Down-regulation of Nurr1 in Rat Substantia Nigra Impairs Cognition

Parkinson’s Disease (PD), features a progressive loss of dopamine (DA) neurons in the Substantia Nigra (SN) which leads to motor deficits and cognitive impairments (Owen, 2004). Nurr1, a nuclear receptor within the SN, is vital for differentiation and development of DA neurons.  Moreover, down-regulation of Nurr1 elicits a significant decrease of DA levels in striatum (Galleguillos, 2010).  We hypothesized that down-regulation of Nurr1 induces cognitive deficits due to this DA reduction. To test this, our goal is to down-regulate Nurr1 by injecting adult rats unilaterally and bilaterally with an adeno-associated vector-delivered anti-Nurr1 ribozyme (rAAV5-Nurr1rz). To assure that animals are not inflicted with forelimb akinesia (a symptom of DA depletion), we will test unilaterally injected rats in the cylinder test. Subsequently, working memory Morris Water Maze (MWM) training will be conducted with bilateral subjects to test cognition. Preliminary rAAV5-Nurr1rz titers determined by RT-PCR have the propensity to down-regulate Nurr1 as demonstrated by Galleguillos et. al. (2010); 4.67E¹⁰ genome copies/ml. MWM optimizes our ability to detect cognitive deficits correlated with prefrontal cortex function (Vorhees, 2006). If our hypothesis is confirmed, this would provide substantial evidence that nigral dopaminergic input to the striatum is involved in spatial working memory. From the findings of Galleguillos et. al. (2010), we speculate that down-regulation of Nurr1 will affect learning via the nigrostriatal pathway. In order to recognize cognitive deficits associated with PD, we must understand the neuronal mechanisms within the SN.  Ergo, down-regulation of Nurr1 has the potential to be an important marker for nigral pathology.