Organizing Fear: Exploring how Thyroid Hormone Shapes Early-Life Stress Through Excitatory/Inhibitory Transcriptomic Signatures in the Amygdala

Abstract

Early life stress (ELS) is associated with onset of mental health disorders later in life. It is also an extremely common exposure, with 60% of American adults reporting at least one and 16% reporting four or more experiences. In particular, ELS is associated with risk of generalized anxiety disorder (GAD), major depressive disorder (MDD), and posttraumatic stress disorder (PTSD). ELS is particularly damaging because the brain is still actively developing, and during this sensitive period, can disrupt brain development and thus lifelong function. The mechanisms are multifactorial, but studies in humans and animals have clearly established that this effect is maintained by distinct transcriptomes arising from ELS. These patterns of gene expression affect a variety of brain regions, particularly those associated with cognitive function and emotion. One of the most well-established are via neuroendocrine pathways during development. Indeed, TH has previously been shown to mediate ELS in areas whose disruption is implicated in ELS pathology. This study aims to develop on this basis in the amygdala, whose greater excitation is associated with ELS and whose role is to integrate stress and neuroendocrine function. I hypothesized that the expression of genes of interest (GOI) during ELS and hypothyroidism will similarly disrupt the E/I balance in the amygdala via increased glutamatergic signaling, increased glucocorticoid signaling, and decreased GABA signaling/inhibitory structural integrity mediated thyroid hormone, and that thyroid supplement LT4 treatment will therefore rescue for this effect by regulating genes associated with MDD and PTSD in a sex-specific manner. To answer this question, I utilized snRNA sequencing data from the amygdala of mice in four conditions: standard reared controls, ELS-reared, thyroid suppressed mice, and ELS-reared, LT4 treated from postnatal day 21 at weaning. In GABA and glutamatergic cells, I investigated how each condition affected expression of genes involved in neuron excitability, inhibition, and GABA/glutamate transmission. I further observed this within the distinct subnuclei of the amygdala and observed how these expression patterns vary by sex. I provide evidence that ELS is mediated by reduced thyroid hormone activity in glutamatergic and GABAergic neurons and that LT4 may reverse and rescue this effect by altering ion channels and glutamate transporter expression with some variance in treatment sensitivity by sex. By better isolating the effects of thyroid hormone in the amygdala during ELS, this research suggests potential mechanisms by which it does so. This contributes to a greater understanding of thyroid hormone’s mediation of ELS and, importantly, LT4’s potential efficacy for treating ELS-associated psychiatric illnesses.