1. ¹Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
2. ²Neuropathology Group, European Neuroscience Institute, Goettingen, Germany
3. ³Institute of Signaling, Developmental Biology and Cancer Research, CNRS, University of Nice Sophia Antipolis, Nice, France

Correspondence: Dr NC Tronson, Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, 303 E Chicago Avenue, Ward 9-188, Chicago, IL 60611, USA. Tel: +1 312 503 1379; Fax: +1 312 503 0466; E-mail: n-tronson@northwestern.edu

Received 1 May 2007; Revised 26 July 2007; Accepted 27 July 2007; Published online 22 August 2007.

Abstract

Human anxiety is frequently accompanied by depression, and when they co-occur both conditions exhibit greater severity and resistance to treatment. Little is known, however, about the molecular processes linking these emotional and mood disorders. Based on previously reported phosphorylation patterns of extracellular signal-regulated kinase (ERK) in the brain, we hypothesized that ERK's upstream activators intertwine fear and mood regulation through their hippocampal actions. We tested this hypothesis by studying the upstream regulation of ERK signaling in behavioral models of fear and depression. Wild-type and ERK1-deficient mice were used to study the dorsohippocampal actions of the putative ERK activators: mitogen-activated and extracellular signal-regulated kinase (MEK), protein kinase C (PKC), and cAMP-dependent protein kinase (PKA). Mice lacking ERK1 exhibited enhanced fear extinction and reduced depression caused by overactivation of ERK2. Both behaviors were reversed by inhibition of MEK, however the extinction phenotype depended on hippocampal, whereas the depression phenotype predominantly involved extrahippocampal MEK. Unexpectedly, inhibition of PKC accelerated extinction and decreased depression by ERK-independent mechanisms, whereas inhibition of PKA did not produce detectable molecular or behavioral effects in the employed paradigm. These results indicate that, contrary to fear conditioning but similar to mood stabilization, extinction of fear required upregulation of MEK/ERK and downregulation of ERK-independent PKC signaling. The dissociation of these pathways may thus represent a common mechanism for fear and mood regulation, and a potential therapeutic option for comorbid anxiety and depression.