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- Imaging of Neural Ensemble for the Retrieval of a Learned Behavioral Program. [JOURNAL ARTICLE]
- Neuron 2013 May 14.
The encoding of long-term associative memories for learned behaviors is a fundamental brain function. Yet, how behavior is stably consolidated and retrieved in the vertebrate cortex is poorly understood. We trained zebrafish in aversive reinforcement learning and measured calcium signals across their entire brain during retrieval of the learned response. A discrete area of dorsal telencephalon that was inactive immediately after training became active the next day. Analysis of the identified area indicated that it was specific and essential for long-term memory retrieval and contained electrophysiological responses entrained to the learning stimulus. When the behavioral rule changed, a rapid spatial shift in the functional map across the telencephalon was observed. These results demonstrate that the retrieval of long-term memories for learned behaviors can be studied at the whole-brain scale in behaving zebrafish in vivo. Moreover, the findings indicate that consolidated memory traces can be rapidly modified during reinforcement learning.
- Protocadherin 17 Regulates Presynaptic Assembly in Topographic Corticobasal Ganglia Circuits. [JOURNAL ARTICLE]
- Neuron 2013 May 15.
Highly topographic organization of neural circuits exists for the regulation of various brain functions in corticobasal ganglia circuits. Although neural circuit-specific refinement during synapse development is essential for the execution of particular neural functions, the molecular and cellular mechanisms for synapse refinement are largely unknown. Here, we show that protocadherin 17 (PCDH17), one of the nonclustered δ2-protocadherin family members, is enriched along corticobasal ganglia synapses in a zone-specific manner during synaptogenesis and regulates presynaptic assembly in these synapses. PCDH17 deficiency in mice causes facilitated presynaptic vesicle accumulation and enhanced synaptic transmission efficacy in corticobasal ganglia circuits. Furthermore, PCDH17(-/-) mice exhibit antidepressant-like phenotypes that are known to be regulated by corticobasal ganglia circuits. Our findings demonstrate a critical role for PCDH17 in the synaptic development of specific corticobasal ganglia circuits and suggest the involvement of PCDH17 in such circuits in depressive behaviors.
- Social manipulation of preference in the human brain. [Journal Article]
- Neuron 2013 May 8; 78(3):563-73.
Our preferences are influenced by what other people like, but depend critically on how we feel about those people, a classical psychological effect called "cognitive balance." Here, we manipulated preferences for goods by telling participants the preferences of strongly liked or disliked groups of other people. Participants' preferences converged to those of the liked group, but diverged from the disliked group. Activation of dorsomedial prefrontal cortex (dmPFC) tracked the discrepancy between one's own preference and its social ideal and was associated with subsequent preference change (toward the liked and away from the disliked group), even several months later. A follow-up study found overlapping activation in this same region of dmPFC with negative monetary outcomes, but no overlap with nearby activations induced by response conflict. A single social encounter can thus result in long-lasting preference change, a mechanism that recruits dmPFC and that may reflect the aversive nature of cognitive imbalance.
- Motion-Dependent Representation of Space in Area MT+. [Journal Article]
- Neuron 2013 May 8; 78(3):554-62.
How is visual space represented in cortical area MT+? At a relatively coarse scale, the organization of MT+ is debated; retinotopic, spatiotopic, or mixed representations have all been proposed. However, none of these representations entirely explain the perceptual localization of objects at a fine spatial scale-a scale relevant for tasks like navigating or manipulating objects. For example, perceived positions of objects are strongly modulated by visual motion; stationary flashes appear shifted in the direction of nearby motion. Does spatial coding in MT+ reflect these shifts in perceived position? We performed an fMRI experiment employing this "flash-drag" effect and found that flashes presented near motion produced patterns of activity similar to physically shifted flashes in the absence of motion. This reveals a motion-dependent change in the neural representation of object position in human MT+, a process that could help compensate for perceptual and motor delays in localizing objects in dynamic scenes.
- Robust Gamma Coherence between Macaque V1 and V2 by Dynamic Frequency Matching. [Journal Article]
- Neuron 2013 May 8; 78(3):523-36.
Current theories propose that coherence of oscillatory brain activity in the gamma band (30-80 Hz) constitutes an avenue for communication among remote neural populations. However, reports documenting stimulus dependency and time variability of gamma frequency suggest that distant neuronal populations may, at any one time, operate at different frequencies precluding synchronization. To test this idea, we recorded from macaque V1 and V2 simultaneously while presenting gratings of varying contrast. Although gamma frequency increased with stimulus contrast in V1 and V2 (by ∼25 Hz), V1-V2 gamma coherence was maintained for all contrasts. Moreover, while gamma frequency fluctuated by ∼15 Hz during constant contrast stimulation, this fluctuation was highly correlated between V1 and V2. The strongest coherence connections showed a layer-specific pattern, matching feedforward anatomical connectivity. Hence, gamma coherence among remote populations can occur despite large stimulus-induced and time-dependent changes in gamma frequency, allowing communication through coherence to operate without a stimulus independent, fixed-frequency gamma channel.
- Excitatory/Inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. [Journal Article]
- Neuron 2013 May 8; 78(3):510-22.
Neural circuits are regulated by activity-dependent feedback systems that tightly control network excitability and which are thought to be crucial for proper brain development. Defects in the ability to establish and maintain network homeostasis may be central to the pathogenesis of neurodevelopmental disorders. Here, we examine the function of the tuberous sclerosis complex (TSC)-mTOR signaling pathway, a common target of mutations associated with epilepsy and autism spectrum disorder, in regulating activity-dependent processes in the mouse hippocampus. We find that the TSC-mTOR pathway is a central component of a positive feedback loop that promotes network activity by repressing inhibitory synapses onto excitatory neurons. In Tsc1 KO neurons, weakened inhibition caused by deregulated mTOR alters the balance of excitatory and inhibitory synaptic transmission, leading to hippocampal hyperexcitability. These findings identify the TSC-mTOR pathway as a regulator of neural network activity and have implications for the neurological dysfunction in disorders exhibiting deregulated mTOR signaling.
- Competition between α-actinin and Ca(2+)-Calmodulin Controls Surface Retention of the L-type Ca(2+) Channel CaV1.2. [Journal Article]
- Neuron 2013 May 8; 78(3):483-97.
Regulation of neuronal excitability and cardiac excitation-contraction coupling requires the proper localization of L-type Ca(2+) channels. We show that the actin-binding protein α-actinin binds to the C-terminal surface targeting motif of α11.2, the central pore-forming CaV1.2 subunit, in order to foster its surface expression. Disruption of α-actinin function by dominant-negative or small hairpin RNA constructs reduces CaV1.2 surface localization in human embryonic kidney 293 and neuronal cultures and dendritic spine localization in neurons. We demonstrate that calmodulin displaces α-actinin from their shared binding site on α11.2 upon Ca(2+) influx through L-type channels, but not through NMDAR, thereby triggering loss of CaV1.2 from spines. Coexpression of a Ca(2+)-binding-deficient calmodulin mutant does not affect basal CaV1.2 surface expression but inhibits its internalization upon Ca(2+) influx. We conclude that α-actinin stabilizes CaV1.2 at the plasma membrane and that its displacement by Ca(2+)-calmodulin triggers Ca(2+)-induced endocytosis of CaV1.2, thus providing an important negative feedback mechanism for Ca(2+) influx.
- Three mechanisms assemble central nervous system nodes of ranvier. [Journal Article]
- Neuron 2013 May 8; 78(3):469-82.
Rapid action potential propagation in myelinated axons requires Na(+) channel clustering at nodes of Ranvier. However, the mechanism of clustering at CNS nodes remains poorly understood. Here, we show that the assembly of nodes of Ranvier in the CNS involves three mechanisms: a glia-derived extracellular matrix (ECM) complex containing proteoglycans and adhesion molecules that cluster NF186, paranodal axoglial junctions that function as barriers to restrict the position of nodal proteins, and axonal cytoskeletal scaffolds (CSs) that stabilize nodal Na(+) channels. We show that while mice with a single disrupted mechanism had mostly normal nodes, disruptions of the ECM and paranodal barrier, the ECM and CS, or the paranodal barrier and CS all lead to juvenile lethality, profound motor dysfunction, and significantly reduced Na(+) channel clustering. Our results demonstrate that ECM, paranodal, and axonal cytoskeletal mechanisms ensure robust CNS nodal Na(+) channel clustering.
- Plum, an Immunoglobulin Superfamily Protein, Regulates Axon Pruning by Facilitating TGF-β Signaling. [Journal Article]
- Neuron 2013 May 8; 78(3):456-68.
Axon pruning during development is essential for proper wiring of the mature nervous system, but its regulation remains poorly understood. We have identified an immunoglobulin superfamily (IgSF) transmembrane protein, Plum, that is cell autonomously required for axon pruning of mushroom body (MB) γ neurons and for ectopic synapse refinement at the developing neuromuscular junction in Drosophila. Plum promotes MB γ neuron axon pruning by regulating the expression of Ecdysone Receptor-B1, a key initiator of axon pruning. Genetic analyses indicate that Plum acts to facilitate signaling of Myoglianin, a glial-derived TGF-β, on MB γ neurons upstream of the type-I TGF-β receptor Baboon. Myoglianin, Baboon, and Ecdysone Receptor-B1 are also required for neuromuscular junction ectopic synapse refinement. Our study highlights both IgSF proteins and TGF-β facilitation as key promoters of developmental axon elimination and demonstrates a mechanistic conservation between MB axon pruning during metamorphosis and the refinement of ectopic larval neuromuscular connections.
- The cell-autonomous role of excitatory synaptic transmission in the regulation of neuronal structure and function. [Journal Article]
- Neuron 2013 May 8; 78(3):433-9.
The cell-autonomous role of synaptic transmission in the regulation of neuronal structural and electrical properties is unclear. We have now employed a genetic approach to eliminate glutamatergic synaptic transmission onto individual CA1 pyramidal neurons in a mosaic fashion in vivo. Surprisingly, while electrical properties are profoundly affected in these neurons, as well as inhibitory synaptic transmission, we found little perturbation of neuronal morphology, demonstrating a functional segregation of excitatory synaptic transmission from neuronal morphological development.