Research

Mechanisms of Circadian Dysfunction in Ageing and Neurodegeneration

Circadian clocks anticipate predictable variations of the environment prompted by the solar cycle to optimise our metabolism, physiology and behaviour and synchronise them to the external world. Energy consumption, inflammatory processes and sleep/wake cycles are just a few key examples of the complex orchestration executed by our inner body clock, day by day.

Figure i, left -  recording of circadian rhythms of intracellular calcium in neurons of the suprachiasmatic nucleus

Although the molecular mechanisms underlying clock function and embedded in our cells and tissues are well characterised, we know little about how their activities are more widely coordinated amongst different tissues and organs. This is especially important in the brain, whereby activities of glial and neuronal populations have been found to be oppositely coordinated during day and night with their fine reciprocal tuning essential for circadian time-keeping.*

Breakage of mutual relationships amongst astrocytes, neurons and microglia and other brain cells emerges as a common leitmotif in neurodegenerative conditions, such as Alzheimer’s Disease**. Therefore, we aim to investigate their cell-type specific intracellular clock mechanisms and their mutual daily relationship, to understand how glia and neurons work together to ensure the circadian tempo in the brain.

Our circadian system is constantly and unnaturally challenged in modern society: 75% of the world population is exposed to light at night and up to 40% of the work force is engaged in shift work. Therefore, we aim to model the effects of such modern life-style and chrono-disruptive events, (e.g. jet-lag, sleep deprivation and shift work) on these internal brain clock mechanisms and their contributions to early neurodegenerative processes and cognitive decline.

Finally, can we molecularly manipulate these inter(c)locked, cell-type specific circadian mechanisms to “lock” brain function in a favourable state, with the aim of preventing and/ or delaying onset of neurodegenerative conditions?

In the Brancaccio laboratory, established in late 2018 in the Department of Brain Sciences at Imperial College London and funded by the UK Dementia Research Institute, we use a wide range of techniques to investigate such questions, including live imaging of circadian function, pharmacological and virally-based gene delivery, behavioural testing in preclinical models of dementia. However, our most important resource is our own brain power…

* Brancaccio M*, Edwards MD, Patton AP, Smyllie NJ, Chesham JE, Maywood ES, Hastings MH*: Cell-autonomous clock of astrocytes drives circadian behavior in mammals. Science, 2019

Brancaccio M*, Patton AP, Chesham JE, Maywood ES, and Hastings MH*: Astrocytes Control Circadian Timekeeping in the Suprachiasmatic Nucleus via Glutamatergic Signaling. Neuron, 2017

Hastings MH, Maywood ES, Brancaccio M: Generation of circadian rhythm in the suprachiasmatic nucleus: neurons, astrocytes and circuits. Nat. Rev. Neurosc. 2018

** De Strooper B, Karran E. The Cellular Phase of Alzheimer's Disease. Cell. 2016;164(4):603‐615. doi:10.1016/j.cell.2015.12.056