Although distinct neural regions code for separate reward processes, the circuits connecting these regions allow an individual to: 1) sense a pleasant stimulus; 2) compute reward value and associated costs; 3) determine effort requirements to obtain that stimulus; 4) decide to obtain that stimulus; and 5) anticipate and increase motivation to obtain that stimulus (). The hedonic perception of rewards is mediated primarily by endogenous opioid, GABA, and endocannabinoid systems in the NAc, ventral pallidum, and OFC. The OFC and ventral striatum receive inputs from sensory cortices and calculate the reward values. The OFC then projects reward value information to the ACC to incorporate costs, benefits, and reinforcement history to determine the effort required for different possible actions. The ACC sends projections to the anterior vmPFC and dlPFC, that are involved in decision-making based on reward value, effort, and reinforcement history regarding future actions. Glutamatergic efferents relay this information to the NAc, that receives dopaminergic and glutamatergic input from the VTA and amygdala, respectively, providing incentive salience properties and increasing motivation to carry out the goal-directed action planned in the PFC. Indeed, there is focus on glutamate for its putative antidepressant properties (reviewed in [84
]). Ketamine, a NMDA receptor antagonist, produces rapid antidepressant effects hypothesized to be partly mediated by increased glutamatergic signaling via AMPA receptors [86
] (see also [87
] in this Issue). In animal studies, disruption of glutamatergic signaling between the mPFC and NAc or administration of an AMPA receptor antagonist in the NAc shell resulted in avolition for rewards [32
]. Further, nicotine withdrawal-induced elevations of ICSS thresholds were exacerbated by decreasing glutamatergic activity, and conversely, attenuated by increasing glutamatergic activity [88
]. Disruption in any of these circuits can lead to different types of reward deficits. For example, blocking (i) dopaminergic transmission from the VTA to NAc; (ii) opioid signaling in the BLA; (iii) ACC activity; or (iv) glutamate transmission from the vmPFC to NAc each decreased motivation for a large reward.
Simplified model of a rodent brain illustrating the neural circuitry of anhedonia and other reward-related deficits
The circuit presented here likely represents an incomplete view of the neurobiology mediating different aspects of anhedonia and other reward-related deficits. Indeed, additional neurotransmitter systems regulate various reward processes (). The multiple reciprocal connections between different PFC subregions, as well as reciprocal connections with the NAc, VTA, amygdala, and hippocampus likely play an important role in regulating the behavioral response to rewards. For example, decreased neurogenesis in the dentate gyrus reduced sucrose preference in mice [89
] and reversed the therapeutic effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on separation stress-induced anhedonia in non-human primates [90
]. Serotonin (5-HT) originating from the midbrain raphe nuclei (RN) also regulates reward processing and anhedonic behaviors. For example, chronic treatment with SSRI antidepressants increased ventral striatal activity in humans [91
] and sucrose preference in mice [92
]. Interestingly, agomelatine, an antagonist of 5-HT2C
receptors, also increased sucrose preference in mice [92
] and improved SHAPS anhedonia scores in MDD patients [93
receptors inhibit NAc dopamine release, and antidepressant treatment increases striatal dopamine levels by decreasing 5-HT2C
mediated dopamine inhibition [94
]. Furthermore, fluoxetine treatment combined with a 5-HT1A
antagonist, that rapidly elevates 5-HT levels in forebrain structures, reversed psychostimulant withdrawal-induced anhedonia in rats [67
Effects of gene knockouts in mice on measures of natural reward.
The lateral habenula (LHb) may also play an important role in reward processes given its reciprocal connections with the VTA and RN. LHb neurons inhibit dopaminergic and 5-HT cells in the VTA and RN, respectively (reviewed in [95
]). Consequently, DBS of the LHb, purported to inhibit LHb activity and disinhibit dopamine and 5-HT activity, has been reported to have antidepressant effects, although it should be noted this is a single case study [96
]. Other regions have been implicated also, such as the insula and precuneus/medial parietal cortex, based on imaging studies of anhedonic individuals [35
]. The anterior insula encodes the subjective value of rewards [97
] and representations of interoceptive effects of rewards (reviewed in [98
]). Furthermore, the parietal cortex encodes reward values relative to other available options (reviewed in [99
]). Future integration of these reciprocal connections and identification of additional structures will provide a more comprehensive neural framework by which to investigate reward-related deficits.
In particular, the advent of DBS has provided a new and promising treatment for otherwise refractory depression and has promoted our understanding of the neurobiology of depression and other neuropsychiatric disorders. For example, DBS of the subgenual PFC [45
], ventral striatum [76
], inferior thalamic peduncle [100
], and LHb [96
] each have antidepressant effects. Unfortunately, with the exception of one study [77
], anhedonia was not specifically assessed and one can only speculate whether these brain regions are involved in anhedonia or depression per se
based on current DBS studies.