Parallel pathways for sound processing and functional connectivity among layer 5 and 6 auditory corticofugal neurons

Abstract

Cortical layers (L) 5 and 6 are populated by intermingled cell-types with distinct inputs and downstream targets. Here, we made optogenetically guided recordings from L5 corticofugal (CF) and L6 corticothalamic (CT) neurons in the auditory cortex of awake mice to discern differences in sensory processing and underlying patterns of functional connectivity. Whereas L5 CF neurons showed broad stimulus selectivity with sluggish response latencies and extended temporal non-linearities, L6 CTs exhibited sparse selectivity and rapid temporal processing. L5 CF spikes lagged behind neighboring units and imposed weak feedforward excitation within the local column. By contrast, L6 CT spikes drove robust and sustained activity, particularly in local fast-spiking interneurons. Our findings underscore a duality among sub-cortical projection neurons, where L5 CF units are canonical broadcast neurons that integrate sensory inputs for transmission to distributed downstream targets, while L6 CT neurons are positioned to regulate thalamocortical response gain and selectivity.

The Synaptic Organization of Layer 6 Circuits Reveals Inhibition as a Major Output of a Neocortical Sublamina

“…Since Cre recombinase is expressed in both VPM-only and VPM/POm L6 CThNs in Ntsr1-Cre mice (Chevé e et al, 2018), using this line to modulate the activity of L6 CThNs in vitro and in vivo likely engages the circuits of both L6 U and L6 L , although perhaps to different degrees Guo et al, 2017;Kim et al, 2014;Olsen et al, 2012;Pauzin and Krieger, 2018;Williamson and Polley, 2019). Thus, disambiguating contributions from the two L6a sublayers to sensory processing using Ntsr1-Cre mice is challenging Crandall et al, 2017;Guo et al, 2017;Olsen et al, 2012;Pauzin and Krieger, 2018;Williamson and Polley, 2019), although the circuit organization we show here suggests that the two sublayers have distinct functions. VPM-only L6 U CThNs project to L4, the main thalamorecipient layer, and activate IL-PV INs, which also receive strong TC input, suggesting that L6 U is involved in gain control and the modulation of cortical activity in response to sensory input Mease et al, 2014;Olsen et al, 2012;Pauzin and Krieger, 2018).…”

“…Whether the circuit organization we find in L6 U represents a generalized implementation of a mechanism that broadly influences cortical activity to generate feedforward inhibition across the cortical layers, possibly regulating response gain or oscillations among neurons in the overlying cortical column, remains to be tested ( Figure 3E) and L6 L CThN/L6 U PV pairs (L6 U CThN/L6 U PV: 37%, n = 32 of 86 tested connections; L6 L CThN/L6 U PV: 0%, 0 of 28 tested connections; p = 2.2863 3 10 À5 , Fisher's exact test). Kim et al, 2014;Olsen et al, 2012;Pauzin and Krieger, 2018;Williamson and Polley, 2019). IL-PV and local PV INs are found in the visual cortex of the rodent , as are two classes of L6 CThNs, one in L6 U that projects to the lateral geniculate nucleus (LGN; LGN-only L6 CThNs) and another in L6 L that projects to the LGN and lateral posterior (LP) nucleus (LGN/LP L6 CThNs) .…”

“…L6 INH INs are thought to receive preferential input from L6 corticothalamic neurons (CThNs), one of the two major types of L6 PNs (West et al, 2006). This privileged relation is hypothesized to contribute to the modulation of the cortical response to sensory input by L6 CThNs, generating the broad cortical inhibition following the activation of L6 CThNs in vivo mediated by local and interlaminar projections of PV INs Guo et al, 2017;Kim et al, 2014;Olsen et al, 2012;Pauzin and Krieger, 2018;Williamson and Polley, 2019), and is thought to distinguish L6 CThNs from the other major class of L6 PNs, L6 corticocortical neurons (CCNs) (Thomson, 2010).…”

Auditory Corticothalamic Neurons are Recruited by Motor Preparatory Inputs

“…Because they are spatially intermingled with other L6 cell types, and because of the strong reciprocal connectivity of the thalamus and cortex, traditional methods for in vivo neural recordings, stimulation or inactivation have made it challenging to identify a specific role for L6 CTs in sensory processing. The advent of optogenetic approaches to activate and silence genetically targeted L6 CT neurons in Ntsr1-Cre transgenic mice has reinvigorated research on CT circuits, inspiring new hypotheses about their role in sensory gain control and predictive coding (Crandall et al, 2015;Gong et al, 2007;Guo et al, 2017;Olsen et al, 2012;Vélez-Fort et al, 2014;Voigts et al, 2019;Williamson and Polley, 2019). However, any role for L6 CTs in active sensing has been purely speculative, as targeted recordings from L6 CTs have never been made in behaving animals.…”

“…Optogenetics provides a means to artificially manipulate activity in genetically targeted cell types, but can also be used to antidromically identify or "phototag" targeted cell types during extracellular single unit recordings, enabling analysis of cell type-specific activity profiles in response to sensory stimuli, movement or other task-related variables (Guo et al, 2019;Li et al, 2015;Lima et al, 2009;Williamson and Polley, 2019). Here, we used high-density 64-channel linear probes to make extracellular recordings from single units in all layers of A1 in awake, head-fixed Ntsr1-cre mice (Fig.…”