Understanding the Intricate Interplay Among Diabetes, Brain Function, and Mood Disorders

Depression and diabetes frequently occur together, and the presence of one disorder increases the risk for the other, but very little is known about the effects of diabetes on the brain. Major depressive disorder (MDD) is the leading cause of disability worldwide and the most common mood disorder.

The prevalence of MDD in people with diabetes is nearly double that in unaffected individuals, and measures of glucose control track with suicidal behavior and resistance to current treatments. With the growing epidemic of diabetes in our country and the significant impairments of depression and anxiety in individuals and on society, it is critical to understand how diabetes affects the brain to identify potential interventions.

Neuroimaging data examining the brains of people with diabetes point to circuits involved in mood and motivated behavior as being the most affected. If we think about motivated behavior as being key for survival—driving acquisition of food and resources—this is not surprising. The brain needs to coordinate survival needs, including metabolic state, with behavior.

In our society, where calories are plentiful and food is highly palatable, the coordination of motivated behavior and metabolic need breaks down. Inflammatory disease and cardiovascular disease, often complications of diabetes, also contribute to metabolic derangement and increased risk for mood dysregulation (see a related article about the work of Filip Swirski, PhD, and Scott J. Russo, PhD). Conversely, treatments for MDD, including commonly prescribed selective serotonin-reuptake inhibitors (SSRIs) and antipsychotic drugs used to augment SSRIs, induce weight gain and glucose dysregulation, highlighting the bidirectional relationship between metabolism and reward circuitry function. Indeed, metabolic interventions such as the ketogenic diet are now being tested to treat serious mood disorders such as bipolar disorder.

Research led by Jessica Ables, MD, PhD, is now taking a multidisciplinary approach to study how diabetes affects reward processing in animal models and how diabetes affects neurons within the brain’s reward circuitry that play a role in anhedonia and response to stressful stimuli. In collaboration with Brian Sweis, MD, PhD, and Romain Durand-de Cuttoli, PhD, the researchers have found that mice that lack insulin make different decisions about food compared to mice with intact insulin levels (see published work in Communications Biology).

In a neuroeconomics task called Restaurant Row, mice are trained to forage for different flavors of food on a time-limited budget, allowing for assessment of several different reward-based decision-making processes. Despite increased food consumption in the home cage, in this task, mice that lack insulin earned fewer pellets, caused in large part by a bias to seek their favorite flavor, even when the cost was high. The level of bias correlated with glycemic control measured by blood glucose and by hemoglobin A1C, suggesting that altered glucose metabolism was driving this behavior. The task also allows for evaluation of change-of-mind decisions, for example, choosing to accept an offer but leaving early before the pellet was dispensed. While normal mice display adaptive behavior that can be interpreted as “regret,” this was absent in mice that lack insulin. When mice were allowed to eat before the task, the insulin-deficient mice were willing to wait even longer for food, unlike the intact mice. Notably, restoration of insulin was not able to reverse the altered behavior, suggesting lasting alterations in neuronal function within the reward circuitry. Examination of neuronal activity in response to least or most preferred flavors points to differences in the nucleus accumbens, a key brain reward region.

Current work in the Ables Laboratory is now focused on understanding the molecular and circuit-level alterations induced by models of both type 1 and type 2 diabetes and how these contribute to altered reward-related behavior. (See Figure.)

Figure. Using mouse models of diabetes, the Ables lab, in collaboration with the Sweis Laboratory, has found that reward-based decision-making is disrupted, and the level of disruption correlates with glucose control. The Ables Laboratory is now using cellular and molecular approaches to probe which of the many changes in the brain induced by diabetes underlie the disrupted behavior and may contribute to mood disorders. Some of the areas of exploration include changes in gene expression, mitochondrial function, and neuronal activity.

In another recent publication, led by Mohammad Jodeiri Farshbaf, PhD, the medial habenula, a cholinergic nucleus linked to both mood and nicotine addiction (see related published work in Nature by Paul J. Kenny, PhD), demonstrated changes in the shape and size of energy-producing mitochondria, changes specific to this brain region. Interestingly, these changes occurred at six weeks after onset of increased glucose, but returned to normal by 12 weeks, suggesting that the mitochondria undergo adaptive metabolic reprogramming. Current efforts are now focused on understanding how gene expression changes in these neurons, and how neuronal activity in the circuit is altered as a result of diabetes. Future work will seek to understand whether these changes are reversible and how they relate to depressive behavior such as anhedonia, or the inability to feel pleasure, a key function of the medial habenula.

Understanding the intricate interplay among diabetes, brain function, and mood disorders will reveal new insights into the bidirectional relationship between metabolic and reward circuitry dysfunction. By uncovering the molecular and circuit-level mechanisms underlying these interactions, ongoing research holds the promise of identifying innovative therapeutic strategies to mitigate the debilitating effects of diabetes and its comorbid mood disorders, ultimately improving the quality of life for affected individuals.