Hippocampal theta and gamma oscillations coordinate the timing of multiple inputs to hippocampal neurons and have been linked to information processing and the dynamics of encoding and retrieval. One major influence on hippocampal rhythmicity is from cholinergic afferents. In both humans and rodents, aging is linked to impairments in hippocampus-dependent function along with degradation of cholinergic function. Cholinomimetics can reverse some age-related memory impairments and modulate oscillations in the hippocampus. Therefore, one would expect corresponding changes in these oscillations and possible rescue with the cholinomimetic physostigmine. Hippocampal activity was recorded while animals explored a familiar or a novel maze configuration. Reexposure to a familiar situation resulted in minimal aging effects or changes in theta or gamma oscillations. In contrast, exploration of a novel maze configuration increased theta power; this was greater in adult than old animals, although the deficit was reversed with physostigmine. In contrast to the theta results, the effects of novelty, age, and/or physostigmine on gamma were relatively weak. Unrelated to the behavioral situation were an age-related decrease in the degree of theta-gamma coupling and the fact that physostigmine lowered the frequency of theta in both adult and old animals. The results indicate that age-related changes in gamma and theta modulation of gamma, while reflecting aging changes in hippocampal circuitry, seem less related to aging changes in information processing. In contrast, the data support a role for theta and the cholinergic system in encoding and that hippocampal aging is related to impaired encoding of new information.

Aging and stroke alter the composition of the basement membrane and reduce the perivascular distribution of cerebrospinal fluid and solutes, which may contribute to poor functional recovery in elderly patients. Following stroke, TGF-β induces astrocyte activation and subsequent glial scar development. This is dysregulated with aging and could lead to chronic, detrimental changes within the basement membrane. We hypothesized that TGF-β induces basement membrane fibrosis after stroke, leading to impaired perivascular CSF distribution and poor functional recovery in aged animals. We found that CSF entered the aged brain along perivascular tracts; this process was reduced by experimental stroke and was rescued by TGF-β receptor inhibition. Brain fibronectin levels increased with experimental stroke, which was reversed with inhibitor treatment. Exogenous TGF-β stimulation increased fibronectin expression, both in vivo and in primary cultured astrocytes. Oxygen-glucose deprivation of cultured astrocytes induced multiple changes in genes related to astrocyte activation and extracellular matrix

Cerebral amyloid angiopathy occurs after stroke, but the mechanism underlying the initial amyloid-β deposition is not fully understood. This study investigates whether overexpression of fibronectin and its receptor, integrin-α5, induces the perivascular deposition of cerebrospinal fluid-derived amyloid-β after stroke in young and aged animals. We found that stroke impaired the bulk flow of cerebrospinal fluid into the brain parenchyma and further showed that perivascular amyloid-β deposition was enhanced in aged animals with stroke, which colocalized with integrin-α5 in the basement membrane. Furthermore, we found that stroke dramatically increased the cortical levels of fibronectin and integrin-α5, with further increases in integrin-α5 in aged animals with stroke, fibronectin bound amyloid-β in vitro, and fibronectin administration increased amyloid-β deposition in vivo. Finally, aging and stroke impaired performance on the Barnes maze. These results indicate that fibronectin induces the perivascular deposition of amyloid-β and that increased integrin-α5 further "primes" the aged brain for amyloid-β binding. This provides a novel molecular and physiological mechanism for perivascular amyloid-β deposition after stroke, particularly in aged individuals.

Brain microvascular endothelial cells play an essential role in maintaining blood–brain barrier (BBB) integrity, and disruption of the BBB aggravates the ischemic injury. CaMKK (α and β) is a major kinase activated by elevated intracellular calcium. Previously, we demonstrated that inhibition of CaMKK exacerbated outcomes, conversely, overex-pression reduced brain injury after stroke in mice. Interestingly, CaMKK has been shown to activate a key endothelial protector, sirtuin 1 (SIRT1). We hypothesized that CaMKK protects brain endothelial cells via SIRT1 activation after stroke. In this study, Oxygen-Glucose Deprivation (OGD) was performed in human brain microvascular endothelial cells. Stroke was induced by middle cerebral artery occlusion (MCAO) in male mice. Knockdown of CaMKK β using siRNA increased cell death following OGD. Inhibition of CaMKK β by STO-609 significantly and selectively down-regulated levels of phos-phorylated SIRT1 after OGD. Changes in the downstream targets of SIRT1 were observed following STO-609 treatment. The effect of STO-609 on cell viability after OGD was absent, when SIRT1 was concurrently inhibited. We also demonstrated that STO-609 increased endothelial expression of the proinflammatory proteins ICAM-1 and VCAM-1 and inhibition of CaMKK exacerbated OGD-induced leukocyte-endothelial adhesion. Finally, intracerebroventricular injection of STO-609 exacerbated endothelial apoptosis and reduced BBB integrity after 24-hr reperfusion following MCAO in vivo. Collectively, these results demonstrated that CaMKK inhibition reduced endothelial cell viability, exacerbated inflammatory responses and aggravated BBB impairment after is-chemia. CaMKK activation may attenuate ischemic brain injury via protection of the microvascular system and a reduction in the infiltration of pro-inflammatory factors.

Stroke is the leading cause of acquired disability and the third leading cause of death in women worldwide. Sex differences in risk factors, treatment response and quality of life after stroke complicate stroke management in women. Women have an increased lifetime incidence of stroke compared to men, largely due to a sharp increase in stroke risk in older postmenopausal women. Women also have an increased lifetime prevalence of stroke risk factors, including hypertension and atrial fibrillation in postmenopausal women, as well as abdominal obesity and metabolic syndrome in middle-aged women. Controversy continues over the risks of oral contraceptives, hormone therapy and surgical intervention for carotid stenosis in women. Pregnancy and the postpartum period represent a time of increased risk, presenting challenges to stroke management. Recognition of these issues is critical to improving acute care and functional recovery after stroke in women.