Scientist Stories: Valerie Darcey, Is your diet influencing your habits?

Hi, everyone. Thank you very much to the Next Generation Organizers for the opportunity to share some of my work, postdoctoral work, in the lab of Dr. Kevin Hall at the National Institute of Diabetes and Digestive and Kidney Diseases. We just heard some incredible mechanistic work, and I'm going to do more than switch gears. We're going to switch vehicles completely. It's incredible to know that we have all this molecular information, and now we want to know how this all translates to humans. Particularly with respect to complex behaviors. I study the neuroscience behind a complex behavior that's almost certainly vexed all of us. I'm sure we can all recall a time when we set out to either start a new positive behavior or stop a bad habit. We may have success towards our goal in the short term, but many times our old established habits prevail in the long term. Take the example of wanting to improve your health by adhering to a new diet. The enjoyment we get from our favorite food and the habit of reaching for it is governed largely by the striatum, while the prefrontal cortex helps us to control these desires, impulses, and habits that won't help us towards our new goal. But consider for a moment that our diets and the nutrients they do or do not provide constitutes a major environmental exposure. It's pretty widely accepted that our diet can affect the function of our peripheral organs, right, like our heart and our liver. I'll show you today that your diet can also causally affect the function of your brain, and specifically the neurochemistry of brain systems involved in reward and habit-driven behavior, which is the overarching goal of my work as a neuroscientist and registered dietitian, to bridge the gap between these largely siloed fields to answer the fundamental question about how aspects of our diet and nutritional status influence our brain and ultimately our behavior. My doctoral work found a link between the prefrontal function, impulse control, and a class of essential dietary nutrients, omega-3 fatty acids, in typically developing adolescents. Here though, I'll tell you about one example from my postdoctoral work on how diet might influence the striatum and the neurochemistry behind our desire for reward and habits, dopamine. You might already be familiar with the link between dopamine and reward, But central dopamine pathways also contribute to a range of processes, including reinforcement learning and routine or habitual behavior. Animal models and genetic tools give us great insights about dopamine system function and behavior. As a neuromodulatory neurotransmitter, dopamine can either increase or decrease the likelihood of subsequent neuronal activity in a receptor-subtype-dependent way. Previous work from our lab links the availability of the inhibitory dopamine D2 receptor to habit-driven eating in humans, so it's a focus of this work as well. To validate these preclinical insights and study how environmental inputs like diet contribute to the neuroscience of decision-making in humans, we need appropriate tools and techniques, though. We can measure the availability of D2 receptors using positron emission tomography, or PET for short. In which a radiolabeled tracer targets the receptor of interest. One limitation, though, is that it's difficult to tell whether a decrease in signal is a result of fewer receptors physically present versus the tracer being blocked by more endogenous dopamine or both. We can also use a strong magnetic field, as in functional magnetic resonance imaging or fMRI, to measure the brain's activity in response to certain stimuli. One limitation here, though, is that it's hard to resolve the specific neurochemical system responsible for that change in brain activity. By combining both of these tools, we can resolve limitations and determine the causal effect of manipulating environmental inputs on specific facets of brain function in humans. Regarding diet, perhaps one of the most famous dichotomies that's received the greatest attention is that of low-carbohydrate versus low-fat diets. Animal work tells us both, that both carbohydrate and fat influence central dopamine system function, but through distinct pathways. But there's no indication yet that these diets influence the dopamine system in the human brain. If we wanted to make a prediction though, we might look to how the periphery responds. Dietary carb and fat elicit distinct endocrine and metabolic effects in the periphery, such that while reducing dietary fat causes relatively few peripheral changes in, for example, insulin levels, how much adipose tissue is burned or used, by comparison, a reduced-carb diet promotes— produces more pronounced metabolic and endocrine changes, including elevated production of ketones. Based on the comparatively greater peripheral effects of a reduced-carb diet, We hypothesize then that the reduced carbohydrate diet will also impact central dopamine function. You might be thinking, I can't even remember what I ate for dinner last night, how can you be sure these people are reporting accurately? And you'd be right. Most neuroimaging studies in humans do not have control over dietary input. We use controlled feeding studies in an inpatient hospital setting so that we have precise, precise control over not only the timing of measurements, but also the timing, size, and composition of their meals. In this study, 15 healthy adults with obesity completed 2 14-day inpatient admissions where after eating a baseline control diet to keep them weight stable, they were randomized to consume either a reduced-carb diet followed by a reduced-fat diet or the reverse order. Now, this study design is key because it allows participants to serve as their own controls. Importantly, all 3 diets, including the baseline diet, were matched on protein content. And while the reduced fat and reduced carb diets were matched in total calories, the reduced carb diet— for the reduced carb diet, we cut their calories coming specifically from carbohydrates, and for the reduced fat diet, we cut their calories specifically from fat by an equal amount. With these tight controls, we can isolate the effect of the dietary manipulation on brain function after 5 days on each diet condition. So, while we were expecting that the reduced-carb diet was going to produce essential effects, we found something surprising. Contrary to the hypothesis, the reduced-fat but not reduced-carb diet decreased D2 receptor availability bilaterally in the dorsal aspect of the striatum from baseline. As exemplified here in this box plot of the reduction of binding in the right caudate shown in blue compared to the binding during the control diet shown in green. Let me pause for a second because this is really interesting. It's the first demonstration that in the same people each consuming the calorie and protein-matched reduced-fat and reduced-carb diets in random order, 5 days on a diet selectively reduced in fat but not carbohydrate reduces D2 receptor availability in the dorsal striatum. But remember now, it's challenging to interpret this decreased signal on its own, right? Because the same outcome could reflect less receptors physically present to bind, more endogenous dopamine displacing the tracer from the receptor, or a combination of the two. One of the things that we know about neurons that express D2 receptors is that the dopaminergic stimulation quiets down their activity. When we look at fMRI, our fMRI result on the next slide, that's exactly what we see. That only the reduced-fat diet resulted in a reduction in dorsal striatal response to food images during fMRI compared to viewing the same images while eating the control diet at baseline. As exemplified here in this box plot showing the reduced left putamen activity during the reduced-fat diet in blue compared to the control diet in in gold. Some elegant multimodal imaging studies of primates tell us that more endogenous dopamine binding to these inhibitory D2 receptors, which decreases our PET signal, also decreases the fMRI signal. These converging lines of evidence then point to the same answer, that the reduced-fat but not the reduced-carb diet increases synaptic dopamine function in the human— synaptic dopamine in the human brain. So, what is it about cutting down on dietary fat that's causing this effect on neurochemistry? Well, at this point we can only speculate on mechanisms, but one intriguing potential mechanism comes from elegant rodent work showing production of dietary fat-derived molecule in the gut can signal via the autonomic nervous system to influence striatal dopamine levels. And as far as what this means for dopamine-linked behaviors, even beyond how easy or difficult it is for you to stick to a new goal or a new diet in the long term remains to be seen, but now we have at least the first evidence of a diet-specific effect on neurochemistry in humans. As far as what's next, my ongoing work is exploring the link between another facet of nutritional status, body weight, and dopamine function in the context of habit-driven eating. Dopamine is also bidirectionally regulated by another neurochemical, GABA, and so my ongoing and future work will combine another tool, magnetic MR spectroscopy, with PET imaging to explore the effect of diet and body weight on GABA, dopamine, and behavioral control. Of course, to get at the fine-grained mechanism, my horizon will include collaborations with scientists to translate this work to genetic models. All towards the ultimate goal of determining whether we can help strengthen good habits or weaken bad ones just by changing what's on our plate. Thanks for tuning in, and a big thanks to Dr. Kevin Hall and the team members who contributed to these analyses. This work would not be possible without the support from Hall Lab members past and present, our collaborators and clinical center teams, and of course funding. Thank you.