title: Induction of activating transcription factors (ATFs) ATF2, ATF3, and ATF4 in the nucleus accumbens and their regulation of emotional behavior.
abstract: 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.
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Green
authors.forename: Imran N
authors.initials: IN
authors.lastname: Alibhai
authors.forename: Stephen
authors.initials: S
authors.lastname: Unterberg
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Subroto
authors.initials: S
authors.lastname: Ghose
authors.forename: Carol A
authors.initials: CA
authors.lastname: Tamminga
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism*; D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D005518:Food Preferences / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D008297:Male; D018782:Maze Learning / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000378:metabolism / Q000473:pathology*; D013550:Swimming; D013997:Time Factors
chemical_list: D051698:Activating Transcription Factor 2; D051700:Activating Transcription Factor 3; C497107:Atf2 protein, rat; C497108:Atf3 protein, rat; C497110:Atf4 protein, rat; D000697:Central Nervous System Stimulants; D012333:RNA, Messenger; D051701:Activating Transcription Factor 4; D049452:Green Fluorescent Proteins; D000661:Amphetamine