title: Single episode of mild murine malaria induces neuroinflammation, alters microglial profile, impairs adult neurogenesis, and causes deficits in social and anxiety-like behavior.
abstract: Cerebral malaria is associated with cerebrovascular damage and neurological sequelae. However, the neurological consequences of uncomplicated malaria, the most prevalent form of the disease, remain uninvestigated. Here, using a mild malaria model, we show that a single Plasmodium chabaudi adami infection in adult mice induces neuroinflammation, neurogenic, and behavioral changes in the absence of a blood-brain barrier breach. Using cytokine arrays we show that the infection induces differential serum and brain cytokine profiles, both at peak parasitemia and 15days post-parasite clearance. At the peak of infection, along with the serum, the brain also exhibited a definitive pro-inflammatory cytokine profile, and gene expression analysis revealed that pro-inflammatory cytokines were also produced locally in the hippocampus, an adult neurogenic niche. Hippocampal microglia numbers were enhanced, and we noted a shift to an activated profile at this time point, accompanied by a striking redistribution of the microglia to the subgranular zone adjacent to hippocampal neuronal progenitors. In the hippocampus, a distinct decline in progenitor turnover and survival was observed at peak parasitemia, accompanied by a shift from neuronal to glial fate specification. Studies in transgenic Nestin-GFP reporter mice demonstrated a decline in the Nestin-GFP(+)/GFAP(+) quiescent neural stem cell pool at peak parasitemia. Although these cellular changes reverted to normal 15days post-parasite clearance, specific brain cytokines continued to exhibit dysregulation. Behavioral analysis revealed selective deficits in social and anxiety-like behaviors, with no change observed in locomotor, cognitive, and depression-like behaviors, with a return to baseline at recovery. Collectively, these findings indicate that even a single episode of mild malaria results in alterations of the brain cytokine profile, causes specific behavioral dysfunction, is accompanied by hippocampal microglial activation and redistribution, and a definitive, but transient, suppression of adult hippocampal neurogenesis.
authors: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors: Suman K
authors: SK
authors: Guha
authors: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors: Rucha
authors: R
authors: Tillu
authors: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors: Ankit
authors: A
authors: Sood
authors: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors: Mandar
authors: M
authors: Patgaonkar
authors: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors: Ishira N
authors: IN
authors: Nanavaty
authors: Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors: Arjun
authors: A
authors: Sengupta
authors: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors: Shobhona
authors: S
authors: Sharma
authors: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India. Electronic address: vvaidya@tifr.res.in.
authors: Vidita A
authors: VA
authors: Vaidya
authors: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India. Electronic address: pathaksue@gmail.com.
authors: Sulabha
authors: S
authors: Pathak
mesh_terms: D000818:Animals; D001007:Anxiety / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008288:Malaria / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D017628:Microglia / Q000473:pathology*; D055495:Neurogenesis / Q000502:physiology*; D012919:Social Behavior
keywords: Cytokine; Doublecortin; Hippocampus; Infection; Neural stem cell; Neuroimmune; Open-field test; Plasmodium