Everything You Wanted to Know About Our “Little Brain”: An Interview with Neuroscientist Sam Wang

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BW: For example?

SW: Imagine if a baby lacked the neural circuitry to recognize a friendly touch or voice. It would be like being raised in isolation. It is well documented from Eastern European and Russian orphanages that such treatment leads to symptoms that often resemble autism. Both orphanage and autistic children may be missing out on this critical social-learning period, with consequences that last a lifetime. This might also explain how intensive therapy of young autistic children can succeed.

Applied behavioral analysis (ABA), the only autism therapy with strong peer-reviewed support, involves rewards such as food each time the child is touched. After a while the child views a cuddle or a hug as being positive. Whatever the brain regions are that convey social valence in a nonautistic child, ABA seems to compensate for their lost function. If we can show that one such brain region is the cerebellum, it would give a target for early intervention. For example, we could stimulate or silence it, just as the basal ganglia are targeted for treatment in Parkinson’s disease.

BW: Let’s turn now to reward. How could the cerebellum be involved?

SW: Reward is unexpected — finding a dollar bill on the sidewalk feels good, because we weren’t anticipating it. One manifestation of unexpected reward in the brain is well known: dopamine signals originating from neurons in the ventral tegmental area (VTA). But how does the VTA figure out that an event was rewarding?

As it turns out, the cerebellum probably sends signals to the VTA. Decades ago it was shown that rats preferred to press a lever that stimulated a specific part of the cerebellum — one with possible connectivity to VTA—opting for that choice in preference to sex or food. This is reminiscent of some very famous experiments that first indicated a role for the hypothalamus in relaying pleasure. And anatomical tracing has demonstrated direct connections between the deep nuclei of the cerebellum and the VTA.

BW: Could autism be based on an inability to interpret reward?

SW: That is a very interesting speculation. Unpredicted events aren’t just sensorimotor — a mother’s smile is also rewarding. The sensory information that comes into our minds has no intrinsic valence — or attractiveness/value — until we’ve made sense of it. I see a curve of light, but until I’ve processed it I don’t know whether it’s a gap between branches or a smile. Not all rectangles of paper are rewarding, but if they are pieces of money, yes. Any brain region involved in making that interpretation — the VTA, the basal ganglia, and maybe the cerebellum — could play a role in the developmental road to autism.

BW: How might you go about exploring links between cerebellum and reward or autism?

SW: In the case of reward, one way would be to stimulate or block the cerebellum at a time when an animal is learning how to get a reward. This can be done pharmacologically or by optogenetic means. In my lab, we do in vivo experiments using head-fixed animals, which allows in vivo imaging with single-cell resolution, using the method of two-photon fluorescence microscopy. We use synthetic fluorescent molecules and genetically encodable proteins to assess neuron activity. In the case of the proteins, we’re redesigning them to make them even more sensitive. The molecules become brighter after neural activity — a lasting “footprint” that tells us if a neural circuit has been recently active. So we have the ability to see if rewarding events are associated with unique brain signals.

BW: What does that mean in terms of autism?

SW: In the case of autism, one would temporarily stimulate or block cerebellar activity in early life, then look at adult social behaviors. Some mouse models of autism show little interest in grooming other mice, or fail to differentiate between a new and a familiar mouse. These animals are attractive targets for seeing what is wrong at the level of circuits — or of strategies for restoring function. It’s not yet known if their cerebellum is affected, and we’re working on that.

BW: What do you hope for the future in this field?

SW: One could imagine a future in which early detection of autism risk in individual human patients could be addressed by treatments to restore lost function and make life easier for those children later in life. By the way, I should say that in terms of helping children, the apparent increase in autism is not the bad news it appears to be. Combined with mental retardation and other developmental disabilities, the overall rate of problems has not changed. My sister is autistic, but back in the 1970s she was classified as mentally retarded. In national statistics, reported increases in autism have been matched by a decrease in diagnosed mental retardation — to an almost identical degree. This indicates that perhaps autism isn’t on the rise, but we’re just better at diagnosing specific syndromes. The better we’re able to diagnose, the better the treatments can be guided.

This is an update of an article originally published in Brain World Magazine’s Summer 2012 issue.

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