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The active electrical properties of dendrites shape neuronal input and output and are fundamental to brain function. However, our knowledge of active dendrites has been almost entirely acquired from studies of rodents. In this work, we investigated the dendrites of layer 2 and 3 (L2/3) pyramidal neurons of the human cerebral cortex ex vivo. In these neurons, we discovered a class of calcium-mediated dendritic action potentials (dCaAPs) whose waveform and effects on neuronal output have not been previously described. In contrast to typical all-or-none action potentials, dCaAPs were graded; their amplitudes were maximal for threshold-level stimuli but dampened for stronger stimuli. These dCaAPs enabled the dendrites of individual human neocortical pyramidal neurons to classify linearly nonseparable inputs—a computation conventionally thought to require multilayered networks.

How neuronal connections are established and organized into functional networks determines brain function. In the mammalian cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made toward parsing interneuron diversity, yet the molecular mechanisms by which interneuron-specific connectivity motifs emerge remain unclear. In this study, we investigated transcriptional dynamics in different classes of interneurons during the formation of cortical inhibitory circuits in mouse. We found that whether interneurons form synapses on the dendrites, soma, or axon initial segment of pyramidal cells is determined by synaptic molecules that are expressed in a subtype-specific manner. Thus, cell-specific molecular programs that unfold during early postnatal development underlie the connectivity patterns of cortical interneurons.

There is as yet no consensus concerning the neural basis of perception and how it operates at a mechanistic level. We found that Ca²⁺ activity in the apical dendrites of a subset of layer 5 (L5) pyramidal neurons in primary somatosensory cortex (S1) in mice is correlated with the threshold for perceptual detection of whisker deflections. Manipulating the activity of apical dendrites shifted the perceptual threshold, demonstrating that an active dendritic mechanism is causally linked to perceptual detection.

In addition to providing well-characterized excitatory inputs, the entorhinal cortex also sends long-range inhibitory projections to the hippocampus. Basu et al. described this input in detail and characterized its role for learning and memory. Multimodal sensory stimuli activate long-range inhibitory input in vivo. This input enables precisely timed information transfer within the cortico-hippocampal circuit. In this way, long-range inhibitory projections play an important role in providing specificity of fear conditioning, and thus help prevent overgeneralization. Science , this issue p. 10.1126/science.aaa5694 Inhibitory inputs from the lateral entorhinal cortex help to make contextual memory associations specific. The cortico-hippocampal circuit is critical for storage of associational memories. Most studies have focused on the role in memory storage of the excitatory projections from entorhinal cortex to hippocampus. However, entorhinal cortex also sends inhibitory projections, whose role in memory storage and cortico-hippocampal activity remains largely unexplored. We found that these long-range inhibitory projections enhance the specificity of contextual and object memory encoding. At the circuit level, these γ-aminobutyric acid (GABA)–releasing projections target hippocampal inhibitory neurons and thus act as a disinhibitory gate that transiently promotes the excitation of hippocampal CA1 pyramidal neurons by suppressing feedforward inhibition. This enhances the ability of CA1 pyramidal neurons to fire synaptically evoked dendritic spikes and to generate a temporally precise form of heterosynaptic plasticity. Long-range inhibition from entorhinal cortex may thus increase the precision of hippocampal-based long-term memory associations by assessing the salience of mnemonic information to the immediate sensory input.

In vivo calcium imaging from axons provides direct interrogation of afferent neural activity, informing the neural representations that a local circuit receives. Unlike in somata and dendrites, axonal recording of neural activity—both electrically and optically—has been difficult to achieve, thus preventing comprehensive understanding of neuronal circuit function. Here we developed an active transportation strategy to enrich GCaMP6, a genetically encoded calcium indicator, uniformly in axons with sufficient brightness, signal-to-noise ratio, and photostability to allow robust, structure-specific imaging of presynaptic activity in awake mice. Axon-targeted GCaMP6 enables frame-to-frame correlation for motion correction in axons and permits subcellular-resolution recording of axonal activity in previously inaccessible deep-brain areas. We used axon-targeted GCaMP6 to record layer-specific local afferents without contamination from somata or from intermingled dendrites in the cortex. We expect that axon-targeted GCaMP6 will facilitate new applications in investigating afferent signals relayed by genetically defined neuronal populations within and across specific brain regions.

The retina extracts visual features for transmission to the brain. Different types of bipolar cell split the photoreceptor input into parallel channels and provide the excitatory drive for downstream visual circuits. Mouse bipolar cell types have been described at great anatomical and genetic detail, but a similarly deep understanding of their functional diversity is lacking. Here, by imaging light-driven glutamate release from more than 13,000 bipolar cell axon terminals in the intact retina, we show that bipolar cell functional diversity is generated by the interplay of dendritic excitatory inputs and axonal inhibitory inputs. The resulting centre and surround components of bipolar cell receptive fields interact to decorrelate bipolar cell output in the spatial and temporal domains. Our findings highlight the importance of inhibitory circuits in generating functionally diverse excitatory pathways and suggest that decorrelation of parallel visual pathways begins as early as the second synapse of the mouse visual system. The functional diversity of bipolar cells, which split visual inputs into different excitatory channels within the retina, arises from centre–surround interactions in their receptive fields that tune both spatial and temporal signalling. Representation of visual features in the retina Visual features such as edges or motion are extracted by the retina for transmission to the brain. This is made possible by bipolar cells, which split photoreceptor input into separate channels, owing to their neuroanatomical and molecular diversity. By imaging 13,000 bipolar cells in the mouse retina, Tom Baden and colleagues now describe the excitatory and inhibitory inputs that allow for the vast functional diversity of bipolar cells. The results suggest that the centre and surround receptive-field interactions, which are classically associated with spatial contrast, also serve to tune temporal signalling.

Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders, but little is known about the dendritic mechanisms underlying these phenomena. We found that the primary somatosensory neocortex (S1) was hyperexcited in response to tactile sensory stimulation in Fmr1(-/y) mice. This correlated with neuronal and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major aspects of neuronal computation, from the integration of synaptic input to the generation of action potential output. Using dendritic electrophysiological recordings, calcium imaging, pharmacology, biochemistry and a computer model, we found that this defect was, at least in part, attributable to the reduction and dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BKCa channels. Our results provide strong evidence pointing to the utility of BKCa channel openers for the treatment of the sensory hypersensitivity aspects of FXS.

The output of cortical columns is routed to different downstream targets via distinct pathways: cortico-cortical and cortico-subcortical. It is as yet unclear what roles these pathways play in perception, and which cellular and circuit mechanisms regulate their gating. We recently showed that activation of the apical dendrites of layer 5 (L5) pyramidal neurons correlates with the threshold for perception, but these neurons come in two classes that target either other cortical or subcortical areas. In the present study, we took advantage of transgenic mouse lines for these L5 subclasses to determine their relative contributions to the perceptual process. We found that the activation of apical dendrites in neurons of the somatosensory cortex, which project to subcortical regions, almost exclusively determined the detection of tactile stimuli in mice. Our results suggest that dendritic activation drives context-dependent interactions between cortex and subcortical regions, including the higher-order thalamus, superior colliculus and striatum, which are crucial for perception.The authors showed that the ‘moment of perception’ is causally related to dendritic activity in subcortically projecting layer 5 pyramidal neurons that project to the higher-order thalamus, superior colliculus and striatum.

Imaging neuronal networks provides a foundation for understanding the nervous system, but resolving dense nanometer-scale structures over large volumes remains challenging for light microscopy (LM) and electron microscopy (EM). Here we show that X-ray holographic nano-tomography (XNH) can image millimeter-scale volumes with sub-100-nm resolution, enabling reconstruction of dense wiring in Drosophila melanogaster and mouse nervous tissue. We performed correlative XNH and EM to reconstruct hundreds of cortical pyramidal cells and show that more superficial cells receive stronger synaptic inhibition on their apical dendrites. By combining multiple XNH scans, we imaged an adult Drosophila leg with sufficient resolution to comprehensively catalog mechanosensory neurons and trace individual motor axons from muscles to the central nervous system. To accelerate neuronal reconstructions, we trained a convolutional neural network to automatically segment neurons from XNH volumes. Thus, XNH bridges a key gap between LM and EM, providing a new avenue for neural circuit discovery.Kuan, Phelps, et al. used synchrotron X-ray imaging and deep learning to map dense neuronal wiring in fly and mouse tissue, enabling examination of individual cells and connectivity in circuits governing motor control and perceptual decision-making.

Dendrites have always fascinated researchers: from the artistic drawings by Ramon y Cajal to the beautiful recordings of today, neuroscientists have been striving to unravel the mysteries of these structures. Theoretical work in the 1960s predicted important dendritic effects on neuronal processing, establishing computational modelling as a powerful technique for their investigation. Since then, modelling of dendrites has been instrumental in driving neuroscience research in a targeted manner, providing experimentally testable predictions that range from the subcellular level to the systems level, and their relevance extends to fields beyond neuroscience, such as machine learning and artificial intelligence. Validation of modelling predictions often requires — and drives — new technological advances, thus closing the loop with theory-driven experimentation that moves the field forward. This Review features the most important, to our understanding, contributions of modelling of dendritic computations, including those pending experimental verification, and highlights studies of successful interactions between the modelling and experimental neuroscience communities.Models of dendrites have been instrumental in our understanding of their functions. Poirazi and Papoutsi review the major contributions of dendritic models, including those already proved or waiting to be experimentally verified, and highlight successful interactions between the modelling and experimental neuroscience communities.