A MOUSE MODEL OF ECONOMIC DECISIONS.

许多精神和神经疾病——包括额颞叶痴呆、精神分裂症和药物

Many mental and neurological disorders – including frontotemporal dementia, schizophrenia and drug addiction – can be broadly characterized as patients making “poor choices.” While these disorders disrupt choices in a variety of domains, deficits can be unitarily described as affecting decisions based on subjective preferences. This behavior is referred to as “economic choice”. Thus to better understand the origins of these disorders, and to pave the way for treatments, it is critical to understand the neural underpinnings of this behavior. Evidence from neurophysiology in non-human primates, functional imaging in humans and lesions studies in multiple species establishes a link between economic decisions and the orbitofrontal cortex (OFC). In particular, previous research in the PI's lab examined the activity of single neurons in the OFC of monkeys choosing between different liquid rewards. This work identified three groups of cells encoding the identity and subjective values of offered and chosen goods. The three groups of cells identified in the primate OFC capture both the input and the output of the choice process, suggesting that decisions are formed in a circuit composed by these neurons. Recent results support this hypothesis. However, most aspects of this neural circuit remain poorly understood. For example, it is unclear whether the three groups of cells correspond to different morphologically identified cell types, whether they reside in different cortical layers, whether they use different neuro-transmitters and/or whether they can be manipulated genetically. Also, a causal link between neurons in the OFC and the decision made by the animal has not yet been established. Addressing these questions using traditional neurophysiology is technically difficult. However, all of these questions can in principle be addressed using genetic approaches developed in recent years. The overarching goal of this proposal is to take this field of investigation to a genetically tractable model ‒ the mouse. Specific aims are (1) to develop such animal model, (2) to recapitulate in mice the main physiological findings from the monkey work, and (3) to exploit this model to address some of the outstanding questions. Specifically, we will combine optogenetics and neuronal recordings to assess whether different groups of cells identified in relation to behavior are inhibitory or excitatory, and whether they are located in different cortical layers. If successful, this research will provide the opportunity for a quantum leap and open new avenues to address numerous fundamental questions. This is a collaboration between Dr Padoa-Schioppa (PI), an expert of economic decisions in primates, and Dr Holy (co-I), an expert of olfaction in mice. The experiments will break new ground and extend previous work in a new and promising direction. While preliminary results argue for feasibility, it remains unclear whether the critical experiments will provide interpretable results. Thus this research is high-risk high-reward. Finally, our ultimate goal is to establish a new model that will significantly impact future research on decision making. For all these reasons, the proposal is closely aligned with the purposes of the R21 funding mechanism. 1