AlzPain

Theoretical Background
The global aging population is leading to an increase in chronic pain, which is particularly pronounced in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). More than 30% of people over the age of 65 suffer from it, with rates as high as 75% in AD and 86% in PD. This pain significantly impairs quality of life.

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

Two major hypotheses have been proposed regarding the PAG in Alzheimer's disease:
1. Indirect impairment**: Structures of the limbic system (amygdala, hippocampus) that connect to the PAG are affected early on in Alzheimer's disease.
2. Direct impairment**: The presence of amyloid plaques and pathological tau proteins has been detected in the PAG of patients with Alzheimer's disease.

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

Practical context and student work

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

1. Months 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. Months 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 single-cell and network activity.

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

Objectives and Outcomes
This project will:
- Provide a better understanding of pain mechanisms in AD through the PAG.
- Train students in advanced electrophysiology techniques.
- Generate preliminary data for future funding (thesis, interdisciplinary collaborations).