An investigation of hyperglycemia-induced region-specific changes in brain metabolism and behavior

This federal Project Grant award from the National Institute of Mental Health (NIMH) under the Mental Health Research Grants program (CFDA 93.242) provides $420,000 to Baylor University to conduct research on the relationship between hyperglycemia, brain metabolism, and depression. The key objectives are to:

1. Identify region-specific changes in brain metabolism in animal models of hyperglycemia.
2. Evaluate behavioral domains associated with these brain region changes.
3. Analyze mitochondrial structure, function, and gene expression related to inflammation and metabolism in the target brain regions.

The research aims to provide novel insights into the mechanisms underlying the "immuno-metabolic" subtype of depression, which may encompass up to 25% of all depressive cases. The grant was awarded on December 19, 2024 and has a planned completion date of December 18, 2027.

Abstract

Depression remains one of the leading causes of disability worldwide. Despite the number of pharmacological interventions, approximately one-third of patients are treatment resistant. The variability in treatment response suggests that there is diversity in the pathophysiological mechanisms of depression. Therefore, improving response rates will require a better understanding of their distinct pathophysiology and then personalize treatment. One proposed depressive subtype is immuno-metabolic depression. This is characterized by elevated levels of peripheral inflammation and increased expression of neurovegetative symptoms. This subtype may encompass up to 25% of all depressive cases. Individuals with chronic disease, such as diabetes and cardiovascular disease, are more likely than the general population to develop depression and are more likely to fall into this "immuno-metabolic" category. While there are descriptive studies on this depressive subtype, empirical studies directly examining the relationship between inflammation, metabolic dysfunction, and behavior in a region-specific manner are limited. Within this grant we aim to identify the region-specific changes in brain metabolism in two models of hyperglycemia and to evaluate behavioral domains associated with these brain regions. We propose to use multiple levels of region-specific tissue analyses including mitochondrial structure, mitochondrial function, and gene transcriptional changes related to inflammation and metabolism. We hypothesized that chronic hyperglycemia will induce region-specific neuroinflammation, mitochondrial dysfunction, and behavioral changes. We will focus on the hypothalamus, amygdala, basal ganglia, cerebellum, and auditory cortex as these regions represent areas with high and low expression of glucose sensing neurons. The proposed studies will provide novel insights into the mechanisms underlying immuno-metabolic depressive and may inform future personalized therapeutic interventions. These studies will also engage undergraduate students in meritorious research, helping to foster their enthusiasm for biomedical research careers.