Date of Completion


Embargo Period



Preterm Infants, Stress, Epigenetics, Serotonin, Hypoxic-Ischemia, Rodents

Major Advisor

Angela Starkweather

Associate Advisor

Xiaomei Cong

Associate Advisor

Roslyn H. Fitch

Field of Study



Doctor of Philosophy

Open Access

Open Access


Children born prematurely (weeks, GW) risk numerous adverse medical events, with risks increasing as GW/size decreases. Preterm infants may experience ischemic and/or hemorrhagic events due to cardiovascular immaturity, leading to negative neural sequelae. These same infants are exposed to repeated painful/stressful procedures as part of life-saving care within the neonatal intensive care unit (NICU). Although necessary, chronic painful/stressful events have been associated with methylation of SLC6A4, a gene coding for serotonin transport proteins. Methylation of the gene is associated with reduced serotonergic tone, increased anxiety, depression, and incidence of autism. To gain a deeper understanding of the events associated with altered SLC6A4methylation due to chronic stress, a neonate rodent model with or without exposure to hypoxic-ischemic (HI) brain injury was used. On postnatal day 6 -- the equivalent of a moderately preterm human infant—Wistar rat pups were randomly assigned to the HI injury or sham group. Pups were treated with a chronic SSRI (Citalopram HBr) or saline, mimicking SLC6A4methylation. Subjects were assessed on behavioral tasks, and later neuroanatomic indices were obtained. Behavioral findings related to HI injuries were consistent with previously conducted studies in that HI injured subjects performed. SSRI subjects also performed worse on tasks, displaying greater anxiety although not statistically significant. HI + SSRI subjects learned faster than HI + NS, without reaching statistical significance. Histologically, there was no statistically significant treatment effect, however SSRI subjects had predominantly larger brain volumes than NS. This may be related to serotonin-induced neurogenesis.

HI subjects showed expected cognitive and motor deficits relative to controls. SSRI treated subjects without injury showed patterns of increased anxiety, consistent with theories of developmental SLC6A4methylation effects. HI + SSRI subjects showed a paradoxical trend to improved cognition relative to HI alone, which may reflect an unexpected SSRI neuroprotective effect in the presence of injury. The study results expand knowledge on the putative behavioral and cellular mechanisms of chronic stress exposure in premature infants suggesting that increased SLC6A4 methylation is associated with increased anxiety and larger brain volumes.

Casavant. dissertation 03-29.docx (7263 kB)
Dissertation text

Available for download on Saturday, March 16, 2024