Obesity-induced type 2 diabetes impairs neurological recovery after stroke in correlation with decreased neurogenesis and persistent atrophy of parvalbumin-positive interneurons

Abstract

Type 2 diabetes (T2D) hampers stroke recovery though largely undetermined mechanisms. Few preclinical studies have investigated the effect of genetic/toxin-induced diabetes on long-term stroke recovery. However, the effects of obesity-induced T2D are mostly unknown. We aimed to investigate whether obesity-induced T2D worsens long-term stroke recovery through the impairment of brain's self-repair mechanisms - stroke-induced neurogenesis and parvalbumin (PV)+ interneurons-mediated neuroplasticity. To mimic obesity-induced T2D in the middle-age, C57bl/6j mice were fed 12 months with high-fat diet (HFD) and subjected to transient middle cerebral artery occlusion (tMCAO). We evaluated neurological recovery by upper-limb grip strength at 1 and 6 weeks after tMCAO. Gray and white matter damage, stroke-induced neurogenesis, and survival and potential atrophy of PV-interneurons were quantitated by immunohistochemistry (IHC) at 2 and 6 weeks after tMCAO. Obesity/T2D impaired neurological function without exacerbating brain damage. Moreover, obesity/T2D diminished stroke-induced neural stem cell (NSC) proliferation and neuroblast formation in striatum and hippocampus at 2 weeks after tMCAO and abolished stroke-induced neurogenesis in hippocampus at 6 weeks. Finally, stroke resulted in the atrophy of surviving PV-interneurons 2 weeks after stroke in both non-diabetic and obese/T2D mice. However, after 6 weeks, this effect selectively persisted in obese/T2D mice. We show in a preclinical setting of clinical relevance that obesity/T2D impairs neurological functions in the stroke recovery phase in correlation with reduced neurogenesis and persistent atrophy of PV-interneurons, suggesting impaired neuroplasticity. These findings shed light on the mechanisms behind impaired stroke recovery in T2D and could facilitate the development of new stroke rehabilitative strategies for obese/T2D patients.