Exploring the brain in a dish: how iPSC-derived brain models help us understand mental health at a molecular level

August 18, 2025

As a PhD candidate at UMC Utrecht, Anna Wiersema investigates how genetic targets are linked to brain cell behaviour. Elucidating this connection can shed light on key molecular mechanisms underlying mental health.

Anna’s work focuses on using iPSC-derived models to study mental health at a molecular level. During her time as a researcher in the Youth-GEMs project, her lab has developed many different 2D and 3D models to help study mental health in a more robust way.

In this article, Anna explains more on how these models were developed and how they will be used in the Youth-GEMs project.

Exploring the brain in a dish: how iPSC-derived brain models help us understand mental health at a molecular level

Mental health plays a crucial role in our overall well-being. But what is really happening inside the brain when someone develops a mental health condition? Scientists still don’t fully understand the biological or molecular processes behind mental health, which is why current treatments are not always effective for everyone.

To tackle this, researchers are studying how our genes affect the brain and how this might lead to mental health issues. Genetic studies have already identified many small changes in the DNA – called risk variants – that might play a role. However, it is still a challenge to figure out exactly how these variants affect brain development and functioning.

That is where advanced lab-based in vitro models come into play. In our research within the Youth-GEMs consortium, we’re using a technique called induced pluripotent stem cells (iPSCs) to create human brain-like cells in the lab that we can observe and study over time. These models help us connect the dots between genes and their function in the brain.

What are iPSCs and why are they useful?

iPSCs are generated by turning adult cells – like skin or blood cells – back into a more flexible state. In this state, called pluripotent, they regain the ability to become any cell type in the body including brain cells. This technology, first developed in 2006, has changed how scientists study disease because it allowed us to grow human and patient-derived cells in the lab and observe their behaviour (Takahashi & Yamanaka, 2006).

One of the major advantages of iPSC-derived models is their versatility. In mental health research, we can use them to generate various types of brain cells. These include excitatory and inhibitory neurons, which are essential for maintaining the brain’s delicate balance of activity, as well as astrocytes and other glial cells that support neuronal function and modulate synaptic communication.

From 2D cultures to cortical organoids

At first, scientists mostly used 2D in vitro models, where brain cells grow flat on a surface, like a sheet on a dish. These are easy to use and great for certain experiments, but they can’t capture the complexity and 3D architecture of the real brain, which consists of many layers and connections.

To overcome this, researchers developed 3D models such as cortical organoids, which are small brain-like structures grown from iPSCs and more closely resemble the developing human brain (Yoon et al., 2019). These organoids aren’t actual brains, but they mimic parts of the human brain, especially the cortex, which is involved in thinking, emotions, and decision-making. Scientists add special molecules to the cell cultures, which guide the organoids to form multilayered structures that resemble how the cortex normally develops.

However, traditional cortical organoids come with their own set of challenges. One problem is that the center of the organoid can become starved of nutrients and oxygen, forming a “necrotic core.” To overcome this, researchers – including our lab – use a new approach called air-liquid interface cortical organoids (ALICOs)(Giandomenico et al., 2019). These are grown at the boundary between air and liquid so that oxygen and nutrients can reach all the cells more easily. This helps keep the tissue healthier and more suitable for long-term studies.

Connecting genes to brain function

In our Youth-GEMs research, we focus on understanding how specific genetic targets—identified within our work package—impact brain development and function. Using our 2D and 3D iPSC-derived models, we test how these genetic risk variants affect:

Neuronal structure – looking at how neurons grow, branch out, and connect;
Synaptic function – how neurons send and receive messages;
Cell health – how cells respond to stress or damage.

For example, we use techniques like calcium imaging – which makes active neurons visible under the microscope – and multi-electrode arrays, which let us record electrical signals from many cells at once. These tools let us watch neurons in action and see how well they communicate.

To make the models even more relevant, we can create iPSCs from people who carry specific genetic risk variants or introduce these changes in the lab using CRISPR gene-editing technology. This helps us to better understand how they affect brain cells.

By linking genes to cell behaviour, we hope to better understand what is happening at a molecular level in mental health conditions. In the long run, this knowledge could help researchers develop better, more personalised treatments that target the root causes of disease.