Cholinergic signaling for sensorimotor acquisition and implicit learning

About This Grant

PROJECT SUMMARY In a dynamic environment, learning is an evolutionary advantage. When faced with a novel situation, animals that adapt their behavior appropriately may live to reproduce another day. Associative learning requires linking distinct events across time, such as a sensory event with a motor command that results in the desired outcome. How are flexible sensorimotor associations implemented in the brain? The brain regions supporting the encoding of these events are broadly distributed suggesting that learning- related plasticity would benefit from neural mechanisms that operate across multiple timescales and brain regions. Ascending neuromodulatory systems—with their broad projection architecture and multiple timescales of activity—fulfill these criteria and could serve as a potent mechanism to link the different sensory, motor and outcome components. More specifically, the cholinergic basal forebrain (CBF) is the ideal candidate to support rapid learning-related plasticity across multiple cortical regions. This builds on a robust literature showing a pleiotropic role of the CBF to establish both sensory and motor cortical plasticity. Additionally, CBF neurons respond precisely to reinforcement, movement, and sensory events. The overall hypothesis is that the CBF phasic activity serves as a ‘teaching’ signal, locally integrating distinct events, and then projecting conjoint signals (i.e., sensory-motor contingencies) to recipient regions on the timescale of contingency acquisition. The mentored phase will exploit a novel behavioral approach that isolates the timing of acquisition of novel sensorimotor contingencies combined with state-of-the-art optical and physiological tools to test this specific hypothesis. Aim 1 will determine the spatiotemporal dynamics of cholinergic signaling to the Auditory Cortex (AC) and Motor Cortex (MC) during early task acquisition. Aim 2 will identify the causal role of CBF in associative audiomotor acquisition. In the R00 phase this framework will be expanded to implicit learning, when previously acquired sensorimotor contingencies are subject to rapid changes. Aim 3 will determine the role of CBF in implicit learning of auditory regularities. Using a combination of state-of the art optical tools, cell-type specific and temporally precise optogenetics and custom computational analysis and tools, this project unveils the role of cholinergic inputs to distinct cortical targets in learning. There is growing evidence that hearing loss and dementia are tightly linked. Cholinergic circuits play a prominent role in essential cognitive functions which are impacted during cognitive decline. Interestingly, it is one of the earliest regions to exhibit neurodegeneration in Alzheimer’s disease. Understanding how cortical networks are modulated by cholinergic inputs to produce the appropriate behavior will advance our understanding of basic cognitive functions and help develop targeted approaches to fend-off cognitive decline.