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The Journal of Neuroscience, February 27, 2008, 28(9):2025-2032; doi:10.1523/JNEUROSCI.5273-07.2008

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Behavioral/Systems/Cognitive
Induction of Activating Transcription Factors (ATFs) ATF2, ATF3, and ATF4 in the Nucleus Accumbens and Their Regulation of Emotional Behavior

Thomas A. Green,¹ Imran N. Alibhai,¹ Stephen Unterberg,¹ Rachael L. Neve,² Subroto Ghose,¹ Carol A. Tamminga,¹ and Eric J. Nestler¹

¹Departments of Psychiatry and Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, and ²McLean Hospital, Department of Psychiatry, Harvard University School of Medicine, Belmont, Massachusetts 02478

Correspondence should be addressed to Eric J. Nestler at the above address. Email: eric.nestler{at}utsouthwestern.edu

Previous research has shown that cAMP response element (CRE) binding protein (CREB) in the nucleus accumbens gates behavioral responses to emotional stimuli. For example, overexpression of CREB decreases anxiety, sucrose preference, and sensitivity to drugs of abuse and increases depression-like behavior, whereas blocking CREB via overexpression of inducible cAMP early repressor (ICER) or other dominant-negative inhibitors of CRE-mediated transcription has the opposite effects. However, CREB and ICER are but two members of a larger family of leucine zipper-containing transcription factors composed of multiple products of the creb, crem (cAMP response element modulator), and atf (activating transcription factor) genes. We demonstrate here that ATF2, ATF3, and ATF4 are each robustly induced in the nucleus accumbens and dorsal striatum by restraint stress or by amphetamine administration. In contrast, little induction is seen for ATF1 or CREM. Using viral-mediated gene transfer, we show that ATF2 overexpression in nucleus accumbens produces increases in emotional reactivity and antidepressant-like responses, a behavioral phenotype similar to that caused by dominant-negative antagonists of CREB. In contrast, ATF3 or ATF4 overexpression in nucleus accumbens decreases emotional reactivity and increases depression-like behavior, consistent with the behavioral phenotype induced by CREB. Because amphetamine and stress induce ATF2, ATF3, and ATF4 in nucleus accumbens, and overexpression of these transcription factors in this brain region in turn alters behavioral responsiveness to amphetamine and stress, our findings support novel roles for these ATF family members in regulating emotional behavior.

Key words: elevated plus maze; anhedonia; porsolt; forced swim test; addiction; anxiety; drugs of abuse; stimulants; CREB; CREM; striatum; sucrose preference; neophobia; behavior; CRE-BP1; CREB2

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Received Dec. 27, 2006; revised Jan. 9, 2008; accepted Jan. 9, 2008.

Correspondence should be addressed to Eric J. Nestler at the above address. Email: eric.nestler{at}utsouthwestern.edu

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