Featured Lendület Researcher: Balázs Hangya

Balázs Hangya, Head of the Momentum Systems Neuroscience Research Group at the HUN-REN Institute of Experimental Medicine (KOKI), and his colleagues are currently investigating a specific group of cholinergic (i.e. acetylcholine-communicating) cells in the brain. These cholinergic cells are known to play an important role in a wide variety of cognitive (thinking) brain functions, so it is not surprising that the research team has worked with cholinergic cells before. Their current studies target basal forebrain cholinergic cells. This group of cells is well known in neurobiology, as it was detailed in the 1980s that their death in Alzheimer’s disease correlates well with memory impairment.

Forgotten cells

Balázs Hangya

“We have been working with these cells for a long time and in the process we made a chance discovery. We created a transgenic mouse line in which the brain’s cholinergic cells are very strongly marked with a fluorescent protein. And we saw that there are not only cholinergic cells in the known locations, but also in another area, the lateral septum,” says Hangya. “The lateral septum is part of the septal complex, which consists of a middle (medial) and a side (lateral) part. Although these parts belong to the same structure according to the nomenclature, they actually, functionally, belong to separate systems of the brain.”

The medial septum is part of the basal forebrain system, where these cholinergic cells have been studied extensively. The lateral septum, on the other hand, is best known for its role in aggression, social behaviour, reward processing and anxiety: most people believe that the processing of these functions takes place in the lateral part of the septum. When brain researchers saw that there were cholinergic cells in the lateral septum, they initially thought that something was wrong with the new mouse line, that is, it was expressing genes that do not normally appear in the mouse brain. However, when the phenomenon was tested in several ways, it turned out that there were indeed cholinergic cells in the lateral septum.

These cells had already been described in rats, monkeys and raccoons in the 1990s, but they were completely forgotten and no one has studied them since: no functional research has followed the anatomical studies. “We thought that, since cholinergic cells play a very important role in brain areas where their function is known, similar cells in the lateral septum are probably not irrelevant either,” continued Hangya. “At the same time, we don't know anything about them, which is why we started investigating them. We assume that the function of these cells will be related to the tasks of the lateral septum as a structure. Specifically, in the context of this Momentum project, we are mainly looking at reward and punishment processing.”

In other words, they will examine whether these cells are involved, and if so, how they are involved in the interpretation of reward and punishment.

Reward processing is also indirectly linked to learning, social behaviour and anxiety processing. Of these, they will focus primarily on learning, but will also investigate the role of cholinergic cells in ageing and Alzheimer’s disease-related dementia. This area is affected relatively early by Alzheimer’s disease-induced nerve cell damage, so the amyloid plaques, or deposits, characteristic of Alzheimer’s disease, appear early in this area.

“We will be working primarily with mice, which we will supplement with an examination of human post-mortem tissues. Here at the HUN-REN Institute of Experimental Medicine, we have a very good tissue bank where we store brains from autopsies and take samples of the best possible quality,” says the team leader. “We usually use them to test whether discoveries made in mice can be translated to the human brain. We will perform in vivo experiments on mice while the animals are awake and doing some kind of task. For example, we will teach them a task and monitor the activity of the cholinergic cells in the lateral septum while they are learning.”

Implicit learning and brain mechanisms

The planned learning tasks will be relatively complex; these types of tasks are rarely performed in mouse experiments. In this area, the research group has an advantage over rival laboratories because they have a long history of developing complex learning tasks for rodents and have developed teaching protocols through which these tasks can be taught to animals. One of the teaching tasks that will be used in the Momentum project is “implicit learning”. While performing the task, mice learn things that are not strictly necessary to perform the given operation, but their brains still process the statistical regularities in the environment and store the experience, as they may use it later.

For example, the mice must respond to some sensory stimuli that appear in different places. Mice, unlike humans or primates, do not press buttons, but have four reward gates at their disposal which are relatively close together. They stick their heads into these gates to indicate that they have chosen the option. Lights flash above the gates, and the mice have to choose the one that lights up. “If we flash these gates in a constant order that reflects some regularity, the brain learns this order (although this knowledge is not necessary to solve the task),” says Hangya. “This learning can be demonstrated by the fact that after we have presented the stimuli (flashing the lights) in a regular order, and then change this order, the animals (and also humans) complete the task more slowly. They can still do it because they understand the rule, but their speed decreases – and the mice make more mistakes.”

The researchers are investigating the brain mechanisms of this implicit (or statistical) learning.

They speculate that the cholinergic cells of the lateral septum, which may be involved in more complex learning tasks, may also play a role in implicit learning.

This is also suggested by the fact that they have anatomically very complex dendritic structures (dendrites are short extensions of nerve cells where incoming stimuli arrive). This is usually a sign of complex integration and complex calculations taking place in the cell. It is therefore conceivable that these cells play a significant role in this learning task which requires considerable integration skills. “Perhaps these cholinergic cells are involved in learning tasks where the cognitive load is greater because of more uncertain associations or because the stimulus is confounded by sensory uncertainties,” the brain researcher suggests. “And this may also play a role in the development of Alzheimer’s disease. We have mice that can be considered a mouse model of Alzheimer’s disease, so we introduced human genetic defects into the mice that cause changes similar to Alzheimer’s disease. We will also train these mice to do the same task at different ages and then compare their performance with the activity of cholinergic neurons in the lateral septum of their brains. If we find a correlation, it could suggest that these neurons are indeed involved in processing implicit learning.”