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Pheno-connectomics of human neurodevelopmental diseases

Periodic Reporting for period 1 - PhenoConnectomics (Pheno-connectomics of human neurodevelopmental diseases)

Período documentado: 2021-09-01 hasta 2023-08-31

The brain, with its myriad of neurons, operates like a vast, intricate network. Each neuron in this network connects to several others, forming the very essence of our thoughts, behaviors, and emotions. However, understanding precisely how each neuron connects and communicates with its counterparts remains a daunting challenge. This gap in our knowledge is of great societal significance because many psychiatric illnesses, from depression to autism, are deeply intertwined with abnormalities in these connections.

Addressing this profound challenge, the project embarked on a journey to develop a novel method that can map these neural connections on a single-cell level. Using advanced techniques like single-cell mRNA sequencing, viral tracing, and barcoding, the aim was not only to chart the 'roads' each neuron takes but also to understand the 'language' they speak – their gene expression. The project's ultimate objective was fourfold. Firstly, to pioneer a new technological assay that can unravel the synaptic networks spanning thousands of neurons. Secondly, to delve into the basic biology of neurons, questioning the nature and number of connections each neuron forms and whether their connectivity influences their genetic expression. The third goal was conceptual, introducing the idea of viewing the connectome at a single-cell level as a unique phenotype, coined "pheno-connectomics", which holds the key to understanding various diseases at their most foundational level. Lastly, the project aimed to decode how genetic anomalies can simultaneously influence a neuron's gene expression and its connections, and whether this impact is uniformly distributed across different neuron types.

In conclusion, this project holds the promise of bridging the gap between genetic expression and neural connectivity. Its success has the potential to reshape our understanding of psychiatric diseases at a fundamental level.
Work Performed and Key Results Achieved

From the project's inception to the conclusion of the reporting period, a meticulous and multi-pronged approach was employed to understand the intricacies of neuronal connections and their implications.

1. Technological Development: We successfully developed the proposed "connectomics-by-sequencing" assay. This method allowed us to map synaptic networks covering thousands of neurons with unparalleled precision. The technological edge provided by this assay is offering researchers a tool to dive deeper into neural networks than ever before.

2. Exploring Basic Biology: Our investigations into individual neurons unveiled fascinating insights. We discovered that the number and nature of connections a neuron forms vary widely. Furthermore, there was a clear correlation between a neuron's connectivity and tissue composition.

3. Concept of Pheno-connectomics: This project laid the foundation for the conceptual understanding of connectivity as disease phenotype. By studying the connectome at a single-cell level, we identified unique patterns associated with certain diseases. These findings have broadened the horizons for future research in the realm of psychiatric disorders.

4. Disease Mechanism Exploration: Delving into the impact of genetic defects, our research showed that genetic anomalies do influence both gene expression and neuronal connectivity. However, intriguingly, not all cell types displayed a uniform response.

Exploitation and Dissemination:
The results have been disseminated across various platforms to ensure maximum outreach:

- Submission for Academic publication is in progress (0 publication to date).

- Conferences & Seminars: Team members have presented at various international and local conferences, fostering discussions and collaborations with experts in the field (2 conferences).

- Collaborative Research: The tools and methodologies developed have been shared with other research groups, promoting a collaborative approach towards understanding the human brain's complexities.

In essence, the work performed has not only achieved a subset of the objectives but has also set the stage for future research in the domain of neural connectivity and psychiatric disorders.
Progress Beyond the State of the Art

The "connectomics-by-sequencing" approach pioneered by this project has pushed the boundaries of our current understanding of the brain. Traditionally, the realm of connectomics was confined to mapping neuronal connections, but the integration of single-cell mRNA sequencing provided a new dimension, adding depth to these maps by incorporating genetic expression data. By diving into the very genetic essence of each neuron and its connectivity, we've advanced beyond the conventional methods, offering a more holistic view of the brain's intricate network.

Expected Results Until the End of the Project

As the project continues, we anticipate several groundbreaking results:

1. High-throughput Connectome Maps: Building on the foundation laid, we aim to produce extensive sets of maps detailing the connections and genetic expressions of a broader spectrum of neurons, offering an even more intricate overview.

2. Deeper Insight into Diseases: By employing the concept of "pheno-connectomics", we expect to unearth deeper insights into multiple psychiatric disorders, pinpointing the foundational genetic and connective anomalies responsible for each.

3. Refinement of Techniques: Constant iterative feedback from our research will lead to the refinement of our connectomics-by-sequencing assay, making it more accurate and efficient.

Potential Impacts

1. Socio-economic Impact: Our findings hold the potential to a better understanding of psychiatric disorders, which eventually may translate to improving the quality of life for millions of patients affected globally.

2. Wider Societal Implications: As our understanding of the brain deepens, it's not just the medical realm that benefits. Sectors ranging from education to human-machine interfaces can leverage these insights to develop more advanced approaches.

In summary, the project's trajectory indicates not just an advancement in scientific knowledge, but on the long term, also holds the promise of improved medical care. The intersection of genetic expression and neuronal connectivity provides a potent lens to view and address the challenges of psychiatric disorders, and its implications reverberate far beyond the confines of the lab, promising a brighter future for many.
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