The ability to learn associations between events is critical for survival, but it has not been clear how different pieces of information stored in memory may be linked together by populations of neurons. In a study published April 2nd in Cell Reports, synchronous activation of distinct neuronal ensembles caused mice to artificially associate the memory of a foot shock with the unrelated memory of exploring a safe environment, triggering an increase in fear-related behavior when the mice were re-exposed to the non-threatening environment. The findings suggest that co-activated cell ensembles become wired together to link two distinct memories that were previously stored independently in the brain.
“Memory is the basis of all higher brain functions, including consciousness, and it also plays an important role in psychiatric diseases such as post-traumatic stress disorder,” says senior study author Kaoru Inokuchi of the University of Toyama. “By showing how the brain associates different types of information to generate a qualitatively new memory that leads to enduring changes in behavior, our findings could have important implications for the treatment of these debilitating conditions.”
Recent studies have shown that subpopulations of neurons activated during learning are reactivated during subsequent memory retrieval, and reactivation of a cell ensemble triggers the retrieval of the corresponding memory. Moreover, artificial reactivation of a specific neuronal ensemble corresponding to a pre-stored memory can modify the acquisition of a new memory, thereby generating false or synthetic memories. However, these studies employed a combination of sensory input and artificial stimulation of cell ensembles. Until now, researchers had not linked two distinct memories using completely artificial means.
With that goal in mind, Inokuchi and Noriaki Ohkawa of the University of Toyama used a fear-learning paradigm in mice followed by a technique called optogenetics, which involves genetically modifying specific populations of neurons to express light-sensitive proteins that control neuronal excitability, and then delivering blue light through an optic fiber to activate those cells. In the behavioral paradigm, one group of mice spent six minutes in a cylindrical enclosure while another group explored a cube-shaped enclosure, and 30 minutes later, both groups of mice were placed in the cube-shaped enclosure, where a foot shock was immediately delivered. Two days later, mice that were re-exposed to the cube-shaped enclosure spent more time frozen in fear than mice that were placed back in the cylindrical enclosure.
The researchers then used optogenetics to reactivate the unrelated memories of the safe cylinder-shaped environment and the foot shock. Stimulation of neuronal populations in memory-related brain regions called the hippocampus and amygdala, which were activated during the learning phase, caused mice to spend more time frozen in fear when they were later placed back in the cylindrical enclosure, as compared with stimulation of neurons in either the hippocampus or amygdala, or no stimulation at all.
The findings show that synchronous activation of distinct cell ensembles can generate artificial links between unrelated pieces of information stored in memory, resulting in long-lasting changes in behavior. “By modifying this technique, we will next attempt to artificially dissociate memories that are physiologically connected,” Inokuchi says. “This may contribute to the development of new treatments for psychiatric disorders such as post-traumatic stress disorder, whose main symptoms arise from unnecessary associations between unrelated memories.”
More information: Cell Reports, Ohkawa et al.: “Artificial Association of Pre-Stored Information to Generate a Qualitatively New Memory” www.cell.com/cell-reports/abst… 2211-1247(15)00270-3
Grad student Chi Lu and colleagues demonstrate a highly flexible polymer probe for triggering spinal-cord neurons with light and simultaneously recording their activity.
MIT researchers have demonstrated a highly flexible neural probe made entirely of polymers that can both optically stimulate and record neural activity in a mouse spinal cord — a step toward developing prosthetic devices that can restore functionality to damaged nerves.
“Our goal was to create a tool that would enable neuroscientists and physicians to investigate spinal-cord function on both cellular and systems levels with minimal impact on the tissue integrity,” notes Polina Anikeeva, the AMAX Assistant Professor in Materials Science and Engineering and a senior author of the paper published Nov. 7 in Advanced Functional Materials.
Department of Materials Science and Engineering graduate student Chi (Alice) Lu, who designed and implanted the probe, is the lead author of the study. Co-authors include Ulrich Froriep of the Simons Center for the Social Brain; Ryan Koppes of the Research Laboratory of Electronics; Andres Canales and Jennifer Selvidge of the Department of Materials Science and Engineering; and Vittorio Caggiano and Emilio Bizzi of the McGovern Institute for Brain Research. Professor Yoel Fink provided access to the fiber-drawing tower.
Although optogenetics, a method that makes mammalian nerve cells sensitive to light via genetic modification, has been applied extensively in investigation of brain function over the past decade, spinal-cord research has lagged. Earlier this year Caggiano and Bizzi have demonstrated inhibition of motor functions using optogenetics, and now the collaboration between the two groups yielded a device suitable for spinal optical excitation of muscle activity, while giving the researchers an electrical readout.
“Working in a spinal cord is significantly more difficult than in the brain because it experiences more movements. The radius of the mouse spinal cord is about 1 millimeter, and it is very soft, so it took some time to figure out how to design a device that would perform the stimulation and recording without damaging that tissue,” Lu explains.
The fiber was drawn from a template nearly 1.5 inches thick to its final diameter comparable to that of a human hair. It is flexible enough to be tied in a knot. The probe consists of a transparent polycarbonate optical core; parallel conductive polyethylene electrodes for recording neuronal electrical activity; and cyclic olefin copolymer acting both as electrical insulation and optical cladding. The flexible probe maintains its optical and electrical functions when bent by up to 270 degrees at very small radii of curvature (e.g. 500 µm), albeit with somewhat diminished light-carrying capacity at those conditions. The device still performed well after repeated bending and straightening, holding up under stresses expected from normal body movements, the report shows. MIT has filed a patent on the device platform.
The researchers conducted experiments with their neural probe in genetically-altered mice that express the light-sensitive protein channelrhodopsin 2 (ChR2) labeled with yellow fluorescent protein. The ChR2 makes neurons in the mice respond to blue light. These mice, developed by Professor Guoping Feng and colleagues at the McGovern Institute for Brain Research, provide a convenient model system for optoelectronic neural prosthetics. “When pulses of blue light are delivered to the spinal cord, we can directly observe neuronal response by getting an electrical recording,” explains Lu, who entered the third year of her doctoral program this fall.
“Laser pulses … delivered through the [polycarbonate] core of the fiber probe robustly evoked neural activity in the spinal cord, as recorded with the … electrodes integrated within the same device,” the researchers report.
The fiber was inserted into the proximal lumbar section of the spinal cord in mice, and light delivered through it triggered activity in one of the calf muscles, the gastrocnemius muscle. The results in the optically-sensitive mice were validated by comparison with results in wild type mice, which showed no response to the optical trigger. A toe pinch showed the device could still record mechanically stimulated neuronal activity in the wild-type mice. The researchers monitored muscle activity through electromyographical (EMG) recording, while the conductive polyethylene electrodes in the new device recorded neuronal activity in the spinal cord.
The MIT researchers’ combination in a single system of both recording activity from neurons and stimulating neurons with light is new, says Ravi V. Bellamkonda, the Wallace H. Coulter Professor and Department Chair of Biomedical Engineering at Georgia Institute of Technology and the Emory School of Medicine. “In principle, one would like to use ‘closed-loop’ systems, i.e., you detect a neurological event — like the brain wanting to move a limb — and then stimulate to affect that function when the natural link between them is severed due to an injury like spinal cord damage,” he explains.
“This is excellent engineering combining electrical and optical engineering for an important biological application — modulation of neural function in a closed-loop way. I am eager to see this technology being used in a biologically significant ways in the future,” Bellamkonda says.
The work was funded in part by grants from the National Science Foundation through the Center for Sensorimotor Neural Engineering and Center for Materials Science and Engineering; the McGovern Institute for Brain Research Neurotechnology Program; and the Simons Foundation.
Source: MIT press release
Image Source: The image is credited to the Chi (Alice) Lu and Polina Anikeeva and is adapted from the MIT press release
Original Research: Abstract for “Polymer Fiber Probes Enable Optical Control of Spinal Cord and Muscle Function In Vivo” by Chi Lu, Ulrich P. Froriep, Ryan A. Koppes, Andres Canales, Vittorio Caggiano, Jennifer Selvidge, Emilio Bizzi and Polina Anikeeva in Advanced Functional Materials. Published online August 26 2014 doi:10.1002/adfm.201401266
Swedish researchers at Uppsala University have, together with Brazilian collaborators, discovered a new group of nerve cells that regulate processes of learning and memory. These cells act as gatekeepers and carry a receptor for nicotine, which can help explain our ability to remember and sort information.
The discovery of the gatekeeper cells, which are part of a memory network together with several other nerve cells in the hippocampus, reveal new fundamental knowledge about learning and memory. The study is published today in Nature Neuroscience.
The hippocampus is an area of the brain that is important for consolidation of information into memories and helps us to learn new things. The newly discovered gatekeeper nerve cells, also called OLM-alpha2 cells, provide an explanation to how the flow of information is controlled in the hippocampus. Read more…
Simply activating a tiny number of neurons can conjure an entire memory.
Our fond or fearful memories — that first kiss or a bump in the night — leave memory traces that we may conjure up in the remembrance of things past, complete with time, place and all the sensations of the experience. Neuroscientists call these traces memory engrams.
But are engrams conceptual, or are they a physical network of neurons in the brain? In a new MIT study, researchers used optogenetics to show that memories really do reside in very specific brain cells, and that simply activating a tiny fraction of brain cells can recall an entire memory — explaining, for example, how Marcel Proust could recapitulate his childhood from the aroma of a once-beloved madeleine cookie.
“We demonstrate that behavior based on high-level cognition, such as the expression of a specific memory, can be generated in a mammal by highly specific physical activation of a specific small subpopulation of brain cells, in this case by light,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience at MIT and lead author of the study reported online today in the journal Nature. “This is the rigorously designed 21st-century test of Canadian neurosurgeon Wilder Penfield’s early-1900s accidental observation suggesting that mind is based on matter.” Read more…