Synaptic transmission constitutes the primary mode of communication between neurons. It is extensively studied in rodent but not human neocortex. We characterized synaptic transmission between pyramidal neurons in layers 2 and 3 using neurosurgically resected human middle temporal gyrus (MTG, Brodmann area 21), which is part of the distributed language circuitry. We find that local connectivity is comparable with mouse layer 2/3 connections in the anatomical homologue (temporal association area), but synaptic connections in human are 3-fold stronger and more reliable (0% vs 25% failure rates, respectively). We developed a theoretical approach to quantify properties of spinous synapses showing that synaptic conductance and voltage change in human dendritic spines are 3–4-folds larger compared with mouse, leading to significant NMDA receptor activation in human unitary connections. This model prediction was validated experimentally by showing that NMDA receptor activation increases the amplitude and prolongs decay of unitary excitatory postsynaptic potentials in human but not in mouse connections. Since NMDA-dependent recurrent excitation facilitates persistent activity (supporting working memory), our data uncovers cortical microcircuit properties in human that may contribute to language processing in MTG.

The axonal projections of the adrenergic system to the neocortex, originating from the locus coeruleus (LC), form a dense network. These axons release the neuromodulator norepinephrine (NE) which is involved in many cognitive functions such as attention, arousal, and working memory. Using two-photon Ca 2+ imaging of NE axons in the 15 cortex of awake mice, we investigated what drives their phasic activity. We discovered that NE axons in the primary somatosensory cortex responded robustly and reliably to somatosensory stimulation. Surprisingly, the same axons also responded to stimuli of other modalities (auditory and visual). Similar responses to all three modalities were observed in the primary visual cortex as well. These results indicate that phasic 20 responses of NE axons to sensory stimuli provide a robust multimodal signal. However, despite the robustness, we also noticed consistent variations in the data. For example, responses to whisker stimulations were larger than to auditory and visual stimulations in both the barrel and the visual cortices. To test whether the variations in NE axonal responses can carry behaviorally meaningful information, we trained mice in an 25 associative auditory fear conditioning paradigm. We found that following conditioning the response of NE axons increased only for CS+, namely the signal undergoes experience-dependent plasticity and is specific to meaningful sounds. To test if variations in NE axonal responses can differentially affect the cortical microcircuit, we used dual-color two-photon Ca 2+ imaging and studied the relationship between the 30 activity of NE axons and local dendrites. We found dendritic Ca 2+ signals in barrel cortex in response to auditory stimuli, but these responses were variable and unreliable. Strikingly, the probability of such dendritic signals increased nonlinearly with the Ca 2+ signals of NE axons. Our results demonstrate that the phasic activity of the noradrenergic neurons may serve as a robust multimodal and plastic signal in sensory 35 cortices. Furthermore, the variations in the NE axonal activity carry behaviorally meaningful signals and can predict the probability of local dendritic Ca 2+ events. 2 Keywords 40Norepinephrine, dendritic computation, sensory cortices, locus coeruleus, cortical microcircuit, axonal two-photon imaging

Human-specific cognitive abilities depend on information processing in the cerebral cortex, where neurons are significantly larger and sparser compared to rodents. We found that, in synaptically-connected layer 2/3 pyramidal cells (L2/3 PCs), soma-to-soma signal propagation delay is similar in humans and rodents. Thus, to compensate for the increase in neurons size, membrane potential changes must propagate faster in human axons and/or dendrites. Dual somato-dendritic and somato-axonal patch recordings show that action potentials (APs) propagation speed is similar in human and rat axons, but the forward propagation of the EPSPs and the back-propagating APs are ~1.7-fold faster in human dendrites. Faithful biophysical models of human and rat L2/3 PCs, combined with pharmacological manipulations of membrane properties, showed that the larger dendritic diameter, combined with differences in cable properties, underlie the accelerated signal propagation in human cortical circuits. The implication for information processing in the human brain are discussed.