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The Role of the Subgenual Anterior Cingulate Cortex in the Brain

By: Crystal Ling

Major depressive disorder is a debilitating disorder of low affect and altered mood regulation that affects approximately 17% of the population at some point in life, resulting in serious personal, social, and economic burdens. The prevalence of major depressive disorder is two times higher in women than in men. Female patients with the disorder tend to have higher symptom numbers, a more severe type of depression, and a greater risk of recurring episodes compared with male patients, but the underlying biological vulnerabilities have not been characterized.

Low neurotrophic support in limbic brain regions has been proposed as a unifying hypothesis for the reduced density or cell numbers in the frontal cortex and amygdala and the reduced hippocampal volume observed in individuals with major depression. Rodent studies have demonstrated that various antidepressant treatments increase brain-derived neurotrophic factor (BDNF) expression, and BDNF infusion into the hippocampus is sufficient to produce an antidepressant-like effect.

The subgenual anterior cingulate cortex, which is a part of the limbic brain regions, plays an important role in regulating emotion, and degeneration in this area correlates with depressed mood and anhedonia. Despite this understanding, it remains unknown how this part of the prefrontal cortex causally contributes to emotion, especially positive emotions.

Recently, a new study was published which suggested that the subgenual anterior cingulate cortex (sgACC) is a crucial region in depression and anxiety, and targeted treatment based on a patient’s symptoms could lead to better outcomes.

Over-activity in the subgenual anterior cingulate cortex underlies several key symptoms of mood and anxiety disorders, but an antidepressant only successfully treats some of the symptoms.

Depression is a debilitating disorder affecting hundreds of millions of people worldwide, but people experience it differently. Some mainly have symptoms of elevated negative emotion like guilt and anxiety; some have a loss of ability to experience pleasure (called anhedonia); and others a mix of the two.

Research at the University of Cambridge has found that increased activity in sgACC – a key part of the emotional brain- could underlie increased negative emotion, reduced pleasure, and a higher risk of heart disease in depressed and anxious people. More revealing still is the discovery that these symptoms differ in their sensitivity to treatment with an antidepressant, despite being caused by the same change in brain activity.

Using marmosets, a type of non-human primate, the team of researchers infused tiny concentrations of an excitatory drug into sgACC to over-activate it. Marmosets are used because their brains share important similarities with those of humans and it is possible to manipulate brain regions to understand causal effects.

The researchers found that sgACC over-activity increases heart rate elevates cortisol levels and exaggerates animals’ responsiveness to threat, mirroring the stress-related symptoms of depression and anxiety.

To explore threat and anxiety processing, the researchers trained marmosets to associate a tone with the presence of a rubber snake, an imminent threat that marmosets find innately stressful. Once marmosets learned this, the researchers ‘extinguished’ the association by presenting the tone without the snake. They wanted to measure how quickly the marmosets could dampen down and ‘regulate’ their fear response.

By over-activating sgACC, the marmosets stayed fearful for longer as measured by both their behavior and blood pressure, which showed the researchers that in stressful situations their emotion regulation was disrupted.

Similarly, when the marmosets were confronted with a more uncertain threat in the form of an unfamiliar human, they appeared more anxious following the over-activation of sgACC. According to the researchers, the marmosets were much warier of an unfamiliar person following over-activation of this key brain region – keeping their distance and displaying vigilance behaviors.

The researchers used brain imaging to explore other brain regions affected by sgACC over-activity during a threat. Over-activation of sgACC increased activity within the amygdala and hypothalamus, two key parts of the brain’s stress network. By contrast, it reduced activity in parts of the lateral prefrontal cortex – a region important in regulating emotional responses and shown to be underactive in depression.

The brain regions the researchers identified as being affected during threat processing differed from those they had previously shown as being affected during reward processing.

The researchers have previously shown that ketamine – which has rapidly acting antidepressant properties – can ameliorate anhedonia-like symptoms. But they found that it could not improve the elevated anxiety-like responses the marmosets displayed towards the human intruder following sgACC over-activation.

The researchers believe that they have definitive evidence for the differential sensitivity of different symptom clusters to treatment – on the one hand, anhedonia-like behavior was reversed by ketamine; on the other, anxiety-like behaviors were not. Their research shows that the sgACC may sit at the head and the heart of the matter when it comes to symptoms and treatment of depression and anxiety.

The subgenial anterior cingulate cortex is an area of the brain known to be involved in the control of several automatic processes, such as the regulation of blood pressure and heart rate. It is also thought to be important in higher-level functions, including reward anticipation, impulse control, decision-making, and emotion.

The findings in this study are interesting in their own right, but they also hold potential for future psychiatric interventions. Because certain mental disorders involve a loss or lack of empathy, knowing which regions of the brain are likely affected could help in the design of more targeted drugs further down the line. Thus, it is important that we continue to research and understand the role of the sgACC in our complexly interconnected brain.


1. Adam Tripp, Hyunjung Oh, Jean-Philippe Guilloux. Brain-Derived Neurotrophic Factor Signaling and Subgenual Anterior Cingulate Cortex Dysfunction in Major Depressive Disorder. American Journal of Psychiatry. 2013.

2. Laith Alexander, Christian M. Wood, Philip L.R. Gaskin, Stephen J. Sawiak. Over-activation of primate subgenual cingulate cortex enhances the cardiovascular, behavioral, and neural responses to threat. Nature Communications. 2020.

3. Rolls ET. The cingulate cortex and limbic systems for emotion, action, and memory. Brain Structure and Function. 2019.


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