An exciting and longstanding idea in neuroscience is that brainwide activity is important for the generation of complex behaviors; that is, they emerge from spatiotemporal dynamics spanning multiple brain regions. Underscoring the importance of these brainwide networks, changes in functional connectivity of resting state networks as surveyed with functional magnetic resonance imaging have been linked to disease subtypes, such as with MDD1. Understanding the neural circuit mechanisms of these networks and how they generate behavior would be a crucial step towards a mechanistic understanding of many psychiatric disorders (cite?). Traditional studies, however, have tended to emphasize the functional specialization of single brain areas – memory in the hippocampal formation, motor planning in the premotor cortex, reward and motivation in the striatum – reflecting past limitations in neural recording techniques. The shortcomings of this approach have been especially apparent in the study of interval timing, which is the ability to track elapsed time using an internal clock for the purposes of behavior2. As time is often a key variable in reward anticipation, memory formation, and motor planning, it is no surprise that cells encoding interval timing have been discovered in diverse areas including the striatum, the prefrontal cortex, and the hippocampal formation. But an essential question has been left unanswered: where is the internal sense of timing generated in the brain? Does a single brain region generate this clock or is it an emergent property of brainwide networks? This latter possibility would provide an explanation for why timing behaviors are often altered in psychiatric diseases such as MDD or schizophrenia as these disorders demonstrate changes in brainwide networks3. I propose to develop innovative techniques for probing the brainwide circuits that support interval timing. This work is divided into two aims. In the first aim, I will establish an experimental paradigm that allows for monitoring activity across brain regions while mice perform an interval timing behavior and use this approach to decipher whether different brain regions encode time independently or as part of a single cohesive network. In the second aim, I will test the hypothesis of coordinated activity by selectively perturbing regions or pathways and observing the changes in brainwide activity and timing behavior. These approaches will be buoyed by the revolution in optical techniques available in rodent neuroscience for probing neural circuits at the macroscale level. The hypothesis of this work is that an internal sense of time is not found in one brain region but is instead generated by coordinated activity across regions. Together this work will determine the underlying connectivity patterns that generate interval timing, allowing for future work to map alterations in timing to the responsible changes in brain activation patterns.
|Effective start/end date||1/15/22 → 1/14/24|
- Brain & Behavior Research Foundation (Award Letter 8/6/21)
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