Search for tag: "neurobiology"

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.

Interviewer: Alzheimer's, autism, fragile X syndrome, and memory loss all have something in common. There's a protein in the cell called Arc, which is thought to be an important part in causing all of these syndromes. My guest, Jason Shepherd, an assistant professor in neurobiology and anatomy, is investigating this protein and what it can tell us about how the brain works. Dr. Shepherd, what is it that all of these diseases have in common?

Dr. Shepherd: Well, we think that the way information is stored in the brain is through the way the cells in the brain connect to each other, and those connections are called synapses. A lot of what we're studying is how those synapses work, how they change when you experience something. This protein, Arc, we think is critical for transducing information from the outside, so changing anything you experience or something that you're learning into molecular changes at those synapses in the brain.

Interviewer: So it has to do with memories or learning or both?

Dr. Shepherd: Both. Memories are just learning that's been stored for a certain amount of time. Really, that's the main question my lab is trying to answer: at the cellular molecular level, how is information stored in the brain for the long term? This is really critical for what the brain does.

Interviewer: I can kind of understand how that might work with, say, memory loss and Alzheimer's. But how would that figure in to something like autism?

Dr. Shepherd: The brain evolved to store information and use that information to modulate behavior. The [inaudible 00:01:47] of behaviors that go wrong in autism are very complicated behaviors like social interaction and language acquisition. We think that because this gene is so critical for maintaining those synaptic changes, any way that you can have a deficiency in that gene or it's misregulated, you get cognitive dysfunction.

Interviewer: And an Arc could be a way that the organism, the animal or the person, is processing their environment and learning from their environment.

Dr. Shepherd: Yes. Arc is one of those genes that's really tightly regulated by experience. In a normal brain, if you're just sitting in a room, not learning thing, its expression is very low. As soon as you start to learn something or you experience something novel, the gene gets turned on and the protein itself is highly regulated at the synapse. So it's downstream of all these signaling events in the cell.
The cell really just wants it to be on and off very quickly. A lot of these diseases seem to result from other mutations or something going wrong in one of those signaling events and because Arc is the protein that seems to be doing a lot of the work at the synapse, we think that it's involved in a lot of these diseases because it's sort of the endpoint of those signaling cascades.

Interviewer: What are you investigating?

Dr. Shepherd: Well, right now we're sort of taking a very multi-pronged approach, so everything from trying to figure out what the structure of the protein is, what it's doing at the synapse, all the way to how it affects circuits in the brain. So we have a microscope that allows us to image into a mouse even while it's awake and behaving so we can image the activity of the neurons and how they change during a learning experience.
Then we can see how Arc has changed during that experience. If we manipulate the protein level, what happens to the way the animal learns. We can do that both in a normal mouse as well as in mice that we model those autism spectrum disorders or Alzheimer's or even schizophrenia.
There was a recent study that came out looking at human patients, and one of the exciting things in psychiatric disorders is that we can now sequence genomes of people and find out what are the genetic inheritants, or what are the genes involved in some of these diseases.
One of the sets of genes that have come out are the ones that seem to act at the synapse, and Arc is one of those as well. So we think that there's really tight links between these psychiatric disorders and I think the big issue now is trying to figure out why some are causing schizophrenia, why some are causing bipolar, why some are causing autism. Even within the same family that has similar mutations, you can get all three of those psychiatric disorders.

Interviewer: I mean, we know that these disorders run in families, but yet, sometimes it's not a single disorder. So you think this might be a link?

Dr. Shepherd: Yeah. Because I think the whole question of nature versus nurture is not really a question anymore. It's clearly an interaction of both. So this gene is one of those genes that is in the middle. It's a gene that's regulated by genetics because it's regulated by a bunch of other proteins that are involved in those signaling cascades, but then it's also responsive to the environment so that whatever is happening to the brain and that circuit, that's acting in response to what the organism is doing at any given time.
We know that, obviously, experiences and the environment affect a lot of these psychiatric disorders and when they manifest. So we think that, yes, there could be a link between the two.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.

Announcer: Examining the latest research and telling you about the latest breakthroughs, the science and research show is on The Scope.

Host: As regretful spring breakers are recovering from their binge drinking escapades, it may be hard for them to appreciate that there is a positive side to the nausea, sleepiness, and stumbling. Dr. Sharif Taha, a professor of neurobiology and anatomy at the University of Utah, is lead author on a study that shows that there's a certain brain region that mediates learning from a bad hangover experience; an effect that could be important in keeping individuals from becoming problem drinkers in the future. Dr. Taha, what are some of the hallmarks of alcohol addiction?

Dr. Sharif Taha: So addiction I think of is just continued drug taking despite negative consequences. I think that's really what's at the core of addictive behaviors. And we study that specifically in the context of alcoholism. We study alcohol in our lab.

Host: So your work is involved in understanding who will become a problem drinker?

Dr. Sharif Taha: Addiction itself, obviously, there, you know, it's this multi-faceted thing. There's a lot going on in human addiction. And we can't study all of those many complicated facets in our rodent models, they are much simpler. So what we try to do instead, is we just try to look at a reduced set of behaviors that we think are relevant to subsets of human addictive behaviors.
One of the things we're very interested in is the transition from being a social drinker to becoming alcoholic. Right? What separates that small minority of people who do eventually develop these problems from other folks in terms of what's actually going on in brain circuits that controls that escalation of intake. That's really one of the things we'd like to understand.
And then another thing, another behavior that we'd like to understand that we talked about a little bit, is sort of further along in the timeline of addiction, or alcoholism. So people who are addicted to the drug, obviously they're aware of the negative consequences that are occurring because of this excessive intake, and they'd like to quit. Right? And they put a lot of effort into quitting, may be highly motivated. And there's lots of ways that you can try to do this. There's Alcoholics Anonymous, they have people go into rehab, but most of those efforts fail. Even after, even in very highly motivated individuals who can maintain abstinence for even years sometimes. So we'd like to understand the factors and signaling in the brain that underlies relapse to alcohol seeking after a period of abstinence.

Host: You're focused really on a specific part of the brain called the lateral habenula. Can you talk about what that is? And how it figures into alcohol [inaudible 00:02:40].

Dr. Sharif Taha: Sure. So yeah, the lateral habenula is a brain region that is fascinating, but it's perhaps best understood if I take a step back and talk about a different signaling molecule.
Most people know about dopamine. And they know that drugs of abuse actually cause dopamine to be released in the brain. And the dopamine is important in terms of the rewarding effects of drugs of abuse, and that's true of alcohol, that's true of other drugs of abuse as well.
We think that the lateral habenula is playing a role that's kind of complementary to the dopamine neurons. Instead of being important in terms of learning about the rewarding properties of drugs, it's important in learning about the aversive properties of drugs. So, this may be easiest to understand in terms of the basic, this experiment that we did. Do you want to transition to that?

Host: Yeah, let's hear about your research.

Dr. Sharif Taha: Yeah, so the basic finding that we have is that we can look at rats, or rodents, that are voluntarily consuming ethanol, and we use a paradigm in which we give them access to ethanol every other day, and a pretty potent ethanol solution, 20%. It's about as strong as gin. And if you give rats ethanol access in this schedule then they gradually escalate their intake over time. And eventually, they consume amounts that are quite substantial and they'll reach blood alcohol concentrations that exceed the 80 milligram percent. And so legally these would be drunk rats if they were driving.
And what we found is that if we compare intact rats to those in which we've inactivated the habenula, that these rats escalate their alcohol consumption much more rapidly, they do this over days, they escalate more rapidly than the intact rats. That's what separates a social drinker from someone who eventually becomes an alcoholic, is the fact that in the latter case they may start as someone who drinks socially. It's a glass or two of wine. But that becomes two or three, and three or four, and so on, and eventually they have a problem and their addicted.

Host: Okay. So let me just make sure I have this right. So the rats with an inactive lateral habenula drink more alcohol over time, and you think that might be significant because they may not feel the negative consequences of drinking.

Dr. Sharif Taha: That's right. So they escalate their drinking more rapidly than those control animals. And it's interesting, we don't know quite why that happens. It could be, our hypothesis is that it's one of two things, maybe a combination of both. It could be that as you said, they just don't experience the aversive consequences. Maybe the hangover is somehow not experienced as being quite as bad.
But we think that's less likely. We think instead what's happening is that they may experience something like a hangover effect, but they just can't learn from that hangover effect. So they can't associate that negative feeling they had with the taste of the alcohol that actually produced it. Right? And so, if you have some deficit in being able to associate that alcohol taste with negative consequence, the next time you get that alcohol taste you're likely to increase consumption.

Host: And so you actually did some experiments to address that very question. Right?

Dr. Sharif Taha: That's right. What we did in this experiment is we offered rats about 20 minutes access to a very sweet saccharin solution, but immediately after that what we did was we gave them some ethanol. We gave them a dose that was sufficient, that we know is sufficient to cause aversive effects. So the next time you give them the same sweet saccharin taste then their intake is reduced. Because they think now that this sweet taste is going to produce that negative outcome. Or, that visceral malaise. This is what happens in food poisoning. You taste something that you like, but then you become sick afterwards and you associate that taste you used to like with sickness so you avoid it thereafter. And that's exactly what's happening here.
So that's what happens in normal intact animals, but we can do exactly the same experiment in rats in which we inactivate the lateral habenula. And when we do that what we find is that when you give them access to that saccharin solution for the second time, then they don't show as much aversion. So it's as if they just haven't learned to associate that sweet taste with a negative outcome. And so, they don't show as much initial aversion and they also seem to recover from the aversion that they had more quickly. So they resume drinking the saccharin just after a couple of days, rather than having this aversion present for perhaps even a period of a week or so.
Obviously all kinds of different alcoholic beverages have their own taste and flavor components. And so voluntarily ingesting those can condition an aversion to all those tastes and flavors that you're experiencing. So that's why I feel like people move away from Jagermeister after college.

Host: Yeah, right.

Dr. Sharif Taha: It has a very distinctive taste and it's usually consumed to excess. And then, of course, as you said, right? If you've had a bad experience with that, then that taste is not something you want to experience any longer because you associate it with that bad outcome.

Host: Now that you have an idea of what neural circuit is involved in this, I mean, how can you use that to help people who might have problems?

Dr. Sharif Taha: We think this is particularly interesting and perhaps relevant to human alcoholism because there is a whole clinical literature that suggests that something similar may be going on in human drinking behaviors. And what they showed specifically was that those individuals that were least sensitive to the acute effects of alcohol, including the aversive effects, are the ones who eventually were at most risk to develop alcohol use disorders.
We think or results in the rodents are relevant to this result because what the human studies are telling us is that if you're less sensitive to alcohol's aversive effects, then you're likely to escalate your intake and become a problem drinker. And here what we have, what we think we have, is a brain circuit that controls specifically learning from the aversive effects of the drug. And we've made this, we've at least shown that this circuit is involved both in learning from aversive outcomes and then inactivating it also produces increases in intake. And so, these findings fit together in the way that we would expect. What we have to show now is that it's specifically an attenuation of learning from aversive effects that's driving this increased alcohol intake, and that's a link we haven't shown yet.
You can imagine that if we could actually understand the brain circuits that determine sensitivity to aversive effects of drugs, and determine, you know, may be involved in learning about these aversive effects. Then we might get a handle on at least vulnerability to developing, for instance, an alcohol use disorder, or becoming an alcoholic.

Announcer: Interesting. Informative. And all in the name of better health.

Interviewer: Examining the latest research and telling you about the latest breakthroughs, The Science and Research Show is on The Scope. Who your parents are matter. Dr. Christopher Gregg, a professor in neurobiology and anatomy, is researching patterns of inheritance that long-term effects on behavior and the development of mental health disorders. Dr. Gregg, what motivates your work?

Dr. Christopher Gregg: The cost of mental health in society, mental health issues, are unbelievable. Unbelievable. Most of the people in prisons, most of the people that are homeless, most of the people that are struggling to get by in life are suffering from some mental health issue.

Addiction, all of these problems are brain related and behavior related. At the moment, most of the pharmaceutical companies are pulling money out because the brain is so hard to figure out. It's so hard to find targets and it's so hard to find effective ways to influence behaviors in a predicable manner.

So in my mind, I think because we think we are able to decode these pathways in the brain, I think we have a very unique place in the field. I think we have a real opportunity to make a difference.

Interviewer: You're interested in how behavior is inherited?

Dr. Christopher Gregg: When people think about behavior I think they think a lot about the factors in their environment. So you might think about what role your parents played in your upbringing, what are your socioeconomic circumstances, what sorts of stresses and pressures do you have in your life, and so you think about the behaviors that you have or maybe why a particular disorder or addiction or some stress or anxiety disorder might emerge and you might think about those issues.

But, in fact, it looks like most psychiatric disorders are strongly influenced by your genes. So as a consequence, we have focused an enormous amount of effort in our research program in trying to define the genes that influence specific behaviors.

Interviewer: So why is that interesting to you?

Dr. Christopher Gregg: We had known before that there were these rare examples of genes called imprinted genes that exclusively express the copy you get from your father or exclusively express the copy you get from your mother, but people didn't have any way to study them in a kind of unbiased manner. So we set about to find all of these imprinting effects in the genome.

The bigger vision continues to be a general interest in finding antagonistic pathways in the brain. So when you think about many behaviors or different physiological states, they're opposing. You can be hungry or you can be satiated. You can be anxious or you can be calm. You can be social or you can be antisocial.

Naively, we thought maybe we could kind of decode the genome into the genes that push you down one path versus the genes that push you down the other path.

Interviewer: Why did you look into that in the first place?

Dr. Christopher Gregg: There was a theory proposed several years ago by an evolutionary biologist named David Higg. David proposed that there would be a conflict between mothers and fathers in placental mammals. The reason was that mothers are the only ones that make a metabolic investment by supplying nutrients through the placenta or through the nursing through lactation and fathers don't make any investment.
David predicted that mothers would evolve mechanisms that make the offspring less demanding and fathers would evolve mechanisms that make the offspring more demanding so they grow bigger, consume more resources, and outcompete the offspring for mother and father.

Interviewer: So how do you think how genes are expressed in the brain might fit Higg's hypothesis?

Dr. Christopher Gregg: We think the weaning period is sort of a major point of conflict because this is the period when offspring develop behavioral traits that are required for them to be independent from the mother. They become independent in terms of being able to find their own food. They have changes to anxiety and exploratory behaviors, changes to learning and cognition. Those changes have a major impact on the mother. The faster and more effectively that the offspring transition to being independent the less the demand on the mother's resources.

Interviewer: A lot of your work focuses on genes that regulate brain function or behavior and whether they're inherited from your mother or your father.

Dr. Christopher Gregg: The researchers in my lab have spent time developing technologies that allow us to study the expression of genes you get from your mother and compare them to the expressions of genes you get from your father. We find there are a lot of really interesting differences.

What's particularly compelling about some of those differences is that they seem to be particularly enriched in the brain. So we looked at differences in the expression of genes from maternally and paternally inherited chromosomes in the liver, in the muscle, and now in two brain regions, and in the developing brain and we find there are a lot of differences in the developing brain and in the adult brain but not very many differences in the liver and in the muscle. The chromosomes you get from your mother and the chromosomes you get from your father are used differently in the brain.

Interviewer: Were you surprised to find that? Did you actually think it would turn out that way?

Dr. Christopher Gregg: We were very surprised. We continue to be surprise as we discover more and more things as we're doing this work. Now what I think is important to recognize is the implications of our study for human disease are that if you inherit mutations from your mother versus your father in these genes, it will have different effects on you.

Imagine you did a mutation in a particular gene that's imprinted and you inherent that mutation from your father. If you don't express the copy that you get from your father because there's a bias to express to copy that you get from your mother because it's a maternally expressed imprinting, then that mutation is not going to have such a deleterious effect on you. On the other hand, if you inherited that same mutation from your mother for that gene, then the effect is expected to be much stronger because there's no other healthy copy to buffer the effect.

Interviewer: So the idea is that one day, if you find that a susceptibility to being autistic is more likely to come from your mother, then the healthcare system can come up with a way to test for that?

Dr. Christopher Gregg: We already are able to analyze the genome sequence of a patient and we're able to analyze a genome sequence of that patient's parents. We can determine whether a mutation has been inherited from a mother or a father and by looking at that mutation, as well as many other mutations in an individual's genome, we think that we'll be able to infer whether that person is at risk for developing psychiatric disorders at later stages in life.

Interviewer: Are there some genes that you found that might suggest this antagonistic control, where one side has the opposite function of the other and that might be connected to a behavior?

Dr. Christopher Gregg: In very preliminary work we think we have defined antagonistic gene pathways that regulate anxiety and maybe risk for panic disorders.

Interviewer: So what's the next step to take that work?

Dr. Christopher Gregg: I think we have a very clear path ahead of use. We're going to define these pathways that are antagonistic and make you less or more anxious, for example. Then we have developed software in the lab that builds on those insights to find how those pathways intersect with known drugged pathways and our goal is to develop novel therapeutics and novel therapeutic strategies by leveraging that insight.

Then on the diagnostic side, by finding novel pathways that influence anxiety we can more accurately identify individuals that are at risk for developing an anxiety disorder.

The greater vision of the work in the lab is to define all of the sort of these functionally antagonistic pathways in the brain that drive different aspects of behavior and to develop a panel of markers that will help diagnose susceptibility for aberrant motivated behaviors and to develop novel therapeutics that modulate these pathways so that you can treat people that have problems with addiction, anxiety, social behaviors, eating disorders, these types of things.

Interviewer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.