Adaptation to the environment is a central problem for all organisms, and adaptive behaviors are therefore essential for organismal life. Epigenetic mechanisms, notably DNA methylation, post-translational histone modification, and chromatin remodeling have been shown to regulate environmentally-responsive dynamic gene expression in the nervous systems of many organisms, facilitating adaptive behavioral repertoires. However, specific pathways responsible for the establishment, maintenance, and modification of neuronal gene expression patterns related to behavioral adaptation remain elusive. To address this problem, our lab studies behavioral epigenetics using two disparate and complementary systems: mammals and ants.
In mammals, memory formation is a central component of virtually all complex behaviors. This process involves plasticity of neuronal synapses, which is in part driven by activity-dependent transcriptional programs regulated by epigenetic mechanisms. Our lab has recently identified a strong connection between neuronal plasticity, epigenetics and cellular metabolism. In particular, we have shown that ACSS2 (acelyl-CoA synthetase 2) acts as a chromatin-bound transcriptional co-activator in hippocampal neurons, a brain area required for the formation of spatial memories. During formation and reconsolidation of spatial object memory, ACSS2 drives histone acetylation and transcription of immediate early genes with key functions in neuronal plasticity. This is achieved by the tight regulation of local acetyl-CoA levels that in turn fuel histone acetyltransferase activity. Strikingly, while dorsal hippocampal ACSS2 knock-down did not cause gross behavioral alterations, it specifically ablated spatial object recognition. Our data provide a better understanding for the role of the metabolic-epigenetic axis in memory and have far-reaching consequences for the treatment of cognitive and neuropsychiatric illnesses.
As a major biological source of acetate is alcohol metabolism in the liver, we next explored whether alcohol-derived acetate affects the epigenetic landscape in the brain following binge drinking. Indeed, using heavy isotope labeling in mice, we found that liver alcohol metabolism rapidly fuels histone acetylation in the brain by direct deposition of alcohol-derived acetyl groups onto histones in an ACSS2-dependent manner. In isolated primary hippocampal neurons in vitro and in mouse brain in vivo, acetate induced learning and memory-related transcriptional programs that were sensitive to ACSS2 inhibition. Strikingly, we found that ACSS2 is required for ethanol-induced associative learning, which underlies craving and relapse after protracted periods of abstinence. These findings establish a direct and dynamic link between peripheral alcohol metabolism and neuronal histone acetylation with significant therapeutic potential.
(a) ACSS2, in red, localizes to the cytoplasm in undifferentiated CAD neurons. ACSS2 was imaged by immunofluorescence microscopy in CAD cells. Immunostaining for DAPI (blue) and α-tubulin (α-tub, red) shows nuclei and cytoplasm, respectively. (b) ACSS2 localizes to the nucleus in differentiated CAD neurons.
Alcohol-derived acetate is incorporated into brain histone acetylation. A. We used stable isotope labeling of alcohol to trace alcohol metabolites in vivo. B. Using mass spectrometry, we found that alcohol-derived acetate is rapidly incorporated into histone acetylation in the brain. This incorporation was blocked by specific knock-down of ACSS2.
Dorsal hippocampal ACSS2 is required for alcohol-related learning. A. We used ethanol-induced conditioned place preference to test whether ACSS2 is required for the learning of alcohol-related contextual spatial information. B. We found that dorsal hippocampal knock-down of ACSS2 attenuated conditioned place preference to ethanol.
(a) Stereotactic surgery was performed to deliver knockdown vector into the dorsal hippocampus. Once recovered, habituated mice were trained in object location memory assay: three unique objects were placed in arena and each mouse was allowed to freely explore. Twenty-four hours later, mice were given a retention test in which one object was moved to a novel location. At training, control and ACSS2 knockdown mice exhibit no preference for any of three objects (TR O1–3). In the retention test, control mice show a preference for the novel object location (NL). In contrast, ACSS2 knockdown mice display no such preference, indicating a spatial memory defect.
Nativio R, Donahue G, Berson A, Lan Y, Amlie-Wolf A, Tuzer F, Toledo J, Gosai S, Gregory BD, Torres C, Trojanowski JQ, Wang LS, *Johnson FB, *Bonini NM, *Berger SL. (2018). Nature Neuroscience, in press. *co-corr authors