Pharmacological and chemogenetic orexin/hypocretin intervention ameliorates Hipp-dependent memory impairment in the A53T mice model of Parkinson\u2019s disease

Milos Stanojlovic,Michael K Lee,Catherine M Kotz,Jean Pierre Pallais

doi:10.1186/s13041-019-0514-8

Abstract

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.

Highlights

Parkinson’s disease is the most prevalent neurodegenerative disease second only to Alzheimer’s [1]
While Parkinson’s disease (PD) is classified as a movement disorder accompanied by the presence of abnormal protein particles, Lewy bodies, and the loss of dopamine neurons in the substantia nigra, recent studies have established the importance of non-motor symptoms of PD, including cognitive decline [36,37,38,39]
We hypothesized that early cognitive decline in the A53T mouse model of PD can be ameliorated by administration of orexin and by chemogenetic targeting of orexin-neurons

Summary

Introduction

Parkinson’s disease is the most prevalent neurodegenerative disease second only to Alzheimer’s [1]. Mood, cognition, and metabolic impairments are recognized as non-motor symptoms of PD and have been the subject of increasing research in recent decades. Recent studies indicate that orexins contribute to mood, sleep, cognition, stress, anxiety, and pain regulation [14,15,16,17,18,19,20]. Reduced levels of Stanojlovic et al Molecular Brain (2019) 12:87 orexin in cerebrospinal fluid [21, 22] as well as orexin neuronal loss occur in the late stages of the disease [23, 24], and impairment in orexin circuitry function leads to sleep deficits in PD [25, 26]

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