High trait anxiety and hyporeactivity to stress of the dorsomedial prefrontal cortex: A combined phMRI and Fos study in rats

The neural basis of trait anxiety is poorly understood. In genetically selected hyperanxious (high anxiety-related behavior; HAB) rats, diazepam induces a stronger anxiolytic response than in hypoanxious (low anxiety-related behavior; LAB) rats. A screen for neuronal response differences to diazepam between HAB and LAB rats using pharmacologic fMRI (phMRI) at 7 T revealed a blunted diazepam-induced neuronal deactivation in the dorsomedial prefrontal cortex (dmPFC) of HABs. This was not due to reduced benzodiazepine (BDZ) receptor densities in this region. Instead, dmPFC tissue oxygenation at baseline was found to be significantly lower in HABs. This suggests a tonic relative hypoactivity under the highly stressful phMRI conditions, offering an explanation for the reduced responsivity to the neural depressant effect of diazepam in the sense of a floor effect. Subsequently, Fos immunoreactivity (Fos-IR) showed that ethologically relevant stressors also cause less dmPFC activation in HABs. In the context of an anxiety-inhibiting role of the dmPFC, we propose that failure to sufficiently activate this region in stressful situations may contribute to high trait anxiety.