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.
The presynaptic protein α-synuclein (αSyn) has been suggested to be involved in the pathogenesis of Parkinson’s disease (PD). In PD, the amygdala is prone to develop insoluble αSyn aggregates, and it has been suggested that circuit dysfunction involving the amygdala contributes to the psychiatric symptoms. Yet, how αSyn aggregates affect amygdala function is unknown. In this study, we examined αSyn in glutamatergic axon terminals and the impact of its aggregation on glutamatergic transmission in the basolateral amygdala (BLA). We found that αSyn is primarily present in the vesicular glutamate transporter 1-expressing (vGluT1+) terminals in mouse BLA, which is consistent with higher levels of αSyn expression in vGluT1+ glutamatergic neurons in the cerebral cortex relative to the vGluT2+ glutamatergic neurons in the thalamus. We found that αSyn aggregation selectively decreased the cortico-BLA, but not the thalamo-BLA, transmission; and that cortico-BLA synapses displayed enhanced short-term depression upon repetitive stimulation. In addition, using confocal microscopy, we found that vGluT1+ axon terminals exhibited decreased levels of soluble αSyn, which suggests that lower levels of soluble αSyn might underlie the enhanced short-term depression of cortico-BLA synapses. In agreement with this idea, we found that cortico-BLA synaptic depression was also enhanced in αSyn knockout mice. In conclusion, both basal and dynamic cortico-BLA transmission were disrupted by abnormal aggregation of αSyn and these changes might be relevant to the perturbed cortical control of the amygdala that has been suggested to play a role in psychiatric symptoms in PD.
Animals can evolve dramatic sensory functions in response to environmental constraints, but little is known about the neural mechanisms underlying these changes. The Mexican tetra, Astyanax mexicanus, is a leading model to study genetic, behavioral, and physiological evolution by comparing eyed surface populations and blind cave populations. We compared neurophysiological responses of posterior lateral line afferent neurons and motor neurons across A. mexicanus populations to reveal how shifts in sensory function may shape behavioral diversity. These studies indicate differences in intrinsic afferent signaling and gain control across populations. Elevated endogenous afferent activity identified a lower response threshold in the lateral line of blind cavefish relative to surface fish leading to increased evoked potentials during hair cell deflection in cavefish. We next measured the effect of inhibitory corollary discharges from hindbrain efferent neurons onto afferents during locomotion. We discovered that three independently derived cavefish populations have evolved persistent afferent activity during locomotion, suggesting for the first time that partial loss of function in the efferent system can be an evolutionary mechanism for neural adaptation of a vertebrate sensory system.