Claire Rampon, PhD,

Research Director CNRS

Research Center of Animal Cognition, Univ of Toulouse 3, Toulouse, France

I. The research group

The REMEMBeR team, headed by Dr Claire Rampon, belongs to the Research Center on Animal Cognition (CRCA, CNRS, University Paul Sabatier, Toulouse, France). Research projects carried out in the team address the fundamental question of how enduring memories are formed in the brain, therefore placing our goals and strategy at the core of the CRCA’s main focus on phenotypic and experience-dependent plasticity. We are studying more specifically mechanisms of cerebral plasticity related to spatial and episodic memory in normal mice and in mouse models of memory dysfunctions or pathologies. We focus on learning-induced plasticity processes at different levels from the activity of neuronal networks (cerebral oscillations, synaptic plasticity, inhibitory networks), to cells (neurogenesis, morphology of neurons or glial cells, interactions between neurons and glia), neurobiological issues (protein or gene expression, release of neurotransmitters, role of mitochondria) to finally work at the molecular level (epigenetic regulations, role of transcription factors).

These mechanisms are studied in the context of normal and pathological aging (e.g. Alzheimer’s disease) and also in mouse models of mood disorders (e.g. post traumatic stress disorders).

We use multiple and complementary approaches: behavioral analysis, electrophysiology in behaving animals, EEG, pharmacology, intracerebral microdialysis, confocal imaging, molecular and cellular biology.

 

II. Participation in the MADGIC project

The team will participate in the 4 work packages of the project. Our main role will be to contribute to the:

1. Generation and validation of new advanced models of AD.

Through a time course study of up to 1.5 years, we will assess structural and functional integration of the labeled transplanted cells using confocal microscopy followed by 3D morphological analysis.

2. Behavioral analysis of humanized female and male chimeric mice.

We will concentrate on those 2-3 humanized chimeric mouse models that show the most robust AD-like pathology and the mouse model that received cells derived from control patients. We will focus on hippocampus-dependent forms of memory as they are the first and most altered in AD. As several AD mouse models show robust gender differences regarding the onset of symptoms, we will test separately both male and female mice for longitudinal test of contextual fear conditioning, spatial Morris water maze and object location to assess short and long term memory after cell grafting.

3. Identification of modifiers of AD

We will examine whether a previously identified candidate gene for AD, NeuroD1, can rescue memory deficits in the humanized mice. We will transplant NeuroD1-overexpressing AD neurons (labelled tagRFP), generating HNeuroAD/NeuroD1rescue-mice. Anatomical analysis will be carried on to follow the development and evaluate the connectivity of these engrafted cells at the dendritic and synaptic levels using a combination of markers detected by immunohistochemistry. Next, NeuroD1 rescued animals will be tested for memory performances. The object location task allows addressing short (2h) and long-term (24h) spatial memory. The Barnes maze and water maze paradigms allow addressing remote hippocampal-dependent memory. These tests will be employed to assess spatial memory improvement in these mice, overtime.

III.  Key publications relevant for the project

1. Transient enriched housing before amyloidosis onset sustains cognitive improvement in Tg2576 mice. Verret L, Krezymon A, Halley H, Trouche S, Zerwas M, Lazouret M, Lassalle JM, Rampon C. Neurobiol Aging. 2013;34(1):211-25.

2. Modifications of hippocampal circuits and early disruption of adult neurogenesis in the Tg2576 mouse model of Alzheimer's disease. Krezymon A, Richetin K, Halley H, Roybon L, Lassalle JM, Francès B, Verret L, Rampon C. PLoS One. 2013;8(9):e76497.

3. Genetic manipulation of adult-born hippocampal neurons rescues memory in a mouse model of Alzheimer's disease. Richetin K, Leclerc C, Toni N, Gallopin T, Pech S, Roybon L, Rampon C. Brain. 2015;138(Pt 2):440-55.

4. Environmental enrichment does not influence hypersynchronous network activity in the Tg2576 mouse model of Alzheimer's disease. Bezzina C, Verret L, Halley H, Dahan L, Rampon C. Front Aging Neurosci. 2015;7:178.

5. Memory formation orchestrates the wiring of adult-born hippocampal neurons into brain circuits. Petsophonsakul P, Richetin K, Andraini T, Roybon L, Rampon C. Brain Struct Funct. 2017. in press.