The shapes of dendritic arbors are fascinating and important, yet the principles underlying these complex and diverse structures remain unclear. Here, we analyzed basal dendritic arbors of 2,171 pyramidal neurons sampled from mammalian brains and discovered 3 statistical properties: the dendritic arbor size scales with the total dendritic length, the spatial correlation of dendritic branches within an arbor has a universal functional form, and small parts of an arbor are self-similar. We proposed that these properties result from maximizing the repertoire of possible connectivity patterns between dendrites and surrounding axons while keeping the cost of dendrites low. We solved this optimization problem by drawing an analogy with maximization of the entropy for a given energy in statistical physics. The solution is consistent with the above observations and predicts scaling relations that can be tested experimentally. In addition, our theory explains why dendritic branches of pyramidal cells are distributed more sparsely than those of Purkinje cells. Our results represent a step toward a unifying view of the relationship between neuronal morphology and function.

The distinct electrical properties of axonal and dendritic membranes are largely a result of specific transport of vesicle-bound membrane proteins to each compartment. How this specificity arises is unclear because kinesin motors that transport vesicles cannot autonomously distinguish dendritically projecting microtubules from those projecting axonally. We hypothesized that interaction with a second motor might enable vesicles containing dendritic proteins to preferentially associate with dendritically projecting microtubules and avoid those that project to the axon. Here we show that in rat cortical neurons, localization of several distinct transmembrane proteins to dendrites is dependent on specific myosin motors and an intact actin network. Moreover, fusion with a myosin-binding domain from Melanophilin targeted Channelrhodopsin-2 specifically to the somatodendritic compartment of neurons in mice in vivo. Together, our results suggest that dendritic transmembrane proteins direct the vesicles in which they are transported to avoid the axonal compartment through interaction with myosin motors.

Real-time lineage tracing in flies gets a boost with three techniques to specifically label a progenitor’s daughter cells.

Nuclear receptors (NRs) comprise a family of ligand-regulated transcription factors that control diverse critical biological processes including various aspects of brain development. Eighteen NR genes exist in the Drosophila genome. To explore their roles in brain development, we knocked down individual NRs through the development of the mushroom bodies (MBs) by targeted RNAi. Besides recapitulating the known MB phenotypes for three NRs, we found that unfulfilled (unf), an ortholog of human photoreceptor specific nuclear receptor (PNR), regulates axonal morphogenesis and neuronal subtype identity. The adult MBs develop through remodeling of gamma neurons plus de-novo elaboration of both alpha’/beta’ and alpha/beta neurons. Notably, unf is largely dispensable for the initial elaboration of gamma neurons, but plays an essential role in their re-extension of axons after pruning during early metamorphosis. The subsequently derived MB neuron types also require unf for extension of axons beyond the terminus of the pruned bundle. Tracing single axons revealed misrouting rather than simple truncation. Further, silencing unf in single-cell clones elicited misguidance of axons in otherwise unperturbed MBs. Such axon guidance defects may occur as MB neurons partially lose their subtype identity, as evidenced by suppression of various MB subtype markers in unf knockdown MBs. In sum, unf governs axonal morphogenesis of multiple MB neuron types, possibly through regulating neuronal subtype identity.

Input comparison is thought to occur in many neuronal circuits, including the hippocampus, where functionally important interactions between the Schaffer collateral and perforant pathways have been hypothesized. We investigated this idea using multisite, whole-cell recordings and Ca2+ imaging and found that properly timed, repetitive stimulation of both pathways results in the generation of large plateau potentials in distal dendrites of CA1 pyramidal neurons. These dendritic plateau potentials produce widespread Ca2+ influx, large after-depolarizations, burst firing output, and long-term potentiation of perforant path synapses. Plateau duration is directly related to the strength and temporal overlap of pathway activation and involves back-propagating action potentials and both NMDA receptors and voltage-gated Ca2+ channels. Thus, the occurrence of highly correlated SC and PP input to CA1 is signaled by a dramatic change in output mode and an increase in input efficacy, all induced by a large plateau potential in the distal dendrites of CA1 pyramidal neurons.

Subiculum, the primary efferent pathway of hippocampus, participates in memory for spatial tasks, relapse to drug abuse, and temporal lobe seizures. Subicular pyramidal neurons exhibit low-threshold burst firing driven by a spike afterdepolarization. Here we report that burst firing can be regulated by stimulation of afferent projections to subiculum. Unlike synaptic plasticity, burst plasticity did not require synaptic depolarization, activation of AMPA or NMDA receptors, or action potential firing. Rather, enhancement of burst firing required synergistic activation of group I, subtype 1 metabotropic glutamate receptors (mGluRs) and muscarinic acetylcholine receptors (mAChR). When either of these receptors was blocked, a suppression of bursting was revealed, which in turn was blocked by antagonists of group I, subtype 5 mGluRs. These results indicate that the output of subiculum can be strongly and bidirectionally regulated by activation of glutamatergic inputs within the hippocampus and cholinergic afferents from the medial septum.

Spine growth and retraction with synapse formation and elimination plays an important role in shaping brain circuits during development and in the adult brain, yet the temporal relationship between spine morphogenesis and the formation of functional synapses remains poorly defined. We imaged hippocampal pyramidal neurons to identify spines of different ages. We then used two-photon glutamate uncaging, whole-cell recording, and Ca(2+) imaging to analyze the properties of nascent spines and their older neighbors. New spines expressed glutamate-sensitive currents that were indistinguishable from mature spines of comparable volumes. Some spines exhibited negligible AMPA receptor-mediated responses, but the occurrence of these "silent" spines was uncorrelated with spine age. In contrast, NMDA receptor-mediated Ca(2+) accumulations were significantly lower in new spines. New spines reconstructed using electron microscopy made synapses. Our data support a model in which outgrowth and enlargement of nascent spines is tightly coupled to formation and maturation of glutamatergic synapses.

One of the central problems in neuroscience is reconstructing synaptic connectivity in neural circuits. Synapses onto a neuron can be probed by sequentially stimulating potentially pre-synaptic neurons while monitoring the membrane voltage of the post-synaptic neuron. Reconstructing a large neural circuit using such a "brute force" approach is rather time-consuming and inefficient because the connectivity in neural circuits is sparse. Instead, we propose to measure a post-synaptic neuron's voltage while stimulating sequentially random subsets of multiple potentially pre-synaptic neurons. To reconstruct these synaptic connections from the recorded voltage we apply a decoding algorithm recently developed for compressive sensing. Compared to the brute force approach, our method promises significant time savings that grow with the size of the circuit. We use computer simulations to find optimal stimulation parameters and explore the feasibility of our reconstruction method under realistic experimental conditions including noise and non-linear synaptic integration. Multineuronal stimulation allows reconstructing synaptic connectivity just from the spiking activity of post-synaptic neurons, even when sub-threshold voltage is unavailable. By using calcium indicators, voltage-sensitive dyes, or multi-electrode arrays one could monitor activity of multiple postsynaptic neurons simultaneously, thus mapping their synaptic inputs in parallel, potentially reconstructing a complete neural circuit.

Behaviour is governed by activity in highly structured neural circuits. Genetically targeted sensors and switches facilitate measurement and manipulation of activity in vivo, linking activity in defined nodes of neural circuits to behaviour. Because of access to specific cell types, these molecular tools will have the largest impact in genetic model systems such as the mouse. Emerging assays of mouse behaviour are beginning to rival those of behaving monkeys in terms of stimulus and behavioural control. We predict that the confluence of new behavioural and molecular tools in the mouse will reveal the logic of complex mammalian circuits.