The Functioning of a Cortex without Layers

Abstract

A major hallmark of cortical organization is the existence of a variable number of layers, i.e., sheets of neurons stacked on top of each other, in which neurons have certain commonalities. However, even for the neocortex, variable numbers of layers have been described and it is just a convention to distinguish six layers from each other. Whether cortical layers are a structural epiphenomenon caused by developmental dynamics or represent a functionally important modularization of cortical computation is still unknown. Here we present our insights from the reeler mutant mouse, a model for a developmental, “molecular lesion”-induced loss of cortical layering that could serve as ground truth of what an intact layering adds to the cortex in terms of functionality. We could demonstrate that the reeler neocortex shows no inversion of cortical layers but rather a severe disorganization that in the primary somatosensory cortex leads to the complete loss of layers. Nevertheless, the somatosensory system is well organized. When exploring an enriched environment with specific sets of whiskers, activity-dependent gene expression takes place in the corresponding modules. Precise whisker stimuli lead to the functional activation of somatotopically organized barrel columns as visualized by intrinsic signal optical imaging. Similar results were obtained in the reeler visual system. When analyzing pathways that could be responsible for preservation of tactile perception, lemniscal thalamic projections were found to be largely intact, despite the smearing of target neurons across the cortical mantle. However, with optogenetic experiments we found evidence for a mild dispersion of thalamic synapse targeting on layer IV-spiny stellate cells, together with a general weakening in thalamocortical input strength. This weakening of thalamic inputs was compensated by intracortical mechanisms involving increased recurrent excitation and/or reduced feedforward inhibition. In conclusion, a layer loss so far only led to the detection of subtle defects in sensory processing by reeler mice. This argues in favor of a view in which cortical layers are not an essential component for basic perception and cognition. A view also supported by recent studies in birds, which can have remarkable cognitive capacities despite the lack of a neocortex with multiple cortical layers. In conclusion, we suggest that future studies directed toward understanding cortical functions should rather focus on circuits specified by functional cell type composition than mere laminar location.

The Reeler Mouse: A Translational Model of Human Neurological Conditions, or Simply a Good Tool for Better Understanding Neurodevelopment?

“…In addition, when studied at the fine-scale electron microscopic level, the basic synaptic organization of misplaced cortical neurons was unchanged [87]. Therefore, although the laminar organization is thought to be critical for cortical computation [88,89], evidences obtained in Reeler mice led Guy and Staiger [90] to challenge the importance of cortical lamination, affirming that "future studies directed toward understanding cortical functions should rather focus on circuits specified by functional cell type composition than mere laminar location".…”

Why Does the Neocortex Have Columns, A Theory of Learning the Structure of the World

“…This is a convenience as the connectivity and physiology of cell populations is what matters. Cells we describe as residing in separate layers may actually intermingle in cortical tissue (Guy and Staiger, 2017).…”

Circuits in the absence of cortical layers: increased callosal connectivity in reeler mice revealed by brain-wide input mapping of VIP neurons in barrel cortex

“…Despite the absence of layers, reeler mice display no severe decline in cognitive abilities, have largely preserved sensory function, and only have a slight impairment of spatial memory and executive function (Imai et al, 2017; Pielecka-Fortuna et al, 2015; Salinger et al, 2003; Wagener et al, 2010). So far this preservation of cognitive abilities has been attributed to the fact that in reeler neurons seem not only to retain their physiological properties but also their connectivity, implying the formation of the same circuits despite the malposition of its parts (Guy and Staiger, 2017). However, our map of brain-wide inputs to VIP neurons reveals that reeler mice have a different proportion of ipsi- and contralateral input.…”

“…However, the notion of layers structuring the flow of cortical processing might be misleading. Cortical computations require foremost a functional neuronal circuit between defined cell types (Guy and Staiger, 2017; Harris and Shepherd, 2015). Because neurons exhibit surprising specificity in targeting of other neurons, there seem to be strict rules of connectivity (Kasthuri et al, 2015; Motta et al, 2019).…”

“…Therefore, we asked the question if correct laminar position is a necessary prerequisite for a neuron to receive inputs and become properly embedded in brain-wide circuits. An excellent model system to study the significance of layers is the reeler mouse (Guy and Staiger, 2017). Homozygous mice lack the protein reelin, which is secreted by Cajal-Retzius cells during development, to orchestrate the migration of neurons during development (Lee and D’Arcangelo, 2016).…”