PhD Project - Mapping brain-wide neural dynamics to understand sensorimotor dysfunction and recovery in a mouse model of Rett Syndrome

Vacancy Reference Number
2022-SIDB-DUGUID
Closing Date
16 Jan 2022
Address
University of Edinburgh

Background

Rett syndrome is a devastating neurological disorder where early in development patients present with severe neonatal encephalopathy, loss of motor control, breathing abnormalities and epileptic seizures. Loss-of-function mutations in the X linked Mecp2 gene, which encodes the methyl-CpG binding protein MeCP2, restricts brain development, severely impacting basic and high-level brain function in Rett patients1. The generation of Mecp2 mutant mice has advanced our understanding of molecular and cellular dysfunction associated with Rett syndrome, but to date, little is known about how loss of MeCP2 affects brain-wide neural dynamics during sensorimotor learning or whether high-level brain function can be restored using viral-mediated gene reintroduction approaches. Although the notion that MeCP2 reintroduction can induce phenotypic rescue is supported by proof-of-concept studies2, recovery appears to be restricted to simple behavioural phenotypes that require reflexes or central pattern generators (e.g., respiration, locomotion and grip strength) while more complex cortical-dependent behaviours remain affected.

Rationale & hypothesis

The development of high-density silicone probes has provided new opportunities to explore brain-wide neural dynamics in freely moving rodents3. This approach will drive our understanding of how interconnected brain areas combine to facilitate sensorimotor learning, but to date studies have concentrated solely on the healthy brain. Given that disrupted MeCP2 expression results in aberrant synaptic connectivity and excitability within individual brain areas, we hypothesise that MeCP2 is necessary for the transformation of brain-wide information flow during sensorimotor learning. Determining how inter-areal neural dynamics are affected by the absence of MeCP2 during learning and whether re-expression drives complete phenotypic rescue is a prerequisite for understanding the role of MeCP2 in facilitating brain wide neural flexibility and high-level brain function during behaviour.

Aims

We will combine a novel touchscreen-based two-alternative forced choice (2-AFC) reaching task for mice with multiple, simultaneous high-density neural recordings of connected brain areas associated with sensorimotor learning (e.g., sensorimotor cortices (M1/M2/S1/V1), prefrontal cortex (PFC),  posterior parietal cortex (PPC), motor thalamus, basal ganglia), to address 3 main aims:

Aim 1: Determine how loss of MeCP2 affects brain-wide neural dynamics across sensorimotor learning.

Aim 2: Determine whether inter-areal neural dynamics reorganise after MeCP2 re-expression in a mouse model of Rett syndrome and the extent to which this drives recovery of high-level brain function and behaviour.

Given that female Mecp2 mice develop a delayed and variable phenotype due to X chromosome inactivation (XCI) and cellular mosaicism for MeCP2. The project will involve a collaboration with the SIDB whole-brain lightsheet imaging facility to generate brain-wide MeCP2 expression maps before and after gene-reactivation.

Training outcomes

The student will form part of a dedicated research team exploring the role of MeCP2 in health and disease, developing skills in experimental design, in vivo electrophysiology, quantitative behaviour, and whole-brain immunohistochemistry / imaging.