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Anhedonia is defined as reduced interest or pleasure in activities previously considered enjoyable and is a cardinal symptom of many neuropsychiatric disorders including major depression, schizophrenia and substance dependence. Pleasurable experiences involve a variety of psychobiological components including learning, memory and motivation that influence engagement with rewarding events and can therefore impact affective responding. Despite the capacity to dissociate these processes in humans and nonhuman animals, contemporary preclinical animal models of anhedonia emphasize responses to immediately pleasurable stimuli including palatable food and drugs of abuse. This limits translatability to the clinic as human patients exhibiting anhedonia largely display normalized responsivity to pleasurable stimuli and instead show deficits in responding for associative cues. Conditioned motivators can serve to bridge the gap between clinical and preclinical knowledge, as they can be dissociated into each independent component process associated with anhedonia. Following several distinct temporally-contingent associations with reward, neutral stimuli acquire meaning and become conditioned motivators, which can be uniquely manipulated to parse several component processes within a variety of tasks. Thus, the properties of conditioned motivators in anhedonia and the neural substrates underlying them will be critical in translating knowledge about these independent neuropsychiatric processes to the clinic. This review emphasizes the utilization of ‘reverse-translation’, integrating patient-based findings with preclinical animal models to experimentally parse component processes of anhedonia and develop holistic experimental models to measure it. Dissociating the independent, measurable component processes of anhedonia is critical for accurate representation in preclinical animal models and for acceleration of treatment strategies to the clinic. introduction Healthcare systems have naturally relied on preclinical animal models to reveal potential indications of etiology and diagnosis, foster drug discovery, and guide treatment regimens in clinical populations. The term ‘translational research’ has been devised to describe this approach of exporting basic research findings into clinical practice.1,2 Although experimental animal models are indispensable in terms of informing future medical practice, clinical discoveries are evidently shaping the aims and directions of preclinical neuropsychiatric research.2,3 Indeed, evolving diagnostic criteria and insights into the nature of clinical phenomena continue to refine our understanding of psychiatric illness.4 This method of drawing on patient-based findings to develop assays that measure the fundamental characteristics of clinically relevant symptoms in preclinical animal models is known as ‘reverse-translational research’.5,6 Anhedonia presents as a fundamental symptom in many psychiatric disorders including major depression, substance dependence and schizophrenia, among others which affect significant portions of the population worldwide.7-9 Despite its prevalence, there has been limited success in developing novel treatments for anhedonia.10 One major reason for this dearth may be the lack of precision in preclinical animal models of anhedonia, the majority of which emphasize hedonic responses to primary reinforcers (rewards) such as palatable food, drugs of abuse, sex, and sociability.11,12 However, evidence suggests that human patients exhibiting anhedonia frequently display normal subjective reports of ‘liking’ for primary rewards.13-15 Rather, deficits in hedonic responding can be better characterized by responses to conditioned stimuli which have become associated with primary reinforcers through numerous contingent pairings, such as contextual or associative cues that signal reward.16-18 An example of a response engendered by a conditioned motivator would be that of an alcohol addict to the sight or presence of a beer bottle. The following review emphasizes ‘reverse-translational’ strategies, integrating patient-based findings with preclinical models to experimentally parse component processes of anhedonia (see Figure 1) and develop holistic experimental models to measure it. Shortfalls from insufficient models are addressed and some existing examples of this strategy are highlighted including models that have provided insight into neurobiological mechanisms underlying anhedonia. Parsing anhedonia into its independent, measurable component processes is critical for accurate representation in preclinical animal models and for accelerating treatment strategies to clinical populations. dissociating component processes of anhedonia Exposure to rewarding stimuli stimulates memory consolidation and increases the prospect that behaviours that lead to reward will be performed in the future.19 Rewarding stimuli can be categorized as 1) primary rewards that are instinctively and consciously

uwomj/medical journal

Parsing Anhedonia: A reverse-translational strategy for treatment of anhedonia in clinical populations and potential implications of conditioned motivators