The claustrum is a highway not a hub : organizing principles of claustrocortical synaptic transmission

The claustrum (CLA) is a brain nucleus wedged between the cortex and striatum. The behaviors it has been implicated in include consciousness, attention, memory and salience detection; dysfunction of CLA circuits is associated with schizophrenia, epilepsy, parkinsonism and disrupted consciousness. While previous research has focused on the gross anatomy of the CLA, it is the functional communication of the CLA with other brain regions that generates behavioral output. Understanding CLA functional connectivity will bring us closer to understanding how the CLA is involved in different behaviors and how these dysfunctions can be remedied.

The anterior cingulate cortex-projecting (CLA-ACC) neuron population was used as a model to investigate claustrocortical synaptic transmission. This thesis proposes that the CLA is organized as a highway for connections between brain regions. Paper I revealed that the CLA is organized as functional modules. Specifically, it showed that CLA-ACC neurons receive multicortical input biased towards frontal & limbic cortices rather than sensory cortices, and that CLA-ACC neurons could be segmented into at least two cortical targeting systems. An insular-claustrum- anterior cingulate cortex circuit, which may be the substrate underpinning the Salience Network, was also identified. These findings support feedforward inhibition as a mechanism of action within the CLA. Paper II extended the concept of topological selectivity in the CLA to the single- cell level. Topological selectivity was previously known to exist at a population level. Characterization of the intrinsic electrophysiological properties of individual CLA-ACC neurons revealed four types of CLA-ACC populations. These CLA- ACC neurons were distributed heterogeneously with one type predominant in the anterior and posterior CLA and a second type prominent in the middle of the CLA. Paper III identified the cell-type and layer-specific cortical targets of the CLA. It showed that CLA-ACC neurons provide excitatory monosynaptic input to all layers of the ACC and that different neuron populations receive CLA input in a layer-dependent fashion. From these data, Paper III derived a scheme of CLA targets within a cortex.

The findings from this thesis can be summarized using a transportation analogy. Although commonly described as a hub for cortical inputs and outputs, the CLA is likely organized as a collection of highways. A significantly large input should arrive within a small time-window to generate action potentials and enable downstream signal propagation. This is akin to a toll booth with a high toll fee that must be paid-in-full, without delays, before a vehicle can pass through. Projection neurons directed to the same cortical region may have different cell/layer targets. This is comparable to different vehicles on the same highway ending up in different destinations. The findings in this thesis add to our understanding of CLA functional organization by suggesting that any input received by the CLA must be sufficiently strong in order to overcome FFI and for the signal to be propagated. This implies that only input of ethological relevance is processed. Such a mechanism could underlie CLA action across behaviors. This thesis is divided into 6 chapters. Chapter 1 is a preamble. Chapter 2 encompasses the state-of-the-art in CLA and describes the gaps in knowledge that this thesis aims to fill. Chapter 3 clarifies the aims of this thesis. Chapter 4 provides an overview of the methods used. Chapter 5 presents and discusses the main results. Chapter 6 explores the main conclusions from this work. Manuscripts and publications are appended after.

List of scientific papers

I. Chia, Z., Augustine, G.J., Silberberg, G. (2020a). Synaptic connectivity between the cortex and claustrum is organized into functional modules. Curr Biol. 2020 Jul 20;30(14):2777-2790.e4.
https://doi.org/10.1016/j.cub.2020.05.031

II. Chia, Z., Silberberg, G., Augustine, G.J. (2017). Functional properties, topological organization and sexual dimorphism of claustrum neurons projecting to anterior cingulate cortex. Claustrum. 2:1, 1357412.
https://doi.org/10.1080/20023294.2017.1357412

III. Chia, Z., Augustine, G.J., Silberberg, G. (2020b). Claustrum projections to the ACC are layer and cell-type dependent. [Manuscript]