Diverse Representations of Olfactory Information in Centrifugal Feedback Projections

Abstract

Although feedback or centrifugal projections from higher processing centers of the brain to peripheral regions have long been known to play essential functional roles, the anatomical organization of these connections remains largely unknown. Using a virus-based retrograde labeling strategy and 3D whole-brain reconstruction methods, we mapped the spatial organization of centrifugal projections from two olfactory cortical areas, the anterior olfactory nucleus (AON) and the piriform cortex, to the granule cell layer of the main olfactory bulb in the mouse. Both regions are major recipients of information from the bulb and are the largest sources of feedback to the bulb, collectively constituting circuits essential for olfactory coding and olfactory behavior. We found that, although ipsilateral inputs from the AON were uniformly distributed, feedback from the contralateral AON had a strong ventral bias. In addition, we observed that centrifugally projecting neurons were spatially clustered in the piriform cortex, in contrast to the distributed feedforward axonal inputs that these cells receive from the principal neurons of the bulb. Therefore, information carried from the bulb to higher processing structures by anatomically stereotypic projections is likely relayed back to the bulb by organizationally distinct feedback projections that may reflect different coding strategies and therefore different functional roles.

Distinct projection patterns of different classes of layer 2 principal neurons in the olfactory cortex

“…In our hands AAV capsid serotype 8 (AAV2/8-CAG-Flex-eGFP) worked the best to retrogradely label APC somas using this mouse line ( Figure 1C; Figure S1). Following OB injections, retrogradely-labeled neurons were not evenly distributed across the different layers, as previously observed [23][24][25] . 74.8 ± 6.1 % of the neurons were found in the layer 2, while 3.6 ± 1.0 % were located in layer 1, and 21.6 ± 4.3 % in layer 3 and the EndoP (Figure 1D), confirming the results from a similar study 23 .…”

“…However, it is unclear how prevalent are these cells that project both anterogradely and retrogradely. Recent work 23,24 confirmed original findings from 25 , showing that feedback fibers from the APC to the OB do not originate homogeneously from all layers but appear to come from layers 2b and layer 3. In the present work, we used tracing techniques with pure retrograde activity, viral labeling, as well as mouse genetics to dissect the contribution of APC to upstream or downstream projections, with an emphasis on layer 2 principal neuron populations.…”

“…Since we do not know how many APC neurons are actually projecting to the OB or PPC, we cannot estimate the fraction of actually projecting cells we are labeling using our beads injection protocol. Evidence for a certain degree of topography in OB-projection patterns 24,36 suggest that our restricted bead injection limits the number of possible retrogradely labeled neurons to those projecting to the precise injection locus. Notably, Matsutani (2010) 36 described patchy axon terminals in the OB.…”

Top-down modulation of olfactory-guided behaviours by the anterior olfactory nucleus pars medialis and ventral hippocampus

“…In fact, cortical feedback projections to the OB outnumber olfactory sensory neuron inputs to the OB36. The largest source of cortical feedback projections to the OB originates in the AON, a ring-like cortical structure situated immediately caudal to the OB and rostral to the piriform cortex, which provides direct excitatory inputs to both inhibitory interneurons and mitral cells178. Despite the apparent importance of AON-derived cortical feedback in olfaction, the function of this input has not been directly demonstrated in awake behaving animals, leaving its relevance unknown910.…”

Dynamic inhibition of sensory responses mediated by an olfactory corticofugal system

“…The AON is the largest source of cortical projections to the OB (Carson, 1984;Shipley and Adamek, 1984). AON-derived axons have been shown to project to multiple layers of the OB (Reyher et al, 1988;Padmanabhan et al, 2016;Wen et al, 2019). This includes the granule cell layer which contains the majority of inhibitory interneurons of the OB, as well as the layers containing the output neurons of the OB, the external plexiform and the mitral cells layer.…”