Obesity Weighs down Memory through a Mechanism Involving the Neuroepigenetic Dysregulation of Sirt1.

Aberrant gene expression within the hippocampus has recently been implicated in the pathogenesis of obesity-induced memory impairment. Whether a dysregulation of epigenetic modifications mediates this disruption in gene transcription has yet to be established. Here we report evidence of obesity-induced alterations in DNA methylation of memory-associated genes, including Sirtuin 1 (Sirt1), within the hippocampus, and thus offer a novel mechanism by which SIRT1 expression within the hippocampus is suppressed during obesity. Forebrain neuron-specific Sirt1 knock-out closely recapitulated the memory deficits exhibited by obese mice, consistent with the hypothesis that the high-fat diet-mediated reduction of hippocampal SIRT1 could be responsible for obesity-linked memory impairment. Obese mice fed a diet supplemented with the SIRT1-activating molecule resveratrol exhibited increased hippocampal SIRT1 activity and preserved hippocampus-dependent memory, further strengthening this conclusion. Thus, our findings suggest that the memory-impairing effects of diet-induced obesity may potentially be mediated by neuroepigenetic dysregulation of SIRT1 within the hippocampus. SIGNIFICANCE STATEMENT: Previous studies have implicated transcriptional dysregulation within the hippocampus as being a relevant pathological concomitant of obesity-induced memory impairment, yet a deeper understanding of the basis for, and etiological significance of, transcriptional dysregulation in this context is lacking. Here we present the first evidence of epigenetic dysregulation (i.e., altered DNA methylation and hydroxymethylation) of memory-related genes, including Sirt1, within the hippocampus of obese mice. Furthermore, experiments using transgenic and pharmacological approaches strongly implicate reduced hippocampal SIRT1 as being a principal pathogenic mediator of obesity-induced memory impairment. This paper offers a novel working model that may serve as a conceptual basis for the development of therapeutic interventions for obesity-induced memory impairment.

Adult mice maintained on a high-fat diet exhibit object location memory deficits and reduced hippocampal SIRT1 gene expression.

Mounting evidence has established that diet-induced obesity (DIO) is associated with deficits in hippocampus-dependent memory. The bulk of research studies dealing with this topic have utilized rats fed a high-fat diet as an experimental model. To date, there has been a paucity of research studies that have established whether the memory deficits exhibited in DIO rats can be recapitulated in mice. Moreover, the majority of experiments that have evaluated memory performance in rodent models of DIO have utilized memory tests that are essentially aversive in nature (i.e., Morris water maze). The current study sought to fill an empirical void by determining if mice maintained on a high-fat diet exhibit deficits in two non-aversive memory paradigms: novel object recognition (NOR) and object location memory (OLM). Here we report that mice fed a high-fat diet over 23 weeks exhibit intact NOR, albeit a marked impairment in hippocampus-dependent OLM. We also determined the existence of corresponding aberrations in gene expression within the hippocampus of DIO mice. DIO mice exhibited significant reductions in both SIRT1 and PP1 mRNA within the hippocampus. Our data suggest that mice maintained on a high-fat diet present with impaired hippocampus-dependent spatial memory and a corresponding alteration in the expression of genes that have been implicated in memory consolidation.

Sound propagation in the vicinity of an isolated building: an experimental investigation.

Recently, the study of acoustics in urban terrain has been concerned with the propagation of sound through street canyons typical of residential areas in large cities, while sparsely built suburban and rural areas have received little attention. An isolated building's effect on propagating sound is a fundamental case of suburban acoustics and urban acoustics in general. Its study is a necessity in order to determine the processes that might be required to model the sound field in the building's vicinity, e.g., diffraction and wind effects. The work herein presents the results of an experimental effort to characterize the interaction between propagating sound and a single story, gabled-roof building typical of some North American suburban and rural areas. Recorded data are found to reasonably compare to a common diffraction model in some instances.