The genetics of neuroticism: Insights from the Maudsley rat model and human studies

Abstract

We examine some of the genetic features of neuroticism (N) taking as an animal model the Maudsley Reactive (MR) and Maudsley Nonreactive (MNR) rat strains which were selectively bred, respectively, for high and low open-field defecation (OFD) starting in the late 1950s. To draw analogies with human genetic studies, we explore the genetic correlation of N with irritable bowel syndrome (IBS). We review progress with the rat model and developments in the field of human complex trait genetics, including genetic association studies that relate to current understanding of the genetics of N. The widespread differences in the tone of the peripheral sympathetic nervous system that have been found between the Maudsley strains, particularly those observed in the colon, may underly the differences in OFD (MNR, higher sympathetic tone and zero defecation). In humans, a large genome-wide association study (GWAS) reported six genes contributing to IBS, four of which were implicated in mood and anxiety disorders or were expressed in the brain, with three of the four also expressed in the nerve fibers and ganglia of the gut. Heritability of N is estimated at around 50% in twin and family studies, and GWASs identified hundreds of loci, enabling estimation of genome-wide correlations (rg) with other traits. Significantly, the estimate for rg between risk of IBS, anxiety, N, and depression was >0.5 and suggested genetic pleiotropy without evidence for causal mechanisms. Findings on the adrenergic pharmacology of the colon, coupled with new understanding of the role of the locus ceruleus in modifying afferent information from this organ, generate hypotheses that challenge traditional cause/effect notions about the relationship of the central nervous system to peripheral events in response to stress, suggest specific targets for gene action in the Maudsley model and emphasize the value of reciprocal evaluation of genetic architecture underlying N in rodents and humans.

Non-human contributions to personality neuroscience: From fish through primates – a concluding editorial overview

“…Blizard et al ( 2023 ) aim at investigating the genetic background of Neuroticism using the Maudsley rat strains as a model. The Maudsley reactive (MR) and Maudsley nonreactive (MNR) rat strains were bidirectionally selectively bred (Broadhurst, 1960 ), respectively, for high and low open-field defecation (OFD) in the 1950s.…”

“…Based on Calvin Hall’s work (Hall, 1934 , 1951 ), OFD would be a measure of anxiety-like behavior and reactivity to threat, with face validity to humans in combat. Behind their behavioral selection, important genetic restriction occurred in relation to the “noradrenergic system where MNRs exhibit greater sustained cerulean response to chronic stress, and in the peripheral noradrenergic system where MNRs possess increased sympathetic tone in many organs” (Blizard et al, 2023 , p. 3). This broad change in tone provides a basis for an attempt to show how alterations in the crosstalk between the central and the peripheral neuro-systems (CNS and PNS, respectively), using the irritable bowel syndrome (IBS) model that can be associated to neuroticism (once understood as “emotionality”), compares between the Maudsley rats and humans.…”

“…After describing evidence of disrupted norepinephrine (NE) pathways in the CNS (in particular the locus coeruleus) and the PNS (and its intestinal enervation) especially in response to stress in the MNRs, the authors establish the relationship between these alterations and the IBS syndrome in humans in regard to previously observed changes in NE receptors: “We hypothesize that alterations in sympathetic tone, such as we have suggested to exist in the Maudsley model, could interact with these receptors to produce these functional disorders. Aside from presynaptic influences, the possibility exists that genetic selection for OFD may have also assorted different densities of colonic α 1 receptors or different colonic receptor types in the two strains.” Blizard et al ( 2023 , p. 4) …”

“…Fernández-Teruel et al ( 2023 ) extend this perspective and frame the RLA rats within the domain of “Internalizing” spectra of HiTOP (Michelini et al, 2021 ). Similarly, based on the genetic background and neurophysiological alterations of the Maudsley Reactive rats, in particular the disrupted norepinephrine (NE) pathways in the CNS and the PNS, Blizard et al ( 2023 ) trace a parallel between this model and Neuroticism in humans, rather than a cause-consequence relationship, the concomitant heritability of anxiety traces, alterations in bowel functioning due to stress, and neuroticism happen in both humans and rat lines, making the comparison between them, plausible.…”

“…Evidence described previously with CLF, RHA, MNR, and SHR rats show alterations in the reward machinery and dopaminergic pathways, which suggests them as prospective models of attention deficits and hyperactive disorders given that similar deficits are seen in humans (Bonvicini et al, 2016 ; Del Campo et al, 2011 ). In the view of Blizard et al ( 2023 ), hyperactivity, relative asociality, and impairments of inhibitory control (impulsivity) and attentional/cognitive processes place these animals as proxy of “disinhibited externalizing” spectra of human personality.…”