In both humans and rodents, males typically excel on a number of tasks requiring spatial ability. However, human females exhibit advantages in memory for the spatial location of objects. This study investigated whether rats would exhibit similar sex differences on a task of object location memory (OLM) and on the watermaze (WM). We predicted that females should outperform males on the OLM task and that males should outperform females on the WM. To control for possible effects of housing environment, rats were housed in either complex environments or in standard shoebox housing. Eighty Long-Evans rats (40 males and 40 females) were housed in either complex (Complex rats) or standard shoebox housing (Control rats). Results indicated that males had superior performance on the WM, whereas females outperformed males on the OLM task, regardless of housing environment. As these sex differences cannot be easily attributed to differences in cognitive style related to linguistic processing of environmental features or to selection pressures related to the hunting gathering evolutionary prehistory of humans, these data suggest that sex differences in spatial ability may be related to traits selected for by polygynous mating strategies.

The proteinase-activated receptors (PARs) are a novel family of G protein-coupled receptors, and their effects in neurodegenerative diseases remain uncertain. Alzheimer’s disease (AD) is a neurodegenerative disorder defined by misfolded protein accumulation with concurrent neuroinflammation and neuronal death. We report suppression of proteinase-activated receptor-2 (PAR2) expression in neurons of brains from AD patients, whereas PAR2 expression was increased in proximate glial cells, together with up-regulation of proinflammatory cytokines and chemokines and reduced IL-4 expression (p < 0.05). Glial PAR2 activation increased expression of formyl peptide receptor-2 (p < 0.01), a cognate receptor for a fibrillar 42-aa form of β-amyloid (Aβ1–42), enhanced microglia-mediated proinflammatory responses, and suppressed astrocytic IL-4 expression, resulting in neuronal death (p < 0.05). Conversely, neuronal PAR2 activation protected human neurons against the toxic effects of Aβ1–42 (p < 0.05), a key component of AD neuropathogenesis. Amyloid precursor protein-transgenic mice, displayed glial fibrillary acidic protein and IL-4 induction (p < 0.05) in the absence of proinflammatory gene up-regulation and neuronal injury, whereas PAR2 was up-regulated at this early stage of disease progression. PAR2-deficient mice, after hippocampal Aβ1–42 implantation, exhibited enhanced IL-4 induction and less neuroinflammation (p < 0.05), together with improved neurobehavioral outcomes (p < 0.05). Thus, PAR2 exerted protective properties in neurons, but its activation in glia was pathogenic with secretion of neurotoxic factors and suppression of astrocytic anti-inflammatory mechanisms contributing to Aβ1–42-mediated neurodegeneration.

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