CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli

Abstract

The transcription factor cAMP response element (CRE)-binding protein (CREB) has been shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been shown to affect cocaine reward, suggesting an active role of CREB in adaptive processes that follow exposure to drugs of abuse. Using CRE-LacZ reporter mice, we show that not only rewarding stimuli such as morphine, but also aversive stimuli such as stress, activate CRE-mediated transcription in the nucleus accumbens shell. Using viral-mediated gene transfer to locally alter the activity of CREB, we show that this manipulation affects morphine reward, as well as the preference for sucrose, a more natural reward. We then show that local changes in CREB activity induce a more general syndrome, by altering reactions to anxiogenic, aversive, and nociceptive stimuli as well. Increased CREB activity in the nucleus accumbens shell decreases an animal's responses to each of these stimuli, whereas decreased CREB activity induces an opposite phenotype. These results show that environmental stimuli regulate CRE-mediated transcription within the nucleus accumbens shell, and that changes in CREB activity within this brain area subsequently alter gating between emotional stimuli and their behavioral responses. This control appears to be independent of the intrinsic appetitive or aversive value of the stimulus. The potential relevance of these data to addiction and mood disorders is discussed.T ranscription factors, by regulating protein expression, participate in neural plasticity and adaptation. Stimuli that change transcriptional activity in a brain structure may alter over time the way information is processed by that structure. At more integrated levels, this plasticity can lead to changes in the interaction between an individual and its environment. Examples include learning processes, and changes in perception, interpretation, and behavioral responses to environmental stimuli. The cAMP response element (CRE)-binding protein, CREB, is a constitutively expressed transcription factor activated by phosphorylation through the cAMP pathway and other intracellular signaling cascades (1). Within the central nervous system, CREB has been associated with learning and memory (2-6), as well as with molecular and behavioral changes induced by antidepressants (7, 8) and drugs of abuse (9-15). In these latter cases, changes in second messenger pathways activating CREB (7, 9), changes in CREB levels (12), and changes in CRE-mediated transcription (8, 15) have been observed in several discrete brain areas.The nucleus accumbens, a forebrain structure critical for reward and motivation (16-23), has a key role in reinforcing properties of drugs of abuse (12,(17)(18)(19)(20)(21). Chronic exposure to cocaine or to several other drugs of abuse increases cAMP levels and cAMP-dependent protein kinase (PKA) activity in the nucleus accumbens (9, 12). These adaptations cause...

Nicotinic acetylcholine receptor-mediated calcium signaling in the nervous system

“…Phosphorylated CREB also decreased in the NAc in mice following chronic consumption of nicotine in their drinking water [79] . Changes in phosphorylated CREB in the NAc are consistent with previous reports that decreased CREB activity in this region contributes to drug reinforcement [80] .…”

Increased Dopamine Receptor Activity in the Nucleus Accumbens Shell Ameliorates Anxiety during Drug Withdrawal

“…Furthermore, reduced dopaminergic signaling in the NAc is associated with emotional signs of nicotine withdrawal (Cryan et al, 2003;Paterson et al, 2007). Further confirmation that the mesolimbic dopaminergic system contributes to withdrawal from other addictive drugs would cohere with a growing body of literature demonstrating that it is also involved in a wide variety of aversive behaviors, including conditioned place aversion (Acquas et al, 1989;Calcagnetti and Schechter, 1991;Schechter and Meechan, 1994;Liu et al, 2008), fear conditioning (Borowski and Kokkinidis, 1996;Nader and LeDoux, 1999;Pezze and Feldon, 2004;Fadok et al, 2009;Muschamp et al, 2011), anxiety (Fride and Weinstock, 1988;Barrot et al, 2002;Barrot et al, 2005;Meloni et al, 2006;Rezayof et al, 2009;Richard and Berridge, 2011;Zweifel et al, 2011), intrinsic aversion to gustatory cues (Roitman et al, 2008), conditioned taste aversion Fenu et al, 2001), responses to stress (Geyer and Segal, 1974;Herman et al, 1982;Inglis and Moghaddam, 1999;Belda and Armario, 2009), and responses to nociceptive stimulation (Gear et al, 1999;Becerra et al, 2001;Barrot et al, 2002).…”

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

“…These results suggest that the age-dependent cognitive impairment of Tg-hCTF99/B6 mice could be related to a CREBrelated signaling pathway. Moreover, CREB activity in the nucleus accumbens was found to influence anxiety-like behavioral responses (Barrot et al, 2002). And, because Tg-hCTF99/B6 mice showed anxiety-like behaviors in the elevated plus maze (Fig.…”