Optical interrogation of the claustrum from synapses to behavior

Project Information

CLAUSTRUM

Grant agreement ID: 852765

DOI

10.3030/852765

Project closed

EC signature date 2 October 2019

Start date 1 October 2019

End date 30 September 2024

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 500 000,00

EU contribution

€ 1 500 000,00

Coordinated by

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom

Periodic Reporting for period 4 - CLAUSTRUM (Optical interrogation of the claustrum from synapses to behavior)

Reporting period: 2024-04-01 to 2024-09-30

Summary of the context and overall objectives of the project

How does the brain integrate inputs from the environment to generate perception and drive decisions? An enigmatic brain region called the claustrum has been suggested to play a role by integrating inputs from multiple brain regions. There is strong interconnectivity between claustrum and nearly every neocortical brain region, indicating that it exerts widespread influence on brain function. However, approaches to specifically record from or manipulate activity in the claustrum have been hindered by the inability to target it selectively. This has been difficult due to the anatomy of the claustrum: it is a long, thin bilateral nucleus buried between the neocortex and the striatum. This proposal aims to understand the role of the claustrum in multisensory integration and behaviour by developing new approaches for monitoring and manipulating the activity of the claustrum. We will harness recent advances in electrophysiological, genetic, optical, and behavioural tools to probe its connectivity, activity, and function in a precise manner. Understanding the role of the claustrum in brain function will provide fundamental insight into information processing in the neocortex, which is a major goal in neuroscience. The claustrum is unique because of its dense reciprocal connectivity with neocortex but nearly complete lack of direct subcortical sensory input. This particular anatomical structure indicates the possibility of a unique function, but none has been observed yet. This proposal will rectify the paucity of data on this distinctive structure by applying a battery of modern tools to address the function of the claustrum. Experiments will address the following key questions:

1. How are claustrocortical inputs integrated and what is the effect of corticoclaustral feedback?

2. What is the activity of claustral neurons during sensory stimulation and motor output?

3. What are the causal relationships between claustrum activity and animal behaviour?

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

In initial work, we compared the developmental and evolutionary origin of the claustrum and subplate (Bruguier et al 2020), and further assessed how human lesions and animal studies link the claustrum to perception, salience, sleep and pain (Atilgan et al 2022). This framework allowed us to then go on – in collaboration with experts in neurodevelopment - to determined the temporal origin of the claustrum and development of its projections into neocortex (Hoerder-Suabedissen et al 2022). Along with others in the field we have worked to better define claustrum in animal models and used advanced anatomical tracing approaches to target and understand how single claustrum neurons and the networks in which they are embedded, integrate synaptic inputs from widespread cortical sources (Shelton et al 2024). We have also contributed to a multifaceted framework of the mouse claustrum complex with European collaborators (Grimstvedt et al 2022) as well as collaborated internationally to perform intravital imaging of the murine subventricular zone with three-photon microscopy (Sun et al 2022). In recent years, we have advanced our understanding of the role this brain structure plays in behaviour, using optical strategies to stimulate claustrum neurons in the medial prefrontal cortex – an area associated with higher order cognitive abilities (Atilgan et al 2024), as well as understand how prefrontal cortex neurons that form reciprocal connections with claustrum are engaged in advanced economic decision-making behaviours (Majumdar et al., 2024). Work ongoing at the end of the project used further optogenetic and transcriptomic approaches to further resolve the heterogeneity and connectivity of specific sub-circuits within claustrum, revealing further complexity in the structure (core versus claustrum shell) and function (feed-forward inhibition of cortex) of this brain area. The sum of these results reveal that claustrum is important for integrating multimodal sensory and association cortex inputs to regulate forebrain function due complex decision making tasks.

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)

We have uncovered the major building blocks of the claustrum in mice as well as elucidated its potential roles in humans. We have also determined when the claustrum is active in response to sensory stimuli and identified the consequences of clastrum activiation on downstream cortical areas.

Retrograde labelling with fluorescent tracers can be used to identify claustrum in the mouse.