Biology subjects

Frick, A.

Publications and source records attributed to Frick, A..

15 recordsLinked to original sources

bioRxiv2026

Sex Differences in Acute Responses to Psychedelics: Evidence for Greater Subjective Intensity and Impairment in Female Participants

Serotonergic psychedelics are advancing as psychiatric treatments, yet acute responses vary between individuals and the contribution of sex, a fundamental biological variable, remains largely unexamined. We pooled two double-blind, placebo-controlled randomized studies in healthy volunteers (N = 94 drug observations; 43 male, 51 female) comparing psilocybin 15 mg, 2C-B 20 mg, and LSD 50 ug. Linear mixed models tested sex differences in acute subjective effects (visual analogue scales), retrospective altered-states ratings (5D- and 11-ASC), empathy (Multifaceted Empathy Test), and peak (Cmax) and total (AUC) drug exposure, with treatment and sex as fixed factors and age as a covariate. Female participants reported numerically higher subjective ratings than male participants on most measures. After adjustment for age, sex differences were significant on five measures, most robustly for feeling under the drugs influence, reduced vigilance, and impaired control and cognition, with medium-to-large effects. These effects were largely consistent across the three drugs. No sex differences emerged on any empathy measure or in peak drug concentrations, indicating that female's stronger responses occurred at equivalent drug exposure. Female participants may experience more intense acute subjective effects and greater perceived impairment under psychedelics, independent of age and not explained by drug exposure. These preliminary findings, implicating pharmacodynamic rather than pharmacokinetic mechanisms, have implications for dosing, informed consent, and safety monitoring, and underscore the need to treat sex as a biological variable in adequately powered psychedelic trials.

neuroscience↗

bioRxiv2026

Host-derived bile acids drive dysbiosis by selecting bile-resistant epimerizing bacteria in inflammatory bowel disease

Microbial dysbiosis is a hallmark of inflammatory bowel diseases (IBD); however, its drivers and impact on disease pathophysiology are poorly understood. Applying neural network-based feature attribution to metabolomics and metagenomics datasets from >5000 individuals, we identified epimerized host derived bile acids (BAs) produced by microbial hydroxysteroid dehydrogenases (HSDHs) as a novel hallmark of IBD-associated dysbiosis. Epimerized BAs reduce FXR activity in intestinal epithelial cells and dampen their production of FGF19, a negative feedback regulator of host-derived bile acid (HBA) production in the liver. Increased HBA levels drive colonic epithelial remodeling by impacting goblet cell maturation and select for HSDH-carrying bacteria that transform bactericidal HBA into less toxic, epimerized forms. Confirming the translational relevance of these findings, we demonstrated that high HBA levels limit fecal microbiota transplant engraftment and show that BA sequestering drugs support microbiome recovery in patients with high HBA levels. Together, we discover that elevated HBAs deplete BA-sensitive commensals and favor the growth of HSDH-encoding pathobionts that disrupt host BA feedback signaling, establishing a causal link between changes in microbial ecology and IBD pathophysiology.

microbiology↗

bioRxiv2026

Virtual screening and zebrafish phenotype-based evaluation argues against repurposing 4-phenylbutyrate for STXBP1-relateddisorders

Syntaxin-binding protein 1 (STXBP1) mutations lead to severe epilepsy, intellectual disability, developmental delay, and movement disorder. Effective treatments for these conditions do not exist. Recent studies in Munc18-1 (STXBP1) C. elegans models demonstrate that 4-phenylbutyrate (4-PBA) or related pharmacological chaperones stabilize Munc18-1 protein levels and rescue locomotion deficits. These studies suggest a novel treatment strategy for these patients. Here, we used a stxbp1a zebrafish model with a profound movement disorder to screen 4-PBA and alternative structural analogs identified using artificial intelligence (AI)-based screening. Automated locomotion assays conducted on larval stxbp1a mutant zebrafish at 5 days post-fertilization (dpf) confirm and extend the movement disorder endophenotype. Drug treatment (4-PBA or 16 identified candidates) failed to rescue the stxbp1a mutant zebrafish locomotion deficit. Electrophysiology studies in a stxbp1b zebrafish model characterized by spontaneous seizure activity (i.e., epilepsy) failed to detect a reduction in ictal-like events with 4-PBA treatment. Taken together, our results suggest caution in repurposing 4-PBA or related compounds for treatment of STXBP1 disorders.

pharmacology and toxicology↗

bioRxiv2026

Cerebellar Gray Matter Volume Changes Across Development: Posterolateral and Vermal Transient Increases during Adolescence

The cerebellum undergoes substantial maturation with regionally distinct developmental trajectories. This study examined cerebellar gray matter volume (GMV) in healthy children, adolescents, and adults, using voxel-based morphometry, the ACAPULCO algorithm, and the SUIT toolbox for cerebellum-optimized analyses. A total of 104 typically developing children (n=31, 6-9 years), adolescents (n=35, 13-17 years), and adults (n=38, 30-40 years) were included. We hypothesized age group differences in cerebellar GMV, with adolescents showing the greatest volume, specifically in posterolateral regions. Results revealed significant group differences in GMV. We observed region-specific volumetric patterns, with some areas (e.g., Crus II, lobule X) increasing from childhood to adolescence followed by stabilization, whereas other areas (e.g., lobules I-IV and VI, Crus I, vermis VI and VIIb) exhibited peak GMV during adolescence, with lower volumes in both children and adults. These patterns were partly consistent with our hypothesis. Notably, no regions had greater GMV in adults than adolescents, suggesting that cerebellar growth peaks in adolescence before stabilizing. Our findings indicate differential developmental patterns both between and within lobules of the cerebellum, and highlight adolescence as a peak period of cerebellar growth, with potential implications for the development of cerebellar-supported cognitive and emotional functions that undergo significant changes during this period.

neuroscience↗

bioRxiv2025

Altered cognitive processes shape tactile perception in autism.

Altered sensory perception is a hallmark of autism and shapes how individuals engage with their environment, with tactile perception playing a critical role in daily functioning and for social interactions. While sensory alterations are thought to contribute to cognitive differences in autism, the impact of cognition on sensory perception remains unclear. Here, we investigated how cognitive processes modulate tactile perception in the Fmr1-KO genetic mouse model of autism through a translational perceptual decision-making task. Our results revealed salience-dependent cognitive alterations that influenced sensory performance. During training, Fmr1-/y male mice distinguishing between a high- and a low-salience stimulus exhibited an increased choice consistency bias in low-salience trials. When tested across a continuum of intermediate stimulus intensities, these mice demonstrated enhanced tactile discrimination of low-salience stimuli but reduced discrimination facilitation for stimuli crossing category boundaries. These effects were accompanied by diminished integration of sensory history and were dissociable from the attention deficits that emerged under high cognitive load. Together, our findings reveal that tactile perceptual alterations reflect context-dependent weighting and integration of sensory information during decision-making rather than uniform sensory deficits or enhancements, supporting a shift beyond traditional sensory-cognitive dichotomies.

neuroscience↗

bioRxiv2024

deadtrees.earth - An Open-Access and Interactive Database for Centimeter-Scale Aerial Imagery to Uncover Global Tree Mortality Dynamics

Excessive tree mortality is a global concern and remains poorly understood as it is a complex phenomenon. We lack global and temporally continuous coverage on tree mortality data. Ground-based observations on tree mortality, e.g., derived from national inventories, are very sparse, not standardized and not spatially explicit. Earth observation data, combined with supervised machine learning, offer a promising approach to map tree mortality over time. However, global-scale machine learning requires broad training data covering a wide range of environmental settings and forest types. Drones provide a cost-effective source of training data by capturing high-resolution orthophotos of tree mortality events at sub-centimeter resolution. Here, we introduce deadtrees.earth, an open-access platform hosting more than a thousand centimeter-resolution orthophotos, covering already more than 300,000 ha, of which more than 58,000 ha are fully annotated. This community-sourced and rigorously curated dataset shall serve as a foundation for a global initiative to gather comprehensive reference data. In concert with Earth observation data and machine learning it will serve to uncover tree mortality patterns from local to global scales. This will provide the foundation to attribute tree mortality patterns to environmental changes or project tree mortality dynamics to the future. Thus, the open and interactive nature of deadtrees.earth together with the collective effort of the community is meant to continuously increase our capacity to uncover and understand tree mortality patterns.

ecology↗

bioRxiv2024

Early intrinsic plasticity of ACC engram neurons defines memory formation and precision

Neocortical memory engrams are thought to stabilize and mature via enhanced interconnectivity during the so-called systems-consolidation process 1,2. While synaptic plasticity of these engram connections is considered an important mechanism for storing memories 3,4, it cannot fully account for the dynamic vividness of remote, cortically-based memories. Indeed, cell-intrinsic plasticity has been touted as the crucial early priming mechanism that renders nascent engram neurons susceptible to ongoing plastic processes while providing flexibility for later encoding events 5-7. Here, we reveal that learning-related neuron-wide intrinsic excitability (IE) plasticity of nascent cortical engram neurons is a permissive mechanism for the formation and specificity of remote associative memories. Using a c-fos-dependent genetic and viral system for the targeted labeling of engram neurons in the anterior cingulate cortex (ACC) combined with ex vivo electrophysiology, we found that contextual fear learning triggered a time-dependent increase in their IE signature expressed over days during the early, but not late, phase of memory formation. Remarkably, chemogenetically hyperpolarizing engram neurons during this early plastic phase enhanced their maturation, increasing the strength and context-precision of consolidated memories and preventing memory disturbance caused by an interference event. Altogether, our findings identify cell-intrinsic plasticity within nascent ACC engram neurons as an essential tagging mechanism whose features determine the fate and dynamic content of remote memories.

neuroscience↗

bioRxiv2024

Disrupted stimulus encoding shapes tactile perception in autism.

Touch is essential for interacting with the world, and atypical tactile experience is a core feature of autism that profoundly affects daily life. However, we do not know the neural mechanisms of low-level tactile perception and their alterations in autism. Using a translational perceptual task, we recapitulate the multifaceted tactile features of autistic individuals in the Fmr1-/y mouse model of autism, showing tactile hyposensitivity, interindividual variability, and unreliable responses. We reveal that impaired detection decoding in Fmr1-/y-hyposensitive mice stems from diminished single-neuron signal-to-noise ratio in the primary somatosensory cortex that leads to weak population encoding of the tactile stimulus and its detection. This manifests as reduced stimulus-dependent neural recruitment, impaired response precision, and disrupted ensemble dynamics. Decreasing neuronal hyperexcitability strengthens sensory encoding and improves tactile perception. This work provides a translational framework for probing neuronal-perceptual changes in neurodevelopmental conditions, reveals inter-individual variability in preclinical models, and uncovers the neural basis of tactile hyposensitivity in autism.

neuroscience↗

bioRxiv2024

Specific amygdala and hippocampal subfield volumes in social anxiety disorder and their relation to clinical characteristics; an international mega-analysis

Social anxiety disorder (SAD) has been associated with alterations in amygdala and hippocampal volume but there is mixed evidence for the direction of volumetric alterations. Additionally, little is known about the involvement of the distinct subfields in the pathophysiology of SAD. Volumetric data from a large multi-centre sample of 107 adult individuals with SAD and 140 healthy controls (HCs) was segmented using FreeSurfer to produce 9 amygdala and 12 hippocampal subfield volumes. Volumes were compared between groups using linear mixed-effects models adjusted for age, age-squared, sex, site and whole amygdala and hippocampal volumes. Subgroup analyses examined subfield volumes in relation to comorbid anxiety disorder, and comorbid major depressive disorder (MDD), psychotropic medication status, and symptom severity. In the full sample, SAD was associated with smaller amygdala volumes in the basal (d=-0.32, pFDR=0.022), accessory basal (d=- 0.42, pFDR=0.005) and corticoamygdaloid transition area (d=-0.37, pFDR=0.014), and larger hippocampal volume in the CA3 (d=0.34, pFDR=0.024), CA4 (d=0.44, pFDR=0.007), dentate gyrus (d=0.35, pFDR=0.022) and molecular layer (d=0.28, pFDR= 0.033), compared to HCs. SAD without comorbid anxiety, in addition, demonstrated smaller lateral amygdala (d=-0.30, pFDR=0.037) and hippocampal amygdala transition area (d=-0.33, pFDR=0.027) relative to HCs. In SAD without comorbid MDD, only the smaller accessory basal amygdala remained significant (d=-0.41, pFDR=0.017). No association was found between subfield volume and medication status or symptom severity. In conclusion, we observed distinct patterns of volumetric differences across specific amygdala and hippocampal subfields, regions that are associated with sensory information processing, threat evaluation and fear generalization. These findings suggest a possible disruption in information flow between the amygdala and hippocampal formation for fear processing in SAD.

neuroscience↗

bioRxiv2021

Evaluating an internet-delivered fear conditioning and extinction protocol using response times and affective ratings.

Pavlovian fear conditioning is widely used to study mechanisms of fear learning, but high-throughput studies are hampered by the labor-intensive nature of examining participants in the lab. To circumvent this bottle-neck, fear conditioning tasks have been developed for remote delivery. Previous studies have examined remotely delivered fear conditioning protocols using expectancy and affective ratings. Here we replicate and extend these findings using an internet-delivered version of the Screaming Lady paradigm, evaluating the effects on negative affective ratings and response time to an auditory probe during stimulus presentations. In a sample of 80 adults, we observed clear evidence of both fear acquisition and extinction using affective ratings. Response times were faster when probed early, but not later, during presentation of stimuli paired with an aversive scream. The response time findings are at odds with previous lab-based studies showing slower responses to threat-predicting cues. The findings underscore the feasibility of employing remotely delivered fear conditioning paradigms with affective ratings as outcome, and highlight the need for further research examining optimal parameters for concurrent response time measures or alternate modes of non-verbal estimation of conditioned responses in Pavlovian conditioning protocols.

neuroscience↗

bioRxiv2021

Dopamine facilitates fear memory formation in the human amygdala

Learning which environmental cues that predict danger is crucial for survival and accomplished through Pavlovian fear conditioning. In humans and rodents alike, fear conditioning is amygdala-dependent and rests on similar neurocircuitry. Rodent studies have implicated a causative role for dopamine in the amygdala during fear memory formation, but the role of dopamine in aversive learning in humans is unclear. Here, we show dopamine release in the amygdala and striatum during fear learning in humans. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we demonstrate that the amount of dopamine release is linked to strength of conditioned fear responses and linearly coupled to learning-induced memory trace activity in the amygdala. Thus, like in rodents, formation of amygdala-dependent fear memories in humans seems to be facilitated by endogenous dopamine release, supporting an evolutionary conserved neurochemical mechanism for aversive memory formation.

neuroscience↗

bioRxiv2020

GABA quantification in human anterior cingulate cortex

{gamma}-Aminobutyric acid (GABA) is a primary inhibitory neurotransmitter in the human brain. It has been shown that altered GABA concentration plays an important role in a variety of psychiatric and neurological disorders. The main purpose of this study was to propose a combination of PRESS and MEGA-PRESS acquisitions for absolute GABA quantification and to compare GABA estimations obtained using total choline (tCho), total creatine (tCr), and total N-acetyl aspartate (tNAA) as the internal concentration references with water referenced quantification. The second aim was to demonstrate the fitting approach of MEGA-PRESS spectra with QuasarX algorithm using a basis set of GABA, glutamate, glutamine, and NAA in vitro spectra. Thirteen volunteers were scanned with the MEGA-PRESS sequence at 3T. Interleaved water referencing was used for quantification, B0 drift correction and to update the carrier frequency of RF pulses in real time. Reference metabolite concentrations were acquired using a PRESS sequence with short TE (30 ms) and long TR (5000 ms). Absolute concentration were corrected for cerebrospinal fluid, gray and white matter water fractions and relaxation effects. Water referenced GABA estimations were significantly higher compared to the values obtained by metabolite references. We conclude that QuasarX algorithm together with the basis set of in vitro spectra improves reliability of GABA+ fitting. The proposed GABA quantification method with PRESS and MEGA-PRESS acquisitions enables the utilization of tCho, tCr, and tNAA as internal concentration references. The use of different concentration references have a good potential to improve the reliability of GABA estimation.

neuroscience↗

bioRxiv2020

Sensory stimulus evoked responses in layer 2/3 pyramidal neurons of the hind paw-related mouse primary somatosensory cortex

The mouse primary somatosensory cortex (S1) processes tactile sensory information and is the largest neocortex area emphasizing the importance of this sensory modality for rodent behavior. Most of our knowledge regarding information processing in S1 stems from studies of the whisker-related barrel cortex (S1-BC), yet the processing of tactile inputs from the hind-paws is poorly understood. We used in vivo whole-cell patch-clamp recordings from layer (L) 2/3 pyramidal neurons (PNs) of the S1 hind-paw (S1-HP) region of anaesthetized wild type (WT) mice to investigate their evoked sub- and supra-threshold activity, intrinsic properties, and spontaneous activity. Approximately 45% of these L2/3 PNs responded to brief contralateral HP stimulation in a subthreshold manner, ~5% fired action potentials, and ~50% of L2/3 PNs did not respond at all. The evoked subthreshold responses had long onset- (~23 ms) and peak-latencies (~61 ms). The majority (86%) of these L2/3 PNs responded to prolonged (stance-like) HP stimulation with both on- and off-responses. HP stimulation responsive L2/3 PNs had a greater intrinsic excitability compared to non-responsive ones, possibly reflecting differences in their physiological role. Similar to S1-BC, L2/3 PNs displayed up- and down-states, and low spontaneous firing rates (~0.1 Hz). Our findings support a sparse coding scheme of operation for S1-HP L2/3 PNs and highlight both differences and similarities with L2/3 PNs from other somatosensory cortex areas. KEY POINTSO_LIResponses of layer (L) 2/3 pyramidal neurons (PNs) of the primary somatosensory hind-paw cortex (S1-HP) to contralateral hind-paw stimulation reveal both differences and similarities compared to those of somatosensory neurons responding to other tactile (e.g. whiskers, forepaw, tongue) modalities. C_LIO_LISimilar to whisker-related barrel cortex (S1-BC) and forepaw cortex (S1-FP) S1-HP L2/3 PNs show a low spontaneous firing rate and a sparse action potential coding of evoked activity. C_LIO_LIIn contrast to S1-BC, brief hind-paw stimulus evoked responses display a long latency in S1-HP neurons consistent with their different functional role. C_LIO_LIThe great majority of L 2/3 PNs respond to prolonged hind-paw stimulation with both on- and off-responses. C_LIO_LIThese results help us to better understand sensory information processing within layer 2/3 of the neocortex and the regional differences related to various tactile modalities. C_LI

neuroscience↗

bioRxiv2020

Detecting fine and elaborate movements with piezo sensors, from heartbeat to the temporal organization of behavior

Behavioral phenotyping devices have been successfully used to build ethograms, but studying the temporal dynamics of individual movements during spontaneous, ongoing behavior, remains a challenge. We now report on a novel device, the Phenotypix, which consists in an open-field platform resting on highly sensitive piezoelectric (electro-mechanical) pressure-sensors, with which we could detect the slightest movements from freely moving rats and mice. The combination with video recordings and signal analysis based on time-frequency decomposition, clustering and machine learning algorithms allowed to quantify various behavioral components with unprecedented accuracy, such as individual heartbeats and breathing cycles during rest, shaking in response to pain or fear, and the dynamics of balance within individual footsteps during spontaneous locomotion. We believe that this device represents a significant progress and offers new opportunities for the awaited advance of behavioral phenotyping.

animal behavior and cognition↗

bioRxiv2019

Probing the polarity of GABAergic transmission in vivo

Several studies suggest a contribution of reversed, excitatory GABA to epileptogenesis. But GABAergic transmission critically depends on the very dynamic combination of membrane potential, conductance and occurrence of other synaptic inputs. Taking this complexity into account implies measuring the postsynaptic responses to spontaneously occurring GABAergic events, in vivo, without interfering with neuronal [Cl-]i. Because of technical difficulties, this has not been achieved yet. We have overcome this challenge by combining in vivo extracellular detection of both optogenetically-evoked and spontaneously occurring unitary inhibitory postsynaptic field-potentials (fIPSPs), with the silicon probe recording of neuronal firing activity, with single cell resolution. We report that isolated acute seizures induced a global reversal of the polarity of CA3 hippocampal GABAergic transmission, shifting from inhibitory to excitatory for a duration of several tens of seconds before returning to normal polarity. Nevertheless we observed this reversed polarity only in the post-ictal period during which neurons (including GABAergic interneurons) were silent. Perisomatic inhibition was also affected during the course of epileptogenesis in the Kainate model of chronic epilepsy. One week after Kainate injection, the majority of pyramidal cells escaped inhibitory control by perisomatic GABAergic events. Besides, we did not observe a reversed polarity of fIPSPs, but fIPSPs provided time-locked excitation to a minor subset of CA3 pyramidal neurons. Beside methodological interests, our results suggest that subtle alterations in the regulation of [Cl-]i and perisomatic GABAergic transmission already operate in the hippocampal circuit during the latent period that precedes the establishment of chronic epilepsy.

neuroscience↗