Metabolic and Neuropsychiayric disorders: role of hippocampe plasticity

The prevalence of diabetes among the general population is of 5% and can reach 10% in elderly subjects. This metabolic disorder may have important consequences on the brain and the mental health. Indeed, it has been shown that diabetes accelerates cognitive decline and increases the risk of developing depressive symptoms, two markers of early ageing.  However, improving our life-style (well-balanced food, regular physical activity, enriched environment) helps people live longer, in better health with lower neuropsychiatric complications.  

Insulin might be instrumental in the relationships between metabolic and neuropsychiatric disorders. In agreement with this hypothesis, we have recently identified the insulin receptor in various cell types of the brain (neurons and astrocytes) notably in discrete areas involved in memory (hippocampus) and emotion (monoaminergic circuits). Remarkably, insulin resistance observed in peripheral tissues in diabetic mice fed an High Fat Diet, is also found in the brain. This leads us to envision that diabetes could cause negative effects on brain functioning. However, the underpinning mechanisms have yet to be solved.

In the team, we have raised the possibility that an impairment in brain insulin signaling could interfere with various forms of hippocampal plasticity such as the production of new neurons (neurogenesis), new astrocytes (gliogenesis) or a defect in the bidirectional dialogues between these cell types.  Using different in vivo and in vitro approaches combining electrophysiology, intracerebral microdialysis, behavioral analyses but also imaging and immunohistochemisty, we aim to better understand the links between insulin and the activity of the hippocampus in relevant animal models. The ultimate goal is to propose new pharmacological or non-pharmacological intrventions based on insulin-sensitizing strategies (either preventive or curative) to treat cognitive decline and mood disorders.  As an example, we have recently shown that metformin stimulates serotonergic neurotransmission in the hippocampus thereby favoring memory and reducing depressive-like phenotype.  We also test the possibility that such strategies might potentiate the beneficial effects of currently available antidepressant drugs.   

Finally, through the collaboration with clinicians (psychiatrists, gerontologists, epidemiologists), we have access to prospective cohorts of diabetic and/or depressed patients to validate our preclinical hypotheses to Human. This offers new opportunities to defy accelerated ageing related to metabolic disorders

The ongoing projects are :  

• The impact of high fat diet-induced T2DM and central insulin sensitivity on the electrophysiological and neurochemical activity of the serotonergic system and related adult hippocampal neurogenesis (Bruno Guiard, Claire Rampon)
• The impact of T2DM on the therapeutic activity of antidepressant drugs and their mechanism of action (Bruno Guiard)
• The identification of the beneficial effects of insulin-sensitizing strategies (physical exercice / antidiabetics / fish oil enriched diets) on mood and cognition in animal models of depression or Alzheimer’s disease (Bruno Guiard, Claire Rampon).
• The possibility that the comorbidity of metabolic and neuropsychiatric disorders is inherited accross several generations though epigenetic modifications (Bruno Guiard).

Funding