Hot off the presses! Jul 30 Neuron

The Jul 30 issue of the Neuron is now up on Pubget (About Neuron): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Amyloid + Activation = Alzheimer's?
  Jagust W - Neuron 63(2):141-143 (2009)
  PET imaging of Alzheimer's disease (AD) patients demonstrates Aβ-protein accumulation in a default mode network. In this issue of Neuron, Sperling and colleagues show that cognitively intact individuals with Aβ in this network fail to deactivate it during memory tasks, a finding with important implications for cognitive aging and early detection of AD.
• Traffic Jams during Vesicle Cycling Lead to Synaptic Depression
  Kim JH von Gersdorff H - Neuron 63(2):143-145 (2009)
  During prolonged stimulation, fusion of thousands of synaptic vesicles poses a challenge for the temporal and spatial coordination of exocytosis and endocytosis. In this issue of Neuron, Hosoi and colleagues reveal that [Ca2+]i-microdomains trigger compensatory endocytosis. Block of endocytosis enhances short-term depression by delaying vesicle recruitment to docking sites on active zones.
• Past Performance Is Indicative of Future Returns
  Smith NJ Narayanan NS Laubach M - Neuron 63(2):146-148 (2009)
  Neuronal activity observed in response to trial outcome is hypothesized to drive learning and performance adjustment. The study by Histed et al. in this issue of Neuron observes persistent outcome-related neuronal activity lasting until the subsequent trial in both prefrontal cortex and the caudate nucleus which is correlated with behavioral adjustment.
• Which Object Appeared Longer?
  Tanji J Mushiake H - Neuron 63(2):148-149 (2009)
  In this issue of Neuron, Genovesio et al. report that neurons in the frontal cortex encode the relative duration of appearance of two sensory signals, together with the features of each signal. Such representations could provide a neural basis for episodic memory.
• Neuroeconomics: Decision Making and the Brain
  - Neuron 63(2):150-153 (2009)
  
• Activity-Dependent Regulation of Synapses by Retrograde Messengers
  Regehr WG Carey MR Best AR - Neuron 63(2):154-170 (2009)
  Throughout the brain, postsynaptic neurons release substances from their cell bodies and dendrites that regulate the strength of the synapses they receive. Diverse chemical messengers have been implicated in retrograde signaling from postsynaptic neurons to presynaptic boutons. Here, we provide an overview of the signaling systems that lead to rapid changes in synaptic strength. We consider the capabilities, specializations, and physiological roles of each type of signaling system.
• Synapse Distribution Suggests a Two-Stage Model of Dendritic Integration in CA1 Pyramidal Neurons
  Katz Y Menon V Nicholson DA Geinisman Y Kath WL Spruston N - Neuron 63(2):171-177 (2009)
  Competing models have been proposed to explain how neurons integrate the thousands of inputs distributed throughout their dendritic trees. In a simple global integration model, inputs from all locations sum in the axon. In a two-stage integration model, inputs contribute directly to dendritic spikes, and outputs from multiple branches sum in the axon. These two models yield opposite predictions of how synapses at different dendritic locations should be scaled if they are to contribute equally to neuronal output. We used serial-section electron microscopy to reconstruct individual apical oblique dendritic branches of CA1 pyramidal neurons and observe a synapse distribution consistent with the two-stage integration model. Computational modeling suggests that the observed synapse distribution enhances the contribution of each dendritic branch to neuronal output.
• Amyloid Deposition Is Associated with Impaired Default Network Function in Older Persons without Dementia
  Sperling RA Laviolette PS O'Keefe K O'Brien J Rentz DM Pihlajamaki M Marshall G Hyman BT Selkoe DJ Hedden T Buckner RL Becker JA Johnson KA - Neuron 63(2):178-188 (2009)
  Alzheimer's disease (AD) has been associated with functional alterations in a distributed network of brain regions linked to memory function, with a recent focus on the cortical regions collectively known as the default network. Posterior components of the default network, including the precuneus and posterior cingulate, are particularly vulnerable to early deposition of amyloid β-protein, one of the hallmark pathologies of AD. In this study, we use in vivo amyloid imaging to demonstrate that high levels of amyloid deposition are associated with aberrant default network functional magnetic resonance imaging (fMRI) activity in asymptomatic and minimally impaired older individuals, similar to the pattern of dysfunction reported in AD patients. These findings suggest that amyloid pathology is linked to neural dysfunction in brain regions supporting memory function and provide support for the hypothesis that cognitively intact older individuals with evidence of amyloid pa! thology may be in early stages of AD.
• Mammalian Par3 Regulates Progenitor Cell Asymmetric Division via Notch Signaling in the Developing Neocortex
  Bultje RS Castaneda-Castellanos DR Jan LY Jan YN Kriegstein AR Shi SH - Neuron 63(2):189-202 (2009)
  Asymmetric cell division of radial glial progenitors produces neurons while allowing self-renewal; however, little is known about the mechanism that generates asymmetry in daughter cell fate specification. Here, we found that mammalian partition defective protein 3 (mPar3), a key cell polarity determinant, exhibits dynamic distribution in radial glial progenitors. While it is enriched at the lateral membrane domain in the ventricular endfeet during interphase, mPar3 becomes dispersed and shows asymmetric localization as cell cycle progresses. Either removal or ectopic expression of mPar3 prevents radial glial progenitors from dividing asymmetrically yet generates different outcomes in daughter cell fate specification. Furthermore, the expression level of mPar3 affects Notch signaling, and manipulations of Notch signaling or Numb expression suppress mPar3 regulation of radial glial cell division and daughter cell fate specification. These results reveal a critical molec! ular pathway underlying asymmetric cell division of radial glial progenitors in the mammalian neocortex.
• Tweek, an Evolutionarily Conserved Protein, Is Required for Synaptic Vesicle Recycling
  Verstreken P Ohyama T Haueter C Habets RL Lin YQ Swan LE Ly CV Venken KJ De Camilli P Bellen HJ - Neuron 63(2):203-215 (2009)
  Synaptic vesicle endocytosis is critical for maintaining synaptic communication during intense stimulation. Here we describe Tweek, a conserved protein that is required for synaptic vesicle recycling. tweek mutants show reduced FM1-43 uptake, cannot maintain release during intense stimulation, and harbor larger than normal synaptic vesicles, implicating it in vesicle recycling at the synapse. Interestingly, the levels of a fluorescent PI(4,5)P2 reporter are reduced at tweek mutant synapses, and the probe is aberrantly localized during stimulation. In addition, various endocytic adaptors known to bind PI(4,5)P2 are mislocalized and the defects in FM1-43 dye uptake and adaptor localization are partially suppressed by removing one copy of the phosphoinositide phosphatase synaptojanin, suggesting a role for Tweek in maintaining proper phosphoinositide levels at synapses. Our data implicate Tweek in regulating synaptic vesicle recycling via an action mediated at least in pa! rt by the regulation of PI(4,5)P2 levels or availability at the synapse.
• Calcium Dependence of Exo- and Endocytotic Coupling at a Glutamatergic Synapse
  Hosoi N Holt M Sakaba T - Neuron 63(2):216-229 (2009)
  The mechanism coupling exocytosis and endocytosis remains to be elucidated at central synapses. Here, we show that the mechanism linking these two processes is dependent on microdomain-[Ca2+]i similar to that which triggers exocytosis, as well as the exocytotic protein synaptobrevin/VAMP. Furthermore, block of endocytosis has a limited, retrograde action on exocytosis, delaying recruitment of release-ready vesicles and enhancing short-term depression. This effect sets in so rapidly that it cannot be explained by the nonavailability of recycled vesicles. Rather, we postulate that perturbation of a step linking exocytosis and endocytosis temporarily prevents new vesicles from docking at specialized sites for exocytosis.
• GABAB Receptor Activation Inhibits Neuronal Excitability and Spatial Learning in the Entorhinal Cortex by Activating TREK-2 K+ Channels
  Deng PY Xiao Z Yang C Rojanathammanee L Grisanti L Watt J Geiger JD Liu R Porter JE Lei S - Neuron 63(2):230-243 (2009)
  The entorhinal cortex (EC) is regarded as the gateway to the hippocampus and thus is essential for learning and memory. Whereas the EC expresses a high density of GABAB receptors, the functions of these receptors in this region remain unexplored. Here, we examined the effects of GABAB receptor activation on neuronal excitability in the EC and spatial learning. Application of baclofen, a specific GABAB receptor agonist, inhibited significantly neuronal excitability in the EC. GABAB receptor-mediated inhibition in the EC was mediated via activating TREK-2, a type of two-pore domain K+ channels, and required the functions of inhibitory G proteins and protein kinase A pathway. Depression of neuronal excitability in the EC underlies GABAB receptor-mediated inhibition of spatial learning as assessed by Morris water maze. Our study indicates that GABAB receptors exert a tight control over spatial learning by modulating neuronal excitability in the EC.
• Learning Substrates in the Primate Prefrontal Cortex and Striatum: Sustained Activity Related to Successful Actions
  Histed MH Pasupathy A Miller EK - Neuron 63(2):244-253 (2009)
  Learning from experience requires knowing whether a past action resulted in a desired outcome. The prefrontal cortex and basal ganglia are thought to play key roles in such learning of arbitrary stimulus-response associations. Previous studies have found neural activity in these areas, similar to dopaminergic neurons' signals, that transiently reflect whether a response is correct or incorrect. However, it is unclear how this transient activity, which fades in under a second, influences actions that occur much later. Here, we report that single neurons in both areas show sustained, persistent outcome-related responses. Moreover, single behavioral outcomes influence future neural activity and behavior: behavioral responses are more often correct and single neurons more accurately discriminate between the possible responses when the previous response was correct. These long-lasting signals about trial outcome provide a way to link one action to the next and may allow rew! ard signals to be combined over time to implement successful learning.
• Feature- and Order-Based Timing Representations in the Frontal Cortex
  Genovesio A Tsujimoto S Wise SP - Neuron 63(2):254-266 (2009)
  We examined activity in the frontal cortex as monkeys performed a duration-discrimination task. Two stimuli, one red and the other blue, appeared sequentially on a video screen—in either order. Later, both stimuli reappeared, and to receive a reward the monkeys had to choose the stimulus that had lasted longer during its initial presentation. Some neurons encoded stimulus duration, but a larger number of cells represented their relative duration, which was encoded in three ways: whether the first or second stimulus had lasted longer; whether the red or blue stimulus had lasted longer; or, less commonly, as the difference between the two durations. As the monkeys' choice approached, the signal encoding which stimulus (red or blue) had lasted longer increased as the order-based signal dissipated. By representing stimulus durations and relative durations—both bound to stimulus features and event order—the frontal cortex could contribute to both temporal perception a! nd episodic memory.
• Mind the Gap: Binding Experiences across Space and Time in the Human Hippocampus
  Staresina BP Davachi L - Neuron 63(2):267-276 (2009)
  A fundamental goal in memory research is to understand what class of learning problem the hippocampus is uniquely designed to solve. While much controversy surrounds the particular types of memories the hippocampus is thought to support, one hypothesized function possibly linking divergent frameworks is the capacity to bind mnemonic representations across spatial and temporal gaps in our experience. In our current functional magnetic resonance imaging (fMRI) study, we systematically controlled the extent to which a target and an event detail have to be integrated across spatiotemporal discontiguities during associative memory formation. Although the encoding task, the type of association, and subsequent memory performance were held constant, engagement of the hippocampus during successful associative binding was directly modulated by increases in spatial and temporal discontiguities across episodic elements. These results suggest that a core mnemonic function of the hi! ppocampus is to bridge representational gaps in our experience.