Bridging the gap between single receptor type activity and whole-brain dynamics

Data de publicació electrònica: 02-04-2021What is the effect of activating a single modulatory neuronal receptor type on entire brain network dynamics? Can such effect be isolated at all? These are important questions because characterizing elementary neuronal processes that influence network activity across the given anatomical backbone is fundamental to guide theories of brain function. Here, we introduce the concept of the cortical ‘receptome’ taking into account the distribution and densities of expression of different modulatory receptor types across the brain's anatomical connectivity matrix. By modelling whole‐brain dynamics in silico, we suggest a bidirectional coupling between modulatory neurotransmission and neuronal connectivity hardware exemplified by the impact of single serotonergic (5‐HT) receptor types on cortical dynamics. As experimental support of this concept, we show how optogenetic tools enable specific activation of a single 5‐HT receptor type across the cortex as well as in vivo measurement of its distinct effects on cortical processing. Altogether, we demonstrate how the structural neuronal connectivity backbone and its modulation by a single neurotransmitter system allow access to a rich repertoire of different brain states that are fundamental for flexible behaviour. We further propose that irregular receptor expression patterns—genetically predisposed or acquired during a lifetime—may predispose for neuropsychiatric disorders like addiction, depression and anxiety along with distinct changes in brain state. Our long‐term vision is that such diseases could be treated through rationally targeted therapeutic interventions of high specificity to eventually recover natural transitions of brain states.Deutsche Forschungsgemeinschaft (DFG): Dirk Jancke, JA 945/5‐1; JA 945/4‐1; Deutsche Forschungsgemeinschaft (DFG): Stefan Herlitze, HE 2471/12‐1; 2471/18‐1; Deutsche Forschungsgemeinschaft (DFG): Stefan Herlitze, Dirk Jancke, Project ID 122679504 ‐ SFB 874, (project part A2, DJ and project part B10, SH); Deutsche Forschungsgemeinschaft (DFG): Dirk Jancke, JA 945/3‐1 and Hamutal Slovin SL 185/1‐1, German‐Israeli Project Cooperation (DIP); Deutsche Forschungsgemeinschaft (DFG): Melanie D Mark, MA 5806/1‐2; MA 5806/2‐1; Deutsche Forschungsgemeinschaft (DFG): Stefan Herlitze, SFB 1280, DFG project no. 316803389; GD is supported by a Spanish national research project (ref. PID2019‐105772GB‐I00 MCIU AEI) funded by the Spanish Ministry of Science, Innovation and Universities (MCIU), State Research Agency (AEI); HBP SGA3 Human Brain Project Specific Grant Agreement 3 (grant agreement no. 945539), funded by the EU H2020 FET Flagship programme; SGR Research Support Group support (ref. 2017 SGR 1545), funded by the Catalan Agency for Management of University and Research Grants (AGAUR); Neurotwin Digital twins for model‐driven noninvasive electrical brain stimulation (grant agreement ID: 101017716) funded by the EU H2020 FET Proactive programme; euSNN European School of Network Neuroscience (grant agreement ID: 860563) funded by the EU H2020 MSCA‐ITN Innovative Training Networks; CECH The Emerging Human Brain Cluster (ID: 001‐P‐001682) within the framework of the European Research Development Fund Operational Program of Catalonia 2014‐2020; Brain‐Connects: Brain Connectivity during Stroke Recovery and Rehabilitation (ID: 201725.33) funded by the Fundacio La Marato TV3; Corticity, FLAG–ERA JTC 2017, (ref. PCI2018‐092891) funded by the Spanish Ministry of Science, Innovation and Universities (MCIU), State Research Agency (AEI). The funders had no role in study design, decision to publish, or preparation of the manuscript