The black box of the human brain is beginning to open. Although animal models are crucial to our understanding of the mammalian brain, the less frequently collected human data is revealing important features. In a paper published in Cell, a team led by the Jonas Group at the Institute of Science and Technology Austria (ISTA) and neurosurgeons at the Medical University of Vienna has shed light on the human hippocampal region CA3, which is central to memory storage.

Klosterneuenburg/Austria, December 11th, 2024 Many of us have enjoyed magical moments with grandma or grandpa by the fireplace: Listening to the exciting stories from the good old days, which they told with vivid images and a pinch of imagination. Our human brain has the remarkable ability to store and reproduce memories for a lifetime. A physical space, a familiar situation or even a smell alone can evoke a memory, and our brain links this information to complete the pattern of the memory. Although the human brain is optimised for this purpose, we are only just beginning to understand how it integrates information about our environment. This process of pattern completion is a remarkable processing ability of our brain called associative memory.

Most of our neuroscientific knowledge about the brain comes from well-studied animal models such as rodents, which are indispensable for science. But is the human brain simply an enlarged version of the mouse brain, or does it have special features that make it human? Researchers from the Institute of Science and Technology Austria (ISTA) and neurosurgeons from the Medical University of Vienna are now shedding light on how the human brain stores and retrieves associative memories. Peter Jonas, Magdalena Walz Professor for Life Sciences at ISTA, and postdoctoral researcher Jake Watson initiated the collaboration with Professor Karl Rössler from the Department of Neurosurgery at the Medical University of Vienna, and analysed samples from epilepsy patients who had undergone neurosurgery. This collaboration enabled them to gain insights directly from intact, living human tissue.

Humans do not have a ‘big mouse brain’

The hippocampus is the centre for learning and associative memory in the brain. A region called CA3 in the hippocampus stores and processes information and completes patterns. As it is rarely possible to use healthy human material, most studies to date have focussed on animal models. Jonas and Watson solved this problem by collaborating with Rössler, a neurosurgeon who specialises in treatment-resistant forms of epilepsy. ‘While patients undergoing neurosurgery have a wide range of clinical presentations, Prof Rössler identified a subset of epilepsy patients who have an intact hippocampus,’ says Jonas. The scientists could not pass up this opportunity. ‘With this form of epilepsy, unilateral removal of the hippocampus is necessary so that patients have a chance to recover and lead an epilepsy-free life,’ explains Jonas. The team was able to obtain intact hippocampus tissue from 17 epilepsy patients with their consent.

The researchers combined modelling with state-of-the-art experimental techniques – multicellular patch-clamp technology to measure the dynamic functional properties of neurons, and super-resolution microscopy. This led to astonishing results. They showed that the human hippocampus is far from being an enlarged version of the well-studied mouse hippocampus. In fact, neuronal connectivity in the human CA3 region was sparser, and its synapses – the connections that enable the transmission of signals between neurons – appeared to be more reliable and precise. In this way, the team discovered special features of the wiring of the human brain.

‘We had the feeling we knew nothing’

Despite the special cell structure and synaptic connectivity of the human hippocampus, data from animal models remains very important. They serve as a reference and help researchers to develop the technology for analysing human tissue. ‘When you work with rodents, you sometimes get the feeling that everything about the hippocampus is already known,’ says Watson. ‘As soon as I started studying the first samples, I realised how little we knew about the human hippocampus. Although this is the best-studied region of the brain in rodents, we felt we knew nothing about human physiology, cellular organisation or connectivity.’ Based on their experience with rodent hippocampal tissue, Watson and Jonas therefore had to find new ways to study this part of the brain in humans.



Modelling the computing power of the human brain

Using their experimental data, the team aimed to create a model of the computational power of the CA3 network in the human hippocampus. They realised that the human-specific circuitry and synaptic connectivity allowed them to measure the extent to which memories were reliably stored and retrieved. ‘We were able to test how many patterns fit into this model. This allowed us to show that human-specific sparse synaptic connectivity and increased synaptic reliability increase memory capacity,’ says Jonas. In other words, they have discovered how the human CA3 network efficiently encodes information to maximise the storage and linking of memories.


The best day in a physiologist’s career

This study contributes to changing the way scientists and physicians perceive the human brain. ‘Our work emphasises the need to rethink our understanding of the brain in relation to humans. Future research on the brain’s circuitry, even when conducted with rodents, must have the human brain in mind,’ says Jonas. This work is the result of a synergy between the right neurosurgeon and the right physiologists, Jonas and Watson emphasise. ‘Prof. Rössler is very interested in promoting basic research and has developed sophisticated techniques to obtain patient tissue in the best possible condition for laboratory examinations,’ emphasises Watson. This collaboration has given ISTA researchers access to a scarce resource in science: intact, living human brain tissue. As the availability of tissue depended on the operations, the team only received new biological material sporadically every few months. This had an impact on the logistics of their laboratory: They often had to interrupt all projects involving non-human material at short notice and clear the lab space to receive and analyse the fresh human samples.

‘It seemed surreal to think that the epilepsy patient who had undergone neurosurgery that morning was recovering in hospital while we were examining an intact and living tissue slice from her brain,’ says Watson. ‘Looking back, the best day of my career as a physiologist was when the first human tissues arrived in our lab.’


Funding information
This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Advanced Grant No 692692; Marie Skłodowska-Curie Actions Individual Fellowship No 101026635), the Austrian Science Fund (FWF; Grant PAT 4178023; Grant DK W1232), the Austrian Academy of Sciences (DOC Fellowship 26137) and a NOMIS-ISTA Fellowship.

Information on tissue samples from human patients
Human tissue samples were obtained with informed consent from 17 individuals with temporal lobe epilepsy. This work was approved by the Ethics Committee of the Medical University of Vienna (MUW) (EC No: 2271/2021). Further information can be found under ‘Experimental model and study participant details’ in the publication.

Information on human post-mortem tissue samples
Three blocks (approx. 1 cm3 each) of post-mortem tissue were obtained from the Normal Ageing Brain Collection Amsterdam (NABCA) biobank (project agreement METC: 2023.0733; ISTA ethics committee application: 2023-03). Further information can be found under ‘Experimental model and study participant details’ in the publication.

Information on animal experiments
In order to better understand fundamental processes in areas such as neuroscience, immunology or genetics, the use of animals in research is essential. No other methods, such as in-silico models, can serve as an alternative. The animals are reared, kept and treated in accordance with strict legal guidelines. The research with animals was carried out at ISTA.

Translated with DeepL_com

Originalpublication:

Jake F. Watson, Victor Vargas-Barroso, Rebecca J. Morse-Mora, Andrea Navas-Olive, Mojtaba R. Tavakoli, Johann G. Danzl, Matthias Tomschik, Karl Rössler, and Peter Jonas. 2024. Human hippocampal CA3 uses specific functional connectivity rules for efficient associative memory. Cell. DOI: (https://doi.org/10.1016/j.cell.2024.11.022)

Further Information:

(https://ista.ac.at/de/forschung/jonas-gruppe/) Forschungsgruppe Zelluläre Neurowissenschaft am ISTA

Bildquelle: © Jake Watson, Menschliche CA3-Pyramidalneuronen, aufgezeichnet in einer Patient:innengewebeprobe.