Modeling the Contributions of the Exocytotic Machinery and Receptor Desensitization to Short- and Long-Term Plasticity of Synapses Between Neocortical Pyramidal Neurons

Short-term synaptic depression (STD) refers to the progressive decrease in synaptic efficacy during a spike train. This decrease may be explained in terms of presynaptic and postsynaptic processes, such as a decrease in the probability of transmitter release, and postsynaptic receptor desensitization. STD may be very strong, and is release-dependent in neocortical pyramid-pyramid synapses. Using a stochastic synapse model, we suggest that the main source of depression in these synapses is the step of vesicle priming, while vesicle depletion and postsynaptic receptor desensitization are proposed to play a lesser role. Our results suggest that vesicle priming may explain not only the release-dependent nature of STD, but also the observation that an average of about one vesicle per active zone is released in central synapses, without positing forced univesicular release. We propose that the latter phenomenon is due to a low priming probability. Our results also explain the effect of paired pre- and postsynaptic activity on STD. In neocortical pyramid-pyramid synapses pairing induces a form of long-term potentiation that has been described as a redistribution of synaptic efficacy (RSE). We propose that RSE is due to a pairing-induced increase in the probability that a primed vesicle will undergo release in response to a presynaptic action potential. This increase may be due to an increased Ca^2+ influx through voltage-gated Ca^2+ channels, or to an increased sensitivity of primed vesicles to this influx. The results were obtained by constraining the model with experimentally observed levels of release probability and other synaptic variables.Defense Advanced Research Projects Agency and the Office of Naval Research (N00014-95-l-0409); Office of Naval Research (N00014-95-l-0657)

GABA Regulation of Burst Firing in Hippocampal Astrocyte Neural Circuit: A Biophysical Model

It is now widely accepted that glia cells and gamma-aminobutyric acidergic (GABA) interneurons dynamically regulate synaptic transmission and neuronal activity in time and space. This paper presents a biophysical model that captures the interaction between an astrocyte cell, a GABA interneuron and pre/postsynaptic neurons. Specifically, GABA released from a GABA interneuron triggers in astrocytes the release of calcium (Ca2+) from the endoplasmic reticulum via the inositol 1, 4, 5-trisphosphate (IP3) pathway. This results in gliotransmission which elevates the presynaptic transmission probability rate (PR) causing weight potentiation and a gradual increase in postsynaptic neuronal firing, that eventually stabilizes. However, by capturing the complex interactions between IP3, generated from both GABA and the 2-arachidonyl glycerol (2-AG) pathway, and PR, this paper shows that this interaction not only gives rise to an initial weight potentiation phase but also this phase is followed by postsynaptic bursting behavior. Moreover, the model will show that there is a presynaptic frequency range over which burst firing can occur. The proposed model offers a novel cellular level mechanism that may underpin both seizure-like activity and neuronal synchrony across different brain regions

How feedback inhibition shapes spike-timing-dependent plasticity and its implications for recent Schizophrenia models

It has been shown that plasticity is not a fixed property but, in fact, changes depending on the location of the synapse on the neuron and/or changes of biophysical parameters. Here we investigate how plasticity is shaped by feedback inhibition in a cortical microcircuit. We use a differential Hebbian learning rule to model spike-timing dependent plasticity and show analytically that the feedback inhibition shortens the time window for LTD during spike-timing dependent plasticity but not for LTP. We then use a realistic GENESIS model to test two hypothesis about interneuron hypofunction and conclude that a reduction in GAD67 is the most likely candidate as the cause for hypofrontality as observed in Schizophrenia

The Murine Accessory Olfactory Bulb as a Model Chemosensory System: Experimental and Computational Analysis of Chemosensory Representations

A common challenge across sensory processing modalities is forming meaningful associations between the neural responses and the outside world. These neural representations of the world must then be integrated across different sensory systems contributing to each individuals perceptual experience. While there has been considerable study of sensory representations in the visual system of humans and multiple model organisms, other sensory domains, including olfaction, are less well understood. In this thesis, I set out to better understand the sensory representations of the mouse accessory olfactory system (AOS), a part of the olfactory system. The mouse AOS, our model chemosensory system, comprises peripheral vomeronasal sensory neurons (VSNs), the accessory olfactory bulb (AOB), and downstream effectors. Our work describes the neural representations of multiple sensory inputs in the AOS, specifically the representations of odorants in high dimensional chemical sensory space in the AOB, and how these representations are shaped by interactions within the circuit. Given the complex nature of olfactory chemosensory representations, the features of our model system may give new perspectives on the neural representation of the outside world. In a neural representation of olfactory information, both the interactions between each receptor and odor compounds as well as the circuit mediated interactions could potentially affect the neural representations of the outside world. The initial neural response comprises component interactions between each receptor and the odor; chemical signals must interact with physical receptors. However, chemosensory processing, such as olfaction, requires interpreting a large variety of potentially overlapping chemical cues from the environment with only a finite number of receptor types. This means that each chemical cue does not necessarily activate only one receptor type or region of the circuit, but rather the cue is likely to be represented by multiple receptor and odor component interactions. Also, the component parts of odors may be processed differently when presented in isolation versus in a more complex mixture, thus allowing the response to a particular odor to vary with chemical context. Moreover, once these component representations exist, interactions within the neural circuit may further shape these responses. For example, one might expect component parts of a complex odor to specifically inhibit other component parts. In the case of the accessory olfactory system this inhibition could be at the receptor level or at the level of the sensory representation in the accessory olfactory bulb (AOB). In Chapter 3, I describe the overall organization of chemosensory representations in the accessory olfactory bulb (AOB), which is found to be a modular map in which the primary associations of functional sensory responses are spatially organized relative to one another. I find these primary associations are condensations of the first order sensory neuron axon terminals, which form population response pooling structures called glomeruli. In these glomeruli, similar response types from those sensory neurons expressing one of the approximately 300 receptor types in the vomeronasal organ (VNO) co-converge. One purpose of converging inputs of neurons expressing the same receptor is likely to minimize noise, and I demonstrate that pooling of like receptor responses into glomeruli does increase neural signal relative to noise. However, I also observed a modular organization among and between glomeruli in which certain types or patterns of chemosensory responses are always spatially adjacent to one another, while others are much farther apart than would be expected by chance. I found this spatial modularity for both ethological stimuli (urine collected from conspecifics with widely divergent physiological endocrine status) and individual sulfated steroids. In Chapter 4, I explore the consequences of changing sensory context, specifically the presentation of multiple compounds, and the role that inhibition plays in the neural representation of the sensory stimuli. First, I tested whether the circuit responds differently to demands to represent a single odor than to demands to represent multiple odors by using odors that activate glomeruli both inside and outside of modules. I found that responses to mixtures rapidly diverge from the responses of individual component parts. Moreover, there was an effect of inhibition in modulating the response to preferred stimuli in all glomeruli. However, initial analysis of one type of pregnanolone responsive glomeruli demonstrated that the divergent response to mixtures in this type of glomerulus was not mediated by inhibition at the glomerular level, but was rather attributable to bottom-up effects from the interactions of multiple ligands with chemosensory receptors in the VNO. Nonetheless, I also demonstrated that in the AOB, the axon terminals of the same sensory neurons (glomeruli) are organized into modules that allow for feedback inhibition. Significant ionotropic glutamate receptor signal modulation was observed within modules, demonstrating that there are inhibition mediated effects in the representation of complex mixtures when glomeruli are co-locally arranged. Specifically, at both the level of the VSNs and also in AOB glomeruli, the response to allopregnanolone sulfate is inhibited by co-presentation with estradiol sulfate. This both significantly increases the relative representation of estradiol sulfate and shifts representation of allopregnanolone primarily within modules. These types of context dependent interactions depend on the spatial organization described in Chapter 3 as well as mixture context, and have the potential to optimize the representation of some chemical cues in a context specific manner

Computational model of extracellular glutamate in the nucleus accumbens predicts neuroadaptations by chronic cocaine

Notice: this is the author's version of a work that was accepted for publication in Neuroscience. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neuroscience, Vol. 158, Issue #4 (2008) doi:10.1016/j.neuroscience.2008.11.014 . http://journals.elsevier.com/03064522/neuroscience/Chronic cocaine administration causes instability in extracellular glutamate in the nucleus accumbens that is thought to contribute to the vulnerability to relapse. A computational framework was developed to model glutamate in the extracellular space, including synaptic and nonsynaptic glutamate release, glutamate elimination by glutamate transporters and diffusion, and negative feedback on synaptic release via metabotropic glutamate receptors (mGluR2/3). This framework was used to optimize the geometry of the glial sheath surrounding excitatory synapses, and by inserting physiological values, accounted for known stable extracellular, extrasynaptic concentrations of glutamate measured by microdialysis and glutamatergic tone on mGluR2/3. By using experimental values for cocaine-induced reductions in cystine-glutamate exchange and mGluR2/3 signaling, the computational model successfully represented the experimentally observed increase in glutamate that is seen in rats during cocaine-seeking. This model provides a mathematical framework for describing how pharmacological or pathological conditions influence glutamate transmission measured by microdialysis

Disruption of a neural microcircuit in the rod pathway of the mammalian retina by diabetes mellitus

Diabetes leads to dysfunction of the neural retina before and independent of classical microvascular diabetic retinopathy, but previous studies have failed to demonstrate which neurons and circuits are affected at the earliest stages. Here, using patch-clamp recording and two-photon Ca2+ imaging in rat retinal slices, we investigated diabetes-evoked changes in a microcircuit consisting of rod bipolar cells and their dyad postsynaptic targets, AII and A17 amacrine cells, which play an essential role in processing scotopic visual signals. AII amacrines forward their signals to ON- and OFF-cone bipolar cells and A17 amacrines provide GABAergic feedback inhibition to rod bipolar cells. Whereas Ca2+-permeable AMPA receptors mediate input from rod bipolar cells to both AII and A17 amacrines, diabetes changes the synaptic receptors on A17, but not AII amacrine cells. This was expressed as a change in pharmacological properties and single-channel conductance of the synaptic receptors, consistent with an upregulation of the AMPA receptor GluA2 subunit and reduced Ca2+ permeability. In addition, two-photon imaging revealed reduced agonist-evoked influx of Ca2+ in dendritic varicosities of A17 amacrine cells from diabetic compared with normal animals. Because Ca2+-permeable receptors in A17 amacrine cells mediate synaptic release of GABA, the reduced Ca2+ permeability of these receptors in diabetic animals leads to reduced release of GABA, followed by disinhibition and increased release of glutamate from rod bipolar cells. This perturbation of neuron and microcircuit dynamics can explain the decreased dynamic range and sensitivity of scotopic vision that has been observed in diabetes.publishedVersio

Timing of Quantal Release from the Retinal Bipolar Terminal Is Regulated by a Feedback Circuit

AbstractIn isolation, a presynaptic terminal generally releases quanta according to Poisson statistics, but in a circuit its release statistics might be shaped by synaptic interactions. We monitored quantal glutamate release from retinal bipolar cell terminals (which receive GABA-ergic feedback from amacrine cells) by recording spontaneous EPSCs (sEPSCs) in their postsynaptic amacrine and ganglion cells. In about one-third of these cells, sEPSCs were temporally correlated, arriving in brief bursts (10–55 ms) more often than expected from a Poisson process. Correlations were suppressed by antagonizing the GABAC receptor (expressed on bipolar terminals), and correlations were induced by raising extracellular calcium or osmolarity. Simulations of the feedback circuit produced “bursty” release when the bipolar cell escaped intermittently from inhibition. Correlations of similar duration were present in the light-evoked sEPSCs and spike trains of sluggish-type ganglion cells. These correlations were suppressed by antagonizing GABAC receptors, indicating that glutamate bursts from bipolar terminals induce spike bursts in ganglion cells

Wakefulness affects synaptic and network activity by increasing extracellular astrocyte-derived adenosine

Loss of sleep causes an increase in sleep drive and deficits in hippocampal-dependent memory. Both of these responses are thought to require activation of adenosine A1 receptors (adorA1Rs) and release of transmitter molecules including ATP, which is rapidly converted to adenosine in the extracellular space, from astrocytes in a process termed gliotransmission. Although it is increasingly clear that astrocyte-derived adenosine plays an important role in driving the homeostatic sleep response and the effects of sleep loss on memory (Halassa et al., 2009; Florian et al., 2011), previous studies have not determined whether the concentration of this signaling molecule increases in response to wakefulness. Here, we show that the level of adorA1R activation increases in response to wakefulness in mice (Mus musculus). We found that this increase affected synaptic transmission in the hippocampus and modulated network activity in the cortex. Direct biosensor-based measurement of adenosine showed that the net extracellular concentration of this transmitter increased in response to normal wakefulness and sleep deprivation. Genetic inhibition of gliotransmission prevented this increase and attenuated the wakefulness-dependent changes in synaptic and network regulation by adorA1R. Consequently, we conclude that wakefulness increases the level of extracellular adenosine in the hippocampus and that this increase requires the release of transmitters from astroctyes

Advances in Neural Signal Processing

Neural signal processing is a specialized area of signal processing aimed at extracting information or decoding intent from neural signals recorded from the central or peripheral nervous system. This has significant applications in the areas of neuroscience and neural engineering. These applications are famously known in the area of brain–machine interfaces. This book presents recent advances in this flourishing field of neural signal processing with demonstrative applications