Latest Articles Include:
- Pericytes: Blood-Brain Barrier Safeguards against Neurodegeneration?
- Neuron (Cambridge Mass ) 68(3):321-323 (2010)
The role of pericytes in the control of blood-brain barrier (BBB) integrity has remained enigmatic. In this issue, Bell et al. and two concurrent studies highlight that pericyte loss causes BBB breakdown and hypoperfusion. Remarkably, these vascular changes precede neurodegeneration and cognitive defects in old age.
- Vesicle Priming in a SNAP
- Neuron (Cambridge Mass ) 68(3):324-326 (2010)
In this issue of Neuron, Burgalossi et al. investigate synaptic vesicle priming by using presynaptic Ca2+ uncaging at a small, glutamatergic, central synapse. Combining this technique with mouse genetics, the authors demonstrate that vesicle priming during ongoing neural activity can be limited by the recycling of recently used SNARE complexes.
- Homeostatic Plasticity: Single Hippocampal Neurons See the Light
- Neuron (Cambridge Mass ) 68(3):326-328 (2010)
Neurons adapt to altered network activity through homeostatic changes in synaptic function. In this issue of Neuron, Goold and Nicoll report that chronic hyperactivation of individual CA1 pyramidal neurons drives cell-autonomous, compensatory synapse elimination via CaMKIV-dependent transcription. These findings suggest that neurons gauge their intrinsic activity to instruct homeostatic regulation of synaptic inputs.
- Spike Timing Improves Olfactory Capabilities in Mammals
- Neuron (Cambridge Mass ) 68(3):329-331 (2010)
An issue that has puzzled neuroscientists for decades is what role, if any, temporal patterning of action potentials has in determining behavior. A study in this issue of Neuron by Cury and Uchida in the rat olfactory system provides evidence that such patterns could help mammals to identify and discriminate odors.
- What Body Parts Reveal about the Organization of the Brain
- Neuron (Cambridge Mass ) 68(3):331-333 (2010)
In this issue of Neuron, Orlov et al. show that the human occipitotemporal cortex contains regions responding preferentially to body part categories, such as upper limbs (hand, elbow), torsos, or lower faces (mouth, chin). This organization may reflect differences in the connectivity of these regions with other brain regions, to support the efficient processing of the different types of information different body parts provide.
- An Itch To Be Scratched
- Neuron (Cambridge Mass ) 68(3):334-339 (2010)
The description of itch (formally known as pruritus) as an "unpleasant sensation that elicits the desire or reflex to scratch" (Ikoma et al., 2006) is immediately familiar. Research in the field of pruritoception has added to our understanding of this area of sensory neurobiology as it pertains to both normal and pathological conditions. In particular, much progress has been made on the mechanisms and circuits of itch, which we review here.
- Small G Protein Signaling in Neuronal Plasticity and Memory Formation: The Specific Role of Ras Family Proteins
- Neuron (Cambridge Mass ) 68(3):340-361 (2010)
Small G proteins are an extensive family of proteins that bind and hydrolyze GTP. They are ubiquitous inside cells, regulating a wide range of cellular processes. Recently, many studies have examined the role of small G proteins, particularly the Ras family of G proteins, in memory formation. Once thought to be primarily involved in the transduction of a variety of extracellular signals during development, it is now clear that Ras family proteins also play critical roles in molecular processing underlying neuronal and behavioral plasticity. We here review a number of recent studies that explore how the signaling of Ras family proteins contributes to memory formation. Understanding these signaling processes is of fundamental importance both from a basic scientific perspective, with the goal of providing mechanistic insights into a critical aspect of cognitive behavior, and from a clinical perspective, with the goal of providing effective therapies for a range of disorde! rs involving cognitive impairments.
- Neural Syntax: Cell Assemblies, Synapsembles, and Readers
- Neuron (Cambridge Mass ) 68(3):362-385 (2010)
A widely discussed hypothesis in neuroscience is that transiently active ensembles of neurons, known as "cell assemblies," underlie numerous operations of the brain, from encoding memories to reasoning. However, the mechanisms responsible for the formation and disbanding of cell assemblies and temporal evolution of cell assembly sequences are not well understood. I introduce and review three interconnected topics, which could facilitate progress in defining cell assemblies, identifying their neuronal organization, and revealing causal relationships between assembly organization and behavior. First, I hypothesize that cell assemblies are best understood in light of their output product, as detected by "reader-actuator" mechanisms. Second, I suggest that the hierarchical organization of cell assemblies may be regarded as a neural syntax. Third, constituents of the neural syntax are linked together by dynamically changing constellations of synaptic weights ("syn! apsembles"). The existing support for this tripartite framework is reviewed and strategies for experimental testing of its predictions are discussed.
- Cortical Preparatory Activity: Representation of Movement or First Cog in a Dynamical Machine?
- Neuron (Cambridge Mass ) 68(3):387-400 (2010)
The motor cortices are active during both movement and movement preparation. A common assumption is that preparatory activity constitutes a subthreshold form of movement activity: a neuron active during rightward movements becomes modestly active during preparation of a rightward movement. We asked whether this pattern of activity is, in fact, observed. We found that it was not: at the level of a single neuron, preparatory tuning was weakly correlated with movement-period tuning. Yet, somewhat paradoxically, preparatory tuning could be captured by a preferred direction in an abstract "space" that described the population-level pattern of movement activity. In fact, this relationship accounted for preparatory responses better than did traditional tuning models. These results are expected if preparatory activity provides the initial state of a dynamical system whose evolution produces movement activity. Our results thus suggest that preparatory activity may not repre! sent specific factors, and may instead play a more mechanistic role.
- Dynamic Neuroplasticity after Human Prefrontal Cortex Damage
- Neuron (Cambridge Mass ) 68(3):401-408 (2010)
Memory and attention deficits are common after prefrontal cortex (PFC) damage, yet people generally recover some function over time. Recovery is thought to be dependent upon undamaged brain regions, but the temporal dynamics underlying cognitive recovery are poorly understood. Here, we provide evidence that the intact PFC compensates for damage in the lesioned PFC on a trial-by-trial basis dependent on cognitive load. The extent of this rapid functional compensation is indexed by transient increases in electrophysiological measures of attention and memory in the intact PFC, detectable within a second after stimulus presentation and only when the lesioned hemisphere is challenged. These observations provide evidence supporting a dynamic and flexible model of compensatory neural plasticity.
- Pericytes Control Key Neurovascular Functions and Neuronal Phenotype in the Adult Brain and during Brain Aging
- Neuron (Cambridge Mass ) 68(3):409-427 (2010)
- Transsynaptic Progression of Amyloid-β-Induced Neuronal Dysfunction within the Entorhinal-Hippocampal Network
- Neuron (Cambridge Mass ) 68(3):428-441 (2010)
The entorhinal cortex (EC) is one of the earliest affected, most vulnerable brain regions in Alzheimer's disease (AD), which is associated with amyloid-β (Aβ) accumulation in many brain areas. Selective overexpression of mutant amyloid precursor protein (APP) predominantly in layer II/III neurons of the EC caused cognitive and behavioral abnormalities characteristic of mouse models with widespread neuronal APP overexpression, including hyperactivity, disinhibition, and spatial learning and memory deficits. APP/Aβ overexpression in the EC elicited abnormalities in synaptic functions and activity-related molecules in the dentate gyrus and CA1 and epileptiform activity in parietal cortex. Soluble Aβ was observed in the dentate gyrus, and Aβ deposits in the hippocampus were localized to perforant pathway terminal fields. Thus, APP/Aβ expression in EC neurons causes transsynaptic deficits that could initiate the cortical-hippocampal network dysfunction in mouse models! and human patients with AD.
- Visual Activity Regulates Neural Progenitor Cells in Developing Xenopus CNS through Musashi1
- Neuron (Cambridge Mass ) 68(3):442-455 (2010)
Regulation of progenitor cell fate determines the numbers of neurons in the developing brain. While proliferation of neural progenitors predominates during early central nervous system (CNS) development, progenitor cell fate shifts toward differentiation as CNS circuits develop, suggesting that signals from developing circuits may regulate proliferation and differentiation. We tested whether activity regulates neurogenesis in vivo in the developing visual system of Xenopus tadpoles. Both cell proliferation and the number of musashi1-immunoreactive progenitors in the optic tectum decrease as visual system connections become stronger. Visual deprivation for 2 days increased proliferation of musashi1-immunoreactive radial glial progenitors, while visual experience increased neuronal differentiation. Morpholino-mediated knockdown and overexpression of musashi1 indicate that musashi1 is necessary and sufficient for neural progenitor proliferation in the CNS. These data demo! nstrate a mechanism by which increased brain activity in developing circuits decreases cell proliferation and increases neuronal differentiation through the downregulation of musashi1 in response to circuit activity.
- Monosynaptic Rabies Virus Reveals Premotor Network Organization and Synaptic Specificity of Cholinergic Partition Cells
- Neuron (Cambridge Mass ) 68(3):456-472 (2010)
Movement is the behavioral output of neuronal activity in the spinal cord. Motor neurons are grouped into motor neuron pools, the functional units innervating individual muscles. Here we establish an anatomical rabies virus-based connectivity assay in early postnatal mice. We employ it to study the connectivity scheme of premotor neurons, the neuronal cohorts monosynaptically connected to motor neurons, unveiling three aspects of organization. First, motor neuron pools are connected to segmentally widely distributed yet stereotypic interneuron populations, differing for pools innervating functionally distinct muscles. Second, depending on subpopulation identity, interneurons take on local or segmentally distributed positions. Third, cholinergic partition cells involved in the regulation of motor neuron excitability segregate into ipsilaterally and bilaterally projecting populations, the latter exhibiting preferential connections to functionally equivalent motor neuron ! pools bilaterally. Our study visualizes the widespread yet precise nature of the connectivity matrix for premotor interneurons and reveals exquisite synaptic specificity for bilaterally projecting cholinergic partition cells.
- SNARE Protein Recycling by αSNAP and βSNAP Supports Synaptic Vesicle Priming
- Neuron (Cambridge Mass ) 68(3):473-487 (2010)
Neurotransmitter release proceeds by Ca2+-triggered, SNARE-complex-dependent synaptic vesicle fusion. After fusion, the ATPase NSF and its cofactors α- and βSNAP disassemble SNARE complexes, thereby recycling individual SNAREs for subsequent fusion reactions. We examined the effects of genetic perturbation of α- and βSNAP expression on synaptic vesicle exocytosis, employing a new Ca2+ uncaging protocol to study synaptic vesicle trafficking, priming, and fusion in small glutamatergic synapses of hippocampal neurons. By characterizing this protocol, we show that synchronous and asynchronous transmitter release involve different Ca2+ sensors and are not caused by distinct releasable vesicle pools, and that tonic transmitter release is due to ongoing priming and fusion of new synaptic vesicles during high synaptic activity. Our analysis of α- and βSNAP deletion mutant neurons shows that the two NSF cofactors support synaptic vesicle priming by determining the availab! ility of free SNARE components, particularly during phases of high synaptic activity.
- Extracellular Calcium Controls Background Current and Neuronal Excitability via an UNC79-UNC80-NALCN Cation Channel Complex
- Neuron (Cambridge Mass ) 68(3):488-499 (2010)
In contrast to its extensively studied intracellular roles, the molecular mechanisms by which extracellular Ca2+ regulates the basal excitability of neurons are unclear. One mechanism is believed to be through Ca2+'s interaction with the negative charges on the cell membrane (the charge screening effect). Here we show that, in cultured hippocampal neurons, lowering [Ca2+]e activates a NALCN channel-dependent Na+-leak current (IL-Na). The coupling between [Ca2+]e and NALCN requires a Ca2+-sensing G protein-coupled receptor, an activation of G-proteins, an UNC80 protein that bridges NALCN to a large novel protein UNC79 in the same complex, and the last amino acid of NALCN's intracellular tail. In neurons from nalcn and unc79 knockout mice, IL-Na is insensitive to changes in [Ca2+]e, and reducing [Ca2+]e fails to elicit the excitatory effects seen in the wild-type. Therefore, extracellular Ca2+ influences neuronal excitability through the UNC79-UNC80-NALCN complex in a G ! protein-dependent fashion.
- Dopaminergic Modulation of Axon Initial Segment Calcium Channels Regulates Action Potential Initiation
- Neuron (Cambridge Mass ) 68(3):500-511 (2010)
Action potentials initiate in the axon initial segment (AIS), a specialized compartment enriched with Na+ and K+ channels. Recently, we found that T- and R-type Ca2+ channels are concentrated in the AIS, where they contribute to local subthreshold membrane depolarization and thereby influence action potential initiation. While periods of high-frequency activity can alter availability of AIS voltage-gated channels, mechanisms for long-term modulation of AIS channel function remain unknown. Here, we examined the regulatory pathways that control AIS Ca2+ channel activity in brainstem interneurons. T-type Ca2+ channels were downregulated by dopamine receptor activation acting via protein kinase C, which in turn reduced neuronal output. These effects occurred without altering AIS Na+ or somatodendritic T-type channel activity and could be mediated by endogenous dopamine sources present in the auditory brainstem. This pathway represents a new mechanism to inhibit neurons by ! specifically regulating Ca2+ channels directly involved in action potential initiation.
- Single-Cell Optogenetic Excitation Drives Homeostatic Synaptic Depression
- Neuron (Cambridge Mass ) 68(3):512-528 (2010)
Homeostatic processes have been proposed to explain the discrepancy between the dynamics of synaptic plasticity and the stability of brain function. Forms of synaptic plasticity such as long-term potentiation alter synaptic activity in a synapse- and cell-specific fashion. Although network-wide excitation triggers compensatory homeostatic changes, it is unknown whether neurons initiate homeostatic synaptic changes in response to cell-autonomous increases in excitation. Here we employ optogenetic tools to cell-autonomously excite CA1 pyramidal neurons and find that a compensatory postsynaptic depression of both AMPAR and NMDAR function results. Elevated calcium influx through L-type calcium channels leads to activation of a pathway involving CaM kinase kinase and CaM kinase 4 that induces synaptic depression of AMPAR and NMDAR responses. The synaptic depression of AMPARs but not of NMDARs requires protein synthesis and the GluA2 AMPAR subunit, indicating that downstream! of CaM kinase activation divergent pathways regulate homeostatic AMPAR and NMDAR depression.
- VGLUT2-Dependent Sensory Neurons in the TRPV1 Population Regulate Pain and Itch
- Neuron (Cambridge Mass ) 68(3):529-542 (2010)
The natural response to itch sensation is to scratch, which relieves the itch through an unknown mechanism. Interaction between pain and itch has been frequently demonstrated, and the selectivity hypothesis of itch, based on data from electrophysiological and behavioral experiments, postulates the existence of primary pain afferents capable of repressing itch. Here, we demonstrate that deletion of vesicular glutamate transporter (VGLUT) 2 in a subpopulation of neurons partly overlapping with the vanilloid receptor (TRPV1) primary afferents resulted in a dramatic increase in itch behavior accompanied by a reduced responsiveness to thermal pain. The increased itch behavior was reduced by administration of antihistaminergic drugs and by genetic deletion of the gastrin-releasing peptide receptor, demonstrating a dependence on VGLUT2 to maintain normal levels of both histaminergic and nonhistaminergic itch. This study establishes that VGLUT2 is a major player in TRPV1 therm! al nociception and also serves to regulate a normal itch response.
- VGLUT2-Dependent Glutamate Release from Nociceptors Is Required to Sense Pain and Suppress Itch
- Neuron (Cambridge Mass ) 68(3):543-556 (2010)
Itch can be suppressed by painful stimuli, but the underlying neural basis is unknown. We generated conditional null mice in which vesicular glutamate transporter type 2 (VGLUT2)-dependent synaptic glutamate release from mainly Nav1.8-expressing nociceptors was abolished. These mice showed deficits in pain behaviors, including mechanical pain, heat pain, capsaicin-evoked pain, inflammatory pain, and neuropathic pain. The pain deficits were accompanied by greatly enhanced itching, as suggested by (1) sensitization of both histamine-dependent and histamine-independent itch pathways and (2) development of spontaneous scratching and skin lesions. Strikingly, intradermal capsaicin injection promotes itch responses in these mutant mice, as opposed to pain responses in control littermates. Consequently, coinjection of capsaicin was no longer able to mask itch evoked by pruritogenic compounds. Our studies suggest that synaptic glutamate release from a group of peripheral nocic! eptors is required to sense pain and suppress itch. Elimination of VGLUT2 in these nociceptors creates a mouse model of chronic neurogenic itch.
- NMDA Receptor Ablation on Parvalbumin-Positive Interneurons Impairs Hippocampal Synchrony, Spatial Representations, and Working Memory
- Neuron (Cambridge Mass ) 68(3):557-569 (2010)
Activity of parvalbumin-positive hippocampal interneurons is critical for network synchronization but the receptors involved therein have remained largely unknown. Here we report network and behavioral deficits in mice with selective ablation of NMDA receptors in parvalbumin-positive interneurons (NR1PVCre−/−). Recordings of local field potentials and unitary neuronal activity in the hippocampal CA1 area revealed altered theta oscillations (5-10 Hz) in freely behaving NR1PVCre−/− mice. Moreover, in contrast to controls, in NR1PVCre−/− mice the remaining theta rhythm was abolished by the administration of atropine. Gamma oscillations (35-85 Hz) were increased and less modulated by the concurrent theta rhythm in the mutant. Positional firing of pyramidal cells in NR1PVCre−/− mice was less spatially and temporally precise. Finally, NR1PVCre−/− mice exhibited impaired spatial working as well as spatial short- and long-term recognition memory but showed ! no deficits in open field exploratory activity and spatial reference learning.
- Robust Odor Coding via Inhalation-Coupled Transient Activity in the Mammalian Olfactory Bulb
- Neuron (Cambridge Mass ) 68(3):570-585 (2010)
It has been proposed that a single sniff generates a "snapshot" of the olfactory world. However, odor coding on this timescale is poorly understood, and it is not known whether coding is invariant to changes in respiration frequency. We investigated this by recording spike trains from the olfactory bulb in awake, behaving rats. During rapid sniffing, odor inhalation triggered rapid and reliable cell- and odor-specific temporal spike patterns. These fine temporal responses conveyed substantial odor information within the first 100 ms, and correlated with behavioral discrimination time on a trial-by-trial basis. Surprisingly, the initial transient portions of responses were highly conserved between rapid sniffing and slow breathing. Firing rates over the entire respiration cycle carried less odor information, did not correlate with behavior, and were poorly conserved across respiration frequency. These results suggest that inhalation-coupled transient activity forms ! a robust neural code that is invariant to changes in respiration behavior.
- Topographic Representation of the Human Body in the Occipitotemporal Cortex
- Neuron (Cambridge Mass ) 68(3):586-600 (2010)
Large-scale topographic representations of the body have long been established in the somatosensory and motor cortices. Using functional imaging, we identified a topographically organized body part map within the occipitotemporal cortex (OTC), with distinct clusters of voxels showing clear preference for different visually presented body parts. This representation was consistent both across hemispheres and participants. Using converging methods, the preference for specific body parts was demonstrated to be robust and did not merely reflect shape differences between the categories. Finally, execution of (unseen) movements with different body parts resulted in a limited topographic representation of the limbs and trunk, which partially overlapped with the visual body part map. This motor-driven activation in the OTC could not be explained solely by visual or motor imagery of the body parts. This suggests that visual and motor-related information converge within the OTC i! n a body part specific manner.