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Translational Mouse Models of Psychiatric Disorders: Genetic, Pharmacological, and Neurodevelopmental Approaches

  • Author(s): Kwiatkowski, Molly Anne
  • Advisor(s): Young, Jared W
  • et al.
Abstract

Psychiatric disorder pathogenesis is driven by interactions between multiple genetic and environmental risk factors. Many genes have been associated with increased risk for psychiatric disorder development. Polymorphisms in the dopamine transporter (DAT) gene have been linked to bipolar disorder (BD), schizophrenia, and attention deficit hyperactivity disorder (ADHD), and may functionally reduce DAT expression. Assessing animals with manipulated DAT expression in cross-species translatable tasks will bridge the gap between rodent and human work and aide development of better therapeutic options for patients. An example of disease-relevant manipulation is the DAT knockdown (KD) mouse line, created to model the hyperdopaminergic state thought to drive mania symptoms in patients with BD. In the behavioral pattern monitor (BPM), which quantitatively measures locomotor activity and exploratory behaviors in both rodents and humans, patients with mania and DAT KD mice both exhibit hyperactivity and increased exploration. Using a meta-analytic approach, I showed that BPM behavioral outcomes of DAT KD mice were reproducible. Given the need for reproducible models in psychiatric research to test novel therapeutics, I assessed potential anti-mania drugs in the DAT KD/BPM model. Nicotine acetylcholine receptor agonism, via chronic nicotine administration, partially normalized hyperactivity and hyperexploration in DAT KD mice.

Given the neurodevelopmental origins of many psychiatric disorders, it is important to assess early gene x environment interactions that might drive abnormal behaviors in patients. Increased psychiatric disorder diagnoses are observed in people born in late winter/early spring. While many factors have been studied to explain this observation, altered light and activity levels during gestation/early life have been largely ignored. In adult male rodents, reduced active (dark) period (short active (SA) photoperiod) exposure induces depression-relevant behaviors and a stress response. Here, I confirmed SA photoperiod-induced stress response in adult female mice. I then examined the behavioral effects of stress-inducing gestational/early life SA photoperiod exposure in heterozygous DAT KD (DAT-HT) and wildtype (WT) littermates. SA-born WT mice exhibited behavioral changes in multiple cross-species translatable tasks, while DAT-HT mice were largely resilient. Future work will assess SA-induced changes in placental gene expression that contribute to behaviors observed following gestational SA exposure in WT mice.

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