Early life stress induces sex-specific changes in behavior and parallel locus coeruleus neuron excitability

Abstract

AbstractStress-related psychiatric disorders are more common in female clinical populations after adolescence, but the exact mechanism behind this difference is unknown. The locus coeruleus (LC) is a brain area that contains adrenergic norepinephrine (NE)-releasing neurons previously found to display basal sex differences in excitability and stress neuropeptide responses in animal models. Corticotropin releasing factor (CRF), the neuropeptide responsible for stress signaling, has been shown to directly alter LC neuron firing, thereby providing one mechanism by which stress may modulate noradrenergic function in either acute or chronic stress. Such activation of CRF receptor 1 (CRF1) by CRF in the LC is fundamentally different in male and female mice due to increased CRF receptor expression, G-protein coupling, and CRF-stimulated NE release in female compared to males. Despite evidence for an interaction between sex, LC adrenergic neuron activity, and stress, how early life stress affects LC neuronal behavior in parallel to anxiety, activity, and cognition (i.e. components of PTSD and ADHD) in a sexual dimorphic manner has not been explored. The effects of an early life variable stress (ELVS) paradigm inducing stress at both early life and adolescence were assessed in C57 male and female mice using behavioral and electrophysiological measures for hyperactivity, anxiety, short-term memory, repetitive behaviors and LC neuron excitability. Hyperactivity in open field and deficits in Y-maze performance were observed in ELVS female mice when compared to controls. ELVS females, but not males, showed a reduction in LC excitability when compared to controls of the same sex, which was due to hyperpolarization and an increase in the action potential delay time. LC neurons form naïve mice indicated that CRF1receptor-mediated effects on LC neuron excitability were largely due to Gq-mediated (Ca2+-dependent) signaling in male mice and non Ca2+-dependent (likely Gs) in female mice. Through this animal model of early life stress inducing impaired memory and hyperactivity in a sex-specific manner, further investigation to ameliorate these symptoms may benefit more targeted treatment approaches for stress-related disorders based on sex and developmental stage of trauma exposure(s).