Stress-Induced Executive Dysfunction in GDNF-Deficient Mice, A Mouse Model of Parkinsonism

Mona Buhusi,Kaitlin Olsen,Catalin V Buhusi,Benjamin Z Yang

doi:10.3389/fnbeh.2016.00114

Mona Buhusi, Kaitlin Olsen + Show 2 more

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https://doi.org/10.3389/fnbeh.2016.00114

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Abstract

Maladaptive reactivity to stress is linked to improper decision making, impulsivity, and discounting of delayed rewards. Chronic unpredictable stress (CUS) alters dopaminergic function, re-shapes dopaminergic circuits in key areas involved in decision making, and impairs prefrontal-cortex dependent response inhibition and working memory. Glial-derived neurotrophic factor (GDNF) is essential for regulating dopamine (DA) release in the basal ganglia and for the survival of dopaminergic neurons; GDNF-deficient mice are considered an animal model for aging-related Parkinsonism. Recently, GDNF expression in the striatum has been linked to resilience to stress. Here we investigated the effects of CUS on decision making in GDNF-heterozygous (HET) mice and their wild-type littermate controls (WT). Before CUS no differences in temporal discounting (TD) were found between genotypes. However, following CUS GDNF HET mice, having a partial reduction of GDNF levels, showed increased impulsive choice indexed by a reduction in percent Larger-Later (LL) choices in the TD paradigm, and a reduction in area under the TD curve. Moreover, stressed GDNF HET mice, but not their WT controls, showed decreased neuronal activation (number of cFos positive neurons) in the orbitofrontal cortex (OFC), nucleus accumbens (NA) core, and NA shell, suggestive of a maladaptive response to stress. Interestingly, area under the TD curve positively correlated with cFos activation in the NA core, and NA shell, but not with orbitofrontal activity. These results provide further evidence of the differential involvement of the OFC, NA core, and NA shell in impulsive choice, and identify GDNF-deficient mice as a double-hit (gene × environment) model of stress-related executive dysfunction, particularly relevant to substance abuse and Parkinson’s disease (PD).

Highlights

Stress—defined as a real or perceived threat to homeostasis or well-being of the organism—initiates adaptive processes to promote survival
Mice were tested in the temporal discounting (TD) paradigm before stress (Pre-Stress condition, Figure 1 left panel), after which they were exposed for 21 days to a Chronic unpredictable stress (CUS) stress paradigm and re-tested in the TD paradigm (Post-Stress condition, Figure 1 right panel)
Analyses of %LL choices further indicated a main effect of stress (F(1,25) = 18.37, p < 0.01), suggesting that the CUS regimen resulted in overall fewer LL choices in the Post-Stress condition relative to the Pre-Stress condition, though this effect was mainly seen in the Glial-derived neurotrophic factor (GDNF) HET mice

Summary

Introduction

Stress—defined as a real or perceived threat to homeostasis or well-being of the organism—initiates adaptive processes to promote survival. Maladaptive reactivity to stress is linked to improper decision making, impulsivity, and discounting of delayed. Stress-Induced Executive Dysfunction in GDNF-Deficient Mice consequences (Dias-Ferreira et al, 2009; George and Koob, 2010; Jezierski et al, 2014; Wang et al, 2014), leading to substance abuse (Decressac et al, 2011; Miller, 2011; OrtizOrtiz et al, 2011) and abnormal behavior (Starcke and Brand, 2012; Littrell et al, 2013). Exposure to stress-relieving stimuli, like natural scenes (Hauck et al, 2006), decreases impulsive decision making in the temporal discounting (TD) paradigm in human participants. Chronic unpredictable stress (CUS) alters dopamine (DA) release and metabolism (Ahmad et al, 2010), re-shapes fronto-striatal circuitry involved in decision making (Dias-Ferreira et al, 2009), and impairs prefrontal cortex-dependent response inhibition and working memory (Revilla et al, 2014)

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