A layer-specific model of cortical sensory aging

Sensory processing is organized in a layered architecture with segregated input, output and modulatory circuits. This layered architecture of sensory systems is a convergent feature in animal evolution . A comprehensive understanding of (dys)functional sensory systems requires a detailed understanding of alterations in the layer-specific architecture and the associated phenotypes. This is so far lacking, not only for sensory systems but for cortical dysfunction in general.

Sensory dysfunction comes with different cortical phenotypes, including increases in receptive field (RF) sizes, functional overactivation, decreases in lateral inhibition and structural alterations such as cortical thinning. However, it is unclear how changes in the layer architecture may contribute to the alterations characterizing sensory cortices with reduced functionality.

Here, we employed a unique approach to target this question by combining layer-specific structural and layer-specific functional 7T-MRI of primary somatosensory cortex (SI) with behavioral assessments from two cohorts of healthy younger and older adults. Cortical aging serves as a suitable model system to investigate the layer-specific architecture of sensory dysfunction as structural and functional reorganization is observed at different levels of the processing hierarchy, and affects behavior. To better understand the mechanistic underpinnings of the observed changes, we used in vivo 2-photon calcium imaging (2PCI) in younger and older mice to investigate neuronal response differences at different cortical depths. We also used post mortem histological examination on mice as it provides deeper insights into layer-specific structural changes.

Our study presents four major results that we used to develop a novel layer model of sensory aging: (1) Increased sensory input channel: In older adults, in spite of overall cortical thinning, the middle layer (i.e., input layer IV, identified using a previously published approach) presents with increased thickness, higher myelin content, and a more pronounced antagonistic center-surround relationship between signals and cortical depth. An adult with congenital arm loss shows, on the other hand, a shrinkage specifically of layer IV of SI. This speaks towards a plasticity-mediated mechanism of layer IV thickness modulation in humans. (2) Cortical thinning driven by deep layer thinning: Reduced cortical thickness in older compared with younger adults is not homogenous across layers but driven by deep layer thinning. (3) Preserved low-myelin hand-face border in layer IV: Low-myelin borders in input layer IV are preserved older compared to younger adults as well as in an individual with congenital arm loss. (4) Altered modulation channel: Older adults show less thickness but more myelin in deep layers, which is mirrored by overall cell loss and increased PV+ cell density in older mice. This is accompanied by no alterations or even an increase in inhibitory interactions in older adults and mice, making PV-cell driven inhibition a likely underlying mechanism.

Taken together, the novel layer model of aging provides key and novel information on SI organization and aging sensory circuits that may explain cortical dysfunction in health and disease, which is of particular importance for developing intervention to preserve sensory functions in aging and neurodegeneration in the future. This work also provides impactful relevance for understanding the neuronal mechanisms that underlie topographic organization and plasticity in general by transferring mechanistic insights from animal to human research. Given the layer-specific profile was different from primary motor cortex, our data also motivate the detailed assessment of layer-specific circuits in different cortical areas.