Systems-level identification and analysis of cellular circuits in the brain will require the development of whole-brain imaging with single-cell resolution. To this end, we performed comprehensive chemical screening to develop a whole-brain clearing and imaging method, termed CUBIC (clear, unobstructed brain imaging cocktails and computational analysis). CUBIC is a simple and efficient method involving the immersion of brain samples in chemical mixtures containing aminoalcohols, which enables rapid whole-brain imaging with single-photon excitation microscopy. CUBIC is applicable to multicolor imaging of fluorescent proteins or immunostained samples in adult brains and is scalable from a primate brain to subcellular structures. We also developed a whole-brain cell-nuclear counterstaining protocol and a computational image analysis pipeline that, together with CUBIC reagents, enable the visualization and quantification of neural activities induced by environmental stimulation. CUBIC enables time-course expression profiling of whole adult brains with single-cell resolution.

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Experience-induced expression of immediate-early gene Arc/Arg3.1 is known to play a pivotal role in the consolidation of memory. Here we use in-vivo longitudinal multiphoton imaging to show orchestrated activity-dependent expression of Arc in the mouse extrastriate visual cortex in response to a structured visual stimulation. In wild-type mice, the amplitude of the Arc response in individual neurons strongly predicts the probability of reactivation by a subsequent presentation of the same stimulus. In a mouse model of Alzheimer’s disease, this association is markedly disrupted in the cortex specifically near senile plaques. Neurons in the vicinity of plaques are less likely to respond but, paradoxically, there is stronger response in those few neurons around plaques that do respond. To the extent that the orchestrated pattern of Arc expression reflects nervous system responses to, and physiological consolidation of, behavioral experience, the disruption in Arc patterns reveals plaque-associated interference with neural network integration.

These results clearly demonstrate that gAd and fAd mediate distinct and time-dependent effects on cardiomyocyte energy metabolism via AdipoR1 and AdipoR2.

Background:The proinflammatory adipokine lipocalin-2 is associated with obesity-related complications, such as heart failure. Results: Lipocalin-2 induces cardiomyocyte apoptosis via elevating intracellular iron levels and mediates detrimental effects on cardiac function. Conclusion: Lipocalin-2 is an important mediator of cardiac remodeling. Significance: Regulation of cardiomyocyte apoptosis by lipocalin-2, and the mechanistic role of changes in intracellular iron, may contribute to the pathogenesis of obesity-related heart failure.