Environmental enrichment produces a behavioral phenotype mediated by low cyclic adenosine monophosphate response element binding (CREB) activity in the nucleus accumbens.
BACKGROUND
Previous research has shown that rats reared in an enriched condition (EC) are more sensitive to the acute effects of amphetamine than rats reared in an isolated condition (IC); yet, EC rats self-administer less amphetamine than IC rats. The present study used cocaine to further explore this environmental enrichment behavioral phenotype, as well as the underlying molecular mechanisms involved.


METHODS
Enriched condition and IC rats were studied in a broad battery of behavioral tests, including cocaine conditioned place preference (CPP) and self-administration and several measures of anxiety- and depression-related behavior. The involvement of the transcription factor, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), in mediating EC versus IC differences was investigated.


RESULTS
Enriched condition rats exhibited less cocaine self-administration, despite showing enhanced cocaine CPP. Enriched condition rats also displayed less depression-like behavior but higher levels of anxiety-like behavior. This behavioral phenotype is consistent with low CREB activity in the nucleus accumbens, a key brain reward region. Indeed, EC rats have less phospho-CREB (the transcriptionally active form of the protein) in the nucleus accumbens than IC rats, and a selective knockdown of CREB in this brain region of normally reared rats, by use of a novel viral vector expressing a short hairpin RNA (shRNA) directed against CREB, reproduced the EC behavioral phenotype.


CONCLUSIONS
These studies identify a potential molecular mechanism for how rearing environment-a nonpharmacological, nonsurgical manipulation-can modify a wide range of complex emotional behaviors.
Green
Thomas A
TA
Departments of Psychiatry and Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas, USA. tom.green@utmb.edu
Alibhai
Imran N
IN
Roybal
C Nathaniel
CN
Winstanley
Catharine A
CA
Theobald
David E H
DE
Birnbaum
Shari G
SG
Graham
Ami R
AR
Unterberg
Stephen
S
Graham
Danielle L
DL
Vialou
Vincent
V
Bass
Caroline E
CE
Terwilliger
Ernest F
EF
Bardo
Michael T
MT
Nestler
Eric J
EJ
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology; D001526:Behavioral Symptoms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage; D003216:Conditioning, Operant / Q000187:drug effects; D003863:Depression / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004777:Environment; D005518:Food Preferences / Q000502:physiology; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D012646:Self Administration
D019208:Brain-Derived Neurotrophic Factor; D018765:Dopamine Uptake Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050882:CREB-Binding Protein; D003042:Cocaine