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Role for novel ventral tegmental area neuromedin S neurons in morphine responses

Role for novel ventral tegmental area neuromedin S neurons in morphine responses
新型腹侧被盖区神经调节素 S 神经元在吗啡反应中的作用
批准号:
10739543
负责人:
Michelle Suzanne Mazei-Robison
金额:
$22.76万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-06-15 至 2025-05-31

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Summary Although opioid dependence and addiction continue to constitute a major health and economic burden, our limited understanding of the underlying neurobiology limits better diagnostics and interventions. Dysregulation of the mesocorticolimbic reward circuit is acknowledged to contribute to various aspects of drug addiction, with alteration in the activity and output of dopamine (DA) neurons in the ventral tegmental area (VTA) known to contribute to the rewarding aspects of drug use. However, the molecular mechanisms underlying these changes in VTA DA function remain relatively unexplored. Therefore, our overarching goal is to identify molecular mechanisms in VTA DA neurons mediating long-term changes in drug reward that contribute to the persistence of drug addiction. To this end, we used translating ribosome affinity purification (TRAP) to identify gene expression changes in mice that specifically occur in VTA DA neurons following chronic morphine exposure. While we found approximately the same number of gene expression changes by morphine in our input and VTA DA fractions, our RNA sequencing analysis found very little overlap between these datasets emphasizing the importance of this approach to identify mechanisms in VTA DA neurons as these are likely obscured in whole tissue analyses. We have validated gene expression changes via qPCR and intriguingly, we find that expression of number of neuropeptides not traditionally described in the VTA are robustly induced by morphine exposure. Neuromedin S (NMS) was of particular interest as it was enriched in VTA DA neurons, and its expression was robustly increased following chronic morphine exposure. While a role for NMS neurons has been described in the suprachiasmatic nucleus in circadian regulation, NMS function outside this structure has not been characterized, making it a highly novel gene of study. It is known that the primary receptor with which NMS interacts, neuromedin U receptor 2 (NMUR2), is expressed within the target regions of VTA DA neurons, such as the nucleus accumbens (NAc). However, whether all VTA DA neurons express NMS, and their potential functional impact has yet to be determined. Thus, in this application we seek to characterize the expression and functional impact of VTA DA neurons that co-express NMS via completion of three specific aims: 1) identify the VTA DA neurons that express NMS and their projection sites, 2) determine whether modulation of VTA NMS neuronal activity alters morphine-elicited behavior, and 3) determine if NMS knockout in VTA DA neurons alters morphine-elicited behavior. Our studies will utilize cell type-specific CRISPR-mediated deletion to manipulate the output of these novel VTA NMS-expressing neurons to assess their functional role in adult mice along with transgenic mice and DREADDs to identify and alter VTA-NMS neuron activity. Critically, our new preliminary data suggest that activation of VTA-NMS neurons affects morphine-elicited behavior, supporting the premise and feasibility. These studies are expected to set the stage for future work investigating the role of specific VTA- DANMS circuits, their activity during behavior, and their potential as targets for therapeutic intervention.
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Projection-specific gene expression in resilience to chronic stress
  • 批准号:
    10683942
  • 项目类别:
  • 资助金额:
    $60.94万
  • 财政年份:
    2016
  • 负责人:
    Michelle Suzanne Mazei-Robison
  • 依托单位:
Neurobiological Mechanisms Underlying Stress-Induced Changes in Opiate Reward
  • 批准号:
    9352306
  • 项目类别:
  • 资助金额:
    $33.64万
  • 财政年份:
    2016
  • 负责人:
    Michelle Suzanne Mazei-Robison
  • 依托单位:
Projection-specific gene expression in resilience to chronic stress
  • 批准号:
    10444242
  • 项目类别:
  • 资助金额:
    $60.0万
  • 财政年份:
    2016
  • 负责人:
    Michelle Suzanne Mazei-Robison
  • 依托单位:
A Novel Emotional Stress Model of Co-morbid Opiate Use and Mood Disorders
  • 批准号:
    8824128
  • 项目类别:
  • 资助金额:
    $11.51万
  • 财政年份:
    2015
  • 负责人:
    Michelle Suzanne Mazei-Robison
  • 依托单位:
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