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PubMed2005

Microtubule-independent and protein kinase A-mediated function of kinesin KIF17b controls the intracellular transport of activator of CREM in testis (ACT).

Kinesins are motor proteins that transport their cargos along microtubules in an ATP-dependent manner. The testis-specific kinesin KIF17b was shown to directly regulate cAMP-response element modulator (CREM)-dependent transcription by determining the subcellular localization of the activator of CREM in testis (ACT), the testis-specific coactivator of CREM in postmeiotic male germ cells. CREM is a crucial transcriptional regulator of many important genes required for spermatid maturation, as demonstrated by the complete block of sperm development at the first steps of spermiogenesis in crem-null mice. To better understand the complex regulation of postmeiotic germ cell differentiation, we further characterized the ACT-KIF17b interaction, the function of KIF17b, and the signaling pathways governing its action. In this study, we demonstrated that the abilities of KIF17b to shuttle between the nuclear and the cytoplasmic compartments and to transport ACT are neither dependent on its motor domain nor on microtubules, thus revealing a novel microtubule-independent function for kinesins. We also showed that the cyclic AMP-dependent protein kinase A mediates the phosphorylation of KIF17b, and this modification is important for its subcellular localization. These results indicate that cyclic AMP signaling controls CREM-mediated transcription in male germ cells through modification of KIF17b function.

Animals↗
PubMed1993

Induction of CREM activator proteins in spermatids: down-stream targets and implications for haploid germ cell differentiation.

The cAMP-responsive element modulator (CREM) gene encodes a family of transcriptional regulators that bind to promoter sequences activated by increased intracellular cAMP levels. Both activators and repressors are generated by alternative splicing and alternative translational initiation. During the development of male germ cells, there is a switch in the transcripts generated by CREM. Specifically, from the prophase of meiosis, there is an increase in the CREM tau activator transcript. Here we present results showing that expression of the CREM activator protein is restricted to postmeiotic germ cells. We show that CREM tau is efficiently phosphorylated at a serine residue at position 117 by the protein kinase-A endogenous to germ cells, indicating that it constitutes a natural target of the adenylyl cyclase pathway during spermatogenesis. Phosphorylation of serine-117 turns CREM tau into a powerful activator. The rise in CREM tau protein coincides with the transcriptional activation of several genes. We show that CREM tau efficiently binds to CREs present in the promoters of these genes, suggesting that they could constitute down-stream targets of CREM. We have analyzed in more detail the regulation of one of these genes, the male germ cell-specific RT7. The RT7 promoter is cAMP inducible and activated by CREM tau in transfection assays. The RT7 promoter is efficiently transcribed in vitro with nuclear extracts from seminiferous tubules. CREM-specific antibodies block RT7 in vitro transcription, implicating a role for CREM tau in a cascade of transcriptional events during spermatogenesis.

Animals↗
PubMed2001

Distribution and partial characterization of CREB-like immunoreactivity in the medicinal leech Hirudo.

The presence and distribution of immunoreactivity to the cyclic AMP response element binding protein (CREB) were determined in the central nervous system (CNS) and in peripheral tissues of the medicinal leech Hirudo. Western blots revealed several CREB-immunoreactive (CREB-IR) bands including one whose molecular weight (43-44 kDa) was similar to mammalian CREB. The 43-44 kDa CREB-like protein was detected in nuclear extracts of the ventral nerve cord and was not observed following preincubation of the primary antiserum with the epitope sequence. CREB-like immunoreactivity was detected in extracts from each of six regions of the leech CNS, and in extracts from leech body wall musculature, crop, intestine, jaw musculature, pharynx, and salivary tissues. Whole mounts of leech ganglia revealed specific CREB-IR in a restricted population of neurons distributed throughout the leech CNS. Apparent homologues to a pair of CREB-IR dorsolateral neurons were observed in most ganglia along the ventral nerve cord. Several CREB-IR neurons exhibited segmental specificity. A number of neurons stained with an antiserum to the cyclic AMP response element modulator (CREM). These neurons showed no overlap in location with CREB-IR neurons, and this staining was not eliminated with a preabsorption control. Possible roles for a CREB-like protein in the leech are discussed.

Animals↗
PubMed2005

Antisense-induced reduction in nucleus accumbens cyclic AMP response element binding protein attenuates cocaine reinforcement.

Repeated cocaine exposure up-regulates cyclic AMP signaling and increases the transcriptional activity of cyclic AMP response element binding protein (CREB) in the nucleus accumbens. To study the possibility that nucleus accumbens CREB activity regulates self-administration behavior, we tested the effects of a single, bilateral infusion of CREB antisense oligonucleotide into nucleus accumbens core and shell sub-regions on cocaine self-administration in rats. Nucleus accumbens core infusions of CREB antisense reduced CREB and the CREB-regulated immediate early gene brain-derived neurotrophic factor by 31 and 27%, respectively, but failed to alter levels of the homologous CREB family proteins cyclic AMP response element modulator and activating transcription factor 1, and had no effect on CREB levels in adjacent nucleus accumbens shell tissue. Similar infusions of CREB antisense in either core or shell produced a transient downward shift in cocaine self-administration dose-response curves on a fixed ratio 5 (five responses/injection) reinforcement schedule, indicating a reduction in cocaine reinforcement that fully recovered 3 days after treatment. CREB antisense also increased the threshold dose of cocaine required for reinstating cocaine self-administration, indicating that nucleus accumbens CREB levels regulate the incentive properties of cocaine. When access to cocaine was less restricted on a fixed ratio 1 schedule, infusion of CREB antisense in the core, but not shell, caused a transient (1-2 days) reduction in stabilized cocaine self-administration, but had no effect on responding maintained by sucrose pellets, indicating that basal CREB levels in the nucleus accumbens core regulate drug intake. None of these effects were produced by nucleus accumbens infusions of complementary sense oligonucleotide. These results suggest a necessary role for nucleus accumbens CREB activity in cocaine reinforcement, and, by converse analogy, up-regulation in CREB activity after chronic cocaine use could contribute to addiction-related increases in cocaine self-administration.

Animals↗
PubMed2003

Analysis of gene expression following norepinephrine stimulation in the rat pineal gland using DNA microarray technique.

Several studies have demonstrated that norepinephrine (NE) is the critical neurotransmitter for the regulation of gene expression in the pineal gland. We studied the acute effect of NE stimulation in cultured rat pineal glands using Affymetrix rat genome microarray GeneChip probe arrays. Our data demonstrate that NE stimulation affects regulation of several genes; 44 and 29 genes were up- or down-regulated more than 2.5-fold, respectively. As shown in previous studies, arylalkylamine N-acetyltransferase, cyclic AMP responsive element modulator, jun-B and c-fos mRNA levels were increased by NE stimulation. Genes that were not previously reported and increased by NE stimulation in the pineal gland were protein tyrosine phosphatase, nuclear receptors, and activity and neurotransmitter-induced early genes. Unlike up-regulated genes, most of the down-regulated genes were not reported previously. Genes encoding enzymes involved in metabolism and structural proteins were decreased following NE stimulation. Identification of genes affected by NE stimulation would provide valuable information to understanding pineal biology fully.

Adrenergic alpha-Agonists↗
PubMed2005

A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis.

cAMP plays crucial roles in cardiac remodeling and the progression of heart failure. Recently, we found that expression of cAMP hydrolyzing phosphodiesterase 3A (PDE3A) was significantly reduced in human failing hearts, accompanied by up-regulation of inducible cAMP early repressor (ICER) expression. Angiotensin II (Ang II) and the beta-adrenergic receptor agonist isoproterenol (ISO) also induced persistent PDE3A down-regulation and concomitant ICER up-regulation in vitro, which is important in Ang II- and ISO-induced cardiomyocyte apoptosis. We hypothesized that interactions between PDE3A and ICER may constitute an autoregulatory positive feedback loop (PDE3A-ICER feedback loop), and this loop would cause persistent PDE3A down-regulation and ICER up-regulation. Here, we demonstrate that ICER induction repressed PDE3A gene transcription. PDE3A down-regulation activated cAMP/PKA signaling, leading to ICER up-regulation via PKA-dependent stabilization of ICER. With respect to Ang II, the initiation of the PDE3A-ICER feedback loop depends on activation of Ang II type 1 receptor (AT1R), classical PKC(s), and CREB (cAMP response element binding protein). We further show that the PDE3A-ICER feedback loop is essential for Ang II-induced cardiomyocyte apoptosis. ISO and PDE3 inhibitors also induced the PDE3A-ICER feedback loop and subsequent cardiomyocyte apoptosis, highlighting the importance of this PDE3A-ICER feedback loop and cAMP signaling in cardiomyocyte apoptosis. Our findings may provide a therapeutic paradigm to prevent cardiomyocyte apoptosis and the progression of heart failure by inhibiting the PDE3A-ICER feedback loop.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2002

Biphasic developmental changes in Ca2+/calmodulin-dependent proteins in R6/2 Huntington's disease mice.

Widespread disturbances in calcium-dependent proteins are reported both in humans with advanced Huntington's disease (HD) and in symptomatic HD transgenic mice. Using a HD mouse model transgenic for exon 1 of the abnormal gene (e.g. the Bates R6/2 mouse), we found increased expression of calmodulin kinase IV and neuronal nitric oxide synthase (NOS) in 3-week-old presymptomatic HD mice striatum and cortex. Conversely, reduced expression was found at 6 weeks (early symptom onset) and 11 weeks (advanced disease) of age. The changes in protein expression may have a broad impact on the HD striatum. Calmodulin kinase IV directly regulates the activation of the transcription factors CREB (cyclic AMP response element binding protein) and CREM (cyclic AMP response element modulator) and, as well, modulates the activity of neuronal NOS. In homeostasis, nitric oxide is involved in long-term potentiation, neurotransmission, endocrine regulation and cerebral blood flow regulation, among others, while under pathological conditions nitric oxide combines with superoxide to produce the potent neurotoxin peroxynitrite. The current findings suggest that mutant HD protein may alter these processes by disturbing the regulation of calmodulin kinase IV and neuronal NOS expression across the lifespan of the HD mouse.

Animals↗
PubMed1993

Transcription of the rat glucagon gene by the cyclic AMP response element-binding protein CREB is modulated by adjacent CREB-associated proteins.

The cyclic AMP (cAMP) response element (CRE) of the rat glucagon gene (Glu-CRE, 5'-TGACGTCA-3') mediates transcriptional responses to 8-bromo-cAMP and protein kinase A (PKA) in a glucagon-producing hamster islet cell line (InR1G9). By several different DNA-protein binding assays, we show that the transcription factor CREB binds to the CRE octamer and that additional nuclear proteins bind to sequences adjacent to the CRE. Mutation of the Glu-CRE octamer attenuates both the binding of CREB and cAMP-dependent PKA-stimulated transcriptional activity in transient transfection experiments but does not affect the binding of adjacent CREB-associated proteins. Progressive deletions and clustered point mutations of the sequences flanking the Glu-CRE identify sequences (5'-TCATT-3') located both 5' and 3' to the core CRE octamer that bind several proteins. Two proteins with molecular masses of 80 and 100 kDa bind to each of the 5' and 3' TCATT sites. Formation of additional protein-DNA complexes containing 45- and 20-kDa proteins depends upon the integrity of both TCATT sequences. Deletion or point mutation of the TCATT motif located on the 3' side of the CRE octamer results in enhanced transcriptional responses to PKA, suggesting that the CREB-associated proteins decrease the ability of CREB to mediate PKA-stimulated transcription. Results from these studies demonstrate that nucleotides flanking the core CRE octamer can influence the activity of the CRE by serving as binding sites for proteins that modulate the function of CREB and suggest a mechanism to explain why some consensus palindromic CREs are less responsive to cAMP stimulation than others.

Animals↗
PubMed1996

Adrenergic regulation of ICER (inducible cyclic AMP early repressor) and beta1-adrenergic receptor gene expression in C6 glioma cells.

ICER (inducible cyclic AMP early repressor), a member of the cyclic AMP response element (CRE) modulator (CREM) family of transcription factors, is a powerful repressor of cyclic AMP-mediated transactivation. Our studies characterize the regulation of ICER in C6 glioma cells and investigate its role in repressing transcription of the beta1-adrenergic receptor (beta1AR) gene. Incubation with isoproterenol (100 nM) results in a rapid induction in levels of mRNA for ICER and its splice variant ICERgamma, with maximal induction occurring after 2 h of treatment. Incubation with isoproterenol also increased levels of CREM isoforms within 1 h; this was unexpected given previous reports that these isoforms are not rapidly induced. Increased expression of ICER and CREM was accompanied by induction of two CRE-binding complexes. The presence of ICER in these two CRE-binding complexes is demonstrated by their disruption with CREM antibody and by their comigration with recombinant ICER. Because the time course for isoproterenol induction of ICER mRNA and CRE binding corresponds to that for down-regulation of beta1AR mRNA levels in C6 glioma cells, the influence of ICER beta1AR transcription was directly examined. Coexpression of ICER significantly decreased transcriptional activity of a rat beta1AR promoter-luciferase reporter construct that contains a CRE. In contrast, coexpression of ICER did not influence two truncated rat beta1AR promoter constructs that lack the CRE site. These data demonstrate that ICER can interact at the beta1AR promoter to repress transcription.

Animals↗
PubMedDate not supplied

Preservation of spermatogenesis in spinal cord injured rats with exogenous testosterone. Relationship with serum testosterone levels and cellular localization of cAMP responsive element modulator.

UNLABELLED: The current experiment examined the effects of exogenous testosterone (T) on spermatogenesis in rats with spinal cord injury (SCI) and their relationship with the cellular distribution of a cyclic AMP-responsive element modulator (CREM) in testicular cells. Implantation of T-filled Silastic capsules (TCs, 1-20 cm) resulted in dose-dependent, biphasic changes in testicular T levels and spermatogenesis in SCI rats. However, dose responsiveness of spermatogenesis to exogenous T in SCI rats differed from that in sham control rats. Specifically, implantation of 2-cm TCs enhanced the effects of SCI on spermatogenesis, resulting in total regression of the seminiferous epithelium. Although 3-cm TCs maintained complete spermatogenesis in sham control rats, this regimen failed to support complete spermatogenesis in SCI rats. Although complete spermatogenesis was maintained in SCI rats given 5-20-cm TC implants, various abnormalities persisted. Cellular distribution of CREM remained normal in SCI rats but was altered in those SCI rats that received 3- or 5-cm TC implants. Such effects were associated with reduced CREM proteins in testicular tissues. These results were consistent with altered cAMP signaling and its regulation in testicular cells after SCI and provided possible mechanistic explanations for the effects of SCI on spermatogenesis. CONCLUSION: SCI resulted in changes in the responsiveness of spermatogenesis to exogenous T. These effects were associated with altered cAMP/CREM signaling in testicular cells. Further studies, including a study of the relationship between serum T levels and normalcy of sperm functions and the role of neural-endocrine interactions in mediating the effects of SCI on spermatogenesis and sperm function, are needed so that therapeutic regimens can be designed for clinical use.

Androgens↗
PubMed1992

Developmental switch of CREM function during spermatogenesis: from antagonist to activator.

Mammalian spermatogenesis consists of a series of complex developmental processes controlled by the pituitary-hypothalamic axis. This flow of biochemical information is directly regulated by the adenylate cyclase signal transduction pathway. We have previously described the CREM (cyclic AMP-responsive element modulator) gene which generates, by cell-specific splicing, alternative antagonists of the cAMP transcriptional response. Here we report the expression of a novel CREM isoform (CREM tau) in adult testis. CREM tau differs from the previously characterized CREM antagonists by the coordinate insertion of two glutamine-rich domains that confer transcriptional activation function. During spermatogenesis there was an abrupt switch in CREM expression. In premeiotic germ cells CREM is expressed at low amounts in the antagonist form. Subsequently, from the pachytene spermatocyte stage onwards, a splicing event generates exclusively the CREM tau activator, which accumulates in extremely high amounts. This splicing-dependent reversal in CREM function represents an important example of developmental modulation in gene expression.

Aging↗
PubMed2000

CREM: a master-switch regulating the balance between differentiation and apoptosis in male germ cells.

Cyclic AMP-responsive element modulator (CREM) is a transcription factor highly expressed in the post-meiotic germ cells of the testis. Its pivotal role is to regulate the expression of several germ cell-specific genes, a crucial function as demonstrated by the severe phenotype of mice whose CREM gene was mutated by homologous recombination. CREM-deficient male animals are sterile and display a ten-fold increase in the apoptosis of germ cells. Recent results have shown that CREM needs a tissue-specific co-activator, ACT (activator of CREM in testis) to elicit its regulatory function in testis.

Animals↗
PubMed1993

Pituitary hormone FSH directs the CREM functional switch during spermatogenesis.

The CREM (cyclic AMP-responsive element modulator) gene encodes multiple regulators of the cAMP-transcriptional response by alternative splicing. A developmental switch in CREM expression occurs during spermatogenesis, whereby CREM function is converted from an antagonist to an activator (CREM tau; ref. 2) which accumulates to extremely high levels from the premeiotic spermatocyte stage onwards. To define the physiological mechanisms controlling the CREM developmental switch, we have hypophysectomized rats and observed the extinction of CREM tau expression in testis, thereby demonstrating a central role of the pituitary-hypothalamic axis. We then used the seasonal-dependent modulation of spermatogenesis in hamsters to dissect the hormonal programme controlling this developmental process. By this approach, combined with direct administration of pituitary-derived hormones, we have established that follicle-stimulating hormone (FSH) is responsible for the CREM switch. FSH appears to regulate CREM expression by alternative polyadenylation, which results in a dramatic enhancement of transcript stability.

Animals↗
PubMed2006

The transcription factor CREMtau and cAMP regulate promoter activity of the Na,K-ATPase alpha4 isoform.

The Na,K-ATPase is an essential enzyme of the plasma membrane that plays a key role in numerous cell processes that depend on the transcellular gradients of Na(+) and K(+). Among the various isoforms of the catalytic subunit of the Na,K-ATPase, alpha4 exhibits the most limited pattern of expression, being restricted to male germ cells. Activity of alpha4 is essential for sperm function, and alpha4 is upregulated during spermatogenesis. The present study addressed the transcriptional control of the human Na,K-ATPase alpha4 gene, ATP1A4. We describe that a 5' untranslated region of the ATP1A4 gene (designated -339/+480 based on the ATP1A4 transcription initiation site) has promoter activity in luciferase reporter assays. Computer analysis of this promoter region revealed consensus sites (CRE) for the cyclic AMP (cAMP) response element modulator (CREM). Accordingly, dibutyryl cAMP (db-cAMP) and ectopic expression of CREMtau, a testis specific splice variant of CREM were able to activate the ATP1A4 promoter driven expression of luciferase in HEK 293 T, JEG-3 and GC-1 cells. Further characterization of the effect of db-cAMP and CREMtau on deleted constructs of the ATP1A4 promoter (-339/+80, and +25/+480), and on the -339/+480 region carrying mutations in the CRE sites showed that db-cAMP and CREMtau effect required the CRE motif located 263 bp upstream the transcription initiation site. EMSA experiments confirmed the CRE sequence as a bonafide CREMtau binding site. These results constitute the first demonstration of the transcriptional control of ATP1A4 gene expression by cAMP and by CREMtau, a transcription factor essential for male germ cell gene expression.

Animals↗
PubMed1996

Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice.

Spermiogenesis is a complex process by which postmeiotic male germ cells differentiate into mature spermatozoa. This process involves remarkable structural and biochemical changes including nuclear DNA compaction and acrosome formation. Transcription activator CREM (cyclic AMP-responsive element modulator) is highly expressed in postmeiotic cells, and CREM may be responsible for the activation of several haploid germ cell-specific genes involved in the structuring of the spermatozoon. The specific role of CREM in spermiogenesis was addressed using CREM-mutant mice generated by homologous recombination. Analysis of the seminiferous epithelium in mutant male mice reveals postmeiotic arrest at the first step of spermiogenesis. Late spermatids are completely absent, and there is a significant increase in apoptotic germ cells. We show that CREM deficiency results in the lack of postmeiotic cell-specific gene expression. The complete lack of spermatozoa in the mutant mice is reminiscent of cases of human infertility.

Animals↗
PubMed1996

Occupancy and composition of proteins bound to the AP-1 sites in the glucocorticoid receptor and c-jun promoters after glucocorticoid treatment and in different cell types.

The glucocorticoid receptor (GR) and c-jun promoters both contain activator protein-1 (AP-1) sites (GR AP-1 site and c-jun AP-1 site, respectively) that vary from the consensus AP-1 site. Electrophoretic mobility shift assays (EMSAs) were used to monitor GR AP-1 and c-jun AP-1 oligonucleotide binding by nuclear extracts from AtT-20 and L929 cells that were hormone- and vehicle-treated for 1, 6, or 24 h. Both AtT-20 and L929 cell nuclear extracts bound the c-jun AP-1 site somewhat better than the GRAP-1 site and, in the majority of cases, extracts from hormone-treated cells shifted both GRAP-1 and c-jun AP-1 oligonucleotides more than nontreated nuclear extracts. Supershift assays, using Jun and Fos family member-specific antibodies, showed that protein complexes formed by AtT-20 cell nuclear extracts bound to the c-jun AP-1 site were comprised of Jun family members, JunD, JunB, and cJun. No Fos family members were present. However, protein complexes from AtT-20 nuclear extracts that bound the GR AP-1 site were supershifted by JunD, JunB, cJun, and Fra-2 specific antibodies. In L929 cell nuclear extracts, the c-jun AP-1 site is bound by JunD and cJun. No clear association of Fos family members with the c-jun AP-1 site could be demonstrated. The GR AP-1 site bound protein complexes composed of JunD, JunB, Fra-2, and Fra-1 from L929 nuclear extracts. This demonstrates that the composition of the protein complexes that associate with the c-jun AP-1 site differs from those that bind the GR AP-1 site. These data also indicate that the protein complexes that bind the GR and c-jun AP-1 sites are cell-type-specific. Computer analysis also revealed five putative cyclic AMP response elements (CREs) in the GR promoter. Relative mobility shift and binding studies suggest that CRE binding protein (CREB), CREB modulator (CREM), or CREB/CREM may be associated with the c-jun AP-1 and/or GR AP-1 sites, but the association at these sites occurs at a lower binding affinity than for a consensus CRE. Nuclear extracts from AtT-20 and L929 cells were able to shift the CRE, and supershift analysis revealed that Jun family members are part of the protein complexes that bind the CRE. Pan Jun and pan Fos antibodies were able to supershift protein-CRE complexes formed using NIH 3T3 nuclear extracts. These data raise the possibility that the promiscuous binding of CREB and/or CREM to the AP-1 site, and AP-1 transcription factors to one or more CREs, in the GR promoter may contribute to the regulation of GR gene expression.

3T3 Cells↗
PubMed2001

Estrogen modulation of the cyclic AMP response element-binding protein pathway. Effects of long-term and acute treatments.

Actions of estrogen include mechanisms leading to alterations in gene transcription that may be independent of nuclear estrogen receptors, as well as those involving direct action of the estrogen receptor on the genome. Also, the influence of estrogen in the brain appears to extend well beyond areas associated with reproduction and may include forebrain areas linked to affective and cognitive behaviors. We investigated the effects of acute and long-term estradiol benzoate (E2) treatment on total and phosphorylated cyclic AMP responsive element-binding (CREB) protein levels and on cyclic AMP response element (CRE)-DNA binding in forebrain areas of ovariectomized (OVX) rats. Long-term E2 treatment increased CRE-DNA binding in the amygdala but not in hippocampus, frontal cortex, or cerebellum. The increase in CRE-DNA binding in the amygdala was associated with increased levels of total and phosphorylated CREB (pCREB) protein during protracted E2 exposure. To localize the estrogenic effect in the amygdala and determine if an effect in one hippocampal region was masked by a lack of effect in another subregion, we performed immunolabeling of pCREB in brain structures of chronically treated OVX animals with or without E2. This treatment resulted in a significant increase in relative total immunolabeled nuclei in the anteroventral subdivision of the medial amygdala. In the hippocampus, a significant increase in relative total immunolabeled nuclei was seen in the CA1 and CA3 regions, but not in the dentate gyrus or hilus of the dentate gyrus. Acute E2 treatment resulted in increased CRE-DNA binding in the frontal cortex but not in amygdala, hippocampus, or cerebellum. However, no changes in levels of total CREB or pCREB protein were observed in the frontal cortex under E2 treatment. No changes were observed either in basal or cAMP-stimulated protein kinase A (PKA) activity or in PKA-alpha catalytic subunit immunoreactivity in the amygdala or the frontal cortex. Our study indicates that both long-term and acute treatments with estrogens influence the function of CREB in specific brain structures.

Animals↗