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Circuit Tweak Boosts Social Memory in Mice

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Music: I've just seen a face I can't forget

Narrator: We've all heard the expression love at first sight. Now an NIMH-funded study on how mice form social memories gives new meaning to that timeless phrase.  A study that may hold clues on how to improve treatments for people with faltering memory due to brain disorders. Scientists have boosted the staying power of social memory in mice at least 80-fold, by stimulating a brain circuit they discovered. A male mouse that would normally forget a female mouse it had just met within an hour instead remembered it at least a week later. Curiously, the memory boost only worked if the male received the stimulation during the animals' first encounter. The discovery may someday lead to new ways to treat impaired social memory, as occurs in dementia and some mental illnesses.

Scott Young: We want to understand social memory because without forming social memories we won't be able to interact with other people in our environment. In various disease states, like dementia, the ability to recognize people that you've known for years -- or to even form new memories -- decreases. So if we can find a way to improve or reverse some of these deficits, this could be useful. What we're doing, we believe, is similar to what happens in everyday experiences. So if you were to be confronted by a bully, for example, your level of stress would go up. The PVN, the paraventricular nucleus of the hypothalamus, is a region of the brain that activates in response to stress. And so by projecting to the CA2 region of the hippocampus, it might make that encounter with the bully more salient -- something you're less likely to forget.  So that would have survival instincts. Love at first sight is something similar, in which again probably there's a slight increase in your stress. And it makes the encounter that you just had that much more memorable. So I think these are everyday experiences that are probably occurring in humans, and by stimulating similar circuits in mice we're just taking a shortcut to making that activation occur.  And one of the approaches we took was to eliminate one of the receptors for vasopressin -- in this case the vasopressin 1B receptor -- in mice. When we did that, we found that the mice had a decrease in social memory and a decrease in social aggression. Eventually, we found out where this receptor was expressed in the brain of mice and rats. And found that predominantly it is located in a particular region of the hippocampus called the CA2 region. The hippocampus is best known for its role in allowing memory formation and recalling events that have occurred in a person or animal's life.  So we knew that this area was mostly likely responsible for the social memory and social aggression deficits that we made when we eliminated the receptor from this area.  We wanted to know exactly how the CA2 area regulates the acquisition of social memories. So one approach that we've taken to study the role of the vasopressin 1 receptor in the CA@ region of the hippocampus is to use other genetically modified mice that enable the vasopressin fibers that are going to the CA2 region of the hippocampus to express a light sensitive compound. And when light is shown on that compound, the fibers are excited.

Adam Smith: So what we did in this experiment was use a technique called optogenetics which allows us to genetically alter some of the cells within the brain of our animals so that they become light-sensitive. The value of that is that we can then target these cells that are expressed in these light-sensitive proteins so that we can stimulate them within a very narrow window of time.

Scott Young: Our idea was that by stimulating these terminals, we could enhance memory.  So to test this, we have a male mouse with the optic fiber. We stimulate the CA2 region of the hippocampus when we have a female present in the cage.  Then we take the female out after 5 minutes of stimulation, let the male mouse sit around for say an hour or two hours, and then place the female mouse back in the cage with the male mouse.  If the male mouse remembers the female mouse, he will show this by showing less interest. He will sniff less. Normally, in the experimental paradigm that we're using, the male mouse will not remember the female mouse after 2 hours. But when we stimulate the CA2 region, he can remember for 2 hours. In fact, the male mouse can remember for 24 hours -- or even 7 days! We have shown that this receptor is found in the hippocampus of humans, but we don't know yet if exactingly the same circuitry is there. But if it is, it is possible that using a technique such as deep brain stimulation, which people use to treat various neurological and psychiatric disorders could be used.