Abstract
Stress-related disorders such as depression and anxiety are characterized by enhanced negative emotion and physiological dysfunction. Whilst elevated activity within area 25 of the subgenual anterior cingulate cortex (sgACC/25) has been implicated in these illnesses, it is unknown whether this over-activity is causal. By combining targeted intracerebral microinfusions with cardiovascular and behavioral monitoring in marmosets, we show that over-activation of sgACC/25 reduces vagal tone and heart rate variability, alters cortisol dynamics during stress and heightens reactivity to proximal and distal threat. 18F-FDG PET imaging shows these changes are accompanied by altered activity within a network of brain regions including the amygdala, hypothalamus and dorsolateral prefrontal cortex. Ketamine, shown to have rapid antidepressant effects, fails to reverse elevated arousal to distal threat contrary to the beneficial effects we have previously demonstrated on over-activation induced reward blunting, illustrating the symptom-specificity of its actions.
Highlights
Stress-related disorders such as depression and anxiety are characterized by enhanced negative emotion and physiological dysfunction
The novel question we addressed here was whether this effect could be ameliorated by ketamine, in the same way we had previously demonstrated that ketamine could ameliorate the blunting of appetitive anticipatory arousal
Over-activation of sgACC/25 with dihydrokainic acid (DHK) had no effect on blood pressure but significantly increased heart rate (Fig. 2b, c), reduced heart rate variability (HRV) (Fig. 2d) and altered the sympathetic-parasympathetic balance as measured by an increase in the ratio between the cardiac sympathetic index (CSI) and cardiac vagal index (CVI, Fig. 2e)
Summary
Stress-related disorders such as depression and anxiety are characterized by enhanced negative emotion and physiological dysfunction. Countless correlative human neuroimaging studies have related dysfunctional activity within the ventromedial prefrontal cortex (vmPFC) to impairments in cardiovascular, endocrine and behavioral indices of negative emotion, but there are two important outstanding issues. It is unknown whether these activity changes are causal, and second, if causal, whether this region acts to promote or inhibit stressrelated symptoms. The question remains as to whether the over-activity in sgACC/25 reported in neuroimaging studies of people with depression and anxiety[5,18,19,20] is causally related to their cardiovascular and emotional dysfunction, and if so, how?. The wide and persistent translational gap between advances in preclinical research and a relative failure to develop more effective treatments for psychiatric disorders is due, in part, to a lack of understanding of the complex control of negative affect exerted by the highly evolved primate vmPFC
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