DESCRIPTION (provided by applicant): The mammalian auditory system can be modified by experience and by behavioral context. This is an important feature of the primary auditory cortex (A1), especially in forming representations of sensory signals such as speech, music and other forms of acoustic communication. With time and experience, animals can learn that specific sounds and not others can signal rewards. Moreover, animals can also learn that the same sound in different contexts requires distinct behavioral responses. In humans, for example, the sound of a gunshot heard on the street versus during a movie will likely lead to divergent behavioral responses. Conversely, PTSD patients hear a loud bang and may be unable to make the same differentiation. Such deficits are also implicated in developmental and language disorders including autism. Understanding the mechanisms of perceptual flexibility is thus essential for studies of normal or pathological auditory processing. Classically, sensory information was thought to be processed in a linear manner where each successive brain area extracts more complex features and then transmits this to higher-order areas that confer meaning (feed-forward processing). However, in the auditory cortex, this model is increasingly challenged by neural recordings in behaving animals in which context or behavioral state plays an important role in modulating neuronal activity. What happens during behavioral conditions where the same sound draws attention in one context (active context) but does not require attention in another (passive context)? The preliminary data in this proposal shows that auditory cortical neurons have distinctly different activity patterns in those two contexts. The precise mechanisms that govern this context-dependent activity in auditory cortex remain unknown. Neuromodulatory centers involved in attention may play a critical role in context-switching, given their importance in long-term plasticity and learning. This proposal will test the hypothesis that context- dependence in auditory cortex arises because long-range attentional signals directly act on local circuits. First, experiments will be conducted to test whether synaptic inputs, the building blocks of neuronal activity, are different in auditory cortex in both contexts (Aim 1). Second, experiments will test whether acetylcholine- releasing projections from the nucleus basalis, a brain region involved in attention, are naturally active during the active task and directly alter the synaptic weights in auditory cortex (Aim 2). Third, experiments will test how context-dependent activity emerges over the course of learning by looking at both the attentional signal from the nucleus basalis and the local neuronal population in auditory cortex (Aim 3). An experienced team of mentors and collaborators will provide training critical for the candidate's short- and long-term success, including: in vivo whole-cell recordings, genetic targe...