Expression of α-synuclein is increased in the hippocampus of rats with high levels of innate anxiety

Abstract

A genomic region neighboring the a-synuclein gene, on rat chromosome 4, has been associated with anxiety-and alcohol-related behaviors in different rat strains. In this study, we have investigated potential molecular and physiological links between a-synuclein and the behavioral differences observed between Lewis (LEW) and Spontaneously Hypertensive (SHR) inbred rats, a genetic model of anxiety. As expected, LEW rats appeared more fearful than SHR rats in three anxiety models: open field, elevated plus maze and light/dark box. Moreover, LEW rats displayed a higher preference for alcohol and consumed higher quantities of alcohol than SHR rats. a-Synuclein mRNA and protein concentrations were higher in the hippocampus, but not the hypothalamus of LEW rats. This result inversely correlated with differences in dopamine turnover in the hippocampus of LEW and SHR rats, supporting the hypothesis that a-synuclein is important in the downregulation of dopamine neurotransmission. A novel single nucleotide polymorphism was identified in the 3 0 -untranslated region (3 0 -UTR) of the asynuclein cDNA between these two rat strains. Plasmid constructs based on the LEW 3 0 -UTR sequence displayed increased expression of a reporter gene in transiently transfected PC12 cells, in accordance with in-vivo findings, suggesting that this nucleotide exchange might participate in the differential expression of a-synuclein between LEW and SHR rats. These results are consistent with a novel role for a-synuclein in modulating rat anxiety-like behaviors, possibly through dopaminergic mechanisms. Since the behavioral and genetic differences between these two strains are the product of independent evolutionary histories, the possibility that polymorphisms in the a-synuclein gene may be associated with vulnerability to anxiety-related disorders in humans requires further investigation.

Genetical Genomics of Behavior: A Novel Chicken Genomic Model for Anxiety Behavior

“…Successful examples of behavioral QTG identification are almost exclusively limited to mouse and rat models (Yalcin et al 2004;Chiavegatto et al 2008;Kim et al 2009;Tomida et al 2009;Gyetvai et al 2011;Wang et al 2012;Heyne et al 2014), Drosophila (Anholt and Mackay 2004;Mackay 2004;Fitzpatrick et al 2005), and the honeybee (Robinson et al , 2008. The ramifications for the identification of such behavioral genes are many and varied.…”

Effects of physical exercise and social isolation on anxiety-related behaviors in two inbred rat strains

“…Our results confirm the behavioral profiles of LEW and SHR rats reported in previously published articles. SHR rats approach more and spent more time exploring potentially dangerous situations, such as the center of the OF and the open arms of the EPM, than LEW rats (Ramos et al, 1997;Izídio et al, 2005a;Vendruscolo et al, 2006;Chiavegatto et al, 2009). We show that forced PE on a treadmill decreases anxiety-like behavior and increases locomotion in both LEW and SHR rats.…”

“…The results of the present study suggest that LEW and SHR rats constitute a good rat model for the search of the genetic bases underlying voluntary PE because of their contrasting voluntary running patterns. As already reported for anxiety-like behaviors (Ramos et al, 1997;Izídio et al, 2005a;Vendruscolo et al, 2006;Chiavegatto et al, 2009), this genetic model can also be an important tool for the identification of genes influencing voluntary PE.…”

“…Results in the literature vary greatly, both in rats or mice, with SI increasing anxiety levels in the OF (Hall et al, 2000) and in the EPM (Maisonnette et al, 1993;Weiss et al, 2004) or showing anxiolytic-like effects in the EPM (Voikar et al, 2005;Thorsell et al, 2006). The LEW and SHR inbred rat strains have already been tested in OF and EPM showing contrasting anxiety-like behaviors, with the former presenting higher levels of anxiety/emotionality than the latter (Chiavegatto et al, 2009). Such differences are robust and have been confirmed using different substrains, at different laboratories and countries.…”

“…This procedure allows one to monitor PE levels for each individual; however, social isolation (SI) per se may be associated with anxiety-like behaviors (Butler et al, 2014;Skelly et al, 2015), cognitive dysfunction (Li et al, 2016) and depressive behaviors (Zanier-Gomes et al, 2015) in rodents, which could confound data interpretation. The Lewis (LEW) and Spontaneously Hypertensive Rats (SHR) inbred rat strains show contrasting levels of anxiety-related behavior, with the former exhibiting increased levels of anxiety-like behavior (Chiavegatto et al, 2009). These strain differences were reliably found in different substrains, testing conditions, laboratories and countries (Ramos et al, 2002;Izídio et al, 2005a;Vendruscolo et al, 2006).…”