Sex differences in amygdalohippocampal oscillations and neuronal activation in a rodent anxiety model and in response to infralimbic deep brain stimulation.

Introduction: Depression and anxiety are highly comorbid mental disorders with marked sex differences. Both disorders show altered activity in the amygdala, hippocampus, and prefrontal cortex. Infralimbic deep brain stimulation (DBS-IL) has anxiolytic and antidepressant effects, but the underlying mechanisms remain unclear. We aimed to contribute to understanding sex differences in the neurobiology of these disorders. Methods: In male and female rats, we recorded neural oscillations along the dorsoventral axis of the hippocampus and the amygdala in response to an anxiogenic drug, FG-7142. Following this, we applied DBS-IL. Results: Surprisingly, in females, the anxiogenic drug failed to induce most of the changes observed in males. We found sex differences in slow, delta, theta, and beta oscillations, and the amygdalo-hippocampal communication in response to FG-7142, with modest changes in females. Females had a more prominent basal gamma, and the drug altered this band only in males. We also analyzed c-Fos expression in both sexes in stress-related structures in response to FG-7142, DBS-IL, and combined interventions. With the anxiogenic drug, females showed reduced expression in the nucleus incertus, amygdala, septohippocampal network, and neocortical levels. In both experiments, the DBS-IL reversed FG-7142-induced effects, with a more substantial effect in males than females. Discussion: Here, we show a reduced response in female rats which contrasts with the higher prevalence of anxiety in women but is consistent with other studies in rodents. Our results open compelling questions about sex differences in the neurobiology of anxiety and depression and their study in animal models.

The Oscillatory Profile Induced by the Anxiogenic Drug FG-7142 in the Amygdala-Hippocampal Network Is Reversed by Infralimbic Deep Brain Stimulation: Relevance for Mood Disorders.

Anxiety and depression exhibit high comorbidity and share the alteration of the amygdala-hippocampal-prefrontal network, playing different roles in the ventral and dorsal hippocampi. Deep brain stimulation of the infralimbic cortex in rodents or the human equivalent-the subgenual cingulate cortex-constitutes a fast antidepressant treatment. The aim of this work was: (1) to describe the oscillatory profile in a rodent model of anxiety, and (2) to deepen the therapeutic basis of infralimbic deep brain stimulation in mood disorders. First, the anxiogenic drug FG-7142 was administered to anaesthetized rats to characterize neural oscillations within the amygdala and the dorsoventral axis of the hippocampus. Next, deep brain stimulation was applied. FG-7142 administration drastically reduced the slow waves, increasing delta, low theta, and beta oscillations in the network. Moreover, FG-7142 altered communication in these bands in selective subnetworks. Deep brain stimulation of the infralimbic cortex reversed most of these FG-7142 effects. Cross-frequency coupling was also inversely modified by FG-7142 and by deep brain stimulation. Our study demonstrates that the hyperactivated amygdala-hippocampal network associated with the anxiogenic drug exhibits an oscillatory fingerprint. The study contributes to comprehending the neurobiological basis of anxiety and the effects of infralimbic deep brain stimulation.