Adapting non-invasive human recordings along multiple task-axes shows unfolding of spontaneous and over-trained choice
- University of Oxford, United Kingdom
Abstract
Choices rely on a transformation of sensory inputs into motor responses. Using invasive single neuron recordings, the evolution of a choice process has been tracked by projecting population neural responses into state spaces. Here we develop an approach that allows us to recover similar trajectories on a millisecond timescale in non-invasive human recordings. We selectively suppress activity related to three task-axes, relevant and irrelevant sensory inputs and response direction in magnetoencephalography data acquired during context-dependent choices. Recordings from premotor cortex show a progression from processing sensory input to processing the response. In contrast to previous macaque recordings, information related to choice-irrelevant features is represented more weakly than choice-relevant sensory information. To test whether this mechanistic difference between species is caused by extensive overtraining common in non-human primate studies, we trained humans on >20,000 trials of the task. Choice-irrelevant features were still weaker than relevant features in premotor cortex after overtraining.
Data availability
Source data files for figures 2, 3, 4, and are provided.All datasets and codes for reproducing the results will be uploaded to Open Science Framework (OSF) after acceptance.
Article and author information
Author details
Laurence Tudor Hunt
Miriam C Klein-Flügge
Funding
Japan Society for the Promotion of Science (23118001,23118002)
- Yu Takagi
Uehara Memorial Foundation
- Yu Takagi
Sir Henry Wellcome Fellowship (103184/Z/13/Z)
- Miriam C Klein-Flügge
Wellcome Senior Research Fellowship (104765/Z/14/Z)
- Timothy E Behrens
Wellcome Principal Research Fellowship (219525/Z/19/Z)
- Timothy E Behrens
JS McDonnell Foundation award (JSMF220020372)
- Timothy E Behrens
Wellcome Collaborator award (214314/Z/18/Z)
- Timothy E Behrens
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The study was approved by the University College London (UCL) Research Ethics Committee (reference 1825/005) and all participants gave written informed consent.
Copyright
© 2021, Takagi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Adapting non-invasive human recordings along multiple task-axes shows unfolding of spontaneous and over-trained choice
eLife 10:e60988.
https://doi.org/10.7554/eLife.60988
Further reading
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- Medicine
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Background:
Alcohol use disorder (AUD) is a global health problem with limited therapeutic options. The biochemical mechanisms that lead to this disorder are not yet fully understood, and in this respect, metabolomics represents a promising approach to decipher metabolic events related to AUD. The plasma metabolome contains a plethora of bioactive molecules that reflects the functional changes in host metabolism but also the impact of the gut microbiome and nutritional habits.
Methods:
In this study, we investigated the impact of severe AUD (sAUD), and of a 3-week period of alcohol abstinence, on the blood metabolome (non-targeted LC-MS metabolomics analysis) in 96 sAUD patients hospitalized for alcohol withdrawal.
Results:
We found that the plasma levels of different lipids ((lyso)phosphatidylcholines, long-chain fatty acids), short-chain fatty acids (i.e. 3-hydroxyvaleric acid) and bile acids were altered in sAUD patients. In addition, several microbial metabolites, including indole-3-propionic acid, p-cresol sulfate, hippuric acid, pyrocatechol sulfate, and metabolites belonging to xanthine class (paraxanthine, theobromine and theophylline) were sensitive to alcohol exposure and alcohol withdrawal. 3-Hydroxyvaleric acid, caffeine metabolites (theobromine, paraxanthine, and theophylline) and microbial metabolites (hippuric acid and pyrocatechol sulfate) were correlated with anxiety, depression and alcohol craving. Metabolomics analysis in postmortem samples of frontal cortex and cerebrospinal fluid of those consuming a high level of alcohol revealed that those metabolites can be found also in brain tissue.
Conclusions:
Our data allow the identification of neuroactive metabolites, from interactions between food components and microbiota, which may represent new targets arising in the management of neuropsychiatric diseases such as sAUD.
Funding:
Gut2Behave project was initiated from ERA-NET NEURON network (Joint Transnational Call 2019) and was financed by Academy of Finland, French National Research Agency (ANR-19-NEUR-0003-03) and the Fonds de la Recherche Scientifique (FRS-FNRS; PINT-MULTI R.8013.19, Belgium). Metabolomics analysis of the TSDS samples was supported by grant from the Finnish Foundation for Alcohol Studies.
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- Neuroscience
Monitoring neuronal activity at single-cell resolution in freely moving Drosophila engaged in social behaviors is challenging because of their small size and lack of transparency. Extant methods, such as Flyception, are highly invasive. Whole-brain calcium imaging in head-fixed, walking flies is feasible but the animals cannot perform the consummatory phases of social behaviors like aggression or mating under these conditions. This has left open the fundamental question of whether neurons identified as functionally important for such behaviors using loss- or gain-of-function screens are actually active during the natural performance of such behaviors, and if so during which phase(s). Here, we perform brain-wide mapping of active cells expressing the Immediate Early Gene hr38 using a high-sensitivity/low background fluorescence in situ hybridization (FISH) amplification method called HCR-3.0. Using double-labeling for hr38 mRNA and for GFP, we describe the activity of several classes of aggression-promoting neurons during courtship and aggression, including P1a cells, an intensively studied population of male-specific interneurons. Using HI-FISH in combination with optogenetic activation of aggression-promoting neurons (opto-HI-FISH), we identify candidate downstream functional targets of these cells in a brain-wide, unbiased manner. Finally, we compare the activity of P1a neurons during sequential performance of courtship and aggression, using intronic vs. exonic hr38 probes to differentiate newly synthesized nuclear transcripts from cytoplasmic transcripts synthesized at an earlier time. These data provide evidence suggesting that different subsets of P1a neurons may be active during courtship vs. aggression. HI-FISH and associated methods may help to fill an important lacuna in the armamentarium of tools for neural circuit analysis in Drosophila.
