Neuromodulation and Dendritic Integration in the Neocortex

How do individual neurons contribute to functional (and sometimes tragically dysfunctional) behavior in animals? Since the days of Ramon y Cajal, the remarkable morphology of neurons’ dendrites has inspired neuroscientists to wonder how these elaborate structures contribute to an individual neuron’s function. For the pyramidal neurons within the neocortex, dendritic (tree-like) structures extend throughout the cortical column, integrating thousands of synaptic inputs from other neurons. Since the advent of patch clamp physiology and calcium imaging in the last century, we now appreciate that the complement of ion channels in the soma, dendrite and axons critically shape how a neuron responds to barrages of synaptic activity. Furthermore, it is well demonstrated that these intrinsic properties are malleable: neuromodulation by serotonin, dopamine, acetylcholine, noradrenaline and even neuropeptides can alter the intrinsic properties of these cells. Many of the drugs used for treatment of mental health disorders, epilepsy, and neurodegeneration alter neurons’ intrinsic properties as well.

Intriguingly, a great deal of evidence points to the fact that neocortex is not comprised of a single pyramidal neuron type with universal properties. Rather, pyramidal neurons can be divided into distinct “types” that are physiologically, transcriptomically and morphologically different. Several emerging lines of evidence suggest that human brain disorders may have cell type-specific etiologies, wherein different classes of neurons make distinct contributions to the pathophysiology of the disease. Using state-of-the-art patch clamping techniques in combination with 2-photon calcium imaging and synaptic activation we explore how different types of cells (both within and across neocortical areas) integrate inputs and how integration is altered by neuromodulation. Our work lays the foundation to better understand how neuron types contribute to epilepsy, neurodegenerative and affective disorders, and may provide a path to cell-type specific genetic and pharmacological treatment approaches to these conditions.