Effects of diabetes on hippocampal neurogenesis: links to cognition and depression

Abstract

Diabetes often leads to a number of complications involving brain function, including cognitive decline and depression. In addition, depression is a risk factor for developing diabetes. A loss of hippocampal neuroplasticity, which impairs the ability of the brain to adapt and reorganize key behavioral and emotional functions, provides a framework for understanding this reciprocal relationship. The effects of diabetes on brain and behavioral functions in experimental models of type 1 and type 2 diabetes are reviewed, with a focus on the negative impact of impaired hippocampal neurogenesis, dendritic remodeling and increased apoptosis. Mechanisms shown to regulate neuroplasticity and behavior in diabetes models, including stress hormones, neurotransmitters, neurotrophins, inflammation and aging, are integrated within this framework. Pathological changes in hippocampal function can contribute to the brain symptoms of diabetes-associated complications by failing to regulate the hypothalamic-pituitary-axis, maintain learning and memory and govern emotional expression. Further characterization of alterations in neuroplasticity along with glycemic control will facilitate the development and evaluation of pharmacological interventions that could successfully prevent and/or reverse the detrimental effects of diabetes on brain and behavior.

Keywords: Cognition; Depression; Diabetes; Hippocampus; Neurogenesis; Neuroplasticity.

Figure 1

Caption The diabetic milieu showing pathological mechanisms contributing to neurobehavioral complications and examples of pathways that have been examined as therapeutic approaches. Diabetes leads to hyperglycemia, HPA axis dysregulation, and increased oxidative stress causing altered neuroplasticity in the brain resulting in symptoms such as depression and cognitive impairment. Various pharmacological and nonpharmacological interventions targeted at different pathological processes are depicted in the figure and discussed in the text. For instance, targeting the primary pathological mechanisms such as improved glycemic control (insulin, GLP-1 agonists), reversal of HPA axis dysregulation (mifepristone or ADX with CORT replacement), or oxidative stress can improve brain structure and function (neuroplasticity) and lead to improved behaviors (mood and cognition). GLP-1 agonists may improve behavior by combining two mechanisms, directly facilitating glycemic control and improving neuroplasticity. Fluoxetine is thought to produce antidepressant effects and counteract the impairing effects of stress on neuroplasticity through BDNF and TrKB signaling. Hypothesized relationships are described with a dotted line, while solid lines support relationships that have been demonstrated by scientific evidence.