title: Perturbed neural activity disrupts cerebral angiogenesis during a postnatal critical period.
abstract: During the neonatal period, activity-dependent neural-circuit remodelling coincides with growth and refinement of the cerebral microvasculature. Whether neural activity also influences the patterning of the vascular bed is not known. Here we show in neonatal mice, that neither reduction of sensory input through whisker trimming nor moderately increased activity by environmental enrichment affects cortical microvascular development. Unexpectedly, chronic stimulation by repetitive sounds, whisker deflection or motor activity led to a near arrest of angiogenesis in barrel, auditory and motor cortices, respectively. Chemically induced seizures also caused robust reductions in microvascular density. However, altering neural activity in adult mice did not affect the vasculature. Histological analysis and time-lapse in vivo two-photon microscopy revealed that hyperactivity did not lead to cell death or pruning of existing vessels but rather to reduced endothelial proliferation and vessel sprouting. This anti-angiogenic effect was prevented by administration of the nitric oxide synthase (NOS) inhibitor L-NAME and in mice with neuronal and inducible NOS deficiency, suggesting that excessive nitric oxide released from hyperactive interneurons and glia inhibited vessel growth. Vascular deficits persisted long after cessation of hyperstimulation, providing evidence for a critical period after which proper microvascular patterning cannot be re-established. Reduced microvascular density diminished the ability of the brain to compensate for hypoxic challenges, leading to dendritic spine loss in regions distant from capillaries. Therefore, excessive sensorimotor stimulation and repetitive neural activation during early childhood may cause lifelong deficits in microvascular reserve, which could have important consequences for brain development, function and pathology.
authors.affiliation: 1] Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06511, USA [2] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Whiteus
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Catarina
authors.initials: C
authors.lastname: Freitas
authors.affiliation: 1] Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06511, USA [2] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Grutzendler
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development*; D001808:Blood Vessels / Q000254:growth & development*; D002196:Capillaries / Q000378:metabolism; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000098:blood supply* / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D005260:Female; D002534:Hypoxia, Brain / Q000378:metabolism; D007395:Interneurons / Q000378:metabolism; D008297:Male; D051379:Mice; D008833:Microcirculation; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000172:deficiency; D010100:Oxygen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014738:Vibrissae / Q000502:physiology
chemical_list: D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester