Overactivating the Brain Causes Elevated Arousal and Threat Response

Human brain and waves, conceptual computer artwork. The front of the brain is at bottom.
By combining targeted intracerebral microinfusions with cardiovascular and behavioral monitoring in marmosets, we show that overactivation of sgACC/25 reduces vagal tone and heart rate variability, alters cortisol dynamics during stress and heightens reactivity to proximal and distal threat.

Overactivating area 25 (sgACC/25) of the brain reduces vagal tone and heart rate variability, alters cortisol dynamics during stress, and heightens reactivity to proximal and distal threat in marmosets, according to a study published in Nature Communications.

Elevated activity within area 25 of the subgenual anterior cingulate cortex (sgACC/25) has been associated with the negative emotions that characterize depression and anxiety. The researchers in this study determined the relationship is causal.

Using targeted intracerebral microinfusions of the excitatory amino acid transporter-2 (EAAT-2) inhibitor dihydrokainic acid (DHK) to reduce glutamate re-uptake from synapses, the researchers looked at the impact of area 25 overactivation on cortisol levels and cardiovascular response in a neutral condition. The researchers then looked at these areas in a threatening condition.

The researchers found sgACC/25 overactivation increases heart rate and reduces heart rate variability without affecting blood pressure or cortisol levels. Overactivation also “disrupts the extinction of conditioned proximal threat.” When discriminating between threat and safety cues, overactivation again increases arousal. Increases in anxiety were not alleviated by Ketamine.

“This work lays the fundamental groundwork for several exciting future avenues exploring prefrontal contributions to stress-related disorders,” the researchers concluded. “The manipulations described in this study were acute whereas depression and anxiety are chronic conditions, so the effects of sustained sgACC/25 over-activity should be ascertained by using, for example, viral-mediated technologies.”


Alexander L, Wood CM, Gaskin PLR, et al.  Over-activation of primate subgenual cingulate cortex enhances the cardiovascular, behavioral and neural responses to threat. Nat Commun. 2020 Oct 26;11(1):5386. doi: 10.1038/s41467-020-19167-0