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Distinctive brain pattern helps habits form

Posted: 08 Feb 2018 08:59 AM PST

Our daily lives include hundreds of routine habits. Brushing our teeth, driving to work, or putting away the dishes are just a few of the tasks that our brains have automated to the point that we hardly need to think about them.

Although we may think of each of these routines as a single task, they are usually made up of many smaller actions, such as picking up our toothbrush, squeezing toothpaste onto it, and then lifting the brush to our mouth. This process of grouping behaviors together into a single routine is known as "chunking," but little is known about how the brain groups these behaviors together.

MIT neuroscientists have now found that certain neurons in the brain are responsible for marking the beginning and end of these chunked units of behavior. These neurons, located in a brain region highly involved in habit formation, fire at the outset of a learned routine, go quiet while it is carried out, then fire again once the routine has ended.

This task-bracketing appears to be important for initiating a routine and then notifying the brain once it is complete, says Ann Graybiel, an Institute Professor at MIT, a member of the McGovern Institute for Brain Research, and the senior author of the study.

Nuné Martiros, a recent MIT PhD recipient who is now a postdoc at Harvard University, is the lead author of the paper, which appears in the Feb. 8 issue of Current Biology. Alexandra Burgess, a recent MIT graduate and technical associate at the McGovern Institute, is also an author of the paper.

Routine activation

Graybiel has previously shown that a part of the brain called the striatum, which is found in the basal ganglia, plays a major role in habit formation. Several years ago, she and her group found that neuron firing patterns in the striatum change as animals learn a new habit, such as turning to the right or left in a maze upon hearing a certain tone.

When the animal is just starting to learn the maze, these neurons fire continuously throughout the task. However, as the animal becomes better at making the correct turn to receive a reward, the firing becomes clustered at the very beginning of the task and at the very end. Once these patterns form, it becomes extremely difficult to break the habit.

However, these previous studies did not rule out other explanations for the pattern, including the possibility that it might be related to the motor commands required for the maze-running behavior. In the new study, Martiros and Graybiel set out to determine whether this firing pattern could be conclusively linked with the chunking of habitual behavior.

The researchers trained rats to press two levers in a particular sequence, for example, 1-2-2 or 2-1-2. The rats had to figure out what the correct sequence was, and if they did, they received a chocolate milk reward. It took several weeks for them to learn the task, and as they became more accurate, the researchers saw the same beginning-and-end firing patterns develop in the striatum that they had seen in their previous habit studies.

Because each rat learned a different sequence, the researchers could rule out the possibility that the patterns correspond to the motor input required to preform a particular series of movements. This offers strong evidence that the firing pattern corresponds specifically to the initiation and termination of a learned routine, the researchers say.

"I think this more or less proves that the development of bracketing patterns serves to package up a behavior that the brain — and the animals — consider valuable and worth keeping in their repertoire. It really is a high-level signal that helps to release that habit, and we think the end signal says the routine has been done," Graybiel says.

Distinctive patterns

The researchers also discovered a distinct pattern in a set of inhibitory neurons in the striatum. Activity in these neurons, known as interneurons, displayed a strong inverse relationship with the activity of the excitatory neurons that produce the bracketing pattern.

"The interneurons were activated during the time when the rats were in the middle of performing the learned sequence, and could possibly be preventing the principal neurons from initiating another routine until the current one was finished. The discovery of this opposite activity by the interneurons also gets us one step closer to understanding how brain circuits can actually produce this pattern of activity," Martiros says.

Graybiel's lab is now investigating further how the interaction between these two groups of neurons helps to encode habitual behavior in the striatum.

The research was funded by the National Institutes of Health/National Institute of Mental Health, the Office of Naval Research, and a McGovern Institute Mark Gorenberg Fellowship.

Study reveals molecular mechanisms of memory formation

Posted: 08 Feb 2018 08:59 AM PST

MIT neuroscientists have uncovered a cellular pathway that allows specific synapses to become stronger during memory formation. The findings provide the first glimpse of the molecular mechanism by which long-term memories are encoded in a region of the hippocampus called CA3.

The researchers found that a protein called Npas4, previously identified as a master controller of gene expression triggered by neuronal activity, controls the strength of connections between neurons in the CA3 and those in another part of the hippocampus called the dentate gyrus. Without Npas4, long-term memories cannot form.

"Our study identifies an experience-dependent synaptic mechanism for memory encoding in CA3, and provides the first evidence for a molecular pathway that selectively controls it," says Yingxi Lin, an associate professor of brain and cognitive sciences and a member of MIT's McGovern Institute for Brain Research.

Lin is the senior author of the study, which appears in the Feb. 8 issue of Neuron. The paper's lead author is McGovern Institute research scientist Feng-Ju (Eddie) Weng.

Synaptic strength

Neuroscientists have long known that the brain encodes memories by altering the strength of synapses, or connections between neurons. This requires interactions of many proteins found in both presynaptic neurons, which send information about an event, and postsynaptic neurons, which receive the information.

Neurons in the CA3 region play a critical role in the formation of contextual memories, which are memories that link an event with the location where it took place, or with other contextual information such as timing or emotions. These neurons receive synaptic inputs from three different pathways, and scientists have hypothesized that one of these inputs, from the dentate gyrus, is critical for encoding new contextual memories. However, the mechanism of how this information is encoded was not known.

In a study published in 2011, Lin and colleagues found that Npas4, a gene that is turned on immediately following new experiences, appears to act as a master controller of the program of gene expression required for long-term memory formation. They also found that Npas4 is most active in the CA3 region of the hippocampus during learning. This activity was already known to be required for fast contextual learning, such is required during a type of task known as contextual fear conditioning. During the conditioning, mice receive a mild electric shock when they enter and explore a specific chamber. Within minutes, the mice learn to fear the chamber, and the next time they enter it, they freeze.

When the researchers knocked out the Npas4 gene, they found that mice could not remember the fearful event. They also found the same effect when they knocked out the gene just in the CA3 region of the hippocampus. Knocking it out in other parts of the hippocampus, however, had no effect on memory.

In the new study, the researchers explored in further detail how Npas4 exerts its effects. Lin's lab had previously developed a method that makes it possible to fluorescently label CA3 neurons that are activated during this fear conditioning. Using the same fear conditioning process, the researchers showed that during learning, certain synaptic inputs to CA3 neurons are strengthened, but not others. Furthermore, this strengthening requires Npas4.

The inputs that are selectively strengthened come from another part of the hippocampus called the dentate gyrus. These signals convey information about the location where the fearful experience took place.

Without Npas4, synapses coming from the dentate gyrus to CA3 failed to strengthen, and the mice could not form memories of the event. Further experiments revealed that this strengthening is required specifically for memory encoding, not for retrieving memories already formed. The researchers also found that Npas4 loss did not affect synaptic inputs that CA3 neurons receive from other sources.

Kimberly Raab-Graham, an associate professor of physiology and pharmacology at Wake Forest University School of Medicine, says the researchers used an impressive variety of techniques to unequivocally show that contextual memory formation is tightly controlled by Npas4.

"The major finding of the study is that contextual memory is driven by a single circuit and comes down to a single transcription factor," says Raab-Graham, who was not involved in the study. "When they knocked out the transcription factor, they removed contextual memory formation, and they could restore it by adding the transcription factor."

Synapse maintenance

The researchers also identified one of the genes that Npas4 controls to exert this effect on synapse strength. This gene, known as plk2, is involved in shrinking postsynaptic structures. Npas4 turns on plk2, thereby reducing synapse size and strength. This suggests that Npas4 itself does not strengthen synapses, but maintains synapses in a state that allows them to be strengthened when necessary. Without Npas4, synapses become too strong and therefore cannot be induced to encode memories by further strengthening them.

"When you take out Npas4, the synaptic strength is almost saturated," Lin says. "And then when learning takes place, although the memory-encoding cells can be fluorescently labeled, you no longer see the strengthening of those connections."

In future work, Lin hopes to study how the circuit connecting the dentate gyrus to CA3 interacts with other pathways required for memory retrieval. "Somehow there's some crosstalk between different pathways so that once the information is stored, it can be retrieved by the other inputs," she says.

The research was funded by the National Institutes of Health, the James H. Ferry Fund, and a Swedish Brain Foundation Research Fellowship.