Abstract

Early life stress or childhood trauma is associated with psychiatric disorders later in life. However, it is unclear what potential neurobiological changes lead those who become exposed to early life stress to experience these behavioral changes in adulthood. The locus coeruleus norepinephrine (LC-NE) system is an important neuromodulatory system for stress-induced behaviors. We sought to determine if the LC-NE system is influenced by early life stress and plays a role in early life stress-induced changes in adult behavior in mice. Using maternal separation stress (MSS) as our early life stress paradigm, we analyzed LC spontaneous baseline activity across the lifespan, expression of genes related to LC function in adulthood, and adult behaviors related to stress. We saw an increase in LC baseline activity during early development and adulthood. Additionally, the genes for the alpha2a adrenergic receptor and dopamine beta-hydroxylase mRNA levels were decreased in the LC. Next, we tested whether stress-related behaviors during adulthood and observed that male MSS mice increased in exploratory behavior and locomotion in both the elevated-plus maze and the open field test. During the forced swim test, an assessment that measures coping strategies, MSS mice significantly increased immobility time compared to the no MSS group. Due to the increase in immobility in MSS mice, we determined that MSS causes an increase in the use of passive coping strategies versus active coping strategies. We attempted to reverse the effect of MSS on immobility by inhibiting the LC during the forced swim test but ultimately saw no change. We suspect that the lack of LC control over the coping strategy within the forced swim test after MSS is due to the MSS-induced dysregulation of the LC. Consequently, we sought to test whether no MSS and MSS mice respond to the forced swim following LC excitation. We saw no significant differences in immobility in either groups, however, there was a trending decrease in immobility in the no MSS group after LC activation. This trending result in no MSS mice after LC stimulation is the inverse of no MSS mice after LC inhibition, showing that driving LC activity up or down can drive opposite behavioral effects during the forced swim test. In summary, the increase in exploratory behavior and locomotion in MSS mice may be assumed to be a resilient type of behavior or even an impulsive type of behavior, though these concepts merit further testing. Additionally, it is clear that MSS mice prefer passive coping strategies in the forced swim test. The effect of early life stress on locus coeruleus function and adult behavior should be further analyzed to determine potential future therapeutic solutions for those who have experienced trauma in early life.

Committee Chair

Jordan McCall

Committee Members

Deanna Barch; Leah Roesch; Ream Al-Hasani; Steven Mennerick; Susan Maloney

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

8-6-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0002-0077-9224

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Available for download on Thursday, August 05, 2027

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Biology Commons

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