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e strongly attenuating the plasticity evoked by EPSP bursts. Our findings shed light on how changes in tonic conductances can selectively affect different forms of learning and memory. Copyright © 2020 Dembitskaya et al.Time-dependent frequency trajectories are an inherent feature of many behaviorally relevant sounds, such as species-specific vocalizations. Dynamic frequency trajectories, even in short sounds, often convey meaningful information, which may be used to differentiate sound categories. However, it is not clear what and where neural responses in the auditory cortical pathway are critical for conveying information about behaviorally relevant frequency trajectories, and how these responses change with experience. Here, we uncover tuning to subtle variations in frequency trajectories in auditory cortex of female mice. We found that auditory cortical responses could be modulated by variations in a pure tone trajectory as small as 1/24th of an octave, comparable to what has been reported in primates. In particular, late spiking after the end of a sound stimulus was more often sensitive to the sound’s subtle frequency variation compared to spiking during the sound. Such “Off” responses in the adult A2, but not those inuration sounds. We studied this in mice, where infants use ultrasonic whistles to communicate to adults. We found that late neural firing after a sound ends can be tuned to how the pitch changes in time, and that this response in a secondary auditory cortical field changes with experience to acquire a pitch change’s meaning. Copyright © 2020 Chong et al.The ability to exert flexible instrumental control over one’s environment is a defining feature of adaptive decision-making. Here, we investigated neural substrates mediating a preference for environments with greater instrumental divergence – the distance between outcome probability distributions associated with alternative actions. A formal index of agency, instrumental divergence allows an organism to flexibly obtain the currently most desired outcome as preferences change. As such, it may have intrinsic utility, guiding decisions towards environments that maximize instrumental power. Consistent with this notion, we found that a measure of expected value that treats instrumental divergence as a reward surrogate provided a better account of male and female human participants’ choice preferences than did a conventional model, sensitive only to monetary reward. Liraglutidum Using model-based functional MRI, we found that activity in the rostrolateral and ventromedial prefrontal cortex, regions respectively associated withmic choice preferences. Our results elucidate neural mechanisms mediating the utility of agency. Copyright © 2020 Norton and Liljeholm.The forelimb representation in motor cortex (M1) is an important model system in contemporary neuroscience. Efforts to understand the organization of the M1 forelimb representation in monkeys have focused on inputs and outputs. In contrast, intrinsic M1 connections remain mostly unexplored, which is surprising given that intra-areal connections universally outnumber extrinsic connections. To address this knowledge gap, we first mapped the M1 forelimb representation with intracortical microstimulation (ICMS) in male squirrel monkeys. Then we determined the connectivity of individual M1 sites with ICMS + intrinsic signal optical imaging (ISOI). Every stimulation site activated a distinctive pattern of patches (∼0.25-1.0 mm radius) that we quantified in relation to the motor map. Arm sites activated patches that were mostly in arm zones. Hand sites followed the same principle, but to a lesser extent. The results collectively indicate that preferential connectivity between functionally matched patches is a prominmicrostimulation concurrently with intrinsic signal optical imaging. Quantifying the activation patterns from dozens of M1 sites allowed us to uncover a fundamental principle of M1 organization M1 patches are preferentially connected with functionally matched patches. Relationship between intrinsic connections and neurophysiological map is well-established for sensory cortical areas, but our study is the first to extend this framework to M1. Microstimulation+imaging opened a unique possibility for investigating the connectivity of dozens of tightly spaced M1 sites, which was the linchpin for uncovering organizational principles. Copyright © 2020 Card and Gharbawie.Volatile anesthetics are widely used for surgery, but neuronal mechanisms of anesthesia remain unidentified. At the calyx of Held in brainstem slices from rats of either sex, isoflurane at clinical doses attenuated excitatory post-synaptic currents by decreasing the release probability and the number of readily releasable vesicles. In presynaptic recordings of Ca2+ currents and exocytic capacitance changes, isoflurane attenuated exocytosis by inhibiting Ca2+ currents evoked by a short presynaptic depolarization, whereas it inhibited exocytosis evoked by a prolonged depolarization via directly blocking exocytic machinery downstream of Ca2+ influx. Since the length of presynaptic depolarization can simulate the frequency of synaptic inputs, isoflurane anesthesia is likely mediated by distinct dual mechanisms, depending upon input frequencies. In simultaneous pre- and postsynaptic action potential recordings, isoflurane impaired the fidelity of repetitive spike transmission, more strongly at higher frequencies. Furthermore, in the cerebrum of adult mice, isoflurane inhibited monosynaptic cortico-cortical spike transmission, preferentially at a higher frequency. We conclude that dual presynaptic mechanisms operate for the anesthetic action of isoflurane, of which direct inhibition of exocytic machinery plays a low-pass filtering role in spike transmission at central excitatory synapses.Significance StatementSynaptic mechanisms of general anesthesia remain unidentified. In rat brainstem slices, isoflurane inhibits excitatory transmitter release by blocking presynaptic Ca2+ channels and exocytic machinery, with the latter mechanism predominating in its inhibitory effect on high-frequency transmission. Both in slice and in vivo, isoflurane preferentially inhibits spike transmission induced by high-frequency presynaptic inputs. This low-pass filtering action of isoflurane likely plays a significant role in general anesthesia. Copyright © 2020 Wang et al.