Parkinson's disease (PD) is characterized by three main motor symptoms: bradykinesia, rigidity and tremor. PD is also associated with diverse nonmotor symptoms that may develop in parallel or precede motor dysfunctions, ranging from autonomic system dysfunctions and impaired sensory perception to cognitive deficits and depression. Here, we examine the role of the progressive loss of dopaminergic transmission in behaviors related to the nonmotor symptoms of PD in a mouse model of the disease (the TIF IADATCreERT2 strain). We found that in the period from 5 to 12 weeks after the induction of a gradual loss of dopaminergic neurons, mild motor symptoms became detectable, including changes in the distance between paws while standing as well as the step cadence and sequence. Male mutant mice showed no apparent changes in olfactory acuity, no anhedonia-like behaviors, and normal learning in an instrumental task; however, a pronounced increase in the number of operant responses performed was noted. Similarly, female mice with progressive dopaminergic neuron degeneration showed normal learning in the probabilistic reversal learning task and no loss of sweet-taste preference, but again, a robustly higher number of choices were performed in the task. In both males and females, the higher number of instrumental responses did not affect the accuracy or the fraction of rewarded responses. Taken together, these data reveal discrete, dopamine-dependent nonmotor symptoms that emerge in the early stages of dopaminergic neuron degeneration.

The development of Parkinson's disease (PD) causes dysfunction of the frontal cortex, which contributes to hallmark motor symptoms and is regarded as one of the primary causes of the affective and cognitive impairments observed in PD. Treatment with L-DOPA alleviates motor symptoms but has mixed efficacy in restoring normal cognitive functions, which is further complicated by the psychoactive effects of the drug. In this study, we investigated how L-DOPA affects gene expression in the frontal cortex in an animal model of unilateral PD. We performed an RNA-seq analysis of gene expression in the frontal cortex of rats with 6-hydroxydopamine (6-OHDA)-induced unilateral dopaminergic lesion that were treated with L-3,4-dihydroxyphenylalanine (L-DOPA) , for 2 weeks.We used analysis of variance to identify differentially expressed genes and found 48 genes with significantly altered transcript abundance after L-DOPA treatment. We also performed a weighted gene coexpression network analysis (WGCNA), which resulted in the detection of 5 modules consisting of genes with similar expression patterns. The analyses led to three primary observations. First, the changes in gene expression induced by L-DOPA were bilateral, although only one hemisphere was lesioned. Second, the changes were not restricted to neurons but also appeared to emerge in immune or endothelial cells. Finally, comparisons with databases of drug-induced gene expression signatures revealed multiple nonspecific effects, which indicates that a part of the observed response is a common pattern activated by multiple types of pharmaceuticals in different target tissues.Taken together, our results identify cellular mechanisms in the frontal cortex that are involved in the response to L-DOPA treatment.

The development of Parkinson's disease (PD) causes dysfunction of the frontal cortex, which contributes to the hallmark motor symptoms and is regarded as one of the primary causes of the affective and cognitive impairments observed in PD. Treatment with L-DOPA alleviates motor symptoms but has mixed efficacy in restoring normal cognitive functions, which is further complicated by the psychoactive effects of the drug. We investigated how L-DOPA affects gene expression in the frontal cortex in an animal model of unilateral PD. We performed RNASeq analysis of gene expression in the frontal cortex of rats with 6-hydroxydopamine (6-OHDA)-induced unilateral dopaminergic lesions treated with L-3,4-dihydroxyphenylalanine (L-DOPA), for 2 weeks. The analysis of variance identified 48 genes with a significantly altered transcript abundance after L-DOPA treatment. We also performed a weighted gene coexpression network analysis (WGCNA), which resulted in the detection of 5 modules consisting of genes with similar expression patterns. The analyses led to three primary observations. First, the changes in gene expression induced by L-DOPA were bilateral, although only one hemisphere was lesioned. Second, the changes were not restricted to neurons but also appeared to affect immune or endothelial cells. Finally, comparisons with databases of drug-induced gene expression signatures revealed multiple nonspecific effects, indicating that a part of the observed response is a common pattern activated by multiple types of drugs in different target tissues. Taken together, our results identify cellular mechanisms in the frontal cortex that are involved in the response to L-DOPA treatment. 4 Significance statement The development of Parkinson's disease (PD) causes dysfunction of the frontal cortex, which contributes to the motor and cognitive impairments observed in PD. L-DOPA improves motor symptoms but has mixed efficacy in restoring normal cognitive functions. We investigated how L-DOPA affects gene expression in the frontal cortex in an animal model of unilateral PD. We identified 48 genes with L-DOPA-altered expression levels and gene clusters that follow similar drug-evoked expression patterns. Our findings suggest that the response to L-DOPA was bilateral, involved distinct cell types and overlapped with expression changes evoked by drugs of multiple classes in different tissues. Overall, our results identify cellular mechanisms in the frontal cortex that are involved in the response to L-DOPA treatment.