Neurobehavioral and Imaging Correlates of Hippocampal Atrophy in a Mouse Model of Vascular Cognitive Impairment

Zuloaga, Kristen L.; Zhang, Wenri; Yeiser, Lauren A.; Stewart, Blair; Kukino, Ayaka; Nie, Xiao; Roese, Natalie; Grafe, Marjorie R.; Pike, Martin M.; Raber, Jacob; Alkayed, Nabil J.

doi:10.1007/s12975-015-0412-z

Cited by 46 publications

(58 citation statements)

References 18 publications

(42 reference statements)

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“…A remarkably positive correlation between hippocampal integrity and spatial cognitive functions has been confirmed by previous studies [29, 30]. The significantly improved spatial learning and memory observed in the Morris water maze led us to suspect that there might be more intact hippocampal neurons in post-ischemic mice receiving n-3 PUFAs.…”

Section: Resultssupporting

confidence: 73%

Delayed Docosahexaenoic Acid Treatment Combined with Dietary Supplementation of Omega-3 Fatty Acids Promotes Long-Term Neurovascular Restoration After Ischemic Stroke

Jiang

et al. 2016

Transl. Stroke Res.

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Prophylactic dietary intake of omega-3 polyunsaturated fatty acids (n-3 PUFAs) has been shown to remarkably ameliorate ischemic brain injury. However, the therapeutic efficacy of n-3 PUFA administration post stroke, especially its impact on neurovascular remodeling and long-term neurological recovery, has not been fully characterized thus far. In this study, we investigated the effect of n-3 PUFA supplementation, as well as in combination with docosahexaenoic acid (DHA) injections, on long-term stroke outcomes. Mice were subjected to transient middle cerebral artery occlusion (MCAO) before randomly assigned to 4 groups to receive: 1) low dose of n-3 PUFAs as the vehicle control; 2) intraperitoneal DHA injections; 3) n-3 PUFA dietary supplement; or 4) combined treatment of 2) and 3). Neurological deficits and brain atrophy, neurogenesis, angiogenesis, and glial scar formation were assessed up to 28 days after MCAO. Results revealed that groups 2 and 3 showed only marginal reduction in post-stroke tissue loss and attenuation of cognitive deficits. Interestingly, group 4 exhibited significantly reduced tissue atrophy and improved cognitive functions compared to groups 2 and 3 with just a single treatment. Mechanistically, the combined treatment promoted post-stroke neurogenesis and angiogenesis, and reduced glial scar formation, all of which significantly correlated with the improved spatial memory in the Morris water maze. These results demonstrate an effective therapeutic regimen to enhance neurovascular restoration and long-term cognitive recovery in the mouse model of MCAO. Combined post-stroke DHA treatment and n-3 PUFA dietary supplementation thus may be a potential clinically-translatable therapy for stroke or related brain disorders.

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Section: Resultssupporting

confidence: 73%

Delayed Docosahexaenoic Acid Treatment Combined with Dietary Supplementation of Omega-3 Fatty Acids Promotes Long-Term Neurovascular Restoration After Ischemic Stroke

Jiang

et al. 2016

Transl. Stroke Res.

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“…Several rodent models of VaD have been developed, most of which rely on induction of chronic cerebral hypoperfusion to induce VaD‐related pathology (Jiwa, Garrard, & Hainsworth, ). In mice, UCCAo model has been previously used to produce a variety of VaD pathologies including white matter damage, inflammation, neuronal degeneration, and cognitive deficits (Bink, Ritz, Aronica, van der Weerd, & Daemen, ; Yoshizaki et al, ; Zhao et al, ; Zuloaga et al, ). At 30 days following UCCAo, LCN2 expression was induced in hippocampal astrocytes, similar to that of the tBCCAo animal model (Figure a,b).…”

Section: Resultsmentioning

confidence: 99%

Astrocyte‐derived lipocalin‐2 mediates hippocampal damage and cognitive deficits in experimental models of vascular dementia

Kim

Lee

et al. 2017

Glia

133

152

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Lipocalin-2 (LCN2) has diverse functions in multiple pathophysiological conditions; however, its pathogenic role in vascular dementia (VaD) is unknown. Here, we investigated the role of LCN2 in VaD using rodent models of global cerebral ischemia and hypoperfusion with cognitive impairment and neuroinflammation. Mice subjected to transient bilateral common carotid artery occlusion (tBCCAo) for 50 min showed neuronal death and gliosis in the hippocampus at 7 days post-tBCCAo. LCN2 expression was observed predominantly in the hippocampal astrocytes, whereas its receptor was mainly detected in neurons, microglia, and astrocytes. Furthermore, Lcn2-deficient mice, compared with wild-type animals, showed significantly weaker CA1 neuronal loss, cognitive decline, white matter damage, blood-brain barrier permeability, glial activation, and proinflammatory cytokine production in the hippocampus after tBCCAo. Lcn2 deficiency also attenuated hippocampal neuronal death and cognitive decline at 30 days after unilateral common carotid artery occlusion (UCCAo). Furthermore, intracerebroventricular (i.c.v) injection of recombinant LCN2 protein elicited CA1-neuronal death and a cognitive deficit. Our studies using cultured glia and hippocampal neurons supported the decisive role of LCN2 in hippocampal neurotoxicity and microglial activation, and the role of the HIF-1α-LCN2-VEGFA axis of astrocytes in vascular injury. Additionally, plasma levels of LCN2 were significantly higher in patients with VaD than in the healthy control subjects. These results indicate that hippocampal damage and cognitive impairment are mediated by LCN2 secreted from reactive astrocytes in VaD.

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“…The capability of improving long-term neurofunctional outcomes after stroke is imperative for a potential therapy to be translated from bench to bedside [30–33]. Our recent study revealed beneficial effects of post-stroke DHA injections combined with FO dietary supplementation against stroke-induced cognitive decline [25].…”

Section: Resultsmentioning

confidence: 99%

A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia

Jiang

et al. 2016

Transl. Stroke Res.

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White matter injury induced by ischemic stroke elicits sensorimotor impairments, which can be further deteriorated by persistent proinflammatory responses. We previously reported that delayed and repeated treatments with omega-3 polyunsaturated fatty acids (n-3 PUFAs) improve spatial cognitive functions and hippocampal integrity after ischemic stroke. In the present study, we report a post-stroke n-3 PUFA therapeutic regimen that not only confers protection against neuronal loss in the gray matter but also promotes white matter integrity. Beginning 2 hours after 60 minutes of middle cerebral artery occlusion (MCAO), mice were randomly assigned to receive intraperitoneal docosahexaenoic acid (DHA) injections (10 mg/kg, daily for 14 days), alone or in combination with dietary fish oil (FO) supplements starting 5 days after MCAO. Sensorimotor functions, gray and white matter injury, and microglial responses were examined up to 28 days after MCAO. Our results showed that DHA and FO combined treatment facilitated long-term sensorimotor recovery and demonstrated greater beneficial effect than DHA injections alone. Mechanistically, n-3 PUFAs not only offered direct protection on white matter components, such as oligodendrocytes, but also potentiated microglial M2 polarization, which may be important for white matter repair. Notably, the improved white matter integrity and increased M2 microglia were strongly linked to the mitigation of sensorimotor deficits after stroke upon n-3 PUFA treatments. Together, our results suggest that post-stroke DHA injections in combination with FO dietary supplement benefit white matter restoration and microglial responses, thereby dictating long-term functional improvements.

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Neurobehavioral and Imaging Correlates of Hippocampal Atrophy in a Mouse Model of Vascular Cognitive Impairment

Cited by 46 publications

References 18 publications

Delayed Docosahexaenoic Acid Treatment Combined with Dietary Supplementation of Omega-3 Fatty Acids Promotes Long-Term Neurovascular Restoration After Ischemic Stroke

Delayed Docosahexaenoic Acid Treatment Combined with Dietary Supplementation of Omega-3 Fatty Acids Promotes Long-Term Neurovascular Restoration After Ischemic Stroke

Astrocyte‐derived lipocalin‐2 mediates hippocampal damage and cognitive deficits in experimental models of vascular dementia

A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia

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