AlzDouleur

Theoretical background
Global aging is leading to a rise in chronic pain, particularly pronounced in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). More than 30% of people over 65 suffer from it, with peaks of 75% in AD and 86% in PD. This pain significantly impairs quality of life.

In Alzheimer's disease, pain perception and modulation mechanisms appear to be altered. Studies show hypersensitivity to pain and prolonged activation of brain regions related to pain (insula, cingulate cortex, somatosensory cortex). These disruptions may result from dysfunction in the brain's descending inhibitory mechanisms, particularly the periaqueductal gray (PAG), a central structure in pain management via the release of endogenous opioids.

Two major hypotheses are proposed regarding the PAG in AD:
1. Indirect alteration**: structures of the limbic system (amygdala, hippocampus) that connect to the PAG are affected early in AD.
2. Direct alteration**: the presence of amyloid plaques and pathological tau proteins has been detected in the PAG of AD patients.

However, the functional state of the PAG in AD has never been studied, hence the need for this research.

Practical context and student's work

The project is based on a **preclinical study** in Alzheimer's transgenic mice **APP/PS1-21**, and will take place in three main phases:

1. Month 0-3: In vivo electrophysiology
- Recording of PAG neuronal activity in anesthetized mice.
- Use of two types of electrodes (glass pipettes and flexible microelectrode arrays).
- Evaluation of PAG responses to painful stimuli (electric shocks).

2. Month 3-5: Ex vivo electrophysiology
- Brain slices including the PAG will be analyzed.
- Measurement of the electrophysiological properties of GABAergic and glutamatergic neurons.
- Combined use of patch-clamp and transparent electrodes to record both individual and network activity.

3. Month 6: Final analyses
- Histological and electrophysiological analyses.
- Writing of the final report.

Objectives and outcomes
This project will make it possible to:
- Better understand pain mechanisms in AD via the PAG.
- Train the student in advanced electrophysiology techniques.
- Produce preliminary data for future funding (thesis, interdisciplinary collaborations).