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.

No abstract

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.

Background: Recent evidence suggests that epigenetic mechanisms have an important role in the development of addictive behavior. However, little is known about the role of epigenetic mechanisms in the extinction of drug-induced behavioral changes. In this study we examined the ability of histone deacetylase (HDAC) inhibitors to facilitate extinction and attenuate reinstatement of cocaine-induced conditioned place preference (CPP). Methods: C57BL/6 mice were subject to cocaine-induced CPP using 20mg/kg dose. To facilitate extinction, mice were administered an HDAC inhibitor following non-reinforced exposure to the conditioned context. To measure persistence, mice were subject to a reinstatement test using 10mg/kg dose of cocaine. Results: We demonstrate that HDAC inhibition during extinction consolidation can facilitate extinction of cocaine-induced CPP. Animals treated with an HDAC inhibitor extinguished cocaine-induced CPP both more quickly and to a greater extent than did vehicle-treated animals. We also show that the extinction of context-drug associated memories via HDAC inhibition modulates extinction learning such that reinstatement behavior is significantly attenuated. Acetylation of histone H3 in the nucleus accumbens following extinction was increased by HDAC inhibition. Conclusions: This study provides the first evidence that modulation of chromatin modification can facilitate extinction and prevent reinstatement of drug-induced behavioral changes. These findings provide a potential novel approach to the development of treatments that facilitate extinction of drug-seeking behavior.

Spaced training is generally more effective than massed training for learning and memory, but the molecular mechanisms underlying this trial spacing effect remain poorly characterized. One potential molecular basis for the trial spacing effect is the differential modulation, by distinct temporal patterns of neuronal activity, of protein synthesis-dependent processes that contribute to the expression of specific forms of synaptic plasticity in the mammalian brain. Long-term potentiation (LTP) is a type of synaptic modification that may be important for certain forms of memory storage in the mammalian brain. To explore the role of protein synthesis in the trial spacing effect, we assessed the protein synthesis dependence of hippocampal LTP induced by 100-Hz tetraburst stimulation delivered to mouse hippocampal slices in either a temporally massed (20-s interburst interval) or spaced (5-min interburst interval) fashion. To extend our studies to the behavioral level, we trained mice in fear conditioning using either a massed or spaced training protocol and examined the sensitivity of long-term memory to protein synthesis inhibition. Larger LTP was induced by spaced stimulation in hippocampal slices. This improvement of synaptic potentiation following temporally spaced synaptic stimulation in slices was attenuated by bath application of an inhibitor of protein synthesis. Further, the maintenance of LTP induced by spaced synaptic stimulation was more sensitive to disruption by anisomycin than the maintenance of LTP elicited following massed stimulation. Temporally spaced behavioral training improved long-term memory for contextual but not for cued fear conditioning, and this enhancement of memory for contextual fear was also protein synthesis dependent. Our data reveal that altering the temporal spacing of synaptic stimulation and behavioral training improved hippocampal LTP and enhanced contextual long-term memory. From a broad perspective, these results suggest that the recruitment of protein synthesis-dependent processes important for long-term memory and for long-lasting forms of LTP can be modulated by the temporal profiles of behavioral training and synaptic stimulation.

Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine’s function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes.