Solange Pezon Brown

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 inputoutput 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.

Flexible decision-making relies on interactions between frontal cortex and subcortical structures. The claustrum, a subcortical nucleus highly interconnected with frontal cortex, influences cortical activity and has been implicated in cognitive functions. Recording from claustrum neurons as mice performed a reinforcement learning task, we found that the activity of almost half of recorded neurons scaled with reward rate and predicted trial- by-trial adjustments in reaction time and choice switching. Individual neurons sustained this activity over seconds between trials. Our recordings identified two electrophysiologically distinct populations. One was excited during task execution and bidirectionally scaled its activity with reward rate. The other was suppressed during task execution, scaled activity inversely with reward rate and projected to frontal cortex, indicating that claustrocortical outputs produce graded increases in activity with decreasing reward rate. Our results identify the claustrum as a subcortical locus for stable value representations and integrate it into neuronal circuits for value-based decision-making.

The function of mammalian neocortex relies on the timing of axon extension and establishment of cell-type-biased patterns of excitatory synaptic connections. A subtype of excitatory neurons, layer 6 corticothalamic neurons (L6CThNs), ultimately exhibit a marked preference for synapsing onto parvalbumin-positive (PV) inhibitory interneurons over more common excitatory cells in layers 6 and 4 (L6, L4). We show that the intracortical axons of L6CThNs develop in phases, elongating within L6, then pausing before extending translaminar branches into L4. Decreasing L6CThN excitability selectively enhanced axon growth in L6 but not later elaboration in L4. For both layers, we tested whether preferential synaptogenesis onto rarer PV interneurons, or promiscuous synapse formation followed by selective pruning, generated adult connectivity. We found that L6CThNs formed functional AMPA-receptor-containing synapses preferentially onto PV interneurons. Silent L6CThN synapses were not detected. Our findings show that cell-type-biased synaptogenesis underlies the formation of functional cell-type-specific excitatory connections in the neocortex.

To understand neocortical function, we must first define its cell types. Recent studies indicate that neurons in the deepest cortical layer play roles in mediating thalamocortical interactions and modulating brain state and are implicated in neuropsychiatric disease. However, understanding the functions of deep layer 6 (L6b) neurons has been hampered by the lack of agreed upon definitions for these cell types. We compared commonly used methods for defining L6b neurons, including molecular, transcriptional and morphological approaches as well as transgenic mouse lines, and identified a core population of L6b neurons. This population does not innervate sensory thalamus, unlike layer 6 corticothalamic neurons (L6CThNs) in more superficial layer 6. Rather, single L6b neurons project ipsilaterally between cortical areas. Although L6b neurons undergo early developmental changes, we found that their intrinsic electrophysiological properties were stable after the first postnatal week. Our results provide a consensus definition for L6b neurons, enabling comparisons across studies.

The brain helps us survive by forming internal representations of the external world ^1,2 . Excitatory cortical neurons are often precisely tuned to specific external stimuli ^3,4 . However, inhibitory neurons, such as parvalbumin-positive (PV) interneurons, are generally less selective ⁵ . PV interneurons differ from excitatory cells in their neurotransmitter receptor subtypes, including AMPA receptors ^6,7 . While excitatory neurons express calcium-impermeable AMPA receptors containing the GluA2 subunit, PV interneurons express receptors that lack the GluA2 subunit and are calcium-permeable (CP-AMPARs). Here we demonstrate a causal relationship between CP-AMPAR expression and the low feature selectivity of PV interneurons. We find a low expression stoichiometry of GluA2 mRNA relative to other subunits in PV interneurons which is conserved across ferrets, rodents, marmosets, and humans, causing abundant CP-AMPAR expression. Replacing CP-AMPARs in PV interneurons with calcium-impermeable AMPARs increased their orientation selectivity in the visual cortex. Sparse CP-AMPAR manipulations demonstrated that this increase was cell-autonomous and could occur well beyond development. Interestingly, excitatory-PV interneuron connectivity rates and unitary synaptic strength were unaltered by CP-AMPAR removal, suggesting that the selectivity of PV interneurons can be altered without drastically changing connectivity. In GluA2 knockout mice, where all AMPARs are calcium-permeable, excitatory neurons showed significantly reduced orientation selectivity, suggesting that CP-AMPARs are sufficient to drive lower selectivity regardless of cell type. Remarkably, hippocampal PV interneurons, which usually exhibit low spatial tuning, became more spatially selective after removing CP-AMPARs, indicating that CP-AMPARs suppress the feature selectivity of PV interneurons independent of modality. These results reveal a novel role of CP-AMPARs in maintaining a low-selectivity sensory representation in PV interneurons and suggest a conserved molecular mechanism that distinguishes the unique synaptic computations of inhibitory and excitatory neurons.

The cerebral cortex contains numerous neuronal cell types, distinguished by their molecular identity as well as their electrophysiological and morphological properties. Cortical function is reliant on stereotyped patterns of synaptic connectivity and synaptic function among these neuron types, but how these patterns are established during development remains poorly understood. Selective targeting not only of different cell types but also of distinct postsynaptic neuronal domains occurs in many brain circuits and is directed by multiple mechanisms. These mechanisms include the regulation of axonal and dendritic guidance and fine-scale morphogenesis of pre- and postsynaptic processes, lineage relationships, activity dependent mechanisms and intercellular molecular determinants such as transmembrane and secreted molecules, many of which have also been implicated in neurodevelopmental disorders. However, many studies of synaptic targeting have focused on circuits in which neuronal processes target different lamina, such that cell-type-biased connectivity may be confounded with mechanisms of laminar specificity. In the cerebral cortex, each cortical layer contains cell bodies and processes from intermingled neuronal cell types, an arrangement that presents a challenge for the development of target-selective synapse formation. Here, we address progress and future directions in the study of cell-type-biased synaptic targeting in the cerebral cortex. We highlight challenges to identifying developmental mechanisms generating stereotyped patterns of intracortical connectivity, recent developments in uncovering the determinants of synaptic target selection during cortical synapse formation, and current gaps in the understanding of cortical synapse specificity.

Although corticothalamic neurons (CThNs) represent the largest source of synaptic input to thalamic neurons, their role in regulating thalamocortical interactions remains incompletely understood. CThNs in sensory cortex have historically been divided into two types, those with cell bodies in Layer 6 (L6) that project back to primary sensory thalamic nuclei and those with cell bodies in Layer 5 (L5) that project to higher‐order thalamic nuclei and subcortical structures. Recently, diversity among L6 CThNs has increasingly been appreciated. In the rodent somatosensory cortex, two major classes of L6 CThNs have been identified: one projecting to the ventral posterior medial nucleus (VPM‐only L6 CThNs) and one projecting to both VPM and the posterior medial nucleus (VPM/POm L6 CThNs). Using rabies‐based tracing methods in mice, we asked whether these L6 CThN populations integrate similar synaptic inputs. We found that both types of L6 CThNs received local input from somatosensory cortex and thalamic input from VPM and POm. However, VPM/POm L6 CThNs received significantly more input from a number of additional cortical areas, higher order thalamic nuclei, and subcortical structures. We also found that the two types of L6 CThNs target different functional regions within the thalamic reticular nucleus (TRN). Together, our results indicate that these two types of L6 CThNs represent distinct information streams in the somatosensory cortex and suggest that VPM‐only L6 CThNs regulate, via their more restricted circuits, sensory responses related to a cortical column while VPM/POm L6 CThNs, which are integrated into more widespread POm‐related circuits, relay contextual information.