Trace Amines as Novel Modulators of Spinal Motor Function

描述（由申请人提供）：长期目标是了解微量胺（TA）作为内在脊髓调节系统的生理相关性。TA因其在哺乳动物中的低内源性浓度而得名，与经典的单胺递质有关，但一直未得到充分研究，并被视为假递质。然而，有指标表明其潜在的重要性：其异构的中枢神经系统分布，其高周转率，并在2001年的开创性发现的一类新的受体优先激活的TA。TA是由芳香族氨基酸（AAAs）前体通过芳香族-L-氨基酸脱羧酶（AADC）合成的。我们已经发现，TA，微量胺受体1，和AADC中发现运动神经元和其他神经元在脊髓。此外，在离体脊髓中的体外研究中，TA对运动活动包括运动样活动发挥调节作用。到目前为止，我们的工作只研究了从脊髓出来的神经根的运动行为，并提供了有限的信息运动协调。现在，我们建议进行详细的研究，使用肌电图（EMG）记录附着后肢肌肉测试2个假设。第一个假设，不同的TA有不同的动作对运动池招聘和运动模式。使用EMG记录，我们将识别由不同TA（即髋关节，膝关节，踝关节和足部肌肉的伸肌和屈肌）招募的运动池，并分析其放电特性。第二个假设是与检查“饮食”AAAs和TAs对脊髓运动功能的变化。我们假设生物可利用的TA水平的改变本质上调节脊髓运动系统。在这里，我们将使用上述后肢EMG记录来研究“循环”AAA水平和运动活动之间的关联。将在体内进行相关研究，以检查全身注射AAA和TA后产生的后肢运动。在此，将通过包括运动学在内的各种测量（例如，发作、持续时间、运动表型）来评估运动活动。结论性证据表明，TA调节运动协调将确定一个迄今未知的内在脊髓调制系统。如果它们的作用部分地由循环的AAA和TA控制，则新的基于饮食的疗法可以补充或取代试图在神经损伤后促进脊髓运动功能的现有治疗策略。

DESCRIPTION (provided by applicant): The long-term goal is to understand the physiological relevance of the trace amines (TAs) as an intrinsic spinal modulatory system. TAs, named for their low endogenous concentrations in mammals, are related to the classic monoamine transmitters, but have been understudied and cast off as false transmitters. However, there are indicators of their potential importance: their heterogeneous central nervous system distribution, their high turnover rates, and the seminal discovery in 2001 of a new class of receptors preferentially activated by TAs. TAs are synthesized from precursor aromatic amino acids (AAAs) by the enzyme, aromatic-L-amino acid decarboxylase (AADC). We have found that the TAs, trace amine receptor 1, and AADC are found in motoneurons and other neurons in the spinal cord. Moreover, in in vitro studies in the isolated cord, the TAs exert modulatory actions on motor activity including locomotor-like activity. Our work so far only examined motor actions from nerve roots exiting the spinal cord, and provides limited information on motor coordination. We now propose to undertake detailed studies using electromyographic (EMG) recordings from attached hindlimb muscles to test 2 hypotheses. The first hypothesizes that different TAs have distinct actions on motor pool recruitment and locomotor patterning. Using EMG recordings, we will identify the motor pools recruited by the different TAs (i.e. extensors and flexors of hip, knee, ankle, and foot muscles) and analyze their firing properties. The second hypothesis is associated with examining changes in 'dietary' AAAs and TAs on spinal motor function. We hypothesize that alterations in bioavailable levels of TAs intrinsically modulate spinal motor systems. Here, we will use hindlimb EMG recordings as above to study the association between 'circulating' AAA levels and motor activity. Related studies will be undertaken in vivo to examine hindlimb movements produced following systemic injection of AAAs and TAs. Here, motor activity will be assessed by various measures (e.g. onset, duration, movement phenotype) including kinematics. Conclusive evidence that the TAs modulate motor coordination would identify a hitherto unknown intrinsic spinal modulatory system. If their actions are in part controlled by circulating AAAs and TAs, novel diet- based therapies may supplement or supplant existing therapeutic strategies that attempt to facilitate spinal motor function after neurological injuries.