CRCNS: Gradients of receptors underlying distributed cognitive functions

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A key goal of the NIMH is to define the mechanisms of complex behaviors. This necessitates an approach that spans biological scales, but we have been lacking a single theoretical framework that links neurotransmitter receptor function, large-scale patterns of brain activity and cognition. Working memory is a key building block of cognition, but our understanding of why working memory emerges in sorne parts of cortex, but not others, is limited. The macaque is an important model for studying higher cognitive function with relevance to psychiatric disease, due to their intelligent behavior and relatively similar brains. We propose the creation of a high-resolution 3D atlas of the macaque brain, and use it to create data-driven neural circuit models that will give us key insights into the relationship between regional variations in receptor densities and the emergence of distributed working memory. The atlas will enable quantification of the regional and laminar distribution of 14 types of receptors (receptor fingerprints) and cell densities across the entire macaque cortex. This will allow for interrogation of receptor fingerprints and cell densities with submillimeler precision. It will be accompanied by a novel parcellation scheme based on the gradients of cyto- and receptor-architecture across cortex. This atlas will be registered lo the NIMH Macaque Template for easy integration with macaque /MRI data. We will identify the principal gradients that underlie the distribution of receptors across cortex and compare these to hierarchies of sensory systems and cognitive networks using open-access laminar tract-tracing and /MRI data. This approach will uncover the receptor signature underlying distinct functional hierarchies. We will use the idea of bifurcations from mathematics to interrogate how changes lo the density of receptors across cortex may lead to the emergence of working-memory like persistent activity in particular regions of cortex. Crucially, we will allow the experimentally measured receptor densities lo scale the effects of each receptor in each cortical area and layer. We hypothesize that the pattern of working memory activity observed across cortical areas and lamina depends critically on the regional distribution of the receptors. Further, we will expand our model to include inter-areal connectivity data and investigate how release of neuromodulators can shift cortical activity between cognitive networks. The results of our proposed research are likely to significantly advance this area of research, with broad implications. The highly promising preliminary results have confirmed the validity of the approach, ensuring that all aspects of the program have a high likelihood of success. RELEVANCE (See instructions): Cognitive symptoms of mental illnesses are difficult to treat, but can be the biggest impediment to patients living independently. Cognitive functions rely on many brain areas communicating through chemicals and receptors, which are affected by mental illness and medication. We will map the pattern of these receptors in the brain, so we can build computer models to understand why cognitive functions differ across brain regions. This could lead to the development of new treatments for cognitive symptoms in mental illness.