Human CA3 pyramidal neurons recorded in a patient tissue sample. CREDIT: © Jake Watson.

Biologists and neurosurgeons in Austria have teamed up to unravel the distinct nerve wiring of human memory.

The black box of the human brain is starting to open. Although animal models are instrumental in shaping our understanding of the mammalian brain, scarce human data is uncovering important specificities.

In a new paper, a team led by the Jonas group at the Institute of Science and Technology Austria (ISTA) and neurosurgeons from the Medical University of Vienna shed light on the human hippocampal CA3 region, central for memory storage.

Our human brain has a remarkable capacity for storing and recollecting memories over a lifetime.

A physical space, a smell, or a familiar situation can alone bring back a memory, and our brain uses these associations to complete the pattern.

Although the human brain is optimised for this purpose, we are only starting to understand how it integrates information about our surroundings. This pattern-completion process is a remarkable computational property of our brain called associative memory.

The bulk of our neuroscience knowledge about the brain stems from well-studied animal models, like rodents, which are indispensable for science.

But is the human brain simply a scaled-up version of the mouse brain, or does it have distinct features that make it human?

Now, researchers have shed light on how the human brain forms and retrieves associative memories.

Magdalena Walz, professor for life cciences at ISTA, Peter Jonas and ISTA postdoc Jake Watson, who initiated the collaboration with Professor Karl Rössler from the Department of Neurosurgery of the Medical University of Vienna, examined samples from epilepsy patients who underwent neurosurgery to gain insights directly from intact, living human tissue.

Multicellular recorded CA3 neurons (red), in human hippocampal tissue slice (green/ blue). CREDIT: © Jake Watson.

Humans do not have a ‘big mouse brain’

The brain’s centre for learning and associative memory is the hippocampus. Within it, a region called CA3 is responsible for storing and processing information and completing patterns.

Because healthy human material is scarce, most studies have so far focused on animal models.

Jonas and Watson overcame this problem by teaming up with Rössler, a neurosurgeon specialising in treatment-resistant forms of epilepsy.

Jonas said: “While patients undergoing neurosurgery have a wide variety of clinical presentations, Professor Rössler identified a subpopulation of epilepsy patients who presented an intact hippocampus.”

The scientists could not possibly miss this opportunity.

Jonas explained: “In this form of epilepsy, a unilateral resection of the hippocampus is necessary to ensure the patients have a chance to recover and lead an epilepsy-free life.”

Thus, the team could obtain intact hippocampal tissue from 17 epilepsy patients with informed consent.

The researchers combined cutting-edge experimental techniques — multicellular patch-clamp recording to measure dynamic functional properties of neurons and super-resolution microscopy — with modelling and made eye-opening findings.

Far from being a scaled-up version of the well-studied mouse hippocampus, the neural connectivity in the human CA3 region was sparser, and its synapses — the connections that allow signals to be passed between the neurons — appeared more reliable and precise.

Thus, the team uncovered distinct properties of the human brain’s wiring.

Postsynaptic structures on a human hippocampal neuron from patient tissue. CREDIT: © Jake Watson.

“It felt like we didn’t know a thing”

Despite the important differences in the cellular structure and synaptic connectivity of the human hippocampus compared to that of mice and rats, data from animal models remains very important.

It serves as a reference and helps scientists develop the technology for studying human tissue.

Watson said: “Coming from a background working with rodents, it can feel like everything about the hippocampus is already known.

“As soon as I started examining the first patient samples, I realised how much we didn’t know about the human hippocampus.

“Although this is the best-studied brain region in rodents, it felt like we didn’t know a thing about human physiology, cellular organisation, or connectivity.”

Thus, based on their experience working with rodent hippocampal tissue, Watson and Jonas needed to find new ways to re-examine this part of the brain in humans.

Modelling the human brain’s computational power

With their experimental data, the team sought to build a model of the computational power of the CA3 network in the human hippocampus.

They realised the human-specific circuitry and synaptic connectivity allowed them to measure the extent to which memories were stored and retrieved reliably.

Jonas said: “We could test how many patterns fit in this model. This helped us demonstrate that the human-specific sparse synaptic connectivity and enhanced synaptic reliability increased storage capacity.”

In other words, they uncovered how the human CA3 network codes information efficiently to maximise associations and memory storage.

Perception

The present study helps change how scientists and healthcare professionals perceive the human brain.

Jonas said: “Our work highlights the need to rethink our understanding of the brain from a human perspective.

“Future research on brain circuitry, even if using rodent model organisms, must be conducted with the human brain in mind.”

According to the scientists, this work is the fruit of a synergy between the right neurosurgeon and the right physiologists.

Watson said: “Professor Rössler is very keen on promoting basic research and has developed sophisticated techniques to extract patient tissue in the best possible condition for laboratory examination.”

This collaboration has given the ISTA researchers access to a scarce resource in science: intact, living human brain tissue.

The study is published in Cell.