Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance both memory and synaptic plasticity. The current model for the action of HDAC inhibitors assumes that they alter gene expression globally and thus affect memory processes in a nonspecific manner. Here, we show that the enhancement of hippocampus-dependent memory and hippocampal synaptic plasticity by HDAC inhibitors is mediated by the transcription factor cAMP response element-binding protein (CREB) and the recruitment of the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CBP) via the CREB-binding domain of CBP. Furthermore, we show that the HDAC inhibitor trichostatin A does not globally alter gene expression but instead increases the expression of specific genes during memory consolidation. Our results suggest that HDAC inhibitors enhance memory processes by the activation of key genes regulated by the CREB:CBP transcriptional complex.

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Noninvasive functional imaging holds great promise for serving as a translational bridge between human and animal models of various neurological and psychiatric disorders. However, despite a depth of knowledge of the cellular and molecular underpinnings of atypical processes in mouse models, little is known about the large-scale functional architecture measured by functional brain imaging, limiting translation to human conditions. Here, we provide a robust processing pipeline to generate high-resolution, wholebrain resting-state functional connectivity MRI (rs-fcMRI) images in the mouse. Using a mesoscale structural connectome (i.e., an anterograde tracer mapping of axonal projections across the mouse CNS), we show that rs-fcMRI in the mouse has strong structural underpinnings, validating our procedures. We next directly show that largescale network properties previously identified in primates are present in rodents, although they differ in several ways. Last, we examine the existence of the so-called default mode network (DMN)-a distributed functional brain system identified in primates as being highly important for social cognition and overall brain function and atypically functionally connected across a multitude of disorders. We show the presence of a potential DMN in the mouse brain both structurally and functionally. Together, these studies confirm the presence of basic network properties and functional networks of high translational importance in structural and functional systems in the mouse brain. This work clears the way for an important bridge measurement between human and rodent models, enabling us to make stronger conclusions about how regionally specific cellular and molecular manipulations in mice relate back to humans.connectivity | mouse | resting-state functional MRI | structural connectivity | default mode network U nderstanding the functional architecture of brain systems in both typical and atypical populations has the potential to improve diagnosis, prevention, and treatment of various neurologic and mental illnesses. Human functional neuroimaging, because of its ease of use, noninvasive nature, and wide availability, has significantly advanced this goal. However, because functional brain imaging is an indirect measure of the underlying neuronal dynamics (1), a number of basic questions about the molecular and structural underpinnings of these functional signals needs to be answered before the full clinical promise of the technique can be realized. Insight into these underpinnings would be vastly enhanced by translation to rodent models, where rich methodology for studying high-throughput genetic, histological, and therapeutic conditions in a tightly controlled environment exists. Mouse models, in particular, are likely to contribute significantly to this end.Efforts aimed at using mouse models to enrich findings obtained in humans with noninvasive imaging would benefit greatly from bridge measurements-measurements that can be obtained and compared directly between species, such as resting-...

Recent accounts of memory suggest that retrieval of a learning experience transforms that memory into a labile state that requires a period of protein synthesis to be reconsolidated into a fixed state. In this article, we show that the impairments in behavior caused by the protein synthesis inhibitor anisomycin given after retrieval are temporary and are thus not likely to reflect disruptions in a protein synthesis-dependent reconsolidation process. Mice received injections of anisomycin after either initial acquisition or retrieval of contextual fear conditioning. When anisomycin injections followed acquisition, freezing was impaired during memory tests the next day and 21 days later. When anisomycin injections followed normal retrieval of contextual fear conditioning, freezing was impaired the next day but recovered to levels of control mice when testing occurred 21 days later. This recovery effect occurred after short or long durations of exposure during the retrieval period and was specific to the conditioning context. These results suggest that anisomycin injections after retrieval do not retroactively affect the memory from conditioning.

Several recent studies have shown that chromatin, the DNA-protein complex that packages genomic DNA, has an important function in learning and memory. Dynamic chromatin modification via histone deacetylase (HDAC) inhibitors and histone acetyltransferases may enhance hippocampal synaptic plasticity and hippocampus-dependent memory. Little is known about the effects of HDAC inhibitors on extinction, a learning process through which the ability of a previously conditioned stimulus, such as a conditioning context, to evoke a conditioned response is diminished. The authors demonstrate that administration of the HDAC inhibitors sodium butyrate (NaB) systemically or trichostatin A (TSA) intrahippocampally prior to a brief (3-min) contextual extinction session causes context-evoked fear to decrease to levels observed with a long (24-min) extinction session. These results suggest that HDAC inhibitors may enhance learning during extinction and are consistent with other studies demonstrating a role for the hippocampus in contextual extinction. Molecular and behavioral mechanisms through which this enhanced extinction effect may occur are discussed.