Altered emotional and locomotor responses in mice deficient in the transcription factor CREM

Maldonado, Rafaël; Smadja, Claire; Mazucchelli, Cristina; Sassone–Corsi, Paolo

doi:10.1073/pnas.96.24.14094

Cited by 66 publications

(48 citation statements)

References 44 publications

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“…Although the current behavioral experiments concern specific induction of ICER in the nucleus accumbens shell, another study found that deletion of all CREM gene products in mice causes hyperactivity and an anxiolytic-like phenotype (Maldonado et al, 1999). Our data raise the possibility that the anxiolytic phenotype seen in these mice may be attributable to the loss of ICER per se in the nucleus accumbens.…”

Section: Discussionmentioning

confidence: 51%

Induction of Inducible cAMP Early Repressor Expression in Nucleus Accumbens by Stress or Amphetamine Increases Behavioral Responses to Emotional Stimuli

et al. 2006

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Previous research has shown that cAMP response element (CRE)-mediated transcription is activated in the nucleus accumbens, a major brain reward region, by a variety of environmental stimuli and contributes to neuroadaptations to these stimuli. CRE-binding protein (CREB) is the most studied activator of CRE transcription and has been implicated in this brain region as a gating mechanism for behavioral responses to emotional stimuli. Little attention, however, has been given to naturally occurring inhibitors of CRE-mediated transcription, such as the inducible cAMP early repressor (ICER), an inhibitory product of the CRE modulator gene. In the present study, we investigated the extent to which ICER is induced in the nucleus accumbens by two types of environmental stimuli, stress and amphetamine, and characterized how induction of ICER in this region affects complex behavior. We show that stress and amphetamine each induces ICER expression and that overexpression of ICER in the nucleus accumbens, using viral-mediated gene transfer, increases behavioral responses to both rewarding and aversive emotional stimuli. For example, ICER overexpression increases sensitivity to amphetamine-stimulated locomotor activity as well as to natural rewards such as sucrose and social grooming. However, ICER overexpression also increases measures of anxiety in the elevated plus maze and neophobia to novel tastes. Finally, ICER produces an antidepressant-like effect in the forced swim test, further indication of an enhanced active response to stress. These results suggest that ICER is an important mechanism for modulating CRE-mediated transcription in the nucleus accumbens.

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Section: Discussionmentioning

confidence: 51%

Induction of Inducible cAMP Early Repressor Expression in Nucleus Accumbens by Stress or Amphetamine Increases Behavioral Responses to Emotional Stimuli

et al. 2006

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“…In this sense, the CREB-related transcription factor CREM has also been implicated in the control of emotional-like behavior as Crem À/À mice exhibit a rather complex alteration in emotional and locomotor behaviors. Indeed, Crem À/À mice show an increase in spontaneous locomotor activity and reduced anxiety-like behavior (Maldonado et al, 1999). These results underscore the complexity of the genetics and transcription factor balance underlying such behaviors, as CREB-deficient mice have increased the levels of both activator and repressor CREM isoforms and given that lack of CREM leads to an apparently contrasting phenotype (Maldonado et al, 1999).…”

Section: ) Inmentioning

confidence: 96%

“…Indeed, Crem À/À mice show an increase in spontaneous locomotor activity and reduced anxiety-like behavior (Maldonado et al, 1999). These results underscore the complexity of the genetics and transcription factor balance underlying such behaviors, as CREB-deficient mice have increased the levels of both activator and repressor CREM isoforms and given that lack of CREM leads to an apparently contrasting phenotype (Maldonado et al, 1999). In agreement with our results, mice with Creb1 aD mutation on a defined B6/129F1 background have also been reported to show anxiogeniclike responses in the elevated plus maze (Graves et al, 2002).…”

Section: ) Inmentioning

confidence: 99%

Modulation of Anxiety-Like Behavior and Morphine Dependence in CREB-Deficient Mice

Valverde

Mantamadiotis

Torrecilla

et al. 2004

Neuropsychopharmacol

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115

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The transcription factor cAMP-responsive element binding protein (CREB) has been shown to regulate different physiological responses including drug addiction and emotional behavior. Molecular changes including adaptive modifications of the transcription factor CREB are produced during drug dependence in many regions of the brain, including the locus coeruleus (LC), but the molecular mechanisms involving CREB within these regions have remained controversial. To further investigate the involvement of CREB in emotional behavior, drug reward and opioid physical dependence, we used two independently generated CREB-deficient mice. We employed the Cre/loxP system to generate mice with a conditional CREB mutation restricted to the nervous system, where all CREB isoforms are lacking in the brain (Creb1 NesCre ). A genetically defined cohort of the previously described hypomorphic Creb1 aD mice, in which the two major transcriptionally active isoforms (a and D) are disrupted throughout the organism, were also used. First, we investigated the responses to stress of the CREB-deficient mice in several paradigms, and we found an increased anxiogenic-like response in the both Creb1 mutant mice in different behavioral models. We investigated the rewarding properties of drugs of abuse (cocaine and morphine) and natural reward (food) using the conditioned place-preference paradigm. No modification of motivational responses of morphine, cocaine, or food was observed in mutant mice. Finally, we evaluated opioid dependence by measuring the behavioral expression of morphine withdrawal and electrophysiological recordings of LC neurons. We showed an important attenuation of the behavioral expression of abstinence and a decrease in the hyperactivity of LC neurons in both Creb1 mutant mice. Our results emphasize the selective role played by neuronal CREB in emotional-like behavior and the somatic expression morphine withdrawal, without participating in the rewarding properties induced by morphine and cocaine.

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“…CREM transcription factors play an important role in a variety of physiological systems including cardiac function (2,3), circadian rhythms (4) and locomotion (5). However, CREM is most notable for its role in fertility as male CREM deficient mice have a block in the maturation of sperm (6,7).…”

Section: Introductionmentioning

confidence: 99%

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

Liu

Lee

Adams

et al. 2007

Bone

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CREM belongs to the ATF/CREB family of basic leucine zipper transcription factors. We previously showed that PTH induces ICER (inducible cAMP early repressor) in osteoblasts. ICER proteins, which are transcribed from the P2 promoter of the CREM gene, act as transcriptional attenuators. The objective of this study was to determine whether the Crem gene plays a role in the response of bone to intermittent PTH. Adult Crem knockout (KO) and wild type (WT) male mice were given daily subcutaneous injections of vehicle or hPTH(1-34) (160 μg/kg) for 10 days. Bone mineral content and density (BMC and BMD, respectively) were measured in femur and tibia by dual energy X-ray absorptiometry (DEXA). Bone morphometry was analyzed by X-ray computed microtomography (microCT) and histomorphometry. Serum bone turnover markers were measured. In vitro osteoclast formation assays were performed in bone marrow cultures treated with PTH or the combination of RANKL and M-CSF. KO mice had slightly higher basal bone mass than wild type mice. PTH treatment increased tibial BMC and BMD to a greater extent in WT mice compared to KO mice. PTH increased both cortical area and trabecular bone area in WT but not in KO femurs. PTH increased the bone formation rate and percent osteoblast surface to the same extent in femurs of WT and KO mice but increased osteoclast parameters and calvarial porosity to a greater extent in KO mice. PTH increased serum osteocalcin levels to the same extent in WT and KO mice. PTHinduced osteoclast formation was 2-fold greater in bone marrow cultures from KO mice. Collectively, our data suggest that the Crem deficiency in mice alters the response of bone to intermittent PTH treatment such that osteoclastogenesis is increased. Crem gene may specify the anabolic response to intermittent PTH treatment by restraining PTH-induced osteoclastogenesis.

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Altered emotional and locomotor responses in mice deficient in the transcription factor CREM

Cited by 66 publications

References 44 publications

Induction of Inducible cAMP Early Repressor Expression in Nucleus Accumbens by Stress or Amphetamine Increases Behavioral Responses to Emotional Stimuli

Induction of Inducible cAMP Early Repressor Expression in Nucleus Accumbens by Stress or Amphetamine Increases Behavioral Responses to Emotional Stimuli

Modulation of Anxiety-Like Behavior and Morphine Dependence in CREB-Deficient Mice

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

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