Brain Works

In 2020, an estimated 21 million adults in the U.S. experienced at least one major depressive episode in the past 12 months, and 500,000 people in the U.S. suffer from postpartum depression (PPD) every year. While depression manifests differently in people because each person’s brain is unique, one leading hypothesis explains that depression may be the effect of a dysregulated neural system affected by stress.


Click and explore the ways various regions of the brain can be affected by MDD and PPD

Cortex (think)

The prefrontal cortex (PFC) is the conductor, orchestrating brain processing for important functions like attention, impulse control and emotional regulation.


In MDD, the PFC may shrink or become less active, impacting a person's ability to regulate their emotions and control other important cognitive functions, potentially contributing to depression.


In PPD, some areas of the PFC may have lower levels of activity and other areas may have higher activity, which can disrupt communication with other areas of the brain, like the amygdala.


The thalamus delivers the news. It has many functions in the brain but is primarily responsible for relaying information from our senses and communicating with the prefrontal cortex to influence high-level thinking, decision-making and attention.


In MDD, the thalamus may be overly active. As a central hub of sensory processing - connecting the amygdala to the prefrontal cortex - changes in activity could be impairing decision-making and emotional regulation, making even the smallest of tasks more difficult.


This is Memory Central. The hippocampus helps control how people remember facts and locations, as well as the process of turning short-term memories into long-term memories. It communicates with many regions of the brain and helps connect these memories to emotions and sensations.


In MDD, parts of the hippocampus may shrink. This could potentially contribute to decreased brain activity in the hippocampus, which could lead to undesired emotions and an impaired ability to process them, for example feeling frustrated over something you'd otherwise brush off.


The amygdala is the “heart” of the brain – the place we associate with emotion. It processes emotions and plays an important role in the emotional aspect of memories. The amygdala also helps control emotions by assessing emotional significance in different situations, ultimately communicating with other areas of the brain to determine whether or not stimuli are a threat.


In MDD, the amygdala may be overly active or oversized (particularly in people with both MDD and anxiety). Over-stimulation of the amygdala is associated with increased fear and anxiety, which may have a negative impact on mood.


In PDD, a mother may experience more depressive symptoms, such as sadness and lethargy, due to lower amygdala activity. A mis-regulated amygdala that lacks balance with the prefrontal cortex may lead to depressive symptoms.


The hypothalamus is the main connection to other bodily systems - including regulation of body temperature, appetite and emotions. The hypothalamus is at the center of PPD because it plays a crucial role in how hormones are made and used in the brain.


In PPD, mothers may have a smaller hypothalamus. As the main link between hormones and the brain, the hypothalamus requires a delicate balance of network activity to properly regulate hormone levels that allow a mother to respond to and bond with her baby after birth. Changes to the structure of the hypothalamus may contribute to depressive symptoms.

Parietal Lobe

The parietal lobe makes sense of the senses – like touch, smell, sight, and hearing. It is a large area of the brain with many functions related to sensory processing, including attention and perception.


In PPD, regions of the parietal lobe may be smaller in volume or have stronger connectivity with other areas of the brain. Mothers with PPD may experience a negative impact on emotional wellbeing as a result of lower sensory processing abilities.

GABA Circuitry

Evaluating modulation of the GABA receptor system for the potential treatment of MDD and PPD:

GABA circuitry

The healthy human brain has networks that connect regions of the brain to govern behavior. For these networks to function properly, neurons need to communicate through complex electrical-like circuits with the proper balance of excitation and inhibition. There are two main receptors responsible for maintaining this balance: glutamate controls excitation while GABA handles inhibition. Dysfunction in the GABA system disrupts network communication and contributes to depressive symptoms.

People diagnosed with MDD and PPD may have lower GABA activity than those without depression. They can have disrupted network activity that shows up as depressive behaviors and symptoms.

GABA-A receptor PAM

Scientists at Sage believe compounds that are designed to address the imbalance between excitatory and inhibitory signals within the brain have the potential to treat a range of brain disorders, including depression.

When targeting the GABA neural pathway, receptor activation can be inappropriately enhanced or diminished by naturally produced substances or man-made products. This may result in unwanted effects. At Sage, our goal is to modulate the receptor so that we find a balance between activation and inhibition that has the potential to improve the function of the GABAergic neuron.

Balanced ion flow helps stabilize GABA network connectivity GABA receptor PAM


Sage scientists have been evaluating whether adjusting the performance of GABA receptors – which may function differently in MDD, PPD and other brain health disorders – could potentially balance the brain’s neural activity.

Through this interactive module, we invite you to explore how a hypothetical model of the “Brain Works” when affected by MDD and PPD*. You will learn how regions of the brain can change and influence behavior and how the GABA system may regulate brain activity.

* While depression manifests differently in people because each person’s brain is unique, “Brain Works” includes a representation of the most commonly affected regions in the brain due to MDD and PPD.

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