Dendritic integration of sensory and reward information facilitates learning

Learning goal-directed behaviours requires integration of separate information streams representing context, relevant stimuli and reward. Dendrites of pyramidal neurons are suitable sites for such integration, but it remains elusive how their responses adapt when an animal learns a new task. Here, we identify two distinct classes of dendritic responses that represent either contextual/sensory information or reward information and that differ in their task- and learning-related dynamics. Using longitudinal calcium imaging of apical dendritic tufts of L5 pyramidal neurons in mouse barrel cortex, we tracked dendritic activity across learning and analyzed both local dendritic branch signals and global apical tuft activity. During texture discrimination learning, sensory representations (including contextual and touch information) strengthened and converged on the reward-predicting tactile stimulus when mice became experts. In contrast, reward-associated responses were particularly strong in the naive condition and became less pronounced upon learning. When we blocked the representation of unexpected reward in naive animals with optogenetic inhibition, animals failed to learn until we released the block and learning proceeded normally. Our results suggest that reward signals in dendrites are essential for adjusting neuronal integration of converging inputs to facilitate adaptive behaviour.

Input to layer 1 of somatosensory cortex: Local input outweighs long-range and can modulate the activity of layer 1 interneurons

Neocortical layer (L) 1 is a locus for interactions between long-range inputs, L1 interneurons and apical tuft dendrites of pyramidal neurons. Even though we have a wealth of information about L1, the level and effect of local input to this layer have not been quantified. Here we characterized the input to L1 of mouse somatosensory cortex with fast blue, monosynaptic rabies and optogenetics. Our work shows that most of the input to L1 is local, and that both local and long-range inputs to this layer arise predominantly from L2/3 and L5 neurons. Subtypes of L5 and L6b neurons project to the overlying L1 with different probabilities. VIP and SST interneurons in L2/3 and L5 also innervate L1. A subset of local L5, the intratelencephalic, pyramidal neurons, drive L1 interneurons but have no effect on L5 apical tuft dendrites. Monosynaptic rabies-based retrograde labelling reveals presynaptic boutons covering the entire somato-dendritic axis of pyramidal neurons, including in L1. When fast blue application was combined with rabies virus, we found that only a fraction of local and long-range neurons was both presynaptic to L5 neurons and projected to L1. These results demonstrate that L1 receives a large proportion of its input from local neurons, and that some of these inputs specifically target interneurons. We conclude that L1 is not just a site for interaction between long-range feedback and apical tuft dendrites of pyramidal cells, it is also a site for complex modulation of pyramidal neurons and interneurons by local inputs.

Learning enhances behaviorally relevant representations in apical dendrites

Learning alters cortical representations and improves perception. Apical tuft dendrites in Layer 1, which are unique in their connectivity and biophysical properties, may be a key site of learning-induced plasticity. We used both two-photon and SCAPE microscopy to longitudinally track tuft-wide calcium spikes in apical dendrites of Layer 5 pyramidal neurons as mice learned a tactile behavior. Mice were trained to discriminate two orthogonal directions of whisker stimulation. Reinforcement learning, but not repeated stimulus exposure, enhanced tuft selectivity for both directions equally, even though only one was associated with reward. Selective tufts emerged from initially unresponsive or low-selectivity populations. Animal movement and choice did not account for changes in stimulus selectivity. Enhanced selectivity persisted even after rewards were removed and animals ceased performing the task. We conclude that learning produces long-lasting realignment of apical dendrite tuft responses to behaviorally relevant dimensions of a task.

Burst control: Synaptic conditions for burst generation in cortical layer 5 pyramidal neurons

The output of neocortical layer 5 pyramidal cells (L5PCs) is expressed by a train of single spikes with intermittent bursts of multiple spikes at high frequencies. The bursts are the result of nonlinear dendritic properties, including Na+, Ca2+, and NMDA spikes, that interact with the ~10,000 synapses impinging on the neuron’s dendrites. Output spike bursts are thought to implement key dendritic computations, such as coincidence detection of bottom-up inputs (arriving mostly at the basal tree) and top-down inputs (arriving mostly at the apical tree). In this study we used a detailed nonlinear model of L5PC receiving excitatory and inhibitory synaptic inputs to explore the conditions for generating bursts and for modulating their properties. We established the excitatory input conditions on the basal versus the apical tree that favor burst and show that there are two distinct types of bursts. Bursts consisting of 3 or more spikes firing at < 200 Hz, which are generated by stronger excitatory input to the basal versus the apical tree, and bursts of ~2-spikes at ~250 Hz, generated by prominent apical tuft excitation. Localized and well-timed dendritic inhibition on the apical tree differentially modulates Na+, Ca2+, and NMDA spikes and, consequently, finely controls the burst output. Finally, we explored the implications of different burst classes and respective dendritic inhibition for regulating synaptic plasticity.

Early embryogenesis and organogenesis in the annelid Owenia fusiformis

Background Annelids are a diverse group of segmented worms within Spiralia, whose embryos exhibit spiral cleavage and a variety of larval forms. While most modern embryological studies focus on species with unequal spiral cleavage nested in Pleistoannelida (Sedentaria + Errantia), a few recent studies looked into Owenia fusiformis, a member of the sister group to all remaining annelids and thus a key lineage to understand annelid and spiralian evolution and development. However, the timing of early cleavage and detailed morphogenetic events leading to the formation of the idiosyncratic mitraria larva of O. fusiformis remain largely unexplored. Results Owenia fusiformis undergoes equal spiral cleavage where the first quartet of animal micromeres are slightly larger than the vegetal macromeres. Cleavage results in a coeloblastula approximately 5 h post-fertilization (hpf) at 19 °C. Gastrulation occurs via invagination and completes 4 h later, with putative mesodermal precursors and the chaetoblasts appearing 10 hpf at the dorso-posterior side. Soon after, at 11 hpf, the apical tuft emerges, followed by the first neurons (as revealed by the expression of elav1 and synaptotagmin-1) in the apical organ and the prototroch by 13 hpf. Muscles connecting the chaetal sac to various larval tissues develop around 18 hpf and by the time the mitraria is fully formed at 22 hpf, there are FMRFamide+ neurons in the apical organ and prototroch, the latter forming a prototrochal ring. As the mitraria feeds, it grows in size and the prototroch expands through active proliferation. The larva becomes competent after ~ 3 weeks post-fertilization at 15 °C, when a conspicuous juvenile rudiment has formed ventrally. Conclusions Owenia fusiformis embryogenesis is similar to that of other equal spiral cleaving annelids, supporting that equal cleavage is associated with the formation of a coeloblastula, gastrulation via invagination, and a feeding trochophore-like larva in Annelida. The nervous system of the mitraria larva forms earlier and is more elaborated than previously recognized and develops from anterior to posterior, which is likely an ancestral condition to Annelida. Altogether, our study identifies the major developmental events during O. fusiformis ontogeny, defining a conceptual framework for future investigations.

Early Embryogenesis and Organogenesis in the Annelid Owenia Fusiformis

Background : Annelids are a diverse group of segmented worms within Spiralia, whose embryos exhibit spiral cleavage and a variety of larval forms. While most modern embryological studies focus on species with unequal spiral cleavage nested in Pleistoannelida (Sedentaria + Errantia), a few recent studies looked into Owenia fusiformis , a member of the sister group to all remaining annelids and thus a key lineage to understand annelid and spiralian evolution and development. However, the timing of early cleavage and detailed morphogenetic events leading to the formation of the idiosyncratic mitraria larva of O. fusiformis remain largely unexplored.Results : O. fusiformis undergoes equal spiral cleavage where the first quartet of animal micromeres are slightly larger than the vegetal macromeres. Cleavage results in a coeloblastula approximately five hours post fertilization (hpf) at 19 ºC. Gastrulation occurs via invagination and completes four hours later, with putative mesodermal precursors and the chaetoblasts appearing 10 hpf at the dorsoposterior side. Soon after, at 11 hpf, the apical tuft emerges, followed by the first neurons (as revealed by the expression of elav1 and synaptotagmin1 ) in the apical organ and the prototroch by 13 hpf. Muscles connecting the chaetal sac to various larval tissues develop around 18 hpf and by the time the mitraria is fully formed at 22 hpf, there are FMRFamide + neurons in the apical organ and prototroch, the latter forming a prototrochal ring. As the mitraria feeds, it grows in size and the prototroch expands through active proliferation. The larva becomes competent after ~3 weeks post fertilization at 15 ºC, when a conspicuous juvenile rudiment has formed ventrally.Conclusions : O. fusiformis embryogenesis is similar to that of other equal spiral cleaving annelids, supporting that equal cleavage is associated with the formation of a coeloblastula, gastrulation via invagination, and a feeding trochophore-like larva in Annelida. The nervous system of the mitraria larva forms earlier and is more complex than previously recognized and develops from anterior to posterior, which is likely an ancestral condition to Annelida. Altogether, our study identifies the major developmental events during O. fusiformis ontogeny, defining a conceptual framework for future investigations.

Early embryogenesis and organogenesis in the annelid Owenia fusiformis

BackgroundAnnelids are a diverse group of segmented worms within Spiralia, whose embryos exhibit spiral cleavage and a variety of larval forms. While most modern embryological studies focus on species with unequal spiral cleavage nested in Pleistoannelida (Sedentaria + Errantia), a few recent studies looked into Owenia fusiformis, a member of the sister group to all remaining annelids and thus a key lineage to understand annelid and spiralian evolution and development. However, the timing of early cleavage and detailed morphogenetic events leading to the formation of the idiosyncratic mitraria larva of O. fusiformis remain largely unexplored.ResultsO. fusiformis undergoes equal spiral cleavage where the first quartet of animal micromeres are slightly larger than the vegetal macromeres. Cleavage results in a coeloblastula approximately five hours post fertilization (hpf) at 19 °C. Gastrulation occurs via invagination and completes four hours later, with putative mesodermal precursors and the chaetoblasts appearing 10 hpf at the dorsoposterior side. Soon after, at 11 hpf, the apical tuft emerges, followed by the first neurons (as revealed by the expression of elav1 and synaptotagmin1) in the apical organ and the prototroch by 13 hpf. Muscles connecting the chaetal sac to various larval tissues develop around 18 hpf and by the time the mitraria is fully formed at 22 hpf, there are FMRFamide+ neurons in the apical organ and prototroch, the latter forming a prototrochal ring. As the mitraria feeds, it grows in size and the prototroch expands through active proliferation. The larva becomes competent after ∼3 weeks post fertilization at 15 °C, when a conspicuous juvenile rudiment has formed ventrally.ConclusionsO. fusiformis embryogenesis is similar to that of other equal spiral cleaving annelids, supporting that equal cleavage is associated with the formation of a coeloblastula, gastrulation via invagination, and a feeding trochophore-like larva in Annelida. The nervous system of the mitraria larva forms earlier and is more complex than previously recognised and develops from anterior to posterior, which is likely an ancestral condition to Annelida. Altogether, our study identifies the major developmental events during O. fusiformis ontogeny, defining a conceptual framework for future investigations.

Burst Control

The output of neocortical layer 5 pyramidal cells (L5PCs) is expressed by a train of single spikes with intermittent bursts of multiple spikes at high frequencies. The bursts are the result of nonlinear dendritic properties, including Na+, Ca2+, and NMDA spikes, that interact with the ∼10,000 synapses impinging on the neuron’s dendrites. Output spike bursts are thought to implement key dendritic computations, such as coincidence detection of bottom-up inputs (arriving mostly at the basal tree) and top-down inputs (arriving mostly at the apical tree). In this study we used a detailed nonlinear model of L5PC receiving excitatory and inhibitory synaptic inputs to explore the conditions for generating bursts and for modulating their properties. We established the excitatory input conditions on the basal versus the apical tree that favor burst and show that there are two distinct types of bursts. Bursts consisting of 3 or more spikes firing at < 200 Hz, which are generated by stronger excitatory input to the basal versus the apical tree, and bursts of ∼2-spikes at ∼250 Hz, generated by prominent apical tuft excitation. Localized and well-timed dendritic inhibition on the apical tree differentially modulates Na+, Ca2+, and NMDA spikes and, consequently, finely controls the burst output. Finally, we explored the implications of different burst classes and respective dendritic inhibition for regulating synaptic plasticity.

High and asymmetric somato-dendritic coupling of V1 layer 5 neurons independent of visual stimulation and locomotion

Active dendrites impact sensory processing and behaviour. However, it remains unclear how active dendritic integration relates to somatic output in vivo. We imaged semi-simultaneously GCaMP6s signals in the soma, trunk and distal tuft dendrites of layer 5 pyramidal neurons in the awake mouse primary visual cortex. We found that apical tuft signals were dominated by widespread, highly correlated calcium transients throughout the tuft. While these signals were highly coupled to trunk and somatic transients, the frequency of calcium transients was found to decrease in a distance-dependent manner from soma to tuft. Ex vivo recordings suggest that low-frequency back-propagating action potentials underlie the distance-dependent loss of signals, while coupled somato-dendritic signals can be triggered by high-frequency somatic bursts or strong apical tuft depolarization. Visual stimulation and locomotion increased neuronal activity without affecting somato-dendritic coupling. High, asymmetric somato-dendritic coupling is therefore a widespread feature of layer 5 neurons activity in vivo.