Category: Picower Institute for Learning and Memory

Place cells are well known to encode individual locations, but new experiments and analysis indicate that stitching together a “cognitive map” of a whole environment requires a broader ensemble of cells, aided by sleep, to build a richer network over several days, according to new research from the Wilson Lab.

David Orenstein | The Picower Institute for Learning and Memory

December 10, 2024

On the first day of your vacation in a new city your explorations expose you to innumerable individual places. While the memories of these spots (like a beautiful garden on a quiet side street) feel immediately indelible, it might be days before you have enough intuition about the neighborhood to direct a newer tourist to that same site and then maybe to the café you discovered nearby. A new study in mice by MIT neuroscientists at The Picower Insitute for Learning and Memory provides new evidence for how the brain forms cohesive cognitive maps of whole spaces and highlights the critical importance of sleep for the process.

Scientists have known for decades that the brain devotes neurons in a region called the hippocampus to remembering specific locations. So-called “place cells” reliably activate when an animal is at the location the neuron is tuned to remember. But more useful than having markers of specific spaces is having a mental model of how they all relate in a continuous overall geography. Though such “cognitive maps” were formally theorized in 1948, neuroscientists have remained unsure of how the brain constructs them. The new study in the December edition of Cell Reports finds that the capability may depend upon subtle but meaningful changes over days in the activity of cells that are only weakly attuned to individual locations, but that increase the robustness and refinement of the hippocampus’s encoding of the whole space. With sleep, the study’s analyses indicate, these “weakly spatial” cells increasingly enrich neural network activity in the hippocampus to link together these places into a cognitive map.

“On day 1, the brain doesn’t represent the space very well,” said lead author Wei Guo, a research scientist in the lab of senior author Matthew Wilson, Sherman Fairchild Professor in The Picower Institute and MIT’s Departments of Biology and Brain and Cognitive Sciences. “Neurons represent individual locations, but together they don’t form a map. But on day 5 they form a map. If you want a map, you need all these neurons to work together in a coordinated ensemble.”

Mice mapping mazes

To conduct the study, Guo and Wilson along with labmates Jie “Jack” Zhang and Jonathan Newman introduced mice to simple mazes of varying shapes and let them explore them freely for about half an hour a day for several days. Importantly, the mice were not directed to learn anything specific through the offer of any rewards. They just wandered. Previous studies have shown that mice naturally demonstrate “latent learning” of spaces from this kind of unrewarded experience after several days.

To understand how latent learning takes hold, Guo and his colleagues visually monitored hundreds of neurons in the CA1 area of the hippocampus by engineering cells to flash when a buildup of calcium ions made them electrically active. They not only recorded the neurons’ flashes when the mice were actively exploring, but also while they were sleeping. Wilson’s lab has shown that animals “replay” their previous journeys during sleep, essentially refining their memories by dreaming about their experiences.

Analysis of the recordings showed that the activity of the place cells developed immediately and remained strong and unchanged over several days of exploration.  But this activity alone wouldn’t explain how latent learning or a cognitive map evolves over several days. So unlike in many other studies where scientists focus solely on the strong and clear activity of place cells, Guo extended his analysis to the more subtle and mysterious activity of cells that were not so strongly spatially tuned. Using an emerging technique called “manifold learning” he was able to discern that many of the “weakly spatial” cells gradually correlated their activity not with locations, but with activity patterns among other neurons in the network. As this was happening, Guo’s analyses showed, the network encoded a cognitive map of the maze that increasingly resembled the literal, physical space.

“Although not responding to specific locations like strongly spatial cells, weakly spatial cells specialize in responding to ‘‘mental locations,’’ i.e., specific ensemble firing patterns of other cells,” the study authors wrote. “If a weakly spatial cell’s mental field encompasses two subsets of strongly spatial cells that encode distinct locations, this weakly spatial cell can serve as a bridge between these locations.”

In other words, the activity of the weakly spatial cells likely stitches together the individual locations represented by the place cells into a mental map.

The need for sleep

Studies by Wilson’s lab and many others have shown that memories are consolidated, refined and processed by neural activity, such as replay, that occurs during sleep and rest. Guo and Wilson’s team therefore sought to test whether sleep was necessary for the contribution of weakly spatial cells to latent learning of cognitive maps.

To do this they let some mice explore a new maze twice during the same day with a three-hour siesta in between. Some of the mice were allowed to sleep but some were not. The ones that did showed a significant refinement of their mental map, but the ones that weren’t allowed to sleep showed no such improvement. Not only did the network encoding of the map improve, but also measures of the tuning of individual cells during showed that sleep helped cells become better attuned both to places and to patterns of network activity, so called “mental places” or “fields.”

Mental map meaning

The “cognitive maps” the mice encoded over several days were not literal, precise maps of the mazes, Guo notes. Instead they were more like schematics. Their value is that they provide the brain with a topology that can be explored mentally, without having to be in the physical space. For instance, once you’ve formed your cognitive map of the neighborhood around your hotel, you can plan the next morning’s excursion (e.g. you could imagine grabbing a croissant at the bakery you observed a few blocks west and then picture eating it on one of those benches you noticed in the park along the river).

Indeed, Wilson hypothesized that the weakly spatial cells’ activity may be overlaying salient non-spatial information that brings additional meaning to the maps (i.e. the idea of a bakery is not spatial, even if it’s closely linked to a specific location). The study, however, included no landmarks within the mazes and did not test any specific behaviors among the mice. But now that the study has identified that weakly spatial cells contribute meaningfully to mapping, Wilson said future studies can investigate what kind of information they may be incorporating into the animals’ sense of their environments. We seem to intuitively regard the spaces we inhabit as more than just sets of discrete locations.

“In this study we focused on animals behaving naturally and demonstrated that during freely exploratory behavior and subsequent sleep, in the absence of reinforcement, substantial neural plastic changes at the ensemble level still occur,” the authors concluded. “This form of implicit and unsupervised learning constitutes a crucial facet of human learning and intelligence, warranting further in-depth investigations.”

The Freedom Together Foundation, The Picower Institute for Learning and Memory and the National Institutes of Health funded the study.

System developed by MIT, including co-author Mathew Wilson, and Open Ephys team provides a fast, light, standardized means for combining multiple instruments with minimal hindrance of lab mouse mobility.

David Orenstein | The Picower Institute for Learning and Memory

November 13, 2024

Individual technologies for recording and controlling neural activity in the brains of research mice have each advanced rapidly but the potential of easily mixing and matching them to conduct more sophisticated experiments, all while enabling the most natural behavior possible, has been difficult to realize. To empower a new generation of neuroscience experiments, engineers and scientists at MIT and the Open Ephys cooperative have developed a new standardized, open-source hardware and software platform. They described the system, called ONIX, in a new study Nov. 11 in Nature Methods.

ONIX provides labs with a means to acquire data simultaneously from multiple popular implanted technologies (such as electrodes, microscopes and stimulation probes) while also powering and controlling those independent devices via a very thin coaxial cable and unimposing headstage. The system provides a standardized means of acquiring each instrument’s data and neatly integrating it all for efficient transmission to desktop software where scientists can then see and work with it. In the study the researchers document ONIX’s high data throughput and low latency. They also demonstrate that because the system’s headstage and cable are so physically light and resistant to twisting, mice can behave completely naturally and wear the system for days on end. In a large enclosure at MIT with a complex 3D landscape, for instance, mice wearing the system were able to nimbly scamper, climb and leap in experiments comparably to mice wearing no hardware at all.

“ONIX represents the culmination of many quantitative improvements that all come together to enable a qualitative leap in our ability to perform neural recordings in naturalistic behavior,” said corresponding author Jakob Voigts, an MIT neuroscience alumnus, co-founder of Open Ephys, and a research group leader at the Janelia Research Campus of the Howard Hughes Medical Institute. “We can now study the brain during behaviors that unfold over many hours and allow the animals to learn, to make a lot of complex decisions, and to interact with the world in ways that were previously not accessible.”

Jon Newman, a former MIT postdoc and now president of Open Ephys, and MIT postdoc Jie “Jack” Zhang led the work in the lab of co-author Matt Wilson, Sherman Fairchild Professor in The Picower Institute for Learning and Memory at MIT, together with Aarón Cuevas-López at Open Ephys. Wilson, whose lab studies neural processes underlying memory, said the idea behind developing ONIX was to develop a set of standards that would make it easy for any lab to use multiple technologies to acquire rich neural data while animals performed complex behaviors over long time periods.

“Jon’s motivation, the principle he used, was that if we need to do experiments that combined things like optogenetics, imaging, tetrode electrophysiology, and neuropixels, could we do it in a way that would not only enable experiments we were doing but also more complex experiments, involving more complex behavior, involving the integration of different recording methodologies that advances the whole community and not just one individual lab?,” said Wilson, a faculty member in MIT’s Departments of Biology and Brain and Cognitive Sciences (BCS).

Open origins

As Newman and then Zhang began to develop the technology starting in 2016 with this community-minded, open-source philosophy, Wilson said, it was natural to do so in partnership with Open Ephys, an MIT-born effort, now based in Atlanta, which develops and disseminates open, standardized systems to for neuroscience research. Making systems open-source provides researchers with many advantages, Voigts explained.

“Anyone can download the plans for the hardware as well as the software that make up the system,” Voigts said. “For technically well-versed neuroscientists this means that it is easier to modify aspects of the system. Open source also means that the system works with probes from many manufacturers because the connectors and standards aren’t proprietary. Most importantly, the open standards and design allow hardware and software developers to use ONIX as a starting point for completely new tools.”

Voigts compared ONIX to the USB standard people enjoy on their computers and phones. Any number of accessories can easily work with those devices because all they have to do is plug in. Similarly with ONIX, Wilson said, “You can mix and match and combine and then add new technologies without having to re-engineer the whole system.”

Lab demos

To validate the platform, the researchers conducted several experiments with mice including in Wilson’s lab and in the lab of co-author Mark Harnett, Associate Professor in the McGovern Institute for Brain Research and BCS Department at MIT (where Voigts did his postdoctoral work).

In their experiments they compared the mobility of mice implanted with electrodes but sometimes wearing ONIX (and its 0.3 mm tether cable) vs. sometimes wearing a commonly used and but substantially thicker (1.8 mm) tether cable over an 8-hour neural recording session. The mice proved to be much more mobile while wearing the lighter and thinner ONIX system, showing a broader range of exploration, freer head movement, and much faster running speeds. In a similar experiment in which mice were inplanted with tetrodes in the brain’s retrosplenial cortex, they even were able to jump while wearing ONIX but did not while wearing the more imposing tether. In another experiment the researchers compared mouse mobility around the enclosure between ONIX-wearing and completely unimplanted mice. The mice explored with equal freedom (as measured by motion tracking cameras) though the ONIX mice didn’t run as fast as unimplanted mice.

In further experiments, Voigts’s team at Janelia used ONIX to record for 55 hours because the system kept its cable tangle-free over that long-duration activity.

Finally the researchers showed that ONIX could transmit recordings not only from implanted electrodes and tetrodes but also from miniscopes and neuropixels, via experiments at the Allen Institute for Brain Science. They also showed how Open Ephys’s data acquisition software Bonsai (developed by co-author Goncalo Lopes) enabled the brain activity recordings to be synchronized with behavior tracking cameras to correlate neural activity and behavior.

Voigts said he hopes the system earns widespread adoption, especially as hardware costs continue to come down.

“I hope that this system convinces others to take the plunge and record neural data in more complex animal behaviors,” he said.

In addition to the authors named above, other authors are Nicholas Miller, Takato Honda, Marie-Sophie van der Goes, Alexandra Leighton Felipe Carvalho, Anna Lakunina, and Joshua Siegle, who co-founded Open Ephys with Voigts.

Funding for the study came from the National Institutes of Health, The Picower Institute for Learning and Memory, The JPB Foundation, the National Science Foundation, a Brain Science Foundation Research Grant Award, a Kavli-Grass-MBL Fellowship by the Kavli Foundation, the Grass Foundation, and Marine Biological Laboratory (MBL), an Osamu Hayaishi Memorial Scholarship for Study Abroad, a Uehara Memorial Foundation Overseas Fellowship, and Japan Society for the Promotion of Science (JSPS) Overseas Fellowship. a Mathworks Graduate Fellowship. The Simons Center for the Social Brain at MIT and the Howard Hughes Medical Institute.