Functional connectivity in prenatally stressed rats with and without maternal treatment with ladostigil, a brain‐selective monoamine oxidase inhibitor

Abstract

Stress during pregnancy in humans is known to be a risk factor for neuropsychiatric disorders in the offspring. Prenatal stress in rats caused depressive-like behavior that was restored to that of controls by maternal treatment with ladostigil (8.5 mg/kg per day), a brain-selective monoamine oxidase (MAO) inhibitor that prevented increased anxiety-like behavior in stressed mothers. Ladostigil inhibited maternal striatal MAO-A and -B by 45-50% at the time the pups were weaned. Using resting state-functional connectivity magnetic resonance imaging on rat male offspring of control mothers, and mothers stressed during gestation with and without ladostigil treatment, we identified neuronal connections that differed between these groups. The percentage of significant connections within a predefined predominantly limbic network in control rats was 23.3 within the right and 22.0 within the left hemisphere. Prenatal stress disturbed hemispheric symmetry, resulting in 30.2 and 21.6%, significant connections in the right and left hemispheres, respectively, but this was fully restored in the maternal ladostigil group to 24.6% in both hemispheres. All connections that were modified in prenatally stressed rats and restored by maternal drug treatment were associated with the dopaminergic system. Specifically, we observed that restoration of the connections of the right nucleus accumbens shell with frontal areas, the cingulate, septum and motor and sensory cortices, and those of the right globus pallidus with the infra-limbic and the dentate gyrus, were most important for prevention of depressive-like behavior.

Alterations in the expression of a neurodevelopmental gene exert long-lasting effects on cognitive-emotional phenotypes and functional brain networks: translational evidence from the stress-resilient Ahi1 knockout mouse

“…However, a recent report suggested that, even though local functional properties could become reorganized under isoflurane anesthesia in rats, global topological features were preserved. 105 Moreover, another recent report indicating that the use of isoflurane does not mask network information 43 bolsters the validity of our methodology.…”

“…As previously described, 31 and in line with a recent report using a similar methodology in rats, 43 MRI measurements were performed with a 4.7-T Bruker BioSpec scanner (Bruker Biospin, Ettlington, Germany) using a Dotty quadrature mouse head coil (see Supplementary Methods for further details).…”

“…As previously described, 31, 43 functional data were first processed in the SPM8 software (http://www.fil.ion.ucl.ac.uk/spm/software/spm8) using standard spatial preprocessing steps. Images were slice-time corrected and realigned.…”

“…Based on our previous experience 43 and current hypothesis, regions of interest (ROIs) scattered throughout the brain were preselected. Representative ROIs within the cortices, basal ganglia, limbic system and midbrain were included.…”

Resting State fMRI in Rodents

“…The first two reports of rs-fMRI in the rat were presented at the 2006 ISMRM meeting (Lu et al, 2006;Williams et al, 2006). Subsequent works on the rat have done much to elucidate the neurophysiological origin of the spontaneous BOLD fluctuations (Lu et al, 2007;Pan et al, 2011Pan et al, , 2013Thompson et al, 2013) and is beginning to examine the correlates of disrupted connectivity observed in human studies of brain disorders (Goelman, Ilinca, Zohar, & Weinstock, 2014;Hsu et al, 2016;Williams et al, 2014).…”