Impairment of Spinal Development in Cerebral Palsy

脑性瘫痪（CP）是由多种因素引起的，导致脑损伤和永久性运动障碍。 控制，以肌肉僵硬和痉挛为特征。尽管严重性和患病率（每400人中有1人 分娩），近几十年来治疗方法几乎没有进展，大多数治疗方法都集中在 症状出现后，而不是预防和减少损害。这可能是由于 历史上缺乏一种动物模型，显示出突出的CP样表型，其中可以研究 导致运动障碍的特定机制。在这个项目中，我们提出了平行的纵向研究 在患有CP的儿童和一种新的临床相关的CP动物模型中。兔子出生前缺氧- 缺血（HI）显示与CP相关痉挛的明显运动症状， 四肢张力亢进和反射亢进我们的主要目标是利用这种动物模型直接研究 干扰脊髓神经元和神经元回路的正常发育，而相关的细胞 在有和没有CP和HI损伤的儿童和幼兔中运动行为的变化。而 对大脑和皮质脊髓束的损伤一直是以前许多研究的焦点， CP脊髓回路的发展为运动障碍的治疗提供了一个更容易达到的目标。 功能障碍我们从之前对兔子和啮齿动物模型的研究中得知，在可能导致CP的损伤后， 1）大脑中Cl-转运蛋白KCC 2的表达发生改变，2）脊髓中5-羟色胺水平发生改变。 增加这两个因素都受到严格的发育调控，可以直接促进持续的 未调节时的MN活性：1）随着发育过程中KCC 2表达的增加，抑制中间神经元 在脊髓中从去极化到超极化突触后效应的转换;和2） 持续性内向电流（PIC）可改变运动神经元（MN）的内在兴奋性。PIC增加神经元 兴奋性和持续放电，但突触抑制是非常有效的关闭它们。因此，随着失去 适当的KCC 2表达，PIC有望对MN行为产生更大的影响。我们 总体假设是，导致脑瘫的损伤改变了脊髓的发育， 儿童和动物模型的兴奋性，包括MN PIC和KCC 2的进行性变化 除了对大脑和下行投射造成的损害外，沿着 有充分证据表明，脊髓MN的下行抑制性音调丧失，兴奋性增强，疗效降低 脊髓抑制性突触的数量可能与脑瘫患者的肌张力增高和痉挛状态有关， 这些特性可以作为治疗的目标。

Cerebral palsy (CP) is caused by a variety of factors that result in brain damage and permanently impair motor control, marked by muscle stiffness and spasticity. Despite the seriousness and prevalence (1 in every 400 births), there have been few advancements in therapeutics in recent decades, with most treatments focusing on symptoms after they emerge rather than prevention and reduction of damage. This may be due to the historic lack of an animal model that displays a prominent CP-like phenotype in which it is possible to study the specific mechanisms giving rise to motor impairments. In this project, we propose parallel longitudinal studies in children with CP and in a new, clinically relevant animal model of CP. Rabbits subjected to prenatal hypoxia- ischemia (HI) show clear motor symptoms of spasticity associated with CP, most notably muscle stiffness in the limbs, hypertonia and hyperreflexia. Our main goal is to exploit this animal model to directly investigate perturbations in the normal development of spinal neurons and neuronal circuits, while relating cellular changes to motor behavior in both children and young rabbits with and without CP and HI injuries. While damage to the brain and corticospinal tracts have been the focus of much previous research, aberrant development of spinal circuits in CP provides a more accessible target for treatment and therapy of motor dysfunction. After injuries that can cause CP, we know from previous studies in both rabbit and rodent models that 1) there is altered expression of the Cl- transporter, KCC2 in the brain, and 2) spinal levels of serotonin are increased. Both of these factors are tightly developmentally regulated, and could directly promote sustained MN activity when unregulated: 1) with increasing KCC2 expression during development, inhibitory interneurons in the spinal cord switch from a depolarizing to a hyperpolarizing postsynaptic effect; and 2) development of persistent inward currents (PICs) may alter intrinsic excitability of motoneurons (MNs). PICs increase neuronal excitability and sustain firing, but synaptic inhibition is very effective at turning them off. Hence, with loss of appropriate KCC2 expression, PICs are poised to exert an even greater influence on MN behavior. Our overarching hypothesis is that injuries causing cerebral palsy alter the development of spinal excitability in both children and an animal model, including progressive changes in MN PICs and KCC2 expression, in addition to the damage caused to the brain and the descending projections. Along with the well-documented loss of descending inhibitory tone, enhanced excitability in spinal MNs and reduced efficacy of spinal inhibitory synapses could contribute to hypertonia and spasticity of patients with cerebral palsy and these properties could be targeted for treatment.