722 research outputs found
Inhibitory synchrony as a mechanism for attentional gain modulation
Recordings from area V4 of monkeys have revealed that when the focus of
attention is on a visual stimulus within the receptive field of a cortical
neuron, two distinct changes can occur: The firing rate of the neuron can
change and there can be an increase in the coherence between spikes and the
local field potential in the gamma-frequency range (30-50 Hz). The hypothesis
explored here is that these observed effects of attention could be a
consequence of changes in the synchrony of local interneuron networks. We
performed computer simulations of a Hodgkin-Huxley type neuron driven by a
constant depolarizing current, I, representing visual stimulation and a
modulatory inhibitory input representing the effects of attention via local
interneuron networks. We observed that the neuron's firing rate and the
coherence of its output spike train with the synaptic inputs was modulated by
the degree of synchrony of the inhibitory inputs. The model suggest that the
observed changes in firing rate and coherence of neurons in the visual cortex
could be controlled by top-down inputs that regulated the coherence in the
activity of a local inhibitory network discharging at gamma frequencies.Comment: J.Physiology (Paris) in press, 11 figure
A genetically encoded reporter of synaptic activity in vivo
To image synaptic activity within neural circuits, we tethered the genetically encoded calcium indicator (GECI) GCaMP2 to synaptic vesicles by fusion to synaptophysin. The resulting reporter, SyGCaMP2, detected the electrical activity of neurons with two advantages over existing cytoplasmic GECIs: it identified the locations of synapses and had a linear response over a wider range of spike frequencies. Simulations and experimental measurements indicated that linearity arises because SyGCaMP2 samples the brief calcium transient passing through the presynaptic compartment close to voltage-sensitive calcium channels rather than changes in bulk calcium concentration. In vivo imaging in zebrafish demonstrated that SyGCaMP2 can assess electrical activity in conventional synapses of spiking neurons in the optic tectum and graded voltage signals transmitted by ribbon synapses of retinal bipolar cells. Localizing a GECI to synaptic terminals provides a strategy for monitoring activity across large groups of neurons at the level of individual synapses
Calmodulin as a major calcium buffer shaping vesicular release and short-term synaptic plasticity : facilitation through buffer dislocation
Action potential-dependent release of synaptic vesicles and short-term synaptic plasticity are dynamically regulated by the endogenous Ca2+ buffers that shape [Ca2+] profiles within a presynaptic bouton. Calmodulin is one of the most abundant presynaptic proteins and it binds Ca2+ faster than any other characterized endogenous neuronal Ca2+ buffer. Direct effects of calmodulin on fast presynaptic Ca2+ dynamics and vesicular release however have not been studied in detail. Using experimentally constrained three-dimensional diffusion modeling of Ca2+ influx–exocytosis coupling at small excitatory synapses we show that, at physiologically relevant concentrations, Ca2+ buffering by calmodulin plays a dominant role in inhibiting vesicular release and in modulating short-term synaptic plasticity. We also propose a novel and potentially powerful mechanism for short-term facilitation based on Ca2+-dependent dynamic dislocation of calmodulin molecules from the plasma membrane within the active zone
A mathematical model of aging-related and cortisol induced hippocampal dysfunction
<p>Abstract</p> <p>Background</p> <p>The hippocampus is essential for declarative memory synthesis and is a core pathological substrate for Alzheimer's disease (AD), the most common aging-related dementing disease. Acute increases in plasma cortisol are associated with transient hippocampal inhibition and retrograde amnesia, while chronic cortisol elevation is associated with hippocampal atrophy. Thus, cortisol levels could be monitored and managed in older people, to decrease their risk of AD type hippocampal dysfunction. We generated an in silico<it/>model of the chronic effects of elevated plasma cortisol on hippocampal activity and atrophy, using the systems biology mark-up language (SBML). We further challenged the model with biologically based interventions to ascertain if cortisol associated hippocampal dysfunction could be abrogated.</p> <p>Results</p> <p>The in silico<it/>SBML model reflected the in vivo<it/>aging of the hippocampus and increased plasma cortisol and negative feedback to the hypothalamic pituitary axis. Aging induced a 12% decrease in hippocampus activity (HA), increased to 30% by acute and 40% by chronic elevations in cortisol. The biological intervention attenuated the cortisol associated decrease in HA by 2% in the acute cortisol simulation and by 8% in the chronic simulation.</p> <p>Conclusion</p> <p>Both acute and chronic elevations in cortisol secretion increased aging-associated hippocampal atrophy and a loss of HA in the model. We suggest that this first SMBL model, in tandem with in vitro<it/>and in vivo<it/>studies, may provide a backbone to further frame computational cortisol and brain aging models, which may help predict aging-related brain changes in vulnerable older people.</p
Effect of GABAA Receptor Clustering on Phasic and Tonic Inhibition in the Hippocampus
Inhibitory transmission plays a major role in information processing in the brain since it integrates excitatory signals and defines the gain between neural input and output. \u3b3-Amino butyric acid (GABA) is the main inhibitory neurotransmitter in the adult mammalian brain. By activating GABAA and GABAB receptors this neurotransmitter inhibits neuronal firing and stabilizes the membrane potential near the resting value. In particular GABAA receptors are permeable to chloride ions and are responsible for phasic and tonic hyperpolarizing responses. GABA-mediated currents are the result of rapid, sequential events including transmitter release from the presynaptic terminal, transmitter diffusion within and outside the cleft and post-synaptic receptors gating. The kinetics of each of these processes is crucial in determining the shape of post-synaptic currents. Therefore the modulation of any of these events leads to the heterogeneity of GABAergic responses and to changes in the potency of inhibition. In this thesis I have studied the sources of such variability at presynaptic/cleft and postsynaptic level. At presynaptic/cleft level I have focused on the influence of the agonist concentration profile in the synaptic cleft on GABA-mediated synaptic currents. Fast-off competitive antagonists and computer simulations allowed estimating the range of variability of the peak concentration and the speed of GABA clearance form the synaptic cleft. At postsynaptic level particular attention has been attributed to the impact of GABAA receptors clustering on both phasic and tonic GABAA-mediated inhibition. With ultrafast applications of GABA and computer simulations it was possible to describe the modulation of GABAA receptor gating induced by clustering
Signalling properties at single synapses and within the interneuronal network in the CA1 region of the rodent hippocampus
Understanding how the complexity of connections among the neurons in the brain is
established and modified in an experience- and activity-dependent way is a challenging
task of Neuroscience. Although in the last decades many progresses have been made in
characterising the basic mechanisms of synaptic transmission, a full comprehension of
how information is transferred and processed by neurons has not been fully achieved.
In the present study, theoretical tools and patch clamp experiments were used to further
investigate synaptic transmission, focusing on quantal transmission at single synapses
and on different types of signalling at the level of a particular interneuronal network in
the CA1 area of the rodent hippocampus.
The simultaneous release of more than one vesicle from an individual presynaptic active
zone is a typical mechanism that can affect the strength and reliability of synaptic
transmission. At many central synapses, however, release caused by a single presynaptic
action potential is limited to one vesicle (univesicular release). The likelihood of
multivesicular release at a particular synapse has been tied to release probability (Pr), and
whether it can occur at Schaffer collateral\u2013CA1 synapses, at which Pr ranges widely, is
controversial. In contrast with previous findings, proofs of multivesicular release at this
synapse have been recently obtained at late developmental stages; however, in the case of
newborn hippocampus, it is still difficult to find strong evidence in one direction or
another.
In order to address this point, in the first part of this study a simple and general stochastic
model of synaptic release has been developed and analytically solved. The model
solution gives analytical mathematical expressions relating basic quantal parameters with
average values of quantities that can be measured experimentally. Comparison of these
quantities with the experimental measures allows to determine the most probable values
of the quantal parameters and to discriminate the univesicular from the multivesicular
mode of glutamate release. The model has been validated with data previously collected
at glutamatergic CA3-CA1 synapses in the hippocampus from newborn (P1-P5 old) rats.
The results strongly support a multivesicular type of release process requiring a variable
pool of immediately releasable vesicles. Moreover, computing quantities that are
functions of the model parameters, the mean amplitude of the synaptic response to the release of a single vesicle (Q) was estimated to be 5-10 pA, in very good agreement with
experimental findings. In addition, a multivesicular type of release was supported by
various experimental evidences: a high variability of the amplitude of successes, with a
coefficient of variation ranging from 0.12 to 0.73; an average potency ratio a2/a1 between
the second and first response to a pair of stimuli bigger than 1; and changes in the
potency of the synaptic response to the first stimulus when the release probability was
modified by increasing or decreasing the extracellular calcium concentration. This work
indicates that at glutamatergic CA3-CA1 synapses of the neonatal rat hippocampus a
single action potential may induce the release of more than one vesicle from the same
release site.
In a more systemic approach to the analysis of communication between neurons, it is
interesting to investigate more complex, network interactions. GABAergic interneurons
constitute a heterogeneous group of cells which exert a powerful control on network
excitability and are responsible for the oscillatory behaviour crucial for information
processing in the brain. They have been differently classified according to their
morphological, neurochemical and physiological characteristics.
In the second part of this study, whole cell patch clamp recordings were used to further
characterize, in transgenic mice expressing EGFP in a subpopulation of GABAergic
interneurons containing somatostatin (GIN mice), the functional properties of EGFPpositive
cells in stratum oriens of the CA1 region of the hippocampus, in slice cultures
obtained from P8 old animals. These cells showed passive and active membrane
properties similar to those found in stratum oriens interneurons projecting to stratum
lacunosum-moleculare. Moreover, they exhibited different firing patterns which were
maintained upon membrane depolarization: irregular (48%), regular (30%) and clustered
(22%). Paired recordings from EGFP-positive cells often revealed electrical coupling
(47% of the cases), which was abolished by carbenoxolone (200 mM). On average, the
coupling coefficient was 0.21 \ub1 0.07. When electrical coupling was particularly strong it
acted as a powerful low-pass filter, thus contributing to alter the output of individual
cells. The dynamic interaction between cells with various firing patterns may differently
control GABAergic signalling, leading, as suggested by simulation data, to a wide range
of interneuronal communication. In additional paired recordings of a presynaptic EGFP positive interneuron and a postsynaptic principal cell, trains of action potentials in
interneurons rarely evoked GABAergic postsynaptic currents (3/45 pairs) with small
amplitude and slow kinetics, and that at 20 Hz exhibited short-term depression. In
contrast, excitatory connections between principal cells and EGFP-positive interneurons
were found more often (17/55 pairs) and exhibited a frequency and use-dependent
facilitation, particularly in the gamma band. In conclusion, it appears that EGFP-positive
interneurons in stratum oriens of GIN mice constitute a heterogeneous population of cells
interconnected via electrical synapses, exhibiting particular features in their chemical and
electrical synaptic signalling. Moreover, the dynamic interaction between these
interneurons may differentially affect target cells and neuronal communication within the
hippocampal network
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