The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

Abstract

At early disease stages, Lewy body disorders are characterized by limbic vs. brainstem α‐synucleinopathy, but most preclinical studies have focused solely on the nigrostriatal pathway. Furthermore, male gender and advanced age are two major risk factors for this family of conditions, but their influence on the topographical extents of α‐synucleinopathy and the degree of cell loss are uncertain. To fill these gaps, we infused α‐synuclein fibrils in the olfactory bulb/anterior olfactory nucleus complex—one of the earliest and most frequently affected brain regions in Lewy body disorders—in 3‐month‐old female and male mice and in 11‐month‐old male mice. After 6 months, we observed that α‐synucleinopathy did not expand significantly beyond the limbic connectome in the 9‐month‐old male and female mice or in the 17‐month‐old male mice. However, the 9‐month‐old male mice had developed greater α‐synucleinopathy, smell impairment and cell loss than age‐matched females. By 10.5 months post‐infusion, fibril treatment hastened mortality in the 21.5‐month‐old males, but the inclusions remained centered in the limbic system in the survivors. Although fibril infusions reduced the number of cells expressing tyrosine hydroxylase in the substantia nigra of young males at 6 months post‐infusion, this was not attributable to true cell death. Furthermore, mesencephalic α‐synucleinopathy, if present, was centered in mesolimbic circuits (ventral tegmental area/accumbens) rather than within strict boundaries of the nigral pars compacta, which were defined here by tyrosine hydroxylase immunolabel. Nonprimate models cannot be expected to faithfully recapitulate human Lewy body disorders, but our murine model seems reasonably suited to (i) capture some aspects of Stage IIb of Lewy body disorders, which displays a heavier limbic than brainstem component compared to incipient Parkinson’s disease; and (ii) leverage sex differences and the acceleration of mortality following induction of olfactory α‐synucleinopathy.

Deficits in olfactory sensitivity in a mouse model of Parkinson’s disease revealed by plethysmography of odor-evoked sniffing

“…Surprisingly, males did not show any significant olfactory impairment in this study. This is in contrast to Mason et al (2019) who observed fibril treated males had greater olfactory deficits than females. Sex hormones influence odor perception in rodents (Sorwell, Wesson, and Baum 2008;Wesson et al 2006) and further investigation into how sex and/or gonadal hormones influence perception in this model is necessary to understand the different olfactory outcomes reported following injections of PFFs.…”

“…While there are several non-motor signs and symptoms of PD, including mood, gastric, and sleep disorders, olfactory deficits may be more readily tested for, at a low cost, when compared to other non-motor symptoms (Fullard, Morley, and Duda 2017). Olfactory dysfunction has been observed in several rodent models of PD (Kim et al 2019;Mason et al 2019;Rey et al 2018;. However, in the field of neurodegenerative research, olfactory dysfunction in rodents is usually evaluated using systems 20 which are not semi-automated.…”

“…Additionally, these mice have been reported to develop progressive olfactory deficits for odor retention/memory and detection thresholds, using a testing set-up involving a cartridge containing a paper swab impregnated with odor . In a more recent report, PFFs injections in the OB and/or AON of wild type mice were reported to trigger Lewy Body-like pathology accompanied by sex and age-dependent behavioral deficits, including olfactory dysfunction assessed with the buried pellet test (Mason et al 2019).…”

“…Until now, olfactory deficits have been evaluated in PD animal models using several approaches, such as the buried pellet test, social-odor discrimination test, and odor habituation/dishabituation test (Lehmkuhl, Dirr, and Fleming 2014;Bonito-Oliva, Masini, and Fisone 2014;Zhang, Xiao, and Le 2015;Mason et al 2019;. While these tests have the advantage of being simple with no requirements for a special apparatus or behavioral shaping, several aspects of them present possible downsides.…”

A Neurologist's Guide to REM Sleep Behavior Disorder

“…If and why women are susceptible to underreporting RBD, as in the case of snoring and obstructive sleep apnoea ( 46 , 47 ), therefore needs further investigation. Interestingly, male sex is an identified risk factor for all of the α-synucleinopathies ( 48 – 51 ), though the reason for this remains unknown.…”