In primary sensory cortex, neural circuits are organized vertically among the six cortical layers. Sensory signals propagate between these layers via translaminar, feedforward pathways. This coordinated flow of activity is thought to underlie hierarchical processing of sensory information. Inhibition is essential to regulating the translaminar propagation of activity, but the inhibitory circuits that underlie this are incompletey understood. One key function of these circuits is to generate translaminar feedforward inhibition, which is thought to improve the temporal precision, dynamic range, and tuning of sensory responses. In the circuit from thalamus to layer 4 (L4) and from L4 to layer 2/3 (L2/3), this motif is implemented by a specific circuit in which soma- targeting inhibitory interneurons are recruited to inhibit the cell bodies of nearby neurons. However, it is unclear if this soma-targeting circuitis a general component of all translaminar circuits, or if different translaminar circuits are under specialized forms of inhibitory control. We have recently shown that the L4?L5 circuit is also capable of driving somatic inhibition, similar to other translaminar circuits. Interestingly, preliminary data suggest that the L2/3?L5 circuit is organized very differently. My central hypothesis is that unlike other translaminar circuits, feedforward inhibition in the L2/3?L5 pathway is primarily dendritic, because the L2/3?L5 pathway preferentially recruits dendrite- targeting interneurons over soma-targeting interneurons. This enables L2/3?L5 FFI to control nonlinear dendritic spiking in L5. To test this hypothesis, I will use a combination of spatially patterned optogenetic stimulation, slice electrophysiology, and 2-photon calcium imaging.
In Aim 1, I will optogenetically stimulate L2/3 while monitoring spiking in L5 interneurons to determine which subtypes of interneurons are recruited.
In Aim 2, I will image dendritic activity in L5 pyramidal neurons to determine if L2/3 generates dendritic inhibition. Finally, in Aim 3 I wil deploy a new optical method to silence genetically defined subtypes of interneurons during stimulation of L2/3 in order to observe each subtype's contribution to L2/3?L5 inhibition. These experiments will shed light on how inhibition is generated in cortical circuits, and how the balance of excitation and inhibition regulates signal flow in the cortical microcircuit. This is essential to understanding how the cortex processes sensory information. Because many neurological disorders involve the dysfunction of cortical inhibition, this will also help us move toward a mechanistic knowledge of pathologies such as autism, schizophrenia, and epilepsy.
Many neurological disorders, such as autism, schizophrenia, and epilepsy, are associated with dysfunction of inhibition in the neocortex. This project will explore the circuit mechanisms through which cortical inhibition is generated, which will both shed light on the causes of these diseases and elucidate principles of sensory processing in the cortex in the healthy brain.
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| Naka, Alexander; Adesnik, Hillel (2016) Inhibitory Circuits in Cortical Layer 5. Front Neural Circuits 10:35 |
| Merel, Josh; Shababo, Ben; Naka, Alex et al. (2016) Bayesian methods for event analysis of intracellular currents. J Neurosci Methods 269:21-32 |
