Pharmacological and chemogenetic orexin/hypocretin intervention ameliorates Hipp-dependent memory impairment in the A53T mice model of Parkinson’s disease

Parkinson’s disease (PD), classically defined as a progressive motor disorder accompanied with dopaminergic neuron loss and presence of Lewy bodies, is the second most common neurodegenerative disease. PD also has various non-classical symptoms, including cognitive impairments. In addition, inflammation and astrogliosis are recognized as an integral part of PD pathology. The hippocampus (Hipp) is a brain region involved in cognition and memory, and the neuropeptide orexin has been shown to enhance learning and memory. Previous studies show impairments in Hipp-dependent memory in a transgenic mouse model of Parkinson’s disease (A53T mice), and we hypothesized that increasing orexin tone will reverse this. To test this, we subjected 3, 5, and 7-month old A53T mice to a Barnes maze and a contextual object recognition test to determine Hipp dependent memory. Inflammation and astrogliosis markers in the Hipp were assessed by immuno-fluorescence densitometry. The data show that early cognitive impairment is coupled with an increase in expression of inflammatory and astrogliosis markers. Next, in two separate experiments, mice were given intra-hippocampal injections of orexin or chemogenetic viral injections of an orexin neuron specific Designer Receptor Exclusively Activated by Designer Drug (DREADD). For the pharmacological approach mice were intracranially treated with orexin A, whereas the chemogenetic approach utilized clozapine N-oxide (CNO). Both pharmacological orexin A intervention as well as chemogenetic activation of orexin neurons ameliorated Hipp-dependent early memory impairment observed in A53T mice. This study implicates orexin in PD-associated cognitive impairment and suggests that exogenous orexin treatment and/or manipulation of endogenous orexin levels may be a potential strategy for addressing early cognitive loss in PD.