Parallel claustral networks for behavioral control in health and disease

The claustrum is among the most highly interconnected structures in the mammalian brain, with reciprocal projections spanning the cortical mantle and a growing roster of functions that range from sleep regulation to attentional control. Here we review current understanding of claustral circuit organization and function, synthesizing findings from anatomical, physiological, computational, and behavioral studies. We argue that a unifying logic underlies the apparent diversity of claustral functions: the claustrum operates through projection-defined subnetworks whose input selectivity, output targets, and local circuit interactions collectively determine their functional contribution, and whose impact on cortical targets varies with arousal and ongoing brain state. Corticoclaustral connectivity is organized into matched input-output modules, local inhibitory circuits confer spatial filtering properties that amplify strong cortical signals while suppressing weaker ones, and claustral output populations differ in their laminar targets, postsynaptic cell-type preferences, and molecular properties, producing diverse and context-dependent effects on cortical dynamics. These circuit properties translate into claustral regulation of cortical population dynamics across multiple timescales, from the moment-to-moment coordination of brain states to the consolidation of frontal control strategies. In pain and addiction, specific claustral projection populations are selectively dysregulated, and distinct subnetworks exert opposing influences on nociceptive sensitivity and drug-related behavior according to their cortical targets. Together, these findings position the claustrum as a modular subcortical hub for the selective regulation of distributed cortical networks and identify it as a candidate therapeutic target for disorders characterized by dysregulated cortical network activity, including chronic pain, addiction, and impulsivity.