UC Irvine

Integration of feedforward and feedback synaptic input is a core feature of neural circuits. Proper interaction between these pathways is critical for nearly all cognitive processes, ranging from basic sensory perception to goal-oriented behaviors including decision making, learning, attention shifting, and working memory. Due to a technical inability to selectively manipulate feedforward and feedback synaptic pathways, previous efforts to examine their interaction rely on passive measures of neural activity in human and other animals, revealing a signature, transient enhancement of neural signals during periods of top-down control. In a largely non-overlapping body of work, detailed studies of dendritic physiology have uncovered basic mechanisms underlying nonlinear enhancement of synaptic input, albeit largely agnostic to input identity. Taking advantage of recent advances in multicolor optogenetics, my thesis aims to uncover cellular mechanisms which explain the neural enhancement observed during top-down modulation. In Chapter 1, I report procedural improvements to a dual-color optogenetic approach for selectively stimulating feedforward and feedback afferents. I demonstrate an exhaustive test of experimental parameters influencing crosstalk, and lastly propose a “lookup table” strategy which minimizes cross-activation of synaptic pathways. Next, in Chapter 2 I explore how deep-layer neurons integrate synaptic input from feedforward and feedback sources, using dual-color optogenetics to expand on decades of synaptic integration work based on electrical stimulation methods. I show that layer 5 pyramidal cells in the posterior parietal cortex (PPC) receive monosynaptic dual innervation, combining inputs from sensory and frontal cortex. I then describe the distinct temporal dynamics by which subclasses of layer 5 pyramidal neurons integrate these synapses. Specifically, regular spiking (RS) cells exhibit supralinear enhancement of delayed, but not coincident inputs, while intrinsic burst firing (IB) neurons selectively boost coincident synaptic events. In explanation of this difference, I next present pharmacological and computational modelling data collected in collaboration with a postdoc in the Lur lab, indicating that distinct integration profiles arise from a cell-type specific interaction of ionic mechanisms and feedforward inhibition. Finally, in Chapter 3 I address how nonlinear enhancement of converging synaptic pathways may generate persistent firing, a neural hallmark of working memory in the PPC. In this Chapter I mimic the effect of optogenetically-evoked synaptic input via direct electrical activation of single cells, showing that projection-specific cells corresponding to RS and IB subtypes have differential propensity for persistent firing. Namely, cells corresponding to the IB subtype display longer-lasting, higher-frequency spike firing than RS during periods of sustained activation, which was not driven by differences in network connectivity between the cell types. I end with speculation of the intrinsic mechanisms which may position IB cells as preferentially engaged during periods of persistent firing.