Prenatal Exposure to Ketamine Leads to Anxiety-Like Behaviors and Dysfunction in Bed Nucleus of Stria Terminalis

Abstract

Background: Both the clinical and preclinical studies have suggested embryonic or infant exposure to ketamine, a general anesthetic, pose a great threat to the developing brain. However, it remains unclear how ketamine may contribute to the brain dysfunctions.

Methods: A mouse model of prenatal exposure to ketamine was generated by i.m. injection and continuous i.p. infusion of pregnant mice. Open field test and elevated plus maze test were used to analyze the behavioral alterations induced by ketamine. Immunostaining by c-Fos was used to map the neuron activity. Chemogenetic modulation of the neurons was used to rescue the abnormal neuron activity and behaviors.

Results: Here we show that mice prenatally exposed to ketamine displayed anxiety-like behaviors during adulthood, but not during puberty. C-Fos immunostaining identified abnormal neuronal activity in Bed Nucleus of the Stria Terminalis, the silencing of which by chemogenetics restores the anxiety-like behaviors.

Conclusions: Taken together, these results demonstrate a circuitry mechanism of ketamine-induced anxiety-like behaviors.

Keywords: Bed Nucleus of the Stria Terminalis (BNST); anxiety; chemogenetics; ketamine.