Prof. Dr. Hannah Monyer, neurobiologist from Heidelberg and Leibniz prizewinner, has spent her entire professional career searching for answers to questions as to how human memory functions. Her investigations focus on the role of the hippocampal interneurons that coordinate the activities of nerve cells involved in spatial short- and long-term memory.
Prof. Monyer was invited by the Heidelberg Academy of Sciences to give a talk in the Baden-Württemberg government representation in Berlin entitled “Tracking down human memory”. Monyer presented current research results and interpretations of the development, maintenance and loss of memory in the human brain.
Prof. Monyer described her fascinating field of research with great enthusiasm and humour. “Unfortunately, I have some bad news: your capacity to remember things has been decreasing for a long time,” said Monyer speaking to a mainly white-haired audience consisting of Baden-Württemberg representatives, curious members of the public from Berlin and many members of the National Leopoldina Academy and the Berlin-Brandenburg Academy of Sciences. She went on to say: “But there is also some good news: You can do something about it, and if you are still here at the end of my talk, I will tell you exactly what you can do to prevent memory loss.”
Hannah Monyer has been interested in how memory functions ever since she was a child. Her own research is based on the pioneering work of Eric Kandel who received the Nobel Prize in Physiology and Medicine in the year 2000 for his research on the physiological basis of memory storage in neurons of the marine mollusc Aplysia. Kandel identified the circuits of sensory neurons and motor neurons in this simple animal model and he discovered the so-called interneurons with which sensory neurons establish indirect synaptic contacts with motor neurons. These interneurons are also the major focus of Hannah Monyer’s research. Unlike Kandel, Monyer does not use marine molluscs whose memory storage is carried out by a few hundred neurons. She has chosen to work with mice, which have a much more complex nervous system. The murine nervous system is also much more similar to the human nervous system and studies have shown that learning and memory processes are similar in mice and humans.
The President of the Heidelberg Academy of Sciences, Prof. Dr.-Ing. Hermann Hahn, outlined the professional career of Prof. Hannah Monyer who is also a member of the 260 or so elected members of the Academy:
Hannah Monyer was born in the village of Großlasseln (Romanian: Lasle) in the administrative district of Hermannstadt (Sibiu) in Transylvania, Romania. She comes from a family of Transylvanian Saxons, people of German ethnicity who settled in Transylvania from the 12th century onwards. At the age of 14, she became a student at one of the best grammar schools in Romania, the Special English High school in Cluj (Klausenburg). She became interested in the brain and thinking processes very early on in her life and her ambition was to become a doctor. In 1975, at the age of 17, she left Romania for a life in Germany because she believed that there was no future for her under the regime of Nicolae Ceauşescu. She passed the Abitur (German university entrance qualification) in Heidelberg and began her medical studies with a grant from the German National Academic Foundation.
Hannah Monyer did her doctoral thesis at the Institute of the History of Medicine at the University of Heidelberg on “The phenomenon of jealousy in the work of Marcel Proust and in the field of psychiatry of his time”. In 1983, she qualified as a doctor and started work as an assistant doctor in the Department of Paediatric and Adolescent Psychiatry at the Central Institute of Mental Health in Mannheim before moving onto the Department of Neuropaediatrics at the University Children’s Hospital in Lübeck.
Hannah Monyer told me that it was purely by chance that she entered the field of research. While working in a neurobiology laboratory at Stanford University she became fascinated by research and this fascination has remained with her ever since. She worked as a postdoctoral fellow under Prof. Dennis W. Choi at the Neurology Research Laboratory at the Stanford University Medical Center in California before returning to Heidelberg in 1989 to spend five years as a scientist in Prof. Peter Seeburg’s department at the Centre for Molecular Biology (ZMBH). She was subsequently awarded the venia legendi in biochemistry and an endowed chair. She has been full professor and medical director of the Department of Clinical Neurobiology of the University Hospital of Heidelberg since 1999.
Hannah Monyer has received numerous awards, including the Cross of Merit on ribbon. In 2004, she was awarded the most prestigious science prize in Germany, the German Research Foundation Gottfried Wilhelm Leibniz Prize.
Hannah Monyer describes the interneurons as the conductors of an orchestra of memory. Each interneuron is connected to around 15,000 other nerve cells; it determines the beat that coordinates the activities of the large number of nerve cells that are involved in everything we experience. If the interneurons are switched off in mice, the mice lose their capacity to store memory.
It is known from studies carried out by the Canadian psychologist Brenda Milner on a patient famously known as HM that the conversion of short-time memory into the contents of long-term memory happens in the hippocampus (shaped like a sea horse; Latin: hippocampus) located in the temporal lobes of the cerebrum. HM suffered from memory disorder and intractable epilepsy. HM’s treating physician decided to surgically resect the left and right medial temporal lobes as a last-ditch attempt to treat HM’s epilepsy. Although the removal of the temporal lobes on both sides of his brain was successful in the primary goal of curing HM of epilepsy, he lost the ability to commit new events to long-term memory. An experiment with mice showed that mice whose hippocampus was surgically removed were unable to orient themselves in space after surgery. These animals completely lost their spatial learning capacity.
How can spatial long- and short-term memory be investigated in mice? A classical experimental set-up for investigating spatial learning is the Morris water maze, a round pool of turbid water with an escape platform hidden a few millimetres below the surface of the water. The mice are released into the pool and swim around in search of an exit or protective platform. On subsequent trials, the mice are able to locate the platform more quickly in their quest to escape the unpleasant water. The mice orient themselves on visual cues that are placed around the pool where they can be seen.
The short-term memory of mice can also be tested with a T-maze in the form of a horizontal T. The animals start from the base of the T. During the first test trial, one of the arms of the T is closed off obliging the animal to explore the other arm. A second trial is carried out within seconds of the first one, this time with both arms open. The mouse will then choose to explore the previously closed arm. The fact that the mouse actually remembers the first trial can be confirmed by a random generator that blocks the left or right T arm at random. Both experimental set-ups and the performance of the animals depend on spatial memory and hence on an intact hippocampus.
Ancient scholars such as Simonides, Augustin and Cicero knew that spatial orientation is of key importance for memory. For example, Cicero developed a memory improvement method that enabled people to memorise things by associating them with rooms in houses. Dante gave a profound representation of the spatial structures of human memory in his “Divina Commedia” which was wonderfully illustrated by Botticelli. Hannah Monyer showed a few examples in her talk. Nobody has found more touching words than Dante for describing our knowledge that we are only able to perceive our life by memorising events and things: no one ever dies as long as someone remembers them.
Investigations using mouse models have shown that hippocampal neurons, which are known as place cells, create a cognitive map of their environment. They fire (cause electrical action potentials) whenever the experimental model is at a specific site in a known environment. Repetitions lead to the reinforcement of the electrical signal. Complex interactions between different receptors (AMPA and NMDA), which have been investigated in detail by the Heidelberg researchers over many years, lead to synaptogenesis, i.e. the formation of new synapses that store the long-term memory of the cerebrum. According to the principle “use it or lose it!”, newly formed synapses are degraded when they are no longer used. The cells only survive if they communicate with each other.
The consolidation of what we have previously learned appears to occur when we sleep. Monyer however makes the point that this does not happen during dream phases. This type of brain plasticity decreases considerably as we get older. Another type of brain plasticity is the development of new neurons (neurogenesis). Neurogenesis has been described for higher animals, including zebra finches and later also in the olfactory bulb of rats. Unlike previous scientific thinking, we now know that new neurons are also formed in some parts of the adult human brain. The formation of new neurons, however, decreases considerably with age. Experiments with mice have shown that synaptogenesis and neurogenesis can be stimulated by interesting environments and hormones, but are negatively affected by stress.
The goal of the neurobiologists is to gain a model understanding of spatial learning behaviour on different levels: on the level of signalling molecules, synaptic receptors and gap junctions (membrane structures that couple the synchronisation activities of interneurons), synaptogenesis, neurogenesis and complex behavioural networks. For this, the researchers are using knock-out mice with certain defective receptors to assess the learning ability of the animals in experimental setups designed to test short- and long-term memory.
What can we do to prevent age-related memory loss? At the end of her talk, Hannah Monyer gave the following answer: what is good for mice is also good for humans – a stimulating, varied environment with new and repetitive learning stimuli – and if possible, the environment should be free of stress and chaos.