Rapid synaptic plasticity contributes to a learned conjunctive code of position and choice-related information in the hippocampus.

To successfully perform goal-directed navigation, animals must know where they are and what they are doing-e.g., looking for water, bringing food back to the nest, or escaping from a predator. Hippocampal neurons code for these critical variables conjunctively, but little is known about how this "where/what" code is formed or flexibly routed to other brain regions. To address these questions, we performed intracellular whole-cell recordings in mouse CA1 during a cued, two-choice virtual navigation task. We demonstrate that plateau potentials in CA1 pyramidal neurons rapidly strengthen synaptic inputs carrying conjunctive information about position and choice. Plasticity-induced response fields were modulated by cues only in animals previously trained to collect rewards based on available cues. Thus, we reveal that gradual learning is required for the formation of a conjunctive population code, upstream of CA1, while plateau-potential-induced synaptic plasticity in CA1 enables flexible routing of the code to downstream brain regions.

Kilohertz two-photon fluorescence microscopy imaging of neural activity in vivo.

Understanding information processing in the brain requires monitoring neuronal activity at high spatiotemporal resolution. Using an ultrafast two-photon fluorescence microscope empowered by all-optical laser scanning, we imaged neuronal activity in vivo at up to 3,000 frames per second and submicrometer spatial resolution. This imaging method enabled monitoring of both supra- and subthreshold electrical activity down to 345 µm below the brain surface in head-fixed awake mice.

MeCP2 nuclear dynamics in live neurons results from low and high affinity chromatin interactions.

Methyl-CpG-binding-Protein 2 (MeCP2) is an abundant nuclear protein highly enriched in neurons. Here we report live-cell single-molecule imaging studies of the kinetic features of mouse MeCP2 at high spatial-temporal resolution. MeCP2 displays dynamic features that are distinct from both highly mobile transcription factors and immobile histones. Stable binding of MeCP2 in living neurons requires its methyl-binding domain and is sensitive to DNA modification levels. Diffusion of unbound MeCP2 is strongly constrained by weak, transient interactions mediated primarily by its AT-hook domains, and varies with the level of chromatin compaction and cell type. These findings extend previous studies of the role of the MeCP2 MBD in high affinity DNA binding to living neurons, and identify a new role for its AT-hooks domains as critical determinants of its kinetic behavior. They suggest that limited nuclear diffusion of MeCP2 in live neurons contributes to its local impact on chromatin structure and gene expression.

ShuTu: Open-Source Software for Efficient and Accurate Reconstruction of Dendritic Morphology.

Neurons perform computations by integrating inputs from thousands of synapses-mostly in the dendritic tree-to drive action potential firing in the axon. One fruitful approach to studying this process is to record from neurons using patch-clamp electrodes, fill the recorded neurons with a substance that allows subsequent staining, reconstruct the three-dimensional architectures of the dendrites, and use the resulting functional and structural data to develop computer models of dendritic integration. Accurately producing quantitative reconstructions of dendrites is typically a tedious process taking many hours of manual inspection and measurement. Here we present ShuTu, a new software package that facilitates accurate and efficient reconstruction of dendrites imaged using bright-field microscopy. The program operates in two steps: (1) automated identification of dendritic processes, and (2) manual correction of errors in the automated reconstruction. This approach allows neurons with complex dendritic morphologies to be reconstructed rapidly and efficiently, thus facilitating the use of computer models to study dendritic structure-function relationships and the computations performed by single neurons.

Persistent Sodium Current Mediates the Steep Voltage Dependence of Spatial Coding in Hippocampal Pyramidal Neurons.

The mammalian hippocampus forms a cognitive map using neurons that fire according to an animal's position ("place cells") and many other behavioral and cognitive variables. The responses of these neurons are shaped by their presynaptic inputs and the nature of their postsynaptic integration. In CA1 pyramidal neurons, spatial responses in vivo exhibit a strikingly supralinear dependence on baseline membrane potential. The biophysical mechanisms underlying this nonlinear cellular computation are unknown. Here, through a combination of in vitro, in vivo, and in silico approaches, we show that persistent sodium current mediates the strong membrane potential dependence of place cell activity. This current operates at membrane potentials below the action potential threshold and over seconds-long timescales, mediating a powerful and rapidly reversible amplification of synaptic responses, which drives place cell firing. Thus, we identify a biophysical mechanism that shapes the coding properties of neurons composing the hippocampal cognitive map.

Dendritic sodium spikes are required for long-term potentiation at distal synapses on hippocampal pyramidal neurons.

Dendritic integration of synaptic inputs mediates rapid neural computation as well as longer-lasting plasticity. Several channel types can mediate dendritically initiated spikes (dSpikes), which may impact information processing and storage across multiple timescales; however, the roles of different channels in the rapid vs long-term effects of dSpikes are unknown. We show here that dSpikes mediated by Nav channels (blocked by a low concentration of TTX) are required for long-term potentiation (LTP) in the distal apical dendrites of hippocampal pyramidal neurons. Furthermore, imaging, simulations, and buffering experiments all support a model whereby fast Nav channel-mediated dSpikes (Na-dSpikes) contribute to LTP induction by promoting large, transient, localized increases in intracellular calcium concentration near the calcium-conducting pores of NMDAR and L-type Cav channels. Thus, in addition to contributing to rapid neural processing, Na-dSpikes are likely to contribute to memory formation via their role in long-lasting synaptic plasticity.

A requirement of low-threshold calcium spike for induction of spike-timing-dependent plasticity at corticothalamic synapses on relay neurons in the ventrobasal nucleus of rat thalamus.

Relay neurons in sensory thalamus transmit somatosensory information to cerebral cortex and receive sensory and feedback corticothalamic (CT) synaptic inputs. Their duality of firing modes, in bursts and continuous, underlies state dependence of thalamic information transfer, but the impact of different firing patterns on synaptic plasticity was rarely explored. To address this issue, we made whole-cell recording from relay neurons in the ventrobasal nucleus (VBN) of rat thalamus and compared synaptic plasticity induced by pairing CT-EPSP with two different types of burst spiking: low-threshold spike (LTS)-burst spiking triggered at Vm~-70 mV, and high-frequency spiking induced at Vm~-55 mV. The latter mimics natural burst spiking of relay neurons without activation of LTS. We found that, while backpropagating APs alone were not sufficient, low-threshold calcium spike was required for the induction of spike-timing-dependent LTP at CT synapses. Our results reveal a novel role of the calcium spike plays in the induction of long-term plasticity of CT synapse. Considering the dendritic origin of LTS, this study also implies potential physiological regulations over synaptic plasticity in thalamus. We propose that this form of synaptic plasticity may be involved in the dynamic fine-tuning of thalamocortical information relay.

Comparison of synaptic transmission and plasticity between sensory and cortical synapses on relay neurons in the ventrobasal nucleus of the rat thalamus.

Relay neurons in the ventrobasal nucleus of the thalamus transmit somatosensory information to the cerebral cortex and receive sensory and cortical (feedback) synaptic inputs via, respectively, medial lemniscal (ML) and corticothalamic (CT) fibres. Here, we report that calcium-permeable AMPA receptors are expressed at CT synapses, but not ML synapses, and that the NMDA receptor (NMDAR)-mediated/non-NMDAR-mediated synaptic current ratio is significantly larger at CT synapses than at ML synapses. Moreover, NMDAR-dependent LTP and L-type voltage-gated calcium channel-dependent LTD are readily induced at CT synapses, but not ML synapses. In particular, LTD of CT synaptic transmission is induced by spiking of postsynaptic relay neurons in continuous mode, but not burst mode, in current-clamp recordings. These results show that the strength of the cortical input to thalamic relay neurons is selectively subjected to use-dependent modification, which could be a mechanism for regulation of thalamocortical-corticothalamic interactions and the underlying sensory processing.

Herpes-like virus infection causing mortality of cultured abalone Haliotis diversicolor supertexta in Taiwan.

A herpes-like virus is demonstrated for the first time to be associated with high mortality rates in maricultured abalone Haliotis diversicolor supertexta in Taiwan. Histopathology of moribund abalone indicated that the nerve system was the primary target tissue. The lesions were characterised by tissue necrosis accompanied with infiltration of haemocytes. Electron microscopic examination demonstrated viral particles within the degenerated cerebral ganglion cells. The viruses were hexagonal, approximately 100 nm in diameter and had a single coat. Some viral particles contained a dense nucleoid, while others were empty. The ultrastructure and morphogenesis of the virus particles were consistent with those of the herpesvirus described from the oyster Crassostrea virginica. Experimental infection using supernatant collected from minced visceral organs and muscle of moribund abalone induced 100 % mortality through both intramuscular injection and bath treatments.