Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice

Abstract

Rodents infected with the parasite Toxoplasma gondii show reduced aversion to predator odor and diminished neophobia, and infection in humans is associated with increased risk of neuropsychiatric disorders. Norepinephrine (NE) and dopamine (DA) modulate anxiety and predator odor responses, and T. gondii suppresses dopamine β-hydroxylase (Dbh) expression thereby reducing NE and increasing DA, which may contribute to the disruption of innate host behaviors. We examined the consequences of Dbh knockout (Dbh -/-) on responses to predator odor (bobcat urine) and compared them to Dbh-competent littermate controls. Over the first 10 min of predator odor exposure, controls exhibited robust defensive burying behavior, whereas Dbh -/- mice showed high levels of grooming. Defensive burying was potently suppressed in controls by drugs that reduce NE transmission, while excessive grooming in Dbh -/- mice was blocked by DA receptor antagonism. In response to a cotton square scented with a novel neutral odor (lavender), most control mice shredded the material, built a nest, and fell asleep within 90 min. Dbh -/- mice failed to shred the lavender-scented nestlet, but still fell asleep. In contrast, controls sustained high levels of arousal throughout the predator odor test and did not build nests, while Dbh -/- mice were asleep by the 90-min time point, often in shredded bobcat urine-soaked nesting material. Compared with controls exposed to predator odor, Dbh -/- mice demonstrated decreased c-fos induction in the anterior cingulate cortex (ACC), lateral septum (LS), periaqueductal gray (PAG), and bed nucleus of the stria terminalis, but increased c-fos in the LC and medial amygdala. These data indicate that relative ratios of central NE and DA signaling coordinate the type and valence of responses to predator odor, and suggest that Dbh -/- mice may represent a useful monogenetic model of neurobiological changes conferred by T. gondii infection.