Seeking to understand what happens in the brain to cause mental illness

Robert Malenka, M.D., Ph.D.
Robert Malenka, M.D., Ph.D.

From The Quarterly, Fall 2012

“Psychiatrists don’t treat diseases. They treat symptoms.” This observation by Dr. Robert Malenka reflects the lack of diagnostic tools and biologically-based tests available for mental illness. There is not yet any equivalent of electrocardiography (EKG) for heart disease or a glucose test for diabetes for mental illness. Diagnoses are based on observations of symptoms by clinical psychiatrists.

Dr. Malenka and colleagues have just published a new paper in Nature that he considers a model of an approach that can lead to identifying the root causes of brain and behavior disorders. It involves work that starts in mice to shed new light on brain function and circuitry that, in turn, with advanced imaging techniques, can be explored in humans. When that imaging is completed, it may lead back to more experiments in mice, as he and colleagues in this particular case try to piece together a very complicated circuit that spans several major brain areas.

The circuit studied in his newest paper appears to enable us to discriminate between behaviors that will bring a reward from those that should be avoided (called aversion). A brain area called the VTA (ventral tegmental area) contains neurons sensitive to the neurotransmitter dopamine and has long been thought to have a role in reward / aversion behaviors. But no one has known how. “Using a number of sophisticated technologies and methods, we showed that because of differences in synaptic connectivity, signals coming into the VTA from two other brain areas elicit reward and aversion,” Dr. Malenka reports.

The Stanford research team was able to trace where ‘reward’ signals were coming from (the LDT or laterodorsal tegmentum) and where the ‘aversion’ signals were coming from (a tiny area called the LHb or lateral habenula). They were then able to study the synaptic connections made by neurons in these areas, and found important connections with dopamine neurons and an area in the brain called the nucleus accumbens (or NAc, frequently referred to as the ‘pleasure circuit’).

With this kind of precise work to identify how the brain functions (and can malfunction), there is much hope for new classes of more effective treatments for brain and behavior disorders. The approach is extremely complicated but the concept is simple: if you identify the circuits and how they work, you can rationally design ways of intervening in them when malfunctions give rise to symptoms.

Dr. Malenka discussed his work when he won the Goldman-Rakic Prize for Outstanding Achievement in Cognitive Neuroscience in 2010. Watch the video here.