The impact of noradrenergic neuromodulation by locus coeruleus neurons through astrocytes in Alzheimer’s disease
Although changes of the noradrenaline (NA) system in Alzheimer’s disease (AD) have been long observed in patients, detailed mechanisms that how changes of NA in the brain is effecting the pathogenesis and progression of AD have not yet been clearly addressed. As the main recipient of NA, astrocytes have their intrinsic ability in response to NA via various noradrenergic receptors (ARs). Recently, an increasing number of in vivo studies revealed that cortical astrocytes show global increases of intracellular Ca2+ in awake behaving mice, which are dependent on the widespread release of noradrenaline (NA) throughout the cortex. Despite of these, it remains to be resolved whether and how the LC-NA is modulated by astrocytes in AD. Combining human AD patients' CSF data as references, this project focuses on cortical NA level changes and cortical astrocytic roles in responding to NA release from LC neurons in the AD mouse model (APP/PS1 mice), in particular regarding astrocytic Ca2+ transient patterns during astrocytic responses to NA.
We will perform two-photo imaging (both head-fixed two-photon and freely moving mini-two-photon microscopy methods) combining multiple newly developed molecular approaches (including genetically encoded sensors, optogenetic and chemogenetic manipulation) and animal behavioral tests to delineate astrocytic roles and their subcellular mechanisms in LC-NA neuromodulation in awake behaving wild-type, IP3R2KO and APP/PS1 mice.
To minimize the distress of animals and improve animal well-being, I will provide enriched housing conditions, careful handling and caring before, during and after the surgery, and close monitoring during the whole experimental procedure. Suitable anaesthesia and analgesia will be applied during and after surgery.
This project will potentially identify astrocytes and their ARs as treatment target for AD.
A total number 220 of APP/PS1 mice, 80 IP3R2KO mice and 130 wild-type C57/bl6J mice is planned in histology, behaviour and brain two-photon imaging tasks.
The mouse brain architecture has many similarities to the human brain on the both the macroscopic level andcircuit level. Unfortunately, cell cultures of neurons do not answer questions about how brain cells in the awakebrain are active. We will keep the number of used mice to a minimum. The experience that we have built up in the past years will help us to optimally organize the breeding colonies, and to perform high quality surgeries and image sampling so data can be obtained with fewer mice.
We will perform two-photo imaging (both head-fixed two-photon and freely moving mini-two-photon microscopy methods) combining multiple newly developed molecular approaches (including genetically encoded sensors, optogenetic and chemogenetic manipulation) and animal behavioral tests to delineate astrocytic roles and their subcellular mechanisms in LC-NA neuromodulation in awake behaving wild-type, IP3R2KO and APP/PS1 mice.
To minimize the distress of animals and improve animal well-being, I will provide enriched housing conditions, careful handling and caring before, during and after the surgery, and close monitoring during the whole experimental procedure. Suitable anaesthesia and analgesia will be applied during and after surgery.
This project will potentially identify astrocytes and their ARs as treatment target for AD.
A total number 220 of APP/PS1 mice, 80 IP3R2KO mice and 130 wild-type C57/bl6J mice is planned in histology, behaviour and brain two-photon imaging tasks.
The mouse brain architecture has many similarities to the human brain on the both the macroscopic level andcircuit level. Unfortunately, cell cultures of neurons do not answer questions about how brain cells in the awakebrain are active. We will keep the number of used mice to a minimum. The experience that we have built up in the past years will help us to optimally organize the breeding colonies, and to perform high quality surgeries and image sampling so data can be obtained with fewer mice.