My Research!
My current research revolves around understanding the role of two brain structures in decision making: the lateral habenula and medial prefrontal cortex. Specifically, my lab looks at decision making relating to (1) flexible behavior, or one’s ability to flexibly adapt and change their actions in response to the dynamic and changing environment (e.g. changing your route to work when the usual route is blocked off due to construction), and (2) spatial working-memory, or the decisions that are heavily influenced by the most recent memory (working memory) of the spatial environment (e.g. finding your way out of a corn-maze on halloween). The lateral habenula is a really cool structure in the brain that has consistently been implicated in aversive behavior, or behavior that results from disliking something. Even though most research has isolated the function of the lateral habenula to aversive behavior, there is some research that suggests its function doesn’t end there. Intuitively, this makes some sense because our dislike of something plays a role in how we behave and the actions we decide to take (you wouldn’t go bungee jumping if you’re scared of heights…right?). In addition, the lateral habenula is unique in that it is one of the only regions of the brain that receives such strong input from many other parts of the brain that are important for decision making (e.g. emotions, critical thinking, memory…) and funnels this information to another part of the brain, the midbrain, that is critical for behavior and action. One such structure that sends information to the lateral habenula is the medial prefrontal cortex, which is greatly important for higher-order processing, such as planning, which is critical for decision making. Lastly, the lateral habenula and medial prefrontal cortex display similar functional roles in learning, as well as similarly mediate midbrain structures. Uncovering the role of the lateral habenula and medial prefrontal cortex in decision making may help us understand what leads an individual to make the decisions they make, especially if those decisions are sub-optimal.
I hope this better explains the reasoning for studying the lateral habenula and medial prefrontal cortex in decision making and the potential therapeutic implications that may follow. I briefly describe my two projects below!
Which lateral habenula inputs are important for optimal behavior?
DREADDs involve using a virus (which is an agent that can infect cells) to infect neurons so that they express (or show on their cell membrane) receptors that are genetically engineered (or artificial—they look and function like most receptors in the brain but aren’t in the brain naturally) to open/close when in contact with a specific compound: Clozapine N-Oxide (CNO). Neurons infected with DREADDs (i.e. in the lateral habenula) exhibit no changes in activity when there is no CNO present. Administering CNO causes a transformational change in the neurons infected with DREADDs, and we are then able to control their activity.
But deactivating the entire lateral habenula is not what I am after! The lateral habenula, like all other structures in the brain, have many inputs that it receives from many other structures. To truly understand the nature of the communication between the lateral habenula and other structures, I want to disrupt specific inputs received by the lateral habenula.
Using DREADDs to control a specific input to the lateral habenula is a bit more tricky. This involves using two DREADD viruses that depend on one another to work (one will not work if it is not in contact with the other). To add, one of the two viruses is a retrograde virus, meaning that it will not infect the cells that it is initially in contact with but will travel backwards to the input cells and infect them. This way, one virus can be infused into one region and another virus can be infused in the input region of interest. We can then administer CNO to selectively deactivate this projection and see if it has a significant effect in behavior. If it does, then we can conclude that the specific input to the lateral habenula is important for behavior.
Importantly, if disconnecting a specific input to the lateral habenula leads to sub-optimal behavior, we can theorize about whether this specific input may be an underlying factor in addiction and other disorders.
To better understand the lateral habenula’s role in decision making, it is important to understand the inputs the lateral habenula receives that influence decisions. This project involves deactivating specific projections to the lateral habenula to see if the inputs are important for decision making which involve spatial working memory (described above). For this, I use chemogenetics—which is a blanket term for methods that involve both chemicals and genetics. The specific chemogenetic tool that I use is called designer receptors exclusively activated by designer drugs (DREADDs). The neurons in our brain have many different receptors, some of which allow positively charged ions to flow into and depolarize the cell (make the cell more likely to fire an action potential), while others allow negatively charged ions to flow into and hyperpolarize the cell (make the cell less likely to fire an action potential).
It is really difficult to control these natural receptors that we have in neurons, so instead researchers have developed a way of implanting receptors on cell membranes that we can control in order to control the activity of neurons!
As mentioned above, the lateral habenula plays a major role in aversive and depressive behavior. Importantly, the lateral habenula is one of the only structures in the brain that consistently shows an increased firing rate in people experiencing major depression. Several decades of research has uncovered that the lateral habenula’s role in depression may have something to do with its direct and indirect control of the brain’s dopaminergic and serotonergic system. Dopamine is very important in our brain, not only for elevated mood, but also for cognition, memory, movement, and much more. Likewise, serotonin is one of the major targets in therapy for depression, since lower serotonin levels are linked to depression and anxiety behaviors. Increased lateral habenula activity leads to decreased dopaminergic and serotonergic activity, which can manifest as depression.
What does depression have to do with addiction? If you think about it, addiction has many of the same symptoms as depression—dampened mood, decreased motivation, and impairments in cognition and memory that lead to sub-optimal and inflexible behavior. Not surprisingly, we also see an increase in lateral habenula activity in individuals experiencing addiction. It is clear that the lateral habenula is important for these psychiatric disorders, but more research is needed to better understand how the lateral habenula is contributing to the behavioral manifestations of these disorders.
What is the role of the lateral habenula in psychiatric disorders?
To better understand the lateral habenula’s contributions to the behavioral manifestation of psychiatric disorders, i use calcium imaging (a method of looking at neuronal activity patterns) to image lateral habenula neurons during opiate addiction, withdrawal, and subsequent psilocybin therapy. Using this method, i will be able to characterize lateral habenula activity before, during, and after addiction symptoms and compare this neuronal activity with behavior.
Many therapies for addiction and depression are not effective or result in unwanted side effects for many individuals. Luckily, there are other non-traditional methods of alleviating unwanted symptoms. In previous research, a single dose of psilocybin has been shown to decrease depressive symptoms for months after administration. In my research, i am excited to use psilocybin during opiate withdrawal in hopes that it will decrease withdrawal symptoms, as well as characterize lateral habenula activity during psilocybin administration. Exploring the behavioral and neurological effects of a new therapy will hopefully pave the way for better, more effective therapies.