Induction of neuronal vascular endothelial growth factor expression by cAMP in the dentate gyrus of the hippocampus is required for antidepressant-like behaviors.
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ABSTRACT:
SUBMITTER: Lee JS
PROVIDER: S-EPMC2796224 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundSelective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are the most common form of medication treatment for major depression. However, approximately 50% of depressed patients fail to achieve an effective treatment response. Understanding how gene expression systems respond to treatments may be critical for understanding antidepressant resistance.MethodsWe take a novel approach to this problem by demonstrating that the gene expression system of the dentate gyrus responds to fluoxetine (FLX), a commonly used antidepressant medication, in a stereotyped-manner involving changes in the expression levels of thousands of genes. The aggregate behavior of this large-scale systemic response was quantified with principal components analysis (PCA) yielding a single quantitative measure of the global gene expression system state.ResultsQuantitative measures of system state were highly correlated with variability in levels of antidepressant-sensitive behaviors in a mouse model of depression treated with fluoxetine. Analysis of dorsal and ventral dentate samples in the same mice indicated that system state co-varied across these regions despite their reported functional differences. Aggregate measures of gene expression system state were very robust and remained unchanged when different microarray data processing algorithms were used and even when completely different sets of gene expression levels were used for their calculation.ConclusionsSystem state measures provide a robust method to quantify and relate global gene expression system state variability to behavior and treatment. State variability also suggests that the diversity of reported changes in gene expression levels in response to treatments such as fluoxetine may represent different perspectives on unified but noisy global gene expression system state level responses. Studying regulation of gene expression systems at the state level may be useful in guiding new approaches to augmentation of traditional antidepressant treatments.
| S-EPMC3894967 | biostudies-literature
Project description:Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used medications for mood and anxiety disorders, and adult neurogenesis in the dentate gyrus has been shown to be involved in the behavioral effects of SSRIs in mice. Studies have shown the varied effects of chronic treatment with SSRIs on adult neurogenesis. One such effect is the acceleration of neuronal maturation, which affects the functional integration of new neurons into existing neuronal circuitry. In this study, we labeled new neurons by using GFP-expressing retroviral vectors in mice and investigated the effect of an SSRI, fluoxetine, on these neurons at different time points after neuronal birth. Chronic treatment with fluoxetine accelerated the dendritic development of the newborn neurons and shifted the timing of the expression of the maturational marker proteins, doublecortin and calbindin. This accelerated maturation was observed even after sub-chronic treatment, only when fluoxetine was administered during the second week of neuronal birth. These results suggest the existence of a 'critical period' for the fluoxetine-induced maturation of new neurons. We propose that the modified functional integration of new neurons in the critical period may underlie the behavioral effects of fluoxetine by regulating anxiety-related decision-making processes.
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Project description:Antidepressants that target monoaminergic systems, such as selective serotonin reuptake inhibitors (SSRIs), are widely used to treat neuropsychiatric disorders including major depressive disorder, several anxiety disorders, and obsessive-compulsive disorder. However, these treatments are not ideal because only a subset of patients achieve remission. The reasons why some individuals remit to antidepressant treatments while others do not are unknown. Here, we developed a paradigm to assess antidepressant treatment resistance in mice. Exposure of male C57BL/6J mice to either chronic corticosterone administration or chronic social defeat stress induces maladaptive affective behaviors. Subsequent chronic treatment with the SSRI fluoxetine reverses these maladaptive affective behavioral changes in some, but not all, of the mice, permitting stratification into persistent responders and non-responders to fluoxetine. We found several differences in expression of Activin signaling-related genes between responders and non-responders in the dentate gyrus (DG), a region that is critical for the beneficial behavioral effects of fluoxetine. Enhancement of Activin signaling in the DG converted behavioral non-responders into responders to fluoxetine treatment more effectively than commonly used second-line antidepressant treatments, while inhibition of Activin signaling in the DG converted responders into non-responders. Taken together, these results demonstrate that the behavioral response to fluoxetine can be bidirectionally modified via targeted manipulations of the DG and suggest that molecular- and neural circuit-based modulations of DG may provide a new therapeutic avenue for more effective antidepressant treatments.
| S-EPMC7791138 | biostudies-literature
Project description:Previous studies suggest that reducing the numbers of adult-born neurons in the dentate gyrus (DG) of the mouse increases susceptibility to severe continuous seizures (status epilepticus; SE) evoked by systemic injection of the convulsant kainic acid (KA). However, it was not clear if the results would be the same for other ways to induce seizures, or if SE-induced damage would be affected. Therefore, we used pilocarpine, which induces seizures by a different mechanism than KA. Also, we quantified hippocampal damage after SE. In addition, we used both loss-of-function and gain-of-function methods in adult mice. We hypothesized that after loss-of-function, mice would be more susceptible to pilocarpine-induced SE and SE-associated hippocampal damage, and after gain-of-function, mice would be more protected from SE and hippocampal damage after SE. For loss-of-function, adult neurogenesis was suppressed by pharmacogenetic deletion of dividing radial glial precursors. For gain-of-function, adult neurogenesis was increased by conditional deletion of pro-apoptotic gene Bax in Nestin-expressing progenitors. Fluoro-Jade C (FJ-C) was used to quantify neuronal injury and video-electroencephalography (video-EEG) was used to quantify SE. Pilocarpine-induced SE was longer in mice with reduced adult neurogenesis, SE had more power and neuronal damage was greater. Conversely, mice with increased adult-born neurons had shorter SE, SE had less power, and there was less neuronal damage. The results suggest that adult-born neurons exert protective effects against SE and SE-induced neuronal injury.
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Project description:Gamma oscillations in the dentate gyrus and hippocampal CA3 show variable coherence in vivo, but the mechanisms and relevance for information flow are unknown. We found that carbachol-induced oscillations in rat CA3 have biphasic phase-response curves, consistent with the ability to couple with oscillations in afferent projections. Differences in response to stimulation of either the intrinsic feedback circuit or the dentate gyrus were well described by varying an impulse vector in a two-dimensional dynamical system, representing the relative input to excitatory and inhibitory neurons. Responses to sinusoidally modulated optogenetic stimulation confirmed that the CA3 network oscillation can entrain to periodic inputs, with a steep dependence of entrainment phase on input frequency. CA3 oscillations are therefore suited to coupling with oscillations in the dentate gyrus over a broad range of frequencies.
| S-EPMC3378654 | biostudies-literature
Project description:A recent model of the hippocampus predicts that the unique properties of the dentate gyrus allow for temporal separation of events. This temporal separation is accomplished in part through the continual generation of new neurons, which, due to a transient window of hyperexcitability, could allow for preferential encoding of information present during their development. Here we obtain in vivo electrophysiological recordings and identify a cell population exhibiting activity that is selective to single contexts when rats experience a long temporal separation between context exposures during training. This selectivity is attenuated as the temporal separation between context exposures is shortened and is further attenuated when neurogenesis is reduced. Our data reveal the existence of a temporal orthogonalizing neuronal code within the dentate gyrus, a hallmark feature of episodic memory.
| S-EPMC3929785 | biostudies-literature
Project description:This study is, to the best of our knowledge, the first application of whole transcriptome sequencing (RNA-seq) to cells isolated from postmortem human brain by laser capture microdissection. We investigated the transcriptome of dentate gyrus (DG) granule cells in postmortem human hippocampus in 79 subjects with mental illness (schizophrenia, bipolar disorder, major depression) and nonpsychiatric controls. We show that the choice of normalization approach for analysis of RNA-seq data had a strong effect on results; under our experimental conditions a nonstandard normalization method gave superior results. We found evidence of disrupted signaling by miR-182 in mental illness. This was confirmed using a novel method of leveraging microRNA genetic variant information to indicate active targeting. In healthy subjects and those with bipolar disorder, carriers of a high- vs those with a low-expressing genotype of miR-182 had different levels of miR-182 target gene expression, indicating an active role of miR-182 in shaping the DG transcriptome for those subject groups. By contrast, comparing the transcriptome between carriers of different genotypes among subjects with major depression and schizophrenia suggested a loss of DG miR-182 signaling in these conditions.
| S-EPMC3966046 | biostudies-literature
Project description:BACE1 is validated as Alzheimer's ?-secretase and a therapeutic target for Alzheimer's disease. In examining BACE1-null mice, we discovered that BACE1 deficiency develops abnormal clusters of immature neurons, forming doublecortin-positive neuroblasts, in the developing dentate gyrus, mainly in the subpial zone (SPZ). Such clusters were rarely observed in wild-type SPZ and not reported in other mouse models. To understand their origins and fates, we examined how neuroblasts in BACE1-null SPZ mature and migrate during early postnatal development. We show that such neuroblasts are destined to form Prox1-positive granule cells in the dentate granule cell layer, and mainly mature to form excitatory neurons, but not inhibitory neurons. Mechanistically, higher levels of reelin potentially contribute to abnormal neurogenesis and timely migration in BACE1-null SPZ. Altogether, we demonstrate that BACE1 is a critical regulator in forming the dentate granule cell layer through timely maturation and migration of SPZ neuroblasts.
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Project description:Major depressive disorder is the most prevalent mental illness worldwide, still its pharmacological treatment is limited by various challenges, such as the large heterogeneity in treatment response and the lack of insight into the neurobiological pathways underlying this phenomenon. To decode the molecular mechanisms shaping antidepressant response and to distinguish those from general paroxetine effects, we used a previously established approach targeting extremes (i.e., good vs poor responder mice). We focused on the dentate gyrus (DG), a subregion of major interest in the context of antidepressant mechanisms. Transcriptome profiling on micro-dissected DG granule cells was performed to (i) reveal cell-type-specific changes in paroxetine-induced gene expression (paroxetine vs vehicle) and (ii) to identify molecular signatures of treatment response within a cohort of paroxetine-treated animals. We identified 112 differentially expressed genes associated with paroxetine treatment. The extreme group comparison (good vs poor responder) yielded 211 differentially expressed genes. General paroxetine effects could be distinguished from treatment response-associated molecular signatures, with a differential gene expression overlap of only 4.6% (15 genes). Biological pathway enrichment and cluster analyses identified candidate mechanisms associated with good treatment response, e.g., neuropeptide signaling, synaptic transmission, calcium signaling, and regulation of glucocorticoid secretion. Finally, we examined glucocorticoid receptor (GR)-dependent regulation of selected response-associated genes to analyze a hypothesized interplay between GR signaling and good antidepressant treatment response. Among the most promising candidates, we suggest potential targets such as the developmental gene Otx2 or Htr2c for further investigations into antidepressant treatment response in the future.
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Project description:Gamma oscillations are thought to coordinate the spike timing of functionally specialized neuronal ensembles across brain regions. To test this hypothesis, we optogenetically perturbed gamma spike timing in the rat medial (MEC) and lateral (LEC) entorhinal cortices and found impairments in spatial and object learning tasks, respectively. MEC and LEC were synchronized with the hippocampal dentate gyrus through high- and low-gamma-frequency rhythms, respectively, and engaged either granule cells or mossy cells and CA3 pyramidal cells in a task-dependent manner. Gamma perturbation disrupted the learning-induced assembly organization of target neurons. Our findings imply that pathway-specific gamma oscillations route task-relevant information between distinct neuronal subpopulations in the entorhinal-hippocampal circuit. We hypothesize that interregional gamma-time-scale spike coordination is a mechanism of neuronal communication.
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