Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD symptomology is recognized as heterogeneous and in addition to motor function decline includes cognitive, mood, sleep, and metabolic disorders. Previous studies showed early reductions in anxiety and locomotion in the A53T mice model of PD. Since inflammation and astrogliosis are an integral part of PD pathology and impair proper neuronal function, we were keen to investigate if behavioral changes in A53T mice are accompanied by increased inflammation and astrogliosis in the hippocampus (Hipp) and motor cortex (mCtx) brain regions involved in the regulation of anxiety and locomotion, respectively. To test this, we used 3-, 5-, and 7-month-old A53T mice to examine anxiety-like behavior, locomotion, and expression of inflammation and astrogliosis markers in the Hipp and mCtx. Further, we examined the presence of alpha-synuclein accumulation in orexin neurons and orexin neuronal loss. The data show early reductions in anxiety-like behavior as well as increased locomotor activity, which was accompanied by inflammation and astrogliosis in the Hipp and mCtx. Due to the persistence of the orexin neuron population in A53T mice and the involvement of orexin in anxiety and locomotor regulation, we hypothesized that chemogenetic modulation of orexin neurons would reverse the observed reductions in anxiety-like behavior and the increases in locomotor activity in these animals. We showed that chemogenetic activation of orexin neurons in A53T mice restores anxiety-like behavior back to control levels without affecting locomotor activity, whereas the inhibition of orexin neurons reverses the elevated locomotor activity without any effects on anxiety-like behavior. This study exemplifies the complex role of orexin neurons in this model of PD and demonstrates the novel finding that changes in locomotor and anxiety-like behavior are accompanied by inflammation and astrogliosis. Together, these data suggest that the orexin system may play a significant role in early and late stages of PD.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disease that affects approximately 2–3% of the elderly population (Poewe et al, 2017)
designer receptors exclusively activated by designer drugs (DREADD) excitation using clozapine-N-oxide (CNO) restored anxiety-like behavior to control levels, whereas inhibition of orexin neurons reduced locomotor activity without affecting anxiety-like behavior. These results suggest that orexin neuron circuitry dysfunction in the locomotion and anxiety changes observed in A53T mice, a model of PD
A53T mice showed an increased time spent in the open arms of the elevated plus maze (EPM) at 5 months of age (∗p < 0.05; Figure 1B) and 7 months of age (∗∗∗p < 0.005; Figure 1B), and an increased time spent in the center area of the open field at 5 months of age (∗∗p < 0.01; Figure 1D) and 7 months of age (∗∗∗p < 0.005; Figure 1D)
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disease that affects approximately 2–3% of the elderly population (Poewe et al, 2017). It is defined as a neurodegenerative movement disorder distinguished by bradykinesia, resting tremor, stiffness, postural instability, and periods of freezing (Graham and Sidhu, 2010; Dickson, 2012). PD is characterized by the loss of dopamine neurons in the substantia nigra pars compacta and the formation of the proteinaceous fibrillar cytoplasmic inclusions called Lewy bodies. The main component of the Lewy bodies, the hallmark of PD, is alphasynuclein (α-syn), a small acidic protein expressed in presynaptic terminals, in the neocortex, hippocampus (Hipp), striatum, thalamus, and cerebellum (Iwai et al, 1995). The role of α-syn in PD pathology is well established, and mutations in α-syn genes are responsible for several forms of autosomal dominant PD (Polymeropoulos et al, 1997; Krüger et al, 1998; Singleton et al, 2003; Chartier-Harlin et al, 2004; Zarranz et al, 2004)
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