Biology subjects

van de Lisdonk, D.

Publications and source records attributed to van de Lisdonk, D..

3 recordsLinked to original sources

bioRxiv2026

GFRAL neurons remodel intestinal structure and type 2 immunity

The brain has emerged as a key regulator of immune functions, but the underlying neural mechanisms remain poorly understood. Here we show that brainstem GFRAL-expressing neurons prime type 2 immunity and shape intestinal epithelial structure in mice. Type 2 inflammation results in activation of GFRAL neurons and potentiation of their excitatory synaptic inputs. Enhancing GFRAL neuron excitability is sufficient to remodel intestinal type 2 immunity through a polysynaptic vagal brain-gut circuit, expanding tuft and goblet cell populations and increasing intestinal type 2 cytokine expression; while inhibiting GFRAL neurons leads to largely opposite changes. Accordingly, manipulating GFRAL neuron function reshapes intestinal structure and pathophysiology in food allergy, helminth infection and colitis models. Thus, GFRAL neurons orchestrate type 2 immune responses to facilitate recovery from intestinal diseases.

neuroscience↗

bioRxiv2023

Area postrema neurons mediate interleukin-6 function in cancer-associated cachexia

Interleukin-6 (IL-6) has been long considered a key player in cancer-associated cachexia1-15. It is believed that sustained elevation of IL-6 production during cancer progression causes brain dysfunctions, which ultimately result in cachexia16-20. However, how peripheral IL-6 influences the brain remains poorly understood. Here we show that neurons in the area postrema (AP), a circumventricular structure in the hindbrain, mediate the function of IL-6 in cancer-associated cachexia in mice. We found that circulating IL-6 can rapidly enter the AP and activate AP neurons. Peripheral tumor, known to increase circulating IL-61-5,15,18,21-23, leads to elevated IL-6 and neuronal hyperactivity in the AP, and causes potentiated excitatory synaptic transmission onto AP neurons. Remarkably, neutralization of IL-6 in the brain of tumor-bearing mice with an IL-6 antibody prevents cachexia, reduces the hyperactivity in an AP network, and markedly prolongs lifespan. Furthermore, suppression of Il6ra, the gene encoding IL-6 receptor, specifically in AP neurons with CRISPR/dCas9 interference achieves similar effects. Silencing of Gfral-expressing AP neurons also ameliorates the cancer-associated cachectic phenotypes and AP network hyperactivity. Our study identifies a central mechanism underlying the function of peripheral IL-6, which may serve as a target for treating cancer-associated cachexia.

neuroscience↗

bioRxiv2021

Prefrontal top-down projections control context-dependent strategy selection

The rules governing behavior often vary with behavioral contexts. As a consequence, an action rewarded in one context may be discouraged in another. Animals and humans are capable of switching between behavioral strategies under different contexts and acting adaptively according to the variable rules, a flexibility that is thought to be mediated by the prefrontal cortex (PFC)1-4. However, how the PFC orchestrates context-dependent switch of strategies remains unclear. Here we show that pathway-specific projection neurons in the medial PFC (mPFC) differentially contribute to context-instructed strategy selection. In a decision-making task in which mice have been trained to flexibly switch between a previously established rule and a newly learned rule in a context-dependent manner, the activity of mPFC neurons projecting to the dorsomedial striatum encodes the contexts, and further represents decision strategies conforming to the old and new rules. Moreover, the activity of these neuron is required for context-instructed strategy selection. In contrast, the activity of mPFC neurons projecting to the ventral midline thalamus does not discriminate between the contexts, and represents the old rule even if mice have adopted the new one; furthermore, these neurons act to prevent the strategy switch under the new rule. Our results suggest that the mPFC[->]striatum pathway promotes flexible strategy selection guided by contexts, whereas the mPFC[->]thalamus pathway favors fixed strategy selection by preserving old rules. Balanced activity between the two pathways may be critical for adaptive behaviors.

neuroscience↗