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Stroke is one of the leading causes of adult disability worldwide. After ischemic stroke, damaged tissue surrounding the irreversibly damaged core of the infarct, the penumbra, is still salvageable and is therefore a target for acute therapeutic strategies. The Mediterranean diet (MD) has been shown to lower stroke risk. MD is characterized by increased intake of extra-virgin olive oil, of which hydroxytyrosol (HT) is the foremost phenolic component. This study investigates the effect of an HT-enriched diet directly after stroke on regaining motor and cognitive functioning, MRI parameters, neuroinflammation, and neurogenesis. Stroke mice on an HT diet showed increased strength in the forepaws, as well as improved short-term recognition memory probably due to improvement in functional connectivity (FC). Moreover, mice on an HT diet showed increased cerebral blood flow (CBF) and also heightened expression of brain derived neurotrophic factor (Bdnf), indicating a novel neurogenic potential of HT. This result was additionally accompanied by an enhanced transcription of the postsynaptic marker postsynaptic density protein 95 (Psd-95) and by a decreased ionized calcium-binding adapter molecule 1 (IBA-1) level indicative of lower neuroinflammation. These results suggest that an HT-enriched diet could serve as a beneficial therapeutic approach to attenuate ischemic stroke-associated damage.

Apolipoprotein E4 (ApoE4), one of three common isoforms of ApoE, is a major risk factor for late-onset Alzheimer disease (AD). ApoE-deficient mice, as well as mice expressing human ApoE4, display impaired learning and memory functions and signs of neurodegeneration. Moreover, ApoE protects against high-fat (HF) diet induced neurodegeneration by its role in the maintenance of the integrity of the blood-brain barrier. The influence of a HF diet on the progression of AD-like cognitive and neuropathological changes was assessed in wild-type (WT), human ApoE4 and ApoE-knockout (ApoE-/-) mice to evaluate the modulatory role of ApoE in this process. From 12 months of age, female WT, ApoE4, and ApoE-/- mice were fed either a standard or a HF diet (19% butter, 0.5% cholate, 1.25% cholesterol) throughout life. At 15 months of age mice performed the Morris water maze, evaluating spatial learning and memory. ApoE-/- showed increased spatial learning compared to WT mice (p = 0.009). HF diet improved spatial learning in WT mice (p = 0.045), but did not affect ApoE4 and ApoE-/- mice. Immunohistochemical analyses of the hippocampus demonstrated increased neuroinflammation (CD68) in the cornu ammonis 1 (CA1) region in ApoE4 (p = 0.001) and in ApoE-/- (p = 0.032) mice on standard diet. HF diet tended to increase CD68 in the CA1 in WT mice (p = 0.052), while it decreased in ApoE4 (p = 0.009), but ApoE-/- remained unaffected. A trend towards increased neurogenesis (DCX) was found in both ApoE4 (p = 0.052) and ApoE-/- mice (p = 0.068). In conclusion, these data suggest that HF intake induces different effects in WT mice compared to ApoE4 and ApoE-/- with respect to markers for cognition and neurodegeneration. We propose that HF intake inhibits the compensatory mechanisms of neuroinflammation and neurogenesis in aged female ApoE4 and ApoE-/- mice.

Our results highlight a differential role of serotonergic projections arising from the MRN and DRN in the regulation of cocaine intake. We propose that a cocaine-induced shift from MRN-driven serotonergic control of CRF levels in the hypothalamus to DRN-driven serotonergic control of CRF levels in the amygdala may contribute to the transition from moderate to compulsive intake of cocaine.