RESUMEN
The ability to learn and remember, which is fundamental for behavioral adaptation, is susceptible to stressful experiences during the early postnatal period, such as abnormal levels of maternal care. The exact mechanisms underlying these effects still remain elusive. This study examined whether early life stress (ELS) alters memory and brain activation patterns in male mice. Therefore, we examined the expression of the immediate early genes (IEGs) c-Fos and Arc in the dentate gyrus (DG) and basolateral amygdala (BLA) after training and memory retrieval in a fear conditioning task. Furthermore, we examined the potential of RU38486 (RU486), a glucocorticoid receptor antagonist, to mitigate ELS-induced memory deficits by blocking stress signalling during adolescence. Arc::dVenus reporter mice, which allow investigating experience-dependent expression of the immediate early gene Arc also at more remote time points, were exposed to ELS by housing dams and offspring with limited bedding and nesting material (LBN) between postnatal days (PND) 2-9 and trained in a fear conditioning task at adult age. We found that ELS reduced both fear acquisition and contextual memory retrieval. RU486 did not prevent these effects. ELS reduced the number of Arc::dVenus+ cells in DG and BLA after training, while the number of c-Fos+ cells were left unaffected. After memory retrieval, ELS decreased c-Fos+ cells in the ventral DG and BLA. ELS also altered the colocalization of c-Fos+ cells with Arc::dVenus+ cells in the ventral DG, possibly indicating impaired engram allocation in the ventral DG after memory retrieval. In conclusion, this study shows that ELS alters neuronal activation patterns after fear acquisition and retrieval, which may provide mechanistic insights into enduring impact of ELS on the processing of fear memories, possibly via changes in cell (co-) activation and engram cell allocation.
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Complejo Nuclear Basolateral , Giro Dentado , Miedo , Mifepristona , Estrés Psicológico , Animales , Miedo/fisiología , Masculino , Estrés Psicológico/metabolismo , Ratones , Complejo Nuclear Basolateral/metabolismo , Giro Dentado/metabolismo , Mifepristona/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Femenino , Memoria/fisiología , Condicionamiento Clásico/fisiología , Proteínas del Tejido Nervioso/metabolismo , Genes Inmediatos-Precoces/fisiología , Proteínas del Citoesqueleto/metabolismo , Recuerdo Mental/fisiología , Ratones Endogámicos C57BLRESUMEN
Growth factor-induced, ERK-mediated induction of immediate-early genes (IEGs) is crucial for cell growth and tumorigenesis. Although IEG expression is mainly regulated at the level of transcription elongation by RNA polymerase-II (Pol-II) promoter-proximal pausing and its release, the role of ERK in this process remains unknown. Here, we identified negative elongation factor (NELF)-A as an ERK substrate. Upon growth factor stimulation, ERK phosphorylates NELF-A, which dissociates NELF from paused Pol-II at the promoter-proximal regions of IEGs, allowing Pol-II to resume elongation and produce full-length transcripts. Furthermore, we found that in cancer cells, PP2A efficiently dephosphorylates NELF-A, thereby preventing aberrant IEG expression induced by ERK-activating oncogenes. However, when PP2A inhibitor proteins are overexpressed, as is frequently observed in cancers, decreased PP2A activity combined with oncogene-mediated ERK activation conspire to induce NELF-A phosphorylation and IEG upregulation, resulting in tumor progression. Our data delineate previously unexplored roles of ERK and PP2A inhibitor proteins in carcinogenesis.
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Carcinogénesis , Genes Inmediatos-Precoces , ARN Polimerasa II , Humanos , Carcinogénesis/genética , Carcinogénesis/metabolismo , Genes Inmediatos-Precoces/genética , Genes Inmediatos-Precoces/fisiología , Fosforilación , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismoRESUMEN
BACKGROUND: APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD), and obesity is a strong environmental risk factor for AD. These factors result in multiple central nervous system (CNS) disturbances and significantly increase chances of AD. Since over 20% of the US population carry the APOE4 allele and over 40% are obese, it is important to understand how these risk factors interact to affect neurons and glia in the CNS. METHODS: We fed male and female APOE3 and APOE4 knock-in mice a high-fat diet (HFD-45% kcal fat) or a "control" diet (CD-10% kcal fat) for 12 weeks beginning at 6 months of age. At the end of the 12 weeks, brains were collected and analyzed for gliosis, neuroinflammatory genes, and neuronal integrity. RESULTS: APOE3 mice on HFD, but not APOE4 mice, experienced increases in gliosis as measured by GFAP and Iba1 immunostaining. APOE4 mice on HFD showed a stronger increase in the expression of Adora2a than APOE3 mice. Finally, APOE3 mice on HFD, but not APOE4 mice, also showed increased neuronal expression of immediate early genes cFos and Arc. CONCLUSIONS: These findings demonstrate that APOE genotype and obesity interact in their effects on important processes particularly related to inflammation and neuronal plasticity in the CNS. During the early stages of obesity, the APOE3 genotype modulates a response to HFD while the APOE4 genotype does not. This supports a model where early dysregulation of inflammation in APOE4 brains could predispose to CNS damages from various insults and later result in the increased CNS damage normally associated with the APOE4 genotype.
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Apolipoproteína E3/biosíntesis , Apolipoproteína E4/biosíntesis , Encéfalo/metabolismo , Dieta Alta en Grasa/efectos adversos , Genes Inmediatos-Precoces/fisiología , Gliosis/metabolismo , Animales , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Femenino , Expresión Génica , Técnicas de Sustitución del Gen , Gliosis/etiología , Gliosis/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
As the relationship among diet, brain aging and memory is complex, it provides ample opportunity for research in multiple directions including behaviour, epigenetics and neuroplasticity. Nutritional deficiencies together with genetic and environmental factors are the major cause of many age-associated pathologies including memory loss. A compromised vitamin B12-folate status in older people is highly prevalent worldwide. Researchers have established a close association between the adequate level of B12-folate and the maintenance of cognitive brain functions. One of the main reasons for age-associated memory loss is downregulation of neuronal immediate early genes (nIEGs). Therefore, we hypothesize here that vitamin B12-folic acid supplementation in old mice can improve memory by altering the expression status of nIEGs. To check this, 72-week-old male Swiss albino mice were orally administered with 2 µg of vitamin B12 and 22 µg of folic acid/mouse/day for eight weeks. Such supplementation improved recognition memory in old and altered the expression of nIEGs. The expression of nIEGs was further found to be regulated by changes in DNA methylation at their promoter regions and CREB phosphorylation (pCREB). In addition, Golgi-Cox staining showed significant improvement in dendritic length, number of branching points and spine density of hippocampal CA1 pyramidal neurons by B12-folic acid supplementation. Taken together, these findings suggest that vitamin B12-folic acid supplementation regulates nIEGs expression and improves dendritic arborization of hippocampal neurons and memory in old male mice.
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Envejecimiento/efectos de los fármacos , Ácido Fólico/administración & dosificación , Genes Inmediatos-Precoces/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Plasticidad Neuronal/efectos de los fármacos , Vitamina B 12/administración & dosificación , Envejecimiento/genética , Envejecimiento/metabolismo , Animales , Suplementos Dietéticos , Genes Inmediatos-Precoces/fisiología , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Masculino , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Ratones , Plasticidad Neuronal/fisiologíaRESUMEN
Insulin binding to the insulin receptor triggers intracellular signaling cascades involving the activation of protein and lipid kinases. As a result, multiple biological functions of the cells are changed. Here, we analyzed the regulation and signaling cascades leading to insulin-induced activation of the stimulus-responsive transcription factors. For the analyses, we used chromatin-embedded reporter genes having a cellular nucleosomal organisation, and fibroblasts expressing human insulin receptors (HIRcB cells). The results show that stimulation of the insulin receptor induced the expression of the transcription factor Egr-1. Attenuation of Egr-1 promoter activation was observed following expression of a dominant-negative mutant of the ternary complex factor Elk-1. These data were corroborated by experiments showing that insulin receptor stimulation increased the transcriptional activation potential of Elk-1. In addition, the transcriptional activity of AP-1 was significantly elevated in insulin-stimulated HIRcB cells. Expression of the dominant-negative mutant of Elk-1 reduced insulin-induced activation of AP-1, indicating that Elk-1 controls both serum response element and AP-1-regulated transcription. Moreover, we show that stimulation of the insulin receptor activates cyclic AMP response element (CRE)-controlled transcription, involving the transcription factor CREB. Insulin-induced transcription of Elk-1 and CREB-controlled reporter genes was attenuated by overexpression of MAP kinase phosphatase-1 or a constitutively active mutant of calcineurin A, indicating that both phosphatases are part of a negative feedback loop for reducing insulin-mediated gene transcription. Finally, we show that expression of the adenoviral protein E1A selectively reduced CRE-mediated transcription following stimulation of the insulin receptor. These data indicate that insulin-regulated transcription of CRE-containing genes is under epigenetic control.
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Antígenos CD/genética , Antígenos CD/metabolismo , Genes Inmediatos-Precoces/fisiología , Insulina/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transcripción Genética/fisiología , Línea Celular , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Genes Inmediatos-Precoces/efectos de los fármacos , Humanos , Insulina/farmacología , Receptor de Insulina/agonistas , Transcripción Genética/efectos de los fármacosRESUMEN
In this study, we used the immediate early gene, egr-1, as a marker for neural activation and examined whether egr-1 expression is affected in brain regions associated with the social behavioral network (SBN) when social rank is determined and changed in male medaka fish (Oryzias latipes). Based on the behavioral contest protocol used in this study, we obtained four types of males: social ascending, social descending, dominant, and subordinate. In some brain regions associated with the SBN, we detected higher egr-1 expression in ascending and descending males than in dominant and subordinate males. Social-rank stable males (i.e., dominant and subordinate male fish) showed a similar level of egr-1 expression as the control male fish, which were housed without social stimulus of encountering another conspecific. These findings suggested that the transitioning of social rank could enhance neural activity in some brain regions associated with the SBN in male medaka. The use of medaka fish has many advantages in various fields of research such as genetics, developmental biology, environmental biology, and behavioral neurology. The findings of this study would contribute to future research exploring the roles of the SBN regions in regulating physiological and behavioral events associated with social-rank transition.
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Conducta Animal/fisiología , Conducta Competitiva/fisiología , Regulación de la Expresión Génica/fisiología , Genes Inmediatos-Precoces/fisiología , Oryzias/fisiología , Animales , Encéfalo/metabolismo , Genes Inmediatos-Precoces/genética , MasculinoRESUMEN
In both humans and animals, biological differences between males and females has long been a topic of research. In songbirds, sexual dimorphisms can be seen in many species' plumage and heard in some species' songs. However, not all songbirds have such overt phenotypic sexual differences, leading to the question: are all vocalizations dimorphic? One of the most used and versatile vocalizations of the black-capped chickadee (Poecile atricapillus) is their namesake chick-a-dee call, that is produced by both sexes. This call is composed of four note types: A, B, C (together chick-a), and D (dee). Previous research has found that A notes contain information regarding the sex of the caller. However, chickadees do not categorize full chick-a-dee calls, or altered chick-a calls, based on the sex of the caller. Here we presented both male and female chickadees with altered chick-a calls (dee portion removed) of both sexes and measured the number of ZENK labeled cells in auditory nuclei. We found that calls produced by males and females had more ZENK labeled cells than the control condition; however, there was no significant difference in ZENK labeled cells between male and female listeners. Overall, our results suggest that black-capped chickadees do not perceive sexual differences in the production of chick-a calls.
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Percepción Auditiva/fisiología , Genes Inmediatos-Precoces/fisiología , Pájaros Cantores/fisiología , Telencéfalo/fisiología , Vocalización Animal/fisiología , Animales , Vías Auditivas/fisiología , Femenino , Masculino , Caracteres SexualesRESUMEN
Chronic pain results in a variety of neural adaptations, many of which are maladaptive and result in hypersensitivity to pain. In humans, this hypersensitivity can be debilitating and treatment options are limited. Fortunately, there are numerous animal models that mimic clinical populations and have the potential to aid in the evaluation of underlying mechanisms and ultimately the development of better treatments. One of these is the complete Freund's adjuvant (CFA)-model of chronic inflammatory pain. In rodents, this model requires the injection of CFA into the hindpaw, muscle, or joint, which induces inflammation similar to what might be found in individuals with rheumatoid arthritis or tendonitis. While the mechanistic effects CFA on the spinal cord are well established, less is known about the effects of CFA on the brain. Thus, in this study, neuronal activation, as measured by c-Fos immunocytochemistry, in brain regions important to control of pain was evaluated. Animals that received CFA treatment, and tested 3 days later for mechanical allodynia and edema, had an increase in the number of c-Fos immunopositive cells in the basolateral amygdala, but not in any of the other brain regions that were evaluated. Given that the basolateral amygdala is known to be important for pain-related emotional responses, these data suggest that the CFA-model may provide an opportunity to further explore how pain affects this brain region at a mechanistic level, which in turn may shed light on what may be occurring in clinical populations.
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Complejo Nuclear Basolateral/fisiopatología , Inflamación/fisiopatología , Dolor/fisiopatología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Genes Inmediatos-Precoces/fisiología , Hiperalgesia/fisiopatología , Masculino , Ratones Endogámicos C57BLRESUMEN
kakusei is a non-coding RNA that is overexpressed in foraging bee brain. This study describes a possible role of the IEG kakusei during the daily foraging of honey bees. kakusei was found to be transiently upregulated within two hours during rewarded foraging. Interestingly, during unrewarded foraging the gene was also found to be up-regulated, but immediately lowered when food was not rewarded. Moreover, the kakusei overexpression was diminished within a very short time when the time schedule of feeding was changed. This indicates the potential role of kakusei on the motivation of learned reward foraging. These results provide evidence for a dynamic role of kakusei during for aging of bees, and eventually its possible involvement in learning and memory. Thus the kakusei gene could be used as search tool in finding distinct molecular pathways that mediate diverse behavioral components of foraging.
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Abejas/genética , Abejas/fisiología , Conducta Alimentaria , Genes Inmediatos-Precoces/fisiología , Genes de Insecto/fisiología , Envejecimiento/genética , Animales , Aprendizaje , ARN no Traducido/genéticaRESUMEN
RATIONALE: Patients diagnosed with schizophrenia typically receive life-long treatments with antipsychotic drugs (APDs). However, the impact of chronic APDs treatment on neuroplastic mechanisms in the brain remains largely elusive. OBJECTIVE: Here, we focused on blonanserin, a second-generation antipsychotic (SGA) that acts as an antagonist at dopamine D2, D3, and serotonin 5-HT2A receptors, and represents an important tool for the treatment of schizophrenia. METHODS: We used rats to investigate the ability of chronic treatment blonanserin to modulate the activity of brain structures relevant for schizophrenia, under baseline conditions or in response to an acute forced swim session (FSS). We measured the expression of different immediate early genes (IEGs), including c-Fos, Arc/Arg 3.1, Zif268 and Npas4. RESULTS: Blonanserin per se produced limited changes in the expression of these genes under basal conditions, while, as expected, FSS produced a significant elevation of IEGs transcription in different brain regions. The response of blonanserin-treated rats to FSS show anatomical and gene-selective differences. Indeed, the upregulation of IEGs was greatly reduced in the striatum, a brain structure enriched in dopamine receptors, whereas the upregulation of some genes (Zif268, Npas4) was largely preserved in other regions, such as the prefrontal cortex and the ventral hippocampus. CONCLUSIONS: Taken together, our findings show that chronic exposure to blonanserin modulates selective IEGs with a specific anatomical profile. Moreover, the differential activation of specific brain regions under challenging conditions may contribute to specific clinical features of the drug.
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Antipsicóticos/administración & dosificación , Encéfalo/efectos de los fármacos , Genes Inmediatos-Precoces/efectos de los fármacos , Piperazinas/administración & dosificación , Piperidinas/administración & dosificación , Estrés Psicológico/tratamiento farmacológico , Animales , Encéfalo/fisiología , Esquema de Medicación , Genes Inmediatos-Precoces/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Receptores Dopaminérgicos/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Estrés Psicológico/genética , Estrés Psicológico/psicologíaRESUMEN
In the present work, using in situ hybridization, we studied the expression patterns of three molluscan homologs of vertebrate immediate-early genes C/EBP, c-Fos, and c-Jun in the central nervous system (CNS) of terrestrial gastropod snail Helix. The molluscan C/EBP gene was described in literature, while c-Fos and c-Jun were studied in terrestrial snails for the first time. Localization of the expression was traced in normal conditions, and in preparations physiologically activated using stimulation of suboesophageal ganglia nerves. No expression was detected constitutively. In stimulated preparations, all three genes had individual expression patterns in Helix CNS, and the level of expression was stimulus-dependent. The number of cells expressing the gene of interest was different from the number of cells projecting to the stimulated nerve, and thus activated retrogradely. This difference depended on the ganglia studied. At the subcellular level, the labeled RNA was observed as dots (probably small clusters of RNA molecules) and shapeless mass of RNA, often seen as a circle at the internal border of the cell nuclei. The data provide a basis for further study of behavioral role of these putative immediate-early genes in snail behavior and learning.
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Sistema Nervioso Central/metabolismo , Genes Inmediatos-Precoces/genética , Neuronas/metabolismo , Caracoles/genética , Animales , Genes Inmediatos-Precoces/fisiología , Genes fos/genética , Caracoles Helix/fisiología , Proteínas Proto-Oncogénicas c-fos/biosíntesis , ARN/metabolismoRESUMEN
PURPOSE: The effects of low-intensity pulsed ultrasound (LIPUS) on the expression of immediate-early genes (IEGs) in bone marrow stromal cells (BMSCs) were evaluated to elucidate the early cellular response to LIPUS. METHODS: Mouse ST2 BMSCs were treated with LIPUS (ISATA, 12-34 mW/cm2 for 20 min), then cultured at 37 °C. The expression levels of four IEGs (Fos, Egr1, Jun, and Ptgs2) and ERK1/2, a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), were assessed using real-time quantitative PCR and Western blot analyses, respectively. RESULTS: A single exposure of LIPUS at an intensity of 25 mW/cm2 significantly and transiently increased the expression levels of all four IEGs, and the peak expression was detected at 30-60 min after LIPUS stimulation. LIPUS exposure also significantly increased the phosphorylation level of ERK1/2. U0126, an inhibitor of MAPK/ERK, significantly prevented LIPUS-induced expression of Fos and Egr1, but not that of Jun and Ptgs2. On the other hand, treatment of the cells with LIPUS did not affect cell growth or alkaline phosphatase activity, a marker of osteoblast differentiation. CONCLUSION: These results suggest that LIPUS exposure significantly induces expression of IEGs such as Fos and Egr1 via the MAPK/ERK pathway in ST2 BMSCs.
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Expresión Génica/fisiología , Genes Inmediatos-Precoces/fisiología , Proteína 1 Similar al Receptor de Interleucina-1/genética , Células Madre Mesenquimatosas/fisiología , Ondas Ultrasónicas , Animales , Diferenciación Celular , Proliferación Celular , Células Cultivadas , RatonesRESUMEN
For the past decades, an increasing number of studies has taken advantage of molecular imaging methods involving the detection of immediate-early genes' (IEGs) expression for investigating neural substrates underlying plasticity processes and memory function. The detection of IEGs RNA by Fluorescent In-Situ Hybridization (FISH) yields single-cell as well as high temporal resolution and has recently enabled the mapping of medial temporal lobe subareas/subnetworks activity induced by single or multiple behavioural events in the same animal. After briefly reviewing the function and the ties of the typical IEGs (Fos, Zif268, Arc, Homer1a) used for mapping plasticity, we focus on discussing technical considerations vital for the successful detection of IEGs with FISH with emphasis on the design of RNA probes, the optimization of experimental conditions and the necessity for controls. Finally, we discuss recent developments in brain clearing methods that in combination with FISH detection of IEGs' expression allow for 3D imaging with single cell resolution as well as whole brain analyses. This, in parallel with the recent development of fMRI cognitive tasks in awake rats and the use of high resolution fMRI in humans, holds great promises for bridging further memory in humans and animals.
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Encéfalo/fisiología , Expresión Génica/fisiología , Genes Inmediatos-Precoces/fisiología , Hibridación Fluorescente in Situ/métodos , Memoria/fisiología , Plasticidad Neuronal/fisiología , Neurociencias/métodos , Análisis de la Célula Individual/métodos , AnimalesRESUMEN
RATIONALE: Cocaine base paste (CBP) is an illegal drug of abuse usually consumed by adolescents in a socio-economically vulnerable situation. Repeated drug use targets key brain circuits disrupting the processes that underlie emotions and cognition. At the basis of such neuroadaptations lie changes in the expression of immediate-early genes (IEGs). Nevertheless, changes in transcriptional regulation associated with CBP consumption remain unknown. OBJECTIVES: We aimed to describe behavioral phenotype related to locomotion, anxiety-like behavior, and memory of CBP-injected mice and to study IEGs expression after an abstinence period. METHODS: Five-week-old female CF-1 mice were i.p. injected daily with vehicle or CBP (40 mg/kg) for 10 days and subjected to a 10-day period of abstinence. Open field and novel object recognition tests were used to evaluate locomotion and anxiety-like behaviors and recognition memory, respectively, during chronic administration and after abstinence. After abstinence, prefrontal cortex (mPFC) and nucleus accumbens (NAc) were isolated and gene expression analysis performed through real-time PCR. RESULTS: We found an increase in locomotion and anxiety-like behavior during CBP administration and after the abstinence period. Furthermore, the CBP group showed impaired recognition memory after abstinence. Egr1, FosB, ΔFosB, Arc, Bdnf, and TrkB expression was upregulated in CBP-injected mice in NAc and FosB, ΔFosB, Arc, and Npas4 expression was downregulated in mPFC. We generated an anxiety score and found positive and negative correlations with IEGs expression in NAc and mPFC, respectively. CONCLUSION: Our results suggest that chronic CBP exposure induced alterations in anxiety-like behavior and recognition memory. These changes were accompanied by altered IEGs expression.
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Ansiedad/inducido químicamente , Ansiedad/metabolismo , Cocaína/administración & dosificación , Genes Inmediatos-Precoces/fisiología , Núcleo Accumbens/metabolismo , Corteza Prefrontal/metabolismo , Animales , Ansiedad/psicología , Cocaína/toxicidad , Inhibidores de Captación de Dopamina/administración & dosificación , Inhibidores de Captación de Dopamina/toxicidad , Femenino , Regulación de la Expresión Génica , Genes Inmediatos-Precoces/efectos de los fármacos , Locomoción/efectos de los fármacos , Locomoción/fisiología , Ratones , Núcleo Accumbens/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacosRESUMEN
Female songbirds are thought to make mate choices based on aspects of male song quality. Male canaries (Serinus canaria) produce songs with "special" syllables that have been shown to be highly salient to female listeners - eliciting high rates of sexual displays and enhanced immediate early gene (IEG) expression. Immunohistochemistry for the IEG ZENK was used to examine the effects of experience with these syllables on activity in the caudal mesopallium (CMM) and nidocaudal mesopallium (NCM), two auditory areas important in processing conspecific song. Photostimulated female canaries were housed in sound attenuated chambers and played pseudosongs containing either three special syllables or three non-special syllables, an intro, and an outro sequence. Females that heard special syllable pseudosongs exhibited higher ZENK expression in CMM. To assess the effects of experience, photostimulated females were pair housed and exposed to playback of song with or without special syllables for 14 days. After transfer to individual housing, birds were played one of the aforementioned stimuli or silence. ZENK expression in CMM and NCM was equivalent for song with and without special syllables, but significantly lower for silence. Females who experienced song with special syllables had lower plasma estradiol concentrations after final song playback. This study indicates that CMM exhibits an IEG response bias to special syllables in limited acoustic contexts, but not in full song, which may contain additional biologically relevant information. Furthermore, estradiol concentrations may mediate changes in song responses, serving as a mechanism for modulating mate choice in differing song environments.
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Estimulación Acústica/métodos , Percepción Auditiva/fisiología , Encéfalo/metabolismo , Genes Inmediatos-Precoces/fisiología , Vocalización Animal/fisiología , Animales , Canarios , Femenino , Expresión GénicaRESUMEN
Propensity to relapse following long periods of abstinence is a key feature of substance use disorder. Drugs of abuse, such as cocaine, cause long-term changes in the neural circuitry regulating reward, motivation, and memory processes through dysregulation of various molecular mechanisms, including epigenetic regulation of activity-dependent gene expression. Underlying drug-induced changes to neural circuit function are the molecular mechanisms regulating activity-dependent gene expression. Of note, histone acetyltransferases and histone deacetylases (HDACs), powerful epigenetic regulators of gene expression, are dysregulated following both acute and chronic cocaine exposure and are linked to cocaine-induced changes in neural circuit function. To better understand the effect of drug-induced changes on epigenetic function and behavior, we investigated HDAC3-mediated regulation of Nr4a2/Nurr1 in the medial habenula, an understudied pathway in cocaine-associated behaviors. Nr4a2, a transcription factor critical in cocaine-associated behaviors and necessary for MHb development, is enriched in the cholinergic cell-population of the MHb; yet, the role of NR4A2 within the MHb in the adult brain remains elusive. Here, we evaluated whether epigenetic regulation of Nr4a2 in the MHb has a role in reinstatement of cocaine-associated behaviors. We found that HDAC3 disengages from Nr4a2 in the MHb in response to cocaine-primed reinstatement. Whereas enhancing HDAC3 function in the MHb had no effect on reinstatement, we found, using a dominant-negative splice variant (NURR2C), that loss of NR4A2 function in the MHb blocked reinstatement behaviors. These results show for the first time that regulation of NR4A2 function in the MHb is critical in relapse-like behaviors.
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Cocaína/administración & dosificación , Comportamiento de Búsqueda de Drogas/fisiología , Epigénesis Genética/fisiología , Genes Inmediatos-Precoces/fisiología , Habénula/metabolismo , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Animales , Epigénesis Genética/efectos de los fármacos , Femenino , Genes Inmediatos-Precoces/efectos de los fármacos , Habénula/efectos de los fármacos , Histona Desacetilasas/metabolismo , Masculino , Ratones , Ratones TransgénicosRESUMEN
Males of Drosophila melanogaster exhibit stereotypic courtship behavior through which they assess potential mates by processing multimodal sensory information. Although previous studies revealed important neural circuits involved in this process, the full picture of circuits that participate in male courtship remains elusive. Here, we established a genetic tool to visualize or optogenetically reactivate neural circuits activated upon specific behavior, exploiting promoter activity of a neural activity-induced gene Hr38 With this approach, we visualized neural circuits activated in the male brain and the ventral nerve cord when a male interacted with a female. The labeling of neural circuits was additively dependent on inputs from antennae and foreleg tarsi. In addition, neural circuits that express the sex-determining gene fruitless or doublesex were extensively labeled by interaction with a female. Furthermore, optogenetic reactivation of the labeled neural circuits induced courtship posture. With this mapping system, we found that a fruitless-positive neural cluster aSP2 was labeled when a male interacted with a female, in addition to previously characterized neurons. Silencing of neurons including aSP2 led to frequent interruption of courtship and significant reduction of mating success rate without affecting latency to start courtship, suggesting that these neurons are required for courtship persistency important for successful copulation. Overall, these results demonstrate that activity-dependent labeling can be used as a powerful tool not only in vertebrates, but also in invertebrates, to identify neural circuits regulating innate behavior.
Asunto(s)
Red Nerviosa/diagnóstico por imagen , Optogenética/métodos , Conducta Sexual Animal/fisiología , Animales , Conducta Animal/fisiología , Encéfalo/fisiología , Cortejo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiología , Drosophila melanogaster/genética , Drosophila melanogaster/fisiología , Femenino , Genes Inmediatos-Precoces/fisiología , Masculino , Proteínas del Tejido Nervioso/metabolismo , Neuronas/fisiología , Receptores Citoplasmáticos y Nucleares/metabolismoRESUMEN
Black-capped chickadees (Poecile atricapillus) use their namesake chick-a-dee call for multiple functions, altering the features of the call depending on context. For example, duty cycle (the proportion of time filled by vocalizations) and fine structure traits (e.g., number of D notes) can encode contextual factors, such as predator size and food quality. Wilson and Mennill (2011) found that chickadees show stronger behavioral responses to playback of chick-a-dee calls with higher duty cycles, but not to the number of D notes. That is, independent of the number of D notes in a call, but dependent on the overall proportion of time filled with vocalization, birds responded more to higher duty cycle playback compared to lower duty cycle playback. Here we presented chickadees with chick-a-dee calls that contained either two D (referred to hereafter as 2 D) notes with a low duty cycle, 2 D notes with a high duty cycle, 10 D notes with a high duty cycle, or 2 D notes with a high duty cycle but played in reverse (a non-signaling control). We then measured ZENK expression in the auditory nuclei where perceptual discrimination is thought to occur. Based on the behavioral results of Wilson and Mennill, 2011, we predicted we would observe the highest ZENK expression in response to forward-playing calls with high duty cycles; we predicted we would observe no significant difference in ZENK expression between forward-playing high duty cycle playbacks (2 D or 10 D). We found no significant difference between forward-playing 2 D and 10 D high duty cycle playbacks. However, contrary to our predictions, we did not find any effects of altering the duty cycle or note number presented.
Asunto(s)
Vías Auditivas/fisiología , Percepción Auditiva/fisiología , Genes Inmediatos-Precoces/fisiología , Vocalización Animal/fisiología , Estimulación Acústica/métodos , Acústica , Animales , Pollos , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Genes Inmediatos-Precoces/genética , Masculino , Pájaros Cantores/fisiologíaRESUMEN
Although some of the clinical manifestations of substance use disorders might be superficially similar, it is highly likely that different classes of abused drugs including opioids (heroin, morphine, and oxycodone, other opioids) and psychostimulants (cocaine and amphetamines) cause different neuroadaptations in various brain regions dependent in the distribution and concentration of their biochemical sites of actions. In fact, different molecular networks are indeed impacted by acute and chronic administration of addictive substances. Some of the genes whose expression is influenced by the administration of these substances are immediate-early genes (IEGs). IEGs include classes of low expression genes that can become very highly induced within seconds or minutes of activation by endogenous or exogenous stimuli. These IEGs might play important roles in activating target genes that regulate adaptations implicated in the behavioral manifestations diagnosed as addiction. Therefore, the purpose of this review is to provide an overview of recent data on the effects of psychostimulants and opioids on IEG expression in the brain. The review documents some contrasting effects of these classes of drugs on gene expression and indicates that further studies are necessary to identify the specific effects of each drug class when trying to predict clinical responses to therapeutic agents.