Resetting neurons in the brain
(appeared in May 2019)

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In the early days of computers, the machine language symbols in which a compiled computer program is stored could be accessed and modified. When changes in the final results of programs were desired, but redoing the program was not practical, a line of machine language, to directly change the compiled program, a device called a ‘patch card’, was added. When the program was started, the original program would first load into the computer memory and then the ‘patch’ would modify contents of specific memory cells.A light-pen to create memory of things that did not happen, says S.Ananthanarayanan.

Gisella Vetere, Lina M. Tran, Sara Moberg, Patrick E. Steadman, Leonardo Restivo, Filomene G. Morrison, Kerry J. Ressler, Sheena A. Josselyn and Paul W. Frankland, at hospitals, institutes and universities at Toronto and Boston write in the journal, Nature Neuroscience, that they have done something similar with the memory record of the mouse brain. Memories, which regulate behavior patterns, are the result of a lifetime of experiences. The ability to modify memory records would be a method to cut through the need for time-consuming training or therapy to bring about behavior or other changes

Behavior is acquired because we remember the consequences of how we reacted to different stimuli. Animals readily form associations of cues in the environment with paired events, which may be pleasant events like obtaining food or aversive events like pain or danger. The associations persist in memory. Once the associations are formed (but not till then) appearance of the cues brings about the appropriate behavior – approaching the food source or moving away from the threat. The paper in Nature Neuroscience says that the key components of such associations have been localized to specific parts of the brain or arrangements of nerve cells. As the forms of nerve cell activity in response to experiences have also been understood, it should be possible, the paper says, to “artificially implant a memory for an otherwise never experienced event.”

The way customary cues, like sounds or lights, are received and activate nerve cells, however, is complex, the paper says. It hence becomes challenging to artificially stimulate one part of the brain in the same way as a particular cue. In the case of perception of smell by the mouse, however, the paper says, the mechanism of specific odor causing chemical and the nerve endings that are affected is reasonably well characterized. Hence, in the case of the mouse, it was possible to simulate the effect of an external odor stimulus by stimulating a particular cluster of nerve endings. This artificial stimulation was then paired with rewarding or aversive brain stimulation, followed by trials to see if the real odor produced behavior that reflected the pleasant or opposite association. If it did, it would suggest that the odor triggered a memory that had never been experienced!

The first step in the trials was to train mice to avoid the odor of the chemical acetophenone, as opposed to the chemical carvone. These two chemicals were chosen because they are perceived by their effect on distinct nerve bundles in the nasal, smell perception system of the mouse. The training consisted of administering a mild electric shock to the mice every time they were exposed to acetophonone. When released in a tube which had the acetophenone odor at one end and the carvone odor at the other, the trained mice were seen to consistently move away from the acetophenone end. Conversely, mice that had not been trained showed no preference, which showed that the two odors were neutral in the absence of training.

The paper explains that there are over a thousand kinds of ‘odor receptors’, nerve endings, in the nose and nerve endings that are receptive to the same odors converge to form groups when they connect with brain. And acetophenone, but not carvone, strongly activates one of these groupings. Thanks to this organization, the paper says, it becomes possible to target one group of receptors in preference to the other.

The authors of the paper hence bred a strain of mice where the organ that grouped nerve cells which were sensitive to acetophenone contained a protein that would release a signal when bathed in a shade of blue light. Hence, it was possible, simply by shining light, to stimulate the group that contained the nerve ends that were sensitive to acetophenone, even without the presence of acetophenone. The team now trained this strain of mice with light-stimulation of the group of nerves at the same time as an electric shock. And then, when the mice were released in the tube with acetophenone and carvone at its two ends, the mice avoided the acetophenone end, as if they had been trained with acetophenone itself!

Control tests, with either only light stimulation or with light stimulation and the electric shock, but not together, led to no preference of one smell over the other. As the aversion to a stimulus had to be the result of the memory of the electric shock that was linked, in this case, to the smell, it was clear that artificially stimulating the concerned part of the brain at the time of the shock could create the memory even though the mouse had never encountered the smell.

the electric shock. The authors hence now attempted to replace this aversive event with planting the record of aversion directly into the brain. They note that a portion of the midbrain, linked with processing emotions and motivation, was known to play a role in the feeling of aversion. They hence reasoned that directly stimulating this area could take the place of a real aversive experience. And towards this purpose, they injected a virus which would implant the same, light-sensitive protein, into the part of the midbrain. And they implanted a device that would bathe the part with light when desired.

With this in place, they repeated the trials, this time, training the mice with light at the acetophenone-sensitive connection to the brain and, in place of the electric shock, with the light in the midbrain. Again, the result was that the mice avoided the smell of acetophenone, as if they had been trained with a real, painful, electric shock.

A further trial was with rewarding signals, rather than signals of aversion, with the light-sensitising protein introduced in a different area, a part of the brainstem. This time, the result was that the mice associated light at the part sensitive to acetophenone with the reward signal, and moved towards the acetophenone side when released in the tube, as if the smell was associated with pleasure, like food, in place of pain.

“In these experiments,” the paper says, “mice behaved as if they had experienced a specific past sensory event….. Although memory may be characterized as the retention of experience-created (or modified) representations across time, the current study indicates that it is possible to entirely bypass experience and, via direct stimulation of the brain, implant a specific memory in mice.”

The ability to manipulate the information recorded in the brain, without communication, training or the experience of a person, would place the surgeon in the same, or a better place than the psychiatrist or the counselor, on one hand, and the demagogue or the advertiser, on the other. Work with mice reveals that doing just this is possible, not just in principle, but in practice.

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