positive boutons and inhibitory synaptic transmission onto pyramidal neurons in layer 5/6 of the prelimbic cortex. C_LIO_LISubchronic PCP reduces the strength of ventral hippocampal inputs to the medial prefrontal cortex. C_LIO_LIFrontostriatal circuits show robust dysconnectivity after subchronic PCP treatment. Abstract C_LI

neuroscience↗

bioRxiv2018

How much fear is in anxiety?

The selective breeding for extreme behavior on the elevated plus-maze (EPM) resulted in two mouse lines namely high-anxiety behaving (HAB) and low-anxiety behaving (LAB) mice. Using novel behavioral tests we demonstrate that HAB animals additionally exhibit maladaptive escape behavior and defensive vocalizations, whereas LAB mice show profound deficits in escaping from approaching threats which partially results from sensory deficits. We could relate these behavioral distortions to tonic changes in brain activity within the periaqueductal gray (PAG) in HAB mice and the superior colliculus (SC) in LAB mice, using in vivo manganese-enhanced MRI (MEMRI) followed by pharmacological or chemogenetic interventions. Therefore, midbrain-tectal structures govern the expression of both anxiety-like behavior and defensive responses. Our results challenge the uncritical use of the anthropomorphic terms anxiety or anxiety-like for the description of mouse behavior, as they imply higher cognitive processes, which are not necessarily in place.

neuroscience↗

bioRxiv2017

The role of m6A-RNA methylation in stress response regulation

N6-Methyladenosine (m6A) is an abundant internal RNA modification that regulates transcript processing and translation. The regulation of brain m6A by stressful stimuli in vivo and its role in the stress response are currently unknown.\n\nHere, we provide a detailed analysis of the stress-epitranscriptome using m6A-Seq, global and gene-specific m6A measurements. We show that stress exposure and glucocorticoids alter m6A and its regulatory network in a region- and time-specific manner. We demonstrate that depletion of the methyltransferase Mettl3 and the demethylase Fto in adult neurons increases fear memory, and alters the transcriptome response to fear as well as synaptic plasticity. Finally, we report that regulation of m6A is impaired in major depressive disorder patients following glucocorticoid receptor activation.\n\nOur findings indicate that brain m6A represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m6A-response may contribute to the pathophysiology of stress-related psychiatric disorders.\n\nHighlightsO_LIm6A RNA methylation in adult mouse brain is regulated by stress\nC_LIO_LIBrain m6A levels are temporally and spatially regulated by stress\nC_LIO_LIMettl3 and Fto-KO alter fear memory, transcriptome response and synaptic plasticity\nC_LIO_LIThe m6A-glucocorticoid-response is impaired in major depressive disorder patients\nC_LI\n\neTOC blurbEngel et al. demonstrate a brain-area-specific and time-dependent role for the mRNA modification, m6A, in stress-response regulation. Manipulating m6A-enzymes alters fear-memory, transcriptome-response and synaptic-plasticity. Altered m6A dynamics in depressed patients suggest an involvement of m6A-modifications in stress-related psychiatric disorders.

neuroscience↗