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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.

SUBMITTER: Whiteus C

PROVIDER: S-EPMC3947100 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Perturbed neural activity disrupts cerebral angiogenesis during a postnatal critical period.

Whiteus Christina C Freitas Catarina C Grutzendler Jaime J

Nature 20131204 7483

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 ...[more]

PMID: 24305053

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Project description:Study of the neural deficits caused by mismatched binocular vision in early childhood has predominantly focused on circuits in the primary visual cortex (V1). Recent evidence has revealed that neurons in mouse dorsolateral geniculate nucleus (dLGN) can undergo rapid ocular dominance plasticity following monocular deprivation (MD). It remains unclear, however, whether the long-lasting deficits attributed to MD during the critical period originate in the thalamus. Using in vivo two-photon Ca2+ imaging of dLGN afferents in superficial layers of V1 in female and male mice, we demonstrate that 14 d MD during the critical period leads to a chronic loss of binocular dLGN inputs while sparing response strength and spatial acuity. Importantly, MD leads to profoundly mismatched visual tuning properties in remaining binocular dLGN afferents. Furthermore, MD impairs binocular modulation, reducing facilitation of responses of both binocular and monocular dLGN inputs during binocular viewing. As predicted by our findings in thalamic inputs, Ca2+ imaging from V1 neurons revealed spared spatial acuity but impaired binocularity in L4 neurons. V1 L2/3 neurons in contrast displayed deficits in both binocularity and spatial acuity. Our data demonstrate that critical-period MD produces long-lasting disruptions in binocular integration beginning in early binocular circuits in dLGN, whereas spatial acuity deficits first arise from circuits further downstream in V1. Our findings indicate that the development of normal binocular vision and spatial acuity depend upon experience-dependent refinement of distinct stages in the mammalian visual system.SIGNIFICANCE STATEMENT Abnormal binocular vision and reduced acuity are hallmarks of amblyopia, a disorder that affects 2%-5% of the population. It is widely thought that the neural deficits underlying amblyopia begin in the circuits of primary visual cortex. Using in vivo two-photon calcium imaging of thalamocortical axons in mice, we show that depriving one eye of input during a critical period in development chronically impairs binocular integration in thalamic inputs to primary visual cortex. In contrast, visual acuity is spared in thalamic inputs. These findings shed new light on the role for developmental mechanisms in the thalamus in establishing binocular vision and may have critical implications for amblyopia.

Dataset Information

Perturbed neural activity disrupts cerebral angiogenesis during a postnatal critical period.

Publications

Perturbed neural activity disrupts cerebral angiogenesis during a postnatal critical period.

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