Chayla Vazquez

Program: Neurosciences

Current advisor: Jordan G. McCall, PhD

Undergraduate university: Emory University, 2019

Enrollment year: 2019

Research summary
How Early Life Stress Affects Adult Behavior and Locus Coeruleus Activity

Early life stress (ELS), such as childhood maltreatment or trauma, has been correlated with anxiety and other negative affective disorders from adolescence to late adulthood. Despite ELS eliciting such burdening mental illnesses, there is a lack of basic research on the underlying neurobiology. The locus coeruleus norepinephrine (LC-NE) system plays an important role in stress and anxiety-like behavior. The LC-NE system is a small, tightly packed nucleus in the brainstem that projects globally throughout the forebrain and the spinal cord. LC neurons are spontaneously active and shift from low tonic firing (1-2 Hz) during an awake state to high tonic firing (3-8 Hz) which is often seen during a stressed, hyperarousal state. Identifying ELS-induced physiological changes in stress-related brain regions will help us understand how ELS affects mental health throughout life. Therefore, I am studying the role of the LC-NE system in ELS-induced changes in stress reactivity in adults. In the following aims, I am preparing aims 1 and 3 as a manuscript (see figures and legends attached in the email correspondence). Aim 2 may be used as additional data for the paper or kept for a later story.

Aim 1: To test the hypothesis that ELS increases baseline LC activity throughout life. This aim is set to clarify the role of the LC in ELS-induced changes in stress reactivity. To model ELS, from P10-P17, pups experienced maternal separation stress (MSS). After P17, I conducted ex vivo cell-attached electrophysiology recordings of the LC to measure changes in basal firing rates throughout the lifespan. As hypothesized, the data shows that LC baseline firing is increased after MSS in early development and adulthood. To determine whether this MSS model affects approach-avoidance conflict or coping behaviors in adulthood, I tested mice in an elevated plus maze test (EPM), open field test (OFT), and forced swim test (FST). In the EPM, MSS animals showed increased exploratory behavior and increased distance traveled compared to controls. In the OFT, MSS animals also showed increased distance traveled compared to non-MSS animals. In FST, there was an increase in passive coping behavior in the MSS group characterized by an increase in immobility and a decrease in velocity compared to controls.

Aim 2: To test the hypothesis that decreasing LC activity during FST IN MSS animals will protect against MSS-induced changes in stress reactivity. Here, I tested whether inhibiting the LC in MSS mice during FST will reverse MSS-induced effects on behavior. I injected Gi DREADDs in Dbh-Cre mice to partially inhibit LC baseline activity. DREADDs are altered muscarinic GPCRs that allow experimenters to modify cell activity through chemical activation. Dbh is the catalyst for the synthesis of NE and is found in the majority of LC cells, thus allowing us to get cell type-selective inhibition. Four weeks after injecting the Gi DREADD virus, MSS mice and controls were administered CNO (DREADD agonist) or saline 15 minutes before going through FST. Control mice were injected with a virus that did not contain DREADDs and had a mCherry tag. My data shows that decreasing LC activity causes MSS mice to trend downward in immobility time compared to MSS mice who have only received saline.

Aim 3: To determine if LC α-2a adrenergic receptors are downregulated after MSS. I sought to learn if LC α-2a adrenergic receptors are potential mechanisms for MSS-induced changes in LC baseline activity. During this past summer, I was able to measure α-2a adrenergic receptor mRNA expression between control and MSS mice. Here I found that MSS mice have a significant decrease in α-2a adrenergic receptor mRNA expression in the LC compared to controls. I additionally observed a significant decrease in dbh mRNA expression in the LC of MSS mice as well.

Graduate publications
Norris MR, Becker LJ, Bilbily J, Chang YH, Borges G, Dunn SS, Madasu MK, Vazquez CR, Cariello SA, Al-Hasani R, Creed MC, McCall JG. 2023 Spared nerve injury decreases motivation in long-access homecage-based operant tasks in mice. Pain, 165(6):1247-65. PMCID: PMC11095834