Examination of the role of cGMP in long-term potentiation in the CA1 region of the hippocampus

The mechanisms underlying the generation of NMDA receptor-dependent LTP in the CA1 region of the hippocampus continue to receive a great deal of attention because of the postulated importance of LTP as a synaptic mechanism for learning and memory. It is well accepted that the initial induction of LTP occurs in the postsynaptic cell, but the site of expression remains controversial. One prominent hypothesis is that LTP involves the release of one or more retrograde messengers that act on the presynaptic terminal to enhance transmitter release. Recently, evidence has been presented that retrograde messengers function to activate presynaptic guanylyl cyclase and that the resulting rise in presynaptic cGMP levels, when accompanied by presynaptic activity, is responsible for generating an early component of LTP. We have tested this hypothesis by examining whether synaptic strength is increased by coupling tetanic stimulation with application of a membrane-permeable analog of cGMP. The experiments were done in the presence of an NMDA receptor antagonist to block postsynaptic induction mechanisms. Under a variety of experimental conditions, this manipulation failed to generate LTP, suggesting that an increase in cGMP levels accompanied by presynaptic activity is not sufficient to generate LTP in the CA1 region of the hippocampus

Long-Term Potentiation: One Kind or Many?

Do neurobiologists aim to discover natural kinds? I address this question in this chapter via a critical analysis of classification practices operative across the 43-year history of research on long-term potentiation (LTP). I argue that this 43-year history supports the idea that the structure of scientific practice surrounding LTP research has remained an obstacle to the discovery of natural kinds

Correlation entropy of synaptic input-output dynamics

The responses of synapses in the neocortex show highly stochastic and nonlinear behavior. The microscopic dynamics underlying this behavior, and its computational consequences during natural patterns of synaptic input, are not explained by conventional macroscopic models of deterministic ensemble mean dynamics. Here, we introduce the correlation entropy of the synaptic input-output map as a measure of synaptic reliability which explicitly includes the microscopic dynamics. Applying this to experimental data, we find that cortical synapses show a low-dimensional chaos driven by the natural input pattern.Comment: 7 pages, 6 Figures (7 figure files

Neuronal pentraxins mediate synaptic refinement in the developing visual system

Peer reviewedPublisher PD

Spatial representation of temporal information through spike timing dependent plasticity

We suggest a mechanism based on spike time dependent plasticity (STDP) of synapses to store, retrieve and predict temporal sequences. The mechanism is demonstrated in a model system of simplified integrate-and-fire type neurons densely connected by STDP synapses. All synapses are modified according to the so-called normal STDP rule observed in various real biological synapses. After conditioning through repeated input of a limited number of of temporal sequences the system is able to complete the temporal sequence upon receiving the input of a fraction of them. This is an example of effective unsupervised learning in an biologically realistic system. We investigate the dependence of learning success on entrainment time, system size and presence of noise. Possible applications include learning of motor sequences, recognition and prediction of temporal sensory information in the visual as well as the auditory system and late processing in the olfactory system of insects.Comment: 13 pages, 14 figures, completely revised and augmented versio

Rabies screen reveals GPe control of cocaine-triggered plasticity.

Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations

How robust are value judgements of health inequality aversion? Testing for framing and cognitive effects

Background: Empirical studies have found that members of the public are inequality averse and value health gains for disadvantaged groups with poor health many times more highly than gains for better off groups. However, these studies typically use abstract scenarios that involve unrealistically large reductions in health inequality, and face-to-face survey administration. It is not known how robust these findings are to more realistic scenarios or anonymous online survey administration. Methods: This study aimed to test the robustness of questionnaire estimates of inequality aversion by comparing the following: (1) small versus unrealistically large health inequality reductions; (2) population-level versus individual-level descriptions of health inequality reductions; (3) concrete versus abstract intervention scenarios; and (4) online versus face to face mode of administration. Fifty-two members of the public participated in face-to-face discussion groups, while 83 members of the public completed an online survey. Participants were given a questionnaire instrument with different scenario descriptions for eliciting aversion to social inequality in health. Results: The median respondent was inequality averse under all scenarios. Scenarios involving small rather than unrealistically large health gains made little difference in terms of inequality aversion, as did population-level rather than individual-level scenarios. However, the proportion expressing extreme inequality aversion fell 19 percentage points when considering a specific health intervention scenario rather than an abstract scenario, and was 11-21 percentage points lower among online public respondents compared to the discussion group. Conclusions: Our study suggests that both concrete scenarios and online administration reduce the proportion expressing extreme inequality aversion but still yield median responses implying substantial health inequality aversion

Activation of mGluR5 Induces Rapid and Long-Lasting Protein Kinase D Phosphorylation in Hippocampal Neurons

Metabotropic glutamate receptors (mGluRs), including mGluR5, play a central role in regulating the strength and plasticity of synaptic connections in the brain. However, the signaling pathways that connect mGluRs to their downstream effectors are not yet fully understood. Here, we report that stimulation of mGluR5 in hippocampal cultures and slices results in phosphorylation of protein kinase D (PKD) at the autophosphorylation site Ser-916. This phosphorylation event occurs within 30 s of stimulation, persists for at least 24 h, and is dependent on activation of phospholipase C and protein kinase C. Our data suggest that activation of PKD may represent a novel signaling pathway linking mGluR5 to its downstream targets. These findings have important implications for the study of the molecular mechanisms underlying mGluR-dependent synaptic plasticity.Howard Hughes Medical InstituteFRAXA Research FoundationNational Institute of Mental Health (U.S.)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.

A Mathematical model for Astrocytes mediated LTP at Single Hippocampal Synapses

Many contemporary studies have shown that astrocytes play a significant role in modulating both short and long form of synaptic plasticity. There are very few experimental models which elucidate the role of astrocyte over Long-term Potentiation (LTP). Recently, Perea & Araque (2007) demonstrated a role of astrocytes in induction of LTP at single hippocampal synapses. They suggested a purely pre-synaptic basis for induction of this N-methyl-D- Aspartate (NMDA) Receptor-independent LTP. Also, the mechanisms underlying this pre-synaptic induction were not investigated. Here, in this article, we propose a mathematical model for astrocyte modulated LTP which successfully emulates the experimental findings of Perea & Araque (2007). Our study suggests the role of retrograde messengers, possibly Nitric Oxide (NO), for this pre-synaptically modulated LTP.Comment: 51 pages, 15 figures, Journal of Computational Neuroscience (to appear

Functional Clustering Drives Encoding Improvement in a Developing Brain Network during Awake Visual Learning

Sensory experience drives dramatic structural and functional plasticity in developing neurons. However, for single-neuron plasticity to optimally improve whole-network encoding of sensory information, changes must be coordinated between neurons to ensure a full range of stimuli is efficiently represented. Using two-photon calcium imaging to monitor evoked activity in over 100 neurons simultaneously, we investigate network-level changes in the developing Xenopus laevis tectum during visual training with motion stimuli. Training causes stimulus-specific changes in neuronal responses and interactions, resulting in improved population encoding. This plasticity is spatially structured, increasing tuning curve similarity and interactions among nearby neurons, and decreasing interactions among distant neurons. Training does not improve encoding by single clusters of similarly responding neurons, but improves encoding across clusters, indicating coordinated plasticity across the network. NMDA receptor blockade prevents coordinated plasticity, reduces clustering, and abolishes whole-network encoding improvement. We conclude that NMDA receptors support experience-dependent network self-organization, allowing efficient population coding of a diverse range of stimuli.Canadian Institutes of Health Researc