Midbrain dopamine neurons are thought to play key roles in learning by conveying the difference between expected and actual outcomes. While this teaching signal is often considered to be uniform, recent evidence instead supports diversity in dopamine signaling. However, it remains poorly understood how heterogeneous signals might be organized to facilitate the role of downstream circuits mediating distinct aspects of behavior. Here we investigated the organizational logic of dopaminergic signaling by recording and labeling individual midbrain dopamine neurons during associative behavior. We defined combinations of protein expression and cellular localization to sort recorded neurons according to the striatal regions they innervate. Our findings show that reward information and task variables are not only heterogeneously encoded, with multiplexing, but also differentially distributed across populations of dopamine neurons projecting to different regions of striatum. These data, supported by computational modelling, indicate that such distributional coding can maximize dynamic range and tailor dopamine signals to facilitate the specialized roles of different striatal regions.

Purpose Cognitive enhancers are the primary pharmacological therapy prescribed to those with dementia, comprising of memantine and the acetylcholinesterase inhibitors (AChEIs). The long-term cognitive and behavioural benefits of these medications, as well as their potential contribution to falls is currently debated, with recent Delphi studies being unable to reach consensus on whether these medications should be deprescribed. In this narrative clinical review, as part of a series on deprescribing in people at risk of falls, we explore the potential falls-related side effects experienced in people taking cognitive enhancers, alongside situations where deprescribing may be appropriate. Methods We undertook a literature search of PubMed and Google Scholar, using terms capturing falls and cognitive enhancers, as well as consulting the British National Formulary and published Summary of Medicinal Product Characteristics. These searches informed the subsequent clinical review. Results Cognitive enhancers should be subject to regular review, including confirmation of appropriate treatment indication, and occurrence of side effects in the context of falls. AChEIs, in particular, are associated with a broad range of side effects that can contribute to increased falls risk. These include bradycardia, syncope and neuromuscular effects. Where these have been identified, deprescribing should be considered, as well as alternative treatment options. Deprescribing studies have shown mixed results, likely due to considerable methodological heterogeneity. Several suggested guidelines exist to aid deprescribing decisions, many of which are highlighted in this review. Conclusions The use of cognitive enhancers should be regularly reviewed and decisions to deprescribe made on a case-by-case basis, considering both the risks and benefits of stopping these medications.