Patterns of Spontaneous Activity in the Assembly and Rewiring of Functional Sensory Circuits

Projektinformationen

SPONTSENSE

ID Finanzhilfevereinbarung: 101054313

DOI

10.3030/101054313

EK-Unterschriftsdatum 15 Juli 2022

Startdatum 1 Januar 2023

Enddatum 31 Dezember 2027

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 2 494 220,00

EU-Beitrag

€ 2 494 220,00

Koordiniert durch

AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
Spain

Periodic Reporting for period 1 - SPONTSENSE (Patterns of Spontaneous Activity in the Assembly and Rewiring of Functional Sensory Circuits)

Berichtszeitraum: 2023-01-01 bis 2025-06-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

During early development, a very particular form of activity- commonly referred to as spontaneous activity- is intrinsically generated in the brain before it is able to respond to stimuli form the external world. This highly correlated spontaneous activity coordinates neurons across long distances and is thought to provide a template upon which sensory circuits are built. However, the mechanisms through which this activity influences the formation of cortical areas specialized in processing distinct sensory modalities remain largely unexplored.

The main goal of this project is to uncover how the different regions of the brain that process vision and touch develop and become specialized through their own unique patterns of early neuronal activity. We believe that these early patterns are linked to the brain's genetic instructions that guide the development of sensory areas. By tracking and manipulating these patterns in mice, we aim to discover how changes in this activity could affect sensory development and even lead to long-term changes in brain function.

In this project, we will observe and analyze neuronal activity in mice at embryonic and early postnatal stages of development, using advanced techniques to look at both the activity patterns and the genetic signatures behind them. We will alter these patterns in specific sensory areas to see how it changes the genetic programming of the brain and, ultimately, sensory function. The final step will involve testing how these changes affect the behavior of adult mice, providing insights into the potential for reprogramming sensory circuits.

The impact of this work could be profound. By understanding how sensory areas of the brain develop and how they might be reshaped, we could open up new pathways for addressing sensory impairments. This research could eventually lead to strategies for helping people whose sensory input is damaged or altered, such as those with sensory disorders or injuries, by promoting brain plasticity to restore or adapt sensory functions.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

We conducted in vivo calcium imaging to record neuronal activity from the dorsal surface of the brain in awake mice during early development (embryonic and early postnatal stages). This approach enabled us to characterize the activity patterns across different cortical areas responsible for processing distinct sensory modalities. Our findings show that, although cortical areas initially exhibit similar patterns, they diverge shortly after birth, developing unique, modality-specific activity signatures.

In parallel, we dissected these areas separately and performed single-nucleus RNA sequencing to identify differences in gene expression. Using bioinformatics tools and machine learning, we linked genetic and activity profiles, uncovering candidate genes for targeted manipulation via CRISPR/Cas9. This technology enables the activation or inhibition of specific genes to study their functional roles.

In a previous study, we discovered that sensory modalities initially emerge intermingled in the embryo and later separate due to the arrival of retinal waves to the superior colliculus (SC). To explore the underlying mechanism of SC reconfiguration, we investigated how retinal axons target the SC at the cellular level. To do so, we injected a virus that induced expression of an opsin in the retina. The retinal axons expressing this opsin were stimulated in slices of the SC using LED illumination. Simultaneously, we performed whole-cell patch-clamp recordings to detect potential responses in SC neurons to retinal stimulation. These studies will contribute to our understanding of the circuits responsible for the developmental transition from multimodal to unimodal sensory processing. Complementary histological analyses and single-nucleus RNA sequencing of the SC at various developmental stages will provide further insight.

Finally, we assess the long-term effects of retinal wave loss through behavioral tests. We created models with impaired retinal waves, either pharmacologically or by bilaterally eliminating the eyes at embryonic stages. After normal development, we evaluated these animals’ visual processing and their ability to discriminate texture in adulthood.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

For a long time, it was believed that genes primarily set the broad boundaries of the cortex, with areas specializing through postnatal, activity-dependent mechanisms. For the first time, we provide a combined approach to simultaneously examine both genetic and activity mechanisms during early development. Our findings reveal an early interplay between molecular signatures and activity patterns, occurring bidirectionally. On one hand, the differential expression of area-specific genes early on regulates cortical area identity by modulating ion channels and cell adhesion molecules, which, in turn, influence the activity properties of each area. On the other hand, early activity from brain regions such as the thalamus induces changes in gene expression that modify the genetic identity of cortical areas. Together, these results highlight a novel, earlier-than-previously thought interaction between genes and activity. This discovery promises to offer breakthrough insights into brain development, with potential applications for understanding both health and disease, particularly in neurodevelopmental disorders and sensory deprivation conditions.

Our results also emphasize the important, yet previously unknown, role of the superior colliculus (SC), an evolutionarily conserved structure traditionally linked to motor orientation and avoidance behaviors. We have shown that the SC plays a crucial role in the formation of cortical sensory pathways. This has sparked renewed interest in this well-studied structure and the need to reconsider its roles during development. In fact, a review we wrote on the emerging functions of the SC highlights that little is known about how its circuitry develops and evolves. Our study provides new insights into this structure, opening exciting new avenues for research across multiple fields of neuroscience.

Temporal color-coded projection of a one-minute recording of cortical spontaneous activity at P6