Evidence for Layer-Specific Connectional Heterogeneity in the Mouse Auditory Corticocollicular System

Abstract

The auditory cortex (AC) sends long-range projections to virtually all subcortical auditory structures. One of the largest and most complex of these-the projection between AC and inferior colliculus (IC; the corticocollicular pathway)-originates from layer 5 and deep layer 6. Though previous work has shown that these two corticocollicular projection systems have different physiological properties and network connectivities, their functional organization is poorly understood. Here, using a combination of traditional and viral tracers combined with in vivo imaging in both sexes of the mouse, we observed that layer 5 and layer 6 corticocollicular neurons differ in their areas of origin and termination patterns. Layer 5 corticocollicular neurons are concentrated in primary AC, while layer 6 corticocollicular neurons emanate from broad auditory and limbic areas in the temporal cortex. In addition, layer 5 sends dense projections of both small and large (.1 mm 2 area) terminals to all regions of nonlemniscal IC, while layer 6 sends small terminals to the most superficial 50-100 mm of the IC. These findings suggest that layer 5 and 6 corticocollicular projections are optimized to play distinct roles in corticofugal modulation. Layer 5 neurons provide strong, rapid, and unimodal feedback to the nonlemniscal IC, while layer 6 neurons provide heteromodal and limbic modulation diffusely to the nonlemniscal IC. Such organizational diversity in the corticocollicular pathway may help to explain the heterogeneous effects of corticocollicular manipulations and, given similar diversity in corticothalamic pathways, may be a general principle in top-down modulation.

Highly branched and complementary distributions of layer 5 and layer 6 auditory corticofugal axons in mouse

“…To determine which other brain regions receive branching terminals from L6 corticocollicular axons, analogously to above, injections of a Cre-dependent retrograde tracer that induces flippase expression (Cav-FlxFlp) were made into the IC of 4 mice that expressed Cre-recombinase in FOXP2+ neurons (Figure 4A, n=4, age range 3-6 months). As expected, labeled terminals were found in the IC, mostly in the most distal rim of the IC, and outside of modules in the LC (Figure 4B), consistent with previous work (Yudintsev, Asilador et al 2021). In the AC, consistent with previous reports, the L6 corticocollicular cells were isolated to the deepest regions of L6, adjacent to the white matter with extensive local branching extending into L2/3 (Schofield 2009, Slater, Willis et al 2013, Slater, Yudintsev et al 2019.…”

“…See Figures 1B and 1C for representative injection sites. As we and others have shown (Schofield 2009, Slater, Willis et al 2013, Slater, Yudintsev et al 2019, Yudintsev, Asilador et al 2021, FG injections to the IC retrogradely label primarily L5 neurons in the AC, while a minority (approximately 20-25%) of labeled neurons are in lower L6 (Figure 1D). Conversely, as has also been previously shown (Ojima 1994, Llano andSherman 2008), injection of a retrograde tracer into MGB retrogradely-labels neurons primarily in L6 of the AC, and a minority of labeled cells are in L5 (Figure 1E).…”

“…However, it is possible that these markers may fail to label a subset of corticofugal neurons, thus leaving open the possibility that non-FOXP2+ cells in L6 or non-RBP4+ cells in L5 may have different trends than those seen here. Indeed, roughly 20-30% of L5 and L6 corticocollicular neurons are RBP4-or FOXP2-negative, respectively (Xiong, Liang et al 2015, Yudintsev, Asilador et al 2021. We think that this possibility is unlikely to impact our results at least for L5, because the AAVrg experiments that labeled L5 neurons did not rely on RBP4, but revealed nearly identical projection patterns as seen in the CAV-FlxFlp experiments that relabeled RBP4+ neurons.…”

Absence of the Fragile X messenger ribonucleoprotein alters response patterns to sounds in the auditory midbrain

“…Lower auditory brainstem nuclei, including the cochlear nucleus (CN), the lateral superior olive (LSO), and the nuclei of the lateral lemniscus (LL) almost exclusively project to the central nucleus of the IC, which itself projects upward through the thalamus -the Medial Geniculate Nucleus -finally reaching to the Auditory Cortex (AC). Functionally, the IC mediates ascending streams of information, but also receives direct descending streams of cognitively driven activity from corticofugal projections originating from layer V and VI of the AC and many nonauditory, cortical areas (Olthof et al, 2019;Yudintsev et al, 2021). These latter corticofugal projections likely support the plasticity observed in the IC when facing novelty in auditory stimuli (Ayala and Malmierca, 2013;Ayala et al, 2016).…”

Effects of Cortical Cooling on Sound Processing in Auditory Cortex and Thalamus of Awake Marmosets

“…Thalamic sensory processing can also be influenced by altering activity further downstream e.g. via further corticofugal projections such as the corticocollicular pathway targeting mostly the non-lemniscal pathway (Winer, 2005 ; Yudintsev et al, 2021 ). Thus, more generally, it is apparent that thalamic sensory processing results from the dynamic interplay of feedforward and feedback pathways (Alitto and Usrey, 2003 ).…”