PhD Position in Neuroscience (M/F)

Job Description

Thesis Subject

Impact of Systemic Inflammation on Glial Cell-Mediated Monoamine Metabolism in the Central Nervous System and Its Consequences for Nociception
Project Description
Sepsis, defined as a dysregulated systemic response to severe infection, accounts for approximately 20% of deaths worldwide. This condition is frequently associated with neurological complications, hyperalgesia, and sepsis-associated encephalopathy (SAE), which affects up to 70% of patients. The resulting neuroinflammation leads to the activation of glial cells, particularly microglia and astrocytes.
Glial activation is associated with increased expression of the aryl hydrocarbon receptor (AhR), a transcription factor involved in the regulation of numerous metabolic enzymes, including UDP-glucuronosyltransferases (UGTs). These enzymes catalyze the glucuronidation of a wide range of xenobiotics as well as endogenous compounds.
Among these enzymes, UGT1A6a has been reported to glucuronidate serotonin in vitro, a neurotransmitter strongly affected during sepsis. The same enzyme is also involved in morphine glucuronidation.
Hypothesis
We hypothesize that, during sepsis, glial activation induces the AhR–UGT1A6a signaling pathway in astrocytes, leading to increased glucuronidation of key neurotransmitters, such as serotonin, thereby contributing to neurological dysfunction and sepsis-associated hyperalgesia.
Inhibition of AhR and/or UGT1A6a in astrocytes could therefore reduce this abnormal glucuronidation, restore neurotransmitter levels, and potentially improve neurological recovery and alleviate hyperalgesia.
Proof of Concept
Since UGT1A6a can glucuronidate morphine, we used this analgesic as a probe to assess the activity of this enzyme.
Our preliminary results demonstrate that:
1. Glial cells are capable of glucuronidating morphine in vitro.
2. LPS increases morphine glucuronidation by glial cells both in vitro and in vivo, an effect inhibited by SR1, an AhR antagonist.
3. LPS specifically increases UGT1A6 expression in glial cells.
4. Both global AhR knockout and astrocyte-specific AhR deletion reduce morphine metabolism and enhance its analgesic effect.
5. The brains of LPS-treated mice contain substantial amounts of serotonin glucuronide.
6. shRNA-mediated knockdown of UGT1A6a in primary astrocyte cultures significantly reduces morphine metabolism.
Together, these findings suggest the existence of a functional neuroinflammation–AhR–UGT1A6a–glucuronidation axis in glial cells, potentially affecting not only xenobiotic metabolism but also the metabolism of endogenous neurotransmitters.
Objectives
1. Identify neurotransmitters glucuronidated by glial cells in vitro under basal and LPS-induced inflammatory conditions, focusing particularly on serotonin, adrenaline, noradrenaline, and dopamine.
2. Identify neurotransmitters and other endogenous metabolites glucuronidated in vivo during sepsis, using a differential metabolomics approach in the brains of control and LPS-treated mice.
3. Determine the involvement of AhR and UGT1A6a in neurotransmitter glucuronidation, using pharmacological approaches targeting AhR (SR1) and genetic models involving AhR or UGT1A6a deletion.
4. Investigate the consequences of astrocyte-specific deletion of AhR or UGT1A6a on neurotransmitter metabolism, neurotransmission, and pain, using mouse models allowing targeted gene deletion in astrocytes.
Methods
In vitro studies
The PhD student will establish primary glial cell cultures, particularly astrocytes and microglia, with or without LPS stimulation for 24 hours.
Cells will subsequently be incubated for 24 hours with 10 µM serotonin, adrenaline, noradrenaline, or dopamine.
Culture supernatants will be analyzed using targeted mass spectrometry to identify and quantify the corresponding glucuronidated metabolites: serotonin glucuronide, adrenaline glucuronide, noradrenaline glucuronide, and dopamine glucuronide.
In vivo studies
The PhD student will use a mouse model of systemic inflammation induced by LPS administration.

Technical Skills
Proficiency in biochemical techniques, immunohistochemistry, cell culture methods (particularly primary neuronal cultures), and mass spectrometry.
Twenty-four hours after injection, brains from control and LPS-treated mice will undergo differential metabolomic profiling to detect and identify glucuronidated metabolites and determine which compounds exhibit altered concentrations following treatment.
Analyses will be performed using high-resolution mass spectrometry, focusing particularly on molecules displaying structural characteristics and fragmentation patterns consistent with glucuronide conjugates.
Similar analyses will be conducted in mice with global or astrocyte-specific deletion of AhR or UGT1A6a to determine their respective contributions to these metabolic changes.
Behavioral studies assessing pain sensitivity will also be performed.
In situ studies
In parallel, independent cohorts of animals will be used for molecular imaging by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI).
This approach will allow spatial mapping of the major glucuronidated compounds identified in the brain and comparison of their distribution between control and LPS-treated animals.
These analyses will be complemented by immunohistochemical approaches targeting UGTs and various glial cell markers to investigate the relationship between the observed metabolic alterations and glial activation.
Finally, the specific involvement of the AhR–UGT1A6a pathway will be investigated using complementary pharmacological and genetic approaches, both in vitro and in vivo, including strategies enabling astrocyte-specific deletion of AhR or UGT1A6a.
Perspectives and Public Health Impact
Demonstrating increased glucuronidation of specific neurotransmitters in the brain during sepsis would reveal a previously underexplored metabolic mechanism potentially contributing to the neurological dysfunction associated with SAE.
This project will therefore establish the molecular foundations for future studies investigating the functional consequences of enhanced neurotransmitter glucuronidation on neurotransmission and neurological functions.
In the longer term, pharmacological modulation of the AhR–UGT1A6a axis could represent a novel therapeutic strategy to limit disturbances in neurotransmitter metabolism and potentially improve neurological recovery and pain management in patients with sepsis.
Keywords
Sepsis, neuroinflammation, glial cells, glucuronidation, metabolism, serotonin, neurotransmitters, mass spectrometry, pain.

Your Work Environment

The successful candidate will join the Institute of Cellular and Integrative Neurosciences (INCI) in Strasbourg, a CNRS research institute employing approximately 140 people.
The PhD student will work within the “Opioid System, Nociception and Pain” research team, comprising nine members, including one postdoctoral researcher and two PhD students.
Our institute offers a stimulating, friendly, and international research environment.
INCI provides access to several core facilities, including the Small Molecule Mass Spectrometry Platform (SMPMS), molecular biology facilities, and a functional imaging platform.
The hosting team has strong international recognition in neuroscience, particularly in neuroinflammation, neuropathic pain, and opioid-based treatments.
INCI is located on the University of Strasbourg's Esplanade campus (Green Campus), close to the city center, with convenient access to public transportation and student dining facilities.
The PhD project will be affiliated with Doctoral School 414 – Life and Health Sciences (ED414) at the University of Strasbourg.

Constraints and risks

Occasional work outside standard working hours may and Animal handling are required.

Compensation and benefits

Compensation

2300 € gross monthly

Annual leave and RTT

44 jours

Remote Working practice and compensation

Pratique et indemnisation du TT

Transport

Prise en charge à 75% du coût et forfait mobilité durable jusqu’à 300€

About the offer

About the CNRS

The CNRS is a major player in fundamental research on a global scale. The CNRS is the only French organization active in all scientific fields. Its unique position as a multi-specialist allows it to bring together different disciplines to address the most important challenges of the contemporary world, in connection with the actors of change.

CNRS

The research professions