Mapping neuropeptide signaling in the human brain
Poster No:
1766
Submission Type:
Abstract Submission
Authors:
Eric Ceballos1, Asa Farahani1, Zhen-Qi Liu2, Filip Milisav3, Justine Hansen1, Alain Dagher1, Bratislav Misic2
Institutions:
1McGill University, Montreal, QC, 2Montreal Neurological Institute, Montreal, Quebec, 3Montréal Neurological Institute, McGill University, Montréal, Quebec
First Author:
Co-Author(s):
Introduction:
Neuropeptides are fundamental signaling molecules that, unlike neurotransmitters, are released under sustained neural activity and remain diffused through extracellular space for longer periods, acting across multiple neighboring synaptic regions.
These molecules support diverse brain functions such as sleep, feeding, and social cognition. While traditionally thought to originate in structures like the hypothalamus, emerging evidence suggests neuropeptides and their receptors are more widespread throughout the brain and body.
Here, we map 38 neuropeptide receptors across 14 families to cortical and subcortical regions. We investigate their co-localization with brain structural and functional features, their contribution to connectivity, and their phylogenetic emergence in relation to regional functional specialization.
These molecules support diverse brain functions such as sleep, feeding, and social cognition. While traditionally thought to originate in structures like the hypothalamus, emerging evidence suggests neuropeptides and their receptors are more widespread throughout the brain and body.
Here, we map 38 neuropeptide receptors across 14 families to cortical and subcortical regions. We investigate their co-localization with brain structural and functional features, their contribution to connectivity, and their phylogenetic emergence in relation to regional functional specialization.
Methods:
A: Neuropeptide receptor (NPR) gene expression was obtained from the Allen Human Brain Atlas (n=6, 1 female, ages 24-57) [1]. Microarray probes were filtered based on intensity and correlation to RNA-seq data. Tissue samples were assigned to 455 brain regions in the Schaefer 400 [2], Melbourne Subcortex [3], and CIT168 [4] atlases. Expression values were normalized using robust sigmoid and min-max scaling. Individual donor data was averaged to yield a mean receptor expression matrix.
B: PET tracer density maps for 16 neurotransmitter receptors (NTR) were collected from neuromaps [5]. We used dominance analysis to calculate the co-localization of each NTR to a NPR, expressed as a percentage of total spatial variance they explained. Mean co-localization was then stratified into ionotropic and metabotropic NTR types.
C: We obtained term-specific brain activations using Neurosynth and focused on 125 cross-referenced terms in the Cognitive Atlas [6,7]. We used PLS to relate cognitive term maps and NPR gene expression profiles [8], and found one significant joint latent variable after contrasting our result with random matched genes and spatial nulls. To ensure generalizability, we randomly split observations into training and test sets 1000 times and evaluated how well our model performed on unseen data.
D: We measured the coupling between structural and functional connectivity by fitting multiple communication protocols as linear predictors for functional connectivity matrices from fMRI and MEG, separately [9]. First, communication protocols were computed from a binary template connectome estimated from dMRI. Global coupling was interpreted as the adjusted R² of the overall model. We then re-weighed the connectome edges using NP receptor and ligand availability, allowing us to compare coupling values to the unannotated fits.
E: We compare positive selection between ionotropic and metabotropic NTR, and NPR signaling using orthologous genes across 13 species representing human lineage. Amino acid and coding sequences were aligned and formatted for positive selection analysis as in [10]. We focused on substitution rates to identify evolutionary pressures across the three signaling types.
B: PET tracer density maps for 16 neurotransmitter receptors (NTR) were collected from neuromaps [5]. We used dominance analysis to calculate the co-localization of each NTR to a NPR, expressed as a percentage of total spatial variance they explained. Mean co-localization was then stratified into ionotropic and metabotropic NTR types.
C: We obtained term-specific brain activations using Neurosynth and focused on 125 cross-referenced terms in the Cognitive Atlas [6,7]. We used PLS to relate cognitive term maps and NPR gene expression profiles [8], and found one significant joint latent variable after contrasting our result with random matched genes and spatial nulls. To ensure generalizability, we randomly split observations into training and test sets 1000 times and evaluated how well our model performed on unseen data.
D: We measured the coupling between structural and functional connectivity by fitting multiple communication protocols as linear predictors for functional connectivity matrices from fMRI and MEG, separately [9]. First, communication protocols were computed from a binary template connectome estimated from dMRI. Global coupling was interpreted as the adjusted R² of the overall model. We then re-weighed the connectome edges using NP receptor and ligand availability, allowing us to compare coupling values to the unannotated fits.
E: We compare positive selection between ionotropic and metabotropic NTR, and NPR signaling using orthologous genes across 13 species representing human lineage. Amino acid and coding sequences were aligned and formatted for positive selection analysis as in [10]. We focused on substitution rates to identify evolutionary pressures across the three signaling types.
Results:
We show that
A: Neuropeptide receptors (NPR) spatially organize into predominantly cortical or subcortical, with some being highly expressed in both structures.
B: NPRs co-localize with metabotropic and, to a lesser extent, ionotropic neurotransmitter (NT) systems, suggesting co-transmission to slow signaling systems.
C: NPs are key for regulation, with cortical receptors linked to cognitive mechanisms like attention and subcortical receptors to basal processes like eating and sleep.
D: NP distribution shapes whole-brain connectivity, with some families coupling more to fMRI, some to MEG connectivity, and some to both.
E: NPRs underwent heightened positive selection around early mammalian evolution, with NPRs now found in subcortex selected before this transition and later-selected ones in cortex.
A: Neuropeptide receptors (NPR) spatially organize into predominantly cortical or subcortical, with some being highly expressed in both structures.
B: NPRs co-localize with metabotropic and, to a lesser extent, ionotropic neurotransmitter (NT) systems, suggesting co-transmission to slow signaling systems.
C: NPs are key for regulation, with cortical receptors linked to cognitive mechanisms like attention and subcortical receptors to basal processes like eating and sleep.
D: NP distribution shapes whole-brain connectivity, with some families coupling more to fMRI, some to MEG connectivity, and some to both.
E: NPRs underwent heightened positive selection around early mammalian evolution, with NPRs now found in subcortex selected before this transition and later-selected ones in cortex.
Conclusions:
In conclusion, NPs are crucial molecules that shape synaptic transmission, supporting cognition, bodily regulation and connectivity.
Genetics:
Transcriptomics 2
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural)
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Transmitter Receptors
Transmitter Systems 1
Neuroinformatics and Data Sharing:
Brain Atlases
Keywords:
CHEMOARCHITECTURE
MEG
MRI
Open Data
Positron Emission Tomography (PET)
RECEPTORS
1|2Indicates the priority used for review
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