Dropviz: the mouse brain atlas, Saunders et al. 2018.

[ME/CFS Science Blog]

I had a go at matching genetic data on ME/CFS with the gene expression data from Dropviz.

This is the paper that discovered the eccentric medium spiny neuron (discussed here). It's a mouse brain atlas with RNA data from 0.69 million cells. The main publication is Saunders et al. 2018. but there's also a website with visualization and an option to download the data.

DropViz

Paolo Maccalini already tested this dataset in his paper using the meta-analysis of DecodeME and the Million Veterans Program (MVP) data. Using the level 2 classification of Dropviz he found 6 cell types that passed the bonferonni-correction as shown in Table A1.

https://s4me.info/threads/biologica...encing-of-me-cfs-2026-maccallini-et-al.50225/

This uses the FUMA website approach of grouping the data per dissection and controlling for the average gene expression of that dissection. That's fine but it also means that the results for a cell type are influenced by what else is in the dissection.

As a supplementary to this, I want to do analysis that ignores the dissection groupings and controls for the average of the entire dataset, similar to what we did with the Human Brain Atlas. Luckily the FUMA website provides a dataset that groups all dissections and has the data already in the right format. You can download these here:

Functional Mapping and Annotation of Genome-wide association studies

 

[ME/CFS Science Blog]

Level 1
Here's what I got for the level 1 classification which has 88 cell types. The results show again that only the neuron type reaches statistical significance.



It's also clear that the signal isn't confined to one brain region. The signals in the cerebellum and substantia nigra look a bit weaker though.

 

[ME/CFS Science Blog]

Level 2
Level 2 has 565 cell types. I've tried to deduce some info form the markers they have. For example: Gad1Gad2' = GABAergic, while Slc17a7 or Slc17a6 = Glutamatergic. There were significant hits for both.



Here are the ID's of the 13 cell types that reached bonferonni-significance:


Using the annotation file on the Dropviz website, it seems that the eccentric medium spiny neurons had cluster IDs of 13-1, 13-2, 13-3, 13-4, and 13-5. One of these (STR.Neuron_Gad1Gad2_Drd1-Otof-Sorcs1.13_2) was among the 13 significant cell types but the others didn't really stand out.

 

[ME/CFS Science Blog]

Here are the ID's of the 13 cell types that reached bonferonni-significance:

Here's some more info on these cell types by matching them to the annotation file:

ID	Brain Region	Common name	cell_cluster
GP.Neuron_Gad1Gad2-Th_Adora2a-Th.3_9	Globus Pallidus	Striatum, Th+ SPN	GABAergic
STR.Neuron_Gad1Gad2_Drd1-Cxcl14.10_5	Striatum	dSPN, lateral striatum	GABAergic
HC.Neuron_Slc17a7_C1ql2-Penk.4_2	Hippocampus	Dentate Principal cells	glutamatergic
HC.Neuron_Slc17a7_Pvrl3-Grm5.6_2	Hippocampus	CA3 Principal cells	glutamatergic
HC.Neuron_Slc17a7_C1ql2-Cck.4_1	Hippocampus	Dentate Principal cells	glutamatergic
STR.Neuron_Gad1Gad2_Drd1-Nefm.10_4	Striatum	dSPN	GABAergic
PC.Neuron_Slc17a7_Syt6-Sla.1_4	Posterior Cortex	Layer6a	glutamatergic
FC.Neuron_Gad1Gad2_Synpr-Pcdh11x.1_6	Frontal Cortex	Neuron.Gad1Gad2.Synpr-Pcdh11x	GABAergic
GP.Neuron_Gad1Gad2_Adora2a.3_3	Globus Pallidus	Striatum, Indirect spiny projection neuron iSPN	GABAergic
GP.Neuron_Gad1Gad2_Drd1-Nefm.3_1	Globus Pallidus	Striatum, dSPNs, neurofilament state+	GABAergic
STR.Neuron_Gad1Gad2_Drd1-Otof-Sorcs1.13_2	Striatum	eccentric SPN, dSPN-like markers	GABAergic
STR.Neuron_Gad1Gad2_Adora2a-Nefm.11_1	Striatum	iSPN	GABAergic
PC.Neuron_Slc17a7_Syt6-Nefm.1_8	Posterior Cortex	Layer 6a	glutamatergic

One thing that stands out is that the cells from the Globus Pallidus actually also point to the striatum. They are all from cluster 3 and the Saunders et al. 2018 paper notes about this:

Resolving Neuron Types within the Basal Ganglia
....
To define GPe neuron types, we screened markers of global clusters and subclusters for expression in the GPe (GP/NB dataset). GPe neurons were present in cluster 2 (n = 11,103 cells), one of three neuron clusters (Figure 6A). Cluster 1 contained cholinergic neurons (n = 437 cells), and cluster 3 contained neurons of the adjacent striatum and basolateral amygdala (n = 9,847 cells).

So much like the Human Brain Atlas I think there's a potential link here to medium spiny neurons (not just the eccentric ones) in the striatum.

 

[ME/CFS Science Blog]

So much like the Human Brain Atlas I think there's a potential link here to medium spiny neurons (not just the eccentric ones) in the striatum.

Using conditional analysis, three cell types remain as independent:

- the striatal inhibitory medium spiny neurons,
- the dentate principal cells in the hippocampus
- the layer 6a cells in the posterior cortex.

 

[ME/CFS Science Blog]

If I understand correctly layer 6A form a connection between the cortex and thalamus but perhaps also the claustrum and other inner structures.
Layer 6A Pyramidal Cell Subtypes Form Synaptic Microcircuits with Distinct Functional and Structural Properties - PMC

So one hypothesis for ME/CFS could be a disrupted network of cortico-striatal communication which reminded me of this hypothesis from Peter Behan and Abhijit Chaudhuri from the year 2000:

We have introduced and defined the concept of central fatigue for the latter disorders. We have further proposed, with supportive neuropathological data, that central fatigue may occur due to a failure in the integration of the limbic input and the motor functions within the basal ganglia affecting the striatal–thalamic–frontal cortical system.

Fatigue and basal ganglia - PubMed