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.
ACSS2 translocates to the nucleus during neuronal differentiation. ACSS2 localizes to the cytoplasm in undifferentiated CAD neurons. ACSS2 was imaged by immunofluorescence microscopy in CAD cells (4′,6-diamidino- 2-phenylindole (DAPI) and α-tubulin (α-Tub) immunostaining show nuclei and cytoplasm, respectively). b, ACSS2 localizes to the nucleus in differentiated CAD neurons.
ACSS2 knock-down in the dorsal hippocampus impairs object location memory. a, Stereotactic surgery was performed to deliver AAV9 knockdown vector into the dorsal hippocampus; 4 weeks later, habituated mice were trained in object location memory (OLM; four 5-min training sessions in arena with three different objects). Twenty-four hours later the mice were given a retention test in which one object was moved to a novel location. b, Western blot analysis of hippocampal tissue removed from mice injected into the dorsal (d) or ventral (v) hippocampus with either eGFP control or ACSS2 knockdown vector shows specific reduction of ACSS2 in dorsal hippocampus. c, ACSS2-knockdown mice are impaired in object location memory. eGFP control and shACSS2 AAV9 mice display no preference for any of three objects (O1–3) during the object location memory training session (TR). In the retention test 24 h later, control mice show a preference for the novel object location (NL), whereas the knockdown mice display no such preference. ***P < 0.001; n = 10, mean ± s.d. d, The spatial memory defect in ACSS2-knockdown mice manifests in a lowered discrimination index compared to control mice (*P = 0.02; n = 10, mean ± s.d.).
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