Trace Amines as Novel Modulators of Spinal Motor Function

点击翻译按钮获取中文摘要

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.