Periodic Reporting for period 1 - MyeSync (The role of PV+ basket cell axon myelination in temporal synchrony of the hippocampal CA2 network)
Período documentado: 2021-03-15 hasta 2023-03-14
This specific class of interneuron provides potent, fast, and ultra-precise perisomatic inhibition onto neighboring excitatory pyramidal cells. By doing so PV+ BCs contribute to the synchronized activity of populations of principal neurons during well-defined brain oscillations. One such type of oscillation they entrain is highly specific to the hippocampus and is called the Sharp Wave Ripple complex (SWRs). It Consists out of sharp waves and high frequency ripples (> 200 Hz), is observed during non-REM sleep, and has been demonstrated to fulfill a pivotal role in memory formation and consolidation.
The overarching goal of this MSCA fellowship was to investigate whether myelination of the PV+ BC axon contributes to inhibitory precision within the hippocampus (Objective A) and whether it contributes to fast hippocampal ripple oscillations (Objective B) that are important for mnemonic functions.
Loss of myelin within the central nervous system is the underlying cause of Multiple Sclerosis (MS). Besides motor deficits do MS patients often suffer from a decline in memory and reduced cognitive abilities. The exact mechanisms behind this phenomenon remain up to present largely unknown. This fellowship can be expected to give novel insights in the basic principles underlying alterations in the hippocampal circuitry in MS. The aim is to do so by complementing subcellular and synaptic observations with microcircuit measurements and to carefully link structure to cellular function. Such information can be expected to contribute to future translational studies and the development of novel therapies to ultimately try and relieve the suffering of patients living with MS.
To achieve objective B, we established local field potential (LFP) measurements from thick acute hippocampal slices stored in interface chambers. This configuration keeps the hippocampal microcircuit functionally intact and allows the measurement of the local generation and propagation of Sharp Wave Ripple (SWRs) complexes. Since synaptic precision was exclusively affected by a complete loss of myelin (explained above), for this set of experiments we focused on the full demyelination model. In a nutshell, we found that demyelination led to significant reductions in the frequency of fast hippocampal ripple oscillations. Experiments are currently ongoing to validate these findings in vivo.
As a training grant, this MSCA fellowship allowed me to learn novel techniques (holographic optogenetics, Local Field Potential measurements, Ca2+-imaging) and related analysis methods. It contributed to the broadening of my interests (into structural- and glia cell biology), provided me with mentoring and supervision skills, boosted my managerial capabilities, and created unique networking opportunities that could be of invaluable importance for my future career. In return I was able to transfer my specific knowledge about hippocampal physiology and skills in synaptic electrophysiology to the host lab. Preliminary scientific results have been presented and discussed at conferences and workshops, a manuscript including the findings of both objectives of this fellowship is in its final stages of preparation.