Multimodal optical interrogation of neural activity and neuromodulation during sequence processing

Project Information

EnlightenedLoom

Grant agreement ID: 101024523

DOI

10.3030/101024523

Project terminated on 30 September 2023

EC signature date 19 April 2021

Start date 16 October 2021

End date 17 March 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 183 473,28

EU contribution

€ 183 473,28

Coordinated by

FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
Italy

Periodic Reporting for period 1 - EnlightenedLoom (Multimodal optical interrogation of neural activity and neuromodulation during sequence processing)

Reporting period: 2021-10-16 to 2023-10-15

Summary of the context and overall objectives of the project

EnlightedLoom tackles a long standing question in Neuroscience: what are the neural basis of perception? This question has been researched from several perspectives in the past few decades. Cognitive studies described the strategies used by mammals to recognize a wide range of sensory stimuli. Neurophysiology techniques have revealed the involvement of large brain regions in perceiving specific sensory objects, and mechanistic work has investigated the functional features of single brain cells responding to inputs coming from the external world. However, to date, it remains unclear how multiple brain cells come together to define spatial and temporal patterns of activity when a subject is perceiving an object, and which ones of these patterns are sufficient for perception. The project aims to access such deep level of investigation by combining the most advanced experimental and theoretical tools currently available. Specifically, EnlightedLoom has 2 overall objectives. First, to work out which cortical neurons, and which activity patterns defined by these neurons, are ultimately responsible for the perception of multisensory audio-tactile sequences. Second, to reveal how neuromodulatory signaling correlates with changes in the neural representation of familiar and novel sensory objects. In the project, neural activity and neuromodulation are studied simultaneously, and at an unprecedented level of spatial detail. Overall, EnlightenedLoom aims to offer key instruments to bring neuroscience research to a long sought level of understanding. The object of the research, namely the perception of sensory patterns and regularities, defines how we normally interact with the world, and it is often impaired in conditions such as schizophrenia and depression. Therefore, this research is instrumental for future investigations aimed at unraveling the altered neural mechanisms underlying neurological pathologies. Over the period of its duration, EnlightedLoom has obtained new results about the processing of tactile objects in the cerebral cortex, and it has paved the way for new experiments where the contribution of neuronal firing and neuromodulation are studied together.

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 project has been articulated through the following tasks:
1. Familiarize with optogenetics tools developed in the hosting laboratory by supporting in vivo 2-photon holography experiments led by a fellow researcher. This task has been instrumental for the work described in WP2;
2. Design, develop and test a novel behavioural set up for the presentation of familiar and unexpected tactile sequences in awake mice passively touching the tactile objects. This task was necessary before developing the behavioural paradigm for sensory learning, and was part of WP1
3. Carry out experiments investigating sensory processing of expected and unexpected stimuli in the S1 of awake passive animals. This task was carried out until the last month of my fellowship and was part of WP1;
4. Analysis of the data produced in point 3. Part of WP1 and WP3.
5. Design, develop and test a novel behavioural set up for the presentation of sensory sequences in the context of a sensory-guided perceptual task (2 alternative forced choice task). This is part of WP1
6. Carry out two-photon imaging experiments using a novel noradrenaline sensor in the S1 of mice engaged in a sensory detection task. Design of tailored data analysis pipeline. Part of WP1 and WP2
7. Close interaction with the developers of Information Theoretic measures and analysis of data I produced before the start of my fellowship. Instrumental for WP3.
8. Dissemination of project and results through seminars, posters and peer-reviewed publications.

1) My contribution to the development of a new toolbox for analysis of two-photon calcium imaging and two-photon optogenetics experiments is part of the following paper published on Nature Communications: https://www.nature.com/articles/s41467-022-29180-0
2) The outcomes of the first ever application of Information Theoretic measures to the study of sensory perception in S1 using two-photon calcium imaging is currently deposited on BioRxiv: https://www.biorxiv.org/content/10.1101/2022.12.04.518156v1

Further dissemination of the two-photon imaging data I produced has been carried out through two invited seminars.
- Invited talk 2023 Meeting of the Italian Society for Neuroscience (September 2023, Turin)
- Invited talk University of Sussex, Neuroscience Department (June 2023, Brighton, UK)

Finally, I have presented the work carried out by the hosting laboratory, including my work, at the following events:
- European Researchers’ Night 2021 (Genova, September 2021)
- Festival della Scienza di Genova 2021 (Genova, October 2021)
- European Researchers’ Night 2023 (Genova, September 2023)
- Festival della Scienza di Genova 2023 (Genova, October 2023)

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)

My work is part of the communal effort, among modern neuroscientists, to investigate the nervous system at a deeper and more integrated level.
In particular, the research I carried out impacts future work trying to 1) include the contribution of neuromodulation to the processing of information along the sensory pathways; 2) use multi-disciplinary theoretic frameworks to aid the design and the analysis of large-scale recordings.
The following aspects of my research will pave the way for novel perspectives on cortical function, and will have a significant impact on the neuroscientific community:
1) The two-photon calcium imaging data I produced will constitute a new reference in the investigation of cortical sensory processing. The paradigm can potentially be deployed by the many international laboratories working on similar topics;
2) By applying Information Theory to the study of primary somatosensory cortex for the first time, I have obtained results that offer a new perspective on the role of sensory cortex in information processing. In the short term, they will be a reference for new studies deepening the understanding of primary cortex in new, more complex experimental contexts. In the long run, they will constitute the basis for understanding the role played by these regions in neurological conditions and design targeted intervention towards them;
3) The molecular probes I used in my experiments are a novel, powerful tool for studying the interaction between spiking activity and neuromodulation in real time and at an unprecedented spatial resolution. These results represent a precious reference for those in the neuroscience community who will want to adopt the same molecules.

Group of fluorescent neurons investigated with high-resolution microscopy in a living model