Recurrent cortical circuits implement concentration-invariant odor coding

INTRODUCTION Objects can appear remarkably stable despite the often fickle cues they provide to our senses. For instance, a foraging mouse can identify and locate a piece of cheese several meters away entirely by smell, even though the concentration of airborne “cheese” molecules varies steeply over this distance. How the brain maintains perceptual stability across such widely ranging stimulus intensities remains a fundamental, unanswered question. The response properties of olfactory sensory neurons in the mouse’s nose may provide part of the answer. With each sniff, inhaled odorant molecules activate subsets of sensory neurons that each express a single type of odorant receptor. At low concentrations, when only a few odorant molecules are present, only those cells that express the most sensitive receptors for that particular odorant will be activated. However, many cells that express lower-affinity receptors will also be activated at higher concentrations, potentially degrading the odor representation. Crucially, the sensory neurons that express high-affinity receptors will always be activated earliest in the sniff, regardless of concentration. Could the mouse’s brain exploit this temporal structure to maintain stable odor representations despite changing odorant concentrations? RATIONALE To test this idea, we simultaneously recorded spiking activity from olfactory bulb (OB) mitral cells, which receive input from the olfactory sensory neurons, and from their cortical targets, principal neurons (PNs) in the piriform cortex (PCx), where odor identity is encoded. PNs form extensive, long-range “recurrent” excitatory synapses with each other in addition to forming excitatory synapses on PCx inhibitory interneurons. We hypothesized that this architecture enables the earliest activated—and therefore most selective—PCx PNs to rapidly inhibit less selective PCx PNs, helping to maintain stimulus specificity across odorant concentrations. We directly tested this idea by selectively expressing tetanus toxin in PCx PNs, blocking their ability to excite other PCx neurons but leaving them responsive to OB inputs. RESULTS In control mice, OB responses to different odors were more correlated and were more sensitive to differences in odor concentration than responses in PCx. Individual OB neurons fired bursts of action potentials, with odor-specific latencies and prolonged responses that were strongly concentration-dependent. By contrast, PCx PNs were briefly excited immediately after inhalation and then rapidly truncated by strong and sustained suppression. To identify the source of this suppression, we recorded from feedforward and feedback inhibitory interneurons in PCx. Feedforward interneurons, which are excited exclusively by OB inputs, exhibited little odor-evoked activity. By contrast, feedback interneurons, which are excited by PCx PNs but not by OB, showed robust and sustained spiking that mirrored PN suppression, indicating that PCx itself controls the timing and strength of its own suppression. We eliminated this intracortical communication by silencing recurrent excitatory synapses in PCx with tetanus toxin. This amplified and prolonged PCx PN responses, rendered their responses steeply concentration-dependent, and abolished the ability to stably predict odor identity across concentrations from PCx spiking activity. DISCUSSION The PCx cells that respond earliest after inhalation represent the most odorant-specific and concentration-invariant features of the odor. The extensive, long-range recurrent circuitry broadcasts their activation across PCx, recruiting strong, sustained global inhibition that then suppresses subsequent cortical activity. Recurrent circuitry therefore effectively amplifies the impact of the earliest arriving OB inputs and discounts the impact of less-selective inputs that arrive later. Thus, the recurrent circuitry in the PCx acts as a precisely timed gate to ensure that only the most salient information is relayed further into the brain to guide the mouse’s behavior.