Understanding how the brain processes changes in stimulus salience is essential to survival as it dictates subsequent learning and behavior alike, and the abnormal processing of salience is believed to be the basis of a number of pathologies including schizophrenia, ADHD as well as addiction disorders such as gambling and drug-seeking. Of particular relevance to the latter two disorders is the role predictive learning plays n modulating stimulus salience: Decreasing as the subject learns that no important consequences follow the stimulus, but increasing when the stimulus repeatedly leads to unexpected, motivationally potent events, particularly if those events are not fully predictable (i.e. remain uncertain3). Our current understanding of the neurobiology of how cues capture attention following learning is limited. Recent in-vivo single-unit recording studies in rats have reported signals in basolateral amygdala (ABL) and anterior cingulate cortex (ACC) that act in accordance with the learning mechanism specified by Pearce-Hall model, an intentional theory of learning3,10,11,12,14,18. However, it remains uncertain how these neural signals lead to the acquisition of surprise- driven salience and how these structures fit within a functional neural circuit. In this project, optogenetics and single-unit recording will be used in combination with contrasted behavioral procedures to explore the inner workings of these areas and their interactions in precisely defined, behaviorally relevant temporal windows. The mentored K99 phase will begin by investigating the role of dopamine (DA) in the ABL and ACC signals, a line of inquiry already open in our lab12. The independent R00 section will later examine the relationship that the ABL and ACC signals hold to each other, based on the hypothesis that they correspond to two stages in the neural implementation of salience enhancement. The remaining experiments will further specify the contribution of ABL and ACC to salience by examining their role in salience-mediated differences in learning: a key test of acquired salience. In addition to its significance, the current project will provide the trainee with an excellent opportunity to master the combined use of optogenetics and single-unit recording, the two primary techniques that he intends to use in his future lab. In addition, the K99 phase of this grant will ensure that he also develops his professional skills by gaining valuable experience in mentoring, teaching, presenting data at prominent meetings, and getting to know his equipment inside-out. Importantly, this training will take place at an exceptional research facility-the Intramural Research Program at the National Institute on Drug Abuse- which has an abundance of resources and training opportunities. Training will be facilitated by the expertise provided by NIDA's Optogenetic and Transgenic Technology Core and by interacting with close colleagues in ours and other laboratories at NIDA. This proposal is well-designed to provide Dr. Esber with the necessary professional and scientific training to acquire a tenure-track position at the end of the mentored phase as well as become a leader in his field.
In an inherently unstable world, neural mechanisms have evolved to heighten the salience of stimuli which occur within temporal proximity to unexpected, motivationally potent events, thus giving organisms a better chance to discover relevant causal relationships in their environment. These mechanisms are of vital importance to our understanding of decision making because they modulate attention and thereby impact all subsequent stages of information processing and the actions that ensue. This project evaluates a candidate instantiation of these mechanisms in the healthy brain, with a view to illuminating the neural basis of abnormal salience attribution in psychiatric disorders such as schizophrenia, ADHD, addiction and pathological gambling.