Chemogenetic Modulation of Orexin Neurons Reverses Changes in Anxiety and Locomotor Activity in the A53T Mouse Model of Parkinson’s Disease

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.

Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s Disease

“…Hyperactivity was previously observed in this animal model [ 53 ], but this is not the sole factor contributing to reduced fat mass in the A53T mice. Moreover, in our recent, less extensive study, we observed increased exploratory locomotion in A53T mice as well [ 54 ]. In a similar transgenic mouse model of PD (A53T expression driven by Thy1 promoter), Rothman et al [ 55 ] showed that metabolic perturbations are present.…”

“…After transfection, we subjected them to an experimental procedure assessing exploratory locomotion, SPA, and EE. In our earlier study, we showed that chemogenetic inhibition of orexin neurons ameliorated elevated exploratory locomotion in 5-month-old mice [ 54 ]. As hypothesized, we showed that chemogenetic inhibition of orexin neurons ameliorated exploratory locomotion, SPA, and EE impairments present in 7-month-old A53T mice.…”

Orexin-A in Patients With Lewy Body Disease: A Systematic Review and Meta-Analysis

“…Also, previous postmortem studies revealed the existence of LBs in the hypothalamus of PD patients (40). A recent study also identified a-synuclein accumulation in orexinergic neurons in an A53T mouse model of PD (41). Lessig et al (9) demonstrated a significant negative correlation (r = −0.447, P < 0.05) between orexin-A levels and a-synuclein aggregation in DLB patients, consistent with previous PD studies showing a-synuclein accumulation in hypocretin-containing neurons in the hypothalamus (6,42).…”

Does chronic systemic injection of the DREADD agonists clozapine-N-oxide or compound 21 change behavior relevant to locomotion, exploration, anxiety, and depression in male non-DREADD-expressing mice?

“…While the literature is unanimous that chronic 1mg/kg CNO does not grossly change mouse behavior in non-DREADDexpressing mice, the literature is mixed on the effects of acute CNO given to non-DREADDexpressing rodents. Several studies report acute CNO or C21 does not change behavior in non-DREADD-expressing rodents (1mg/kg [our data, 22] or 3 mg/kg [4,21] CNO, or 3.5mg/kg C21 [4]). Of studies that do report a change in behavior in non-DREADD-expressing rodents after acute CNO, two saw behavioral effects in rats with acute 1mg/kg CNO [7,26] and two in mice and rats with higher CNO doses than the present work [4,6].…”

“…However, other data do not support a behavioral or physiological effect of back-metabolized clozapine [6,21,22]; for example, in non-DREADD expressing animals, CNO (<5mg/kg) does not substitute for clozapine. To understand this apparent discrepancy -1mg/kg acute CNO decreases locomotion, but <5mg/kg CNO is not discriminated -it is important to directly assess the influence of CNO on fundamental behaviors (e.g.…”