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Major depressive disorder (MDD) is one of the leading global causes of disability. Symptoms of MDD can vary person to person, and current treatments often fail to alleviate the poor quality of life that patients experience. One of the two core diagnostic criteria for MDD is the loss of interest in previously pleasurable activities, which suggests a link between the disease aetiology and reward processing. Cognitive impairments are also common in patients with MDD, and more recently, emotional processing deficits known as affective biases have been recognised as a key feature of the disorder. Studies in animals have found similar affective biases related to reward. In this review we consider these affective biases in the context of other reward-related deficits and examine how affective biases associated with learning and memory may interact with the wider behavioural symptoms seen in MDD. We discuss recent developments in how analogues of affective biases and other aspects of reward processing can be assessed in rodents, as well as how these behaviours are influenced in models of MDD. We subsequently discuss evidence for the neurobiological mechanisms contributing to one or more reward-related deficits in preclinical models of MDD, identified using these behavioural assays. We consider how the relationships between these selective behavioural assays and the neurobiological mechanisms for affective bias and reward processing could be used to identify potential treatment strategies.

Finding effective cognitive enhancers is a major health challenge; however, modulating glutamatergic neurotransmission has the potential to enhance performance in recognition memory tasks. Previous studies using glutamate receptor antagonists have revealed that the medial prefrontal cortex (mPFC) plays a central role in associative recognition memory. The present study investigates short-term recognition memory using optogenetics to target glutamatergic neurons within the rodent mPFC specifically. Selective stimulation of glutamatergic neurons during the online maintenance of information enhanced associative recognition memory in normal animals. This cognitive enhancing effect was replicated by local infusions of the AMPAkine CX516, but not CX546, which differ in their effects on EPSPs. This suggests that enhancing the amplitude, but not the duration, of excitatory synaptic currents improves memory performance. Increasing glutamate release through infusions of the mGluR7 presynaptic receptor antagonist MMPIP had no effect on performance.SIGNIFICANCE STATEMENTThese results provide new mechanistic information that could guide the targeting of future cognitive enhancers. Our work suggests that improved associative-recognition memory can be achieved by enhancing endogenous glutamatergic neuronal activity selectively using an optogenetic approach. We build on these observations to recapitulate this effect using drug treatments that enhance the amplitude of EPSPs; however, drugs that alter the duration of the EPSP or increase glutamate release lack efficacy. This suggests that both neural and temporal specificity are needed to achieve cognitive enhancement.