Dentate granule cells encode auditory decisions after reinforcement learning in rats.

Auditory-cued goal-oriented behaviors requires the participation of cortical and subcortical brain areas, but how neural circuits associate sensory-based decisions with goal locations through learning remains poorly understood. The hippocampus is critical for spatial coding, suggesting its possible involvement in transforming sensory inputs to the goal-oriented decisions. Here, we developed an auditory discrimination task in which rats learned to navigate to goal locations based on the frequencies of auditory stimuli. Using in vivo calcium imaging in freely behaving rats over the course of learning, we found that dentate granule cells became more active, spatially tuned, and responsive to task-related variables as learning progressed. Furthermore, only after task learning, the activity of dentate granule cell ensembles represented the navigation path and predicts auditory decisions as early as when rats began to approach the goals. Finally, chemogenetic silencing of dentate gyrus suppressed task learning. Our results demonstrate that dentate granule cells gain task-relevant firing pattern through reinforcement learning and could be a potential link of sensory decisions to spatial navigation.

Cortical ensemble activity discriminates auditory attentional states.

Selective attention modulates sensory cortical activity. It remains unclear how auditory cortical activity represents stimuli that differ behaviorally. We designed a cross-modality task in which mice made decisions to obtain rewards based on attended visual or auditory stimuli. We recorded auditory cortical activity in behaving mice attending to, ignoring, or passively hearing auditory stimuli. Engaging in the task bidirectionally modulates neuronal responses to the auditory stimuli in both the attended and ignored conditions compared to passive hearing. Neuronal ensemble activity in response to stimuli under attended, ignored and passive conditions are readily distinguishable. Furthermore, ensemble activity under attended and ignored conditions are in closer states compared to passive condition, and they share a component of attentional modulation which drives them to the same direction in the population activity space. Our findings suggest that the ignored condition is very different from the passive condition, and the auditory cortical sensory processing under ignored, attended and passive conditions are modulated differently.

Extremely Low Frequency Electromagnetic Fields Facilitate Vesicle Endocytosis by Increasing Presynaptic Calcium Channel Expression at a Central Synapse.

Accumulating evidence suggests significant biological effects caused by extremely low frequency electromagnetic fields (ELF-EMF). Although exo-endocytosis plays crucial physical and biological roles in neuronal communication, studies on how ELF-EMF regulates this process are scarce. By directly measuring calcium currents and membrane capacitance at a large mammalian central nervous synapse, the calyx of Held, we report for the first time that ELF-EMF critically affects synaptic transmission and plasticity. Exposure to ELF-EMF for 8 to 10 days dramatically increases the calcium influx upon stimulation and facilitates all forms of vesicle endocytosis, including slow and rapid endocytosis, endocytosis overshoot and bulk endocytosis, but does not affect the RRP size and exocytosis. Exposure to ELF-EMF also potentiates PTP, a form of short-term plasticity, increasing its peak amplitude without impacting its time course. We further investigated the underlying mechanisms and found that calcium channel expression, including the P/Q, N, and R subtypes, at the presynaptic nerve terminal was enhanced, accounting for the increased calcium influx upon stimulation. Thus, we conclude that exposure to ELF-EMF facilitates vesicle endocytosis and synaptic plasticity in a calcium-dependent manner by increasing calcium channel expression at the nerve terminal.

A Monte Carlo simulation dissecting quantal release at the calyx of Held.

Although quantal release provides a basic control of synaptic strength, its underlying mechanisms remain unclear. Here, we report a refined realistic 3D vesicle fusion model at calyx-type synapses. By refining the micro ultrastructure and combining updated parameters, our model is appropriate for simulating quantal release. First, we confirmed the existence of kiss-and-run fusion and gave a justified estimation of its percentage in spontaneous and stimulated release. Second, we found the location of AMPA receptors caused the huge variation in the mEPSC rise time. Third, glutamate spillover only slightly contributed to the mEPSC decay time in small vesicles but caused a dual-peak event in large vesicles. Fourth, mEPSC rise time increased with amplitude, suggesting the contribution of vesicle size, not glutamate concentration. We also applied our model to the analysis of KCl, CaCl2 and synaptotagmin-2 triggered exocytosis. KCl globally accelerated the mEPSCs, whereas mEPSCs were slowed down in high calcium treatments and synaptotagmin-2 knock-out mice, indicating more kiss-and-run release. In summary, our model provides a convenient method for exploring the detailed mechanism of vesicle fusion.

A three-pool model dissecting readily releasable pool replenishment at the calyx of held.

Although vesicle replenishment is critical in maintaining exo-endocytosis recycling, the underlying mechanisms are not well understood. Previous studies have shown that both rapid and slow endocytosis recycle into a very large recycling pool instead of within the readily releasable pool (RRP), and the time course of RRP replenishment is slowed down by more intense stimulation. This finding contradicts the calcium/calmodulin-dependence of RRP replenishment. Here we address this issue and report a three-pool model for RRP replenishment at a central synapse. Both rapid and slow endocytosis provide vesicles to a large reserve pool (RP) ~42.3 times the RRP size. When moving from the RP to the RRP, vesicles entered an intermediate pool (IP) ~2.7 times the RRP size with slow RP-IP kinetics and fast IP-RRP kinetics, which was responsible for the well-established slow and rapid components of RRP replenishment. Depletion of the IP caused the slower RRP replenishment observed after intense stimulation. These results establish, for the first time, a realistic cycling model with all parameters measured, revealing the contribution of each cycling step in synaptic transmission. The results call for modification of the current view of the vesicle recycling steps and their roles.