Human lesions and animal studies link the claustrum to perception, salience, sleep and pain

Abstract

The claustrum is the most densely interconnected region in the human brain. Despite the accumulating data from clinical and experimental studies, the functional role of the claustrum remains unknown. Here, we systematically review claustrum lesion studies and discuss their functional implications. Claustral lesions are associated with an array of signs and symptoms, including changes in cognitive, perceptual and motor abilities; electrical activity; mental state; and sleep. The wide range of symptoms observed following claustral lesions do not provide compelling evidence to support prominent current theories of claustrum function such as multisensory integration or salience computation. Conversely, the lesions studies support the hypothesis that the claustrum regulates cortical excitability. We argue that the claustrum is connected to, or part of, multiple brain networks that perform both fundamental and higher cognitive functions. As a multifunctional node in numerous networks, this may explain the manifold effects of claustrum damage on brain and behaviour.

Temporal origin of mouse claustrum and development of its cortical projections

“…The profile of RSP projecting cells through development we report here is consistent with the tight cluster of cells observed in the claustrum in the adult (Zingg et al 2018;Marriott et al 2021;Shelton et al 2022). We find no projections to RSP from insula and other claustrum adjacent structures even in the youngest brains.…”

“…Thus, we specifically investigated when claustrum axons first connect to two distinct ipsilateral target regions: anterior cingulate and retrosplenial cortex. RSP projections were chosen, because they are widely used in adult brains as a means to access claustrum cells for genetic manipulation via retrograde viral transfection including in species other than mouse (Zingg et al 2018;Dillingham et al 2019;Shelton et al 2022), and ACA because of its reported dense innervation by claustrum (Wang et al 2017;White et al 2018;Zingg et al 2018;Chia et al 2020).…”

“…CTB-labelling requires injection in vivo, and a long-enough post-injection survival time for adequate transport of CTB back to the cell body. To control for possible variability in the duration over which CTB is present in the extracellular space, we used two different post-injection survival times: five days, which we knew to give adequate back-labelling of claustrum cells in adult brains in our hands (Grimstvedt et al n.d.;Shelton et al 2022), and two days, to reduce the risk of newly arriving axons being able to take up CTB days after the injection took place. There was no significant difference in the number of retrogradely labelled claustrum cells between 2-day and 5-day post-injection survival time (ANOVA, F (1, 17)=1.…”

“…The claustrum is an elongated, bilateral grey matter structure embedded between the insular cortex and the striatum. Its structure was first described over 200 years ago (Vicq d’Azyr 1786), but its function remains elusive, largely because of its experimentally inaccessible location, and the scarcity of claustrum-specific human brain lesions (Atilgan et al 2022). The claustrum is widely interconnected with the cortex (Torgerson et al 2015; Wang et al 2017), and single claustrum neurons have the largest number of target regions of all neurons studied (Peng et al 2021).…”

“…However some, such as the orphan nuclear receptor 4A2 (Nr4a2)/Nurr1, have been used to identify the claustrum in neonatal rat brains (Fang et al 2021). Retrograde tracing from retrosplenial cortex (RSP) in adult mice is increasingly used as a strategy to identify the claustrum (Zingg et al 2018;Marriott et al 2021;Shelton et al 2022). However, retrograde tracing has never been explored as a labelling strategy in developing brains.…”