Characterize corpus callosum-mediated local and global inhibitory effects with novel MRI-compatible photonic crystal fiber-based multifunction probe and wireless amplified NMR detector in rat brain

Project Information

CCMuPWA

Grant agreement ID: 896245

DOI

10.3030/896245

Project closed

EC signature date 4 March 2020

Start date 1 January 2021

End date 30 June 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 205 352,64

EU contribution

€ 205 352,64

Coordinated by

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany

Periodic Reporting for period 2 - CCMuPWA (Characterize corpus callosum-mediated local and global inhibitory effects with novel MRI-compatible photonic crystal fiber-based multifunction probe and wireless amplified NMR detector in rat brain)

Reporting period: 2022-07-01 to 2023-06-30

Summary of the context and overall objectives of the project

The structural anomalies of corpus callosum (CC) in patients are found highly correlated with a wide range of disorders, e.g. epilepsy, autism, schizophrenia, and mental retardation. However, it remains unclear about the causal contributions of CC-mediated functional changes to these disorders and exactly how the changes influence the local cortical circuitry. The project’s overarching goal was to overcome the challenges to optimize the multi-modal fMRI platform and characterizing the brain activity upon optogenetic callosal activation with higher spatial resolution using cutting-edge technologies. Therefore, during the MSCA, we first successfully combined fMRI with fiber optic mediated calcium recordings and optogenetics, i.e. multi-modal fMRI, to study the balance of excitation/inhibition in the barrel cortex in rats by pairing optogenetic corpus callosum activation with ascending thalamocortical activation. Second, we designed and fabricated a novel microstructured optical fiber-based probe integrated with calcium recording, optogenetic manipulation, and fluid injection function. Third, we modified WAND to be incorporated into the multi-modal fMRI platform to achieve brain dynamic signals with enhanced sensitivity from the barrel cortex. Last, we developed a novel bilateral line scanning method combined with the MOF-based probe to better decipher CC-mediated interhemispheric inhibition with layer-specificity.
This proposal merged the neuronal dynamic signals to the functional mapping, partially solved the challenges for CC study across multiple scales in the brain, and enable novel applications of the multi-modal fMRI platform to better decipher the brain function/dysfunction in normal and diseased animal models. For instance, we investigated the role the entorhinal cortex plays in Alzheimer’s disease.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

1.2.1 Work Package 1
The intention of WP1 was to develop a PCF-based MRI-compatible Multifunction Probe (MuP), integrating Ca2+ recording, optogenetic stimulation, and fluidic drug microinjection /delivery function. Interactions with scientists from the MPI for the Science of Light, in particular, Dr. Frosz, the MPL have been instrumental in shaping and improving the project. We developed a pure silica MOF-based probe for optogenetically and sensory-driven single-vessel fMRI with simultaneous Ca2+ signals and Mn2+ injection as a proof of concept to optimize the multi-modal fMRI platform, and to make the calcium recording light-path more methodologic and economic friendly for general labs. In 2021 data were presented in zoom-based meetings with the group members and supervisors bi-weekly to ensure regular and sufficient scientific feedback.

1.2.2 Work package 2
The aim of WP2 was to implement the Wireless Amplified NMR Detector (WAND) to enhance fMRI sensitivity with MuP. Here, we first fabricated inductively coupled detectors to provide a unique MRI scheme for in vivo mapping of the local soft tissue to achieve enhanced sensitivity of brain dynamic signals from the local cortex. Then it was combined with simultaneous brain dynamic signal acquisition using optical fiber with high flexibility and practicability. This work package was mainly implemented in the 7T pre-clinical MRI scanner in the Department of Radiology at MSU. In addition, the small animal facilities and animal support team at MSU made it possible for the WP2 for in vivo evaluation in both healthy and diseased animal models.
The manuscript for the methodology development were published as a journal article in NeuroImage.
Chen Y.*; Wang Q.*; Choi S.; Zeng H.; Takahashi K.; Qian C.; Yu X.: Focal fMRI signal enhancement with implantable inductively coupled detectors. NeuroImage 247, 118793, pp. 1-8 (2022). *Equally contributed to this work.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842502
Moreover, inspired by our work and experimental setup, we also initiated collaboration with Prof. Galit Pelled at MSU to use fMRI to study the novel magnetogenetics stimulation in rats to improve decision-making.
To sum up for the WP2, the project deliverables have mainly been achieved, despite experiencing VISA issue and animal protocol approval issues through the global COVID pandemic in early 2021.

1.2.3 Work package 3
By merging MuP and sensitivity-enhanced fMRI using WAND, these two highly complementary research tools will provide a unique strategy to bridge the gap between cellular/molecular mechanistic studies to the local and whole brain functional mapping level for CC-mediated interhemispheric inhibition in WP3. Since we initiated the experiments before the fellowship was granted and therefore a manuscript without WAND was published as a journal article in 2020. Affected by the pandemic, after careful consideration, we implemented an alternative way to improve the signal sensitivity to answer this question. Thus, we developed a novel bilateral line scanning method to characterize the CC-mediated interhemispheric inhibition with enhanced sensitivity. With this method, we reported that ultra-slow fluctuation (0.01-0.02 Hz) was synchronized across all cortical laminae, and Layer 2/3 specific slow fluctuations (0.08-0.1 Hz). In contrast to the ultra-slow fluctuation related to global brain state changes, the Layer 2/3 specific slow fluctuation is more likely associated with intrinsic neuronal correlation driven by the callosal projection.
The manuscript focused on these results was resubmitted after revisiona and accepted:
Choi S., Zeng H., Chen Y., Sobczak F., Qian C., Yu X.: Laminar-specific functional connectivity mapping with multi-slice line-scanning fMRI. Cerebral Cortex 32(20), pp. 4492-4501 (2022).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9574235
Now we are performing further data analysis on the data acquired from WP3, we are confident about more scientific output in the coming years.

Brief overview of the results and their exploitation and dissemination:
Conferences attended: 11, of which invited talks: 3
Peer reviewed publications: 2
Posters for conferences: 5

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The core of this proposal is to merge a multi-function probe design with advanced MRI methods in the multimodal fMRI platform, to characterize the local and global CC-mediated interhemispheric inhibitory effects. Results from this action refine the small animal multi-modal fMRI imaging scheme and provide a new avenue to merge the multi-scale brain mapping paradigms. Moreover, it highlights a vital aspect of brain-wide activity for circuit-specific causality studies with optogenetic tools used widely in Neuroscience labs. All these results from this action will bridge the cellular and the whole brain network levels for CC-mediated activity, providing the possibility to better understand the functional role of CC in normal rats and the potential causal relationship between CC-mediated malfunction and neurological and psychiatric disorders. In addition, the AD animal models, WAND, and MuP are transferred to the host institution (KYBC) to further strengthen the collaborations with MSU and MPL, providing complementary knowledge and benefiting the Neuroscience community in Tuebingen from the optical neuro probes and novel MRI technologies for animal studies. It also exposed the host institution to scientists at MSU and other institutions to apply for potential grants together in the future by taking advantage of the optimized MRI platform.

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