ACUTE STRESS FACILITATES LONG-LASTING CHANGES IN CHOLINERGIC GENE-EXPRESSION

Acute traumatic stress may lead to post-traumatic stress disorder (PTS D)(1), which is characterized by delayed neuropsychiatric symptoms inc luding depression, irritability, and impaired cognitive performance(2) . Curiously, inhibitors of the acetylcholine-hydrolysing enzyme acetyl cholinesterase may induce psychopathologies that are reminiscent of PT SD3,4. It is unknown how a single stressful event mediates long-term n euronal plasticity. Moreover, no mechanism has been proposed to explai n the convergent neuropsychological outcomes of stress and of acetylch olinesterase inhibition. However, acute stress elicits a transient inc rease in the amounts released of the neurotransmitter acetylcholine an d a phase of enhanced neuronal excitability(5). Inhibitors of acetylch olinesterase also promote enhanced electrical brain activity(6), presu mably by increasing the survival of acetylcholine at the synapse. Here we report that there is similar bidirectional modulation of genes tha t regulate acetylcholine availability after stress and blockade of ace tylcholinesterase. These calcium-dependent changes in gene expression coincide with phases of rapid enhancement and delayed depression of ne uronal excitability, Both of these phases are mediated by muscarinic a cetylcholine receptors, Our results suggest a model in which robust ch olinergic stimulation triggers rapid induction of the gene encoding th e transcription factor c-Fos. This protein then mediates selective reg ulatory effects on the long-lasting activities of genes involved in ac etylcholine metabolism.