Prolonged Intracellular Na+ Dynamics Govern Electrical Activity in Accessory Olfactory Bulb Mitral Cells

Persistent activity has been reported in many brain areas and is hypothesized to mediate working memory and emotional brain states and to rely upon network or biophysical feedback. Here, we demonstrate a novel mechanism by which persistent neuronal activity can be generated without feedback, relying instead on the slow removal of Na+ from neurons following bursts of activity. We show that mitral cells in the accessory olfactory bulb (AOB), which plays a major role in mammalian social behavior, may respond to a brief sensory stimulation with persistent firing. By combining electrical recordings, Ca2+ and Na+ imaging, and realistic computational modeling, we explored the mechanisms underlying the persistent activity in AOB mitral cells. We found that the exceptionally slow inward current that underlies this activity is governed by prolonged dynamics of intracellular Na+ ([Na+]i), which affects neuronal electrical activity via several pathways. Specifically, elevated dendritic [Na+]i reverses the Na+-Ca2+ exchanger activity, thus modifying the [Ca2+]i set-point. This process, which relies on ubiquitous membrane mechanisms, is likely to play a role in other neuronal types in various brain regions.An experimental and computational study reveals a novel mechanism for persistent activity of neurons in response to transient stimulation. Instead of involving feedback mechanisms, it relies on slow changes in intracellular sodium ion concentration, leading to prolonged calcium-dependent inward current.Author Summary: The accessory olfactory system is essential for chemical communication in animals during social interactions. During this process, the principle cells of the accessory olfactory bulb (AOB) may respond to transient stimulation with prolonged activity, sometimes lasting for minutes—a property known as persistent activity. This property, which has been observed in other brain areas, is usually attributed to positive feedback mechanisms either at the cellular or the network level. Here, we show how persistent activity can emerge without feedback, relying on slow changes in internal ionic concentrations, which keep a record of past neuronal activity for long periods of time. We used a combined computational and experimental approach to show that the complex interaction between various ions, their extrusion mechanisms, and the membrane potential leads to stimulus-dependent persistent activity in the AOB. The same mechanism may apply to other neuronal types in various brain regions.