AIM2 inflammasome mediates hallmark neuropathological alterations and cognitive impairment in a mouse model of vascular dementia.

Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long-term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response-particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their downstream products (IL-1ß and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Polarized glial-cell activation, white-matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis, and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioral and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.

Test, rinse, repeat: A review of carryover effects in rodent behavioral assays.

Behavioral phenotyping has been gaining prominence due to the increased use of transgenic animal models of neurological disorders. Repeated testing in the same cohort of animals can reduce the overall number of animals used and is desired especially when animal numbers are difficult to obtain as well as for studies involving within-subject design such as drug treatments or aging. This review aims to provide researchers with a comprehensive overview of the carryover effects when subjecting the same set of animals to the same behavioral test. We have focused on three behavioral domains of testing: anxiety, cognition and depression. Based on a review of the literature and our own experiences as a neurobehavioral core facility, we have found that manipulating inter-test interval, environmental contextual cues and stimuli can mitigate the carryover effects to a large extent, although there are certain tests that still show strong residual effects. In addition, the effects of strain on carryover effects from repeated testing are also discussed in this review.