The striatum receives dense dopaminergic projections making it a key region of the dopaminergic system. Its dysfunction has been implicated in various conditions including Parkinson's disease (PD) and substance use disorder. However, the investigation of dopamine-specific functioning in humans is problematic as current MRI approaches are unable to differentiate between dopaminergic and other projections. Here, we demonstrate that 'connectopic mapping' -a novel approach for characterizing fine-grained, overlapping modes of functional connectivity- can be used to map dopaminergic projections in striatum. We applied connectopic mapping to resting-state functional MRI data of the Human Connectome Project (population cohort; N=839) and selected the second-order striatal connectivity mode for further analyses. We first validated its specificity to dopaminergic projections by demonstrating a high spatial correlation (r=0.884) with dopamine transporter availability -a marker of dopaminergic projections- derived from DaT SPECT scans of 209 healthy controls. Next, we obtained the subject-specific second-order modes from 20 controls, and 39 PD patients scanned under placebo and under dopamine replacement therapy (L-DOPA), and show that our proposed dopaminergic marker tracks PD diagnosis, symptom severity and sensitivity to L-DOPA. Finally, across 30 daily alcohol users and 38 daily smokers, we establish strong associations with self-reported alcohol and nicotine use. Our findings provide evidence that the second-order mode of functional connectivity in striatum maps onto dopaminergic projections, tracks inter-individual differences in PD symptom severity and L-DOPA sensitivity, and exhibits strong associations with levels of nicotine and alcohol use, thereby offering a new biomarker for dopamine-related (dys)function in the human brain.
We made use of publicly available data from the Human Connectome Project (HCP) dataset, from publicly available data from the Parkinson Progression Marker Initiative (PPMI) dataset, and from a local PD dataset that was part of a clinical trial.See https://www.humanconnectome.org/study/hcp-young-adult/document/1200-subjects-data-release for access to the HCP data. The subject identifiers from the HCP dataset used in our first analysis can be found in Appendix 2 - Table 4. Please note that the subject identifiers from the subset of HCP subjects included in the nicotine-use and alcohol-use analyses cannot be provided, since the access to information about substance use is restricted. For more information about applying to get access to the HCP restricted data and for the HCP restricted data use terms see: https://www.humanconnectome.org/study/hcp-young-adult/document/wu-minn-hcp-consortium-restricted-data-use-terms.For access to the PPMI dataset, see https://www.ppmi-info.org/access-data-specimens/download-data. The subject identifiers from the PPMI dataset used in our analyses can be found in Appendix 2 - Tables 5 and 6.All derived and anonymized individual data from our local PD dataset are available at the Donders Repository: https://data.donders.ru.nl/.The code used for the connectopic mapping procedure in all three datasets is available at the following Github repository: https://github.com/koenhaak/congrads.In addition, for supplementary analyses, we further used PET scans available in the JuSpace Toolbox: https://github.com/ juryxy/JuSpace.
The WU-Minn human connectome project: an overview.Human Connectome Project, see Appendix 2 - Table 4.
The parkinson progression marker initiative (PPMI)Parkinson Progression Marker Initiative, see Appendix 2 - Tables 5 and 6.
JuSpace toolboxhttps://github.com/ juryxy/JuSpace.
- Christian F Beckmann
- Christian F Beckmann
- Andre F Marquand
- Koen V Haak
- Rick Helmich
- Christian F Beckmann
- Marianne Oldehinkel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: All participants from whom data was used in this manuscript, provided written informed consent (and consent to publish) according to the declaration of Helsinki. For the HCP dataset ethical approval was given by the Washington University Institutional Review Board (IRB), for the PPMI dataset ethical approval was obtained locally at each of the participating sites, and for our local PD dataset ethical approval was obtained from the local ethical committee (Commissie Mensgebonden Onderzoek MO Arnhem Nijmegen, CMO 2014/014).
- Shella Keilholz, Emory University and Georgia Institute of Technology, United States
© 2022, Oldehinkel 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.
Several discrete groups of feeding-regulated neurons in the nucleus of the solitary tract (nucleus tractus solitarius; NTS) suppress food intake, including avoidance-promoting neurons that express Cck (NTSCck cells) and distinct Lepr- and Calcr-expressing neurons (NTSLepr and NTSCalcr cells, respectively) that suppress food intake without promoting avoidance. To test potential synergies among these cell groups we manipulated multiple NTS cell populations simultaneously. We found that activating multiple sets of NTS neurons (e.g., NTSLepr plus NTSCalcr (NTSLC), or NTSLC plus NTSCck (NTSLCK)) suppressed feeding more robustly than activating single populations. While activating groups of cells that include NTSCck neurons promoted conditioned taste avoidance (CTA), NTSLC activation produced no CTA despite abrogating feeding. Thus, the ability to promote CTA formation represents a dominant effect but activating multiple non-aversive populations augments the suppression of food intake without provoking avoidance. Furthermore, silencing multiple NTS neuron groups augmented food intake and body weight to a greater extent than silencing single populations, consistent with the notion that each of these NTS neuron populations plays crucial and cumulative roles in the control of energy balance. We found that silencing NTSLCK neurons failed to blunt the weight-loss response to vertical sleeve gastrectomy (VSG) and that feeding activated many non-NTSLCK neurons, however, suggesting that as-yet undefined NTS cell types must make additional contributions to the restraint of feeding.
In the fruit fly Drosophila melanogaster, gustatory sensory neurons express taste receptors that are tuned to distinct groups of chemicals, thereby activating neural ensembles that elicit either feeding or avoidance behavior. Members of a family of ligand -gated receptor channels, the Gustatory receptors (Grs), play a central role in these behaviors. In general, closely related, evolutionarily conserved Gr proteins are co-expressed in the same type of taste neurons, tuned to chemically related compounds, and therefore triggering the same behavioral response. Here, we report that members of the Gr28 subfamily are expressed in largely non-overlapping sets of taste neurons in Drosophila larvae, detect chemicals of different valence, and trigger opposing feeding behaviors. We determined the intrinsic properties of Gr28 neurons by expressing the mammalian Vanilloid Receptor 1 (VR1), which is activated by capsaicin, a chemical to which wild-type Drosophila larvae do not respond. When VR1 is expressed in Gr28a neurons, larvae become attracted to capsaicin, consistent with reports showing that Gr28a itself encodes a receptor for nutritious RNA. In contrast, expression of VR1 in two pairs of Gr28b.c neurons triggers avoidance to capsaicin. Moreover, neuronal inactivation experiments show that the Gr28b.c neurons are necessary for avoidance of several bitter compounds. Lastly, behavioral experiments of Gr28 deficient larvae and live Ca2+ imaging studies of Gr28b.c neurons revealed that denatonium benzoate, a synthetic bitter compound that shares structural similarities with natural bitter chemicals, is a ligand for a receptor complex containing a Gr28b.c or Gr28b.a subunit. Thus, the Gr28 proteins, which have been evolutionarily conserved over 260 million years in insects, represent the first taste receptor subfamily in which specific members mediate behavior with opposite valence.