Biology subjects

Ehret, B.

Publications and source records attributed to Ehret, B..

5 recordsLinked to original sources

bioRxiv2026

Organoid-based colorectal tumor microenvironment model for immuno-oncology research

The development of cancer immunotherapies is hindered by the lack of human-relevant models that accurately translate to patient outcomes. We combine patient-derived colorectal tumor organoids (PDOs) and cancer-associated fibroblasts (CAFs) into floating extracellular matrix drops to form miniature colorectal tumors. These SHaking Organoid CO-cultures (SHOCOs) reproducibly capture key features of the tumor microenvironment (TME), including physiologically relevant ECM, hypoxic regions, and a diversified stromal compartment that captures primary CAF states. Compared with traditional PDO-based co-culture models, SHOCOs maintain immune cells in numbers, states and functional interactions that more closely reflect the physiological tumor microenvironment. The modularity of the system allowed controlled simulation of diverse patient tumor archetypes, and defining how TME components shape therapy response. Immune-rich SHOCOs treated with T-cell bispecific antibodies exhibited robust anti-tumor responses that were stronger and more rapid than their PDO-based counterparts. Stroma-rich tumors, on the other hand, diminished therapy responses by physically hindering both immune cell recruitment and limiting antibody penetration. Thus, SHOCOs enable the construction of modular tumor microenvironments, providing a versatile platform to dissect immune and stromal tumor biology and to catalyze the discovery of novel therapeutic approaches.

cancer biology↗

bioRxiv2025

Inhibition from the oxytocin system tunes prefrontal circuit dynamics to promote social behavior

The prefrontal cortex (PFC) plays a central role in the selection and expression of diverse social behaviors. A balance of excitation and inhibition is necessary for normal social functioning, but it remains unclear how inhibition sculpts pyramidal activity to promote specific social behaviors. To address this question, we developed a novel decision-making task in which female mice chose between interaction with a male (sociosexual stimulus) or an appetitive non-social option (milk solution). To explore the role of a task-relevant inhibitory subpopulation, we targeted neurons in the medial PFC (mPFC) expressing oxytocin receptors (OXTR neurons). Combining optogenetic inhibition of OXTR neurons with population calcium imaging of pyramidal neural activity, we found that OXTR neurons normally promote interaction with a male compared to a non-social alternative. OXTR neurons also regulate pyramidal activity, which enables a specific ensemble to represent the male option during decision-making. Computational modeling reproduced these findings through a pyramidal competition mechanism, in which regulation by OXTR neurons allows a male-representing pyramidal ensemble to effectively compete against the remaining pyramidal population to drive male choice. These results provide a candidate mechanism by which inhibition enables mPFC pyramidal activity to select for specific social behaviors and may help explain why excitation/inhibition balance is so important for social functioning.

neuroscience↗

bioRxiv2023

Population-level neural correlates of flexible avoidance learning in medial prefrontal cortex

The medial prefrontal cortex (mPFC) has been proposed to link sensory inputs and behavioral outputs to mediate the execution of learned behaviors. However, how such a link is implemented has remained unclear. To measure prefrontal neural correlates of sensory stimuli and learned behaviors, we performed population calcium imaging during a novel tone-signaled active avoidance paradigm in mice. We developed a novel analysis approach based on dimensionality reduction and decoding that allowed us to identify and isolate population activity patterns related the tone stimulus, learned avoidance actions and general motion. While tone-related activity was not informative about behavior, avoidance-related activity was predictive of upcoming avoidance actions. Moreover, avoidance-related activity distinguished between two different learned avoidance actions, consistent with a model in which mPFC contributes to the selection between different goal-directed actions. Overall, our results suggest that mPFC circuit dynamics transform sensory inputs into specific behavioral outputs through distributed population-level computations.

neuroscience↗

bioRxiv2021

How synaptic strength, short-term plasticity, and temporal factors contribute to neuronal spike output

Neurons integrate from thousands of synapses whose strengths span an order of magnitude. Intriguingly, in mouse neocortex, the few strong synapses are formed between similarly tuned cells, suggesting they determine neuronal spiking output. This raises the question of how other computational primitives, including background activity from the many weak synapses, short-term plasticity, and temporal factors contribute to spiking. We combined extracellular stimulation and whole-cell recordings in mouse barrel cortex to map excitatory postsynaptic potential (EPSP) amplitudes and paired-pulse ratios of excitatory synaptic connections converging onto individual layer 2/3 (L2/3) neurons. While net short-term plasticity was weak, connections with EPSPs > 2 mV were exclusively depressing. There was no evidence for clustering of synaptic properties on individual neurons. Instead, EPSPs and paired-pulse ratios of connections converging onto the same cells spanned the full range observed across L2/3, which critically constrains theoretical models of cortical filtering. To investigate how different computational primitives of synaptic information processing interact to shape spiking, we developed a computational model of a pyramidal neuron in the rodent L2/3 circuitry, which was constrained by our own experiments and published in vivo data. We found that the ability of strong inputs to evoke spiking depended on their high temporal synchrony and high firing rates observed in vivo and on synaptic background activity - and not primarily on synaptic strength, which further amplified information transfer. Our results provide a framework of how cortical neurons exploit complex synergies between temporal coding, synaptic properties, and noise to transform synaptic inputs into output firing.

neuroscience↗

bioRxiv2020

Fast retrograde access to projection neuron circuits underlying vocal learning in songbirds

Understanding the structure and function of neural circuits underlying speech and language is a vital step towards better treatments for diseases of these systems. Songbirds, among the few animal orders that share with humans the ability to learn vocalizations from a conspecific, have provided many insights into the neural mechanisms of vocal development. However, research into vocal learning circuits has been hindered by a lack of tools for rapid genetic targeting of specific neuron populations to meet the quick pace of developmental learning. Here, we present a new viral tool that enables fast and efficient retrograde access to projection neuron populations. In zebra finches, Bengalese finches, canaries, and mice, we demonstrate fast retrograde labeling of cortical or dopaminergic neurons. We further demonstrate the suitability of our construct for detailed morphological analysis, for in vivo imaging of calcium activity, and for multicolor brainbow labeling.

neuroscience↗