The neurobiology of anhedonia and other reward-related deficits

Abstract

Anhedonia, or markedly diminished interest or pleasure, is a hallmark symptom of major depression, schizophrenia and other neuropsychiatric disorders. Over the past three decades, the clinical definition of anhedonia has remained relatively unchanged, although cognitive psychology and behavioral neuroscience have expanded our understanding of other reward-related processes. Here, we review the neural bases of the construct of anhedonia that reflects deficits in hedonic capacity and also closely linked to the constructs of reward valuation, decision-making, anticipation and motivation. The neural circuits subserving these reward-related processes include the ventral striatum, prefrontal cortical regions, and afferent and efferent projections. An understanding of anhedonia and other reward-related constructs will facilitate the diagnosis and treatment of disorders that include reward deficits as key symptoms.

Figure 1. Examples of contemporary measures of anhedonia and reward-related deficits in experimental animals

A. ICSS can be used to assess brain reward function. Self-stimulation of parts of the brain reward circuitries (e.g., lateral hypothalamus) is positively reinforcing at certain current intensities. The current intensity is systematically increased and decreased to determine the threshold that will support self-stimulation. Elevations of this reward threshold indicate that an increased current intensity is required to elicit a behavioral response, reflecting anhedonia. B. Withdrawal from chronic amphetamine exposure elevates reward thresholds (i.e., anhedonia) for up to five days in rats [103]. “Pump in/out” indicates initiation/termination of amphetamine exposure using subcutaneous osmotic minipumps. C. Responding for a palatable reward (e.g., sucrose pellets) on a progressive ratio schedule of reinforcement can be used to assess motivation to obtain rewards. Animals must perform an operant response (e.g., lever press) at an exponentially increasing rate to obtain each subsequent sucrose pellet. Eventually, animals will cease to respond as the response requirement to obtain a single pellet demands too much effort, termed the break point. A decrease in break points is an indication of avolition, or decreased motivation to obtain the reward. D. Withdrawal from chronic amphetamine exposure (10 mg/kg/day for 7 days) decreases break points for a sucrose pellet for up to 29 days in rats [70]. Reproduced, with permission from [103] (B) and [70] (D).

Figure 2. Simplified model of a rodent brain illustrating the neural circuitry of anhedonia and other reward-related deficits

1) The nucleus accumbens (NAc), ventral pallidum (VP), and orbitofrontal cortex (OFC) mediate the perception of pleasure. 2) The relative reward value of the pleasant stimulus is computed by the OFC. 3) The effort required to obtain the stimulus is computed by the anterior cingulate cortex (ACC). 4) The ventromedial prefrontal cortex (vmPFC) is involved in the decision to engage in goal-directed activity to obtain the pleasant stimulus. 5) The ventral tegmental area (VTA) and amygdala (AMY) are responsible for increasing anticipation and motivation to carry out the goal-directed activity. Additional brain areas that interact with these circuits also play critical roles in reward-related behaviors. Decreased neurogenesis in the hippocampus (HC) may lead to anhedonia and prevent the reversal of anhedonia by SSRI treatment. SSRI treatment, which purportedly has antidepressant effects by increasing 5-HT activity from the raphe nuclei (RN), increases striatal activity and sucrose preference, while reversing drug-withdrawal-induced anhedonia. Deep brain stimulation of the LHb,, which purportedly leads to disinhibition of mesolimbic dopamine and RN 5-HT circuits, has been shown to have antidepressant effects.