Picower Institute for Learning and Memory and
News Article | March 21, 2016
When you hold in mind a sentence you have just read or a phone number you’re about to dial, you’re engaging a critical brain system known as working memory. For the past several decades, neuroscientists have believed that as information is held in working memory, brain cells associated with that information fire continuously. However, a new study from MIT has upended that theory, instead finding that as information is held in working memory, neurons fire in sporadic, coordinated bursts. These cyclical bursts could help the brain to hold multiple items in working memory at the same time, according to the researchers. “By having these different bursts coming at different moments in time, you can keep different items in memory separate from one another,” said Earl Miller, the Picower Professor in MIT’s Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences. Miller is the senior author of the study, which appears in the March 17 issue of Neuron. Mikael Lundqvist, a Picower Institute postdoc, and Jonas Rose, now at University of Tubingen in Germany, are the paper’s lead authors. Starting in the early 1970s, experiments showed that when an item is held in working memory, a subset of neurons fires continuously. However, these and subsequent studies of working memory averaged the brain’s activity over seconds or even minutes of performing the task, Miller said. “The problem with that is, that’s not the way the brain works,” he said. “We looked more closely at this activity, not by averaging across time, but from looking from moment to moment. That revealed that something way more complex is going on.” Miller and his colleagues recorded neuron activity in animals as they were shown a sequence of three colored squares, each in a different location. Then, the squares were shown again, but one of them had changed color. The animals were trained to respond when they noticed the square that had changed color — a task requiring them to hold all three squares in working memory for about two seconds. The researchers found that as items were held in working memory, ensembles of neurons in the prefrontal cortex were active in brief bursts, and these bursts only occurred in recording sites in which information about the squares was stored. The bursting was most frequent at the beginning of the task, when the information was encoded, and at the end, when the memories were read out. The findings fit well with a model that Lundqvist had developed as an alternative to the model of sustained activity as the neural basis of working memory. According to the new model, information is stored in rapid changes in the synaptic strength of the neurons. The brief bursts serve to “imprint” information in the synapses of these neurons, and the bursts reoccur periodically to reinforce the information as long as it is needed. The bursts create waves of coordinated activity in the gamma frequency (45 to 100 hertz), like the ones that were observed in the data. These waves occur sporadically, with gaps between them, and each ensemble of neurons, encoding a specific item, produces a different burst of gamma waves. “It’s like a fingerprint,” Lundqvist said. When this activity is averaged over several repeated trials, it appears as a smooth curve of continuous activity, just as the older models of working memory suggested. However, the MIT team’s new way of measuring and analyzing the data suggests that the full picture is much different. “It’s like for years you’ve been listening to music from your neighbor’s apartment and all you can hear is the thumping bass part. You’re missing all the details, but if you get close enough to it you see there’s a lot more going on,” Miller said. The findings suggest that it would be worthwhile to look for this kind of cyclical activity in other cognitive functions such as attention, the researchers say. Oscillations like those seen in this study may help the brain to package information and keep it separate so that different pieces of information don’t interfere with each other. “Your brain operates in a very sporadic, periodic way, with lots of gaps in between the information the brain represents,” Miller said. “The mind is papering over all the gaps and bubbly dynamics and giving us an impression that things are happening in a smooth way, when our brain is actually working in a very periodic fashion, sending packets of information around.” Robert Knight, a professor of psychology and neuroscience at the University of California at Berkeley, said the new study “provides compelling evidence that nonlinear oscillatory dynamics underlie prefrontal dependent working memory capacity.” “The work calls for a new view of the computational processes supporting goal-directed behavior,” adds Knight, who was not involved in the research. “The control processes supporting nonlinear dynamics are not understood, but this work provides a critical guidepost for future work aimed at understanding how the brain enables fluid cognition.”
PubMed | Howard Hughes Medical Institute, Picower Institute for Learning and Memory and and University of Edinburgh
Type: Journal Article | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2016
Rett syndrome (RTT) is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2), an epigenetic regulator of mRNA transcription. Here, we report a test of the hypothesis of shared pathophysiology of RTT and fragile X, another monogenic cause of autism and intellectual disability. In fragile X, the loss of the mRNA translational repressor FMRP leads to exaggerated protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5). We found that mGluR5- and protein-synthesis-dependent synaptic plasticity were similarly altered in area CA1 of Mecp2 KO mice. CA1 pyramidal cell-type-specific, genome-wide profiling of ribosome-bound mRNAs was performed in wild-type and Mecp2 KO hippocampal CA1 neurons to reveal the MeCP2-regulated translatome. We found significant overlap between ribosome-bound transcripts overexpressed in the Mecp2 KO and FMRP mRNA targets. These tended to encode long genes that were functionally related to either cytoskeleton organization or the development of neuronal connectivity. In the Fmr1 KO mouse, chronic treatment with mGluR5-negative allosteric modulators (NAMs) has been shown to ameliorate many mutant phenotypes by correcting excessive protein synthesis. In Mecp2 KO mice, we found that mGluR5 NAM treatment significantly reduced the level of overexpressed ribosome-associated transcripts, particularly those that were also FMRP targets. Some Rett phenotypes were also ameliorated by treatment, most notably hippocampal cell size and lifespan. Together, these results suggest a potential mechanistic link between MeCP2-mediated transcription regulation and mGluR5/FMRP-mediated protein translation regulation through coregulation of a subset of genes relevant to synaptic functions.Altered regulation of synaptic protein synthesis has been hypothesized to contribute to the pathophysiology that underlies multiple forms of intellectual disability and autism spectrum disorder. Here, we show in a mouse model of Rett syndrome (Mecp2 KO) that metabotropic glutamate receptor 5 (mGluR5)- and protein-synthesis-dependent synaptic plasticity are abnormal in the hippocampus. We found that a subset of ribosome-bound mRNAs was aberrantly upregulated in hippocampal CA1 neurons of Mecp2 KO mice, that these significantly overlapped with FMRP direct targets and/or SFARI human autism genes, and that chronic treatment of Mecp2 KO mice with an mGluR5-negative allosteric modulator tunes down upregulated ribosome-bound mRNAs and partially improves mutant mice phenotypes.