Gene expression underlying serotonin axon regrowth in the adult mammalian brain
成年哺乳动物大脑中血清素轴突再生的基因表达
基本信息
- 批准号:9765426
- 负责人:
- 金额:$ 20.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2020-08-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Brain InjuriesAddressAdultAftercareAmphetaminesAnimalsAstrocytesAxonBacterial Artificial ChromosomesBiological ModelsBrainCaliberCellsChemicalsCicatrixCognition DisordersCytosineDataData SetDevelopmentDioxygenasesDopamineDorsalDoseDynein ATPaseEnzymesExpression ProfilingFailureFemaleFiberGene ExpressionGene Expression ProfileGenesHarvestHistonesHomeostasisImageImmediate-Early GenesImmunohistochemistryImpaired cognitionIn Situ HybridizationInflammationInjuryJUNB geneLabelLeftLesionMeasurementMeasuresMolecularMood DisordersMotorMusMyelinNatural regenerationNeocortexNeuronsNeurotransmittersParalysedPathway interactionsPeripheralPopulationProteinsRecoveryRecovery of FunctionResearch PersonnelRetrograde DegenerationRodentRunningSalineSamplingScanningScreening ResultSerotoninSignal TransductionSiteSomatosensory CortexSpinalStrokeSuggestionTPH2TimeTissue-Specific Gene ExpressionTissuesTransgenic OrganismsTransmembrane DomainTraumatic Brain InjuryVentral Tegmental Areaaxon growthaxon injurydensitydifferential expressiondopaminergic neurondorsal raphe nucleusexperimental studygenome-wideimmunoreactivityin vivoinjuredinterestmaleneocorticalnovel therapeuticsplanar cell polarityreceptorresponseserotonin transportertherapy developmenttranscriptome sequencingtwo-photon
项目摘要
Project Summary
It is widely believed that damaged axons in the adult mammalian brain have little capacity to regrow, thereby
impeding functional recovery after injury. Serotonin neurons appear to be a notable exception. We have
produced time-lapse images of serotonin axons in the neocortex of the adult mouse. Serotonin axons undergo
massive retrograde degeneration following amphetamine treatment and show subsequent slow, long-distance
regrowth. A stab injury that transects serotonin axons running in the neocortex is followed by local regression
of cut serotonin axons and by regrowth from cut ends that projects across the stab rift zone. By contrast,
dopamine fibers originating in neurons of the ventral tegmental area (VTA) are also small-diameter unmyelinated
axons, yet they are not damaged by amphetamine treatment and they fail to regrow after stab transection. What
are the molecular specializations that allow serotonin axons to regrow while other injured axons in the brain fail
to do so? To begin to address this question we have harvested pools of serotonin neurons from the dorsal raphe
of adult mice in order to measure gene expression using genome-wide RNA sequencing (RNA-Seq). This was
done 1 week after the end of either amphetamine or saline treatment. Our preliminary data have revealed a set
of genes that are significantly upregulated in serotonin neurons during amphetamine-evoked axon regrowth.
Here, we propose to complete and extend this screen as a first step to define the molecular requirements for
serotonin axon regrowth. Aim 1. What genes are differentially expressed in serotonin neurons during
amphetamine-evoked regrowth of their axons in the neocortex? Our preliminary data reveal ~50
upregulated and ~60 downregulated genes measured ~1 week after the end of amphetamine treatment as
compared with saline-treated-controls (using a false-discovery rate of p<.05). To complete this data set, we shall
extend these RNA-Seq measurements using a time course of amphetamine and saline-treated mice at t= 1 day,
1 week and 18 weeks. There will be 8 animals per group (4 male, 4 female), and we shall validate genes of
interest with in situ hybridization and immunohistochemistry. We shall also compare the gene expression
changes in response to amphetamine challenge in serotonin neurons with those changes produced in dopamine
neurons of the VTA. Aim 2. What genes are differentially expressed in serotonin neurons during regrowth
of serotonin axons following a neocortical stab lesion? In contrast to amphetamine lesions, stab lesions
produce only local axonal regression of serotonin and dopamine axons. Stab lesions form a glial scar, as occurs
in stroke and other forms of acute brain injury. We shall compare dorsal raphe serotonin neuron and VTA
dopamine neuron expression profiles in response to stab and amphetamine injury using the same post-injury
time points. The results of these two complementary injuries in regenerating and non-regenerating neurons will
inform later manipulative experiments to modulate serotonin axon regrowth and, ultimately, confer the capacity
to regrow on non-serotonergic neurons in the brain.
项目摘要
人们普遍认为成年哺乳动物大脑中受损的轴突几乎没有再生的能力,因此
阻碍损伤后的功能恢复。5-羟色胺神经元似乎是一个明显的例外。我们有
制作了成年小鼠新皮质中5-羟色胺轴突的延时图像。5-羟色胺轴突经历
苯丙胺治疗后出现大规模退行性变,并显示出随后缓慢、远距离的
重生。刺伤横断新皮质内的5-羟色胺轴突,继之局部消退。
通过切断5-羟色胺轴突和从穿过刺裂隙区域的切断端重新生长。相反,
起源于腹侧被盖区(VTA)神经元的多巴胺纤维也是小直径的无髓
轴突,然而它们不会被苯丙胺处理破坏,它们在刺伤横断后不能再生。什么
5-羟色胺轴突再生,而大脑中其他受损轴突失效的分子特化
要这么做吗?为了解决这个问题,我们收集了中缝背侧的5-羟色胺神经元池。
为了使用全基因组RNA测序(RNA-Seq)来测量基因表达。这是
在安非他明或生理盐水治疗结束后1周完成。我们的初步数据揭示了一组
在安非他明诱导的轴突再生过程中,5-羟色胺神经元中显著上调的基因。
在这里,我们建议完成并扩展此屏幕,作为定义以下分子要求的第一步
5-羟色胺轴突再生。目的1.在5-羟色胺神经元中差异表达的基因有哪些
安非他命能在大脑皮层引起轴突再生吗?我们的初步数据显示~50
苯丙胺治疗结束后~1周检测到的上调和~60个下调的基因
与生理盐水对照组相比(使用p<;0.05的错误发现率)。为了完成这个数据集,我们将
使用安非他明和生理盐水处理的小鼠在t=1天的时间过程来扩展这些RNA-Seq测量,
1周和18周。每组将有8只动物(4只雄性,4只雌性),我们将验证
对原位杂交和免疫组织化学感兴趣。我们还将比较基因的表达
5-羟色胺神经元对苯丙胺刺激反应的变化与多巴胺产生的变化
室旁核的神经元。目的2.在5-羟色胺神经元再生过程中,哪些基因有差异表达
新皮质刺伤后的5-羟色胺轴突?与苯丙胺损伤不同的是,刺伤
仅产生5-羟色胺和多巴胺轴突的局部轴突退化。刺伤会形成神经胶质疤痕。
中风和其他形式的急性脑损伤。我们将比较中缝背侧5-羟色胺神经元和VTA。
刺伤和苯丙胺损伤后相同部位的多巴胺神经元表达谱
时间点。再生和非再生神经元的这两种互补损伤的结果将
为以后的操纵性实验提供信息,以调节5-羟色胺轴突的再生,并最终赋予
在大脑中的非5-羟色胺能神经元上再生。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Susan M. Dymecki其他文献
Development of an in vitro electroporation assay in the mouse to manipulate gene expression in the lower rhombic lip
- DOI:
10.1016/j.ydbio.2010.05.299 - 发表时间:
2010-08-01 - 期刊:
- 影响因子:
- 作者:
Rebecca L. Landsberg;Susan M. Dymecki;Patrick Holland - 通讯作者:
Patrick Holland
Susan M. Dymecki的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Susan M. Dymecki', 18)}}的其他基金
Early life stress and differential effects on the molecular maturation of specific subtypes of brain serotonin neurons
早期生活压力和对大脑血清素神经元特定亚型分子成熟的不同影响
- 批准号:
10725411 - 财政年份:2023
- 资助金额:
$ 20.74万 - 项目类别:
State-dependent and branch-specific neurotransmitter usage in a serotonergic/glutamatergic neural circuit regulating adaptation to seasonal photoperiod
状态依赖性和分支特异性神经递质在血清素能/谷氨酸能神经回路中的使用调节对季节性光周期的适应
- 批准号:
10666427 - 财政年份:2022
- 资助金额:
$ 20.74万 - 项目类别:
State-dependent and branch-specific neurotransmitter usage in a serotonergic/glutamatergic neural circuit regulating adaptation to seasonal photoperiod
状态依赖性和分支特异性神经递质在血清素能/谷氨酸能神经回路中的使用调节对季节性光周期的适应
- 批准号:
10451908 - 财政年份:2022
- 资助金额:
$ 20.74万 - 项目类别:
Does neurotransmitter plasticity of para-serotonergic neurons augment autoresuscitation following perinatal stress and buffer SIDS risk?
副血清素能神经元的神经递质可塑性是否会增强围产期应激后的自动复苏并缓冲 SIDS 风险?
- 批准号:
10460532 - 财政年份:2020
- 资助金额:
$ 20.74万 - 项目类别:
Does neurotransmitter plasticity of para-serotonergic neurons augment autoresuscitation following perinatal stress and buffer SIDS risk?
副血清素能神经元的神经递质可塑性是否会增强围产期应激后的自动复苏并缓冲 SIDS 风险?
- 批准号:
10672925 - 财政年份:2020
- 资助金额:
$ 20.74万 - 项目类别:
Does neurotransmitter plasticity of para-serotonergic neurons augment autoresuscitation following perinatal stress and buffer SIDS risk?
副血清素能神经元的神经递质可塑性是否会增强围产期应激后的自动复苏并缓冲 SIDS 风险?
- 批准号:
10254240 - 财政年份:2020
- 资助金额:
$ 20.74万 - 项目类别:
Function-specific serotonergic neurons, discrete brain targets, and addiction
功能特异性血清素能神经元、离散大脑目标和成瘾
- 批准号:
8828655 - 财政年份:2014
- 资助金额:
$ 20.74万 - 项目类别:
Developmental gene networks of 5HT neurons in addiction, aggression, and anxiety
成瘾、攻击性和焦虑中 5HT 神经元的发育基因网络
- 批准号:
8836993 - 财政年份:2014
- 资助金额:
$ 20.74万 - 项目类别:
Developmental gene networks of 5HT neurons in addiction, aggression, and anxiety
成瘾、攻击性和焦虑中 5HT 神经元的发育基因网络
- 批准号:
8628623 - 财政年份:2014
- 资助金额:
$ 20.74万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 20.74万 - 项目类别:
Research Grant














{{item.name}}会员




