Background:
Imagine if being touched was a highly irritating experience from the start of life. Sensory, e.g. touch, sensitivities are a prevalent and understudied feature of many psychiatric and neurodevelopmental disorders, including Autism Spectrum Disorder (FXS). More specifically, tactile defensiveness, or a hypersensitive reaction to touch, is a widespread feature among autistic individuals. Fragile X syndrome (FXS) is the leading monogenically inherited form of autism in humans and to study this prevalent neurological disorder (about 1:6000 births) genetic rodent models of Fragile X Syndrome (Fmr1-KO rodents) have been generated. Fmr1-KO rodents also exhibit tactile hypersensitivities. Tactile processing occurs in a part of the brain known as the Somatosensory cortex (S1). Our lab uses the mouse whisker system which is a powerful model for studying sensory processing as it is the touch equivalent to human hands and the pathway from whisker to cortex is well organized. Therefore, an experimenter can deflect a whisker and record neuronal activity in the cortex in awake.
Rationale & hypothesis:
Sensory experience and perceptual learning are thought to be associated with brain plasticity, i.e. a strengthening or weakening of synaptic connections between neurons. There is evidence in the sensory cortex of Fmr1-KO rodents that there are significant alterations in cellular activity and preliminary data suggests that brain plasticity, thought to underpin sensory perception, maybe impaired. We hypothesize that impairments in brain plasticity may underpin impaired sensory perception in the autism mouse models. Moreover, activation of specific GABAergic inhibitory interneurons, or cells that dampen down excitation, maybe key to rescuing sensory and plasticity-related impairments.
Aims:
The aim of this project is to discover how impairments in cellular activity, and brain plasticity, in the sensory cortex of Fmr1-KO mice affects the neuronal circuit, network activity and perceptual behaviour. Can Fmr1-KO mice learn a perceptual task compared to typically developing mice? Is their ability to detect touch altered? By understanding the underlying neuronal circuitry can we rescue sensory impairments by manipulating the circuit with cutting-edge viral vectors? The broad aim of this project is to answer these questions using whole-cell slice electrophysiology combined with multiphoton microscopy to record brain activity during perceptual behavior.
Training outcomes:
You will be trained in ex vivo whole-cell electrophysiology and/or multiphoton imaging and animal behaviour in awake mice. Including how to surgically perform viral injections in the brain and use cutting-edge viral vectors, e.g. Channelrhodopsin, to dissect neuronal circuity. Mastered microscopy techniques include fluorescent, confocal, and multiphoton imaging, You will be trained in perfusions and dissections and will perform these to remove brains ready for histology, immunohistochemistry and post-hoc imaging.
