Whalley, Heather

McColl, Barry

Brunton, Paula

Holmes, Megan

Madden, Rebecca A.

Wellcome Trust

2023-03-13T13:10:56Z

2023-03-13T13:10:56Z

2023-03-13

During development, there are windows in which the brain is particularly susceptible to the impact of challenges – these include the pre-natal, early post-natal, and peri-pubertal periods. As such, adverse childhood experiences (ACEs), such as stress exposure, confer greatly increased risk of developing anxiety and depression in adult life. Previous work has found evidence for dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, alterations in brain structure, and elevated inflammation markers in adults exposed to adverse and traumatic experiences during childhood. Recently, chronic, low-level inflammation has also been associated with depression and anxiety risk, making stress and inflammation potentially cumulative risk factors for the development of psychiatric illness. A rat model of an early life stress paradigm combined with an adolescent immune challenge was designed to evaluate the contributions of these insults to brain development and future behaviour. The early life stress model chosen was the limited bedding and nesting material (LBN) paradigm: a naturalistic model of maternal deprivation previously validated to produce aberrations in maternal behaviour, and anxiety-like traits as well as HPA axis dysregulation in the offspring. Assessment of maternal behaviour during the LBN period revealed disruption to maternal behaviour, including evidence for fragmentation of maternal care, which has been strongly linked to poor outcomes in offspring. Offspring exposed to LBN or control conditions during postnatal days 2-10 were then given an immune challenge via administration of a low-dose of the endotoxin lipopolysaccharide (LPS) or vehicle control injections over five consecutive days during puberty onset. Weight data, and plasma interleukin-6 and corticosterone concentrations from blood samples taken on the first and last days of this inflammatory challenge revealed evidence of a mild inflammatory response. In order to study the influence of these early adverse experiences on long-term behavioural outcomes representative of depression and anxiety, rats were subjected to a battery of behavioural tests once they reached adulthood (>8 weeks). The results revealed a moderate impact of early life stress on anxiety-like behaviour, although the direction of this effect varied across two experimental cohorts. Gene expression was determined in brain regions-of-interest using quantitative polymerase chain reaction (qPCR). This revealed reduced expression of the mineralocorticoid receptor in the hippocampus, and of the glucocorticoid receptor in the amygdala of male LBN condition animals. In addition, both male and female LPS condition animals showed reduced glucocorticoid receptor expression in the hypothalamus, with an interacting effect of stress condition in the males. LPS treatment also significantly reduced Iba1 expression – a marker of microglial abundance – in hippocampus and hypothalamus samples from the adult rat brain. These results demonstrate a long-lasting impact of both elements of the ‘double-hit’ animal model on markers of stress responsivity and on the neuro-immune system. We do see some evidence for an interaction between the two challenges on the expression of the glucocorticoid receptor, but otherwise the two ‘hits’ chiefly appear to impact outcomes separately. In order to study the impact of the double-hit model on brain structure, post-mortem structural magnetic resonance imaging (MRI) scans were conducted in the male rats. Volumetric analysis using a semi-automated protocol for cortical and subcortical parcellation of MRI scans revealed stress-induced reductions in global metrics of brain volume, as well as changes in the volumes of the subiculum (a sub-region of the hippocampus) and the neocortex. A significant interaction between the two challenges on the volume of the superior colliculus – a region involved in threat perception – was observed. These MRI findings indicate effects of early life stress on gross brain development, as well as some regionally-specific effects on brain volumes which may underlie functional outcomes of both early life stress and an adolescent immune challenge. In order to provide a translational context for the outcomes of this novel animal model, analysis of a large cohort neuroimaging study examining the neurostructural sequelae of childhood trauma in two independent, UK-based adult populations was undertaken. There was strong evidence for associations between reports of childhood trauma and the incidence of depression and other psychiatric symptomology in adulthood. Volumes of the whole brain, grey matter, and white matter were found to be lower in adults reporting traumatic childhood events. This indicates a long-lasting effect of childhood adversity on brain structure. In addition, reduced volumes of hippocampal and thalamic structures were negatively associated with self-reported severity of childhood trauma. These data are consistent with the finding of lower global volume in the brains of rats exposed to early life stress. The data presented indicate exposure to early life stress induces alterations in stress-related behaviour, central gene expression, and brain structure in animals. Additionally, long-lasting changes in the resident immune cells of the brain after a mild systemic inflammatory event in adolescence are demonstrated. There is limited evidence for cross-talk between the two hits in this model, although there is evidence of a combined influence on the volume of the superior colliculus in post-mortem MRI data. Data derived from human neuroimaging cohorts provides a translational link to the animal models, with evidence of global brain volume reductions in both humans and experimental animals.

https://hdl.handle.net/1842/40397

http://dx.doi.org/10.7488/era/3165

en

The University of Edinburgh

Maternal stress induced by the limited bedding and nesting paradigm alters maternal behaviour Madden, R. & Brunton, P., Sep 2021, (Unpublished).

A novel rat double-hit model: post-mortem MRI and behavioural findings Madden, R., Smikle, R., Knyzeliene, A., Wimberley, C., Jansen, M., Lennen, R. J., Holmes, M. & Brunton, P., 7 Aug 2022, (Unpublished).

Structural brain correlates of childhood trauma with replication across two large, independent community-based samples Madden, R. A., Atkinson, K., Shen, X., Green, C., Hillary, R. F., Hawkins, E., Såge, E., Sandu, A-L., Waiter, G., McNeil, C., Harris, M., Campbell, A., Porteous, D., Macfarlane, J. A., Murray, A., Steele, D., Romaniuk, L., Lawrie, S. M., McIntosh, A. M. & Whalley, H. C., 26 Jan 2023, (E-pub ahead of print) In: European Psychiatry. p. 1-25 25 p.

Early Life Stress

HPA axis

Inflammation

Adverse Childhood Experiences

Childhood trauma

brain imaging

Depression

Examining the cumulative effects of stress and immune challenge in early life on the risk of depression and anxiety in adulthood

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy