Claustral Projections to Anterior Cingulate Cortex Modulate Engagement with the External World

Abstract

Engagement is a major determinant of performance. Hyper-engagement risks impulsivity and is fatiguing over time, while hypo-engagement could lead to missed opportunities. Even in sleep, when engagement levels are minimal, sensory responsiveness varies. Thus, maintaining an optimal engagement level with the environment is a fundamental cognitive ability. The claustrum, and in particular its reciprocal connectivity with executive regions in the frontal cortex, has been associated with salience, attention and sleep. These apparently disparate roles can be consolidated within the context of engagement. Here we describe the activity of claustro-frontal circuits in a task imposing a tradeoff between response inhibition and sensory acuity (ENGAGE). Recording calcium fiber photometry during >80,000 trials, we characterize claustrum recruitment during salient behavioral events, and find that a moderate level of activity in claustro-cingulate projections defines optimal engagement. Low activity of this pathway is associated with impulsive actions, while high activity is associated with behavioral lapses. Chemogenetic activation of cingulate-projecting claustrum neurons suppressed impulsive behavior and reduced the engagement of mice in the task. This relationship became even clearer upon addressing individual variability in the strategy mice employed during the ENGAGE task. Furthermore, this association of claustrum activity and engagement extends into sleep. Using simultaneous EEG and photometry recordings in the claustrum, we find that cingulate projecting claustrum neurons are most active during deep unresponsive slow-wave sleep, when mice are less prone to awakening by sensory stimuli.

Regional and cell type-specific afferent and efferent projections of the mouse claustrum

“…Therefore, using multiple tracing datasets for cross-validation is crucial. Our finding that the CLA strongly and reciprocally connects with the prefrontal module is consistent with other studies (Chia et al, 2020; Qadir et al, 2018; White et al, 2017), supporting the notion that the CLA is involved in cognitive control but not in sensorimotor processing (Atlan et al, 2021; Krimmel et al, 2019a; White et al, 2018).…”

“…In a second scheme, the CLA is delineated largely underneath the gustatory, agranular insular, and visceral areas, but not subdivided. In a third scheme, the CLA is divided into core and shell subdivisions (Atlan et al, 2017(Atlan et al, , 2021Binks et al, 2019;Erwin et al, 2021;Graf et al, 2020;Marriott et al, 2020;Real et al, 2003Real et al, , 2006. A fourth scheme, advocated for here, avoids any core/shell or dorsal/ventral subdivision and defines the CLA as a single, densely packed group of neurons embedded in the agranular insular area (Dillingham et al, 2017;Wang et al, 2017Wang et al, , 2020.…”

“…It is well-conserved from reptiles to mammals (Bruguier et al, 2020; Norimoto et al, 2020), and is the most highly reciprocally connected structure with the cortex (Peng et al, 2021; Torgerson et al, 2015; Wang et al, 2017; Zingg et al, 2014). Although its function is not fully understood (Atilgan et al, 2021; Crick and Koch 2005), recent studies using a combination of optogenetics and electrophysiological recording or fiber photometry in transgenic mice suggest that the CLA is involved in sleep (Atlan et al, 2021; Narikiyo et al, 2020), inhibition of the medial prefrontal cortex (Jackson et al, 2018), selective attention (Atlan et al, 2018; Fodoulian et al, 2019; Terem et al, 2020), modulation of engagement with the external world (Atlan et al, 2021) and is required for shifting to a complex cognitive task (White et al, 2020). Furthermore, top-down signals from the anterior cingulate cortex may go through the CLA in a circuit that influences posterior sensory and association cortices (White and Mathur, 2018).…”

Influence of claustrum on cortex varies by area, layer, and cell type

“…It may be that CLA neurons perform distinct functions depending on the cortical area or areas to which they project. Evidence for this is emerging, such as in new work studying the roles of subpopulations of CLA neurons projecting to ACA versus ORB (Atlan et al, 2021), and to somatosensory cortex (Chevée et al, 2021). Our observation of the distinct functional impact of CLA on RSP, along with the lack of reciprocal connections from RSP to CLA, suggests this pathway may be particularly important to study as an output of the CLA.…”

“…Due to its widespread and extensive reciprocal connections with the cortex, the CLA has been proposed to underlie various high-level functions including salience detection (Atilgan et al, 2021; Remedios et al, 2014; Smith et al, 2019), attentional control (Goll et al, 2015; White et al, 2020), and consciousness (Crick and Koch, 2005; Smythies et al, 2014). Additionally, results from recent studies suggest that CLA may be involved in associative learning (Reus-garcía et al, 2020; Terem et al, 2020), coordination of slow-wave activity (Narikiyo et al, 2020; Norimoto et al, 2020), distractor suppression (Atlan et al, 2018; White et al, 2018, 2020), attentional set shifting (Fodoulian et al, 2020), task switching (Krimmel et al, 2019), and behavioral engagement (Atlan et al, 2021; Liu et al, 2019).…”