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Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice.

ABSTRACT: Adolescence is a developmental stage in which the incidence of psychiatric disorders, such as anxiety disorders, peaks. Selective serotonin reuptake inhibitors (SSRIs) are the main class of agents used to treat anxiety disorders. However, the impact of SSRIs on the developing brain during adolescence remains unknown. The authors assessed the impact of developmentally timed SSRI administration in a genetic mouse model displaying elevated anxiety-like behaviors.Knock-in mice containing a common human single-nucleotide polymorphism (Val66Met; rs6265) in brain-derived neurotrophic factor (BDNF), a growth factor implicated in the mechanism of action of SSRIs, were studied based on their established phenotype of increased anxiety-like behavior. Timed administration of fluoxetine was delivered during one of three developmental periods (postnatal days 21-42, 40-61, or 60-81), spanning the transition from childhood to adulthood. Neurochemical and anxiety-like behavioral analyses were performed.We identified a "sensitive period" during periadolescence (postnatal days 21-42) in which developmentally timed fluoxetine administration rescued anxiety-like phenotypes in BDNF Val66Met mice in adulthood. Compared with littermate controls, BDNFMet/Met mice exhibited diminished maturation of serotonergic fibers projecting particularly to the prefrontal cortex, as well as decreased expression of the serotonergic trophic factor S100B in the dorsal raphe. Interestingly, deficient serotonergic innervation, as well as S100B levels, were rescued with fluoxetine administration during periadolescence.These findings suggest that SSRI administration during a "sensitive period" during periadolescence leads to long-lasting anxiolytic effects in a genetic mouse model of elevated anxiety-like behaviors. These persistent effects highlight the role of BDNF in the maturation of the serotonin system and the capacity to enhance its development through a pharmacological intervention.

SUBMITTER: Dincheva I

PROVIDER: S-EPMC5711544 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice.

Dincheva Iva I Yang Jianmin J Li Anfei A Marinic Tina T Freilingsdorf Helena H Huang Chienchun C Casey B J BJ Hempstead Barbara B Glatt Charles E CE Lee Francis S FS Bath Kevin G KG Jing Deqiang D

The American journal of psychiatry 20171031 12

<h4>Objective</h4>Adolescence is a developmental stage in which the incidence of psychiatric disorders, such as anxiety disorders, peaks. Selective serotonin reuptake inhibitors (SSRIs) are the main class of agents used to treat anxiety disorders. However, the impact of SSRIs on the developing brain during adolescence remains unknown. The authors assessed the impact of developmentally timed SSRI administration in a genetic mouse model displaying elevated anxiety-like behaviors.<h4>Method</h4>Kno ...[more]

PMID: 29084453

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Project description:BackgroundBrain-derived neurotrophic factor (BDNF) is a candidate for susceptibility locus of Panic disorder (PD). However, the findings about the role of the BDNF Val66Met variant in PD were not consistent. Till now, the relationship between BDNF Val66Met polymorphism and anxiety-related traits in PD patients has been rarely explored. This study aimed to explore the relationship among BDNF Val66Met polymorphism, plasma BDNF level and anxiety-related trait in Chinese PD patients.MethodThis multi-center study included 116 PD patients and 99 health controls. We detected single-nucleotide polymorphism (SNP) of BDNF rs6265 (Val66Met) and BDNF plasma level in the two groups. In addition, PD patients were administered the State-Trait Anxiety Inventory (STAI), Panic Disorder Severity Scale-Chinese Version (PDSS-CV) and Hamilton Anxiety Rating Scale (HAMA-14). Quantitative comparison of the differences of BDNF concentration among subjects with different genotypes and association between BDNF Val66Met genotype and trait anxiety were performed.ResultsThere were no significant differences in the genotype frequency (p = 0.79) or allele frequency (p = 0.88) between PD patients and health controls. BDNF plasma levels of PD patients were significantly lower than those in control group (p = 0.003). BDNF plasma levels of the Met/Met genotype were significantly lower than those of Val/Met genotype in PD patients (p = 0.033). PD patients carried Met/Met genotype showed significantly higher scores in STAI trait compared to those carried Val/Val genotype (p = 0.045) and Val/Met genotype (p = 0.018). STAI trait scores of PD patients with agoraphobia were significantly higher than those of patients without agoraphobia (p < 0.05). The ANCOVA showed that the dependent variable STAI trait score was significantly affected by factor "genotype" (Val/Val, Val/Met, Met/Met, p = 0.029), and covariate "agoraphobia" (p = 0.008). In this model, 11.5% of the variance of the STAI trait score was explained by the BDNF genotype. Contrast analysis showed STAI trait scores of Met/Met subjects were significantly higher than those of Val/Met (p = 0.018) and Val/Val individuals (p = 0.045).ConclusionWe found that anxiety trait was associated with the BDNF polymorphism in PD patients. BDNF Met/Met genotype may decrease plasma BDNF level and increase trait anxiety in panic disorder.

Project description:Purpose: The goal of this study was to compare whole heart transcriptomes of hBDNF trasngenic mice to ascertain underlying molecular mechanisms for differences in cardiac function among genotypes Methods: Total RNA extracted from whole hearts of 8-week-old mice, and RNA libraries were constructed using the Illumina TruSeq Stranded Total RNA kit. Libraries were sequenced using Illumina HiSeq 3000 on paired-end-150 flow cell runs at ~32M PF reads per sample. Raw reads (fastq files) were uploaded to the Partek Flow server and pre-alignment quality assessment was performed. Mean base-call quality scores were above Phred-like values of 36 in all positions of all samples, and no hard trimming of the reads was necessary. Sequences were aligned to the mm10 assembly of the mouse genome using STAR 2.5.3a and resulting summary of reads filtered (<80) and quantified at the gene level to Ensemble transcripts 83 using Partek’s expectation maximization (E/M) annotation model. Gene counts were normalized to total read count per sample and then log-transformed (with an offset of 0.0001). To identify differentially expressed genes, statistical analysis was performed using Partek’s Gene Specific Analysis (GSA) multimodal estimation algorithm, followed by SYBR Green qPCR validation. Results: We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including reduction in the gene encoding SERCA2 (Atp2a2) in homozygous Met/Met mice but more profoundly in females compared to males. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. Homozygous male mice on the other hand exhibited an inflammatory profile characterized by interferon-γ (IFN-γ)-mediated Th1 immune responses. Conclusions: . These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, including female-specific alterations of cardiac-specific transcripts and male-specific activation of inflammatory targets.

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Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice.

Publications

Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice.

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