Decoding the development of physiologic and epileptic cognitive neural networks

Project Information

CoDEC

Grant agreement ID: 799501

DOI

10.3030/799501

Project closed

EC signature date 12 April 2018

Start date 1 June 2018

End date 31 May 2021

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 239 860,80

EU contribution

€ 239 860,80

Coordinated by

UNIVERSITAETSMEDIZIN DER JOHANNES GUTENBERG-UNIVERSITAET MAINZ
Germany

Periodic Reporting for period 2 - CoDEC (Decoding the development of physiologic and epileptic cognitive neural networks)

Reporting period: 2020-06-01 to 2021-05-31

Summary of the context and overall objectives of the project

Cognitive dysfunction is a hallmark of many neuropsychiatric diseases, with potentially devastating effects on functional outcomes and quality of life in affected patients. The neural networks underlying cognitive processes are characterized by bidirectional communication between numerous brain regions, allowing integration and advanced processing of multimodal sensory information. Our main objective is to gain insight into the operations of these cognitive neuronal networks by examining intra- and inter-cortical communication across development.
Effective communication between brain regions requires the creation of discrete temporal windows for dynamic routing of neural signals. Oscillatory activity is an efficient means of creating epochs of synchrony within and between neural networks, providing a means to boost or suppress information transfer. This precisely coordinated interplay of inter-cortical oscillations is not an inborn property of the brain’s neural networks. Maturation of the cortical networks in a developing organism is highly activity-dependent, with synchronized neural activity playing a crucial role in the establishment of stable structural and functional connections. The emergence and refinement of cognitive functions in humans is associated with the appearance of oscillations in specific frequency bands and enhanced long-range synchronization of this oscillatory activity. Preterm babies between the 24th and 37th gestational weeks exhibit a fast frequency alpha-beta spindle-like (8–25 Hz) rhythmic activity superimposed on 0.3–1.5 Hz slow delta waves called delta brush. This pattern is involved in inaugurating synchrony within and between cortical areas, and abnormalities in its occurrence are associated with improper cortical maturation.
Mice are a useful model for studying the development of brain activity, since a substantial portion of cortical development that occurs prior to birth in humans occurs after birth in mice. However, to date, in vivo study of rodent electrophysiology has been severely challenged due to the size and fragility of the mouse pup’s brain. Our second objective was the technological development and use of a novel electrocorticography (ECoG) array called NeuroGrid, which allows us an unprecedented spatiotemporal resolution in our recordings, while acquiring neural data simultaneously from multiple functionally diverse cortical regions. The technological advantages of NeuroGrid and the outstanding options when combining it with other techniques positions us perfectly to initiate a novel characterization of rodent neurophysiology, with important potential applications for human health.

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

The CoDEC project is focused on studying spontaneous brain activity across development in the mouse neocortex, and its role in the establishment of the brain function. For this purpose, we used a new large-scale neural interface device called NeuroGrid. The great advantages of this device are its spatial-temporal resolution, large-scale recording and non-invasiveness. With the aim to localize our neurophysiological signal with greater accuracy, we developed a new histological procedure using chitosan, a biocompatible inexpressive organic polymer that is increasingly being used in neural tissue applications. Its intrinsic fluorescence played a key role in the development of the technology necessary for this experimental approach, allowing the orientation and correct placement of the recording electrodes and interpretation of the results. (Rahaula et al. 2019).
Regarding our objective of gaining insight into the operations of these cognitive neuronal networks by examining intra- and inter-cortical communication across development, (Dominguez et al. 2021) where we investigated the progression of large-scale synaptic and cellular activity patterns across development using high spatiotemporal resolution in vivo electrophysiology in immature mice. We revealed that mature cortical processes emerge rapidly and simultaneously after a discrete but volatile transition period at the beginning of the second postnatal week of rodent development. The transition was characterized by relative neural quiescence, after which activity occurred that was spatially distributed, temporally precise, and internally organized. We demonstrated a similar developmental trajectory in humans, suggesting an evolutionarily conserved mechanism to transition network operation. We hypothesize that this transient quiescent period is a requisite for the subsequent emergence of coordinated cortical networks.
Additionally, we have collaborated with other groups from the Institute for Genomic Medicine (IGM) Columbia University Medical Center, New York, US., This study explored the gain of function by potassium channels versus the traditional concept as a loss-of-function, shedding light on a therapeutic intervention (Shore et al. 2020)
In the second phase of my Marie Curie fellowship (06/2020-05/2021) at Johannes Gutenberg Unimedizin Mainz (Germany), we are working on a multidisciplinary experimental approach in order to obtain a unique neural dataset that is specifically geared toward important questions about development of intra- and inter-cortical communication, while simultaneously aiming to determine the three-dimensional neocortical communication. This combination permits the study of early postnatal development and the consequences of its impairment in neuropediatric disorders.

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)

To address our objective, we needed a tool to record large-scale neural network activity in vivo in developing animals. Few neurophysiologic studies of the developing rodent brain have been performed, and those have used penetrating electrodes that have the potential to damage the brain during implantation. In contrast, during the first phase of this project we used a conformable ECoG array, the NeuroGrid, to record from the brain without penetrating into brain tissue. Additionally, in the second phase of this project we are working with wide field calcium imaging. Furthermore, we have developed molecular techniques such us immunostaining using chitosan (Rahaula et. all 2019) and cleared brains (work in progress) in order to determine our brain areas of study.
The implementation and development of this technology has an economic impact by itself that it is difficult to determine. Moreover, these techniques allow us to shed light on treatments for many brain disorders.
Moreover, the development of different electrophysiological methods of non-invasive recording allows us to study genetic disorders combined with a pharmacological approach, potentially finding therapies for numerous mental disorders and syndromes while saving money to global healthcare systems. In our current manuscript accepted in eLife, we have studied and analyzed the contribution of a relative neural quiescence in the neural network that is necessary for the proper maturation of mouse and human brains. I hope to continue developing new technology and experimental approaches, thus contributing to the study of diverse brain disorders while searching for novel treatments that will eventually reduce the socio-economic impact.
This combination permits the study of early postnatal development and the consequences of its impairment in neuropediatric disorders.

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