Grant: Discovery Grants Program - Individual

Pyramidal neurons are the principal excitatory cells in the brain and they receive thousands of synaptic inputs onto their elaborate dendritic arbors. Remarkable progress has been made in recent decades outlining the integrative properties of pyramidal cell dendrites, and it is now well appreciated that one key aspect of `dendritic computation' involves a wealth on non-linear mechanisms that ultimately controls how synaptic inputs are transformed into spiking activity, therefore powerfully modulating information transfer in neural circuits. A number of recent obtained in vivo further gives credence to the idea that a central component of pyramidal cell computation involves the decoding and transmission of spatiotemporal correlations in synaptic activity. These insights support a growing consensus that neurons, by virtue of their dendrites, are highly compartmentalized information processors. Dendritic excitability is governed by ion channels in the plasma membrane, acting within the constraints of passive cable properties. Activation of voltage-gated sodium channels (VCSCs) and/or voltage-gated calcium channels (VGCCs) are involved in dendritic spike generation, while the presence of potassium channels regulates key aspects of these events. Whereas the computational operations supported by dendrites are themselves highly dynamic in nature, the collective rules guiding these operations in a given neuron have historically largely (though not exclusively) been conceptualized as being static. However, neuromodulators can phasicaly modulate a vast array of active ionic conductances. As such, despite its well-recognized importance, the potential role of neuromodulator systems to dynamically and bi-directionally regulate the rules governing integrative features of dendrites throughout the brain remains largely unexplored experimentally. The disclosure of such a function would provide critical insights into the role played by these modulatory transmitters in regulating information processing in the brain. The overall objective of the current research program is :1) to identify and characterize the catalogue of dendritic operation and compartmentalization features of dendrite function by using a combination of cellular electrophysiology, two-photon (2P) imaging and uncaging of caged analogs of neurotransmitters and to identify how this set of operations is dynamically regulated by neurotransmission; 2) to understand how dendritic events are involved in a novel form of synaptic plasticity we have recently begun to investigate that binds events separated by hundreds of milliseconds. This novel plasticity offers an intriguing solution to the well-known temporal credit assignement problem of modern learning theories. We will investigate with sophisticated and state-of-the-art modeling approaches the computational meanings of our findings.