Post-natal development of the rat connectome and the impacts of early life and adult stress
Poster No:
1575
Submission Type:
Abstract Submission
Authors:
Rachel Smith1,2, Lena Dorfschmidt3, Stephen Sawiak2, Ethan Dutcher4, Francis McMahon1, Armin Raznahan1, Jeffrey Dalley2, Petra Vértes2, Edward Bullmore2
Institutions:
1National Institute of Mental Health, Bethesda, MD, 2University of Cambridge, Cambridge, United Kingdom, 3The Children’s Hospital of Philadelphia, Philadelphia, PA, 4University of California, San Francisco, San Francisco, CA
First Author:
Rachel Smith
National Institute of Mental Health|University of Cambridge
Bethesda, MD|Cambridge, United Kingdom
National Institute of Mental Health|University of Cambridge
Bethesda, MD|Cambridge, United Kingdom
Co-Author(s):
Introduction:
Structural similarity networks are a useful tool for characterizing the coordinated development of brain regions in individuals. However, these networks have been primarily explored in humans, thus limiting mechanistic insights. Rats are a valuable model organism in neuroscience due to their complex behaviors and biological similarities to humans. We present the first characterization of individual structural similarity networks in rats, generated using a magnetic resonance (MR)-derived proxy for myelination, elucidating developmental patterns and environmental susceptibility.
Methods:
In the normative development cohort, 46 male rats underwent MRI scanning at post-natal day (PND) 20 (n = 41), ~PND 63 (n = 41), and ~PND 230 (n = 44; Fig 1A). These timepoints roughly correspond to infancy, late adolescence/early adulthood, and adulthood in humans. No experimental manipulation was performed during this time.
In the early life stress (ELS) cohort, male and female rats were allocated to either the repeated maternal separation (RMS; = 30) or control (n = 28) condition. From PND 5 through PND 19, RMS pups were separated from their dam for 6 hours a day. Beginning around PND 270, all animals (control and RMS groups) underwent a foot shock stress, for a total of 20 shocks per animal across 19 days. All animals were scanned around PND 63 and PND 290 (Fig 1B).
MRI data were registered to the Waxholm rat brain atlas (1), and magnetization transfer ratio (MTR) of each voxel was calculated. Individual gray matter myelination networks were calculated using the MIND toolkit (2) and voxel-based MTR. Linear mixed effects models were used to identify control-RMS differences in weighted degree, and modular edge connectivity in adulthood (PND 63) and following adult stress (PND 290).
In the early life stress (ELS) cohort, male and female rats were allocated to either the repeated maternal separation (RMS; = 30) or control (n = 28) condition. From PND 5 through PND 19, RMS pups were separated from their dam for 6 hours a day. Beginning around PND 270, all animals (control and RMS groups) underwent a foot shock stress, for a total of 20 shocks per animal across 19 days. All animals were scanned around PND 63 and PND 290 (Fig 1B).
MRI data were registered to the Waxholm rat brain atlas (1), and magnetization transfer ratio (MTR) of each voxel was calculated. Individual gray matter myelination networks were calculated using the MIND toolkit (2) and voxel-based MTR. Linear mixed effects models were used to identify control-RMS differences in weighted degree, and modular edge connectivity in adulthood (PND 63) and following adult stress (PND 290).
Results:
The adult rat structural connectome was defined as the median edge weight across PND 230 animals in the normative development cohort (Fig 1C). This network is highly modular in structure, composed of seven functionally relevant modules: (1) cognition and sensory integration, (2) limbic system and sensory integration, (3) auditory and somatosensory processing, (4) motor control and sensory relay, (5) olfactory and reward processing, (6) limbic and stress regulation, (7) higher cognitive function (Fig 1D & 1E). Network hubs, many of which are thalamic nuclei, fell in modules 4 and 6. Across regions of interest (ROIs), weighted degree tended to decrease in early development (PND 20 to 63), with more posterior ROIs demonstrating a steeper decline. The connectome was highly conserved between the normative cohort adults and ELS cohort control adults (r = 0.96).
Furthermore, the rat connectome was sensitive to environmental stress. In the ELS cohort, RMS animals largely demonstrated increases in ROI weighted degree compared to controls. Following adult stress, this relationship was reversed, with RMS animals showing decreased weighted degree compared to controls (Fig 2A). Thalamic nuclei were particularly impacted both pre- and post-adult stress, though the degree effect size maps were not correlated. Patterns of modular connectivity were also perturbed by stress, with adult RMS animals demonstrating increased intermodular connectivity and decreased intramodular connectivity compared to controls. This relationship was also reversed following adult stress, indicating divergent response to adult stress depending on exposure to ELS (Fig 2B). Connections between modules 4 and 7 were notably affected both pre- and post-adult stress, strongly implicating thalamocortical connectivity.
Furthermore, the rat connectome was sensitive to environmental stress. In the ELS cohort, RMS animals largely demonstrated increases in ROI weighted degree compared to controls. Following adult stress, this relationship was reversed, with RMS animals showing decreased weighted degree compared to controls (Fig 2A). Thalamic nuclei were particularly impacted both pre- and post-adult stress, though the degree effect size maps were not correlated. Patterns of modular connectivity were also perturbed by stress, with adult RMS animals demonstrating increased intermodular connectivity and decreased intramodular connectivity compared to controls. This relationship was also reversed following adult stress, indicating divergent response to adult stress depending on exposure to ELS (Fig 2B). Connections between modules 4 and 7 were notably affected both pre- and post-adult stress, strongly implicating thalamocortical connectivity.
Conclusions:
Our study unveils the normative development of the rat structural connectome, describing its reproducibility, functional significance, and environmental sensitivity, with a specific focus on the pivotal role of the thalamus. Importantly, this work establishes a foundation for furthering our understanding of human neurodevelopment, particularly in investigating the impact of environmental stressors.
Lifespan Development:
Early life, Adolescence, Aging 2
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural) 1
Image Registration and Computational Anatomy
Univariate Modeling
Novel Imaging Acquisition Methods:
Anatomical MRI
Keywords:
ANIMAL STUDIES
Development
Morphometrics
MRI
Myelin
Open-Source Code
STRUCTURAL MRI
Thalamus
Trauma
Other - Networks
1|2Indicates the priority used for review
Provide references using author date format
2. Sebenius I.S. (2023), 'Robust estimation of cortical similarity networks from brain MRI', Nature Neuroscience, vol. 26, no. 8, 1461–1471.