RESUMEN
Using a longitudinal approach, we sought to define the interplay between genetic and nongenetic factors in shaping vulnerability or resilience to COVID-19 pandemic stress, as indexed by the emergence of symptoms of depression and/or anxiety. University of Michigan freshmen were characterized at baseline using multiple psychological instruments. Subjects were genotyped, and a polygenic risk score for depression (MDD-PRS) was calculated. Daily physical activity and sleep were captured. Subjects were sampled at multiple time points throughout the freshman year on clinical rating scales, including GAD-7 and PHQ-9 for anxiety and depression, respectively. Two cohorts (2019 to 2021) were compared to a pre-COVID-19 cohort to assess the impact of the pandemic. Across cohorts, 26 to 40% of freshmen developed symptoms of anxiety or depression (N = 331). Depression symptoms significantly increased in the pandemic years and became more chronic, especially in females. Physical activity was reduced, and sleep was increased by the pandemic, and this correlated with the emergence of mood symptoms. While low MDD-PRS predicted lower risk for depression during a typical freshman year, this genetic advantage vanished during the pandemic. Indeed, females with lower genetic risk accounted for the majority of the pandemic-induced rise in depression. We developed a model that explained approximately half of the variance in follow-up depression scores based on psychological trait and state characteristics at baseline and contributed to resilience in genetically vulnerable subjects. We discuss the concept of multiple types of resilience, and the interplay between genetic, sex, and psychological factors in shaping the affective response to different types of stressors.
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COVID-19 , Pandemias , Femenino , Humanos , COVID-19/epidemiología , COVID-19/genética , Ansiedad/epidemiología , Ansiedad/genética , Trastornos de Ansiedad , Afecto , Depresión/epidemiología , Depresión/genéticaRESUMEN
The frontal pole (Brodmann area 10, BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning prior to the age of onset for bipolar disorder (BP) and schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ postmortem samples (n = 72). We chose this method for its high sensitivity to detect low-level expression. We then strengthened our findings by performing a meta-analysis of publicly released BA10 microarray data (n = 101) and identified sources of convergence with our qPCR results. To improve interpretation, we leveraged the unusually large database of clinical metadata accompanying our samples to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABAergic and astrocytic function. We also observed that therapeutics may produce a differential expression that opposes diagnosis effects. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.
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Trastorno Bipolar , Esquizofrenia , Humanos , Adolescente , Trastorno Bipolar/genética , Trastorno Bipolar/metabolismo , Esquizofrenia/metabolismo , Lóbulo Frontal/metabolismo , Expresión Génica , Transmisión Sináptica/genéticaRESUMEN
In previous studies, early-life fibroblast growth factor-2 (FGF2) administration conferred resilience to developing anxiety-like behavior in vulnerable animals in adulthood. To follow up on this work, we administered FGF2 the day after birth to animals that differ in emotional behavior and further explored its long-term effects on affective behavior and circuitry. Selectively-bred "high responder" rats (bHRs) exhibit low levels of anxiety-like and depression-like behavior, whereas selectively-bred "low responders" (bLRs) display high levels of anxiety-like and depression-like behavior. We found that early-life administration of FGF2 decreased negative affect in bLRs during the early post-natal period, as indexed by 40â¯kHz ultrasonic vocalizations (USVs) in response to a brief maternal separation on PND11. FGF2 also increased positive affect during the juvenile period, as measured by 50â¯kHz USVs in response to heterospecific hand play ("tickling") after weaning. In general, we found that bHRs produced more 50â¯kHz USVs than bLRs. In adulthood, we measured opioid ligand and receptor expression in brain regions implicated in USV production and affect regulation by mRNA in situ hybridization. Within multiple affective brain regions, bHRs had greater expression of the mu opioid receptor than bLRs. FGF2 increased mu opioid expression in bLRs. The bLRs had more kappa and less delta receptor expression than bHRs, and FGF2 increased prodynorphin in bLRs. Our results provide support for further investigations into the role of growth factors and endogenous opioids in the treatment of disorders characterized by altered affect, such as anxiety and depression.
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Factor 2 de Crecimiento de Fibroblastos/farmacología , Receptores Opioides mu/metabolismo , Vocalización Animal/fisiología , Animales , Ansiedad/metabolismo , Conducta Animal/efectos de los fármacos , Emociones , Conducta Exploratoria/efectos de los fármacos , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Ondas Ultrasónicas , Vocalización Animal/efectos de los fármacosRESUMEN
Recent evidence highlights the fibroblast growth factor (FGF) family in emotion modulation. Although ligands that activate FGF receptors have antidepressant and anxiolytic effects in animal models, FGF ligands have a broad range of actions both in the brain and the periphery. Therefore, identifying molecular partners that may function as allosteric modulators could offer new avenues for drug development. Since neural cell adhesion molecule (NCAM) activates FGF receptors, we asked whether peripherally administered NCAM peptide mimetics penetrate the brain and alter the behavior of standardized tests that have predictive validity for drug treatments of anxiety or depression. The NCAM peptide mimetic, plannexin, acutely increased and chronically decreased anxiety, but did not have antidepressant effects in rats. Another NCAM peptide mimetic, FGLL, had acute anxiogenic effects and chronic antidepressant effects in rats. A related NCAM peptide mimetic, FGLS, had antidepressant effects without modulating anxiety-like behavior, and these antidepressant effects were blocked by an AMPA receptor antagonist. Cisternal cerebrospinal fluid (CSF) levels of FGLs correlated with blood plasma levels in rats and non-human primates, and CSF-to-blood ratios of FGLS were comparable in both species. Results indicate that NCAM peptide mimetics penetrate the brain and support the suggestion that FGLS may be a candidate for further development as a novel treatment for major depressive disorder in humans.
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Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Emociones/efectos de los fármacos , Moléculas de Adhesión de Célula Nerviosa/farmacología , Oligopéptidos/farmacología , Animales , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Ansiedad/metabolismo , Encéfalo/efectos de los fármacos , Depresión/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Moléculas de Adhesión de Célula Nerviosa/uso terapéutico , Oligopéptidos/metabolismo , Oligopéptidos/uso terapéutico , Ratas , Ratas Sprague-Dawley , SaimiriRESUMEN
Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types in affected brain regions. Despite this, transcriptomic analyses of the human brain have typically been conducted using macro-dissected tissue due to the difficulty of performing single-cell type analyses with donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary cortical cell types in previous publications. Using this database, we predicted the relative cell type content for 833 human cortical samples using microarray or RNA-Seq data from the Pritzker Consortium (GSE92538) or publicly-available databases (GSE53987, GSE21935, GSE21138, CommonMind Consortium). These predictions were generated by averaging normalized expression levels across transcripts specific to each cell type using our R-package BrainInABlender (validated and publicly-released on github). Using this method, we found that the principal components of variation in the datasets strongly correlated with the predicted neuronal/glial content of the samples. This variability was not simply due to dissection-the relative balance of brain cell types appeared to be influenced by a variety of demographic, pre- and post-mortem variables. Prolonged hypoxia around the time of death predicted increased astrocytic and endothelial gene expression, illustrating vascular upregulation. Aging was associated with decreased neuronal gene expression. Red blood cell gene expression was reduced in individuals who died following systemic blood loss. Subjects with Major Depressive Disorder had decreased astrocytic gene expression, mirroring previous morphometric observations. Subjects with Schizophrenia had reduced red blood cell gene expression, resembling the hypofrontality detected in fMRI experiments. Finally, in datasets containing samples with especially variable cell content, we found that controlling for predicted sample cell content while evaluating differential expression improved the detection of previously-identified psychiatric effects. We conclude that accounting for cell type can greatly improve the interpretability of transcriptomic data.
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Encéfalo/metabolismo , Encéfalo/patología , Perfilación de la Expresión Génica , Trastornos Mentales/genética , Trastornos Mentales/patología , Factores de Edad , Animales , Femenino , Ontología de Genes , Humanos , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/mortalidad , Ratones , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
BACKGROUND: While downregulation of several growth factors in major depressive disorder is well established, less attention has been paid to the upregulation of other growth factors. Yet, upregulated growth factors may offer better therapeutic targets. We show that connective tissue growth factor (CTGF) represents a target based on its upregulation in major depressive disorder and studies in animal models implicating it in negative affect. METHODS: CTGF gene expression was first evaluated in the postmortem human amygdala. The findings were followed up in outbred rats and in two rat lines that were selectively bred for differences in novelty-seeking and anxiety behavior (bred low responders and bred high responders). We studied the impact of social defeat and early-life treatment with fibroblast growth factor 2 on CTGF expression. Finally, we assessed the ability of an anti-CTGF antibody (FG-3019) to alter CTGF expression and emotionality. RESULTS: In the human amygdala, CTGF expression was significantly increased in major depressive disorder compared with control subjects. CTGF expression was also significantly increased in the dentate gyrus of adult bred low responders compared with bred high responders. Social defeat stress in bred low responders significantly increased CTGF expression in the dentate gyrus. Early-life fibroblast growth factor 2, a treatment that reduces anxiety-like behavior throughout life, decreased CTGF expression in the adult dentate gyrus. In outbred rats, CTGF administration increased depression-like behavior. Chronic treatment with FG-3019 decreased CTGF expression, and acute and chronic treatment was antidepressant. CONCLUSIONS: This study is the first to implicate CTGF as a prodepressant molecule that could serve as a target for the development of novel therapeutics.
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Anticuerpos Monoclonales/administración & dosificación , Ansiedad/genética , Factor de Crecimiento del Tejido Conjuntivo/genética , Trastorno Depresivo Mayor/genética , Factor 2 de Crecimiento de Fibroblastos/administración & dosificación , Adulto , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/fisiología , Animales , Anticuerpos Monoclonales Humanizados , Ansiedad/patología , Factor de Crecimiento del Tejido Conjuntivo/antagonistas & inhibidores , Giro Dentado/efectos de los fármacos , Giro Dentado/fisiología , Trastorno Depresivo Mayor/patología , Modelos Animales de Enfermedad , Conducta Exploratoria , Femenino , Perfilación de la Expresión Génica , Hipocampo/metabolismo , Humanos , Masculino , Persona de Mediana Edad , RatasRESUMEN
Individual differences in temperament are associated with psychopathology in humans. Moreover, the relationship between temperament and anxiety-, depression-, PTSD- and addiction-related behaviors can be modeled in animals. This review will highlight these relationships with a focus on individual differences in the response to stressors, fear conditioning and drugs of abuse using animals that differ in their response to a novel environment. We will discuss behavioral and neurobiological commonalities amongst these behaviors with a focus on the hippocampus and, in particular, growth factors as promising novel targets for therapeutic intervention.
RESUMEN
Individuals respond differently to traumatic experiences, including their propensity to develop posttraumatic stress disorder (PTSD). Understanding individual differences in PTSD vulnerability will allow the development of improved prevention and treatment options. Here we characterized fear conditioning and extinction in rats selectively bred for differences in their locomotor response to a novel environment. Selectively bred high-responder (bHR) and low-responder (bLR) male rats are known to differ in their emotional reactivity on a range of measures of spontaneous anxiety- and depressive-like behaviors. We demonstrate that bHRs have facilitated extinction learning and retention compared with outbred Sprague Dawley rats, whereas bLRs show reduced extinction learning and retention. This indicates that bLRs are more vulnerable to PTSD-like behavior. Fibroblast growth factor 2 (FGF2) has previously been implicated in the development of these behavioral phenotypes and facilitates extinction learning in outbred animals, therefore we examined the effects of early-life FGF2 on bHR and bLR behavior. FGF2 administered on the day after birth facilitated extinction learning and retention in bHRs, but not in bLRs or control rats, during adulthood. This indicates that, under the current fear conditioning paradigm, early-life FGF2 has protective effects only in resilient animals. This stands in contrast to FGF2's ability to protect vulnerable animals in milder tests of anxiety. These results provide a unique animal model of individual differences in PTSD-like behavior, allowing the study of genetic, developmental, and environmental factors in its expression.
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Conducta Animal , Susceptibilidad a Enfermedades/psicología , Factor 2 de Crecimiento de Fibroblastos/farmacología , Individualidad , Trastornos por Estrés Postraumático/psicología , Envejecimiento/efectos de los fármacos , Animales , Condicionamiento Psicológico , Ambiente , Extinción Psicológica , Miedo , Masculino , Actividad Motora , Ratas , Ratas EndogámicasRESUMEN
We aimed to determine the short-term effects of early-life stress in the form of maternal separation (MS) on anxiety-like behavior in male rat pups. In order to assess anxiety, we measured 40kHz separation-induced ultrasonic vocalizations (USV) on postnatal day (PND) 11. We further aimed to evaluate the potential involvement of two neurochemical systems known to regulate social and anxiety-like behaviors throughout life: oxytocin (OT) and fibroblast growth factor 2 (FGF2). For these purposes, we tested the effects of neonatal administration (on PND1) of an acute dose of FGF2 on USV and its potential interaction with MS. In addition, we validated the anxiolytic effects of OT and measured oxytocin receptor (OTR) gene expression, binding and epigenetic regulation via histone acetylation. Our results show that MS potentiated USV while acute administration of OT and FGF2 attenuated them. Further, we found that both FGF2 and MS increased OTR gene expression and the association of acH3K14 with the OTR promoter in the bed nucleus of the stria terminalis (BNST). Comparable changes, though not as pronounced, were also found for the central amygdala (CeA). Our findings suggest that FGF2 may exert its anxiolytic effects in male MS rats by a compensatory increase in the acetylation of the OTR promoter to overcome reduced OT levels in the BNST.
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Ansiedad/genética , Conducta Animal/efectos de los fármacos , Factor 2 de Crecimiento de Fibroblastos/farmacología , Crecimiento y Desarrollo/efectos de los fármacos , Privación Materna , Receptores de Oxitocina/genética , Núcleos Septales/efectos de los fármacos , Animales , Animales Recién Nacidos , Ansiedad/metabolismo , Ansiedad/fisiopatología , Núcleo Amigdalino Central/efectos de los fármacos , Núcleo Amigdalino Central/crecimiento & desarrollo , Núcleo Amigdalino Central/metabolismo , Epigénesis Genética/efectos de los fármacos , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Crecimiento y Desarrollo/genética , Masculino , Oxitocina/metabolismo , Oxitocina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Oxitocina/metabolismo , Núcleos Septales/crecimiento & desarrollo , Núcleos Septales/metabolismoRESUMEN
The role of the fibroblast growth factor (FGF) system in brain-related disorders has received considerable attention in recent years. To understand the role of this system in neurological and psychiatric disorders, it is important to identify the specific members of the FGF family that are implicated, their location and the various mechanisms they can be modulated. Each disorder appears to impact specific molecular players in unique anatomical locations, and all of these could conceivably become targets for treatment. In the last several years, the issue of how to target this system directly has become an area of increasing interest. To date, the most promising therapeutics are small molecule inhibitors and antibodies that modulate FGF receptor (FGFR) function. Beyond attempting to modify the primary players affected by a given brain disorder, it may prove useful to target molecules, such as membrane-bound or extracellular proteins that interact with FGF ligands or FGFRs to modulate signaling.
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Factores de Crecimiento de Fibroblastos/metabolismo , Trastornos Mentales/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Transducción de Señal , Animales , Humanos , Terapia Molecular Dirigida , Receptores de Factores de Crecimiento de Fibroblastos/metabolismoRESUMEN
Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9's function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.
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Afecto , Factor 9 de Crecimiento de Fibroblastos/metabolismo , Adulto , Afecto/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Animales , Ansiedad/complicaciones , Ansiedad/metabolismo , Reacción de Prevención/efectos de los fármacos , Estudios de Casos y Controles , Demografía , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Trastorno Depresivo Mayor/complicaciones , Trastorno Depresivo Mayor/metabolismo , Femenino , Factor 9 de Crecimiento de Fibroblastos/administración & dosificación , Factor 9 de Crecimiento de Fibroblastos/genética , Factor 9 de Crecimiento de Fibroblastos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Lentivirus/metabolismo , Masculino , Microinyecciones , Persona de Mediana Edad , Cambios Post Mortem , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Estrés Psicológico/complicaciones , Estrés Psicológico/genética , Adulto JovenRESUMEN
Posttranslational modifications of histone tails in chromatin template can result from environmental experiences such as stress and substance abuse. However, the role of epigenetic modifications as potential predisposing factors in affective behavior is less well established. To address this question, we used our selectively bred lines of high responder (bHR) and low responder (bLR) rats that show profound and stable differences in affective responses, with bLRs being prone to anxiety- and depression-like behavior and bHRs prone to addictive behavior. We first asked whether these phenotypes are associated with basal differences in epigenetic profiles. Our results reveal broad between-group differences in basal levels of trimethylated histone protein H3 at lysine 9 (H3K9me3) in hippocampus (HC), amygdala, and nucleus accumbens. Moreover, levels of association of H3K9me3 at Glucocorticoid Receptor (GR) and Fibroblast growth Factor 2 (FGF2) promoters differ reciprocally between bHRs and bLRs in these regions, consistent with these genes' opposing levels of expression and roles in modulating anxiety behavior. Importantly, this basal epigenetic pattern is modifiable by FGF2, a factor that modulates anxiety behavior. Thus, early-life FGF2, which decreases anxiety, altered the levels of H3K9me3 and its binding at FGF2 and GR promoters of bLRs rendering them more similar to bHRs. Conversely, knockdown of HC FGF2 altered both anxiety behavior and levels of H3K9me3 in bHRs, rendering them more bLR-like. These findings implicate FGF2 as a modifier of epigenetic mechanisms associated with emotional responsiveness, and point to H3K9me3 as a key player in the regulation of affective vulnerability.
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Afecto/fisiología , Conducta Animal/fisiología , Emociones/fisiología , Epigénesis Genética , Factor 2 de Crecimiento de Fibroblastos/genética , Histonas/química , Histonas/metabolismo , Animales , Ensamble y Desensamble de Cromatina , Metilación de ADN , Factor 2 de Crecimiento de Fibroblastos/deficiencia , Técnicas de Silenciamiento del Gen , Hipocampo/metabolismo , Regiones Promotoras Genéticas , Ratas , Receptores de Glucocorticoides/genéticaRESUMEN
Given the emergent interest in biomarkers for mood disorders, we assessed gene expression in the choroid plexus (CP), the region that produces cerebrospinal fluid (CSF), in individuals with major depressive disorder (MDD). Genes that are expressed in the CP can be secreted into the CSF and may be potential biomarker candidates. Given that we have previously shown that fibroblast growth factor family members are differentially expressed in post-mortem brain of subjects with MDD and the CP is a known source of growth factors in the brain, we posed the question whether growth factor dysregulation would be found in the CP of subjects with MDD. We performed laser capture microscopy of the CP at the level of the hippocampus in subjects with MDD and psychiatrically normal controls. We then extracted, amplified, labeled, and hybridized the cRNA to Illumina BeadChips to assess gene expression. In controls, the most highly abundant known transcript was transthyretin. Moreover, half of the 14 most highly expressed transcripts in controls encode ribosomal proteins. Using BeadStudio software, we identified 169 transcripts differentially expressed (p < 0.05) between control and MDD samples. Using pathway analysis we noted that the top network altered in subjects with MDD included multiple members of the transforming growth factor-beta (TGFß) pathway. Quantitative real-time PCR (qRT-PCR) confirmed downregulation of several transcripts that interact with the extracellular matrix in subjects with MDD. These results suggest that there may be an altered cytoskeleton in the CP in MDD subjects that may lead to a disrupted blood-CSF-brain barrier.
RESUMEN
In this review, we propose a broader view of the role of the fibroblast growth factor (FGF) family in modulating brain function. We suggest that some of the FGF ligands together with the FGF receptors are altered in individuals with affective disorder and modulate emotionality in animal models. Thus, we propose that members of the FGF family may be genetic predisposing factors for anxiety, depression, or substance abuse; that they play a key organizing role during early development but continue to play a central role in neuroplasticity in adulthood; and that they work not only over extended time frames, but also via rapid signaling mechanisms, allowing them to exert an "on-line" influence on behavior. Therefore, the FGF family appears to be a prototype of "switch genes" that are endowed with organizational and modulatory properties across the lifespan, and that may represent molecular candidates as biomarkers and treatment targets for affective and addictive disorders.
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Encéfalo/fisiopatología , Factores de Crecimiento de Fibroblastos/fisiología , Trastornos del Humor/genética , Trastornos del Humor/fisiopatología , Neurotransmisores/fisiología , Animales , Predisposición Genética a la Enfermedad , HumanosAsunto(s)
Antidepresivos/farmacología , Factor 2 de Crecimiento de Fibroblastos/farmacología , Neuroglía/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Pirroles/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Estrés Psicológico/metabolismo , Animales , MasculinoRESUMEN
Growth factors are critical in neurodevelopment and neuroplasticity, and recent studies point to their involvement in addiction. We previously reported increased levels of basic fibroblast growth factor (FGF2) in high novelty/drug-seeking rats (bred high responders, bHR) compared to low novelty/drug-seeking rats(bred low responders, bLRs). The present study asked whether an early life manipulation of the FGF system(a single FGF2 injection on postnatal day 2) can impact cocaine sensitization and associated neurobiological markers in adult bHR/bLR animals. Neonatal FGF2- and vehicle-treated bHR/bLR rats were sensitized to cocaine(7 daily injections, 15 mg/kg/day, i.p.) in adulthood. Neonatal FGF2 markedly increased bLRs' typically low psychomotor sensitization to cocaine (day 7 locomotor response to cocaine), but had little effect on bHRs' cocaine sensitization. Gene expression studies examined dopaminergic molecules as well as FGF2 and the FGFR1 receptor in cocaine naïve animals, to investigate possible neurobiological alterations induced by neonatal FGF2 exposure that may influence behavioral response to cocaine. bLRs showed decreased tyrosine hydroxylase in the ventral tegmental area (VTA), decreased D1 and increased D2 receptor expression in the nucleus accumbens core, as well as decreased FGF2 in the VTA, substantia nigra, accumbens core, and caudate putamen compared to bHRs. Neonatal FGF2 selectively increased D1 receptor and FGF2 mRNA in the accumbens core of bLRs, which may contribute to their heightened cocaine sensitization. Our results suggest increased FGF2 in the mesodopaminergic circuit (as in baseline bHRs and neonatal FGF2-exposed bLRs vs. baseline bLRs) enhances an individual's susceptibility to cocaine sensitization and may increase vulnerability to drug seeking and addiction.
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Trastornos Relacionados con Cocaína/etiología , Factor 2 de Crecimiento de Fibroblastos/administración & dosificación , Animales , Animales Recién Nacidos , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Trastornos Relacionados con Cocaína/genética , Trastornos Relacionados con Cocaína/fisiopatología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/fisiología , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Femenino , Factor 2 de Crecimiento de Fibroblastos/genética , Factor 2 de Crecimiento de Fibroblastos/fisiología , Expresión Génica/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/fisiologíaRESUMEN
Individuals with mood disorders exhibit alterations in the fibroblast growth factor system, including reduced hippocampal fibroblast growth factor-2 (FGF2). It is difficult, however, to pinpoint whether these alterations are a cause or consequence of the disorder. The present study asks whether FGF2 administered the day after birth has long-lasting effects on hippocampal development and emotionality. We show that early-life FGF2 shifts the pace of neurogenesis, with an early acceleration around weaning followed by a deceleration in adulthood. This, in turn, results in a denser dentate gyrus with more neurons. To assess the impact of early-life FGF2 on emotionality, we use rats selectively bred for differences in locomotor response to novelty. Selectively bred low-responder (bLR) rats show low levels of novelty-induced locomotion and exhibit high levels of anxiety- and depression-like behavior compared with their selectively bred high-responder counterparts. Early-life FGF2 decreased anxiety-like behavior in highly anxious bLRs without altering other behaviors and without affecting high-responder rats. Laser capture microscopy of the dentate gyrus followed by microarray analysis revealed genes that were differentially expressed in bLRs exposed to early-life FGF2 vs. vehicle-treated bLRs. Some of the differentially expressed genes that have been positively associated with anxiety were down-regulated, whereas genes that promote cell survival were up-regulated. Overall, these results show a key role for FGF2 in the developmental trajectory of the hippocampus as well as the modulation of anxiety-like behavior in adulthood, and they point to potential downstream targets for the treatment of anxiety disorders.
Asunto(s)
Ansiedad/prevención & control , Factor 2 de Crecimiento de Fibroblastos/administración & dosificación , Factor 2 de Crecimiento de Fibroblastos/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/crecimiento & desarrollo , Animales , Animales Recién Nacidos , Ansiedad/etiología , Ansiedad/genética , Ansiedad/patología , Ansiedad/fisiopatología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Giro Dentado/efectos de los fármacos , Giro Dentado/crecimiento & desarrollo , Giro Dentado/fisiología , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Femenino , Factor 2 de Crecimiento de Fibroblastos/genética , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Hipocampo/fisiología , Masculino , Trastornos del Humor/etiología , Trastornos del Humor/genética , Trastornos del Humor/patología , Trastornos del Humor/fisiopatología , Neurogénesis/efectos de los fármacos , Neurogénesis/genética , Neurogénesis/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Ratas , Ratas Sprague-Dawley , Receptor trkC/genética , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/genéticaRESUMEN
BACKGROUND: The fibroblast growth factor system has been implicated in the pathophysiology of mood disorders in humans and in affective behavior in animal models. However, the studies have been either correlative or involved exogenous administration of fibroblast growth factor 2 (FGF2). None of them have directly linked endogenous FGF2 to changes in emotional responses. Therefore, we began a series of studies to knockdown FGF2 by RNA interference to examine the role of brain FGF2 in emotional responsiveness. METHODS: We assessed the efficacy of short-hairpin RNA (shRNA) sequences targeted to FGF2 in COS7 cells transfected with a plasmid vector containing the full-length FGF2 sequence. We then sought to assess the effects of knocking down FGF2 gene expression in vivo on behavior. We microinjected a lentiviral vector containing either a shRNA targeting FGF2 or a nonsilencing sequence bilaterally into the dentate gyrus of the rat. RESULTS: In a reporter assay system, three different shRNA sequences resulted in significant FGF2 knockdown in vitro. Five weeks following a single microinjection of one of those sequences in vivo, we observed a significant decrease in FGF2 gene expression by messenger RNA in situ hybridization in the hippocampus. The FGF2 knockdown increased the time spent in the closed arms of the elevated-plus maze, a test of anxiety behavior. CONCLUSIONS: The FGF2 knockdown in the hippocampus resulted in an anxiogenic effect. Together with our findings of an inverse correlation between anxiety and FGF2 expression levels, these results implicate FGF2 in the genesis and expression of anxiety disorders.
Asunto(s)
Ansiedad/patología , Ansiedad/fisiopatología , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Regulación de la Expresión Génica/fisiología , Hipocampo/metabolismo , ARN Interferente Pequeño/metabolismo , Animales , Células COS , Chlorocebus aethiops , Modelos Animales de Enfermedad , Factor 2 de Crecimiento de Fibroblastos/genética , Masculino , Aprendizaje por Laberinto/fisiología , Microinyecciones/métodos , Ratas , Ratas Sprague-Dawley , Transfección/métodosRESUMEN
Human postmortem studies have demonstrated that fibroblast growth factor-2 (FGF2) expression is decreased in the brain of depressed individuals. It remained unclear, however, whether this is a consequence of the illness or whether FGF2 plays a primary role in the control of mood and emotions. In this series of studies, we first ask whether endogenous FGF2 expression correlates with spontaneous anxiety, a trait associated with vulnerability to severe mood disorders in humans. This is tested in two genetically distinct groups of rats selectively bred to differ dramatically in their response to novelty and anxiety-provoking conditions (HRs = low anxiety/high response to novelty vs LRs = high anxiety/low response to novelty). We demonstrate that high-anxiety LRs have significantly lower levels of hippocampal FGF2 mRNA relative to low-anxiety HRs. We then demonstrate that FGF2 expression is modifiable by environmental factors that alter anxiety--thus, environmental complexity reduces anxiety behavior and induces FGF2 expression in hippocampus, particularly in high-anxiety LRs. Finally, we directly test the role of FGF2 as an anxiolytic and show that a 3 week treatment regimen of peripherally administered FGF2 is highly effective at blunting anxiety behavior, specifically in high-anxiety LRs. This treatment is accompanied by an increase in survival of adult-born hippocampal cells, both neurons and astrocytes, most clearly in LRs. These findings implicate hippocampal FGF2 as a central integrator of genetic and environmental factors that modify anxiety, point to hippocampal neurogenesis and gliogenesis as key in this modulation, and underscore FGF2's potential as a new target for treatment of depression and anxiety disorders.