A spike-based model of binaural sound localization

This paper describes a spike-based model of binaural sound localization using interaural time differences (ITDs). To handle the problem of temporal coding and to facilitate a hardware implementation all neurons are simulated by a spike response model, which includes postsynaptic potentials (PSPs) and a refractory period. A winner-take-all (WTA) network selects the dominant source from the representation of the sound's angles of incidences, and can be biased by a multisensory support. We use simulations on real audio data to investigate the function and the practical application of the system.     

Non-monotonic effects of GABAergic synaptic inputs on neuronal firing

GABA is generally known as the principal inhibitory neurotransmitter in the nervous system, usually acting by hyperpolarizing membrane potential. However, GABAergic currents sometimes exhibit non-inhibitory effects, depending on the brain region, developmental stage or pathological condition. Here, we investigate the diverse effects of GABA on the firing rate of several single neuron models, using both analytical calculations and numerical simulations. We find that GABAergic synaptic conductance and output firing rate exhibit three qualitatively different regimes as a function of GABA reversal potential, E_GABA: monotonically decreasing for sufficiently low E_GABA (inhibitory), monotonically increasing for E_GABA above firing threshold (excitatory); and a non-monotonic region for intermediate values of E_GABA. In the non-monotonic regime, small GABA conductances have an excitatory effect while large GABA conductances show an inhibitory effect. We provide a phase diagram of different GABAergic effects as a function of GABA reversal potential and glutamate conductance. We find that noisy inputs increase the range of E_GABA for which the non-monotonic effect can be observed. We also construct a micro-circuit model of striatum to explain observed effects of GABAergic fast spiking interneurons on spiny projection neurons, including non-monotonicity, as well as the heterogeneity of the effects. Our work provides a mechanistic explanation of paradoxical effects of GABAergic synaptic inputs, with implications for understanding the effects of GABA in neural computation and development.     

Bayesian reconstruction of sound localization cues from responses to random spectra

 The directionally sensitive acoustics of the pinnae enable humans to perceive the up–down and front–back direction of sound. This mechanism complements another, independent mechanism that derives sound-source azimuth from interaural difference cues. The pinnae effectively add direction-dependent spectral notches and peaks to the incoming sound, and it has been shown that such features are used to code sound direction in the median plane. However, it is still unclear which of the pinna-induced features play a role in sound localization. The present study presents a method for the reconstruction of the spatially relevant features in the spectral domain. Broadband sounds with random spectral shapes were presented in rapid succession as subjects made saccadic eye movements toward the perceived stimulus locations. The analysis, which is based on Bayesian statistics, indicates that specific spectral features could be associated with perceived spatial locations. Spectral features that were determined by this psychophysical method resemble the main characteristics of the pinna transfer functions obtained from acoustic measurements in the ear canal. Despite current experimental limitations, the approach may prove useful in the study of perceptually relevant spectral cues underlying human sound localization. Received: 2 December 2000 / Accepted in revised form: 23 October 2001     

Binaural disparity cues available to the barn owl for sound localization

1. Bilateral recording of cochlear potentials was used to measure the variations in interaural time differences (ITDs) and interaural intensity differences (IIDs) as a free-field auditory stimulus was moved to different positions around a barn owl's head. 2. ITD varied smoothly with stimulus azimuth across a broad frequency range. 3. ITD varied minimally with stimulus elevation, except at extreme angles from the horizontal. 4. IID varied with both stimulus elevation and stimulus azimuth. Lower frequencies were more sensitive to variations in azimuth, whereas higher frequencies were more sensitive to variations in elevation. 5. The loci of spatial coordinates that form iso-IID contours and iso-ITD contours form a non-orthogonal grid that relates binaural disparity cues to sound location.     

Probable localization of synaptic inputs evoking generation of slow inhibitory postsynaptic potentials in pyramidal neurons: Simulation studies

In computer-experiments using the interactive program, CRONA, and using data from natural experiments that measured the reversal potential of slow (long-term) inhibitory postsynaptic potentials (slow IPSPs), we determined the probable location of the region of potassium-conducting synapses that are responsible for their generation. Parameters such as the geometric dimensions of neuronal dendritic branches and the intracellular concentration of K⁺ were studied for their effect on the determination of this region. It is concluded that these synaptic inputs are non-somatic, and that allowing for the variability of the initial parameters they probably lie on the apical dendrites at a distance between 110 and 460 µm from the soma.Dnepropetrovsk State University. A. A. Bogomolets Institute of Physiology, Ukrainian Academy of Sciences, Kiev. Translated from Neirofiziologiya, Vol. 23, No. 6, pp. 738–745, November–December, 1991.     

In vivo analysis of inhibitory synaptic inputs and rebounds in deep cerebellar nuclear neurons

Neuronal function depends on the properties of the synaptic inputs the neuron receive and on its intrinsic responsive properties. However, the conditions for synaptic integration and activation of intrinsic responses may to a large extent depend on the level of background synaptic input. In this respect, the deep cerebellar nuclear (DCN) neurons are of particular interest: they feature a massive background synaptic input and an intrinsic, postinhibitory rebound depolarization with profound effects on the synaptic integration. Using in vivo whole cell patch clamp recordings from DCN cells in the cat, we find that the background of Purkinje cell input provides a tonic inhibitory synaptic noise in the DCN cell. Under these conditions, individual Purkinje cells appear to have a near negligible influence on the DCN cell and clear-cut rebounds are difficult to induce. Peripheral input that drives the simple spike output of the afferent PCs to the DCN cell generates a relatively strong DCN cell inhibition, but do not induce rebounds. In contrast, synchronized climbing fiber activation, which leads to a synchronized input from a large number of Purkinje cells, can induce profound rebound responses. In light of what is known about climbing fiber activation under behaviour, the present findings suggest that DCN cell rebound responses may be an unusual event. Our results also suggest that cortical modulation of DCN cell output require a substantial co-modulation of a large proportion of the PCs that innervate the cell, which is a possible rationale for the existence of the cerebellar microcomplex.     

Aggregation of detergent-insoluble tau is involved in neuronal loss but not in synaptic loss

Neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau, are hallmarks of neurodegenerative diseases including Alzheimer disease (AD). In neurodegenerative diseases, neuronal dysfunction due to neuronal loss and synaptic loss accompanies NFT formation, suggesting that a process associated with NFT formation may be involved in neuronal dysfunction. To clarify the relationship between the tau aggregation process and synapse and neuronal loss, we compared two lines of mice expressing human tau with or without an aggregation-prone P301L mutation. P301L tau transgenic (Tg) mice exhibited neuronal loss and produced sarcosyl-insoluble tau in old age but did not exhibit synaptic loss and memory impairment. By contrast, wild-type tau Tg mice neither exhibited neuronal loss nor produced sarcosyl-insoluble tau but did exhibit synaptic loss and memory impairment. Moreover, P301L tau was less phosphorylated than wild-type tau, suggesting that the tau phosphorylation state is involved in synaptic loss, whereas the tau aggregation state is involved in neuronal loss. Finally, increasing concentrations of insoluble tau aggregates leads to the formation of fibrillar tau, which causes NFTs to form.     

Genetic deficiency of neuronal RAGE protects against AGE-induced synaptic injury

Synaptic dysfunction and degeneration is an early pathological feature of aging and age-related diseases, including Alzheimer''s disease (AD). Aging is associated with increased generation and deposition of advanced glycation endproducts (AGEs), resulting from nonenzymatic glycation (or oxidation) proteins and lipids. AGE formation is accelerated in diabetes and AD-affected brain, contributing to cellular perturbation. The extent of AGEs'' involvement, if at all, in alterations in synaptic structure and function is currently unknown. Here we analyze the contribution of neuronal receptor of AGEs (RAGE) signaling to AGE-mediated synaptic injury using novel transgenic neuronal RAGE knockout mice specifically targeted to the forebrain and transgenic mice expressing neuronal dominant-negative RAGE (DN-RAGE). Addition of AGEs to brain slices impaired hippocampal long-term potentiation (LTP). Similarly, treatment of hippocampal neurons with AGEs significantly decreases synaptic density. Such detrimental effects are largely reversed by genetic RAGE depletion. Notably, brain slices from mice with neuronal RAGE deficiency or DN-RAGE are resistant to AGE-induced LTP deficit. Further, RAGE deficiency or DN-RAGE blocks AGE-induced activation of p38 signaling. Taken together, these data show that neuronal RAGE functions as a signal transducer for AGE-induced synaptic dysfunction, thereby providing new insights into a mechanism by which the AGEs–RAGE-dependent signaling cascade contributes to synaptic injury via the p38 MAP kinase signal transduction pathway. Thus, RAGE blockade may be a target for development of interventions aimed at preventing the progression of cognitive decline in aging and age-related neurodegenerative diseases.Advanced glycation endproducts (AGEs) are members of a heterogeneous class of molecules, which modify cellular function by distinct mechanisms, including ligation and activation of signal transduction receptors. The products of non-enzymatic glycation (or oxidation) of proteins and lipids, AGEs contribute to the normal aging process and when accelerated have a causative role in the vasculature complications of diabetes mellitus and several neurodegenerative diseases, including Alzheimer''s (AD), Parkinson''s, and Huntington''s diseases.^{1, 2, 3, 4, 5} In diabetic patients, the concentration of circulating AGEs (serum AGE level) has been reported at 7.2–22 mU/ml (equivalent to 30–88 μg/ml AGE-BSA), which is significantly higher than that of non-diabetic patients (3 mU/ml, equivalent to 12 μg/ml AGE-BSA).^{6, 7, 8} The brain AGE level was also increased to 5-6 μM (equivalent to 325–390 μg/ml AGE-BSA) in the diabetic animal model.⁹ Excess AGE accumulation is detrimental to neurons and is believed to be a key to the pathogenesis of cognitive decline in normal aging and specific chronic diseases of aging. For example, in a recent clinical study, peripheral AGE levels were associated with cognitive decline in older adults with and without diabetes.¹⁰ Diabetes complications affect the brain, increasing risk for depression, dementia, and AD. In fact, patients with type 2 diabetes are at twofold to threefold increased relative risk for AD^{11, 12, 13, 14, 15, 16, 17, 18} and accelerated cognitive dysfunction.Long-lived proteins such as β-amyloid peptide (Aβ) and hyperphosphorylated tau protein that accumulate in AD brain are highly susceptible to AGE modification.^{19, 20, 21, 22} AGE-modified Aβ or tau protein results in increased oxidative stress and chronic inflammation, accelerating AD pathology and neuronal perturbation.^{19, 20, 22, 23, 24, 25} Moreover, Aβ or tau glycation results in increased aggregation and subsequent formation of senile plaques or neurofibrillary tangles, the major pathological feature of AD,^{19, 22} suggesting that AGE modification is an important risk factor for neurodegenerative diseases.²⁶ Although increased accumulation of AGEs in brain, as seen in aging, diabetes, or neurodegenerative diseases, speeds up oxidative damage to neurons contributing to synaptic dysfunction and cognitive decline, its underlying mechanisms are not well understood.Receptor for advanced glycation endproduct (RAGE) was first identified as a cell surface receptor of the immunoglobulin superfamily for AGEs.^{27, 28} Increased expression of RAGE occurs in neuronal and non-neuronal cells in the peripheral and central nervous system in aging, diabetes, and AD-affected individuals, where RAGE ligands are upregulated.^{29, 30} Although it has been shown that AGEs–RAGE interaction contributes to cellular perturbation relevant to the pathogenesis of the cardiovascular disease and the diabetes vascular complications,^{31, 32, 33} little is known about the role of AGEs and its interaction with RAGE on synaptic dysfunction. To understand the mechanisms involved in AGE-mediated synaptic damage, the following questions need to be addressed: (1) ‘Do AGEs alter synaptic structure and function? If so, are these changes dependent on RAGE signaling?'' (2) ‘Does RAGE blockage by genetic depletion protect from AGE-induced synaptic dysfunction and loss?'' and (3) ‘What is the impact of neuronal RAGE in AGE-induced aberrant synaptic function?''. Thus it is important to evaluate the impact of AGEs–RAGE interaction on synaptic dysfunction and to explore the mechanism underlying AGE–RAGE-dependent signal transduction and its contribution to synaptic damage.Here we investigate neuronal RAGE signaling in AGE-induced synaptic injury using our novel conditional RAGE knockout mice targeted to cortical neurons as well as transgenic mice that overexpress signal transduction-deficient mutants of RAGE in neurons. Given that neuronal and non-neuronal cells in the brain may contribute to AGE-induced sustained neuronal and synaptic stress and dysfunction, we assessed the impact of global RAGE deletion in this setting and further delineated the mechanism by which RAGE-dependent activation of p38 MAP kinase potentiates AGE-insulted synaptic injury.     

Conventional measures of intrinsic excitability are poor estimators of neuronal activity under realistic synaptic inputs

Activity-dependent regulation of intrinsic excitability has been shown to greatly contribute to the overall plasticity of neuronal circuits. Such neuroadaptations are commonly investigated in patch clamp experiments using current step stimulation and the resulting input-output functions are analyzed to quantify alterations in intrinsic excitability. However, it is rarely addressed, how such changes translate to the function of neurons when they operate under natural synaptic inputs. Still, it is reasonable to expect that a strong correlation and near proportional relationship exist between static firing responses and those evoked by synaptic drive. We challenge this view by performing a high-yield electrophysiological analysis of cultured mouse hippocampal neurons using both standard protocols and simulated synaptic inputs via dynamic clamp. We find that under these conditions the neurons exhibit vastly different firing responses with surprisingly weak correlation between static and dynamic firing intensities. These contrasting responses are regulated by two intrinsic K-currents mediated by Kv1 and K_ir channels, respectively. Pharmacological manipulation of the K-currents produces differential regulation of the firing output of neurons. Static firing responses are greatly increased in stuttering type neurons under blocking their Kv1 channels, while the synaptic responses of the same neurons are less affected. Pharmacological blocking of K_ir-channels in delayed firing type neurons, on the other hand, exhibit the opposite effects. Our subsequent computational model simulations confirm the findings in the electrophysiological experiments and also show that adaptive changes in the kinetic properties of such currents can even produce paradoxical regulation of the firing output.     

Interrelated modification of excitatory and inhibitory synaptic connections in the olivary-cerebellar neuronal network

The model of simultaneous interrelated modification in the efficacy of synaptic inputs to different neurons of the olivary-cerebellar network is developed. The model is based on the following features of the network: simultaneous activation of the input layer (granule) cells and the output layer (deep cerebellar nuclei) cells by mossy fibers; simultaneous activation of Purkinje cells and cerebellar cells of the input and output layers by climbing fibers and their collaterals; the existence of local feedback excitatory, inhibitory, and disinhibitory circuits. The rise (decrease) of posttetanic Ca2+ concentration in reference to the level produced by previous stimulation causes the decrease (increase) in cGMP-dependent protein kinase G activity, and increase (decrease) inprotein phosphatase 1 activity. Subsequent dephosphorylation (phosphorylation) of ionotropic receptors results in simultaneous LTD (LTP) of the excitatory input together with the LTP (LTD) of the inhibitory input to the same neuron. The character of interrelated modifications of synapses at different cerebellar levels strongly depends on the olivary cell activity. In the presence (absence) of the signal from the inferior olive LTD (LTP) of the output cerebellar signal can be induced.     

Orientation and direction selectivity of synaptic inputs in visual cortical neurons: a diversity of combinations produces spike tuning

This intracellular study investigates synaptic mechanisms of orientation and direction selectivity in cat area 17. Visually evoked inhibition was analyzed in 88 cells by detecting spike suppression, hyperpolarization, and reduction of trial-to-trial variability of membrane potential. In 25 of these cells, inhibition visibility was enhanced by depolarization and spike inactivation and by direct measurement of synaptic conductances. We conclude that excitatory and inhibitory inputs share the tuning preference of spiking output in 60% of cases, whereas inhibition is tuned to a different orientation in 40% of cases. For this latter type of cells, conductance measurements showed that excitation shared either the preference of the spiking output or that of the inhibition. This diversity of input combinations may reflect inhomogeneities in functional intracortical connectivity regulated by correlation-based activity-dependent processes.     

The localization of neuronal nitric oxide synthase may influence its role in neuronal precursor proliferation and synaptic maintenance

Neuronal nitric oxide synthase (nNOS) is implicated in some developmental processes, including neuronal survival, differentiation, and precursor proliferation. To define the roles of nNOS in neuronal development, we utilized the olfactory system as a model. We hypothesized that the role of nNOS may be influenced by its localization. nNOS expression was developmentally regulated in the olfactory system. During early postnatal development, nNOS was expressed in developing neurons in the olfactory epithelium (OE), while in the adult its expression was restricted to periglomerular (PG) cells in the olfactory bulb (OB). At postnatal week 1 (P1W), loss of nNOS due to targeted gene deletion resulted in a decrease in immature neurons in the OE due to decreased proliferation of neuronal precursors. While the pool of neuronal precursors and neurogenesis normalized in the nNOS null mouse by P6W, there was an overgrowth of mitral or tufted cells dendrites and a decreased number of active synapses in the OB. Cyclic GMP (cGMP) immunostaining was reduced in the OE and in the glomeruli of the OB at early postnatal and adult ages, respectively. Our results suggest that nNOS appears necessary for neurogenesis in the OE during early postnatal development and for glomerular organization in the OB in the adult. Thus, the location of nNOS, either within cell bodies or perisynaptically, may influence its developmental role.     

Internalized antibodies to the Abeta domain of APP reduce neuronal Abeta and protect against synaptic alterations

Immunotherapy against beta-amyloid peptide (Abeta) is a leading therapeutic direction for Alzheimer disease (AD). Experimental studies in transgenic mouse models of AD have demonstrated that Abeta immunization reduces Abeta plaque pathology and improves cognitive function. However, the biological mechanisms by which Abeta antibodies reduce amyloid accumulation in the brain remain unclear. We provide evidence that treatment of AD mutant neuroblastoma cells or primary neurons with Abeta antibodies decreases levels of intracellular Abeta. Antibody-mediated reduction in cellular Abeta appears to require that the antibody binds to the extracellular Abeta domain of the amyloid precursor protein (APP) and be internalized. In addition, treatment with Abeta antibodies protects against synaptic alterations that occur in APP mutant neurons.     

Robustness of a meta-network to alternative habitat loss scenarios

Studying how habitat loss affects the tolerance of ecological networks to species extinction (i.e. their robustness) is key for our understanding of the influence of human activities on natural ecosystems. With networks typically occurring as local interaction networks interconnected in space (a meta-network), we may ask how the loss of specific habitat fragments affects the overall robustness of the meta-network. To address this question, for an empirical meta-network of plants, herbivores and natural enemies we simulated the removal of habitat fragments in increasing and decreasing order of area, age and connectivity for plant extinction and the secondary extinction of herbivores, natural enemies and their interactions. Meta-network robustness was characterized as the area under the curve of remnant species or interactions at the end of a fragment removal sequence. To pinpoint the effects of fragment area, age and connectivity, respectively, we compared the observed robustness for each removal scenario against that of a random sequence. The meta-network was more robust to the loss of old (i.e. long-fragmented), large, connected fragments than of young (i.e. recently fragmented), small, isolated fragments. Thus, young, small, isolated fragments may be particularly important to the conservation of species and interactions, while contrary to our expectations larger, more connected fragments contribute little to meta-network robustness. Our findings highlight the importance of young, small, isolated fragments as sources of species and interactions unique to the regional level. These effects may largely result from an unpaid extinction debt, whereby younger fragments are likely to lose species over time. Yet, there may also be more long-lasting effects from cultivated lands (e.g. water, fertilizers and restricted cattle grazing) and network complexity in small, isolated fragments. Such fragments may sustain important biological diversity in fragmented landscapes, but maintaining their conservation value may depend on adequate restoration strategies.     

Analogue model of motoneurons to investigate the distribution of synaptic inputs

Analogue models of lumbar motoneurons of the monkey and cat were built on the basis of measurement of the electrical parameters of these cells and reproduction of the structure and dimensions of their body and dendrites stained intracellularly with procion yellow. Synaptic inputs were simulated by short-acting shunts activated at different points of the membrane. The way in which the amplitudinal and temporal course of the artificial EPSPs and their interaction and sensitivity to a polarizing current depended on the spatial localization of the corresponding inputs was investigated, revealing a correlation between the properties of the EPSP and the localization of its generator. Properties of the synaptic inputs were found to depend not only on their distance from the soma, but also on their arrangement on particular branches of the dendrites. Agreement between the results obtained in experiments on the analogue model and on actual motoneurons and the correlation between the electrophysiological, morphological, and model concepts are discussed.I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Academy of Sciences of the USSR, Leningrad. Translated from Neirofiziologiya, Vol. 5, No. 3, pp. 289–297, May–June, 1973.     

Analysis of synaptic inputs to on-off amacrine cells of the carp retina

To elucidate the synaptic transmission between bipolar cells and amacrine cells, the effect of polarization of a bipolar cell on an amacrine cell was examined by simultaneous intracellular recordings from both cells in the isolated carp retina. When either an ON or OFF bipolar cell was depolarized by an extrinsic current step, an ON-OFF amacrine cell was transiently depolarized at the onset of the current but no sustained polarization during the current was detected. The current hyperpolarizing the OFF bipolar cell also produced the transient depolarization of the amacrine cell at the termination of the current. These responses had a latency of approximately 10 ms. The amplitude of the current-evoked responses changed gradually with current intensity within the range used in these experiments. They were affected by polarization of the amacrine cell membrane; the amplitude of the current-evoked responses as well as the light-evoked responses was increased when the amacrine cell membrane was hyperpolarized, while the amplitude was decreased when the cell was depolarized. These results confirm directly that ON-OFF amacrine cells receive excitatory inputs from both ON and OFF bipolar cells: the ON transient is due to inputs from ON bipolar cells, and the OFF transient to inputs from OFF bipolar cells. The steady polarization of bipolar cells is converted into transient signals during the synaptic process.     

Barriers to diffusion in dendrites and estimation of calcium spread following synaptic inputs

The motion of ions, molecules or proteins in dendrites is restricted by cytoplasmic obstacles such as organelles, microtubules and actin network. To account for molecular crowding, we study the effect of diffusion barriers on local calcium spread in a dendrite. We first present a model based on a dimension reduction approach to approximate a three dimensional diffusion in a cylindrical dendrite by a one-dimensional effective diffusion process. By comparing uncaging experiments of an inert dye in a spiny dendrite and in a thin glass tube, we quantify the change in diffusion constants due to molecular crowding as D_cyto/D_water = 1/20. We validate our approach by reconstructing the uncaging experiments using Brownian simulations in a realistic 3D model dendrite. Finally, we construct a reduced reaction-diffusion equation to model calcium spread in a dendrite under the presence of additional buffers, pumps and synaptic input. We find that for moderate crowding, calcium dynamics is mainly regulated by the buffer concentration, but not by the cytoplasmic crowding, dendritic spines or synaptic inputs. Following high frequency stimulations, we predict that calcium spread in dendrites is limited to small microdomains of the order of a few microns (<5 μm).