Biology subjects

Dewachter, I.

Publications and source records attributed to Dewachter, I..

3 recordsLinked to original sources

bioRxiv2025

Resting-state functional dynamics alterations relate to plasma amyloid markers and explain memory impairments in the TgF344-AD model of Alzheimer's disease

Resting-state (RS) fMRI studies of Alzheimers diseases (AD) impact on brain function commonly use functional connectivity (FC), ignoring short-timescale network dynamics, captured by co-activation patterns (CAPs), shown to accurately classify transgenic rodents from the wild-type (WT). We acquired high temporal resolution RS-fMRI data in the TgF344-AD rat model at pre-plaque and plaque stages and delineated brain functional alterations using FC and CAPs. We also assessed plaque-stage blood amyloid levels and memory performance in the same animals and investigated the statistical relationship between pathological, RS-functional, and behavioral phenotypes. TgF344-AD (TG) rats had elevated blood amyloid levels, committed more working and reference memory errors and showed reduced hippocampal FC with the lateral cortical and default-mode-like network (DMLN) compared to WT at the plaque stage. They showed DMLN and hippocampal hyper- and hypo-activation at pre- and plaque stages respectively in multiple CAPs. While blood amyloid levels were explained better by plaque-stage, than pre-plaque stage, FC values and CAP activations, it was the pre-plaque stage, more than the plaque stage, CAP activations that accurately explained memory impairments. Our findings not only identify early signatures of AD in brain functional dynamics in this translational rat model but demonstrate their relevance for prognosis of memory deficits.

neuroscience↗

bioRxiv2024

IL-34 empowers regulatory T cells with novel non-canonical function to safeguard brain barrier integrity during neuro-inflammation.

In efforts to find reparative strategies for brain damage, brain-associated regulatory T cells (Tregs) have gained increasing attention in recent years. Beyond their textbook immunoregulatory function, Tregs have emerged as key players in the response to brain trauma and the restoration of damaged brain tissue. Here, we are the first to describe a novel, non-canonical function of Tregs in maintaining the sealing capacity of both the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier. Moreover, we identified the cytokine IL-34 as a critical determinant in this newly unveiled Treg function. Mechanistically, IL-34 exerts its influence by modulating the expression and localization of the tight junction protein ZO-1 in both BBB endothelial cells and choroid plexus epithelial cells, thereby reinforcing the strength of the brain barriers. Given the well-established notion of leaky brain barriers and the involvement of immunological components in neurological diseases such as Alzheimers disease (AD) and multiple sclerosis (MS), we further demonstrate diminished IL-34 expression in Tregs derived from patients with relapsing-remitting MS (RR-MS) and patients with AD and even mild cognitive impairment (MCI). Remarkably, our study reveals the potential of IL-34 treatment in reinstating the integrity of brain barriers within murine models mimicking these neurological disorders. These ground-breaking findings shed light on the intricate relationship between Tregs, IL-34, and the integrity of brain barriers. They offer novel avenues for therapeutic approaches to ameliorate brain barrier dysfunction in the context of neurological disorders.

immunology↗

bioRxiv2022

Lack of the glycine alpha 2 receptor impairs reward-motivated behavior and striatal signal integration.

Distinct developmental pathologies, including autism spectrum disorder and schizophrenia, exhibit impaired reward-motivated behavior. Key to proper reward-motivated behavior is dopamine-mediated modulation of striatal activity. The glycine alpha 2 receptor (GlyR2) is the single functionally expressed glycine receptor in adult striatum, and is therefore ideally positioned to modulate striatal behavior and cellular activity. Here, we report excessive appetitive conditioning in male GlyR2 knockout mice. We next show that depletion of GlyR2 enhances dopamine-induced increases in the activity of putative dopamine D1-expressing striatal projection neurons, while not affecting dopamine neuron activity. Moreover, we found that excessive locomotor responses to amphetamine in GlyR2 KO mice correlate with immediate early gene c-fos expression in the dorsal striatum. 3-D modeling revealed an increase in the number of activated cell ensembles in the striatum in response to D-amphetamine in GlyR2 KO mice. Taken together, we show that depletion of GlyR2 impairs reward-motivated behavior and altered striatal signal integration. This sheds important light onto the cellular mechanisms that underlie reward function, and pave the way towards novel therapeutics for the treatment of e.g. schizophrenia and addiction. Significance statementThe glycine receptor alpha 2 has long been studied for its role in development, with expression assumed to decline throughout adulthood in favor of the glycine receptor alpha 1 and 3. Yet, we showed that in the dorsal striatum, the glycine alpha 2 receptor is the only functionally expressed glycine receptor at adult age (Molchanova et al., 2017). In the present work, we show for the first time that the glycine alpha 2 receptor crucially affects striatal cell activity, which lies at the basis of reward-motivated behaviors, and which is impaired in many psychiatric pathologies. Indeed, a link between the mutations in the glycine alpha 2 receptor and autism as well as schizophrenia has been described, but a functional role for the glycine alpha 2 receptor in adult brain structures that are involved in psychiatric pathologies, was never shown before.

neuroscience↗