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Towards restoring memory dysfunction in prodromal Alzheimer’s Disease.


   School of Psychology and Neuroscience

  Dr Michael Kohl  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Project outline:

Brains contain billions of specialised cells, called neurons, which are the fundamental building blocks of every circuit in the nervous system. The principal purpose of a neuron is to transmit information: when they receive sufficient input from other neurons, they send brief electrical pulses, called action potentials, which allows them to communicate with other neurons. Broadly speaking, neurons exist as two types: excitatory neurons, which make other neurons more likely to fire action potentials, and inhibitory interneurons, which make other neurons less likely to fire action potentials. If one were to compare the brain's electrical activity to music, then excitatory neurons provide the notes for the brain's 'music', whilst inhibitory interneurons provide the pauses between notes. All computations in the brain require very precise synchrony between different neurons: without the notes, there would be only silence, and without the pauses, the music would become a cacophony.

Recent research has shown that dementias, such as Alzheimer's Disease, cause a dysfunction in inhibitory interneurons. The resulting effects on normal brain function are severe and thought to translate to the cognitive and memory impairments seen in Alzheimer's Disease. Data from our labs shows that selectively manipulating inhibitory interneuron activity can restore normal brain function in mouse models of Alzheimer's Disease. Intriguingly, a similar rescuing effect has recently been attributed to non-invasive light and acoustic stimulation at frequencies similar to the frame rate of video (40 Hz).

Ongoing work on this subject matter in the Kohl Group is addressing two aims. One is of a basic science nature: We would like to determine the mechanisms underlying the rescue effects following stimulation of inhibitory interneurons and delivery of light and acoustic stimuli in mouse models of Alzheimer's Disease. The other aim is of a translational nature: We would like to see whether stimulation of inhibitory interneurons and delivery of light and acoustic stimuli in mouse models of Alzheimer's Disease can restore memory function in the early stages of Alzheimer's Disease.

This PhD position would contribute to our ongoing work using a combination of state-of-the-art methods. The student would be supervised by the PI and a senior post-doc and receive training in all experimental methods as well as sophisticated analysis.

Summary aim:

Characterise cellular/circuit level dysfunction of genetically identified inhibitory neurons in the retrosplenial cortex in mouse models of dementia; link cellular/circuit level dysfunction to dementia-related behavioural phenotypes; develop and test rescue strategies for dementia-related behavioural phenotypes. 

Techniques to be used:

A variety of cellular, systems and behavioural level techniques will be used, including

  • Electrophysiology
  • Miniature microscope imaging
  • Multiphoton imaging
  • Optogenetic manipulations
  • Behavioural assays
  • Information theory
  • Artificial neural networks

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References

Park, M. et al. Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice. Transl Neurodegener 10, 48 (2021) | Barros, A. C. B. de et al. Retrosplenial cortex is necessary for spatial and non-spatial latent learning in mice. Biorxiv 2021.07.21.453258 (2021) doi:10.1101/2021.07.21.453258. | Park, K. et al. Optogenetic activation of parvalbumin and somatostatin interneurons selectively restores theta-nested gamma oscillations and oscillation-induced spike timing-dependent long-term potentiation impaired by amyloid β oligomers. Bmc Biol 18, 7 (2020). | Chung, H., Park, K., Jang, H. J., Kohl, M. M. & Kwag, J. Dissociation of somatostatin and parvalbumin interneurons circuit dysfunctions underlying hippocampal theta and gamma oscillations impaired by amyloid β oligomers in vivo. Brain Struct Funct 1–20 (2020) doi:10.1007/s00429-020-02044-3. | Iaccarino, H. F. et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature 540, 230–235 (2016).
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