The black box of the human brain is beginning to open. Although animal models are crucial for our understanding of the mammalian brain, the less frequently collected human data reveal important peculiarities. In a recent paper published in the journal Cell, a team led by the Institute of Science and Technology Austria (ISTA) and the Medical University of Vienna has shed light on the human hippocampal region CA3, which is central to memory storage.
Most of the 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 the Medical University of Vienna are now shedding light on how the human brain stores and retrieves associative memories. Peter Jonas, Magdalena Walz and Jake Watson initiated the collaboration with Karl Rössler from the Department of Neurosurgery of 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, Karl 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 to give patients a chance to recover and lead an epilepsy-free life," explains Jonas. The team was able to obtain intact hippocampal 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.
Despite the special cell structure and synaptic connectivity of the human hippocampus, data from animal models remain very important. They serve as a reference and help researchers to develop the technology for studying 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 looking at 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, the research team therefore needed to find new ways to study this part of the brain in humans.
Modelling the computing power of the human brain
Using experimental data, the researchers 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, the research team has discovered how the human CA3 network efficiently encodes information to maximise the storage and linking of memories.
Publication: Cell
Human hippocampal CA3 uses specific functional connectivity rules for efficient associative memory.
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.
DOI: 10.1016/j.cell.2024.11.022
https://doi.org/10.1016/j.cell.2024.11.022
