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Abstract
Nicotine is known to enhance long-term hippocampus dependent learning and memory in both rodents and humans via its activity at nicotinic acetylcholinergic receptors (nAChRs). However, the molecular basis for the nicotinic modulation of learning is incompletely understood. Both the mitogen activated protein kinases (MAPKs) and cAMP response element binding protein (CREB) are known to be integral to the consolidation of long-term memory and the disruption of MAPKs and CREB are known to abrogate some of the cognitive effects of nicotine. In addition, the acquisition of contextual fear conditioning in the presence of nicotine is associated with a β2-subunit containing nAChR-dependent increase in jnk1 (mapk8) transcription in the hippocampus. In the present study, chromatin immunoprecipitation (ChIP) was used to examine whether learning and nicotine interact to alter transcription factor binding or histone acetylation at the jnk1 promoter region. The acquisition of contextual fear conditioning in the presence of nicotine resulted in an increase in phosphorylated CREB (pCREB) binding to the jnk1 promoter in the hippocampus in a β2-subunit containing nAChR dependent manner, but had no effect on CREB binding; neither fear conditioning alone nor nicotine administration alone altered transcription factor binding to the jnk1 promoter. In addition, there were no changes in histone H3 or H4 acetylation at the jnk1 promoter following fear conditioning in the presence of nicotine. These results suggest that contextual fear learning and nicotine administration act synergistically to produce a unique pattern of protein activation and gene transcription in the hippocampus that is not individually generated by fear conditioning or nicotine administration alone.
Highlights
Modulation of nicotinic acetylcholine receptors via acute nicotine administration is known to enhance a number of learning and memory tasks in both rodents and humans with hippocampus dependent tasks being susceptible to modulation [1,2,3]
The samples were analyzed for the presence of the long interspersed nuclear element 1 (LINE1) retrotransposon, elements that makes up approximately 20% of the mouse genome [35] but are not typically expressed at high levels due to the accumulation of mutations and repressive epigenetic modifications [36]. Quantitative Polymerase Chain Reaction (qPCR) analysis of hippocampi subjected to chromatin immunoprecipitation (ChIP) indicated that there was a high level of binding of cAMP response element binding protein (CREB) to the CRE site in the nr4a2 promoter, with somewhat less binding in the jnk1 promoter region and very little binding to LINE1 (Figure 1B)
Tukey post-hoc tests revealed that binding of CREB to the nr4a2 promoter was greater than all other regions (p,0.05) and that binding to the genetic regions covered by the primer sets jnk1a and jnk1b were greater than LINE1 (p9s,0.05)
Summary
Modulation of nicotinic acetylcholine receptors (nAChRs) via acute nicotine administration is known to enhance a number of learning and memory tasks in both rodents and humans with hippocampus dependent tasks being susceptible to modulation [1,2,3]. Infusions of antagonists to high affinity b2-subunit containing nAChRs into the hippocampus prevent the systemic nicotine induced enhancement of contextual and trace fear conditioning [4,6] suggesting that nicotine acting in the hippocampus is sufficient but necessary to enhance learning. We have previously found that the c-jun N-terminal kinase 1 (JNK1 known as MAPK8) gene is upregulated in the hippocampus during the consolidation of a nicotine enhanced contextual fear memory; this effect is mediated through b2-subunit containing nAChRs [15] Taken together, these data suggest that downstream effectors of ERK may be important for the transcriptional regulation of jnk that is involved in the nicotineinduced enhancement of contextual fear conditioning
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