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Transforming the understanding
and treatment of mental illnesses.

Alyssa Luz-Ricca, Winner of the 2021 NIMH Three-Minute Talks Competition

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Alyssa Luz-Ricca: Abnormalities in reward processing are implicated in several psychological disorders. So gaining a better insight into the sub-components of the reward system could help us eventually develop more targeted treatments for those disorders.

In my lab, I helped develop molecular tools to look at the reward system in non-human primates. We've recently identified a population of neurons situated throughout the brain that co-project two brain regions that are important for reward processing, which are the orbital frontal cortex and the rostromedial caudate.

In this project, I want to know how can I use genetic and molecular tools to gain insight into the functional role of this neuron population reward processing? One way that we can look at the function of neurons in a living brain is to use a chemogenetic approach, which involves introducing a new receptor into neurons that allows us to artificially manipulate their activity with a designer drug.

In this project, I'm working on designing a two component chemogenetic system that can be administered to the brain using viral vectors. The way that this works is that each virus has one of the genes necessary to express the chemogenetic receptor. So only neurons that co-project to the two injection sites will be delivered the full genetic material necessary to express that receptor, allowing us to very specifically manipulate only this population during behavioral experiments.

That's the logic behind my approach, but how am I actually going to do it? Well, the first step is to take this existing DNA that we have for the chemogenetic receptor and design a PCR reaction to pull out each gene, and place it into a new DNA backbone. 

Once I've isolated these two pieces of DNA, I can introduce them into bacteria, which will allow me to amplify them to really large amounts so I have enough to work with later on. And then, of course, before moving on to any subsequent steps, I have to make sure I've actually made that DNA correctly. So I'll send it in for sequencing.

After confirming the sequence, the next part is to package that DNA into viral vectors. In my lab, we use viruses as a way to relatively noninvasively introduce DNA into the brains of adult animals. The way that I produce these viruses is that I take that DNA and put it into human cells and cell culture. 

The DNA essentially has instructions for these cells to produce viral particles containing our gene of interest. So after letting them do that for a few days, I can harvest the virus back out of solution. And what I'm left with are these two new viral vectors each containing one of the genes necessary to express the chemogenetic receptor.

At this point, I've made the DNA, sequenced it, packaged it into viruses, and we've actually just injected each virus into its respective brain region in a monkey. So, hopefully, by gaining insight into this one sub-component of the reward system, we can better understand the dysregulation of reward processing that occurs in certain psychological disorders.