A long-neglected layer of cells at the very bottom of the cerebral cortex may play a central role in how the brain directs and sustains attention, according to a new paper published in Neuron. In a Perspective article, Matthew Larkum from Humboldt University of Berlin, Tim Zolnik and Britta Eickholt from the Charité – Universitätsmedizin Berlin, and Zoltán Molnár from University of Oxford, propose that layer 6b, a thin band of neurons once thought to be merely a developmental remnant, acts as a powerful controller of attention-related brain activity. Layer 6b is the adult descendant of the subplate, a transient structure that plays a crucial role during early brain development. Although subplate neurons are essential for wiring the cortex in infancy, their surviving counterparts in the adult brain have largely been ignored. The new work argues that this assumption is no longer tenable and suggests that these neurons are ideally positioned to control some of the brain’s most important circuits—those involved in attention, arousal, and awareness.
A strategic position in the brain.
The review outline how layer 6b neurons are uniquely connected within the brain. Despite being relatively few, they send targeted projections to higher-order thalamic nuclei and to layer 5 pyramidal neurons, key components of cortico–thalamic feedback loops that are widely believed to underpin attention and conscious perception (Figure 1). Crucially, layer 6b neurons are also exceptionally sensitive to neuromodulators associated with arousal and motivation, including orexin, dopamine, neurotensin, acetylcholine and noradrenaline. Orexin is a master regulator of wakefulness and is known to be deficient in narcolepsy. By integrating these chemical signals with top-down input from higher cortical areas, the authors propose that layer 6b can rapidly and precisely switch attention-related circuits on or off, sustain them over time, and flexibly redirect them when attention shifts.
Together, these properties form the basis of what the authors call the Layer 6b Attention Theory (LAT). The theory suggests that layer 6b acts like a conductor of an orchestra, coordinating activity across widely distributed brain regions so that the right circuits are engaged at the right moment. The paper also explores how dysfunction of layer 6b could contribute to neurological and psychiatric conditions marked by attentional deficits, including narcolepsy, attention-deficit hyperactivity disorder (ADHD), and schizophrenia. Increased number of layer 6b equivalent neurons in human has been described in schizophrenia and autism. Attention problems are a core feature of many brain disorders. By identifying a concrete circuit element that sits at the intersection of neuromodulation, cortical control and thalamic communication, the collaborative team hopes to provide a new framework for understanding both normal cognition and disease.
Building on international collaboration
The work builds on a series of recent experimental and theoretical studies led by Matthew Larkum, Britta Eickholt, Timothy Zolnik and Zoltán Molnár and collaborators across Oxford and Berlin, including research on anxiety-related circuits and the functional role of deep cortical layers. The research programme has been supported by funding from the Einstein Stiftung Berlin, which supported Professor Molnár as an Einstein Visiting Fellow at the Charité over the last six years. The authors stress that the Layer 6b Attention Theory now makes clear, testable predictions that can be examined in future experiments, in both animals and humans. 'It is striking that a structure first studied for its role in early brain development may turn out to be central to some of our most sophisticated mental abilities,” Professor Molnár added. “Layer 6b may be a missing link in our understanding of attention.'
Reference: Zolnik TA, Eickholt BJ, Molnár Z, Larkum ME. The layer 6b theory of attention. Neuron (2025). Open access. https://doi.org/10.1016/j.neuron.2025.11.024
Figures:
The first figure is based on Body, Brain, Behavior, Three Views and a Conversation Tamas L. Horváth TL, Hirsch J, Molnár Z (2022) Academic Press, An imprint of Elsevier; ISBN: 9780128180938
The second figure is: Molnar et al., 2020 Transient cortical circuits match spontaneous and sensory-driven activity during development, Z Molnár, HJ Luhmann, PO Kanold
Science 370 (6514), eabb2153