Latest Articles Include:
- Reactivating Memories for Consolidation
Jadhav SP Frank LM - Neuron 62(6):745-746 (2009)
The consolidation of memory is thought to occur via a hippocampal-neocortical dialog involving reactivation of memory patterns in the hippocampus during sharp-wave ripples. In this issue of Neuron, Nakashiba et al. demonstrate that CA3 output is required for consolidation of contextual fear memory. They also show that lack of CA3 output results in a decrease in ripple-related reactivation, providing additional evidence for a role of ripple-related reactivation in the consolidation process. - Tripping the HCN Breaker
Lipscombe D Pan JQ - Neuron 62(6):747-750 (2009)
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability, pacemaking, dendritic integration, and homeostatic plasticity and are culprits in aberrant neuronal activity in certain epilepsies. In this issue of Neuron two manuscripts (Santoro et al. and Zolles et al.) report that HCN channel gating and expression are controlled by Trip8b (Pex5R) but with a bidirectional spin. - Inhibition Acts Globally to Shape Olfactory Cortical Tuning
Schoppa NE - Neuron 62(6):750-752 (2009)
Lateral inhibition between near-neighbor neurons has long been thought to be important for narrowing the receptive fields of neurons in many sensory systems. A new study by Poo and Isaacson in this issue of Neuron examining olfactory processing finds that "global" inhibition within the primary olfactory cortex might accomplish a similar end. - Applying Neuroscience to Architecture
Eberhard JP - Neuron 62(6):753-756 (2009)
Architectural practice and neuroscience research use our brains and minds in much the same way. However, the link between neuroscience knowledge and architectural design—with rare exceptions—has yet to be made. The concept of linking these two fields is a challenge worth considering. - Amygdala Inhibitory Circuits and the Control of Fear Memory
Ehrlich I Humeau Y Grenier F Ciocchi S Herry C Lüthi A - Neuron 62(6):757-771 (2009)
Classical fear conditioning is a powerful behavioral paradigm that is widely used to study the neuronal substrates of learning and memory. Previous studies have clearly identified the amygdala as a key brain structure for acquisition and storage of fear memory traces. Whereas the majority of this work has focused on principal cells and glutamatergic transmission and its plasticity, recent studies have started to shed light on the intricate roles of local inhibitory circuits. Here, we review current understanding and emerging concepts of how local inhibitory circuits in the amygdala control the acquisition, expression, and extinction of conditioned fear at different levels. - Graded Levels of FGF Protein Span the Midbrain and Can Instruct Graded Induction and Repression of Neural Mapping Labels
Chen Y Mohammadi M Flanagan JG - Neuron 62(6):773-780 (2009)
Graded guidance labels are widely used in neural map formation, but it is not well understood which potential strategy leads to their graded expression. In midbrain tectal map development, FGFs can induce an entire midbrain, but their protein distribution is unclear, nor is it known whether they may act instructively to produce graded gene expression. Using a receptor-alkaline phosphatase fusion probe, we find a long-range posterior > anterior FGF protein gradient spanning the midbrain. Heparan sulfate proteoglycan (HSPG) is required for this gradient. To test whether graded FGF concentrations can instruct graded gene expression, a quantitative tectal explant assay was developed. Engrailed-2 and ephrin-As, normally in posterior > anterior tectal gradients, showed graded upregulation. Moreover, EphAs, normally in anterior > posterior countergradients, showed coordinately graded downregulation. These results provide a mechanism to establish graded mapping labels and more! generally provide a developmental strategy to coordinately induce a structure and pattern its cell properties in gradients. - Hippocampal CA3 Output Is Crucial for Ripple-Associated Reactivation and Consolidation of Memory
- Neuron 62(6):781-787 (2009)
A widely held memory consolidation theory posits that memory of events and space is initially stored in the hippocampus (HPC) in a time-limited manner and is consolidated in the neocortex for permanent storage. Although posttraining HPC lesions result in temporally graded amnesia, the precise HPC circuits and mechanisms involved in remote memory storage remain poorly understood. To investigate the role of the trisynaptic pathway in the consolidation process we employed the CA3-TeTX transgenic mouse, in which CA3 output can be specifically and inducibly controlled. We found that posttraining blockade of CA3 output for up to 4 weeks impairs the consolidation of contextual fear memory. Moreover, in vivo hippocampal recordings revealed a reduced intrinsic frequency of CA1 ripples and a significant decrease in the experience-dependent, ripple-associated coordinated reactivation of CA1 cell pairs. Collectively, these results suggest that the posttraining integrity of the tri! synaptic pathway and the ripple-associated reactivation of hippocampal memory engram are crucial for memory consolidation. - Soluble Oligomers of Amyloid β Protein Facilitate Hippocampal Long-Term Depression by Disrupting Neuronal Glutamate Uptake
Li S Hong S Shepardson NE Walsh DM Shankar GM Selkoe D - Neuron 62(6):788-801 (2009)
In Alzheimer's disease (AD), the impairment of declarative memory coincides with the accumulation of extracellular amyloid-β protein (Aβ) and intraneuronal tau aggregates. Dementia severity correlates with decreased synapse density in hippocampus and cortex. Although numerous studies show that soluble Aβ oligomers inhibit hippocampal long-term potentiation, their role in long-term synaptic depression (LTD) remains unclear. Here, we report that soluble Aβ oligomers from several sources (synthetic, cell culture, human brain extracts) facilitated electrically evoked LTD in the CA1 region. Aβ-enhanced LTD was mediated by mGluR or NMDAR activity. Both forms of LTD were prevented by an extracellular glutamate scavenger system. Aβ-facilitated LTD was mimicked by the glutamate reuptake inhibitor TBOA, including a shared dependence on extracellular calcium levels and activation of PP2B and GSK-3 signaling. In accord, synaptic glutamate uptake was significantly decreased b! y soluble Aβ. We conclude that soluble Aβ oligomers perturb synaptic plasticity by altering glutamate recycling at the synapse and promoting synapse depression. - TRIP8b Splice Variants Form a Family of Auxiliary Subunits that Regulate Gating and Trafficking of HCN Channels in the Brain
Santoro B Piskorowski RA Pian P Hu L Liu H Siegelbaum SA - Neuron 62(6):802-813 (2009)
Hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels, which generate the Ih current, mediate a number of important brain functions. The HCN1 isoform regulates dendritic integration in cortical pyramidal neurons and provides an inhibitory constraint on both working memory in prefrontal cortex and spatial learning and memory in the hippocampus. Altered expression of HCN1 following seizures may contribute to the development of temporal lobe epilepsy. Yet the regulatory networks and pathways governing HCN channel expression and function in the brain are largely unknown. Here, we report the presence of nine alternative N-terminal splice forms of the brain-specific cytoplasmic protein TRIP8b and demonstrate the differential effects of six isoforms to downregulate or upregulate HCN1 surface expression. Furthermore, we find that all TRIP8b isoforms inhibit channel opening by shifting activation to more negative potentials. TRIP8b thus functions as an auxiliar! y subunit that provides a mechanism for the dynamic regulation of HCN1 channel expression and function. - Association with the Auxiliary Subunit PEX5R/Trip8b Controls Responsiveness of HCN Channels to cAMP and Adrenergic Stimulation
Zolles G Wenzel D Bildl W Schulte U Hofmann A Müller CS Thumfart JO Vlachos A Deller T Pfeifer A Fleischmann BK Roeper J Fakler B Klöcker N - Neuron 62(6):814-825 (2009)
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are key modulators of neuronal activity by providing the depolarizing cation current Ih involved in rhythmogenesis, dendritic integration, and synaptic transmission. These tasks critically depend on the availability of HCN channels, which is dynamically regulated by intracellular cAMP; the range of this regulation, however, largely differs among neurons in the mammalian brain. Using affinity purification and high-resolution mass spectrometry, we identify the PEX5R/Trip8b protein as the β subunit of HCN channels in the mammalian brain. Coassembly of PEX5R/Trip8b affects HCN channel gating in a subtype-dependent and mode-specific way: activation of HCN2 and HCN4 by cAMP is largely impaired, while gating by phosphoinositides and basal voltage-dependence remain unaffected. De novo expression of PEX5R/Trip8b in cardiomyocytes abolishes β-adrenergic stimulation of HCN channels. These results demonstrate tha! t PEX5R/Trip8b is an intrinsic auxiliary subunit of brain HCN channels and establish HCN-PEX5R/Trip8b coassembly as a mechanism to control the channels' responsiveness to cyclic nucleotide signaling. - Burst-Timing-Dependent Plasticity of NMDA Receptor-Mediated Transmission in Midbrain Dopamine Neurons
- Neuron 62(6):826-838 (2009)
Bursts of spikes triggered by sensory stimuli in midbrain dopamine neurons evoke phasic release of dopamine in target brain areas, driving reward-based reinforcement learning and goal-directed behavior. NMDA-type glutamate receptors (NMDARs) play a critical role in the generation of these bursts. Here we report LTP of NMDAR-mediated excitatory transmission onto dopamine neurons in the substantia nigra. Induction of LTP requires burst-evoked Ca2+ signals amplified by preceding metabotropic neurotransmitter inputs in addition to the activation of NMDARs themselves. PKA activity gates LTP induction by regulating the magnitude of Ca2+ signal amplification. This form of plasticity is associative, input specific, reversible, and depends on the relative timing of synaptic input and postsynaptic bursting in a manner analogous to the timing rule for cue-reward learning paradigms in behaving animals. NMDAR plasticity might thus represent a potential neural substrate for conditio! ned dopamine neuron burst responses to environmental stimuli acquired during reward-based learning. - Metaplasticity of Hypothalamic Synapses following In Vivo Challenge
Kuzmiski JB Pittman QJ Bains JS - Neuron 62(6):839-849 (2009)
Neural networks that regulate an organism's internal environment must sense perturbations, respond appropriately, and then reset. These adaptations should be reflected as changes in the efficacy of the synapses that drive the final output of these homeostatic networks. Here we show that hemorrhage, an in vivo challenge to fluid homeostasis, induces LTD at glutamate synapses onto hypothalamic magnocellular neurosecretory cells (MNCs). LTD requires the activation of postsynaptic α2-adrenoceptors and the production of endocannabinoids that act in a retrograde fashion to inhibit glutamate release. In addition, both hemorrhage and noradrenaline downregulate presynaptic group III mGluRs. This loss of mGluR function allows high-frequency activity to potentiate these synapses from their depressed state. These findings demonstrate that noradrenaline controls a form of metaplasticity that may underlie the resetting of homeostatic networks following a successful response to an a! cute physiological challenge. - Odor Representations in Olfactory Cortex: "Sparse" Coding, Global Inhibition, and Oscillations
Poo C Isaacson JS - Neuron 62(6):850-861 (2009)
The properties of cortical circuits underlying central representations of sensory stimuli are poorly understood. Here we use in vivo cell-attached and whole-cell voltage-clamp recordings to reveal how excitatory and inhibitory synaptic input govern odor representations in rat primary olfactory (piriform) cortex. We show that odors evoke spiking activity that is sparse across the cortical population. We find that unbalanced synaptic excitation and inhibition underlie sparse activity: inhibition is widespread and broadly tuned, while excitation is less common and odor-specific. "Global" inhibition can be explained by local interneurons that receive ubiquitous and nonselective odor-evoked excitation. In the temporal domain, while respiration imposes a slow rhythm to olfactory cortical responses, odors evoke fast (15-30 Hz) oscillations in synaptic activity. Oscillatory excitation precedes inhibition, generating brief time windows for precise and temporally sparse spik! e output. Together, our results reveal that global inhibition and oscillations are major synaptic mechanisms shaping odor representations in olfactory cortex. - The Brain under Self-Control: Modulation of Inhibitory and Monitoring Cortical Networks during Hypnotic Paralysis
Cojan Y Waber L Schwartz S Rossier L Forster A Vuilleumier P - Neuron 62(6):862-875 (2009)
Brain mechanisms of hypnosis are poorly known. Cognitive accounts proposed that executive attentional systems may cause selective inhibition or disconnection of some mental operations. To assess motor and inhibitory brain circuits during hypnotic paralysis, we designed a go-nogo task while volunteers underwent functional magnetic resonance imaging (fMRI) in three conditions: normal state, hypnotic left-hand paralysis, and feigned paralysis. Preparatory activation arose in right motor cortex despite left hypnotic paralysis, indicating preserved motor intentions, but with concomitant increases in precuneus regions that normally mediate imagery and self-awareness. Precuneus also showed enhanced functional connectivity with right motor cortex. Right frontal areas subserving inhibition were activated by nogo trials in normal state and by feigned paralysis, but irrespective of motor blockade or execution during hypnosis. These results suggest that hypnosis may enhance self-m! onitoring processes to allow internal representations generated by the suggestion to guide behavior but does not act through direct motor inhibition.
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