Epidemiological studies indicate that stressful life events are among the most reliable predictors of the onset and course of major depressive disorder (MDD) ([1
], for review see [4
]); however, the mechanisms underlying this relationship remain incompletely understood. A sizeable body of non-human animal research suggests that stress might partially exert its depressogenic effects by inducing anhedonic-like behavior. Specifically, animal studies indicate that exposure to stressors, in particular chronic and inescapable ones, produces blunted reactivity to natural rewards, as well as dysfunction within mesolimbic dopaminergic pathways critically implicated in incentive motivation and reinforcement learning (for reviews, see [5
Emerging evidence suggests that this pattern may translate to humans. An early study focusing on real-world stressors found reduced self-reported hedonic capacity in college students and US Army cadets following stressful final examinations or field training exercises, respectively, and demonstrated that these deficits were more pronounced in participants with a family history of depression [7
]. Two recent independent studies demonstrated that acute stress exposure in a laboratory environment (threat-of-shock) resulted in impaired reward learning in a nonclinical sample, particularly in individuals reporting elevated anhedonic symptoms [8
]. Unlike the former study, which employed self-report measures to assess hedonic capacity, these latter studies used a laboratory-based measure of anhedonia to empirically assess participants’ ability to modulate their behavior as a function of prior reinforcement history [10
]. In addition, using the same laboratory-based reward processing paradigm, Pizzagalli et al. [11
] found that healthy participants appraising their daily life in the week prior to testing as stressful, uncontrollable, and overwhelming were similarly characterized by diminished reward learning.
Consistent with these behavioral effects, acute psychosocial stress decreases the responsiveness of a number of limbic structures involved in the experience of pleasure [12
]. Finally, early childhood adversity (e.g. abuse, maltreatment) has been associated with elevated levels of anhedonic symptoms in adolescent depression [13
] and, perhaps even more strikingly, a blunted response to reward cues in the globus pallidus, a brain region implicated in reward processing, in nondepressed adults [14
]. In sum, results from multiple animal experiments and emerging human research spanning a variety of acute and chronic stressors, suggest that stress-related hedonic impairments may, at least partially, account for the depressogenic effects of life stress.
A complete understanding of the association between stress-related anhedonia and depression is critically dependent on an improved delineation of the neurobiological mechanisms underlying reward processing. While dopamine and the opioids are the primary neurotransmitters linked to reward processing [15
], growing evidence has also implicated serotonin 5-hydroxytryptamine (5-HT). Specifically, genetic knockout of the serotonin transporter (5-HTT) and the resulting 5-HT signaling changes have been found to disrupt the development of the reward system [16
] and interfere with reward-based learning [17
]. Additionally, pharmacologically elevated 5-HT levels decrease dopamine burst firing in the rat ventral tegmental area [18
], thus suppressing neural signals central to reward learning [19
]. Taken together, these studies indicate that 5-HT plays an important modulatory role in reward processing.
Among the factors impacting 5-HT signaling in humans is a common functional polymorphism in the promoter region of 5-HTT (5-HTTLPR), resulting in either a short (S) or a long (L) allele of the gene [20
]. Importantly, the S allele has been linked to reduced 5-HTT expression relative to the L allele [20
]. Furthermore, compared to L homozygotes, S carriers are at increased risk of developing depression following stressful life events [21
], but see also [22
]. Critically, a A/G single nucleotide polymorphism (SNP) within the 5-HTTLPR (rs25531) has been shown to differentially impact L allele function as well as its clinical association with MDD [23
], suggesting that the LG
allele may be functionally similar to the S allele. Thus, this SNP may help clarify inconsistent 5-HTTLPR
interaction results (e.g. [22
]). Based on the literature reviewed above, we reasoned that stress-related anhedonia may contribute to links among stress, 5-HTTLPR/rs25531 genotype, and depression.
The goal of the present study was to investigate how perceived stress associated with a naturalistic stressor (preparation for important school examinations) and 5-HTTLPR/rs25531 genotype impact reward responsiveness, an objective measure of participants’ ability to modulate behavior as a function of previous reinforcement, which has been found to correlate with, and predict, future anhedonic symptoms [10
]. In approaching this question, we addressed the limitations of the few human studies that have assessed the role of stress on anhedonia, including reliance on self-report measures of anhedonia [7
] and the use of acute laboratory stressors with limited ecological validity [8
]. We hypothesized that, relative to L or LA
homozygotes (‘L’ participants’), S or LG
allele carriers (‘S’ participants’) would show larger stress-related reward responsiveness impairments. Based on research suggesting that gender impacts the nature of 5-HTTLPR
interactions with regard to depression [25
], we also explored the putatively moderating role of gender.