Evoking prescribed spike times in stochastic neurons

NASA Astrophysics Data System (ADS)

Doose, Jens; Lindner, Benjamin

2017-09-01

Single cell stimulation in vivo is a powerful tool to investigate the properties of single neurons and their functionality in neural networks. We present a method to determine a cell-specific stimulus that reliably evokes a prescribed spike train with high temporal precision of action potentials. We test the performance of this stimulus in simulations for two different stochastic neuron models. For a broad range of parameters and a neuron firing with intermediate firing rates (20-40 Hz) the reliability in evoking the prescribed spike train is close to its theoretical maximum that is mainly determined by the level of intrinsic noise.

Axonal transport studied in a single vertebrate neuron: the giant electromotor neuron of the electric catfish, Malapterurus electricus.

PubMed

Zimmermann, H; Tashiro, T; Komiya, Y; Kurokawa, M

1989-02-01

Axonal transport was studied using a single vertebrate neuron, the giant electromotor neuron of the electric catfish, Malapterurus electricus. The electric organs of this strongly electric fish are innervated by two neurons whose axons form one electric nerve each. After injection of [35S]methionine into the spinal cord at the level of the two perikarya radioactively labelled material is exported by fast flow as a small wave with a velocity of 5.8 mm/h and a somal release time of 91 min (29 degrees C). Slow flow investigated between 15 and 39 days had a velocity of 1.36 mm/d at 29 degrees C. Analysis of radiolabelled proteins by polyacrylamide gel electrophoresis revealed different patterns of labelling between slow and fast flow. The relative molecular mass of the two major proteins labelled on slow flow correspond to actin and tubulin. Labelled proteins of higher relative molecular mass may correspond to neurofilament proteins. Our results suggest that this vertebrate single-neuron and single-axon system can be used successfully for axonal transport studies.

Single-Cell Memory Regulates a Neural Circuit for Sensory Behavior.

PubMed

Kobayashi, Kyogo; Nakano, Shunji; Amano, Mutsuki; Tsuboi, Daisuke; Nishioka, Tomoki; Ikeda, Shingo; Yokoyama, Genta; Kaibuchi, Kozo; Mori, Ikue

2016-01-05

Unveiling the molecular and cellular mechanisms underlying memory has been a challenge for the past few decades. Although synaptic plasticity is proven to be essential for memory formation, the significance of "single-cell memory" still remains elusive. Here, we exploited a primary culture system for the analysis of C. elegans neurons and show that a single thermosensory neuron has an ability to form, retain, and reset a temperature memory. Genetic and proteomic analyses found that the expression of the single-cell memory exhibits inter-individual variability, which is controlled by the evolutionarily conserved CaMKI/IV and Raf pathway. The variable responses of a sensory neuron influenced the neural activity of downstream interneurons, suggesting that modulation of the sensory neurons ultimately determines the behavioral output in C. elegans. Our results provide proof of single-cell memory and suggest that the individual differences in neural responses at the single-cell level can confer individuality. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Auditory-nerve single-neuron thresholds to electrical stimulation from scala tympani electrodes.

PubMed

Parkins, C W; Colombo, J

1987-12-31

Single auditory-nerve neuron thresholds were studied in sensory-deafened squirrel monkeys to determine the effects of electrical stimulus shape and frequency on single-neuron thresholds. Frequency was separated into its components, pulse width and pulse rate, which were analyzed separately. Square and sinusoidal pulse shapes were compared. There were no or questionably significant threshold differences in charge per phase between sinusoidal and square pulses of the same pulse width. There was a small (less than 0.5 dB) but significant threshold advantage for 200 microseconds/phase pulses delivered at low pulse rates (156 pps) compared to higher pulse rates (625 pps and 2500 pps). Pulse width was demonstrated to be the prime determinant of single-neuron threshold, resulting in strength-duration curves similar to other mammalian myelinated neurons, but with longer chronaxies. The most efficient electrical stimulus pulse width to use for cochlear implant stimulation was determined to be 100 microseconds/phase. This pulse width delivers the lowest charge/phase at threshold. The single-neuron strength-duration curves were compared to strength-duration curves of a computer model based on the specific anatomy of auditory-nerve neurons. The membrane capacitance and resulting chronaxie of the model can be varied by altering the length of the unmyelinated termination of the neuron, representing the unmyelinated portion of the neuron between the habenula perforata and the hair cell. This unmyelinated segment of the auditory-nerve neuron may be subject to aminoglycoside damage. Simulating a 10 micron unmyelinated termination for this model neuron produces a strength-duration curve that closely fits the single-neuron data obtained from aminoglycoside deafened animals. Both the model and the single-neuron strength-duration curves differ significantly from behavioral threshold data obtained from monkeys and humans with cochlear implants. This discrepancy can best be explained by the involvement of higher level neurologic processes in the behavioral responses. These findings suggest that the basic principles of neural membrane function must be considered in developing or analyzing electrical stimulation strategies for cochlear prostheses if the appropriate stimulation of frequency specific populations of auditory-nerve neurons is the objective.

5–HT and 5–HT-SO4, but not tryptophan or 5-HIAA levels in single feeding neurons track animal hunger state

PubMed Central

Hatcher, N. G.; Zhang, X.; Stuart, J. N.; Moroz, L. L.; Sweedler, J. V.; Gillette, R.

2014-01-01

Serotonin (5-HT) is an intrinsic modulator of neural network excitation states in gastropod molluscs. 5-HT and related indole metabolites were measured in single, well-characterized serotonergic neurons of the feeding motor network of the predatory sea-slug Pleurobranchaea californica. Indole amounts were compared between paired hungry and satiated animals. Levels of 5-HT and its metabolite 5-HT-SO4 in the metacerebral giant neurons were observed in amounts approximately four-fold and two-fold, respectively, below unfed partners 24 h after a satiating meal. Intracellular levels of 5-hydroxyindole acetic acid and of free tryptophan did not differ significantly with hunger state. These data demonstrate that neurotransmitter levels and their metabolites can vary in goal-directed neural networks in a manner that follows internal state. PMID:18036151

Coding stimulus amplitude by correlated neural activity

NASA Astrophysics Data System (ADS)

Metzen, Michael G.; Ávila-Åkerberg, Oscar; Chacron, Maurice J.

2015-04-01

While correlated activity is observed ubiquitously in the brain, its role in neural coding has remained controversial. Recent experimental results have demonstrated that correlated but not single-neuron activity can encode the detailed time course of the instantaneous amplitude (i.e., envelope) of a stimulus. These have furthermore demonstrated that such coding required and was optimal for a nonzero level of neural variability. However, a theoretical understanding of these results is still lacking. Here we provide a comprehensive theoretical framework explaining these experimental findings. Specifically, we use linear response theory to derive an expression relating the correlation coefficient to the instantaneous stimulus amplitude, which takes into account key single-neuron properties such as firing rate and variability as quantified by the coefficient of variation. The theoretical prediction was in excellent agreement with numerical simulations of various integrate-and-fire type neuron models for various parameter values. Further, we demonstrate a form of stochastic resonance as optimal coding of stimulus variance by correlated activity occurs for a nonzero value of noise intensity. Thus, our results provide a theoretical explanation of the phenomenon by which correlated but not single-neuron activity can code for stimulus amplitude and how key single-neuron properties such as firing rate and variability influence such coding. Correlation coding by correlated but not single-neuron activity is thus predicted to be a ubiquitous feature of sensory processing for neurons responding to weak input.

Gender differences in human single neuron responses to male emotional faces.

PubMed

Newhoff, Morgan; Treiman, David M; Smith, Kris A; Steinmetz, Peter N

2015-01-01

Well-documented differences in the psychology and behavior of men and women have spurred extensive exploration of gender's role within the brain, particularly regarding emotional processing. While neuroanatomical studies clearly show differences between the sexes, the functional effects of these differences are less understood. Neuroimaging studies have shown inconsistent locations and magnitudes of gender differences in brain hemodynamic responses to emotion. To better understand the neurophysiology of these gender differences, we analyzed recordings of single neuron activity in the human brain as subjects of both genders viewed emotional expressions. This study included recordings of single-neuron activity of 14 (6 male) epileptic patients in four brain areas: amygdala (236 neurons), hippocampus (n = 270), anterior cingulate cortex (n = 256), and ventromedial prefrontal cortex (n = 174). Neural activity was recorded while participants viewed a series of avatar male faces portraying positive, negative or neutral expressions. Significant gender differences were found in the left amygdala, where 23% (n = 15∕66) of neurons in men were significantly affected by facial emotion, vs. 8% (n = 6∕76) of neurons in women. A Fisher's exact test comparing the two ratios found a highly significant difference between the two (p < 0.01). These results show specific differences between genders at the single-neuron level in the human amygdala. These differences may reflect gender-based distinctions in evolved capacities for emotional processing and also demonstrate the importance of including subject gender as an independent factor in future studies of emotional processing by single neurons in the human amygdala.

Multiplicative mixing of object identity and image attributes in single inferior temporal neurons.

PubMed

Ratan Murty, N Apurva; Arun, S P

2018-04-03

Object recognition is challenging because the same object can produce vastly different images, mixing signals related to its identity with signals due to its image attributes, such as size, position, rotation, etc. Previous studies have shown that both signals are present in high-level visual areas, but precisely how they are combined has remained unclear. One possibility is that neurons might encode identity and attribute signals multiplicatively so that each can be efficiently decoded without interference from the other. Here, we show that, in high-level visual cortex, responses of single neurons can be explained better as a product rather than a sum of tuning for object identity and tuning for image attributes. This subtle effect in single neurons produced substantially better population decoding of object identity and image attributes in the neural population as a whole. This property was absent both in low-level vision models and in deep neural networks. It was also unique to invariances: when tested with two-part objects, neural responses were explained better as a sum than as a product of part tuning. Taken together, our results indicate that signals requiring separate decoding, such as object identity and image attributes, are combined multiplicatively in IT neurons, whereas signals that require integration (such as parts in an object) are combined additively. Copyright © 2018 the Author(s). Published by PNAS.

Effects of O 2 and N 2/H 2 plasma treatments on the neuronal cell growth on single-walled carbon nanotube paper scaffolds

NASA Astrophysics Data System (ADS)

Yoon, Ok Ja; Lee, Hyun Jung; Jang, Yeong Mi; Kim, Hyun Woo; Lee, Won Bok; Kim, Sung Su; Lee, Nae-Eung

2011-08-01

The O 2 and N 2/H 2 plasma treatments of single-walled carbon nanotube (SWCNT) papers as scaffolds for enhanced neuronal cell growth were conducted to functionalize their surfaces with different functional groups and to roughen their surfaces. To evaluate the effects of the surface roughness and functionalization modifications of the SWCNT papers, we investigated the neuronal morphology, mitochondrial membrane potential, and acetylcholine/acetylcholinesterase levels of human neuroblastoma during SH-SY5Y cell growth on the treated SWCNT papers. Our results demonstrated that the plasma-chemical functionalization caused changes in the surface charge states with functional groups with negative and positive charges and then the increased surface roughness enhanced neuronal cell adhesion, mitochondrial membrane potential, and the level of neurotransmitter in vitro. The cell adhesion and mitochondrial membrane potential on the negatively charged SWCNT papers were improved more than on the positively charged SWCNT papers. Also, measurements of the neurotransmitter level showed an enhanced acetylcholine level on the negatively charged SWCNT papers compared to the positively charged SWCNT papers.

NBLAST: Rapid, Sensitive Comparison of Neuronal Structure and Construction of Neuron Family Databases.

PubMed

Costa, Marta; Manton, James D; Ostrovsky, Aaron D; Prohaska, Steffen; Jefferis, Gregory S X E

2016-07-20

Neural circuit mapping is generating datasets of tens of thousands of labeled neurons. New computational tools are needed to search and organize these data. We present NBLAST, a sensitive and rapid algorithm, for measuring pairwise neuronal similarity. NBLAST considers both position and local geometry, decomposing neurons into short segments; matched segments are scored using a probabilistic scoring matrix defined by statistics of matches and non-matches. We validated NBLAST on a published dataset of 16,129 single Drosophila neurons. NBLAST can distinguish neuronal types down to the finest level (single identified neurons) without a priori information. Cluster analysis of extensively studied neuronal classes identified new types and unreported topographical features. Fully automated clustering organized the validation dataset into 1,052 clusters, many of which map onto previously described neuronal types. NBLAST supports additional query types, including searching neurons against transgene expression patterns. Finally, we show that NBLAST is effective with data from other invertebrates and zebrafish. VIDEO ABSTRACT. Copyright © 2016 MRC Laboratory of Molecular Biology. Published by Elsevier Inc. All rights reserved.

L-type calcium channels refine the neural population code of sound level

PubMed Central

Grimsley, Calum Alex; Green, David Brian

2016-01-01

The coding of sound level by ensembles of neurons improves the accuracy with which listeners identify how loud a sound is. In the auditory system, the rate at which neurons fire in response to changes in sound level is shaped by local networks. Voltage-gated conductances alter local output by regulating neuronal firing, but their role in modulating responses to sound level is unclear. We tested the effects of L-type calcium channels (CaL: CaV1.1–1.4) on sound-level coding in the central nucleus of the inferior colliculus (ICC) in the auditory midbrain. We characterized the contribution of CaL to the total calcium current in brain slices and then examined its effects on rate-level functions (RLFs) in vivo using single-unit recordings in awake mice. CaL is a high-threshold current and comprises ∼50% of the total calcium current in ICC neurons. In vivo, CaL activates at sound levels that evoke high firing rates. In RLFs that increase monotonically with sound level, CaL boosts spike rates at high sound levels and increases the maximum firing rate achieved. In different populations of RLFs that change nonmonotonically with sound level, CaL either suppresses or enhances firing at sound levels that evoke maximum firing. CaL multiplies the gain of monotonic RLFs with dynamic range and divides the gain of nonmonotonic RLFs with the width of the RLF. These results suggest that a single broad class of calcium channels activates enhancing and suppressing local circuits to regulate the sensitivity of neuronal populations to sound level. PMID:27605536

High-throughput dual-colour precision imaging for brain-wide connectome with cytoarchitectonic landmarks at the cellular level

PubMed Central

Gong, Hui; Xu, Dongli; Yuan, Jing; Li, Xiangning; Guo, Congdi; Peng, Jie; Li, Yuxin; Schwarz, Lindsay A.; Li, Anan; Hu, Bihe; Xiong, Benyi; Sun, Qingtao; Zhang, Yalun; Liu, Jiepeng; Zhong, Qiuyuan; Xu, Tonghui; Zeng, Shaoqun; Luo, Qingming

2016-01-01

The precise annotation and accurate identification of neural structures are prerequisites for studying mammalian brain function. The orientation of neurons and neural circuits is usually determined by mapping brain images to coarse axial-sampling planar reference atlases. However, individual differences at the cellular level likely lead to position errors and an inability to orient neural projections at single-cell resolution. Here, we present a high-throughput precision imaging method that can acquire a co-localized brain-wide data set of both fluorescent-labelled neurons and counterstained cell bodies at a voxel size of 0.32 × 0.32 × 2.0 μm in 3 days for a single mouse brain. We acquire mouse whole-brain imaging data sets of multiple types of neurons and projections with anatomical annotation at single-neuron resolution. The results show that the simultaneous acquisition of labelled neural structures and cytoarchitecture reference in the same brain greatly facilitates precise tracing of long-range projections and accurate locating of nuclei. PMID:27374071

Immunocytochemistry and fluorescence imaging efficiently identify individual neurons with CRISPR/Cas9-mediated gene disruption in primary cortical cultures.

PubMed

Tsunematsu, Hiroto; Uyeda, Akiko; Yamamoto, Nobuhiko; Sugo, Noriyuki

2017-08-01

CRISPR/Cas9 system is a powerful method to investigate the role of genes by introducing a mutation selectively and efficiently to specific genome positions in cell and animal lines. However, in primary neuron cultures, this method is affected by the issue that the effectiveness of CRISPR/Cas9 is different in each neuron. Here, we report an easy, quick and reliable method to identify mutants induced by the CRISPR/Cas9 system at a single neuron level, using immunocytochemistry (ICC) and fluorescence imaging. Dissociated cortical cells were transfected with CRISPR/Cas9 plasmids targeting the transcription factor cAMP-response element binding protein (CREB). Fluorescence ICC with CREB antibody and quantitative analysis of fluorescence intensity demonstrated that CREB expression disappeared in a fraction of the transfected neurons. The downstream FOS expression was also decreased in accordance with suppressed CREB expression. Moreover, dendritic arborization was decreased in the transfected neurons which lacked CREB immunoreactivity. Detection of protein expression is efficient to identify individual postmitotic neurons with CRISPR/Cas9-mediated gene disruption in primary cortical cultures. The present method composed of CRISPR/Cas9 system, ICC and fluorescence imaging is applicable to study the function of various genes at a single-neuron level.

Mitochondrial DNA Depletion in Respiratory Chain-Deficient Parkinson Disease Neurons.

PubMed

Grünewald, Anne; Rygiel, Karolina A; Hepplewhite, Philippa D; Morris, Christopher M; Picard, Martin; Turnbull, Doug M

2016-03-01

To determine the extent of respiratory chain abnormalities and investigate the contribution of mtDNA to the loss of respiratory chain complexes (CI-IV) in the substantia nigra (SN) of idiopathic Parkinson disease (IPD) patients at the single-neuron level. Multiple-label immunofluorescence was applied to postmortem sections of 10 IPD patients and 10 controls to quantify the abundance of CI-IV subunits (NDUFB8 or NDUFA13, SDHA, UQCRC2, and COXI) and mitochondrial transcription factors (TFAM and TFB2M) relative to mitochondrial mass (porin and GRP75) in dopaminergic neurons. To assess the involvement of mtDNA in respiratory chain deficiency in IPD, SN neurons, isolated with laser-capture microdissection, were assayed for mtDNA deletions, copy number, and presence of transcription/replication-associated 7S DNA employing a triplex real-time polymerase chain reaction (PCR) assay. Whereas mitochondrial mass was unchanged in single SN neurons from IPD patients, we observed a significant reduction in the abundances of CI and II subunits. At the single-cell level, CI and II deficiencies were correlated in patients. The CI deficiency concomitantly occurred with low abundances of the mtDNA transcription factors TFAM and TFB2M, which also initiate transcription-primed mtDNA replication. Consistent with this, real-time PCR analysis revealed fewer transcription/replication-associated mtDNA molecules and an overall reduction in mtDNA copy number in patients. This effect was more pronounced in single IPD neurons with severe CI deficiency. Respiratory chain dysfunction in IPD neurons not only involves CI, but also extends to CII. These deficiencies are possibly a consequence of the interplay between nDNA and mtDNA-encoded factors mechanistically connected via TFAM. © 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

Scientific basis for learning transfer from movements to urinary bladder functions for bladder repair in human patients with CNS injury.

PubMed

Schalow, G

2010-01-01

Coordination Dynamics Therapy (CDT) has been shown to be able to partly repair CNS injury. The repair is based on a movement-based re-learning theory which requires at least three levels of description: the movement or pattern (and anamnesis) level, the collective variable level, and the neuron level. Upon CDT not only the actually performed movement pattern itself is repaired, but the entire dynamics of CNS organization is improved, which is the theoretical basis for (re-) learning transfer. The transfer of learning for repair from jumping on springboard and exercising on a special CDT and recording device to urinary bladder functions is investigated at the neuron level. At the movement or pattern level, the improvement of central nervous system (CNS) functioning in human patients can be seen (or partly measured) by the improvement of the performance of the pattern. At the collective variable level, coordination tendencies can be measured by the so-called 'coordination dynamics' before, during and after treatment. At the neuron level, re-learning can additionally be assessed by surface electromyography (sEMG) as alterations of single motor unit firings and motor programs. But to express the ongoing interaction between the numerous neural, muscular, and metabolic elements involved in perception and action, it is relevant to inquire how the individual afferent and efferent neurons adjust their phase and frequency coordination to other neurons to satisfy learning task requirements. With the single-nerve fibre action potential recording method it was possible to measure that distributed single neurons communicate by phase and frequency coordination. It is shown that this timed firing of neurons is getting impaired upon injury and has to be improved by learning The stability of phase and frequency coordination among afferent and efferent neuron firings can be related to pattern stability. The stability of phase and frequency coordination at the neuron level can therefore be assessed integratively at the (non-invasive) collective variable level by the arrhythmicity of turning (coordination dynamics) when a patient is exercising on a special CDT device. Upon jumping on springboard and exercising on the special CDT device, the intertwined neuronal networks, subserving movements (somatic) and urinary bladder functions (autonomic and somatic) in the sacral spinal cord, are synchronously activated and entrained to give rise to learning transfer from movements to bladder functions. Jumping on springboard and other movements primarily repair the pattern dynamics, whereas the exactly coordinated performed movements, performed on the special CDT device for turning, primarily improve the preciseness of the timed firing of neurons. The synchronous learning of perceptuomotor and perceptuobladder functioning from a dynamical perspective (giving rise to learning transfer) can be understood at the neuron level. Especially the activated phase and frequency coordination upon natural stimulation under physiologic and pathophysiologic conditions among a and gamma-motoneurons, muscle spindle afferents, touch and pain afferents, and urinary bladder stretch and tension receptor afferents in the human sacral spinal cord make understandable that somatic and parasympathetic functions are integrated in their functioning and give rise to learning transfer from movements to bladder functions. The power of this human treatment research project lies in the unit of theory, diagnostic/measurement, and praxis, namely that CNS injury can partly be repaired, including urinary bladder functions, and the repair can partly be understood even at the neuron level of description in human.

Single-cell imaging of bioenergetic responses to neuronal excitotoxicity and oxygen and glucose deprivation.

PubMed

Connolly, Niamh M C; Düssmann, Heiko; Anilkumar, Ujval; Huber, Heinrich J; Prehn, Jochen H M

2014-07-30

Excitotoxicity is a condition occurring during cerebral ischemia, seizures, and chronic neurodegeneration. It is characterized by overactivation of glutamate receptors, leading to excessive Ca(2+)/Na(+) influx into neurons, energetic stress, and subsequent neuronal injury. We and others have previously investigated neuronal populations to study how bioenergetic parameters determine neuronal injury; however, such experiments are often confounded by population-based heterogeneity and the contribution of effects of non-neuronal cells. Hence, we here characterized bioenergetics during transient excitotoxicity in rat and mouse primary neurons at the single-cell level using fluorescent sensors for intracellular glucose, ATP, and activation of the energy sensor AMP-activated protein kinase (AMPK). We identified ATP depletion and recovery to energetic homeostasis, along with AMPK activation, as surprisingly rapid and plastic responses in two excitotoxic injury paradigms. We observed rapid recovery of neuronal ATP levels also in the absence of extracellular glucose, or when glycolytic ATP production was inhibited, but found mitochondria to be critical for fast and complete energetic recovery. Using an injury model of oxygen and glucose deprivation, we identified a similarly rapid bioenergetics response, yet with incomplete ATP recovery and decreased AMPK activity. Interestingly, excitotoxicity also induced an accumulation of intracellular glucose, providing an additional source of energy during and after excitotoxicity-induced energy depletion. We identified this to originate from extracellular, AMPK-dependent glucose uptake and from intracellular glucose mobilization. Surprisingly, cells recovering their elevated glucose levels faster to baseline survived longer, indicating that the plasticity of neurons to adapt to bioenergetic challenges is a key indicator of neuronal viability. Copyright © 2014 the authors 0270-6474/14/3410192-14$15.00/0.

Gender differences in human single neuron responses to male emotional faces

PubMed Central

Newhoff, Morgan; Treiman, David M.; Smith, Kris A.; Steinmetz, Peter N.

2015-01-01

Well-documented differences in the psychology and behavior of men and women have spurred extensive exploration of gender's role within the brain, particularly regarding emotional processing. While neuroanatomical studies clearly show differences between the sexes, the functional effects of these differences are less understood. Neuroimaging studies have shown inconsistent locations and magnitudes of gender differences in brain hemodynamic responses to emotion. To better understand the neurophysiology of these gender differences, we analyzed recordings of single neuron activity in the human brain as subjects of both genders viewed emotional expressions. This study included recordings of single-neuron activity of 14 (6 male) epileptic patients in four brain areas: amygdala (236 neurons), hippocampus (n = 270), anterior cingulate cortex (n = 256), and ventromedial prefrontal cortex (n = 174). Neural activity was recorded while participants viewed a series of avatar male faces portraying positive, negative or neutral expressions. Significant gender differences were found in the left amygdala, where 23% (n = 15∕66) of neurons in men were significantly affected by facial emotion, vs. 8% (n = 6∕76) of neurons in women. A Fisher's exact test comparing the two ratios found a highly significant difference between the two (p < 0.01). These results show specific differences between genders at the single-neuron level in the human amygdala. These differences may reflect gender-based distinctions in evolved capacities for emotional processing and also demonstrate the importance of including subject gender as an independent factor in future studies of emotional processing by single neurons in the human amygdala. PMID:26441597

Biomechanics of Single Cortical Neurons

PubMed Central

Bernick, Kristin B.; Prevost, Thibault P.; Suresh, Subra; Socrate, Simona

2011-01-01

This study presents experimental results and computational analysis of the large strain dynamic behavior of single neurons in vitro with the objective of formulating a novel quantitative framework for the biomechanics of cortical neurons. Relying on the atomic force microscopy (AFM) technique, novel testing protocols are developed to enable the characterization of neural soma deformability over a range of indentation rates spanning three orders of magnitude – 10, 1, and 0.1 μm/s. Modified spherical AFM probes were utilized to compress the cell bodies of neonatal rat cortical neurons in load, unload, reload and relaxation conditions. The cell response showed marked hysteretic features, strong non-linearities, and substantial time/rate dependencies. The rheological data were complemented with geometrical measurements of cell body morphology, i.e. cross-diameter and height estimates. A constitutive model, validated by the present experiments, is proposed to quantify the mechanical behavior of cortical neurons. The model aimed to correlate empirical findings with measurable degrees of (hyper-) elastic resilience and viscosity at the cell level. The proposed formulation, predicated upon previous constitutive model developments undertaken at the cortical tissue level, was implemented into a three-dimensional finite element framework. The simulated cell response was calibrated to the experimental measurements under the selected test conditions, providing a novel single cell model that could form the basis for further refinements. PMID:20971217

Elucidating distinct ion channel populations on the surface of hippocampal neurons via single-particle tracking recurrence analysis

NASA Astrophysics Data System (ADS)

Sikora, Grzegorz; Wyłomańska, Agnieszka; Gajda, Janusz; Solé, Laura; Akin, Elizabeth J.; Tamkun, Michael M.; Krapf, Diego

2017-12-01

Protein and lipid nanodomains are prevalent on the surface of mammalian cells. In particular, it has been recently recognized that ion channels assemble into surface nanoclusters in the soma of cultured neurons. However, the interactions of these molecules with surface nanodomains display a considerable degree of heterogeneity. Here, we investigate this heterogeneity and develop statistical tools based on the recurrence of individual trajectories to identify subpopulations within ion channels in the neuronal surface. We specifically study the dynamics of the K+ channel Kv1.4 and the Na+ channel Nav1.6 on the surface of cultured hippocampal neurons at the single-molecule level. We find that both these molecules are expressed in two different forms with distinct kinetics with regards to surface interactions, emphasizing the complex proteomic landscape of the neuronal surface. Further, the tools presented in this work provide new methods for the analysis of membrane nanodomains, transient confinement, and identification of populations within single-particle trajectories.

Selective Neuronal Activation by Cochlear Implant Stimulation in Auditory Cortex of Awake Primate

PubMed Central

Johnson, Luke A.; Della Santina, Charles C.

2016-01-01

Despite the success of cochlear implants (CIs) in human populations, most users perform poorly in noisy environments and music and tonal language perception. How CI devices engage the brain at the single neuron level has remained largely unknown, in particular in the primate brain. By comparing neuronal responses with acoustic and CI stimulation in marmoset monkeys unilaterally implanted with a CI electrode array, we discovered that CI stimulation was surprisingly ineffective at activating many neurons in auditory cortex, particularly in the hemisphere ipsilateral to the CI. Further analyses revealed that the CI-nonresponsive neurons were narrowly tuned to frequency and sound level when probed with acoustic stimuli; such neurons likely play a role in perceptual behaviors requiring fine frequency and level discrimination, tasks that CI users find especially challenging. These findings suggest potential deficits in central auditory processing of CI stimulation and provide important insights into factors responsible for poor CI user performance in a wide range of perceptual tasks. SIGNIFICANCE STATEMENT The cochlear implant (CI) is the most successful neural prosthetic device to date and has restored hearing in hundreds of thousands of deaf individuals worldwide. However, despite its huge successes, CI users still face many perceptual limitations, and the brain mechanisms involved in hearing through CI devices remain poorly understood. By directly comparing single-neuron responses to acoustic and CI stimulation in auditory cortex of awake marmoset monkeys, we discovered that neurons unresponsive to CI stimulation were sharply tuned to frequency and sound level. Our results point out a major deficit in central auditory processing of CI stimulation and provide important insights into mechanisms underlying the poor CI user performance in a wide range of perceptual tasks. PMID:27927962

Individual mediodorsal thalamic neurons project to multiple areas of the rat prefrontal cortex: A single neuron-tracing study using virus vectors.

PubMed

Kuramoto, Eriko; Pan, Shixiu; Furuta, Takahiro; Tanaka, Yasuhiro R; Iwai, Haruki; Yamanaka, Atsushi; Ohno, Sachi; Kaneko, Takeshi; Goto, Tetsuya; Hioki, Hiroyuki

2017-01-01

The prefrontal cortex has an important role in a variety of cognitive and executive processes, and is generally defined by its reciprocal connections with the mediodorsal thalamic nucleus (MD). The rat MD is mainly subdivided into three segments, the medial (MDm), central (MDc), and lateral (MDl) divisions, on the basis of the cytoarchitecture and chemoarchitecture. The MD segments are known to topographically project to multiple prefrontal areas at the population level: the MDm mainly to the prelimbic, infralimbic, and agranular insular areas; the MDc to the orbital and agranular insular areas; and the MDl to the prelimbic and anterior cingulate areas. However, it is unknown whether individual MD neurons project to single or multiple prefrontal cortical areas. In the present study, we visualized individual MD neurons with Sindbis virus vectors, and reconstructed whole structures of MD neurons. While the main cortical projection targets of MDm, MDc, and MDl neurons were generally consistent with those of previous results, it was found that individual MD neurons sent their axon fibers to multiple prefrontal areas, and displayed various projection patterns in the target areas. Furthermore, the axons of single MD neurons were not homogeneously spread, but were rather distributed to form patchy axon arbors approximately 1 mm in diameter. The multiple-area projections and patchy axon arbors of single MD neurons might be able to coactivate cortical neuron groups in distant prefrontal areas simultaneously. Furthermore, considerable heterogeneity of the projection patterns is likely, to recruit the different sets of cortical neurons, and thus contributes to a variety of prefrontal functions. J. Comp. Neurol. 525:166-185, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Regulating anxiety with extrasynaptic inhibition

PubMed Central

Botta, Paolo; Demmou, Lynda; Kasugai, Yu; Markovic, Milica; Xu, Chun; Fadok, Jonathan P.; Lu, Tingjia; Poe, Michael M.; Xu, Li; Cook, James M.; Rudolph, Uwe; Sah, Pankaj; Ferraguti, Francesco; Lüthi, Andreas

2015-01-01

Aversive experiences can lead to complex behavioral adaptations including increased levels of anxiety and fear generalization. The neuronal mechanisms underlying such maladaptive behavioral changes, however, are poorly understood. Here, using a combination of behavioral, physiological and optogenetic approaches in mouse, we identify a specific subpopulation of central amygdala neurons expressing protein kinase C δ (PKCδ) as key elements of the neuronal circuitry controlling anxiety. Moreover, we show that aversive experiences induce anxiety and fear generalization by regulating the activity of PKCδ+ neurons via extrasynaptic inhibition mediated by α5 subunit-containing GABAA receptors. Our findings reveal that the neuronal circuits that mediate fear and anxiety overlap at the level of defined subpopulations of central amygdala neurons and demonstrate that persistent changes in the excitability of a single cell type can orchestrate complex behavioral changes. PMID:26322928

L-type calcium channels refine the neural population code of sound level.

PubMed

Grimsley, Calum Alex; Green, David Brian; Sivaramakrishnan, Shobhana

2016-12-01

The coding of sound level by ensembles of neurons improves the accuracy with which listeners identify how loud a sound is. In the auditory system, the rate at which neurons fire in response to changes in sound level is shaped by local networks. Voltage-gated conductances alter local output by regulating neuronal firing, but their role in modulating responses to sound level is unclear. We tested the effects of L-type calcium channels (Ca L : Ca V 1.1-1.4) on sound-level coding in the central nucleus of the inferior colliculus (ICC) in the auditory midbrain. We characterized the contribution of Ca L to the total calcium current in brain slices and then examined its effects on rate-level functions (RLFs) in vivo using single-unit recordings in awake mice. Ca L is a high-threshold current and comprises ∼50% of the total calcium current in ICC neurons. In vivo, Ca L activates at sound levels that evoke high firing rates. In RLFs that increase monotonically with sound level, Ca L boosts spike rates at high sound levels and increases the maximum firing rate achieved. In different populations of RLFs that change nonmonotonically with sound level, Ca L either suppresses or enhances firing at sound levels that evoke maximum firing. Ca L multiplies the gain of monotonic RLFs with dynamic range and divides the gain of nonmonotonic RLFs with the width of the RLF. These results suggest that a single broad class of calcium channels activates enhancing and suppressing local circuits to regulate the sensitivity of neuronal populations to sound level. Copyright © 2016 the American Physiological Society.

Modeling somatic and dendritic spike mediated plasticity at the single neuron and network level.

PubMed

Bono, Jacopo; Clopath, Claudia

2017-09-26

Synaptic plasticity is thought to be the principal neuronal mechanism underlying learning. Models of plastic networks typically combine point neurons with spike-timing-dependent plasticity (STDP) as the learning rule. However, a point neuron does not capture the local non-linear processing of synaptic inputs allowed for by dendrites. Furthermore, experimental evidence suggests that STDP is not the only learning rule available to neurons. By implementing biophysically realistic neuron models, we study how dendrites enable multiple synaptic plasticity mechanisms to coexist in a single cell. In these models, we compare the conditions for STDP and for synaptic strengthening by local dendritic spikes. We also explore how the connectivity between two cells is affected by these plasticity rules and by different synaptic distributions. Finally, we show that how memory retention during associative learning can be prolonged in networks of neurons by including dendrites.Synaptic plasticity is the neuronal mechanism underlying learning. Here the authors construct biophysical models of pyramidal neurons that reproduce observed plasticity gradients along the dendrite and show that dendritic spike dependent LTP which is predominant in distal sections can prolong memory retention.

Developmental emergence of different forms of neuromodulation in Aplysia sensory neurons.

PubMed

Marcus, E A; Carew, T J

1998-04-14

The capacity for neuromodulation and biophysical plasticity is a defining feature of most mature neuronal cell types. In several cases, modulation at the level of the individual neuron has been causally linked to changes in the functional output of a neuronal circuit and subsequent adaptive changes in the organism's behavioral responses. Understanding how such capacity for neuromodulation develops therefore may provide insights into the mechanisms both of neuronal development and learning and memory. We have examined the development of multiple forms of neuromodulation triggered by a common neurotransmitter, serotonin, in the pleural sensory neurons of Aplysia californica. We have found that multiple signaling cascades within a single neuron develop sequentially, with some being expressed only very late in development. In addition, our data suggest a model in which, within a single neuromodulatory pathway, the elements of the signaling cascade are developmentally expressed in a "retrograde" manner with the ionic channel that is modulated appearing early in development, functional elements in the second messenger cascade appearing later, and finally, coupling of the second messenger cascade to the serotonin receptor appearing quite late. These studies provide the characterization of the development of neuromodulation at the level of an identified cell type and offer insights into the potential roles of neuromodulatory processes in development and adult plasticity.

Estradiol selectively enhances auditory function in avian forebrain neurons

PubMed Central

Caras, Melissa L.; O’Brien, Matthew; Brenowitz, Eliot A.; Rubel, Edwin W

2012-01-01

Sex steroids modulate vertebrate sensory processing, but the impact of circulating hormone levels on forebrain function remains unclear. We tested the hypothesis that circulating sex steroids modulate single-unit responses in the avian telencephalic auditory nucleus, field L. We mimicked breeding or non-breeding conditions by manipulating plasma 17β-estradiol levels in wild-caught female Gambel’s white-crowned sparrows (Zonotrichia leucophrys gambelii). Extracellular responses of single neurons to tones and conspecific songs presented over a range of intensities revealed that estradiol selectively enhanced auditory function in cells that exhibited monotonic rate-level functions to pure tones. In these cells, estradiol treatment increased spontaneous and maximum evoked firing rates, increased pure tone response strengths and sensitivity, and expanded the range of intensities over which conspecific song stimuli elicited significant responses. Estradiol did not significantly alter the sensitivity or dynamic ranges of cells that exhibited non-monotonic rate-level functions. Notably, there was a robust correlation between plasma estradiol concentrations in individual birds and physiological response properties in monotonic, but not non-monotonic neurons. These findings demonstrate that functionally distinct classes of anatomically overlapping forebrain neurons are differentially regulated by sex steroid hormones in a dose-dependent manner. PMID:23223283

Characterizing Human Stem Cell–derived Sensory Neurons at the Single-cell Level Reveals Their Ion Channel Expression and Utility in Pain Research

PubMed Central

Young, Gareth T; Gutteridge, Alex; Fox, Heather DE; Wilbrey, Anna L; Cao, Lishuang; Cho, Lily T; Brown, Adam R; Benn, Caroline L; Kammonen, Laura R; Friedman, Julia H; Bictash, Magda; Whiting, Paul; Bilsland, James G; Stevens, Edward B

2014-01-01

The generation of human sensory neurons by directed differentiation of pluripotent stem cells opens new opportunities for investigating the biology of pain. The inability to generate this cell type has meant that up until now their study has been reliant on the use of rodent models. Here, we use a combination of population and single-cell techniques to perform a detailed molecular, electrophysiological, and pharmacological phenotyping of sensory neurons derived from human embryonic stem cells. We describe the evolution of cell populations over 6 weeks of directed differentiation; a process that results in the generation of a largely homogeneous population of neurons that are both molecularly and functionally comparable to human sensory neurons derived from mature dorsal root ganglia. This work opens the prospect of using pluripotent stem-cell–derived sensory neurons to study human neuronal physiology and as in vitro models for drug discovery in pain and sensory disorders. PMID:24832007

Characterizing human stem cell-derived sensory neurons at the single-cell level reveals their ion channel expression and utility in pain research.

PubMed

Young, Gareth T; Gutteridge, Alex; Fox, Heather DE; Wilbrey, Anna L; Cao, Lishuang; Cho, Lily T; Brown, Adam R; Benn, Caroline L; Kammonen, Laura R; Friedman, Julia H; Bictash, Magda; Whiting, Paul; Bilsland, James G; Stevens, Edward B

2014-08-01

The generation of human sensory neurons by directed differentiation of pluripotent stem cells opens new opportunities for investigating the biology of pain. The inability to generate this cell type has meant that up until now their study has been reliant on the use of rodent models. Here, we use a combination of population and single-cell techniques to perform a detailed molecular, electrophysiological, and pharmacological phenotyping of sensory neurons derived from human embryonic stem cells. We describe the evolution of cell populations over 6 weeks of directed differentiation; a process that results in the generation of a largely homogeneous population of neurons that are both molecularly and functionally comparable to human sensory neurons derived from mature dorsal root ganglia. This work opens the prospect of using pluripotent stem-cell-derived sensory neurons to study human neuronal physiology and as in vitro models for drug discovery in pain and sensory disorders.

Interplay between population firing stability and single neuron dynamics in hippocampal networks

PubMed Central

Slomowitz, Edden; Styr, Boaz; Vertkin, Irena; Milshtein-Parush, Hila; Nelken, Israel; Slutsky, Michael; Slutsky, Inna

2015-01-01

Neuronal circuits' ability to maintain the delicate balance between stability and flexibility in changing environments is critical for normal neuronal functioning. However, to what extent individual neurons and neuronal populations maintain internal firing properties remains largely unknown. In this study, we show that distributions of spontaneous population firing rates and synchrony are subject to accurate homeostatic control following increase of synaptic inhibition in cultured hippocampal networks. Reduction in firing rate triggered synaptic and intrinsic adaptive responses operating as global homeostatic mechanisms to maintain firing macro-stability, without achieving local homeostasis at the single-neuron level. Adaptive mechanisms, while stabilizing population firing properties, reduced short-term facilitation essential for synaptic discrimination of input patterns. Thus, invariant ongoing population dynamics emerge from intrinsically unstable activity patterns of individual neurons and synapses. The observed differences in the precision of homeostatic control at different spatial scales challenge cell-autonomous theory of network homeostasis and suggest the existence of network-wide regulation rules. DOI: http://dx.doi.org/10.7554/eLife.04378.001 PMID:25556699

Tools for probing local circuits: high-density silicon probes combined with optogenetics

PubMed Central

Buzsáki, György; Stark, Eran; Berényi, Antal; Khodagholy, Dion; Kipke, Daryl R.; Yoon, Euisik; Wise, Kensall

2015-01-01

To understand how function arises from the interactions between neurons, it is necessary to use methods that allow the monitoring of brain activity at the single-neuron, single-spike level and the targeted manipulation of the diverse neuron types selectively in a closed-loop manner. Large-scale recordings of neuronal spiking combined with optogenetic perturbation of identified individual neurons has emerged as a suitable method for such tasks in behaving animals. To fully exploit the potential power of these methods, multiple steps of technical innovation are needed. We highlight the current state-of-the-art in electrophysiological recording methods, combined with optogenetics, and discuss directions for progress. In addition, we point to areas where rapid development is in progress and discuss topics where near-term improvements are possible and needed. PMID:25856489

Sensory Afferents Use Different Coding Strategies for Heat and Cold.

PubMed

Wang, Feng; Bélanger, Erik; Côté, Sylvain L; Desrosiers, Patrick; Prescott, Steven A; Côté, Daniel C; De Koninck, Yves

2018-05-15

Primary afferents transduce environmental stimuli into electrical activity that is transmitted centrally to be decoded into corresponding sensations. However, it remains unknown how afferent populations encode different somatosensory inputs. To address this, we performed two-photon Ca 2+ imaging from thousands of dorsal root ganglion (DRG) neurons in anesthetized mice while applying mechanical and thermal stimuli to hind paws. We found that approximately half of all neurons are polymodal and that heat and cold are encoded very differently. As temperature increases, more heating-sensitive neurons are activated, and most individual neurons respond more strongly, consistent with graded coding at population and single-neuron levels, respectively. In contrast, most cooling-sensitive neurons respond in an ungraded fashion, inconsistent with graded coding and suggesting combinatorial coding, based on which neurons are co-activated. Although individual neurons may respond to multiple stimuli, our results show that different stimuli activate distinct combinations of diversely tuned neurons, enabling rich population-level coding. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

One nuclear calcium transient induced by a single burst of action potentials represents the minimum signal strength in activity-dependent transcription in hippocampal neurons.

PubMed

Yu, Yan; Oberlaender, Kristin; Bengtson, C Peter; Bading, Hilmar

2017-07-01

Neurons undergo dramatic changes in their gene expression profiles in response to synaptic stimulation. The coupling of neuronal excitation to gene transcription is well studied and is mediated by signaling pathways activated by cytoplasmic and nuclear calcium transients. Despite this, the minimum synaptic activity required to induce gene expression remains unknown. To address this, we used cultured hippocampal neurons and cellular compartment analysis of temporal activity by fluorescence in situ hybridization (catFISH) that allows detection of nascent transcripts in the cell nucleus. We found that a single burst of action potentials, consisting of 24.4±5.1 action potentials during a 6.7±1.9s depolarization of 19.5±2.0mV causing a 9.3±0.9s somatic calcium transient, is sufficient to activate transcription of the immediate early gene arc (also known as Arg3.1). The total arc mRNA yield produced after a single burst-induced nuclear calcium transient was very small and, compared to unstimulated control neurons, did not lead to a significant increase in arc mRNA levels measured using quantitative reverse transcriptase PCR (qRT-PCR) of cell lysates. Significantly increased arc mRNA levels became detectable in hippocampal neurons that had undergone 5-8 consecutive burst-induced nuclear calcium transients at 0.05-0.15Hz. These results indicate that a single burst-induced nuclear calcium transient can activate gene expression and that transcription is rapidly shut off after synaptic stimulation has ceased. Copyright © 2017 Elsevier Ltd. All rights reserved.

Convergence of Cortical and Sensory Driver Inputs on Single Thalamocortical Cells

PubMed Central

Groh, Alexander; Bokor, Hajnalka; Mease, Rebecca A.; Plattner, Viktor M.; Hangya, Balázs; Stroh, Albrecht; Deschenes, Martin; Acsády, László

2014-01-01

Ascending and descending information is relayed through the thalamus via strong, “driver” pathways. According to our current knowledge, different driver pathways are organized in parallel streams and do not interact at the thalamic level. Using an electron microscopic approach combined with optogenetics and in vivo physiology, we examined whether driver inputs arising from different sources can interact at single thalamocortical cells in the rodent somatosensory thalamus (nucleus posterior, POm). Both the anatomical and the physiological data demonstrated that ascending driver inputs from the brainstem and descending driver inputs from cortical layer 5 pyramidal neurons converge and interact on single thalamocortical neurons in POm. Both individual pathways displayed driver properties, but they interacted synergistically in a time-dependent manner and when co-activated, supralinearly increased the output of thalamus. As a consequence, thalamocortical neurons reported the relative timing between sensory events and ongoing cortical activity. We conclude that thalamocortical neurons can receive 2 powerful inputs of different origin, rather than only a single one as previously suggested. This allows thalamocortical neurons to integrate raw sensory information with powerful cortical signals and transfer the integrated activity back to cortical networks. PMID:23825316

Segregation of feedforward and feedback projections in mouse visual cortex

PubMed Central

Berezovskii, Vladimir K.; Nassi, Jonathan J.; Born, Richard T.

2011-01-01

Hierarchical organization is a common feature of mammalian neocortex. Neurons that send their axons from lower to higher areas of the hierarchy are referred to as “feedforward” (FF) neurons, whereas those projecting in the opposite direction are called “feedback” (FB) neurons. Anatomical, functional and theoretical studies suggest that these different classes of projections play fundamentally different roles in perception. In primates, laminar differences in projection patterns often distinguish the two projection streams. In rodents, however, these differences are less clear, despite an established hierarchy of visual areas. Thus the rodent provides a strong test of the hypothesis that FF and FB neurons form distinct populations. We tested this hypothesis by injecting retrograde tracers into two different hierarchical levels of mouse visual cortex (areas 17 and AL) and then determining the relative proportions of double-labeled FB and FF neurons in an area intermediate to them (LM). Despite finding singly labeled neurons densely intermingled with no laminar segregation, we found few double-labeled neurons (~5% of each singly labeled population). We also examined the development of FF and FB connections. FF connections were present at the earliest time-point we examined (postnatal day two, P2), while FB connections were not detectable until P11. Our findings indicate that, even in cortices without laminar segregation of FF and FB neurons, the two projection systems are largely distinct at the neuronal level and also differ with respect to the timing of their outgrowth. PMID:21618232

Alterations in neuronal activity in basal ganglia-thalamocortical circuits in the parkinsonian state

PubMed Central

Galvan, Adriana; Devergnas, Annaelle; Wichmann, Thomas

2015-01-01

In patients with Parkinson’s disease and in animal models of this disorder, neurons in the basal ganglia and related regions in thalamus and cortex show changes that can be recorded by using electrophysiologic single-cell recording techniques, including altered firing rates and patterns, pathologic oscillatory activity and increased inter-neuronal synchronization. In addition, changes in synaptic potentials or in the joint spiking activities of populations of neurons can be monitored as alterations in local field potentials (LFPs), electroencephalograms (EEGs) or electrocorticograms (ECoGs). Most of the mentioned electrophysiologic changes are probably related to the degeneration of diencephalic dopaminergic neurons, leading to dopamine loss in the striatum and other basal ganglia nuclei, although degeneration of non-dopaminergic cell groups may also have a role. The altered electrical activity of the basal ganglia and associated nuclei may contribute to some of the motor signs of the disease. We here review the current knowledge of the electrophysiologic changes at the single cell level, the level of local populations of neural elements, and the level of the entire basal ganglia-thalamocortical network in parkinsonism, and discuss the possible use of this information to optimize treatment approaches to Parkinson’s disease, such as deep brain stimulation (DBS) therapy. PMID:25698937

Visualizing the spinal neuronal dynamics of locomotion

NASA Astrophysics Data System (ADS)

Subramanian, Kalpathi R.; Bashor, D. P.; Miller, M. T.; Foster, J. A.

2004-06-01

Modern imaging and simulation techniques have enhanced system-level understanding of neural function. In this article, we present an application of interactive visualization to understanding neuronal dynamics causing locomotion of a single hip joint, based on pattern generator output of the spinal cord. Our earlier work visualized cell-level responses of multiple neuronal populations. However, the spatial relationships were abstract, making communication with colleagues difficult. We propose two approaches to overcome this: (1) building a 3D anatomical model of the spinal cord with neurons distributed inside, animated by the simulation and (2) adding limb movements predicted by neuronal activity. The new system was tested using a cat walking central pattern generator driving a pair of opposed spinal motoneuron pools. Output of opposing motoneuron pools was combined into a single metric, called "Net Neural Drive", which generated angular limb movement in proportion to its magnitude. Net neural drive constitutes a new description of limb movement control. The combination of spatial and temporal information in the visualizations elegantly conveys the neural activity of the output elements (motoneurons), as well as the resulting movement. The new system encompasses five biological levels of organization from ion channels to observed behavior. The system is easily scalable, and provides an efficient interactive platform for rapid hypothesis testing.

Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity

PubMed Central

Chiu, Isaac M; Barrett, Lee B; Williams, Erika K; Strochlic, David E; Lee, Seungkyu; Weyer, Andy D; Lou, Shan; Bryman, Gregory S; Roberson, David P; Ghasemlou, Nader; Piccoli, Cara; Ahat, Ezgi; Wang, Victor; Cobos, Enrique J; Stucky, Cheryl L; Ma, Qiufu; Liberles, Stephen D; Woolf, Clifford J

2014-01-01

The somatosensory nervous system is critical for the organism's ability to respond to mechanical, thermal, and nociceptive stimuli. Somatosensory neurons are functionally and anatomically diverse but their molecular profiles are not well-defined. Here, we used transcriptional profiling to analyze the detailed molecular signatures of dorsal root ganglion (DRG) sensory neurons. We used two mouse reporter lines and surface IB4 labeling to purify three major non-overlapping classes of neurons: 1) IB4+SNS-Cre/TdTomato+, 2) IB4−SNS-Cre/TdTomato+, and 3) Parv-Cre/TdTomato+ cells, encompassing the majority of nociceptive, pruriceptive, and proprioceptive neurons. These neurons displayed distinct expression patterns of ion channels, transcription factors, and GPCRs. Highly parallel qRT-PCR analysis of 334 single neurons selected by membership of the three populations demonstrated further diversity, with unbiased clustering analysis identifying six distinct subgroups. These data significantly increase our knowledge of the molecular identities of known DRG populations and uncover potentially novel subsets, revealing the complexity and diversity of those neurons underlying somatosensation. DOI: http://dx.doi.org/10.7554/eLife.04660.001 PMID:25525749

Characteristics of hyperpolarization-activated cyclic nucleotide-gated channels in dorsal root ganglion neurons at different ages and sizes.

PubMed

Hou, Baohua; Chen, Hengling; Qu, Xiangwei; Lin, Xianguang; Luo, Fang; Li, Chenhong

2015-11-11

In rat's sensory neurons, hyperpolarization-activated inward currents (Ih) play an essential role in mediating action potentials and contributing to neuronal excitability. Classified by the size of neurons and ages, we studied the Ih and transcription levels of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels using electrophysiology and the single-cell RT-PCR. In voltage-clamp studies, Ih and half-maximal activation voltage (V1/2) changed with age and size. An analysis of all HCN subtypes in dorsal root ganglion (DRG) neurons by single-cell RT-PCR was carried out. HCN1 and HCN3 in medium-small elderly neurons had a weak expression. HCN2 in newborns and HCN4 in elderly rats also had a weak expression. The aim of this study is to examine the age-related Ih and HCN channels subunits in different ages and sizes of DRG neurons. The results would be significant in understanding the physiological and pathophysiological function of different sizes of DRG neurons in different age periods.

Towards a theory of cortical columns: From spiking neurons to interacting neural populations of finite size.

PubMed

Schwalger, Tilo; Deger, Moritz; Gerstner, Wulfram

2017-04-01

Neural population equations such as neural mass or field models are widely used to study brain activity on a large scale. However, the relation of these models to the properties of single neurons is unclear. Here we derive an equation for several interacting populations at the mesoscopic scale starting from a microscopic model of randomly connected generalized integrate-and-fire neuron models. Each population consists of 50-2000 neurons of the same type but different populations account for different neuron types. The stochastic population equations that we find reveal how spike-history effects in single-neuron dynamics such as refractoriness and adaptation interact with finite-size fluctuations on the population level. Efficient integration of the stochastic mesoscopic equations reproduces the statistical behavior of the population activities obtained from microscopic simulations of a full spiking neural network model. The theory describes nonlinear emergent dynamics such as finite-size-induced stochastic transitions in multistable networks and synchronization in balanced networks of excitatory and inhibitory neurons. The mesoscopic equations are employed to rapidly integrate a model of a cortical microcircuit consisting of eight neuron types, which allows us to predict spontaneous population activities as well as evoked responses to thalamic input. Our theory establishes a general framework for modeling finite-size neural population dynamics based on single cell and synapse parameters and offers an efficient approach to analyzing cortical circuits and computations.

GABA and Gap Junctions in the Development of Synchronized Activity in Human Pluripotent Stem Cell-Derived Neural Networks

PubMed Central

Mäkinen, Meeri Eeva-Liisa; Ylä-Outinen, Laura; Narkilahti, Susanna

2018-01-01

The electrical activity of the brain arises from single neurons communicating with each other. However, how single neurons interact during early development to give rise to neural network activity remains poorly understood. We studied the emergence of synchronous neural activity in human pluripotent stem cell (hPSC)-derived neural networks simultaneously on a single-neuron level and network level. The contribution of gamma-aminobutyric acid (GABA) and gap junctions to the development of synchronous activity in hPSC-derived neural networks was studied with GABA agonist and antagonist and by blocking gap junctional communication, respectively. We characterized the dynamics of the network-wide synchrony in hPSC-derived neural networks with high spatial resolution (calcium imaging) and temporal resolution microelectrode array (MEA). We found that the emergence of synchrony correlates with a decrease in very strong GABA excitation. However, the synchronous network was found to consist of a heterogeneous mixture of synchronously active cells with variable responses to GABA, GABA agonists and gap junction blockers. Furthermore, we show how single-cell distributions give rise to the network effect of GABA, GABA agonists and gap junction blockers. Finally, based on our observations, we suggest that the earliest form of synchronous neuronal activity depends on gap junctions and a decrease in GABA induced depolarization but not on GABAA mediated signaling. PMID:29559893

A Hox regulatory network establishes motor neuron pool identity and target-muscle connectivity.

PubMed

Dasen, Jeremy S; Tice, Bonnie C; Brenner-Morton, Susan; Jessell, Thomas M

2005-11-04

Spinal motor neurons acquire specialized "pool" identities that determine their ability to form selective connections with target muscles in the limb, but the molecular basis of this striking example of neuronal specificity has remained unclear. We show here that a Hox transcriptional regulatory network specifies motor neuron pool identity and connectivity. Two interdependent sets of Hox regulatory interactions operate within motor neurons, one assigning rostrocaudal motor pool position and a second directing motor pool diversity at a single segmental level. This Hox regulatory network directs the downstream transcriptional identity of motor neuron pools and defines the pattern of target-muscle connectivity.

Estrogen receptor-a in medial amygdala neurons regulates body weight

USDA-ARS?s Scientific Manuscript database

Estrogen receptor–a (ERa) activity in the brain prevents obesity in both males and females. However, the ERa-expressing neural populations that regulate body weight remain to be fully elucidated. Here we showed that single-minded–1 (SIM1) neurons in the medial amygdala (MeA) express abundant levels ...

The neuronal and molecular basis of quinine-dependent bitter taste signaling in Drosophila larvae

PubMed Central

Apostolopoulou, Anthi A.; Mazija, Lorena; Wüst, Alexander; Thum, Andreas S.

2014-01-01

The sensation of bitter substances can alert an animal that a specific type of food is harmful and should not be consumed. However, not all bitter compounds are equally toxic and some may even be beneficial in certain contexts. Thus, taste systems in general may have a broader range of functions than just in alerting the animal. In this study we investigate bitter sensing and processing in Drosophila larvae using quinine, a substance perceived by humans as bitter. We show that behavioral choice, feeding, survival, and associative olfactory learning are all directly affected by quinine. On the cellular level, we show that 12 gustatory sensory receptor neurons that express both GR66a and GR33a are required for quinine-dependent choice and feeding behavior. Interestingly, these neurons are not necessary for quinine-dependent survival or associative learning. On the molecular receptor gene level, the GR33a receptor, but not GR66a, is required for quinine-dependent choice behavior. A screen for gustatory sensory receptor neurons that trigger quinine-dependent choice behavior revealed that a single GR97a receptor gene expressing neuron located in the peripheral terminal sense organ is partially necessary and sufficient. For the first time, we show that the elementary chemosensory system of the Drosophila larva can serve as a simple model to understand the neuronal basis of taste information processing on the single cell level with respect to different behavioral outputs. PMID:24478653

Neuropeptide F neurons modulate sugar reward during associative olfactory learning of Drosophila larvae.

PubMed

Rohwedder, Astrid; Selcho, Mareike; Chassot, Bérénice; Thum, Andreas S

2015-12-15

All organisms continuously have to adapt their behavior according to changes in the environment in order to survive. Experience-driven changes in behavior are usually mediated and maintained by modifications in signaling within defined brain circuits. Given the simplicity of the larval brain of Drosophila and its experimental accessibility on the genetic and behavioral level, we analyzed if Drosophila neuropeptide F (dNPF) neurons are involved in classical olfactory conditioning. dNPF is an ortholog of the mammalian neuropeptide Y, a highly conserved neuromodulator that stimulates food-seeking behavior. We provide a comprehensive anatomical analysis of the dNPF neurons on the single-cell level. We demonstrate that artificial activation of dNPF neurons inhibits appetitive olfactory learning by modulating the sugar reward signal during acquisition. No effect is detectable for the retrieval of an established appetitive olfactory memory. The modulatory effect is based on the joint action of three distinct cell types that, if tested on the single-cell level, inhibit and invert the conditioned behavior. Taken together, our work describes anatomically and functionally a new part of the sugar reinforcement signaling pathway for classical olfactory conditioning in Drosophila larvae. © 2015 Wiley Periodicals, Inc.

Synchronous neural networks of nonlinear threshold elements with hysteresis.

PubMed

Wang, L; Ross, J

1990-02-01

We use Hoffmann's suggestion [Hoffmann, G. W. (1986) J. Theor. Biol. 122, 33-67] of hysteresis in a single neuron level and determine its consequences in a synchronous network made of such neurons. We show that the overall retrieval ability in the presence of noise and the memory capacity of the network in the present model are better than in conventional models without such hysteresis. Second-order interaction further improves the retrieval ability of the network and causes hysteresis in the retrieval-noise curve for any arbitrary width of the bistable region. The convergence rate is increased by the hysteresis at high noise levels but is reduced by the hysteresis at low noise levels. Explicit formulae are given for calculations of average final convergence and noise threshold as functions of the width of the bistable region. There is neurophysiological evidence for hysteresis in single neurons, and we propose optical implementations of the present model by using ZnSe interference filters to test the predictions of the theory.

Central auditory neurons have composite receptive fields.

PubMed

Kozlov, Andrei S; Gentner, Timothy Q

2016-02-02

High-level neurons processing complex, behaviorally relevant signals are sensitive to conjunctions of features. Characterizing the receptive fields of such neurons is difficult with standard statistical tools, however, and the principles governing their organization remain poorly understood. Here, we demonstrate multiple distinct receptive-field features in individual high-level auditory neurons in a songbird, European starling, in response to natural vocal signals (songs). We then show that receptive fields with similar characteristics can be reproduced by an unsupervised neural network trained to represent starling songs with a single learning rule that enforces sparseness and divisive normalization. We conclude that central auditory neurons have composite receptive fields that can arise through a combination of sparseness and normalization in neural circuits. Our results, along with descriptions of random, discontinuous receptive fields in the central olfactory neurons in mammals and insects, suggest general principles of neural computation across sensory systems and animal classes.

Single-cell axotomy of cultured hippocampal neurons integrated in neuronal circuits.

PubMed

Gomis-Rüth, Susana; Stiess, Michael; Wierenga, Corette J; Meyn, Liane; Bradke, Frank

2014-05-01

An understanding of the molecular mechanisms of axon regeneration after injury is key for the development of potential therapies. Single-cell axotomy of dissociated neurons enables the study of the intrinsic regenerative capacities of injured axons. This protocol describes how to perform single-cell axotomy on dissociated hippocampal neurons containing synapses. Furthermore, to axotomize hippocampal neurons integrated in neuronal circuits, we describe how to set up coculture with a few fluorescently labeled neurons. This approach allows axotomy of single cells in a complex neuronal network and the observation of morphological and molecular changes during axon regeneration. Thus, single-cell axotomy of mature neurons is a valuable tool for gaining insights into cell intrinsic axon regeneration and the plasticity of neuronal polarity of mature neurons. Dissociation of the hippocampus and plating of hippocampal neurons takes ∼2 h. Neurons are then left to grow for 2 weeks, during which time they integrate into neuronal circuits. Subsequent axotomy takes 10 min per neuron and further imaging takes 10 min per neuron.

HCN1 channels in cerebellar Purkinje cells promote late stages of learning and constrain synaptic inhibition

PubMed Central

Rinaldi, Arianna; Defterali, Cagla; Mialot, Antoine; Garden, Derek L F; Beraneck, Mathieu; Nolan, Matthew F

2013-01-01

Neural computations rely on ion channels that modify neuronal responses to synaptic inputs. While single cell recordings suggest diverse and neurone type-specific computational functions for HCN1 channels, their behavioural roles in any single neurone type are not clear. Using a battery of behavioural assays, including analysis of motor learning in vestibulo-ocular reflex and rotarod tests, we find that deletion of HCN1 channels from cerebellar Purkinje cells selectively impairs late stages of motor learning. Because deletion of HCN1 modifies only a subset of behaviours involving Purkinje cells, we asked whether the channel also has functional specificity at a cellular level. We find that HCN1 channels in cerebellar Purkinje cells reduce the duration of inhibitory synaptic responses but, in the absence of membrane hyperpolarization, do not affect responses to excitatory inputs. Our results indicate that manipulation of subthreshold computation in a single neurone type causes specific modifications to behaviour. PMID:24000178

Converging levels of analysis in the cognitive neuroscience of visual attention.

PubMed Central

Duncan, J

1998-01-01

Experiments using behavioural, lesion, functional imaging and single neuron methods are considered in the context of a neuropsychological model of visual attention. According to this model, inputs compete for representation in multiple visually responsive brain systems, sensory and motor, cortical and subcortical. Competition is biased by advance priming of neurons responsive to current behavioural targets. Across systems competition is integrated such that the same, selected object tends to become dominant throughout. The behavioural studies reviewed concern divided attention within and between modalities. They implicate within-modality competition as one main restriction on concurrent stimulus identification. In contrast to the conventional association of lateral attentional focus with parietal lobe function, the lesion studies show attentional bias to be a widespread consequence of unilateral cortical damage. Although the clinical syndrome of unilateral neglect may indeed be associated with parietal lesions, this probably reflects an assortment of further deficits accompanying a simple attentional imbalance. The functional imaging studies show joint involvement of lateral prefrontal and occipital cortex in lateral attentional focus and competition. The single unit studies suggest how competition in several regions of extrastriate cortex is biased by advance priming of neurons responsive to current behavioural targets. Together, the concepts of competition, priming and integration allow a unified theoretical approach to findings from behavioural to single neuron levels. PMID:9770224

Dissociation between sustained single-neuron spiking and transient β-LFP oscillations in primate motor cortex

PubMed Central

Rule, Michael E.; Vargas-Irwin, Carlos E.; Donoghue, John P.

2017-01-01

Determining the relationship between single-neuron spiking and transient (20 Hz) β-local field potential (β-LFP) oscillations is an important step for understanding the role of these oscillations in motor cortex. We show that whereas motor cortex firing rates and beta spiking rhythmicity remain sustained during steady-state movement preparation periods, β-LFP oscillations emerge, in contrast, as short transient events. Single-neuron mean firing rates within and outside transient β-LFP events showed no differences, and no consistent correlation was found between the beta oscillation amplitude and firing rates, as was the case for movement- and visual cue-related β-LFP suppression. Importantly, well-isolated single units featuring beta-rhythmic spiking (43%, 125/292) showed no apparent or only weak phase coupling with the transient β-LFP oscillations. Similar results were obtained for the population spiking. These findings were common in triple microelectrode array recordings from primary motor (M1), ventral (PMv), and dorsal premotor (PMd) cortices in nonhuman primates during movement preparation. Although beta spiking rhythmicity indicates strong membrane potential fluctuations in the beta band, it does not imply strong phase coupling with β-LFP oscillations. The observed dissociation points to two different sources of variation in motor cortex β-LFPs: one that impacts single-neuron spiking dynamics and another related to the generation of mesoscopic β-LFP signals. Furthermore, our findings indicate that rhythmic spiking and diverse neuronal firing rates, which encode planned actions during movement preparation, may naturally limit the ability of different neuronal populations to strongly phase-couple to a single dominant oscillation frequency, leading to the observed spiking and β-LFP dissociation. NEW & NOTEWORTHY We show that whereas motor cortex spiking rates and beta (~20 Hz) spiking rhythmicity remain sustained during steady-state movement preparation periods, β-local field potential (β-LFP) oscillations emerge, in contrast, as transient events. Furthermore, the β-LFP phase at which neurons spike drifts: phase coupling is typically weak or absent. This dissociation points to two sources of variation in the level of motor cortex beta: one that impacts single-neuron spiking and another related to the generation of measured mesoscopic β-LFPs. PMID:28100654

Using affordable LED arrays for photo-stimulation of neurons.

PubMed

Valley, Matthew; Wagner, Sebastian; Gallarda, Benjamin W; Lledo, Pierre-Marie

2011-11-15

Standard slice electrophysiology has allowed researchers to probe individual components of neural circuitry by recording electrical responses of single cells in response to electrical or pharmacological manipulations(1,2). With the invention of methods to optically control genetically targeted neurons (optogenetics), researchers now have an unprecedented level of control over specific groups of neurons in the standard slice preparation. In particular, photosensitive channel rhodopsin-2 (ChR2) allows researchers to activate neurons with light(3,4). By combining careful calibration of LED-based photostimulation of ChR2 with standard slice electrophysiology, we are able to probe with greater detail the role of adult-born interneurons in the olfactory bulb, the first central relay of the olfactory system. Using viral expression of ChR2-YFP specifically in adult-born neurons, we can selectively control young adult-born neurons in a milieu of older and mature neurons. Our optical control uses a simple and inexpensive LED system, and we show how this system can be calibrated to understand how much light is needed to evoke spiking activity in single neurons. Hence, brief flashes of blue light can remotely control the firing pattern of ChR2-transduced newborn cells.

PhotoMEA: an opto-electronic biosensor for monitoring in vitro neuronal network activity.

PubMed

Ghezzi, Diego; Pedrocchi, Alessandra; Menegon, Andrea; Mantero, Sara; Valtorta, Flavia; Ferrigno, Giancarlo

2007-02-01

PhotoMEA is a biosensor useful for the analysis of an in vitro neuronal network, fully based on optical methods. Its function is based on the stimulation of neurons with caged glutamate and the recording of neuronal activity by Voltage-Sensitive fluorescent Dyes (VSD). The main advantage is that it will be possible to stimulate even at sub-single neuron level and to record with high resolution the activity of the entire network in the culture. A large-scale view of neuronal intercommunications offers a unique opportunity for testing the ability of drugs to affect neuronal properties as well as alterations in the behaviour of the entire network. The concept and a prototype for validation is described here in detail.

Shaping Neuronal Network Activity by Presynaptic Mechanisms

PubMed Central

Ashery, Uri

2015-01-01

Neuronal microcircuits generate oscillatory activity, which has been linked to basic functions such as sleep, learning and sensorimotor gating. Although synaptic release processes are well known for their ability to shape the interaction between neurons in microcircuits, most computational models do not simulate the synaptic transmission process directly and hence cannot explain how changes in synaptic parameters alter neuronal network activity. In this paper, we present a novel neuronal network model that incorporates presynaptic release mechanisms, such as vesicle pool dynamics and calcium-dependent release probability, to model the spontaneous activity of neuronal networks. The model, which is based on modified leaky integrate-and-fire neurons, generates spontaneous network activity patterns, which are similar to experimental data and robust under changes in the model's primary gain parameters such as excitatory postsynaptic potential and connectivity ratio. Furthermore, it reliably recreates experimental findings and provides mechanistic explanations for data obtained from microelectrode array recordings, such as network burst termination and the effects of pharmacological and genetic manipulations. The model demonstrates how elevated asynchronous release, but not spontaneous release, synchronizes neuronal network activity and reveals that asynchronous release enhances utilization of the recycling vesicle pool to induce the network effect. The model further predicts a positive correlation between vesicle priming at the single-neuron level and burst frequency at the network level; this prediction is supported by experimental findings. Thus, the model is utilized to reveal how synaptic release processes at the neuronal level govern activity patterns and synchronization at the network level. PMID:26372048

Towards a theory of cortical columns: From spiking neurons to interacting neural populations of finite size

PubMed Central

Gerstner, Wulfram

2017-01-01

Neural population equations such as neural mass or field models are widely used to study brain activity on a large scale. However, the relation of these models to the properties of single neurons is unclear. Here we derive an equation for several interacting populations at the mesoscopic scale starting from a microscopic model of randomly connected generalized integrate-and-fire neuron models. Each population consists of 50–2000 neurons of the same type but different populations account for different neuron types. The stochastic population equations that we find reveal how spike-history effects in single-neuron dynamics such as refractoriness and adaptation interact with finite-size fluctuations on the population level. Efficient integration of the stochastic mesoscopic equations reproduces the statistical behavior of the population activities obtained from microscopic simulations of a full spiking neural network model. The theory describes nonlinear emergent dynamics such as finite-size-induced stochastic transitions in multistable networks and synchronization in balanced networks of excitatory and inhibitory neurons. The mesoscopic equations are employed to rapidly integrate a model of a cortical microcircuit consisting of eight neuron types, which allows us to predict spontaneous population activities as well as evoked responses to thalamic input. Our theory establishes a general framework for modeling finite-size neural population dynamics based on single cell and synapse parameters and offers an efficient approach to analyzing cortical circuits and computations. PMID:28422957

Proposal for an All-Spin Artificial Neural Network: Emulating Neural and Synaptic Functionalities Through Domain Wall Motion in Ferromagnets.

PubMed

Sengupta, Abhronil; Shim, Yong; Roy, Kaushik

2016-12-01

Non-Boolean computing based on emerging post-CMOS technologies can potentially pave the way for low-power neural computing platforms. However, existing work on such emerging neuromorphic architectures have either focused on solely mimicking the neuron, or the synapse functionality. While memristive devices have been proposed to emulate biological synapses, spintronic devices have proved to be efficient at performing the thresholding operation of the neuron at ultra-low currents. In this work, we propose an All-Spin Artificial Neural Network where a single spintronic device acts as the basic building block of the system. The device offers a direct mapping to synapse and neuron functionalities in the brain while inter-layer network communication is accomplished via CMOS transistors. To the best of our knowledge, this is the first demonstration of a neural architecture where a single nanoelectronic device is able to mimic both neurons and synapses. The ultra-low voltage operation of low resistance magneto-metallic neurons enables the low-voltage operation of the array of spintronic synapses, thereby leading to ultra-low power neural architectures. Device-level simulations, calibrated to experimental results, was used to drive the circuit and system level simulations of the neural network for a standard pattern recognition problem. Simulation studies indicate energy savings by  ∼  100× in comparison to a corresponding digital/analog CMOS neuron implementation.

Multimodal Integration After Unilateral Labyrinthine Lesion: Single Vestibular Nuclei Neuron Responses and Implications for Postural Compensation

PubMed Central

Sadeghi, Soroush G.; Minor, Lloyd B.

2011-01-01

Plasticity in neuronal responses is necessary for compensation following brain lesions and adaptation to new conditions and motor learning. In a previous study, we showed that compensatory changes in the vestibuloocular reflex (VOR) following unilateral vestibular loss were characterized by dynamic reweighting of inputs from vestibular and extravestibular modalities at the level of single neurons that constitute the first central stage of VOR signal processing. Here, we studied another class of neurons, i.e., the vestibular-only neurons, in the vestibular nuclei that mediate vestibulospinal reflexes and provide information for higher brain areas. We investigated changes in the relative contribution of vestibular, neck proprioceptive, and efference copy signals in the response of these neurons during compensation after contralateral vestibular loss in Macaca mulata monkeys. We show that the time course of recovery of vestibular sensitivity of neurons corresponds with that of lower extremity muscle and tendon reflexes reported in previous studies. More important, we found that information from neck proprioceptors, which did not influence neuronal responses before the lesion, were unmasked after lesion. Such inputs influenced the early stages of the compensation process evidenced by faster and more substantial recovery of the resting discharge in proprioceptive-sensitive neurons. Interestingly, unlike our previous study of VOR interneurons, the improvement in the sensitivity of the two groups of neurons did not show any difference in the early or late stages after lesion. Finally, neuronal responses during active head movements were not different before and after lesion and were attenuated relative to passive movements over the course of recovery, similar to that observed in control conditions. Comparison of compensatory changes observed in the vestibuloocular and vestibulospinal pathways provides evidence for similarities and differences between the two classes of neurons that mediate these pathways at the functional and cellular levels. PMID:21148096

Multimodal integration after unilateral labyrinthine lesion: single vestibular nuclei neuron responses and implications for postural compensation.

PubMed

Sadeghi, Soroush G; Minor, Lloyd B; Cullen, Kathleen E

2011-02-01

Plasticity in neuronal responses is necessary for compensation following brain lesions and adaptation to new conditions and motor learning. In a previous study, we showed that compensatory changes in the vestibuloocular reflex (VOR) following unilateral vestibular loss were characterized by dynamic reweighting of inputs from vestibular and extravestibular modalities at the level of single neurons that constitute the first central stage of VOR signal processing. Here, we studied another class of neurons, i.e., the vestibular-only neurons, in the vestibular nuclei that mediate vestibulospinal reflexes and provide information for higher brain areas. We investigated changes in the relative contribution of vestibular, neck proprioceptive, and efference copy signals in the response of these neurons during compensation after contralateral vestibular loss in Macaca mulata monkeys. We show that the time course of recovery of vestibular sensitivity of neurons corresponds with that of lower extremity muscle and tendon reflexes reported in previous studies. More important, we found that information from neck proprioceptors, which did not influence neuronal responses before the lesion, were unmasked after lesion. Such inputs influenced the early stages of the compensation process evidenced by faster and more substantial recovery of the resting discharge in proprioceptive-sensitive neurons. Interestingly, unlike our previous study of VOR interneurons, the improvement in the sensitivity of the two groups of neurons did not show any difference in the early or late stages after lesion. Finally, neuronal responses during active head movements were not different before and after lesion and were attenuated relative to passive movements over the course of recovery, similar to that observed in control conditions. Comparison of compensatory changes observed in the vestibuloocular and vestibulospinal pathways provides evidence for similarities and differences between the two classes of neurons that mediate these pathways at the functional and cellular levels.

Existence of multiple receptors in single neurons: responses of single bullfrog olfactory neurons to many cAMP-dependent and independent odorants.

PubMed

Kashiwayanagi, M; Shimano, K; Kurihara, K

1996-11-04

The responses of single bullfrog olfactory neurons to various odorants were measured with the whole-cell patch clamp which offers direct information on cellular events and with the ciliary recording technique to obtain stable quantitative data from many neurons. A large portion of single olfactory neurons (about 64% and 79% in the whole-cell recording and in the ciliary recording, respectively) responded to many odorants with quite diverse molecular structures, including both odorants previously indicated to be cAMP-dependent (increasing) and independent odorants. One odorant elicited a response in many cells; e.g. hedione and citralva elicited the response in 100% and 92% of total neurons examined with the ciliary recording technique. To confirm that a single neuron carries different receptors or transduction pathways, the cross-adaptation technique was applied to single neurons. Application of hedione to a single neuron after desensitization of the current in response to lyral or citralva induced an inward current with a similar magnitude to that applied alone. It was suggested that most single olfactory neurons carry multiple receptors and at least dual transduction pathways.

Amphetamine regulation of acetylcholine and gamma-aminobutyric acid in nucleus accumbens.

PubMed

Lindefors, N; Hurd, Y L; O'Connor, W T; Brené, S; Persson, H; Ungerstedt, U

1992-01-01

In situ hybridization histochemistry and in vivo microdialysis were combined to study the effect of amphetamine on the expression of choline acetyltransferase and glutamate decarboxylase67 mRNA and in vivo release of acetylcholine and GABA in rat medial nucleus accumbens. Differential effects on acetylcholine and GABA neurons by a single challenge injection of amphetamine (1.5 mg/kg, s.c.) were apparent in saline-pretreated and amphetamine-pretreated (same dose, twice daily for the previous seven days) rats. Extracellular acetylcholine levels were increased up to 50% over a prolonged period following both single and repeated amphetamine. In contrast, extracellular concentrations of GABA were gradually decreased to half the control values, but only in rats receiving repeated amphetamine. Although the increase of acetylcholine release was not associated with any change in choline acetyltransferase mRNA levels, the number of neurons expressing high levels of glutamate decarboxylase67 mRNA was decreased (28%) following repeated injections. Thus we suggest that amphetamine decreases extracellular GABA levels by a slow mechanism, associated with the decreased expression of glutamate decarboxylase67 mRNA in a subpopulation of densely labeled neurons in the medial nucleus accumbens. The delayed response by GABA to amphetamine may reflect supersensitivity in the activity of postsynaptic gamma-aminobutyric acid-containing neurons in nucleus accumbens as a consequence of the repeated amphetamine treatment.

Dynamic neural networking as a basis for plasticity in the control of heart rate.

PubMed

Kember, G; Armour, J A; Zamir, M

2013-01-21

A model is proposed in which the relationship between individual neurons within a neural network is dynamically changing to the effect of providing a measure of "plasticity" in the control of heart rate. The neural network on which the model is based consists of three populations of neurons residing in the central nervous system, the intrathoracic extracardiac nervous system, and the intrinsic cardiac nervous system. This hierarchy of neural centers is used to challenge the classical view that the control of heart rate, a key clinical index, resides entirely in central neuronal command (spinal cord, medulla oblongata, and higher centers). Our results indicate that dynamic networking allows for the possibility of an interplay among the three populations of neurons to the effect of altering the order of control of heart rate among them. This interplay among the three levels of control allows for different neural pathways for the control of heart rate to emerge under different blood flow demands or disease conditions and, as such, it has significant clinical implications because current understanding and treatment of heart rate anomalies are based largely on a single level of control and on neurons acting in unison as a single entity rather than individually within a (plastically) interconnected network. Copyright © 2012 Elsevier Ltd. All rights reserved.

Neural circuit rewiring: insights from DD synapse remodeling.

PubMed

Kurup, Naina; Jin, Yishi

2016-01-01

Nervous systems exhibit many forms of neuronal plasticity during growth, learning and memory consolidation, as well as in response to injury. Such plasticity can occur across entire nervous systems as with the case of insect metamorphosis, in individual classes of neurons, or even at the level of a single neuron. A striking example of neuronal plasticity in C. elegans is the synaptic rewiring of the GABAergic Dorsal D-type motor neurons during larval development, termed DD remodeling. DD remodeling entails multi-step coordination to concurrently eliminate pre-existing synapses and form new synapses on different neurites, without changing the overall morphology of the neuron. This mini-review focuses on recent advances in understanding the cellular and molecular mechanisms driving DD remodeling.

Digital PCR to determine the number of transcripts from single neurons after patch-clamp recording.

PubMed

Faragó, Nóra; Kocsis, Ágnes K; Lovas, Sándor; Molnár, Gábor; Boldog, Eszter; Rózsa, Márton; Szemenyei, Viktor; Vámos, Enikő; Nagy, Lajos I; Tamás, Gábor; Puskás, László G

2013-06-01

Whole-cell patch-clamp recording enables detection of electrophysiological signals from single neurons as well as harvesting of perisomatic RNA through the patch pipette for subsequent gene expression analysis. Amplification and profiling of RNA with traditional quantitative real-time PCR (qRT-PCR) do not provide exact quantitation due to experimental variation caused by the limited amount of nucleic acid in a single cell. Here we describe a protocol for quantifying mRNA or miRNA expression in individual neurons after patch-clamp recording using high-density nanocapillary digital PCR (dPCR). Expression of a known cell-type dependent marker gene (gabrd), as well as oxidative-stress related induction of hspb1 and hmox1 expression, was quantified in individual neurogliaform and pyramidal cells, respectively. The miRNA mir-132, which plays a role in neurodevelopment, was found to be equally expressed in three different types of neurons. The accuracy and sensitivity of this method were further validated using synthetic spike-in templates and by detecting genes with very low levels of expression.

The Emergence of Single Neurons in Clinical Neurology

PubMed Central

Cash, Sydney S.; Hochberg, Leigh R.

2015-01-01

Summary Single neuron actions and interactions are the sine qua non of brain function, and nearly all diseases and injuries of the central nervous system trace their clinical sequelae to neuronal dysfunction or failure. Remarkably, discussion of neuronal activity is largely absent in clinical neuroscience. Advances in neurotechnology and computational capabilities, accompanied by shifts in theoretical frameworks, have led to renewed interest in the information represented by single neurons. Using direct interfaces with the nervous system, millisecond-scale information will soon be extracted from single neurons in clinical environments, supporting personalized treatment of neurologic and psychiatric disease. In this review we focus on single neuronal activity in restoring communication and motor control in patients suffering from devastating neurological injuries. We also explore the single neuron's role in epilepsy and movement disorders, surgical anesthesia, and in cognitive processes disrupted in neurodegenerative and neuropsychiatric disease. Finally, we speculate on how technological advances will revolutionize neurotherapeutics. PMID:25856488

The emergence of single neurons in clinical neurology.

PubMed

Cash, Sydney S; Hochberg, Leigh R

2015-04-08

Single neuron actions and interactions are the sine qua non of brain function, and nearly all diseases and injuries of the CNS trace their clinical sequelae to neuronal dysfunction or failure. Remarkably, discussion of neuronal activity is largely absent in clinical neuroscience. Advances in neurotechnology and computational capabilities, accompanied by shifts in theoretical frameworks, have led to renewed interest in the information represented by single neurons. Using direct interfaces with the nervous system, millisecond-scale information will soon be extracted from single neurons in clinical environments, supporting personalized treatment of neurologic and psychiatric disease. In this Perspective, we focus on single-neuronal activity in restoring communication and motor control in patients suffering from devastating neurological injuries. We also explore the single neuron's role in epilepsy and movement disorders, surgical anesthesia, and in cognitive processes disrupted in neurodegenerative and neuropsychiatric disease. Finally, we speculate on how technological advances will revolutionize neurotherapeutics. Copyright © 2015 Elsevier Inc. All rights reserved.

Sex-switching of the Drosophila brain by two antagonistic chromatin factors

PubMed Central

Ito, Hiroki; Sato, Kosei; Yamamoto, Daisuke

2013-01-01

In Drosophila melanogaster, the fruitless (fru) gene encoding BTB-Zn-finger transcription factors organizes male sexual behavior by controlling the development of sexually dimorphic neuronal circuitry. However, the molecular mechanism by which fru controls the sexual fate of neurons has been unknown. Our recent study represents a first step toward clarification of this mechanism. We have shown that: (1) Fru forms a complex with the transcriptional cofactor Bonus (Bon), which recruits either of two chromatin regulators, Histone deacetylase 1 (HDAC1) or Heterochromatin protein 1a (HP1a), to Fru-target sites; (2) the Fru-Bon complex has a masculinizing effect on single sexually-dimorphic neurons when it recruits HDAC1, whereas it has a demasculinizing effect when it recruits HP1a; (3) HDAC1 or HP1a thus recruited to Fru-target sites determines the sexual fate of single neurons in an all-or-none manner, as manipulations of HDAC1 or HP1a expression levels affect the proportion of male-typical neurons and female-typical neurons without producing neurons of intersexual characteristics. Here, we hypothesize that chromatin landscape changes induced by ecdysone surges direct the HDAC1- or HP1a-containing Fru complex to distinct targets, thereby allowing them to switch the neuronal sexual fate in the brain. PMID:23519136

Method of analysis of local neuronal circuits in the vertebrate central nervous system.

PubMed

Reinis, S; Weiss, D S; McGaraughty, S; Tsoukatos, J

1992-06-01

Although a considerable amount of knowledge has been accumulated about the activity of individual nerve cells in the brain, little is known about their mutual interactions at the local level. The method presented in this paper allows the reconstruction of functional relations within a group of neurons as recorded by a single microelectrode. Data are sampled at 10 or 13 kHz. Prominent spikes produced by one or more single cells are selected and sorted by K-means cluster analysis. The activities of single cells are then related to the background firing of neurons in their vicinity. Auto-correlograms of the leading cells, auto-correlograms of the background cells (mass correlograms) and cross-correlograms between these two levels of firing are computed and evaluated. The statistical probability of mutual interactions is determined, and the statistically significant, most common interspike intervals are stored and attributed to real pairs of spikes in the original record. Selected pairs of spikes, characterized by statistically significant intervals between them, are then assembled into a working model of the system. This method has revealed substantial differences between the information processing in the visual cortex, the inferior colliculus, the rostral ventromedial medulla and the ventrobasal complex of the thalamus. Even short 1-s records of the multiple neuronal activity may provide meaningful and statistically significant results.

Deletion of a single allele of the Pex11β gene is sufficient to cause oxidative stress, delayed differentiation and neuronal death in mouse brain

PubMed Central

Ahlemeyer, Barbara; Gottwald, Magdalena; Baumgart-Vogt, Eveline

2012-01-01

SUMMARY Impaired neuronal migration and cell death are commonly observed in patients with peroxisomal biogenesis disorders (PBDs), and in mouse models of this diseases. In Pex11β-deficient mice, we observed that the deletion of a single allele of the Pex11β gene (Pex11β+/− heterozygous mice) caused cell death in primary neuronal cultures prepared from the neocortex and cerebellum, although to a lesser extent as compared with the homozygous-null animals (Pex11β−/− mice). In corresponding brain sections, cell death was rare, but differences between the genotypes were similar to those found in vitro. Because PEX11β has been implicated in peroxisomal proliferation, we searched for alterations in peroxisomal abundance in the brain of heterozygous and homozygous Pex11β-null mice compared with wild-type animals. Deletion of one allele of the Pex11β gene slightly increased the abundance of peroxisomes, whereas the deletion of both alleles caused a 30% reduction in peroxisome number. The size of the peroxisomal compartment did not correlate with neuronal death. Similar to cell death, neuronal development was delayed in Pex11β+/− mice, and to a further extent in Pex11β−/− mice, as measured by a reduced mRNA and protein level of synaptophysin and a reduced protein level of the mature isoform of MAP2. Moreover, a gradual increase in oxidative stress was found in brain sections and primary neuronal cultures from wild-type to heterozygous to homozygous Pex11β-deficient mice. SOD2 was upregulated in neurons from Pex11β+/− mice, but not from Pex11β−/− animals, whereas the level of catalase remained unchanged in neurons from Pex11β+/− mice and was reduced in those from Pex11β−/− mice, suggesting a partial compensation of oxidative stress in the heterozygotes, but a failure thereof in the homozygous Pex11β−/− brain. In conclusion, we report the alterations in the brain caused by the deletion of a single allele of the Pex11β gene. Our data might lead to the reconsideration of the clinical treatment of PBDs and the common way of using knockout mouse models for studying autosomal recessive diseases. PMID:21954064

Neural correlates of motor learning in the vestibulo-ocular reflex: dynamic regulation of multimodal integration in the macaque vestibular system

PubMed Central

Sadeghi, Soroush G.; Minor, Lloyd B.; Cullen, Kathleen E.

2010-01-01

Motor learning is required for the reacquisition of skills that have been compromised as a result of brain lesion or disease, as well as for the acquisition of new skills. Behaviors with well-characterized anatomy and physiology are required to yield significant insight into changes that occur in the brain during motor learning. The vestibulo-ocular-reflex (VOR) is well suited to establish connections between neurons, neural circuits, and motor performance during learning. Here we examined the linkage between neuronal and behavioural VOR responses in alert behaving monkeys (macaca mulatta) during the impressive recovery that occurs after unilateral vestibular loss. We show, for the first time, that motor learning is characterized by the dynamic reweighting of inputs from different modalities (i.e., vestibular versus extra-vestibular) at the level of the single neurons which constitute the first central stage of vestibular processing. Specifically, two types of information, which did not influence neuronal responses prior to the lesion, had an important role during compensation. First, unmasked neck proprioceptive inputs played a critical role in the early stages of this process demonstrated by faster and more substantial recovery of vestibular responses in proprioceptive sensitive neurons. Second, neuronal and VOR responses were significantly enhanced during active relative to passive head motion later in the compensation process (>3 weeks). Taken together, our findings provide evidence linking the dynamic regulation of multimodal integration at the level of single neurons and behavioural recovery, suggesting a role for homeostatic mechanisms in VOR motor learning. PMID:20668199

Neurons and Objects: The Case of Auditory Cortex

PubMed Central

Nelken, Israel; Bar-Yosef, Omer

2008-01-01

Sounds are encoded into electrical activity in the inner ear, where they are represented (roughly) as patterns of energy in narrow frequency bands. However, sounds are perceived in terms of their high-order properties. It is generally believed that this transformation is performed along the auditory hierarchy, with low-level physical cues computed at early stages of the auditory system and high-level abstract qualities at high-order cortical areas. The functional position of primary auditory cortex (A1) in this scheme is unclear – is it ‘early’, encoding physical cues, or is it ‘late’, already encoding abstract qualities? Here we argue that neurons in cat A1 show sensitivity to high-level features of sounds. In particular, these neurons may already show sensitivity to ‘auditory objects’. The evidence for this claim comes from studies in which individual sounds are presented singly and in mixtures. Many neurons in cat A1 respond to mixtures in the same way they respond to one of the individual components of the mixture, and in many cases neurons may respond to a low-level component of the mixture rather than to the acoustically dominant one, even though the same neurons respond to the acoustically-dominant component when presented alone. PMID:18982113

Mesh electronics: a new paradigm for tissue-like brain probes.

PubMed

Hong, Guosong; Yang, Xiao; Zhou, Tao; Lieber, Charles M

2018-06-01

Existing implantable neurotechnologies for understanding the brain and treating neurological diseases have intrinsic properties that have limited their capability to achieve chronically-stable brain interfaces with single-neuron spatiotemporal resolution. These limitations reflect what has been dichotomy between the structure and mechanical properties of living brain tissue and non-living neural probes. To bridge the gap between neural and electronic networks, we have introduced the new concept of mesh electronics probes designed with structural and mechanical properties such that the implant begins to 'look and behave' like neural tissue. Syringe-implanted mesh electronics have led to the realization of probes that are neuro-attractive and free of the chronic immune response, as well as capable of stable long-term mapping and modulation of brain activity at the single-neuron level. This review provides a historical overview of a 10-year development of mesh electronics by highlighting the tissue-like design, syringe-assisted delivery, seamless neural tissue integration, and single-neuron level chronic recording stability of mesh electronics. We also offer insights on unique near-term opportunities and future directions for neuroscience and neurology that now are available or expected for mesh electronics neurotechnologies. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Recording single neurons' action potentials from freely moving pigeons across three stages of learning.

PubMed

Starosta, Sarah; Stüttgen, Maik C; Güntürkün, Onur

2014-06-02

While the subject of learning has attracted immense interest from both behavioral and neural scientists, only relatively few investigators have observed single-neuron activity while animals are acquiring an operantly conditioned response, or when that response is extinguished. But even in these cases, observation periods usually encompass only a single stage of learning, i.e. acquisition or extinction, but not both (exceptions include protocols employing reversal learning; see Bingman et al.(1) for an example). However, acquisition and extinction entail different learning mechanisms and are therefore expected to be accompanied by different types and/or loci of neural plasticity. Accordingly, we developed a behavioral paradigm which institutes three stages of learning in a single behavioral session and which is well suited for the simultaneous recording of single neurons' action potentials. Animals are trained on a single-interval forced choice task which requires mapping each of two possible choice responses to the presentation of different novel visual stimuli (acquisition). After having reached a predefined performance criterion, one of the two choice responses is no longer reinforced (extinction). Following a certain decrement in performance level, correct responses are reinforced again (reacquisition). By using a new set of stimuli in every session, animals can undergo the acquisition-extinction-reacquisition process repeatedly. Because all three stages of learning occur in a single behavioral session, the paradigm is ideal for the simultaneous observation of the spiking output of multiple single neurons. We use pigeons as model systems, but the task can easily be adapted to any other species capable of conditioned discrimination learning.

Exact subthreshold integration with continuous spike times in discrete-time neural network simulations.

PubMed

Morrison, Abigail; Straube, Sirko; Plesser, Hans Ekkehard; Diesmann, Markus

2007-01-01

Very large networks of spiking neurons can be simulated efficiently in parallel under the constraint that spike times are bound to an equidistant time grid. Within this scheme, the subthreshold dynamics of a wide class of integrate-and-fire-type neuron models can be integrated exactly from one grid point to the next. However, the loss in accuracy caused by restricting spike times to the grid can have undesirable consequences, which has led to interest in interpolating spike times between the grid points to retrieve an adequate representation of network dynamics. We demonstrate that the exact integration scheme can be combined naturally with off-grid spike events found by interpolation. We show that by exploiting the existence of a minimal synaptic propagation delay, the need for a central event queue is removed, so that the precision of event-driven simulation on the level of single neurons is combined with the efficiency of time-driven global scheduling. Further, for neuron models with linear subthreshold dynamics, even local event queuing can be avoided, resulting in much greater efficiency on the single-neuron level. These ideas are exemplified by two implementations of a widely used neuron model. We present a measure for the efficiency of network simulations in terms of their integration error and show that for a wide range of input spike rates, the novel techniques we present are both more accurate and faster than standard techniques.

Comparative Analysis of Human and Rodent Brain Primary Neuronal Culture Spontaneous Activity Using Micro-Electrode Array Technology.

PubMed

Napoli, Alessandro; Obeid, Iyad

2016-03-01

Electrical activity in embryonic brain tissue has typically been studied using Micro Electrode Array (MEA) technology to make dozens of simultaneous recordings from dissociated neuronal cultures, brain stem cell progenitors, or brain slices from fetal rodents. Although these rodent neuronal primary culture electrical properties are mostly investigated, it has not been yet established to what extent the electrical characteristics of rodent brain neuronal cultures can be generalized to those of humans. A direct comparison of spontaneous spiking activity between rodent and human primary neurons grown under the same in vitro conditions using MEA technology has never been carried out before and will be described in the present study. Human and rodent dissociated fetal brain neuronal cultures were established in-vitro by culturing on a glass grid of 60 planar microelectrodes neurons under identical conditions. Three different cultures of human neurons were produced from tissue sourced from a single aborted fetus (at 16-18 gestational weeks) and these were compared with seven different cultures of embryonic rat neurons (at 18 gestational days) originally isolated from a single rat. The results show that the human and rodent cultures behaved significantly differently. Whereas the rodent cultures demonstrated robust spontaneous activation and network activity after only 10 days, the human cultures required nearly 40 days to achieve a substantially weaker level of electrical function. These results suggest that rat neuron preparations may yield inferences that do not necessarily transfer to humans. © 2015 Wiley Periodicals, Inc.

Suppression and Contrast Normalization in Motion Processing

PubMed Central

2017-01-01

Sensory neurons are activated by a range of stimuli to which they are said to be tuned. Usually, they are also suppressed by another set of stimuli that have little effect when presented in isolation. The interactions between preferred and suppressive stimuli are often quite complex and vary across neurons, even within a single area, making it difficult to infer their collective effect on behavioral responses mediated by activity across populations of neurons. Here, we investigated this issue by measuring, in human subjects (three males), the suppressive effect of static masks on the ocular following responses induced by moving stimuli. We found a wide range of effects, which depend in a nonlinear and nonseparable manner on the spatial frequency, contrast, and spatial location of both stimulus and mask. Under some conditions, the presence of the mask can be seen as scaling the contrast of the driving stimulus. Under other conditions, the effect is more complex, involving also a direct scaling of the behavioral response. All of this complexity at the behavioral level can be captured by a simple model in which stimulus and mask interact nonlinearly at two stages, one monocular and one binocular. The nature of the interactions is compatible with those observed at the level of single neurons in primates, usually broadly described as divisive normalization, without having to invoke any scaling mechanism. SIGNIFICANCE STATEMENT The response of sensory neurons to their preferred stimulus is often modulated by stimuli that are not effective when presented alone. Individual neurons can exhibit multiple modulatory effects, with considerable variability across neurons even in a single area. Such diversity has made it difficult to infer the impact of these modulatory mechanisms on behavioral responses. Here, we report the effects of a stationary mask on the reflexive eye movements induced by a moving stimulus. A model with two stages, each incorporating a divisive modulatory mechanism, reproduces our experimental results and suggests that qualitative variability of masking effects in cortical neurons might arise from differences in the extent to which such effects are inherited from earlier stages. PMID:29018158

Spiking irregularity and frequency modulate the behavioral report of single-neuron stimulation.

PubMed

Doron, Guy; von Heimendahl, Moritz; Schlattmann, Peter; Houweling, Arthur R; Brecht, Michael

2014-02-05

The action potential activity of single cortical neurons can evoke measurable sensory effects, but it is not known how spiking parameters and neuronal subtypes affect the evoked sensations. Here, we examined the effects of spike train irregularity, spike frequency, and spike number on the detectability of single-neuron stimulation in rat somatosensory cortex. For regular-spiking, putative excitatory neurons, detectability increased with spike train irregularity and decreasing spike frequencies but was not affected by spike number. Stimulation of single, fast-spiking, putative inhibitory neurons led to a larger sensory effect compared to regular-spiking neurons, and the effect size depended only on spike irregularity. An ideal-observer analysis suggests that, under our experimental conditions, rats were using integration windows of a few hundred milliseconds or more. Our data imply that the behaving animal is sensitive to single neurons' spikes and even to their temporal patterning. Copyright © 2014 Elsevier Inc. All rights reserved.

Latent Herpes Simplex Virus 1 Infection Does Not Induce Apoptosis in Human Trigeminal Ganglia

PubMed Central

Lindemann, Anja; Sinicina, Inga; Strupp, Michael; Brandt, Thomas; Hüfner, Katharina

2015-01-01

Herpes simplex virus 1 (HSV-1) can establish lifelong latency in human trigeminal ganglia. Latently infected ganglia contain CD8+ T cells, which secrete granzyme B and are thus capable of inducing neuronal apoptosis. Using immunohistochemistry and single-cell reverse transcription-quantitative PCR (RT-qPCR), higher frequency and transcript levels of caspase-3 were found in HSV-1-negative compared to HSV-1-positive ganglia and neurons, respectively. No terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay-positive neurons were detected. The infiltrating T cells do not induce apoptosis in latently infected neurons. PMID:25762734

Combination of mild hypothermia with neuroprotectants has greater neuroprotective effects during oxygen-glucose deprivation and reoxygenation-mediated neuronal injury

PubMed Central

Gao, Xiao-Ya; Huang, Jian-Ou; Hu, Ya-Fang; Gu, Yong; Zhu, Shu-Zhen; Huang, Kai-Bin; Chen, Jin-Yu; Pan, Su-Yue

2014-01-01

Co-treatment of neuroprotective reagents may improve the therapeutic efficacy of hypothermia in protecting neurons during ischemic stroke. This study aimed to find promising drugs that enhance the neuroprotective effect of mild hypothermia (MH). 26 candidate drugs were selected based on different targets. Primary cultured cortical neurons were exposed to oxygen-glucose deprivation and reoxygenation (OGD/R) to induce neuronal damage, followed by either single treatment (a drug or MH) or a combination of a drug and MH. Results showed that, compared with single treatment, combination of MH with brain derived neurotrophic factor, glibenclamide, dizocilpine, human urinary kallidinogenase or neuroglobin displayed higher proportion of neuronal cell viability. The latter three drugs also caused less apoptosis rate in combined treatment. Furthermore, co-treatment of those three drugs and MH decreased the level of reactive oxygen species (ROS) and intracellular calcium accumulation, as well as stabilized mitochondrial membrane potential (MMP), indicating the combined neuroprotective effects are probably via inhibiting mitochondrial apoptosis pathway. Taken together, the study suggests that combined treatment with hypothermia and certain neuroprotective reagents provide a better protection against OGD/R-induced neuronal injury. PMID:25404538

Overexpression of cypin alters dendrite morphology, single neuron activity, and network properties via distinct mechanisms

NASA Astrophysics Data System (ADS)

Rodríguez, Ana R.; O'Neill, Kate M.; Swiatkowski, Przemyslaw; Patel, Mihir V.; Firestein, Bonnie L.

2018-02-01

Objective. This study investigates the effect that overexpression of cytosolic PSD-95 interactor (cypin), a regulator of synaptic PSD-95 protein localization and a core regulator of dendrite branching, exerts on the electrical activity of rat hippocampal neurons and networks. Approach. We cultured rat hippocampal neurons and used lipid-mediated transfection and lentiviral gene transfer to achieve high levels of cypin or cypin mutant (cypinΔPDZ PSD-95 non-binding) expression cellularly and network-wide, respectively. Main results. Our analysis revealed that although overexpression of cypin and cypinΔPDZ increase dendrite numbers and decrease spine density, cypin and cypinΔPDZ distinctly regulate neuronal activity. At the single cell level, cypin promotes decreases in bursting activity while cypinΔPDZ reduces sEPSC frequency and further decreases bursting compared to cypin. At the network level, by using the Fano factor as a measure of spike count variability, cypin overexpression results in an increase in variability of spike count, and this effect is abolished when cypin cannot bind PSD-95. This variability is also dependent on baseline activity levels and on mean spike rate over time. Finally, our spike sorting data show that overexpression of cypin results in a more complex distribution of spike waveforms and that binding to PSD-95 is essential for this complexity. Significance. Our data suggest that dendrite morphology does not play a major role in cypin action on electrical activity.

Simultaneous stability and sensitivity in model cortical networks is achieved through anti-correlations between the in- and out-degree of connectivity

PubMed Central

Vasquez, Juan C.; Houweling, Arthur R.; Tiesinga, Paul

2013-01-01

Neuronal networks in rodent barrel cortex are characterized by stable low baseline firing rates. However, they are sensitive to the action potentials of single neurons as suggested by recent single-cell stimulation experiments that reported quantifiable behavioral responses in response to short spike trains elicited in single neurons. Hence, these networks are stable against internally generated fluctuations in firing rate but at the same time remain sensitive to similarly-sized externally induced perturbations. We investigated stability and sensitivity in a simple recurrent network of stochastic binary neurons and determined numerically the effects of correlation between the number of afferent (“in-degree”) and efferent (“out-degree”) connections in neurons. The key advance reported in this work is that anti-correlation between in-/out-degree distributions increased the stability of the network in comparison to networks with no correlation or positive correlations, while being able to achieve the same level of sensitivity. The experimental characterization of degree distributions is difficult because all pre-synaptic and post-synaptic neurons have to be identified and counted. We explored whether the statistics of network motifs, which requires the characterization of connections between small subsets of neurons, could be used to detect evidence for degree anti-correlations. We find that the sample frequency of the 3-neuron “ring” motif (1→2→3→1), can be used to detect degree anti-correlation for sub-networks of size 30 using about 50 samples, which is of significance because the necessary measurements are achievable experimentally in the near future. Taken together, we hypothesize that barrel cortex networks exhibit degree anti-correlations and specific network motif statistics. PMID:24223550

Thalamocortical Oscillations in the Sleeping and Aroused Brain

NASA Astrophysics Data System (ADS)

Steriade, Mircea; McCormick, David A.; Sejnowski, Terrence J.

1993-10-01

Sleep is characterized by synchronized events in billions of synaptically coupled neurons in thalamocortical systems. The activation of a series of neuromodulatory transmitter systems during awakening blocks low-frequency oscillations, induces fast rhythms, and allows the brain to recover full responsiveness. Analysis of cortical and thalamic networks at many levels, from molecules to single neurons to large neuronal assemblies, with a variety of techniques, ranging from intracellular recordings in vivo and in vitro to computer simulations, is beginning to yield insights into the mechanisms of the generation, modulation, and function of brain oscillations.

Diminished A-type potassium current and altered firing properties in presympathetic PVN neurones in renovascular hypertensive rats

PubMed Central

Sonner, Patrick M; Filosa, Jessica A; Stern, Javier E

2008-01-01

Accumulating evidence supports a contribution of the hypothalamic paraventricular nucleus (PVN) to sympathoexcitation and elevated blood pressure in renovascular hypertension. However, the underlying mechanisms resulting in altered neuronal function in hypertensive rats remain largely unknown. Here, we aimed to address whether the transient outward potassium current (IA) in identified rostral ventrolateral medulla (RVLM)-projecting PVN neurones is altered in hypertensive rats, and whether such changes affected single and repetitive action potential properties and associated changes in intracellular Ca2+ levels. Patch-clamp recordings obtained from PVN-RVLM neurons showed a reduction in IA current magnitude and single channel conductance, and an enhanced steady-state current inactivation in hypertensive rats. Morphometric reconstructions of intracellularly labelled PVN-RVLM neurons showed a diminished dendritic surface area in hypertensive rats. Consistent with a diminished IA availability, action potentials in PVN-RVLM neurons in hypertensive rats were broader, decayed more slowly, and were less sensitive to the K+ channel blocker 4-aminopyridine. Simultaneous patch clamp recordings and confocal Ca2+ imaging demonstrated enhanced action potential-evoked intracellular Ca2+ transients in hypertensive rats. Finally, spike broadening during repetitive firing discharge was enhanced in PVN-RVLM neurons from hypertensive rats. Altogether, our results indicate that diminished IA availability constitutes a contributing mechanism underlying aberrant central neuronal function in renovascular hypertension. PMID:18238809

Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models

PubMed Central

Barmada, Sami J.; Serio, Andrea; Arjun, Arpana; Bilican, Bilada; Daub, Aaron; Ando, D. Michael; Tsvetkov, Andrey; Pleiss, Michael; Li, Xingli; Peisach, Daniel; Shaw, Christopher; Chandran, Siddharthan; Finkbeiner, Steven

2014-01-01

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have distinct clinical features but a common pathology—cytoplasmic inclusions rich in TDP43. Rare TDP43 mutations cause ALS or FTD, but abnormal TDP43 levels and localization may cause disease even if TDP43 lacks a mutation. Here we showed that individual neurons vary in their ability to clear TDP43 and are exquisitely sensitive to TDP43 levels. To measure TDP43 clearance, we developed and validated a single-cell optical method that overcomes the confounding effects of aggregation and toxicity, and discovered that pathogenic mutations significantly shorten TDP43 half-life. Novel compounds that stimulate autophagy improved TDP43 clearance and localization, and enhanced survival in primary murine neurons and in human stem cell–derived neurons and astrocytes harboring mutant TDP43. These findings indicate that the levels and localization of TDP43 critically determine neurotoxicity and show that autophagy induction mitigates neurodegeneration by acting directly on TDP43 clearance. PMID:24974230

Treatment with a Clinically-Relevant Dose of Methylphenidate Alters NMDA Receptor Composition and Synaptic Plasticity in the Juvenile Rat Prefrontal Cortex

PubMed Central

Urban, Kimberly R.; Li, Yan-Chun; Gao, Wen-Jun

2013-01-01

Methylphenidate (Ritalin, MPH) is the most commonly prescribed psychoactive drug for children. Used to treat attention-deficit/hyperactivity disorder (ADHD) and for cognitive enhancement in healthy individuals, its cellular mechanisms of action and potential long-term effects are poorly understood. We recently reported that a clinically relevant (1 mg/kg i.p., single injection) dose of MPH significantly decreased neuronal excitability in the juvenile rat prefrontal cortical neurons. Here we further explore the actions of acute treatment with MPH on the level of NMDA receptor subunits and NMDA receptor-mediated short- and long-term synaptic plasticity in the juvenile rat prefrontal cortical neurons. We found that a single dose of MPH treatment (1 mg/kg, intraperitoneal) significantly decreased the surface and total protein levels of NMDA receptor subunits NR1 and NR2B, but not NR2A, in the juvenile prefrontal cortex. In addition, the amplitude, decay time and charge transfer of NMDA receptor-mediated EPSCs were significantly decreased whereas the amplitude and short-term depression of AMPA receptor-mediated EPSCs were significantly increased in the prefrontal neurons. Furthermore, MPH treatment also significantly increased the probability and magnitude of LTP induction, but had only a small effect on LTD induction in juvenile rat prefrontal cortical neurons. Our data thus present a novel mechanism of action of MPH, i.e., changes in glutamatergic receptor-mediated synaptic plasticity following early-life treatment. Furthermore, since a single dosage resulted in significant changes in NMDA receptors, off-label usage by healthy individuals, especially children and adolescents, may result in altered potential for plastic learning. PMID:23333502

Highly scalable multichannel mesh electronics for stable chronic brain electrophysiology

PubMed Central

Fu, Tian-Ming; Hong, Guosong; Viveros, Robert D.; Zhou, Tao

2017-01-01

Implantable electrical probes have led to advances in neuroscience, brain−machine interfaces, and treatment of neurological diseases, yet they remain limited in several key aspects. Ideally, an electrical probe should be capable of recording from large numbers of neurons across multiple local circuits and, importantly, allow stable tracking of the evolution of these neurons over the entire course of study. Silicon probes based on microfabrication can yield large-scale, high-density recording but face challenges of chronic gliosis and instability due to mechanical and structural mismatch with the brain. Ultraflexible mesh electronics, on the other hand, have demonstrated negligible chronic immune response and stable long-term brain monitoring at single-neuron level, although, to date, it has been limited to 16 channels. Here, we present a scalable scheme for highly multiplexed mesh electronics probes to bridge the gap between scalability and flexibility, where 32 to 128 channels per probe were implemented while the crucial brain-like structure and mechanics were maintained. Combining this mesh design with multisite injection, we demonstrate stable 128-channel local field potential and single-unit recordings from multiple brain regions in awake restrained mice over 4 mo. In addition, the newly integrated mesh is used to validate stable chronic recordings in freely behaving mice. This scalable scheme for mesh electronics together with demonstrated long-term stability represent important progress toward the realization of ideal implantable electrical probes allowing for mapping and tracking single-neuron level circuit changes associated with learning, aging, and neurodegenerative diseases. PMID:29109247

Enhanced Peptide Detection Toward Single-Neuron Proteomics by Reversed-Phase Fractionation Capillary Electrophoresis Mass Spectrometry

NASA Astrophysics Data System (ADS)

Choi, Sam B.; Lombard-Banek, Camille; Muñoz-LLancao, Pablo; Manzini, M. Chiara; Nemes, Peter

2018-05-01

The ability to detect peptides and proteins in single cells is vital for understanding cell heterogeneity in the nervous system. Capillary electrophoresis (CE) nanoelectrospray ionization (nanoESI) provides high-resolution mass spectrometry (HRMS) with trace-level sensitivity, but compressed separation during CE challenges protein identification by tandem HRMS with limited MS/MS duty cycle. Here, we supplemented ultrasensitive CE-nanoESI-HRMS with reversed-phase (RP) fractionation to enhance identifications from protein digest amounts that approximate to a few mammalian neurons. An 1 to 20 μg neuronal protein digest was fractionated on a RP column (ZipTip), and 1 ng to 500 pg of peptides were analyzed by a custom-built CE-HRMS system. Compared with the control (no fractionation), RP fractionation improved CE separation (theoretical plates 274,000 versus 412,000 maximum, resp.), which enhanced detection sensitivity (2.5-fold higher signal-to-noise ratio), minimized co-isolation spectral interferences during MS/MS, and increased the temporal rate of peptide identification by up to 57%. From 1 ng of protein digest (<5 neurons), CE with RP fractionation identified 737 protein groups (1,753 peptides), or 480 protein groups ( 1,650 peptides) on average per analysis. The approach was scalable to 500 pg of protein digest ( a single neuron), identifying 225 protein groups (623 peptides) in technical triplicates, or 141 protein groups on average per analysis. Among identified proteins, 101 proteins were products of genes that are known to be transcriptionally active in single neurons during early development of the brain, including those involved in synaptic transmission and plasticity and cytoskeletal organization. [Figure not available: see fulltext.

Enhanced Peptide Detection Toward Single-Neuron Proteomics by Reversed-Phase Fractionation Capillary Electrophoresis Mass Spectrometry

NASA Astrophysics Data System (ADS)

Choi, Sam B.; Lombard-Banek, Camille; Muñoz-LLancao, Pablo; Manzini, M. Chiara; Nemes, Peter

2017-11-01

The ability to detect peptides and proteins in single cells is vital for understanding cell heterogeneity in the nervous system. Capillary electrophoresis (CE) nanoelectrospray ionization (nanoESI) provides high-resolution mass spectrometry (HRMS) with trace-level sensitivity, but compressed separation during CE challenges protein identification by tandem HRMS with limited MS/MS duty cycle. Here, we supplemented ultrasensitive CE-nanoESI-HRMS with reversed-phase (RP) fractionation to enhance identifications from protein digest amounts that approximate to a few mammalian neurons. An 1 to 20 μg neuronal protein digest was fractionated on a RP column (ZipTip), and 1 ng to 500 pg of peptides were analyzed by a custom-built CE-HRMS system. Compared with the control (no fractionation), RP fractionation improved CE separation (theoretical plates 274,000 versus 412,000 maximum, resp.), which enhanced detection sensitivity (2.5-fold higher signal-to-noise ratio), minimized co-isolation spectral interferences during MS/MS, and increased the temporal rate of peptide identification by up to 57%. From 1 ng of protein digest (<5 neurons), CE with RP fractionation identified 737 protein groups (1,753 peptides), or 480 protein groups ( 1,650 peptides) on average per analysis. The approach was scalable to 500 pg of protein digest ( a single neuron), identifying 225 protein groups (623 peptides) in technical triplicates, or 141 protein groups on average per analysis. Among identified proteins, 101 proteins were products of genes that are known to be transcriptionally active in single neurons during early development of the brain, including those involved in synaptic transmission and plasticity and cytoskeletal organization. [Figure not available: see fulltext.

Vertically aligned carbon nanofiber as nano-neuron interface for monitoring neural function.

PubMed

Yu, Zhe; McKnight, Timothy E; Ericson, M Nance; Melechko, Anatoli V; Simpson, Michael L; Morrison, Barclay

2012-05-01

Neural chips, which are capable of simultaneous multisite neural recording and stimulation, have been used to detect and modulate neural activity for almost thirty years. As neural interfaces, neural chips provide dynamic functional information for neural decoding and neural control. By improving sensitivity and spatial resolution, nano-scale electrodes may revolutionize neural detection and modulation at cellular and molecular levels as nano-neuron interfaces. We developed a carbon-nanofiber neural chip with lithographically defined arrays of vertically aligned carbon nanofiber electrodes and demonstrated its capability of both stimulating and monitoring electrophysiological signals from brain tissues in vitro and monitoring dynamic information of neuroplasticity. This novel nano-neuron interface may potentially serve as a precise, informative, biocompatible, and dual-mode neural interface for monitoring of both neuroelectrical and neurochemical activity at the single-cell level and even inside the cell. The authors demonstrate the utility of a neural chip with lithographically defined arrays of vertically aligned carbon nanofiber electrodes. The new device can be used to stimulate and/or monitor signals from brain tissue in vitro and for monitoring dynamic information of neuroplasticity both intracellularly and at the single cell level including neuroelectrical and neurochemical activities. Copyright © 2012 Elsevier Inc. All rights reserved.

Coarse-Grained Clustering Dynamics of Heterogeneously Coupled Neurons.

PubMed

Moon, Sung Joon; Cook, Katherine A; Rajendran, Karthikeyan; Kevrekidis, Ioannis G; Cisternas, Jaime; Laing, Carlo R

2015-12-01

The formation of oscillating phase clusters in a network of identical Hodgkin-Huxley neurons is studied, along with their dynamic behavior. The neurons are synaptically coupled in an all-to-all manner, yet the synaptic coupling characteristic time is heterogeneous across the connections. In a network of N neurons where this heterogeneity is characterized by a prescribed random variable, the oscillatory single-cluster state can transition-through [Formula: see text] (possibly perturbed) period-doubling and subsequent bifurcations-to a variety of multiple-cluster states. The clustering dynamic behavior is computationally studied both at the detailed and the coarse-grained levels, and a numerical approach that can enable studying the coarse-grained dynamics in a network of arbitrarily large size is suggested. Among a number of cluster states formed, double clusters, composed of nearly equal sub-network sizes are seen to be stable; interestingly, the heterogeneity parameter in each of the double-cluster components tends to be consistent with the random variable over the entire network: Given a double-cluster state, permuting the dynamical variables of the neurons can lead to a combinatorially large number of different, yet similar "fine" states that appear practically identical at the coarse-grained level. For weak heterogeneity we find that correlations rapidly develop, within each cluster, between the neuron's "identity" (its own value of the heterogeneity parameter) and its dynamical state. For single- and double-cluster states we demonstrate an effective coarse-graining approach that uses the Polynomial Chaos expansion to succinctly describe the dynamics by these quickly established "identity-state" correlations. This coarse-graining approach is utilized, within the equation-free framework, to perform efficient computations of the neuron ensemble dynamics.

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

PubMed Central

Rygiel, Karolina A.; Hepplewhite, Philippa D.; Morris, Christopher M.; Picard, Martin; Turnbull, Doug M.

2016-01-01

Objective To determine the extent of respiratory chain abnormalities and investigate the contribution of mtDNA to the loss of respiratory chain complexes (CI–IV) in the substantia nigra (SN) of idiopathic Parkinson disease (IPD) patients at the single‐neuron level. Methods Multiple‐label immunofluorescence was applied to postmortem sections of 10 IPD patients and 10 controls to quantify the abundance of CI–IV subunits (NDUFB8 or NDUFA13, SDHA, UQCRC2, and COXI) and mitochondrial transcription factors (TFAM and TFB2M) relative to mitochondrial mass (porin and GRP75) in dopaminergic neurons. To assess the involvement of mtDNA in respiratory chain deficiency in IPD, SN neurons, isolated with laser‐capture microdissection, were assayed for mtDNA deletions, copy number, and presence of transcription/replication‐associated 7S DNA employing a triplex real‐time polymerase chain reaction (PCR) assay. Results Whereas mitochondrial mass was unchanged in single SN neurons from IPD patients, we observed a significant reduction in the abundances of CI and II subunits. At the single‐cell level, CI and II deficiencies were correlated in patients. The CI deficiency concomitantly occurred with low abundances of the mtDNA transcription factors TFAM and TFB2M, which also initiate transcription‐primed mtDNA replication. Consistent with this, real‐time PCR analysis revealed fewer transcription/replication‐associated mtDNA molecules and an overall reduction in mtDNA copy number in patients. This effect was more pronounced in single IPD neurons with severe CI deficiency. Interpretation Respiratory chain dysfunction in IPD neurons not only involves CI, but also extends to CII. These deficiencies are possibly a consequence of the interplay between nDNA and mtDNA‐encoded factors mechanistically connected via TFAM. ANN NEUROL 2016;79:366–378 PMID:26605748

Behavioral demand modulates object category representation in the inferior temporal cortex

PubMed Central

Emadi, Nazli

2014-01-01

Visual object categorization is a critical task in our daily life. Many studies have explored category representation in the inferior temporal (IT) cortex at the level of single neurons and population. However, it is not clear how behavioral demands modulate this category representation. Here, we recorded from the IT single neurons in monkeys performing two different tasks with identical visual stimuli: passive fixation and body/object categorization. We found that category selectivity of the IT neurons was improved in the categorization compared with the passive task where reward was not contingent on image category. The category improvement was the result of larger rate enhancement for the preferred category and smaller response variability for both preferred and nonpreferred categories. These specific modulations in the responses of IT category neurons enhanced signal-to-noise ratio of the neural responses to discriminate better between the preferred and nonpreferred categories. Our results provide new insight into the adaptable category representation in the IT cortex, which depends on behavioral demands. PMID:25080572

Integration of auditory and visual communication information in the primate ventrolateral prefrontal cortex.

PubMed

Sugihara, Tadashi; Diltz, Mark D; Averbeck, Bruno B; Romanski, Lizabeth M

2006-10-25

The integration of auditory and visual stimuli is crucial for recognizing objects, communicating effectively, and navigating through our complex world. Although the frontal lobes are involved in memory, communication, and language, there has been no evidence that the integration of communication information occurs at the single-cell level in the frontal lobes. Here, we show that neurons in the macaque ventrolateral prefrontal cortex (VLPFC) integrate audiovisual communication stimuli. The multisensory interactions included both enhancement and suppression of a predominantly auditory or a predominantly visual response, although multisensory suppression was the more common mode of response. The multisensory neurons were distributed across the VLPFC and within previously identified unimodal auditory and visual regions (O'Scalaidhe et al., 1997; Romanski and Goldman-Rakic, 2002). Thus, our study demonstrates, for the first time, that single prefrontal neurons integrate communication information from the auditory and visual domains, suggesting that these neurons are an important node in the cortical network responsible for communication.

Integration of Auditory and Visual Communication Information in the Primate Ventrolateral Prefrontal Cortex

PubMed Central

Sugihara, Tadashi; Diltz, Mark D.; Averbeck, Bruno B.; Romanski, Lizabeth M.

2009-01-01

The integration of auditory and visual stimuli is crucial for recognizing objects, communicating effectively, and navigating through our complex world. Although the frontal lobes are involved in memory, communication, and language, there has been no evidence that the integration of communication information occurs at the single-cell level in the frontal lobes. Here, we show that neurons in the macaque ventrolateral prefrontal cortex (VLPFC) integrate audiovisual communication stimuli. The multisensory interactions included both enhancement and suppression of a predominantly auditory or a predominantly visual response, although multisensory suppression was the more common mode of response. The multisensory neurons were distributed across the VLPFC and within previously identified unimodal auditory and visual regions (O’Scalaidhe et al., 1997; Romanski and Goldman-Rakic, 2002). Thus, our study demonstrates, for the first time, that single prefrontal neurons integrate communication information from the auditory and visual domains, suggesting that these neurons are an important node in the cortical network responsible for communication. PMID:17065454

Stable Sequential Activity Underlying the Maintenance of a Precisely Executed Skilled Behavior.

PubMed

Katlowitz, Kalman A; Picardo, Michel A; Long, Michael A

2018-05-21

A vast array of motor skills can be maintained throughout life. Do these behaviors require stability of individual neuron tuning or can the output of a given circuit remain constant despite fluctuations in single cells? This question is difficult to address due to the variability inherent in most motor actions studied in the laboratory. A notable exception, however, is the courtship song of the adult zebra finch, which is a learned, highly precise motor act mediated by orderly dynamics within premotor neurons of the forebrain. By longitudinally tracking the activity of excitatory projection neurons during singing using two-photon calcium imaging, we find that both the number and the precise timing of song-related spiking events remain nearly identical over the span of several weeks to months. These findings demonstrate that learned, complex behaviors can be stabilized by maintaining precise and invariant tuning at the level of single neurons. Copyright © 2018 Elsevier Inc. All rights reserved.

Single-neuron labeling with inducible cre-mediated knockout in transgenic mice

PubMed Central

Young, Paul; Qiu, Li; Wang, Dongqing; Zhao, Shengli; Gross, James; Feng, Guoping

2011-01-01

To facilitate functional analysis of neuronal connectivity in a mammalian nervous system tightly packed with billions of cells, we developed a new technique that allows inducible genetic manipulations within fluorescently labeled single neurons in mice. We term this technique SLICK for Single-neuron Labeling with Inducible Cre-mediated Knockout. SLICK is achieved by co-expressing a drug-inducible form of cre recombinase and a fluorescent protein within the same small subsets of neurons. Thus, SLICK combines the powerful cre recombinase system for conditional genetic manipulation and the fluorescent labeling of single neurons for imaging. We demonstrate efficient inducible genetic manipulation in several types of neurons using SLICK. Furthermore, we apply SLICK to eliminate synaptic transmission in a small subset of neuromuscular junctions. Our results provide evidence for the long-term stability of inactive neuromuscular synapses in adult animals. More broadly, these studies demonstrate a cre-LoxP compatible system for dissecting gene functions in single identifiable neurons. PMID:18454144

Distributed Representation of Visual Objects by Single Neurons in the Human Brain

PubMed Central

Valdez, André B.; Papesh, Megan H.; Treiman, David M.; Smith, Kris A.; Goldinger, Stephen D.

2015-01-01

It remains unclear how single neurons in the human brain represent whole-object visual stimuli. While recordings in both human and nonhuman primates have shown distributed representations of objects (many neurons encoding multiple objects), recordings of single neurons in the human medial temporal lobe, taken as subjects' discriminated objects during multiple presentations, have shown gnostic representations (single neurons encoding one object). Because some studies suggest that repeated viewing may enhance neural selectivity for objects, we had human subjects discriminate objects in a single, more naturalistic viewing session. We found that, across 432 well isolated neurons recorded in the hippocampus and amygdala, the average fraction of objects encoded was 26%. We also found that more neurons encoded several objects versus only one object in the hippocampus (28 vs 18%, p < 0.001) and in the amygdala (30 vs 19%, p < 0.001). Thus, during realistic viewing experiences, typical neurons in the human medial temporal lobe code for a considerable range of objects, across multiple semantic categories. PMID:25834044

Arcuate Na+,K+-ATPase senses systemic energy states and regulates feeding behavior through glucose-inhibited neurons.

PubMed

Kurita, Hideharu; Xu, Kai Y; Maejima, Yuko; Nakata, Masanori; Dezaki, Katsuya; Santoso, Putra; Yang, Yifei; Arai, Takeshi; Gantulga, Darambazar; Muroya, Shinji; Lefor, Alan K; Kakei, Masafumi; Watanabe, Eiju; Yada, Toshihiko

2015-08-15

Feeding is regulated by perception in the hypothalamus, particularly the first-order arcuate nucleus (ARC) neurons, of the body's energy state. However, the cellular device for converting energy states to the activity of critical neurons in ARC is less defined. We here show that Na(+),K(+)-ATPase (NKA) in ARC senses energy states to regulate feeding. Fasting-induced systemic ghrelin rise and glucose lowering reduced ATP-hydrolyzing activity of NKA and its substrate ATP level, respectively, preferentially in ARC. Lowering glucose concentration (LG), which mimics fasting, decreased intracellular NAD(P)H and increased Na(+) concentration in single ARC neurons that subsequently exhibited [Ca(2+)]i responses to LG, showing that they were glucose-inhibited (GI) neurons. Third ventricular injection of the NKA inhibitor ouabain induced c-Fos expression in agouti-related protein (AgRP) neurons in ARC and evoked neuropeptide Y (NPY)-dependent feeding. When injected focally into ARC, ouabain stimulated feeding and mRNA expressions for NPY and AgRP. Ouabain increased [Ca(2+)]i in single NPY/AgRP neurons with greater amplitude than in proopiomelanocortin neurons in ARC. Conversely, the specific NKA activator SSA412 suppressed fasting-induced feeding and LG-induced [Ca(2+)]i increases in ARC GI neurons. NPY/AgRP neurons highly expressed NKAα3, whose knockdown impaired feeding behavior. These results demonstrate that fasting, via ghrelin rise and LG, suppresses NKA enzyme/pump activity in ARC and thereby promotes the activation of GI neurons and NPY/AgRP-dependent feeding. This study identifies ARC NKA as a hypothalamic sensor and converter of metabolic states to key neuronal activity and feeding behaviour, providing a new target to treat hyperphagic obesity and diabetes. Copyright © 2015 the American Physiological Society.

Single cell analysis of voltage-gated potassium channels that determines neuronal types of rat hypothalamic paraventricular nucleus neurons.

PubMed

Lee, S K; Lee, S; Shin, S Y; Ryu, P D; Lee, S Y

2012-03-15

The hypothalamic paraventricular nucleus (PVN), a site for the integration of both the neuroendocrine and autonomic systems, has heterogeneous cell composition. These neurons are classified into type I and type II neurons based on their electrophysiological properties. In the present study, we investigated the molecular identification of voltage-gated K+ (Kv) channels, which determines a distinctive characteristic of type I PVN neurons, by means of single-cell reverse transcription-polymerase chain reaction (RT-PCR) along with slice patch clamp recordings. In order to determine the mRNA expression profiles, firstly, the PVN neurons of male rats were classified into type I and type II neurons, and then, single-cell RT-PCR and single-cell real-time RT-PCR analysis were performed using the identical cell. The single-cell RT-PCR analysis revealed that Kv1.2, Kv1.3, Kv1.4, Kv4.1, Kv4.2, and Kv4.3 were expressed both in type I and in type II neurons, and several Kv channels were co-expressed in a single PVN neuron. However, we found that the expression densities of Kv4.2 and Kv4.3 were significantly higher in type I neurons than in type II neurons. Taken together, several Kv channels encoding A-type K+ currents are present both in type I and in type II neurons, and among those, Kv4.2 and Kv4.3 are the major Kv subunits responsible for determining the distinct electrophysiological properties. Thus these 2 Kv subunits may play important roles in determining PVN cell types and regulating PVN neuronal excitability. This study further provides key molecular mechanisms for differentiating type I and type II PVN neurons. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

BlastNeuron for Automated Comparison, Retrieval and Clustering of 3D Neuron Morphologies.

PubMed

Wan, Yinan; Long, Fuhui; Qu, Lei; Xiao, Hang; Hawrylycz, Michael; Myers, Eugene W; Peng, Hanchuan

2015-10-01

Characterizing the identity and types of neurons in the brain, as well as their associated function, requires a means of quantifying and comparing 3D neuron morphology. Presently, neuron comparison methods are based on statistics from neuronal morphology such as size and number of branches, which are not fully suitable for detecting local similarities and differences in the detailed structure. We developed BlastNeuron to compare neurons in terms of their global appearance, detailed arborization patterns, and topological similarity. BlastNeuron first compares and clusters 3D neuron reconstructions based on global morphology features and moment invariants, independent of their orientations, sizes, level of reconstruction and other variations. Subsequently, BlastNeuron performs local alignment between any pair of retrieved neurons via a tree-topology driven dynamic programming method. A 3D correspondence map can thus be generated at the resolution of single reconstruction nodes. We applied BlastNeuron to three datasets: (1) 10,000+ neuron reconstructions from a public morphology database, (2) 681 newly and manually reconstructed neurons, and (3) neurons reconstructions produced using several independent reconstruction methods. Our approach was able to accurately and efficiently retrieve morphologically and functionally similar neuron structures from large morphology database, identify the local common structures, and find clusters of neurons that share similarities in both morphology and molecular profiles.

Latent herpes simplex virus 1 infection does not induce apoptosis in human trigeminal Ganglia.

PubMed

Himmelein, Susanne; Lindemann, Anja; Sinicina, Inga; Strupp, Michael; Brandt, Thomas; Hüfner, Katharina

2015-05-01

Herpes simplex virus 1 (HSV-1) can establish lifelong latency in human trigeminal ganglia. Latently infected ganglia contain CD8(+) T cells, which secrete granzyme B and are thus capable of inducing neuronal apoptosis. Using immunohistochemistry and single-cell reverse transcription-quantitative PCR (RT-qPCR), higher frequency and transcript levels of caspase-3 were found in HSV-1-negative compared to HSV-1-positive ganglia and neurons, respectively. No terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay-positive neurons were detected. The infiltrating T cells do not induce apoptosis in latently infected neurons. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

A microprobe for parallel optical and electrical recordings from single neurons in vivo.

PubMed

LeChasseur, Yoan; Dufour, Suzie; Lavertu, Guillaume; Bories, Cyril; Deschênes, Martin; Vallée, Réal; De Koninck, Yves

2011-04-01

Recording electrical activity from identified neurons in intact tissue is key to understanding their role in information processing. Recent fluorescence labeling techniques have opened new possibilities to combine electrophysiological recording with optical detection of individual neurons deep in brain tissue. For this purpose we developed dual-core fiberoptics-based microprobes, with an optical core to locally excite and collect fluorescence, and an electrolyte-filled hollow core for extracellular single unit electrophysiology. This design provides microprobes with tips < 10 μm, enabling analyses with single-cell optical resolution. We demonstrate combined electrical and optical detection of single fluorescent neurons in rats and mice. We combined electrical recordings and optical Ca²(+) measurements from single thalamic relay neurons in rats, and achieved detection and activation of single channelrhodopsin-expressing neurons in Thy1::ChR2-YFP transgenic mice. The microprobe expands possibilities for in vivo electrophysiological recording, providing parallel access to single-cell optical monitoring and control.

Multiple linear regression to estimate time-frequency electrophysiological responses in single trials

PubMed Central

Hu, L.; Zhang, Z.G.; Mouraux, A.; Iannetti, G.D.

2015-01-01

Transient sensory, motor or cognitive event elicit not only phase-locked event-related potentials (ERPs) in the ongoing electroencephalogram (EEG), but also induce non-phase-locked modulations of ongoing EEG oscillations. These modulations can be detected when single-trial waveforms are analysed in the time-frequency domain, and consist in stimulus-induced decreases (event-related desynchronization, ERD) or increases (event-related synchronization, ERS) of synchrony in the activity of the underlying neuronal populations. ERD and ERS reflect changes in the parameters that control oscillations in neuronal networks and, depending on the frequency at which they occur, represent neuronal mechanisms involved in cortical activation, inhibition and binding. ERD and ERS are commonly estimated by averaging the time-frequency decomposition of single trials. However, their trial-to-trial variability that can reflect physiologically-important information is lost by across-trial averaging. Here, we aim to (1) develop novel approaches to explore single-trial parameters (including latency, frequency and magnitude) of ERP/ERD/ERS; (2) disclose the relationship between estimated single-trial parameters and other experimental factors (e.g., perceived intensity). We found that (1) stimulus-elicited ERP/ERD/ERS can be correctly separated using principal component analysis (PCA) decomposition with Varimax rotation on the single-trial time-frequency distributions; (2) time-frequency multiple linear regression with dispersion term (TF-MLRd) enhances the signal-to-noise ratio of ERP/ERD/ERS in single trials, and provides an unbiased estimation of their latency, frequency, and magnitude at single-trial level; (3) these estimates can be meaningfully correlated with each other and with other experimental factors at single-trial level (e.g., perceived stimulus intensity and ERP magnitude). The methods described in this article allow exploring fully non-phase-locked stimulus-induced cortical oscillations, obtaining single-trial estimate of response latency, frequency, and magnitude. This permits within-subject statistical comparisons, correlation with pre-stimulus features, and integration of simultaneously-recorded EEG and fMRI. PMID:25665966

Ctip2-, Satb2-, Prox1-, and GAD65-Expressing Neurons in Rat Cultures: Preponderance of Single- and Double-Positive Cells, and Cell Type-Specific Expression of Neuron-Specific Gene Family Members, Nsg-1 (NEEP21) and Nsg-2 (P19).

PubMed

Digilio, Laura; Yap, Chan Choo; Winckler, Bettina

2015-01-01

The brain consists of many distinct neuronal cell types, but which cell types are present in widely used primary cultures of embryonic rodent brain is often not known. We characterized how abundantly four cell type markers (Ctip2, Satb2, Prox1, GAD65) were represented in cultured rat neurons, how easily neurons expressing different markers can be transfected with commonly used plasmids, and whether neuronal-enriched endosomal proteins Nsg-1 (NEEP21) and Nsg-2 (P19) are ubiquitously expressed in all types of cultured neurons. We found that cultured neurons stably maintain cell type identities that are reflective of cell types in vivo. This includes neurons maintaining simultaneous expression of two transcription factors, such as Ctip2+/Satb2+ or Prox1+/Ctip2+ double-positive cells, which have also been described in vivo. Secondly, we established the superior efficiency of CAG promoters for both Lipofectamine-mediated transfection as well as for electroporation. Thirdly, we discovered that Nsg-1 and Nsg-2 were not expressed equally in all neurons: whereas high levels of both Nsg-1 and Nsg-2 were found in Satb2-, Ctip2-, and GAD65-positive neurons, Prox1-positive neurons in hippocampal cultures expressed low levels of both. Our findings thus highlight the importance of identifying neuronal cell types for doing cell biology in cultured neurons: Keeping track of neuronal cell type might uncover effects in assays that might otherwise be masked by the mixture of responsive and non-responsive neurons in the dish.

A new era for functional labeling of neurons: activity-dependent promoters have come of age

PubMed Central

Kawashima, Takashi; Okuno, Hiroyuki; Bito, Haruhiko

2014-01-01

Genetic labeling of neurons with a specific response feature is an emerging technology for precise dissection of brain circuits that are functionally heterogeneous at the single-cell level. While immediate early gene mapping has been widely used for decades to identify brain regions which are activated by external stimuli, recent characterization of the promoter and enhancer elements responsible for neuronal activity-dependent transcription have opened new avenues for live imaging of active neurons. Indeed, these advancements provided the basis for a growing repertoire of novel experiments to address the role of active neuronal networks in cognitive behaviors. In this review, we summarize the current literature on the usage and development of activity-dependent promoters and discuss the future directions of this expanding new field. PMID:24795570

Multi-Scale Molecular Deconstruction of the Serotonin Neuron System.

PubMed

Okaty, Benjamin W; Freret, Morgan E; Rood, Benjamin D; Brust, Rachael D; Hennessy, Morgan L; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N; Dymecki, Susan M

2015-11-18

Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-seq to deconstruct the mouse 5HT system at multiple levels of granularity-from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal principles underlying system organization, 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers sertonergic subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance. Copyright © 2015 Elsevier Inc. All rights reserved.

Multi-Scale Molecular Deconstruction of the Serotonin Neuron System

PubMed Central

Okaty, Benjamin W.; Freret, Morgan E.; Rood, Benjamin D.; Brust, Rachael D.; Hennessy, Morgan L.; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N.; Dymecki, Susan M.

2016-01-01

Summary Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-Seq to deconstruct the mouse 5HT system at multiple levels of granularity—from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal: principles underlying system organization, novel 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers new subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance. PMID:26549332

Criticality in the brain

NASA Astrophysics Data System (ADS)

de Arcangelis, L.; Lombardi, F.; Herrmann, H. J.

2014-03-01

Spontaneous brain activity has been recently characterized by avalanche dynamics with critical features for systems in vitro and in vivo. In this contribution we present a review of experimental results on neuronal avalanches in cortex slices, together with numerical results from a neuronal model implementing several physiological properties of living neurons. Numerical data reproduce experimental results for avalanche statistics. The temporal organization of avalanches can be characterized by the distribution of waiting times between successive avalanches. Experimental measurements exhibit a non-monotonic behaviour, not usually found in other natural processes. Numerical simulations provide evidence that this behaviour is a consequence of the alternation between states of high and low activity, leading to a balance between excitation and inhibition controlled by a single parameter. During these periods both the single neuron state and the network excitability level, keeping memory of past activity, are tuned by homoeostatic mechanisms. Interestingly, the same homoeostatic balance is detected for neuronal activity at the scale of the whole brain. We finally review the learning abilities of this neuronal network. Learning occurs via plastic adaptation of synaptic strengths by a non-uniform negative feedback mechanism. The system is able to learn all the tested rules and the learning dynamics exhibits universal features as a function of the strength of plastic adaptation. Any rule could be learned provided that the plastic adaptation is sufficiently slow.

Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons.

PubMed

Tepper, James M; Wilson, Charles J; Koós, Tibor

2008-08-01

There are two distinct inhibitory GABAergic circuits in the neostriatum. The feedforward circuit consists of a relatively small population of GABAergic interneurons that receives excitatory input from the neocortex and exerts monosynaptic inhibition onto striatal spiny projection neurons. The feedback circuit comprises the numerous spiny projection neurons and their interconnections via local axon collaterals. This network has long been assumed to provide the majority of striatal GABAergic inhibition and to sharpen and shape striatal output through lateral inhibition, producing increased activity in the most strongly excited spiny cells at the expense of their less strongly excited neighbors. Recent results, mostly from recording experiments of synaptically connected pairs of neurons, have revealed that the two GABAergic circuits differ markedly in terms of the total number of synapses made by each, the strength of the postsynaptic response detected at the soma, the extent of presynaptic convergence and divergence and the net effect of the activation of each circuit on the postsynaptic activity of the spiny neuron. These data have revealed that the feedforward inhibition is powerful and widespread, with spiking in a single interneuron being capable of significantly delaying or even blocking the generation of spikes in a large number of postsynaptic spiny neurons. In contrast, the postsynaptic effects of spiking in a single presynaptic spiny neuron on postsynaptic spiny neurons are weak when measured at the soma, and unable to significantly affect spike timing or generation. Further, reciprocity of synaptic connections between spiny neurons is only rarely observed. These results suggest that the bulk of the fast inhibition that has the strongest effects on spiny neuron spike timing comes from the feedforward interneuronal system whereas the axon collateral feedback system acts principally at the dendrites to control local excitability as well as the overall level of activity of the spiny neuron.

The Dynamic Brain: From Spiking Neurons to Neural Masses and Cortical Fields

PubMed Central

Deco, Gustavo; Jirsa, Viktor K.; Robinson, Peter A.; Breakspear, Michael; Friston, Karl

2008-01-01

The cortex is a complex system, characterized by its dynamics and architecture, which underlie many functions such as action, perception, learning, language, and cognition. Its structural architecture has been studied for more than a hundred years; however, its dynamics have been addressed much less thoroughly. In this paper, we review and integrate, in a unifying framework, a variety of computational approaches that have been used to characterize the dynamics of the cortex, as evidenced at different levels of measurement. Computational models at different space–time scales help us understand the fundamental mechanisms that underpin neural processes and relate these processes to neuroscience data. Modeling at the single neuron level is necessary because this is the level at which information is exchanged between the computing elements of the brain; the neurons. Mesoscopic models tell us how neural elements interact to yield emergent behavior at the level of microcolumns and cortical columns. Macroscopic models can inform us about whole brain dynamics and interactions between large-scale neural systems such as cortical regions, the thalamus, and brain stem. Each level of description relates uniquely to neuroscience data, from single-unit recordings, through local field potentials to functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), and magnetoencephalogram (MEG). Models of the cortex can establish which types of large-scale neuronal networks can perform computations and characterize their emergent properties. Mean-field and related formulations of dynamics also play an essential and complementary role as forward models that can be inverted given empirical data. This makes dynamic models critical in integrating theory and experiments. We argue that elaborating principled and informed models is a prerequisite for grounding empirical neuroscience in a cogent theoretical framework, commensurate with the achievements in the physical sciences. PMID:18769680

Effects of Calcium Spikes in the Layer 5 Pyramidal Neuron on Coincidence Detection and Activity Propagation

PubMed Central

Chua, Yansong; Morrison, Abigail

2016-01-01

The role of dendritic spiking mechanisms in neural processing is so far poorly understood. To investigate the role of calcium spikes in the functional properties of the single neuron and recurrent networks, we investigated a three compartment neuron model of the layer 5 pyramidal neuron with calcium dynamics in the distal compartment. By performing single neuron simulations with noisy synaptic input and occasional large coincident input at either just the distal compartment or at both somatic and distal compartments, we show that the presence of calcium spikes confers a substantial advantage for coincidence detection in the former case and a lesser advantage in the latter. We further show that the experimentally observed critical frequency phenomenon, in which action potentials triggered by stimuli near the soma above a certain frequency trigger a calcium spike at distal dendrites, leading to further somatic depolarization, is not exhibited by a neuron receiving realistically noisy synaptic input, and so is unlikely to be a necessary component of coincidence detection. We next investigate the effect of calcium spikes in propagation of spiking activities in a feed-forward network (FFN) embedded in a balanced recurrent network. The excitatory neurons in the network are again connected to either just the distal, or both somatic and distal compartments. With purely distal connectivity, activity propagation is stable and distinguishable for a large range of recurrent synaptic strengths if the feed-forward connections are sufficiently strong, but propagation does not occur in the absence of calcium spikes. When connections are made to both the somatic and the distal compartments, activity propagation is achieved for neurons with active calcium dynamics at a much smaller number of neurons per pool, compared to a network of passive neurons, but quickly becomes unstable as the strength of recurrent synapses increases. Activity propagation at higher scaling factors can be stabilized by increasing network inhibition or introducing short term depression in the excitatory synapses, but the signal to noise ratio remains low. Our results demonstrate that the interaction of synchrony with dendritic spiking mechanisms can have profound consequences for the dynamics on the single neuron and network level. PMID:27499740

Effects of Calcium Spikes in the Layer 5 Pyramidal Neuron on Coincidence Detection and Activity Propagation.

PubMed

Chua, Yansong; Morrison, Abigail

2016-01-01

The role of dendritic spiking mechanisms in neural processing is so far poorly understood. To investigate the role of calcium spikes in the functional properties of the single neuron and recurrent networks, we investigated a three compartment neuron model of the layer 5 pyramidal neuron with calcium dynamics in the distal compartment. By performing single neuron simulations with noisy synaptic input and occasional large coincident input at either just the distal compartment or at both somatic and distal compartments, we show that the presence of calcium spikes confers a substantial advantage for coincidence detection in the former case and a lesser advantage in the latter. We further show that the experimentally observed critical frequency phenomenon, in which action potentials triggered by stimuli near the soma above a certain frequency trigger a calcium spike at distal dendrites, leading to further somatic depolarization, is not exhibited by a neuron receiving realistically noisy synaptic input, and so is unlikely to be a necessary component of coincidence detection. We next investigate the effect of calcium spikes in propagation of spiking activities in a feed-forward network (FFN) embedded in a balanced recurrent network. The excitatory neurons in the network are again connected to either just the distal, or both somatic and distal compartments. With purely distal connectivity, activity propagation is stable and distinguishable for a large range of recurrent synaptic strengths if the feed-forward connections are sufficiently strong, but propagation does not occur in the absence of calcium spikes. When connections are made to both the somatic and the distal compartments, activity propagation is achieved for neurons with active calcium dynamics at a much smaller number of neurons per pool, compared to a network of passive neurons, but quickly becomes unstable as the strength of recurrent synapses increases. Activity propagation at higher scaling factors can be stabilized by increasing network inhibition or introducing short term depression in the excitatory synapses, but the signal to noise ratio remains low. Our results demonstrate that the interaction of synchrony with dendritic spiking mechanisms can have profound consequences for the dynamics on the single neuron and network level.

Imaging Action Potential in Single Mammalian Neurons by Tracking the Accompanying Sub-Nanometer Mechanical Motion.

PubMed

Yang, Yunze; Liu, Xian-Wei; Wang, Hui; Yu, Hui; Guan, Yan; Wang, Shaopeng; Tao, Nongjian

2018-03-28

Action potentials in neurons have been studied traditionally by intracellular electrophysiological recordings and more recently by the fluorescence detection methods. Here we describe a label-free optical imaging method that can measure mechanical motion in single cells with a sub-nanometer detection limit. Using the method, we have observed sub-nanometer mechanical motion accompanying the action potential in single mammalian neurons by averaging the repeated action potential spikes. The shape and width of the transient displacement are similar to those of the electrically recorded action potential, but the amplitude varies from neuron to neuron, and from one region of a neuron to another, ranging from 0.2-0.4 nm. The work indicates that action potentials may be studied noninvasively in single mammalian neurons by label-free imaging of the accompanying sub-nanometer mechanical motion.

Distributed representation of visual objects by single neurons in the human brain.

PubMed

Valdez, André B; Papesh, Megan H; Treiman, David M; Smith, Kris A; Goldinger, Stephen D; Steinmetz, Peter N

2015-04-01

It remains unclear how single neurons in the human brain represent whole-object visual stimuli. While recordings in both human and nonhuman primates have shown distributed representations of objects (many neurons encoding multiple objects), recordings of single neurons in the human medial temporal lobe, taken as subjects' discriminated objects during multiple presentations, have shown gnostic representations (single neurons encoding one object). Because some studies suggest that repeated viewing may enhance neural selectivity for objects, we had human subjects discriminate objects in a single, more naturalistic viewing session. We found that, across 432 well isolated neurons recorded in the hippocampus and amygdala, the average fraction of objects encoded was 26%. We also found that more neurons encoded several objects versus only one object in the hippocampus (28 vs 18%, p < 0.001) and in the amygdala (30 vs 19%, p < 0.001). Thus, during realistic viewing experiences, typical neurons in the human medial temporal lobe code for a considerable range of objects, across multiple semantic categories. Copyright © 2015 the authors 0270-6474/15/355180-07$15.00/0.

Spontaneous neuronal activity as a self-organized critical phenomenon

NASA Astrophysics Data System (ADS)

de Arcangelis, L.; Herrmann, H. J.

2013-01-01

Neuronal avalanches are a novel mode of activity in neuronal networks, experimentally found in vitro and in vivo, and exhibit a robust critical behaviour. Avalanche activity can be modelled within the self-organized criticality framework, including threshold firing, refractory period and activity-dependent synaptic plasticity. The size and duration distributions confirm that the system acts in a critical state, whose scaling behaviour is very robust. Next, we discuss the temporal organization of neuronal avalanches. This is given by the alternation between states of high and low activity, named up and down states, leading to a balance between excitation and inhibition controlled by a single parameter. During these periods both the single neuron state and the network excitability level, keeping memory of past activity, are tuned by homeostatic mechanisms. Finally, we verify if a system with no characteristic response can ever learn in a controlled and reproducible way. Learning in the model occurs via plastic adaptation of synaptic strengths by a non-uniform negative feedback mechanism. Learning is a truly collective process and the learning dynamics exhibits universal features. Even complex rules can be learned provided that the plastic adaptation is sufficiently slow.

The Temporal Pattern of Changes in Serum Biomarker Levels Reveals Complex and Dynamically Changing Pathologies after Exposure to a Single Low-Intensity Blast in Mice

PubMed Central

Ahmed, Farid; Plantman, Stefan; Cernak, Ibolja; Agoston, Denes V.

2015-01-01

Time-dependent changes in blood-based protein biomarkers can help identify the ­pathological processes in blast-induced traumatic brain injury (bTBI), assess injury severity, and monitor disease progression. We obtained blood from control and injured mice (exposed to a single, low-intensity blast) at 2-h, 1-day, 1–week, and 1-month post-injury. We then determined the serum levels of biomarkers related to metabolism (4-HNE, HIF-1α, ceruloplasmin), vascular function (AQP1, AQP4, VEGF, vWF, Flk-1), inflammation (OPN, CINC1, fibrinogen, MIP-1a, OX-44, p38, MMP-8, MCP-1 CCR5, CRP, galectin-1), cell adhesion and the extracellular matrix (integrin α6, TIMP1, TIMP4, Ncad, connexin-43), and axonal (NF-H, Tau), neuronal (NSE, CK-BB) and glial damage (GFAP, S100β, MBP) at various post-injury time points. Our findings indicate that the exposure to a single, low-intensity blast results in metabolic and vascular changes, altered cell adhesion, and axonal and neuronal injury in the mouse model of bTBI. Interestingly, serum levels of several inflammatory and astroglial markers were either unchanged or elevated only during the acute and subacute phases of injury. Conversely, serum levels of the majority of biomarkers related to metabolic and vascular functions, cell adhesion, as well as neuronal and axonal damage remained elevated at the termination of the experiment (1 month), indicating long-term systemic and cerebral alterations due to blast. Our findings show that the exposure to a single, low-intensity blast induces complex pathological processes with distinct temporal profiles. Hence, monitoring serum biomarker levels at various post-injury time points may provide enhanced diagnostics in blast-related neurological and multi-system deficits. PMID:26124743

Single-Cell Detection of Secreted Aβ and sAPPα from Human IPSC-Derived Neurons and Astrocytes.

PubMed

Liao, Mei-Chen; Muratore, Christina R; Gierahn, Todd M; Sullivan, Sarah E; Srikanth, Priya; De Jager, Philip L; Love, J Christopher; Young-Pearse, Tracy L

2016-02-03

Secreted factors play a central role in normal and pathological processes in every tissue in the body. The brain is composed of a highly complex milieu of different cell types and few methods exist that can identify which individual cells in a complex mixture are secreting specific analytes. By identifying which cells are responsible, we can better understand neural physiology and pathophysiology, more readily identify the underlying pathways responsible for analyte production, and ultimately use this information to guide the development of novel therapeutic strategies that target the cell types of relevance. We present here a method for detecting analytes secreted from single human induced pluripotent stem cell (iPSC)-derived neural cells and have applied the method to measure amyloid β (Aβ) and soluble amyloid precursor protein-alpha (sAPPα), analytes central to Alzheimer's disease pathogenesis. Through these studies, we have uncovered the dynamic range of secretion profiles of these analytes from single iPSC-derived neuronal and glial cells and have molecularly characterized subpopulations of these cells through immunostaining and gene expression analyses. In examining Aβ and sAPPα secretion from single cells, we were able to identify previously unappreciated complexities in the biology of APP cleavage that could not otherwise have been found by studying averaged responses over pools of cells. This technique can be readily adapted to the detection of other analytes secreted by neural cells, which would have the potential to open new perspectives into human CNS development and dysfunction. We have established a technology that, for the first time, detects secreted analytes from single human neurons and astrocytes. We examine secretion of the Alzheimer's disease-relevant factors amyloid β (Aβ) and soluble amyloid precursor protein-alpha (sAPPα) and present novel findings that could not have been observed without a single-cell analytical platform. First, we identify a previously unappreciated subpopulation that secretes high levels of Aβ in the absence of detectable sAPPα. Further, we show that multiple cell types secrete high levels of Aβ and sAPPα, but cells expressing GABAergic neuronal markers are overrepresented. Finally, we show that astrocytes are competent to secrete high levels of Aβ and therefore may be a significant contributor to Aβ accumulation in the brain. Copyright © 2016 the authors 0270-6474/16/361730-17$15.00/0.

Highly scalable multichannel mesh electronics for stable chronic brain electrophysiology.

PubMed

Fu, Tian-Ming; Hong, Guosong; Viveros, Robert D; Zhou, Tao; Lieber, Charles M

2017-11-21

Implantable electrical probes have led to advances in neuroscience, brain-machine interfaces, and treatment of neurological diseases, yet they remain limited in several key aspects. Ideally, an electrical probe should be capable of recording from large numbers of neurons across multiple local circuits and, importantly, allow stable tracking of the evolution of these neurons over the entire course of study. Silicon probes based on microfabrication can yield large-scale, high-density recording but face challenges of chronic gliosis and instability due to mechanical and structural mismatch with the brain. Ultraflexible mesh electronics, on the other hand, have demonstrated negligible chronic immune response and stable long-term brain monitoring at single-neuron level, although, to date, it has been limited to 16 channels. Here, we present a scalable scheme for highly multiplexed mesh electronics probes to bridge the gap between scalability and flexibility, where 32 to 128 channels per probe were implemented while the crucial brain-like structure and mechanics were maintained. Combining this mesh design with multisite injection, we demonstrate stable 128-channel local field potential and single-unit recordings from multiple brain regions in awake restrained mice over 4 mo. In addition, the newly integrated mesh is used to validate stable chronic recordings in freely behaving mice. This scalable scheme for mesh electronics together with demonstrated long-term stability represent important progress toward the realization of ideal implantable electrical probes allowing for mapping and tracking single-neuron level circuit changes associated with learning, aging, and neurodegenerative diseases. Copyright © 2017 the Author(s). Published by PNAS.

Gold nanoparticle-mediated laser stimulation causes a complex stress signal in neuronal cells

NASA Astrophysics Data System (ADS)

Johannsmeier, Sonja; Heeger, Patrick; Terakawa, Mitsuhiro; Kalies, Stefan; Heisterkamp, Alexander; Ripken, Tammo; Heinemann, Dag

2017-07-01

Gold nanoparticle mediated laser stimulation of neuronal cells allows for cell activation on a single-cell level. It could therefore be considered an alternative to classical electric neurostimulation. The physiological impact of this new approach has not been intensively studied so far. Here, we investigate the targeted cell's reaction to a laser stimulus based on its calcium response. A complex cellular reaction involving multiple sources has been revealed.

Diversity and Homogeneity in Responses of Midbrain Dopamine Neurons

PubMed Central

Fiorillo, Christopher D.; Yun, Sora R.; Song, Minryung R.

2013-01-01

Dopamine neurons of the ventral midbrain have been found to signal a reward prediction error that can mediate positive reinforcement. Despite the demonstration of modest diversity at the cellular and molecular levels, there has been little analysis of response diversity in behaving animals. Here we examine response diversity in rhesus macaques to appetitive, aversive, and neutral stimuli having relative motivational values that were measured and controlled through a choice task. First, consistent with previous studies, we observed a continuum of response variability and an apparent absence of distinct clusters in scatter plots, suggesting a lack of statistically discrete subpopulations of neurons. Second, we found that a group of “sensitive” neurons tend to be more strongly suppressed by a variety of stimuli and to be more strongly activated by juice. Third, neurons in the “ventral tier” of substantia nigra were found to have greater suppression, and a subset of these had higher baseline firing rates and late “rebound” activation after suppression. These neurons could belong to a previously identified subgroup of dopamine neurons that express high levels of H-type cation channels but lack calbindin. Fourth, neurons further rostral exhibited greater suppression. Fifth, although we observed weak activation of some neurons by aversive stimuli, this was not associated with their aversiveness. In conclusion, we find a diversity of response properties, distributed along a continuum, within what may be a single functional population of neurons signaling reward prediction error. PMID:23486943

Identifying cochlear implant channels with poor electrode-neuron interface: partial tripolar, single-channel thresholds and psychophysical tuning curves.

PubMed

Bierer, Julie Arenberg; Faulkner, Kathleen F

2010-04-01

The goal of this study was to evaluate the ability of a threshold measure, made with a restricted electrode configuration, to identify channels exhibiting relatively poor spatial selectivity. With a restricted electrode configuration, channel-to-channel variability in threshold may reflect variations in the interface between the electrodes and auditory neurons (i.e., nerve survival, electrode placement, and tissue impedance). These variations in the electrode-neuron interface should also be reflected in psychophysical tuning curve (PTC) measurements. Specifically, it is hypothesized that high single-channel thresholds obtained with the spatially focused partial tripolar (pTP) electrode configuration are predictive of wide or tip-shifted PTCs. Data were collected from five cochlear implant listeners implanted with the HiRes90k cochlear implant (Advanced Bionics Corp., Sylmar, CA). Single-channel thresholds and most comfortable listening levels were obtained for stimuli that varied in presumed electrical field size by using the pTP configuration for which a fraction of current (sigma) from a center-active electrode returns through two neighboring electrodes and the remainder through a distant indifferent electrode. Forward-masked PTCs were obtained for channels with the highest, lowest, and median tripolar (sigma = 1 or 0.9) thresholds. The probe channel and level were fixed and presented with either the monopolar (sigma = 0) or a more focused pTP (sigma > or = 0.55) configuration. The masker channel and level were varied, whereas the configuration was fixed to sigma = 0.5. A standard, three-interval, two-alternative forced choice procedure was used for thresholds and masked levels. Single-channel threshold and variability in threshold across channels systematically increased as the compensating current, sigma, increased and the presumed electrical field became more focused. Across subjects, channels with the highest single-channel thresholds, when measured with a narrow, pTP stimulus, had significantly broader PTCs than the lowest threshold channels. In two subjects, the tips of the tuning curves were shifted away from the probe channel. Tuning curves were also wider for the monopolar probes than with pTP probes for both the highest and lowest threshold channels. These results suggest that single-channel thresholds measured with a restricted stimulus can be used to identify cochlear implant channels with poor spatial selectivity. Channels having wide or tip-shifted tuning characteristics would likely not deliver the appropriate spectral information to the intended auditory neurons, leading to suboptimal perception. As a clinical tool, quick identification of impaired channels could lead to patient-specific mapping strategies and result in improved speech and music perception.

Anesthetic state modulates excitability but not spectral tuning or neural discrimination in single auditory midbrain neurons

PubMed Central

Schumacher, Joseph W.; Schneider, David M.

2011-01-01

The majority of sensory physiology experiments have used anesthesia to facilitate the recording of neural activity. Current techniques allow researchers to study sensory function in the context of varying behavioral states. To reconcile results across multiple behavioral and anesthetic states, it is important to consider how and to what extent anesthesia plays a role in shaping neural response properties. The role of anesthesia has been the subject of much debate, but the extent to which sensory coding properties are altered by anesthesia has yet to be fully defined. In this study we asked how urethane, an anesthetic commonly used for avian and mammalian sensory physiology, affects the coding of complex communication vocalizations (songs) and simple artificial stimuli in the songbird auditory midbrain. We measured spontaneous and song-driven spike rates, spectrotemporal receptive fields, and neural discriminability from responses to songs in single auditory midbrain neurons. In the same neurons, we recorded responses to pure tone stimuli ranging in frequency and intensity. Finally, we assessed the effect of urethane on population-level representations of birdsong. Results showed that intrinsic neural excitability is significantly depressed by urethane but that spectral tuning, single neuron discriminability, and population representations of song do not differ significantly between unanesthetized and anesthetized animals. PMID:21543752

Visual development in primates: Neural mechanisms and critical periods

PubMed Central

Kiorpes, Lynne

2015-01-01

Despite many decades of research into the development of visual cortex, it remains unclear what neural processes set limitations on the development of visual function and define its vulnerability to abnormal visual experience. This selected review examines the development of visual function and its neural correlates, and highlights the fact that in most cases receptive field properties of infant neurons are substantially more mature than infant visual function. One exception is temporal resolution, which can be accounted for by resolution of neurons at the level of the LGN. In terms of spatial vision, properties of single neurons alone are not sufficient to account for visual development. Different visual functions develop over different time courses. Their onset may be limited by the existence of neural response properties that support a given perceptual ability, but the subsequent time course of maturation to adult levels remains unexplained. Several examples are offered suggesting that taking account of weak signaling by infant neurons, correlated firing, and pooled responses of populations of neurons brings us closer to an understanding of the relationship between neural and behavioral development. PMID:25649764

ENA/VASP downregulation triggers cell death by impairing axonal maintenance in hippocampal neurons.

PubMed

Franco, D Lorena; Rezával, Carolina; Cáceres, Alfredo; Schinder, Alejandro F; Ceriani, M Fernanda

2010-06-01

Neurodegenerative diseases encompass a broad variety of motor and cognitive disorders that are accompanied by death of specific neuronal populations or brain regions. Cellular and molecular mechanisms underlying these complex disorders remain largely unknown. In a previous work we searched for novel Drosophila genes relevant for neurodegeneration and singled out enabled (ena), which encodes a protein involved in cytoskeleton remodeling. To extend our understanding on the mechanisms of ENA-triggered degeneration we now investigated the effect of silencing ena ortholog genes in mouse hippocampal neurons. We found that ENA/VASP downregulation led to neurite retraction and concomitant neuronal cell death through an apoptotic pathway. Remarkably, this retraction initially affected the axonal structure, showing no effect on dendrites. Reduction in ENA/VASP levels blocked the neuritogenic effect of a specific RhoA kinase (ROCK) inhibitor, thus suggesting that these proteins could participate in the Rho-signaling pathway. Altogether these observations demonstrate that ENA/VASP proteins are implicated in the establishment and maintenance of the axonal structure and that a change on their expression levels triggers neuronal degeneration. 2010 Elsevier Inc. All rights reserved.

Mapping cortical mesoscopic networks of single spiking cortical or sub-cortical neurons

PubMed Central

Xiao, Dongsheng; Vanni, Matthieu P; Mitelut, Catalin C; Chan, Allen W; LeDue, Jeffrey M; Xie, Yicheng; Chen, Andrew CN; Swindale, Nicholas V; Murphy, Timothy H

2017-01-01

Understanding the basis of brain function requires knowledge of cortical operations over wide-spatial scales, but also within the context of single neurons. In vivo, wide-field GCaMP imaging and sub-cortical/cortical cellular electrophysiology were used in mice to investigate relationships between spontaneous single neuron spiking and mesoscopic cortical activity. We make use of a rich set of cortical activity motifs that are present in spontaneous activity in anesthetized and awake animals. A mesoscale spike-triggered averaging procedure allowed the identification of motifs that are preferentially linked to individual spiking neurons by employing genetically targeted indicators of neuronal activity. Thalamic neurons predicted and reported specific cycles of wide-scale cortical inhibition/excitation. In contrast, spike-triggered maps derived from single cortical neurons yielded spatio-temporal maps expected for regional cortical consensus function. This approach can define network relationships between any point source of neuronal spiking and mesoscale cortical maps. DOI: http://dx.doi.org/10.7554/eLife.19976.001 PMID:28160463

Right-left asymmetry in the cortical processing of sounds for social communication vs. navigation in mustached bats.

PubMed

Kanwal, Jagmeet S

2012-01-01

In the Doppler-shifted constant frequency processing area in the primary auditory cortex of mustached bats, Pteronotus parnellii, neurons respond to both social calls and to echolocation signals. This multifunctional nature of cortical neurons creates a paradox for simultaneous processing of two behaviorally distinct categories of sound. To test the possibility of a stimulus-specific hemispheric bias, single-unit responses were obtained to both types of sounds, calls and pulse-echo tone pairs, from the right and left auditory cortex. Neurons on the left exhibited only slightly higher peak response magnitudes for their respective best calls, but they showed a significantly higher sensitivity (lower response thresholds) to calls than neurons on the right. On average, call-to-tone response ratios were significantly higher for neurons on the left than for those on the right. Neurons on the right responded significantly more strongly to pulse-echo tone pairs than those on the left. Overall, neurons in males responded to pulse-echo tone pairs with a much higher spike count compared to females, but this difference was less pronounced for calls. Multidimensional scaling of call responses yielded a segregated representation of call types only on the left. These data establish for the first time, a behaviorally directed right-left asymmetry at the level of single cortical neurons. It is proposed that a lateralized cortex emerges from multiparametric integration (e.g. combination-sensitivity) within a neuron and inhibitory interactions between neurons that come into play during the processing of complex sounds. © 2011 The Author. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

High-Dimensional Brain: A Tool for Encoding and Rapid Learning of Memories by Single Neurons.

PubMed

Tyukin, Ivan; Gorban, Alexander N; Calvo, Carlos; Makarova, Julia; Makarov, Valeri A

2018-03-19

Codifying memories is one of the fundamental problems of modern Neuroscience. The functional mechanisms behind this phenomenon remain largely unknown. Experimental evidence suggests that some of the memory functions are performed by stratified brain structures such as the hippocampus. In this particular case, single neurons in the CA1 region receive a highly multidimensional input from the CA3 area, which is a hub for information processing. We thus assess the implication of the abundance of neuronal signalling routes converging onto single cells on the information processing. We show that single neurons can selectively detect and learn arbitrary information items, given that they operate in high dimensions. The argument is based on stochastic separation theorems and the concentration of measure phenomena. We demonstrate that a simple enough functional neuronal model is capable of explaining: (i) the extreme selectivity of single neurons to the information content, (ii) simultaneous separation of several uncorrelated stimuli or informational items from a large set, and (iii) dynamic learning of new items by associating them with already "known" ones. These results constitute a basis for organization of complex memories in ensembles of single neurons. Moreover, they show that no a priori assumptions on the structural organization of neuronal ensembles are necessary for explaining basic concepts of static and dynamic memories.

Dopamine-dependent non-linear correlation between subthalamic rhythms in Parkinson's disease.

PubMed

Marceglia, S; Foffani, G; Bianchi, A M; Baselli, G; Tamma, F; Egidi, M; Priori, A

2006-03-15

The basic information architecture in the basal ganglia circuit is under debate. Whereas anatomical studies quantify extensive convergence/divergence patterns in the circuit, suggesting an information sharing scheme, neurophysiological studies report an absence of linear correlation between single neurones in normal animals, suggesting a segregated parallel processing scheme. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and in parkinsonian patients single neurones become linearly correlated, thus leading to a loss of segregation between neurones. Here we propose a possible integrative solution to this debate, by extending the concept of functional segregation from the cellular level to the network level. To this end, we recorded local field potentials (LFPs) from electrodes implanted for deep brain stimulation (DBS) in the subthalamic nucleus (STN) of parkinsonian patients. By applying bispectral analysis, we found that in the absence of dopamine stimulation STN LFP rhythms became non-linearly correlated, thus leading to a loss of segregation between rhythms. Non-linear correlation was particularly consistent between the low-beta rhythm (13-20 Hz) and the high-beta rhythm (20-35 Hz). Levodopa administration significantly decreased these non-linear correlations, therefore increasing segregation between rhythms. These results suggest that the extensive convergence/divergence in the basal ganglia circuit is physiologically necessary to sustain LFP rhythms distributed in large ensembles of neurones, but is not sufficient to induce correlated firing between neurone pairs. Conversely, loss of dopamine generates pathological linear correlation between neurone pairs, alters the patterns within LFP rhythms, and induces non-linear correlation between LFP rhythms operating at different frequencies. The pathophysiology of information processing in the human basal ganglia therefore involves not only activities of individual rhythms, but also interactions between rhythms.

Dopamine-dependent non-linear correlation between subthalamic rhythms in Parkinson's disease

PubMed Central

Marceglia, S; Foffani, G; Bianchi, A M; Baselli, G; Tamma, F; Egidi, M; Priori, A

2006-01-01

The basic information architecture in the basal ganglia circuit is under debate. Whereas anatomical studies quantify extensive convergence/divergence patterns in the circuit, suggesting an information sharing scheme, neurophysiological studies report an absence of linear correlation between single neurones in normal animals, suggesting a segregated parallel processing scheme. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and in parkinsonian patients single neurones become linearly correlated, thus leading to a loss of segregation between neurones. Here we propose a possible integrative solution to this debate, by extending the concept of functional segregation from the cellular level to the network level. To this end, we recorded local field potentials (LFPs) from electrodes implanted for deep brain stimulation (DBS) in the subthalamic nucleus (STN) of parkinsonian patients. By applying bispectral analysis, we found that in the absence of dopamine stimulation STN LFP rhythms became non-linearly correlated, thus leading to a loss of segregation between rhythms. Non-linear correlation was particularly consistent between the low-beta rhythm (13–20 Hz) and the high-beta rhythm (20–35 Hz). Levodopa administration significantly decreased these non-linear correlations, therefore increasing segregation between rhythms. These results suggest that the extensive convergence/divergence in the basal ganglia circuit is physiologically necessary to sustain LFP rhythms distributed in large ensembles of neurones, but is not sufficient to induce correlated firing between neurone pairs. Conversely, loss of dopamine generates pathological linear correlation between neurone pairs, alters the patterns within LFP rhythms, and induces non-linear correlation between LFP rhythms operating at different frequencies. The pathophysiology of information processing in the human basal ganglia therefore involves not only activities of individual rhythms, but also interactions between rhythms. PMID:16410285

Universal Critical Dynamics in High Resolution Neuronal Avalanche Data

NASA Astrophysics Data System (ADS)

Friedman, Nir; Ito, Shinya; Brinkman, Braden A. W.; Shimono, Masanori; DeVille, R. E. Lee; Dahmen, Karin A.; Beggs, John M.; Butler, Thomas C.

2012-05-01

The tasks of neural computation are remarkably diverse. To function optimally, neuronal networks have been hypothesized to operate near a nonequilibrium critical point. However, experimental evidence for critical dynamics has been inconclusive. Here, we show that the dynamics of cultured cortical networks are critical. We analyze neuronal network data collected at the individual neuron level using the framework of nonequilibrium phase transitions. Among the most striking predictions confirmed is that the mean temporal profiles of avalanches of widely varying durations are quantitatively described by a single universal scaling function. We also show that the data have three additional features predicted by critical phenomena: approximate power law distributions of avalanche sizes and durations, samples in subcritical and supercritical phases, and scaling laws between anomalous exponents.

Irregular spiking of pyramidal neurons organizes as scale-invariant neuronal avalanches in the awake state

PubMed Central

Bellay, Timothy; Klaus, Andreas; Seshadri, Saurav; Plenz, Dietmar

2015-01-01

Spontaneous fluctuations in neuronal activity emerge at many spatial and temporal scales in cortex. Population measures found these fluctuations to organize as scale-invariant neuronal avalanches, suggesting cortical dynamics to be critical. Macroscopic dynamics, though, depend on physiological states and are ambiguous as to their cellular composition, spatiotemporal origin, and contributions from synaptic input or action potential (AP) output. Here, we study spontaneous firing in pyramidal neurons (PNs) from rat superficial cortical layers in vivo and in vitro using 2-photon imaging. As the animal transitions from the anesthetized to awake state, spontaneous single neuron firing increases in irregularity and assembles into scale-invariant avalanches at the group level. In vitro spike avalanches emerged naturally yet required balanced excitation and inhibition. This demonstrates that neuronal avalanches are linked to the global physiological state of wakefulness and that cortical resting activity organizes as avalanches from firing of local PN groups to global population activity. DOI: http://dx.doi.org/10.7554/eLife.07224.001 PMID:26151674

A SCN10A SNP biases human pain sensitivity

PubMed Central

Duan, Guangyou; Han, Chongyang; Wang, Qingli; Guo, Shanna; Zhang, Yuhao; Ying, Ying; Huang, Penghao; Zhang, Li; Macala, Lawrence; Shah, Palak; Zhang, Mi; Li, Ningbo; Dib-Hajj, Sulayman D; Zhang, Xianwei

2016-01-01

Background: Nav1.8 sodium channels, encoded by SCN10A, are preferentially expressed in nociceptive neurons and play an important role in human pain. Although rare gain-of-function variants in SCN10A have been identified in individuals with painful peripheral neuropathies, whether more common variants in SCN10A can have an effect at the channel level and at the dorsal root ganglion, neuronal level leading to a pain disorder or an altered normal pain threshold has not been determined. Results: Candidate single nucleotide polymorphism association approach together with experimental pain testing in human subjects was used to explore possible common SCN10A missense variants that might affect human pain sensitivity. We demonstrated an association between rs6795970 (G > A; p.Ala1073Val) and higher thresholds for mechanical pain in a discovery cohort (496 subjects) and confirmed it in a larger replication cohort (1005 female subjects). Functional assessments showed that although the minor allele shifts channel activation by −4.3 mV, a proexcitatory attribute, it accelerates inactivation, an antiexcitatory attribute, with the net effect being reduced repetitive firing of dorsal root ganglion neurons, consistent with lower mechanical pain sensitivity. Conclusions: At the association and mechanistic levels, the SCN10A single nucleotide polymorphism rs6795970 biases human pain sensitivity. PMID:27590072

Task-Dependent Changes in Cross-Level Coupling between Single Neurons and Oscillatory Activity in Multiscale Networks

PubMed Central

Canolty, Ryan T.; Ganguly, Karunesh; Carmena, Jose M.

2012-01-01

Understanding the principles governing the dynamic coordination of functional brain networks remains an important unmet goal within neuroscience. How do distributed ensembles of neurons transiently coordinate their activity across a variety of spatial and temporal scales? While a complete mechanistic account of this process remains elusive, evidence suggests that neuronal oscillations may play a key role in this process, with different rhythms influencing both local computation and long-range communication. To investigate this question, we recorded multiple single unit and local field potential (LFP) activity from microelectrode arrays implanted bilaterally in macaque motor areas. Monkeys performed a delayed center-out reach task either manually using their natural arm (Manual Control, MC) or under direct neural control through a brain-machine interface (Brain Control, BC). In accord with prior work, we found that the spiking activity of individual neurons is coupled to multiple aspects of the ongoing motor beta rhythm (10–45 Hz) during both MC and BC, with neurons exhibiting a diversity of coupling preferences. However, here we show that for identified single neurons, this beta-to-rate mapping can change in a reversible and task-dependent way. For example, as beta power increases, a given neuron may increase spiking during MC but decrease spiking during BC, or exhibit a reversible shift in the preferred phase of firing. The within-task stability of coupling, combined with the reversible cross-task changes in coupling, suggest that task-dependent changes in the beta-to-rate mapping play a role in the transient functional reorganization of neural ensembles. We characterize the range of task-dependent changes in the mapping from beta amplitude, phase, and inter-hemispheric phase differences to the spike rates of an ensemble of simultaneously-recorded neurons, and discuss the potential implications that dynamic remapping from oscillatory activity to spike rate and timing may hold for models of computation and communication in distributed functional brain networks. PMID:23284276

Informational basis of sensory adaptation: entropy and single-spike efficiency in rat barrel cortex.

PubMed

Adibi, Mehdi; Clifford, Colin W G; Arabzadeh, Ehsan

2013-09-11

We showed recently that exposure to whisker vibrations enhances coding efficiency in rat barrel cortex despite increasing correlations in variability (Adibi et al., 2013). Here, to understand how adaptation achieves this improvement in sensory representation, we decomposed the stimulus information carried in neuronal population activity into its fundamental components in the framework of information theory. In the context of sensory coding, these components are the entropy of the responses across the entire stimulus set (response entropy) and the entropy of the responses conditional on the stimulus (conditional response entropy). We found that adaptation decreased response entropy and conditional response entropy at both the level of single neurons and the pooled activity of neuronal populations. However, the net effect of adaptation was to increase the mutual information because the drop in the conditional entropy outweighed the drop in the response entropy. The information transmitted by a single spike also increased under adaptation. As population size increased, the information content of individual spikes declined but the relative improvement attributable to adaptation was maintained.

Deep learning and shapes similarity for joint segmentation and tracing single neurons in SEM images

NASA Astrophysics Data System (ADS)

Rao, Qiang; Xiao, Chi; Han, Hua; Chen, Xi; Shen, Lijun; Xie, Qiwei

2017-02-01

Extracting the structure of single neurons is critical for understanding how they function within the neural circuits. Recent developments in microscopy techniques, and the widely recognized need for openness and standardization provide a community resource for automated reconstruction of dendritic and axonal morphology of single neurons. In order to look into the fine structure of neurons, we use the Automated Tape-collecting Ultra Microtome Scanning Electron Microscopy (ATUM-SEM) to get images sequence of serial sections of animal brain tissue that densely packed with neurons. Different from other neuron reconstruction method, we propose a method that enhances the SEM images by detecting the neuronal membranes with deep convolutional neural network (DCNN) and segments single neurons by active contour with group shape similarity. We joint the segmentation and tracing together and they interact with each other by alternate iteration that tracing aids the selection of candidate region patch for active contour segmentation while the segmentation provides the neuron geometrical features which improve the robustness of tracing. The tracing model mainly relies on the neuron geometrical features and is updated after neuron being segmented on the every next section. Our method enables the reconstruction of neurons of the drosophila mushroom body which is cut to serial sections and imaged under SEM. Our method provides an elementary step for the whole reconstruction of neuronal networks.

Symmetric Objects Become Special in Perception Because of Generic Computations in Neurons

PubMed Central

Pramod, R. T.

2017-01-01

Symmetry is a salient visual property: It is easy to detect and influences perceptual phenomena from segmentation to recognition. Yet researchers know little about its neural basis. Using recordings from single neurons in monkey IT cortex, we asked whether symmetry—being an emergent property—induces nonlinear interactions between object parts. Remarkably, we found no such deviation: Whole-object responses were always the sum of responses to the object’s parts, regardless of symmetry. The only defining characteristic of symmetric objects was that they were more distinctive compared with asymmetric objects. This was a consequence of neurons preferring the same part across locations within an object. Just as mixing diverse paints produces a homogeneous overall color, adding heterogeneous parts within an asymmetric object renders it indistinct. In contrast, adding identical parts within a symmetric object renders it distinct. This distinctiveness systematically predicted human symmetry judgments, and it explains many previous observations about symmetry perception. Thus, symmetry becomes special in perception despite being driven by generic computations at the level of single neurons. PMID:29219748

Aggressive Encounters Alter the Activation of Serotonergic Neurons and the Expression of 5-HT1A mRNA in the Hamster Dorsal Raphe Nucleus

PubMed Central

Cooper, Matthew A.; Grober, Matthew S.; Nicholas, Christopher; Huhman, Kim L.

2009-01-01

Serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN) have been implicated in stress-induced changes in behavior. Previous research indicates that stressful stimuli activate 5-HT neurons in select subregions of the DRN. Uncontrollable stress is thought to sensitize 5-HT neurons in the DRN and allow for an exaggerated 5-HT response to future stimuli. In the current study, we tested the hypothesis that following aggressive encounters, losing male Syrian hamsters would exhibit increased c-Fos immunoreactivity in 5-HT DRN neurons compared to winners or controls. In addition, we tested the hypothesis that losers would have decreased 5-HT1A mRNA levels in the DRN compared to winners or controls. We found that a single 15-min aggressive encounter increased c-Fos expression in 5-HT and non-5-HT neurons in losers compared to winners and controls. The increased c-Fos expression in losers was restricted to ventral regions of the rostral DRN. We also found that four 5-min aggressive encounters reduced total 5-HT1A mRNA levels in the DRN in losers compared to winners and controls, and that differences in mRNA levels were not restricted to specific DRN subregions. These results suggest that social defeat activates neurons in select subregions of the DRN and reduces message for DRN 5-HT1A autoreceptors. Our results support the hypothesis that social stress can activate 5-HT neurons in the DRN, reduce 5-HT1A autoreceptor-mediated inhibition, and lead to hyperactivity of 5-HT neurons. PMID:19362123

Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients’ neurons

PubMed Central

Havlicek, Steven; Kohl, Zacharias; Mishra, Himanshu K.; Prots, Iryna; Eberhardt, Esther; Denguir, Naime; Wend, Holger; Plötz, Sonja; Boyer, Leah; Marchetto, Maria C.N.; Aigner, Stefan; Sticht, Heinrich; Groemer, Teja W.; Hehr, Ute; Lampert, Angelika; Schlötzer-Schrehardt, Ursula; Winkler, Jürgen; Gage, Fred H.; Winner, Beate

2014-01-01

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of motorneuron diseases characterized by progressive spasticity and paresis of the lower limbs. Mutations in Spastic Gait 4 (SPG4), encoding spastin, are the most frequent cause of HSP. To understand how mutations in SPG4 affect human neurons, we generated human induced pluripotent stem cells (hiPSCs) from fibroblasts of two patients carrying a c.1684C>T nonsense mutation and from two controls. These SPG4 and control hiPSCs were able to differentiate into neurons and glia at comparable efficiency. All known spastin isoforms were reduced in SPG4 neuronal cells. The complexity of SPG4 neurites was decreased, which was paralleled by an imbalance of axonal transport with less retrograde movement. Prominent neurite swellings with disrupted microtubules were present in SPG4 neurons at an ultrastructural level. While some of these swellings contain acetylated and detyrosinated tubulin, these tubulin modifications were unchanged in total cell lysates of SPG4 neurons. Upregulation of another microtubule-severing protein, p60 katanin, may partially compensate for microtubuli dynamics in SPG4 neurons. Overexpression of the M1 or M87 spastin isoforms restored neurite length, branching, numbers of primary neurites and reduced swellings in SPG4 neuronal cells. We conclude that neurite complexity and maintenance in HSP patient-derived neurons are critically sensitive to spastin gene dosage. Our data show that elevation of single spastin isoform levels is sufficient to restore neurite complexity and reduce neurite swellings in patient cells. Furthermore, our human model offers an ideal platform for pharmacological screenings with the goal to restore physiological spastin levels in SPG4 patients. PMID:24381312

Lifting the veil on the dynamics of neuronal activities evoked by transcranial magnetic stimulation

PubMed Central

Li, Bingshuo; Virtanen, Juha P; Oeltermann, Axel; Schwarz, Cornelius; Giese, Martin A; Ziemann, Ulf

2017-01-01

Transcranial magnetic stimulation (TMS) is a widely used non-invasive tool to study and modulate human brain functions. However, TMS-evoked activity of individual neurons has remained largely inaccessible due to the large TMS-induced electromagnetic fields. Here, we present a general method providing direct in vivo electrophysiological access to TMS-evoked neuronal activity 0.8–1 ms after TMS onset. We translated human single-pulse TMS to rodents and unveiled time-grained evoked activities of motor cortex layer V neurons that show high-frequency spiking within the first 6 ms depending on TMS-induced current orientation and a multiphasic spike-rhythm alternating between excitation and inhibition in the 6–300 ms epoch, all of which can be linked to various human TMS responses recorded at the level of spinal cord and muscles. The advance here facilitates a new level of insight into the TMS-brain interaction that is vital for developing this non-invasive tool to purposefully explore and effectively treat the human brain. PMID:29165241

Risk of punishment influences discrete and coordinated encoding of reward-guided actions by prefrontal cortex and VTA neurons

PubMed Central

Park, Junchol

2017-01-01

Actions motivated by rewards are often associated with risk of punishment. Little is known about the neural representation of punishment risk during reward-seeking behavior. We modeled this circumstance in rats by designing a task where actions were consistently rewarded but probabilistically punished. Spike activity and local field potentials were recorded during task performance simultaneously from VTA and mPFC, two reciprocally connected regions implicated in reward-seeking and aversive behaviors. At the single unit level, we found that ensembles of putative dopamine and non-dopamine VTA neurons and mPFC neurons encode the relationship between action and punishment. At the network level, we found that coherent theta oscillations synchronize VTA and mPFC in a bottom-up direction, effectively phase-modulating the neuronal spike activity in the two regions during punishment-free actions. This synchrony declined as a function of punishment probability, suggesting that during reward-seeking actions, risk of punishment diminishes VTA-driven neural synchrony between the two regions. PMID:29058673

Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity

PubMed Central

Li, Chang-Lin; Li, Kai-Cheng; Wu, Dan; Chen, Yan; Luo, Hao; Zhao, Jing-Rong; Wang, Sa-Shuang; Sun, Ming-Ming; Lu, Ying-Jin; Zhong, Yan-Qing; Hu, Xu-Ye; Hou, Rui; Zhou, Bei-Bei; Bao, Lan; Xiao, Hua-Sheng; Zhang, Xu

2016-01-01

Sensory neurons are distinguished by distinct signaling networks and receptive characteristics. Thus, sensory neuron types can be defined by linking transcriptome-based neuron typing with the sensory phenotypes. Here we classify somatosensory neurons of the mouse dorsal root ganglion (DRG) by high-coverage single-cell RNA-sequencing (10 950 ± 1 218 genes per neuron) and neuron size-based hierarchical clustering. Moreover, single DRG neurons responding to cutaneous stimuli are recorded using an in vivo whole-cell patch clamp technique and classified by neuron-type genetic markers. Small diameter DRG neurons are classified into one type of low-threshold mechanoreceptor and five types of mechanoheat nociceptors (MHNs). Each of the MHN types is further categorized into two subtypes. Large DRG neurons are categorized into four types, including neurexophilin 1-expressing MHNs and mechanical nociceptors (MNs) expressing BAI1-associated protein 2-like 1 (Baiap2l1). Mechanoreceptors expressing trafficking protein particle complex 3-like and Baiap2l1-marked MNs are subdivided into two subtypes each. These results provide a new system for cataloging somatosensory neurons and their transcriptome databases. PMID:26691752

Neuron specific metabolic adaptations following multi-day exposures to oxygen glucose deprivation.

PubMed

Zeiger, Stephanie L H; McKenzie, Jennifer R; Stankowski, Jeannette N; Martin, Jacob A; Cliffel, David E; McLaughlin, BethAnn

2010-11-01

Prior exposure to sub toxic insults can induce a powerful endogenous neuroprotective program known as ischemic preconditioning. Current models typically rely on a single stress episode to induce neuroprotection whereas the clinical reality is that patients may experience multiple transient ischemic attacks (TIAs) prior to suffering a stroke. We sought to develop a neuron-enriched preconditioning model using multiple oxygen glucose deprivation (OGD) episodes to assess the endogenous protective mechanisms neurons implement at the metabolic and cellular level. We found that neurons exposed to a five minute period of glucose deprivation recovered oxygen utilization and lactate production using novel microphysiometry techniques. Using the non-toxic and energetically favorable five minute exposure, we developed a preconditioning paradigm where neurons are exposed to this brief OGD for three consecutive days. These cells experienced a 45% greater survival following an otherwise lethal event and exhibited a longer lasting window of protection in comparison to our previous in vitro preconditioning model using a single stress. As in other models, preconditioned cells exhibited mild caspase activation, an increase in oxidized proteins and a requirement for reactive oxygen species for neuroprotection. Heat shock protein 70 was upregulated during preconditioning, yet the majority of this protein was released extracellularly. We believe coupling this neuron-enriched multi-day model with microphysiometry will allow us to assess neuronal specific real-time metabolic adaptations necessary for preconditioning. Copyright © 2010 Elsevier B.V. All rights reserved.

Spike-timing dependent plasticity in primate corticospinal connections induced during free behavior

PubMed Central

Nishimura, Yukio; Perlmutter, Steve I.; Eaton, Ryan W.; Fetz, Eberhard E.

2014-01-01

Motor learning and functional recovery from brain damage involve changes in the strength of synaptic connections between neurons. Relevant in vivo evidence on the underlying cellular mechanisms remains limited and indirect. We found that the strength of neural connections between motor cortex and spinal cord in monkeys can be modified with an autonomous recurrent neural interface that delivers electrical stimuli in the spinal cord triggered by action potentials of corticospinal cells during free behavior. The activity-dependent stimulation modified the strength of the terminal connections of single corticomotoneuronal cells, consistent with a bidirectional spike-timing dependent plasticity rule previously derived from in vitro experiments. For some cells the changes lasted for days after the end of conditioning, but most effects eventually reverted to preconditioning levels. These results provide the first direct evidence of corticospinal synaptic plasticity in vivo at the level of single neurons induced by normal firing patterns during free behavior. PMID:24210907

Comparison of temporal properties of auditory single units in response to cochlear infrared laser stimulation recorded with multi-channel and single tungsten electrodes

NASA Astrophysics Data System (ADS)

Tan, Xiaodong; Xia, Nan; Young, Hunter; Richter, Claus-Peter

2015-02-01

Auditory prostheses may benefit from Infrared Neural Stimulation (INS) because optical stimulation allows for spatially selective activation of neuron populations. Selective activation of neurons in the cochlear spiral ganglion can be determined in the central nucleus of the inferior colliculus (ICC) because the tonotopic organization of frequencies in the cochlea is maintained throughout the auditory pathway. The activation profile of INS is well represented in the ICC by multichannel electrodes (MCEs). To characterize single unit properties in response to INS, however, single tungsten electrodes (STEs) should be used because of its better signal-to-noise ratio. In this study, we compared the temporal properties of ICC single units recorded with MCEs and STEs in order to characterize the response properties of single auditory neurons in response to INS in guinea pigs. The length along the cochlea stimulated with infrared radiation corresponded to a frequency range of about 0.6 octaves, similar to that recorded with STEs. The temporal properties of single units recorded with MCEs showed higher maximum rates, shorter latencies, and higher firing efficiencies compared to those recorded with STEs. When the preset amplitude threshold for triggering MCE recordings was raised to twice over the noise level, the temporal properties of the single units became similar to those obtained with STEs. Undistinguishable neural activities from multiple sources in MCE recordings could be responsible for the response property difference between MCEs and STEs. Thus, caution should be taken in single unit recordings with MCEs.

Short-Term Depression, Temporal Summation, and Onset Inhibition Shape Interval Tuning in Midbrain Neurons

PubMed Central

Baker, Christa A.

2014-01-01

A variety of synaptic mechanisms can contribute to single-neuron selectivity for temporal intervals in sensory stimuli. However, it remains unknown how these mechanisms interact to establish single-neuron sensitivity to temporal patterns of sensory stimulation in vivo. Here we address this question in a circuit that allows us to control the precise temporal patterns of synaptic input to interval-tuned neurons in behaviorally relevant ways. We obtained in vivo intracellular recordings under multiple levels of current clamp from midbrain neurons in the mormyrid weakly electric fish Brienomyrus brachyistius during stimulation with electrosensory pulse trains. To reveal the excitatory and inhibitory inputs onto interval-tuned neurons, we then estimated the synaptic conductances underlying responses. We found short-term depression in excitatory and inhibitory pathways onto all interval-tuned neurons. Short-interval selectivity was associated with excitation that depressed less than inhibition at short intervals, as well as temporally summating excitation. Long-interval selectivity was associated with long-lasting onset inhibition. We investigated tuning after separately nullifying the contributions of temporal summation and depression, and found the greatest diversity of interval selectivity among neurons when both mechanisms were at play. Furthermore, eliminating the effects of depression decreased sensitivity to directional changes in interval. These findings demonstrate that variation in depression and summation of excitation and inhibition helps to establish tuning to behaviorally relevant intervals in communication signals, and that depression contributes to neural coding of interval sequences. This work reveals for the first time how the interplay between short-term plasticity and temporal summation mediates the decoding of temporal sequences in awake, behaving animals. PMID:25339741

Blockade of persistent sodium currents contributes to the riluzole-induced inhibition of spontaneous activity and oscillations in injured DRG neurons.

PubMed

Xie, Rou-Gang; Zheng, Da-Wei; Xing, Jun-Ling; Zhang, Xu-Jie; Song, Ying; Xie, Ya-Bin; Kuang, Fang; Dong, Hui; You, Si-Wei; Xu, Hui; Hu, San-Jue

2011-04-25

In addition to a fast activating and immediately inactivating inward sodium current, many types of excitable cells possess a noninactivating or slowly inactivating component: the persistent sodium current (I(NaP)). The I(NaP) is found in normal primary sensory neurons where it is mediated by tetrodotoxin-sensitive sodium channels. The dorsal root ganglion (DRG) is the gateway for ectopic impulses that originate in pathological pain signals from the periphery. However, the role of I(NaP) in DRG neurons remains unclear, particularly in neuropathic pain states. Using in vivo recordings from single medium- and large-diameter fibers isolated from the compressed DRG in Sprague-Dawley rats, we show that local application of riluzole, which blocks the I(NaP), also inhibits the spontaneous activity of A-type DRG neurons in a dose-dependent manner. Significantly, riluzole also abolished subthreshold membrane potential oscillations (SMPOs), although DRG neurons still responded to intracellular current injection with a single full-sized spike. In addition, the I(NaP) was enhanced in medium- and large-sized neurons of the compressed DRG, while bath-applied riluzole significantly inhibited the I(NaP) without affecting the transient sodium current (I(NaT)). Taken together, these results demonstrate for the first time that the I(NaP) blocker riluzole selectively inhibits I(NaP) and thereby blocks SMPOs and the ectopic spontaneous activity of injured A-type DRG neurons. This suggests that the I(NaP) of DRG neurons is a potential target for treating neuropathic pain at the peripheral level.

Differential regulation of primary afferent input to spinal cord by muscarinic receptor subtypes delineated using knockout mice.

PubMed

Chen, Shao-Rui; Chen, Hong; Yuan, Wei-Xiu; Wess, Jürgen; Pan, Hui-Lin

2014-05-16

Stimulation of muscarinic acetylcholine receptors (mAChRs) inhibits nociceptive transmission at the spinal level. However, it is unclear how each mAChR subtype regulates excitatory synaptic input from primary afferents. Here we examined excitatory postsynaptic currents (EPSCs) of dorsal horn neurons evoked by dorsal root stimulation in spinal cord slices from wild-type and mAChR subtype knock-out (KO) mice. In wild-type mice, mAChR activation with oxotremorine-M decreased the amplitude of monosynaptic EPSCs in ∼67% of neurons but increased it in ∼10% of neurons. The inhibitory effect of oxotremorine-M was attenuated by the M2/M4 antagonist himbacine in the majority of neurons, and the remaining inhibition was abolished by group II/III metabotropic glutamate receptor (mGluR) antagonists in wild-type mice. In M2/M4 double-KO mice, oxotremorine-M inhibited monosynaptic EPSCs in significantly fewer neurons (∼26%) and increased EPSCs in significantly more neurons (33%) compared with wild-type mice. Blocking group II/III mGluRs eliminated the inhibitory effect of oxotremorine-M in M2/M4 double-KO mice. In M2 single-KO and M4 single-KO mice, himbacine still significantly reduced the inhibitory effect of oxotremorine-M. However, the inhibitory and potentiating effects of oxotremorine-M on EPSCs in M3 single-KO and M1/M3 double-KO mice were similar to those in wild-type mice. In M5 single-KO mice, oxotremorine-M failed to potentiate evoked EPSCs, and its inhibitory effect was abolished by himbacine. These findings indicate that activation of presynaptic M2 and M4 subtypes reduces glutamate release from primary afferents. Activation of the M5 subtype either directly increases primary afferent input or inhibits it through indirectly stimulating group II/III mGluRs. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Differential Regulation of Primary Afferent Input to Spinal Cord by Muscarinic Receptor Subtypes Delineated Using Knockout Mice*

PubMed Central

Chen, Shao-Rui; Chen, Hong; Yuan, Wei-Xiu; Wess, Jürgen; Pan, Hui-Lin

2014-01-01

Stimulation of muscarinic acetylcholine receptors (mAChRs) inhibits nociceptive transmission at the spinal level. However, it is unclear how each mAChR subtype regulates excitatory synaptic input from primary afferents. Here we examined excitatory postsynaptic currents (EPSCs) of dorsal horn neurons evoked by dorsal root stimulation in spinal cord slices from wild-type and mAChR subtype knock-out (KO) mice. In wild-type mice, mAChR activation with oxotremorine-M decreased the amplitude of monosynaptic EPSCs in ∼67% of neurons but increased it in ∼10% of neurons. The inhibitory effect of oxotremorine-M was attenuated by the M2/M4 antagonist himbacine in the majority of neurons, and the remaining inhibition was abolished by group II/III metabotropic glutamate receptor (mGluR) antagonists in wild-type mice. In M2/M4 double-KO mice, oxotremorine-M inhibited monosynaptic EPSCs in significantly fewer neurons (∼26%) and increased EPSCs in significantly more neurons (33%) compared with wild-type mice. Blocking group II/III mGluRs eliminated the inhibitory effect of oxotremorine-M in M2/M4 double-KO mice. In M2 single-KO and M4 single-KO mice, himbacine still significantly reduced the inhibitory effect of oxotremorine-M. However, the inhibitory and potentiating effects of oxotremorine-M on EPSCs in M3 single-KO and M1/M3 double-KO mice were similar to those in wild-type mice. In M5 single-KO mice, oxotremorine-M failed to potentiate evoked EPSCs, and its inhibitory effect was abolished by himbacine. These findings indicate that activation of presynaptic M2 and M4 subtypes reduces glutamate release from primary afferents. Activation of the M5 subtype either directly increases primary afferent input or inhibits it through indirectly stimulating group II/III mGluRs. PMID:24695732

A stochastic-field description of finite-size spiking neural networks

PubMed Central

Longtin, André

2017-01-01

Neural network dynamics are governed by the interaction of spiking neurons. Stochastic aspects of single-neuron dynamics propagate up to the network level and shape the dynamical and informational properties of the population. Mean-field models of population activity disregard the finite-size stochastic fluctuations of network dynamics and thus offer a deterministic description of the system. Here, we derive a stochastic partial differential equation (SPDE) describing the temporal evolution of the finite-size refractory density, which represents the proportion of neurons in a given refractory state at any given time. The population activity—the density of active neurons per unit time—is easily extracted from this refractory density. The SPDE includes finite-size effects through a two-dimensional Gaussian white noise that acts both in time and along the refractory dimension. For an infinite number of neurons the standard mean-field theory is recovered. A discretization of the SPDE along its characteristic curves allows direct simulations of the activity of large but finite spiking networks; this constitutes the main advantage of our approach. Linearizing the SPDE with respect to the deterministic asynchronous state allows the theoretical investigation of finite-size activity fluctuations. In particular, analytical expressions for the power spectrum and autocorrelation of activity fluctuations are obtained. Moreover, our approach can be adapted to incorporate multiple interacting populations and quasi-renewal single-neuron dynamics. PMID:28787447

Oxidative damage and neurodegeneration in manganese-induced neurotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Milatovic, Dejan; Zaja-Milatovic, Snjezana; Gupta, Ramesh C.

2009-10-15

Exposure to excessive manganese (Mn) levels results in neurotoxicity to the extrapyramidal system and the development of Parkinson's disease (PD)-like movement disorder, referred to as manganism. Although the mechanisms by which Mn induces neuronal damage are not well defined, its neurotoxicity appears to be regulated by a number of factors, including oxidative injury, mitochondrial dysfunction and neuroinflammation. To investigate the mechanisms underlying Mn neurotoxicity, we studied the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates (HEP), neuroinflammation mediators and associated neuronal dysfunctions both in vitro and in vivo. Primary cortical neuronal cultures showed concentration-dependent alterationsmore » in biomarkers of oxidative damage, F{sub 2}-isoprostanes (F{sub 2}-IsoPs) and mitochondrial dysfunction (ATP), as early as 2 h following Mn exposure. Treatment of neurons with 500 {mu}M Mn also resulted in time-dependent increases in the levels of the inflammatory biomarker, prostaglandin E{sub 2} (PGE{sub 2}). In vivo analyses corroborated these findings, establishing that either a single or three (100 mg/kg, s.c.) Mn injections (days 1, 4 and 7) induced significant increases in F{sub 2}-IsoPs and PGE{sub 2} in adult mouse brain 24 h following the last injection. Quantitative morphometric analyses of Golgi-impregnated striatal sections from mice exposed to single or three Mn injections revealed progressive spine degeneration and dendritic damage of medium spiny neurons (MSNs). These findings suggest that oxidative stress, mitochondrial dysfunction and neuroinflammation are underlying mechanisms in Mn-induced neurodegeneration.« less

Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with γ-secretase and regulates neuronal amyloid β-peptide levels.

PubMed

Schedin-Weiss, Sophia; Inoue, Mitsuhiro; Hromadkova, Lenka; Teranishi, Yasuhiro; Yamamoto, Natsuko Goto; Wiehager, Birgitta; Bogdanovic, Nenad; Winblad, Bengt; Sandebring-Matton, Anna; Frykman, Susanne; Tjernberg, Lars O

2017-08-01

Increased levels of the pathogenic amyloid β-peptide (Aβ), released from its precursor by the transmembrane protease γ-secretase, are found in Alzheimer disease (AD) brains. Interestingly, monoamine oxidase B (MAO-B) activity is also increased in AD brain, but its role in AD pathogenesis is not known. Recent neuroimaging studies have shown that the increased MAO-B expression in AD brain starts several years before the onset of the disease. Here, we show a potential connection between MAO-B, γ-secretase and Aβ in neurons. MAO-B immunohistochemistry was performed on postmortem human brain. Affinity purification of γ-secretase followed by mass spectrometry was used for unbiased identification of γ-secretase-associated proteins. The association of MAO-B with γ-secretase was studied by coimmunoprecipitation from brain homogenate, and by in-situ proximity ligation assay (PLA) in neurons as well as mouse and human brain sections. The effect of MAO-B on Aβ production and Notch processing in cell cultures was analyzed by siRNA silencing or overexpression experiments followed by ELISA, western blot or FRET analysis. Methodology for measuring relative intraneuronal MAO-B and Aβ42 levels in single cells was developed by combining immunocytochemistry and confocal microscopy with quantitative image analysis. Immunohistochemistry revealed MAO-B staining in neurons in the frontal cortex, hippocampus CA1 and entorhinal cortex in postmortem human brain. Interestingly, the neuronal staining intensity was higher in AD brain than in control brain in these regions. Mass spectrometric data from affinity purified γ-secretase suggested that MAO-B is a γ-secretase-associated protein, which was confirmed by immunoprecipitation and PLA, and a neuronal location of the interaction was shown. Strikingly, intraneuronal Aβ42 levels correlated with MAO-B levels, and siRNA silencing of MAO-B resulted in significantly reduced levels of intraneuronal Aβ42. Furthermore, overexpression of MAO-B enhanced Aβ production. This study shows that MAO-B levels are increased not only in astrocytes but also in pyramidal neurons in AD brain. The study also suggests that MAO-B regulates Aβ production in neurons via γ-secretase and thereby provides a key to understanding the relationship between MAO-B and AD pathogenesis. Potentially, the γ-secretase/MAO-B association may be a target for reducing Aβ levels using protein-protein interaction breakers.

hamlet, a binary genetic switch between single- and multiple- dendrite neuron morphology.

PubMed

Moore, Adrian W; Jan, Lily Yeh; Jan, Yuh Nung

2002-08-23

The dendritic morphology of neurons determines the number and type of inputs they receive. In the Drosophila peripheral nervous system (PNS), the external sensory (ES) neurons have a single nonbranched dendrite, whereas the lineally related multidendritic (MD) neurons have extensively branched dendritic arbors. We report that hamlet is a binary genetic switch between these contrasting morphological types. In hamlet mutants, ES neurons are converted to an MD fate, whereas ectopic hamlet expression in MD precursors results in transformation of MD neurons into ES neurons. Moreover, hamlet expression induced in MD neurons undergoing dendrite outgrowth drastically reduces arbor branching.

Two-population model for medial temporal lobe neurons: The vast majority are almost silent

NASA Astrophysics Data System (ADS)

Magyar, Andrew; Collins, John

2015-07-01

Recordings in the human medial temporal lobe have found many neurons that respond to pictures (and related stimuli) of just one particular person of those presented. It has been proposed that these are concept cells, responding to just a single concept. However, a direct experimental test of the concept cell idea appears impossible, because it would need the measurement of the response of each cell to enormous numbers of other stimuli. Here we propose a new statistical method for analysis of the data that gives a more powerful way to analyze how close data are to the concept-cell idea. Central to the model is the neuronal sparsity, defined as the total fraction of stimuli that elicit an above-threshold response in the neuron. The model exploits the large number of sampled neurons to give sensitivity to situations where the average response sparsity is much less than one response for the number of presented stimuli. We show that a conventional model where a single sparsity is postulated for all neurons gives an extremely poor fit to the data. In contrast, a model with two dramatically different populations gives an excellent fit to data from the hippocampus and entorhinal cortex. In the hippocampus, one population has 7% of the cells with a 2.6% sparsity. But a much larger fraction (93%) respond to only 0.1% of the stimuli. This can result in an extreme bias in the responsiveness of reported neurons compared with a typical neuron. Finally, we show how to allow for the fact that some identified units correspond to multiple neurons and find that our conclusions at the neural level are quantitatively changed but strengthened, with an even stronger difference between the two populations.

Comparison of the dynamics of neural interactions between current-based and conductance-based integrate-and-fire recurrent networks

PubMed Central

Cavallari, Stefano; Panzeri, Stefano; Mazzoni, Alberto

2014-01-01

Models of networks of Leaky Integrate-and-Fire (LIF) neurons are a widely used tool for theoretical investigations of brain function. These models have been used both with current- and conductance-based synapses. However, the differences in the dynamics expressed by these two approaches have been so far mainly studied at the single neuron level. To investigate how these synaptic models affect network activity, we compared the single neuron and neural population dynamics of conductance-based networks (COBNs) and current-based networks (CUBNs) of LIF neurons. These networks were endowed with sparse excitatory and inhibitory recurrent connections, and were tested in conditions including both low- and high-conductance states. We developed a novel procedure to obtain comparable networks by properly tuning the synaptic parameters not shared by the models. The so defined comparable networks displayed an excellent and robust match of first order statistics (average single neuron firing rates and average frequency spectrum of network activity). However, these comparable networks showed profound differences in the second order statistics of neural population interactions and in the modulation of these properties by external inputs. The correlation between inhibitory and excitatory synaptic currents and the cross-neuron correlation between synaptic inputs, membrane potentials and spike trains were stronger and more stimulus-modulated in the COBN. Because of these properties, the spike train correlation carried more information about the strength of the input in the COBN, although the firing rates were equally informative in both network models. Moreover, the network activity of COBN showed stronger synchronization in the gamma band, and spectral information about the input higher and spread over a broader range of frequencies. These results suggest that the second order statistics of network dynamics depend strongly on the choice of synaptic model. PMID:24634645

Comparison of the dynamics of neural interactions between current-based and conductance-based integrate-and-fire recurrent networks.

PubMed

Cavallari, Stefano; Panzeri, Stefano; Mazzoni, Alberto

2014-01-01

Models of networks of Leaky Integrate-and-Fire (LIF) neurons are a widely used tool for theoretical investigations of brain function. These models have been used both with current- and conductance-based synapses. However, the differences in the dynamics expressed by these two approaches have been so far mainly studied at the single neuron level. To investigate how these synaptic models affect network activity, we compared the single neuron and neural population dynamics of conductance-based networks (COBNs) and current-based networks (CUBNs) of LIF neurons. These networks were endowed with sparse excitatory and inhibitory recurrent connections, and were tested in conditions including both low- and high-conductance states. We developed a novel procedure to obtain comparable networks by properly tuning the synaptic parameters not shared by the models. The so defined comparable networks displayed an excellent and robust match of first order statistics (average single neuron firing rates and average frequency spectrum of network activity). However, these comparable networks showed profound differences in the second order statistics of neural population interactions and in the modulation of these properties by external inputs. The correlation between inhibitory and excitatory synaptic currents and the cross-neuron correlation between synaptic inputs, membrane potentials and spike trains were stronger and more stimulus-modulated in the COBN. Because of these properties, the spike train correlation carried more information about the strength of the input in the COBN, although the firing rates were equally informative in both network models. Moreover, the network activity of COBN showed stronger synchronization in the gamma band, and spectral information about the input higher and spread over a broader range of frequencies. These results suggest that the second order statistics of network dynamics depend strongly on the choice of synaptic model.

Neuronal overexpression of cyclooxygenase-2 does not alter the neuroinflammatory response during brain innate immune activation.

PubMed

Aid, Saba; Parikh, Nishant; Palumbo, Sara; Bosetti, Francesca

2010-07-12

Neuroinflammation is a critical component in the progression of several neurological and neurodegenerative diseases and cyclooxygenases (COX)-1 and -2 are key regulators of innate immune responses. We recently demonstrated that COX-1 deletion attenuates, whereas COX-2 deletion enhances, the neuroinflammatory response, blood-brain barrier permeability and leukocyte recruitment during lipopolysaccharide (LPS)-induced innate immune activation. Here, we used transgenic mice, which overexpressed human COX-2 via neuron-specific Thy-1 promoter (TgCOX-2), causing elevated prostaglandins (PGs) levels. We tested whether neuronal COX-2 overexpression affects the glial response to a single intracerebroventricular injection of LPS, which produces a robust neuroinflammatory reaction. Relative to non-transgenic controls (NTg), 7 month-old TgCOX-2 did not show any basal neuroinflammation, as assessed by gene expression of markers of inflammation and oxidative stress, neuronal damage, as assessed by Fluoro-JadeB staining, or systemic inflammation, as assessed by plasma levels of IL-1beta and corticosterone. Twenty-four hours after LPS injection, all mice showed increased microglial activation, as indicated by Iba1 immunostaining, neuronal damage, mRNA expression of cytokines (TNF-alpha, IL-6), reactive oxygen expressing enzymes (iNOS and NADPH oxidase subunits), endogenous COX-2, cPLA(2) and mPGES-1, and hippocampal and cortical IL-1beta levels. However, the increases were similar in TgCOX-2 and NTg. In NTg, LPS increased brain PGE(2) to the levels observed in TgCOX-2. These results suggest that PGs derived from neuronal COX-2 do not play a role in the neuroinflammatory response to acute activation of brain innate immunity. This is likely due to the direct effect of LPS on glial rather than neuronal cells. Published by Elsevier Ireland Ltd.

Human Cerebrospinal Fluid Promotes Neuronal Viability and Activity of Hippocampal Neuronal Circuits In Vitro

PubMed Central

Perez-Alcazar, Marta; Culley, Georgia; Lyckenvik, Tim; Mobarrez, Kristoffer; Bjorefeldt, Andreas; Wasling, Pontus; Seth, Henrik; Asztely, Frederik; Harrer, Andrea; Iglseder, Bernhard; Aigner, Ludwig; Hanse, Eric; Illes, Sebastian

2016-01-01

For decades it has been hypothesized that molecules within the cerebrospinal fluid (CSF) diffuse into the brain parenchyma and influence the function of neurons. However, the functional consequences of CSF on neuronal circuits are largely unexplored and unknown. A major reason for this is the absence of appropriate neuronal in vitro model systems, and it is uncertain if neurons cultured in pure CSF survive and preserve electrophysiological functionality in vitro. In this article, we present an approach to address how human CSF (hCSF) influences neuronal circuits in vitro. We validate our approach by comparing the morphology, viability, and electrophysiological function of single neurons and at the network level in rat organotypic slice and primary neuronal cultures cultivated either in hCSF or in defined standard culture media. Our results demonstrate that rodent hippocampal slices and primary neurons cultured in hCSF maintain neuronal morphology and preserve synaptic transmission. Importantly, we show that hCSF increases neuronal viability and the number of electrophysiologically active neurons in comparison to the culture media. In summary, our data indicate that hCSF represents a physiological environment for neurons in vitro and a superior culture condition compared to the defined standard media. Moreover, this experimental approach paves the way to assess the functional consequences of CSF on neuronal circuits as well as suggesting a novel strategy for central nervous system (CNS) disease modeling. PMID:26973467

Characteristics of allelic gene expression in human brain cells from single-cell RNA-seq data analysis.

PubMed

Zhao, Dejian; Lin, Mingyan; Pedrosa, Erika; Lachman, Herbert M; Zheng, Deyou

2017-11-10

Monoallelic expression of autosomal genes has been implicated in human psychiatric disorders. However, there is a paucity of allelic expression studies in human brain cells at the single cell and genome wide levels. In this report, we reanalyzed a previously published single-cell RNA-seq dataset from several postmortem human brains and observed pervasive monoallelic expression in individual cells, largely in a random manner. Examining single nucleotide variants with a predicted functional disruption, we found that the "damaged" alleles were overall expressed in fewer brain cells than their counterparts, and at a lower level in cells where their expression was detected. We also identified many brain cell type-specific monoallelically expressed genes. Interestingly, many of these cell type-specific monoallelically expressed genes were enriched for functions important for those brain cell types. In addition, function analysis showed that genes displaying monoallelic expression and correlated expression across neuronal cells from different individual brains were implicated in the regulation of synaptic function. Our findings suggest that monoallelic gene expression is prevalent in human brain cells, which may play a role in generating cellular identity and neuronal diversity and thus increasing the complexity and diversity of brain cell functions.

A single-neuron tracing study of arkypallidal and prototypic neurons in healthy rats.

PubMed

Fujiyama, Fumino; Nakano, Takashi; Matsuda, Wakoto; Furuta, Takahiro; Udagawa, Jun; Kaneko, Takeshi

2016-12-01

The external globus pallidus (GP) is known as a relay nucleus of the indirect pathway of the basal ganglia. Recent studies in dopamine-depleted and healthy rats indicate that the GP comprises two main types of pallidofugal neurons: the so-called "prototypic" and "arkypallidal" neurons. However, the reconstruction of complete arkypallidal neurons in healthy rats has not been reported. Here we visualized the entire axonal arborization of four single arkypallidal neurons and six single prototypic neurons in rat brain using labeling with a viral vector expressing membrane-targeted green fluorescent protein and examined the distribution of axon boutons in the target nuclei. Results revealed that not only the arkypallidal neurons but nearly all of the prototypic neurons projected to the striatum with numerous axon varicosities. Thus, the striatum is a major target nucleus for pallidal neurons. Arkypallidal and prototypic GP neurons located in the calbindin-positive and calbindin-negative regions mainly projected to the corresponding positive and negative regions in the striatum. Because the GP and striatum calbindin staining patterns reflect the topographic organization of the striatopallidal projection, the striatal neurons in the sensorimotor and associative regions constitute the reciprocal connection with the GP neurons in the corresponding regions.

From in silico astrocyte cell models to neuron-astrocyte network models: A review.

PubMed

Oschmann, Franziska; Berry, Hugues; Obermayer, Klaus; Lenk, Kerstin

2018-01-01

The idea that astrocytes may be active partners in synaptic information processing has recently emerged from abundant experimental reports. Because of their spatial proximity to neurons and their bidirectional communication with them, astrocytes are now considered as an important third element of the synapse. Astrocytes integrate and process synaptic information and by doing so generate cytosolic calcium signals that are believed to reflect neuronal transmitter release. Moreover, they regulate neuronal information transmission by releasing gliotransmitters into the synaptic cleft affecting both pre- and postsynaptic receptors. Concurrent with the first experimental reports of the astrocytic impact on neural network dynamics, computational models describing astrocytic functions have been developed. In this review, we give an overview over the published computational models of astrocytic functions, from single-cell dynamics to the tripartite synapse level and network models of astrocytes and neurons. Copyright © 2017 Elsevier Inc. All rights reserved.

Flow-Based Network Analysis of the Caenorhabditis elegans Connectome

PubMed Central

Bacik, Karol A.; Schaub, Michael T.; Billeh, Yazan N.; Barahona, Mauricio

2016-01-01

We exploit flow propagation on the directed neuronal network of the nematode C. elegans to reveal dynamically relevant features of its connectome. We find flow-based groupings of neurons at different levels of granularity, which we relate to functional and anatomical constituents of its nervous system. A systematic in silico evaluation of the full set of single and double neuron ablations is used to identify deletions that induce the most severe disruptions of the multi-resolution flow structure. Such ablations are linked to functionally relevant neurons, and suggest potential candidates for further in vivo investigation. In addition, we use the directional patterns of incoming and outgoing network flows at all scales to identify flow profiles for the neurons in the connectome, without pre-imposing a priori categories. The four flow roles identified are linked to signal propagation motivated by biological input-response scenarios. PMID:27494178

Origin of heterogeneous spiking patterns from continuously distributed ion channel densities: a computational study in spinal dorsal horn neurons.

PubMed

Balachandar, Arjun; Prescott, Steven A

2018-05-01

Distinct spiking patterns may arise from qualitative differences in ion channel expression (i.e. when different neurons express distinct ion channels) and/or when quantitative differences in expression levels qualitatively alter the spike generation process. We hypothesized that spiking patterns in neurons of the superficial dorsal horn (SDH) of spinal cord reflect both mechanisms. We reproduced SDH neuron spiking patterns by varying densities of K V 1- and A-type potassium conductances. Plotting the spiking patterns that emerge from different density combinations revealed spiking-pattern regions separated by boundaries (bifurcations). This map suggests that certain spiking pattern combinations occur when the distribution of potassium channel densities straddle boundaries, whereas other spiking patterns reflect distinct patterns of ion channel expression. The former mechanism may explain why certain spiking patterns co-occur in genetically identified neuron types. We also present algorithms to predict spiking pattern proportions from ion channel density distributions, and vice versa. Neurons are often classified by spiking pattern. Yet, some neurons exhibit distinct patterns under subtly different test conditions, which suggests that they operate near an abrupt transition, or bifurcation. A set of such neurons may exhibit heterogeneous spiking patterns not because of qualitative differences in which ion channels they express, but rather because quantitative differences in expression levels cause neurons to operate on opposite sides of a bifurcation. Neurons in the spinal dorsal horn, for example, respond to somatic current injection with patterns that include tonic, single, gap, delayed and reluctant spiking. It is unclear whether these patterns reflect five cell populations (defined by distinct ion channel expression patterns), heterogeneity within a single population, or some combination thereof. We reproduced all five spiking patterns in a computational model by varying the densities of a low-threshold (K V 1-type) potassium conductance and an inactivating (A-type) potassium conductance and found that single, gap, delayed and reluctant spiking arise when the joint probability distribution of those channel densities spans two intersecting bifurcations that divide the parameter space into quadrants, each associated with a different spiking pattern. Tonic spiking likely arises from a separate distribution of potassium channel densities. These results argue in favour of two cell populations, one characterized by tonic spiking and the other by heterogeneous spiking patterns. We present algorithms to predict spiking pattern proportions based on ion channel density distributions and, conversely, to estimate ion channel density distributions based on spiking pattern proportions. The implications for classifying cells based on spiking pattern are discussed. © 2018 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

From individual spiking neurons to population behavior: Systematic elimination of short-wavelength spatial modes

NASA Astrophysics Data System (ADS)

Steyn-Ross, Moira L.; Steyn-Ross, D. A.

2016-02-01

Mean-field models of the brain approximate spiking dynamics by assuming that each neuron responds to its neighbors via a naive spatial average that neglects local fluctuations and correlations in firing activity. In this paper we address this issue by introducing a rigorous formalism to enable spatial coarse-graining of spiking dynamics, scaling from the microscopic level of a single type 1 (integrator) neuron to a macroscopic assembly of spiking neurons that are interconnected by chemical synapses and nearest-neighbor gap junctions. Spiking behavior at the single-neuron scale ℓ ≈10 μ m is described by Wilson's two-variable conductance-based equations [H. R. Wilson, J. Theor. Biol. 200, 375 (1999), 10.1006/jtbi.1999.1002], driven by fields of incoming neural activity from neighboring neurons. We map these equations to a coarser spatial resolution of grid length B ℓ , with B ≫1 being the blocking ratio linking micro and macro scales. Our method systematically eliminates high-frequency (short-wavelength) spatial modes q ⃗ in favor of low-frequency spatial modes Q ⃗ using an adiabatic elimination procedure that has been shown to be equivalent to the path-integral coarse graining applied to renormalization group theory of critical phenomena. This bottom-up neural regridding allows us to track the percolation of synaptic and ion-channel noise from the single neuron up to the scale of macroscopic population-average variables. Anticipated applications of neural regridding include extraction of the current-to-firing-rate transfer function, investigation of fluctuation criticality near phase-transition tipping points, determination of spatial scaling laws for avalanche events, and prediction of the spatial extent of self-organized macrocolumnar structures. As a first-order exemplar of the method, we recover nonlinear corrections for a coarse-grained Wilson spiking neuron embedded in a network of identical diffusively coupled neurons whose chemical synapses have been disabled. Intriguingly, we find that reblocking transforms the original type 1 Wilson integrator into a type 2 resonator whose spike-rate transfer function exhibits abrupt spiking onset with near-vertical takeoff and chaotic dynamics just above threshold.

Anatomical characterization of PDF-tri neurons and peptidergic neurons associated with eclosion behavior in Drosophila.

PubMed

Selcho, Mareike; Mühlbauer, Barbara; Hensgen, Ronja; Shiga, Sakiko; Wegener, Christian; Yasuyama, Kouji

2018-06-01

The peptidergic Pigment-dispersing factor (PDF)-Tri neurons are a group of non-clock neurons that appear transiently around the time of adult ecdysis (=eclosion) in the fruit fly Drosophila melanogaster. This specific developmental pattern points to a function of these neurons in eclosion or other processes that are active around pupal-adult transition. As a first step to understand the role of these neurons, we here characterize the anatomy of the PDF-Tri neurons. In addition, we describe a further set of peptidergic neurons that have been associated with eclosion behavior, eclosion hormone (EH), and crustacean cardioactive peptide (CCAP) neurons, to single cell level in the pharate adult brain. PDF-Tri neurons as well as CCAP neurons co-express a classical transmitter indicated by the occurrence of small clear vesicles in addition to dense-core vesicles containing the peptides. In the tritocerebrum, gnathal ganglion and the superior protocerebrum PDF-Tri neurites contain peptidergic varicosities and both pre- and postsynaptic sites, suggesting that the PDF-Tri neurons represent modulatory rather than pure interneurons that connect the subesophageal zone with the superior protocerebrum. The extensive overlap of PDF-Tri arborizations with neurites of CCAP- and EH-expressing neurons in distinct brain regions provides anatomical evidence for a possible function of the PDF-Tri neurons in eclosion behavior. © 2018 Wiley Periodicals, Inc.

In-vivo RGB marking and multicolour single-cell tracking in the adult brain

PubMed Central

Gomez-Nicola, Diego; Riecken, Kristoffer; Fehse, Boris; Perry, V. Hugh

2014-01-01

In neuroscience it is a technical challenge to identify and follow the temporal and spatial distribution of cells as they differentiate. We hypothesised that RGB marking, the tagging of individual cells with unique hues resulting from simultaneous expression of the three basic colours red, green and blue, provides a convenient toolbox for the study of the CNS anatomy at the single-cell level. Using γ-retroviral and lentiviral vector sets we describe for the first time the in-vivo multicolour RGB marking of neurons in the adult brain. RGB marking also enabled us to track the spatial and temporal fate of neural stem cells in the adult brain. The application of different viral envelopes and promoters provided a useful approach to track the generation of neurons vs. glial cells at the neurogenic niche, allowing the identification of the prominent generation of new astrocytes to the striatum. Multicolour RGB marking could serve as a universal and reproducible method to study and manipulate the CNS at the single-cell level, in both health and disease. PMID:25531807

Collateral projections of nucleus raphe dorsalis neurones to the caudate-putamen and region around the nucleus raphe magnus and nucleus reticularis gigantocellularis pars alpha in the rat.

PubMed

Li, Y Q; Kaneko, T; Mizuno, N

2001-02-16

It was examined whether or not the nucleus raphe dorsalis (RD) neurons projecting to the caudate-putamen (CPu) might also project to the motor-controlling region around the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis pars alpha (Gia) in the rat. Single RD neurons projecting to the CPu and NRM/Gia by way of axon collaterals were identified by the retrograde double-labeling method with fluorescent dyes, Fast Blue and Diamidino Yellow, which were injected respectively into the CPu and NRM/Gia. Then, serotonin (5-HT)-like immunoreactivity of the double-labeled RD neurons was examined immunohistochemically; approximately 60% of the double-labeled RD neurons showed 5-HT-like immunoreactivity. The results indicated that some of serotonergic and non-serotonergic RD neurons might control motor functions simultaneously at the levels of the CPu and NRM/Gia by way of axon collaterals.

Biphasic activation of nuclear factor-κB and expression of p65 and c-Rel following traumatic neuronal injury.

PubMed

Zhang, Huasheng; Zhang, Dingding; Li, Hua; Yan, Huiying; Zhang, Zihuan; Zhou, Chenhui; Chen, Qiang; Ye, Zhennan; Hang, Chunhua

2018-06-01

The transcription factor nuclear factor-κB (NF-κB) has been shown to function as a key regulator of cell death or survival in neuronal cells. Previous studies indicate that the biphasic activation of NF-κB occurs following experimental neonatal hypoxia-ischemia and subarachnoid hemorrhage. However, the comprehensive understanding of NF-κB activity following traumatic brain injury (TBI) is incomplete. In the current study, an in vitro model of TBI was designed to investigate the NF-κB activity and expression of p65 and c-Rel subunits following traumatic neuronal injury. Primary cultured neurons were assigned to control and transected groups. NF-κB activity was detected by electrophoretic mobility shift assay. Western blotting and immunofluorescence were used to investigate the expression and distribution of p65 and c-Rel. Reverse transcription-quantitative polymerase chain reaction was performed to assess the downstream genes of NF-κB. Lactate dehydrogenase (LDH) quantification and trypan blue staining were used to estimate the neuronal injury. Double peaks of elevated NF-κB activity were observed at 1 and 24 h following transection. The expression levels of downstream genes exhibited similar changes. The protein levels of p65 also presented double peaks while c-Rel was elevated significantly in the late stage. The results of the trypan blue staining and LDH leakage assays indicated there was no sustained neuronal injury during the late peak of NF-κB activity. In conclusion, biphasic activation of NF-κB is induced following experimental traumatic neuronal injury. The elevation of p65 and c-Rel levels at different time periods suggests that within a single neuron, NF-κB may participate in different pathophysiological processes.

Long-term exposure of mice to nucleoside analogues disrupts mitochondrial DNA maintenance in cortical neurons.

PubMed

Zhang, Yulin; Song, Fengli; Gao, Ziyun; Ding, Wei; Qiao, Luxin; Yang, Sufang; Chen, Xi; Jin, Ronghua; Chen, Dexi

2014-01-01

Nucleoside analogue reverse transcriptase inhibitor (NRTI), an integral component of highly active antiretroviral therapy (HAART), was widely used to inhibit HIV replication. Long-term exposure to NRTIs can result in mitochondrial toxicity which manifests as lipoatrophy, lactic acidosis, cardiomyopathy and myopathy, as well as polyneuropathy. But the cerebral neurotoxicity of NRTIs is still not well known partly due to the restriction of blood-brain barrier (BBB) and the complex microenvironment of the central nervous system (CNS). In this study, the Balb/c mice were administered 50 mg/kg stavudine (D4T), 100 mg/kg zidovudine (AZT), 50 mg/kg lamivudine (3TC) or 50 mg/kg didanosine (DDI) per day by intraperitoneal injection, five days per week for one or four months, and primary cortical neurons were cultured and exposed to 25 µM D4T, 50 µM AZT, 25 µM 3TC or 25 µM DDI for seven days. Then, single neuron was captured from mouse cerebral cortical tissues by laser capture microdissection. Mitochondrial DNA (mtDNA) levels of the primary cultured cortical neurons, and captured neurons or glial cells, and the tissues of brains and livers and muscles were analyzed by relative quantitative real-time PCR. The data showed that mtDNA did not lose in both NRTIs exposed cultured neurons and one month NRTIs treated mouse brains. In four months NRTIs treated mice, brain mtDNA levels remained unchanged even if the mtDNA levels of liver (except for 3TC) and muscle significantly decreased. However, mtDNA deletion was significantly higher in the captured neurons from mtDNA unchanged brains. These results suggest that long-term exposure to NRTIs can result in mtDNA deletion in mouse cortical neurons.

Necroptosis contributes to methamphetamine-induced cytotoxicity in rat cortical neurons.

PubMed

Xiong, Kun; Liao, Huidan; Long, Lingling; Ding, Yanjun; Huang, Jufang; Yan, Jie

2016-09-01

Necroptosis, a programmed necrosis, is involved in various types of neurodegenerative diseases. In this study, we investigated whether necroptosis contributed to neuronal damage in a methamphetamine injury model. Primary cultures of embryonic cortical neurons from Sprague-Dawley rats were subjected to different doses of methamphetamine with/without pre-treatment with a specific necroptosis inhibitor, Necrostatin-1. Necrosis was assessed by determining lactate dehydrogenase release and by Annexin V/propidium iodide double staining, while the neuronal ultra-structure was examined by electron microscopy. Tumor necrosis factor-α protein levels were determined by enzyme-linked immunosorbent assay. At early stages (12h) of post-treatment with methamphetamine, significant necrosis occurred and the viability of neurons decreased in a dose- and time-dependent manner in this model of acute neuronal injury. Pretreatment with Necrostatin-1 led to significant neuronal preservation compared with the methamphetamine-treated groups. Furthermore, tumor necrosis factor-α expression increased in a dose-dependent manner following methamphetamine exposure. Methamphetamine induced necrosis in rat cortical neurons in vitro, both time and dose dependently, and necroptosis may be an important newly identified mode of cortical neuronal death caused by single high-dose methamphetamine administration. Copyright © 2016 Elsevier B.V. All rights reserved.

Differential dynamics of spatial attention, position, and color coding within the parietofrontal network.

PubMed

Astrand, Elaine; Ibos, Guilhem; Duhamel, Jean-René; Ben Hamed, Suliann

2015-02-18

Despite an ever growing knowledge on how parietal and prefrontal neurons encode low-level spatial and color information or higher-level information, such as spatial attention, an understanding of how these cortical regions process neuronal information at the population level is still missing. A simple assumption would be that the function and temporal response profiles of these neuronal populations match that of its constituting individual cells. However, several recent studies suggest that this is not necessarily the case and that the single-cell approach overlooks dynamic changes in how information is distributed over the neuronal population. Here, we use a time-resolved population pattern analysis to explore how spatial position, spatial attention and color information are differentially encoded and maintained in the macaque monkey prefrontal (frontal eye fields) and parietal cortex (lateral intraparietal area). Overall, our work brings about three novel observations. First, we show that parietal and prefrontal populations operate in two distinct population regimens for the encoding of sensory and cognitive information: a stationary mode and a dynamic mode. Second, we show that the temporal dynamics of a heterogeneous neuronal population brings about complementary information to that of its functional subpopulations. Thus, both need to be investigated in parallel. Last, we show that identifying the neuronal configuration in which a neuronal population encodes given information can serve to reveal this same information in a different context. All together, this work challenges common views on neural coding in the parietofrontal network. Copyright © 2015 the authors 0270-6474/15/353174-16$15.00/0.

Neuronal growth on L- and D-cysteine self-assembled monolayers reveals neuronal chiral sensitivity.

PubMed

Baranes, Koby; Moshe, Hagay; Alon, Noa; Schwartz, Shmulik; Shefi, Orit

2014-05-21

Studying the interaction between neuronal cells and chiral molecules is fundamental for the design of novel biomaterials and drugs. Chirality influences all biological processes that involve intermolecular interaction. One common method used to study cellular interactions with different enantiomeric targets is the use of chiral surfaces. Based on previous studies that demonstrated the importance of cysteine in the nervous system, we studied the effect of L- and D-cysteine on single neuronal growth. L-Cysteine, which normally functions as a neuromodulator or a neuroprotective antioxidant, causes damage at elevated levels, which may occur post trauma. In this study, we grew adult neurons in culture enriched with L- and D-cysteine as free compounds or as self-assembled monolayers of chiral surfaces and examined the effect on the neuronal morphology and adhesion. Notably, we have found that exposure to the L-cysteine enantiomer inhibited, and even prevented, neuronal attachment more severely than exposure to the D-cysteine enantiomer. Atop the L-cysteine surfaces, neuronal growth was reduced and degenerated. Since the cysteine molecules were attached to the surface via the thiol groups, the neuronal membrane was exposed to the molecular chiral site. Thus, our results have demonstrated high neuronal chiral sensitivity, revealing chiral surfaces as indirect regulators of neuronal cells and providing a reference for studying chiral drugs.

Distribution of 3H-GABA uptake sites in the nematode Ascaris

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guastella, J.; Stretton, A.O.

1991-05-22

The distribution of uptake sites for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the nematode Ascaris suum was examined by autoradiography of 3H-GABA uptake. Single neural processes in both the ventral and dorsal nerve cords were labeled with 3H-GABA. Serial section analysis identified the cells of origin of these processes as the RMEV-like and RMED-like neurons. These cells belong to a set of four neurons in the nerve ring, all of which are labeled by 3H-GABA. 3H-GABA labeling of at least two other sets of cephalic neurons was seen. One of these pairs consists of medium-sized lateral ganglia neurons, locatedmore » at the level of the amphid commissure bundle. A second pair is located in the lateral ganglia at the level of the deirid commissure bundle. The position and size of these lateral ganglia cells suggest that they are the GABA-immunoreactive lateral ganglia cells frequently seen in whole-mount immunocytochemical preparations. Four neuronal cell bodies located in the retrovesicular ganglion were also labeled with 3H-GABA. These cells, which are probably cholinergic excitatory motor neurons, do not contain detectable GABA-like immunoreactivity. Heavy labeling of muscle cells was also observed. The ventral and dorsal nerve cord inhibitory motor neurons, which are known to contain GABA-like immunoreactivity, were not labeled above background with 3H-GABA. Together with the experiments reported previously, these results define three classes of GABA-associated neurons in Ascaris: (1) neurons that contain endogenous GABA and possess a GABA uptake system; (2) neurons that contain endogenous GABA, but that either lack a GABA uptake system or possess a GABA uptake system of low activity; (3) neurons that possess a GABA uptake system, but that lack endogenous GABA.« less

Single-neuron identification of chemical constituents, physiological changes, and metabolism using mass spectrometry.

PubMed

Zhu, Hongying; Zou, Guichang; Wang, Ning; Zhuang, Meihui; Xiong, Wei; Huang, Guangming

2017-03-07

The use of single-cell assays has emerged as a cutting-edge technique during the past decade. Although single-cell mass spectrometry (MS) has recently achieved remarkable results, deep biological insights have not yet been obtained, probably because of various technical issues, including the unavoidable use of matrices, the inability to maintain cell viability, low throughput because of sample pretreatment, and the lack of recordings of cell physiological activities from the same cell. In this study, we describe a patch clamp/MS-based platform that enables the sensitive, rapid, and in situ chemical profiling of single living neurons. This approach integrates modified patch clamp technique and modified MS measurements to directly collect and detect nanoliter-scale samples from the cytoplasm of single neurons in mice brain slices. Abundant possible cytoplasmic constituents were detected in a single neuron at a relatively fast rate, and over 50 metabolites were identified in this study. The advantages of direct, rapid, and in situ sampling and analysis enabled us to measure the biological activities of the cytoplasmic constituents in a single neuron, including comparing neuron types by cytoplasmic chemical constituents; observing changes in constituent concentrations as the physiological conditions, such as age, vary; and identifying the metabolic pathways of small molecules.

Single-neuron identification of chemical constituents, physiological changes, and metabolism using mass spectrometry

PubMed Central

Zhu, Hongying; Zou, Guichang; Wang, Ning; Zhuang, Meihui; Xiong, Wei; Huang, Guangming

2017-01-01

The use of single-cell assays has emerged as a cutting-edge technique during the past decade. Although single-cell mass spectrometry (MS) has recently achieved remarkable results, deep biological insights have not yet been obtained, probably because of various technical issues, including the unavoidable use of matrices, the inability to maintain cell viability, low throughput because of sample pretreatment, and the lack of recordings of cell physiological activities from the same cell. In this study, we describe a patch clamp/MS-based platform that enables the sensitive, rapid, and in situ chemical profiling of single living neurons. This approach integrates modified patch clamp technique and modified MS measurements to directly collect and detect nanoliter-scale samples from the cytoplasm of single neurons in mice brain slices. Abundant possible cytoplasmic constituents were detected in a single neuron at a relatively fast rate, and over 50 metabolites were identified in this study. The advantages of direct, rapid, and in situ sampling and analysis enabled us to measure the biological activities of the cytoplasmic constituents in a single neuron, including comparing neuron types by cytoplasmic chemical constituents; observing changes in constituent concentrations as the physiological conditions, such as age, vary; and identifying the metabolic pathways of small molecules. PMID:28223513

Precise auditory-vocal mirroring in neurons for learned vocal communication.

PubMed

Prather, J F; Peters, S; Nowicki, S; Mooney, R

2008-01-17

Brain mechanisms for communication must establish a correspondence between sensory and motor codes used to represent the signal. One idea is that this correspondence is established at the level of single neurons that are active when the individual performs a particular gesture or observes a similar gesture performed by another individual. Although neurons that display a precise auditory-vocal correspondence could facilitate vocal communication, they have yet to be identified. Here we report that a certain class of neurons in the swamp sparrow forebrain displays a precise auditory-vocal correspondence. We show that these neurons respond in a temporally precise fashion to auditory presentation of certain note sequences in this songbird's repertoire and to similar note sequences in other birds' songs. These neurons display nearly identical patterns of activity when the bird sings the same sequence, and disrupting auditory feedback does not alter this singing-related activity, indicating it is motor in nature. Furthermore, these neurons innervate striatal structures important for song learning, raising the possibility that singing-related activity in these cells is compared to auditory feedback to guide vocal learning.

Identifying cochlear implant channels with poor electrode-neuron interface: partial tripolar, single-channel thresholds and psychophysical tuning curves

PubMed Central

Bierer, Julie Arenberg; Faulkner, Kathleen F.

2010-01-01

Objectives The goal of this study was to evaluate the ability of a threshold measure, made with a restricted electrode configuration, to identify channels exhibiting relatively poor spatial selectivity. With a restricted electrode configuration, channel-to-channel variability in threshold may reflect variations in the interface between the electrodes and auditory neurons (i.e., nerve survival, electrode placement, tissue impedance). These variations in the electrode-neuron interface should also be reflected in psychophysical tuning curve measurements. Specifically, it is hypothesized that high single-channel thresholds obtained with the spatially focused partial tripolar electrode configuration are predictive of wide or tip-shifted psychophysical tuning curves. Design Data were collected from five cochlear implant listeners implanted with the HiRes 90k cochlear implant (Advanced Bionics). Single-channel thresholds and most comfortable listening levels were obtained for stimuli that varied in presumed electrical field size by using the partial tripolar configuration, for which a fraction of current (σ) from a center active electrode returns through two neighboring electrodes and the remainder through a distant indifferent electrode. Forward-masked psychophysical tuning curves were obtained for channels with the highest, lowest, and median tripolar (σ=1 or 0.9) thresholds. The probe channel and level were fixed and presented with either the monopolar (σ=0) or a more focused partial tripolar (σ ≥ 0.55) configuration. The masker channel and level were varied while the configuration was fixed to σ = 0.5. A standard, three-interval, two-alternative forced choice procedure was used for thresholds and masked levels. Results Single-channel threshold and variability in threshold across channels systematically increased as the compensating current, σ, increased and the presumed electrical field became more focused. Across subjects, channels with the highest single-channel thresholds, when measured with a narrow, partial tripolar stimulus, had significantly broader psychophysical tuning curves than the lowest threshold channels. In two subjects, the tips of the tuning curves were shifted away from the probe channel. Tuning curves were also wider for the monopolar probes than with partial tripolar probes, for both the highest and lowest threshold channels. Conclusions These results suggest that single-channel thresholds measured with a restricted stimulus can be used to identify cochlear implant channels with poor spatial selectivity. Channels having wide or tip-shifted tuning characteristics would likely not deliver the appropriate spectral information to the intended auditory neurons, leading to suboptimal perception. As a clinical tool, quick identification of impaired channels could lead to patient-specific mapping strategies and result in improved speech and music perception. PMID:20090533

Encoding of Spatial Attention by Primate Prefrontal Cortex Neuronal Ensembles

PubMed Central

Treue, Stefan

2018-01-01

Abstract Single neurons in the primate lateral prefrontal cortex (LPFC) encode information about the allocation of visual attention and the features of visual stimuli. However, how this compares to the performance of neuronal ensembles at encoding the same information is poorly understood. Here, we recorded the responses of neuronal ensembles in the LPFC of two macaque monkeys while they performed a task that required attending to one of two moving random dot patterns positioned in different hemifields and ignoring the other pattern. We found single units selective for the location of the attended stimulus as well as for its motion direction. To determine the coding of both variables in the population of recorded units, we used a linear classifier and progressively built neuronal ensembles by iteratively adding units according to their individual performance (best single units), or by iteratively adding units based on their contribution to the ensemble performance (best ensemble). For both methods, ensembles of relatively small sizes (n < 60) yielded substantially higher decoding performance relative to individual single units. However, the decoder reached similar performance using fewer neurons with the best ensemble building method compared with the best single units method. Our results indicate that neuronal ensembles within the LPFC encode more information about the attended spatial and nonspatial features of visual stimuli than individual neurons. They further suggest that efficient coding of attention can be achieved by relatively small neuronal ensembles characterized by a certain relationship between signal and noise correlation structures. PMID:29568798

Is realistic neuronal modeling realistic?

PubMed Central

Almog, Mara

2016-01-01

Scientific models are abstractions that aim to explain natural phenomena. A successful model shows how a complex phenomenon arises from relatively simple principles while preserving major physical or biological rules and predicting novel experiments. A model should not be a facsimile of reality; it is an aid for understanding it. Contrary to this basic premise, with the 21st century has come a surge in computational efforts to model biological processes in great detail. Here we discuss the oxymoronic, realistic modeling of single neurons. This rapidly advancing field is driven by the discovery that some neurons don't merely sum their inputs and fire if the sum exceeds some threshold. Thus researchers have asked what are the computational abilities of single neurons and attempted to give answers using realistic models. We briefly review the state of the art of compartmental modeling highlighting recent progress and intrinsic flaws. We then attempt to address two fundamental questions. Practically, can we realistically model single neurons? Philosophically, should we realistically model single neurons? We use layer 5 neocortical pyramidal neurons as a test case to examine these issues. We subject three publically available models of layer 5 pyramidal neurons to three simple computational challenges. Based on their performance and a partial survey of published models, we conclude that current compartmental models are ad hoc, unrealistic models functioning poorly once they are stretched beyond the specific problems for which they were designed. We then attempt to plot possible paths for generating realistic single neuron models. PMID:27535372

The human amygdala parametrically encodes the intensity of specific facial emotions and their categorical ambiguity

PubMed Central

Wang, Shuo; Yu, Rongjun; Tyszka, J. Michael; Zhen, Shanshan; Kovach, Christopher; Sun, Sai; Huang, Yi; Hurlemann, Rene; Ross, Ian B.; Chung, Jeffrey M.; Mamelak, Adam N.; Adolphs, Ralph; Rutishauser, Ueli

2017-01-01

The human amygdala is a key structure for processing emotional facial expressions, but it remains unclear what aspects of emotion are processed. We investigated this question with three different approaches: behavioural analysis of 3 amygdala lesion patients, neuroimaging of 19 healthy adults, and single-neuron recordings in 9 neurosurgical patients. The lesion patients showed a shift in behavioural sensitivity to fear, and amygdala BOLD responses were modulated by both fear and emotion ambiguity (the uncertainty that a facial expression is categorized as fearful or happy). We found two populations of neurons, one whose response correlated with increasing degree of fear, or happiness, and a second whose response primarily decreased as a linear function of emotion ambiguity. Together, our results indicate that the human amygdala processes both the degree of emotion in facial expressions and the categorical ambiguity of the emotion shown and that these two aspects of amygdala processing can be most clearly distinguished at the level of single neurons. PMID:28429707

Vertically aligned carbon nanofiber as nano-neuron interface for monitoring neural function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ericson, Milton Nance; McKnight, Timothy E; Melechko, Anatoli Vasilievich

2012-01-01

Neural chips, which are capable of simultaneous, multi-site neural recording and stimulation, have been used to detect and modulate neural activity for almost 30 years. As a neural interface, neural chips provide dynamic functional information for neural decoding and neural control. By improving sensitivity and spatial resolution, nano-scale electrodes may revolutionize neural detection and modulation at cellular and molecular levels as nano-neuron interfaces. We developed a carbon-nanofiber neural chip with lithographically defined arrays of vertically aligned carbon nanofiber electrodes and demonstrated its capability of both stimulating and monitoring electrophysiological signals from brain tissues in vitro and monitoring dynamic information ofmore » neuroplasticity. This novel nano-neuron interface can potentially serve as a precise, informative, biocompatible, and dual-mode neural interface for monitoring of both neuroelectrical and neurochemical activity at the single cell level and even inside the cell.« less

Recent behavioral history modifies coupling between cell activity and Arc gene transcription in hippocampal CA1 neurons.

PubMed

Guzowski, John F; Miyashita, Teiko; Chawla, Monica K; Sanderson, Jennifer; Maes, Levi I; Houston, Frank P; Lipa, Peter; McNaughton, Bruce L; Worley, Paul F; Barnes, Carol A

2006-01-24

The ability of neurons to alter their transcriptional programs in response to synaptic input is of fundamental importance to the neuroplastic mechanisms underlying learning and memory. Because of technical limitations of conventional gene detection methods, the current view of activity-dependent neural transcription derives from experiments in which neurons are assumed quiescent until a signaling stimulus is given. The present study was designed to move beyond this static model by examining how earlier episodes of neural activity influence transcription of the immediate-early gene Arc. Using a sensitive FISH method that detects primary transcript at genomic alleles, the proportion of hippocampal CA1 neurons that activate transcription of Arc RNA was constant at approximately 40% in response to both a single novel exploration session and daily sessions repeated over 9 days. This proportion is similar to the percentage of active neurons defined electrophysiologically. However, this close correspondence was disrupted in rats exposed briefly, but repeatedly, to the same environment within a single day. Arc transcription in CA1 neurons declined dramatically after as few as four 5-min sessions, despite stable electrophysiological activity during all sessions. Additional experiments indicate that the decrement in Arc transcription occurred at the cellular, rather than synaptic level, and was not simply linked to habituation to novelty. Thus, the neural genomic response is governed by recent, but not remote, cell firing history in the behaving animal. This state-dependence of neuronal transcriptional coupling provides a mechanism of metaplasticity and may regulate capacity for synaptic modification in neural networks.

The Serotonergic Central Nervous System of the Drosophila Larva: Anatomy and Behavioral Function

PubMed Central

Apostolopoulou, Anthi A.; Widmann, Annekathrin; Pfitzenmaier, Johanna E.; Maiolo, Elena M.; Selcho, Mareike; Pauls, Dennis; von Essen, Alina; Gupta, Tripti; Sprecher, Simon G.; Birman, Serge; Riemensperger, Thomas; Stocker, Reinhard F.; Thum, Andreas S.

2012-01-01

The Drosophila larva has turned into a particularly simple model system for studying the neuronal basis of innate behaviors and higher brain functions. Neuronal networks involved in olfaction, gustation, vision and learning and memory have been described during the last decade, often up to the single-cell level. Thus, most of these sensory networks are substantially defined, from the sensory level up to third-order neurons. This is especially true for the olfactory system of the larva. Given the wealth of genetic tools in Drosophila it is now possible to address the question how modulatory systems interfere with sensory systems and affect learning and memory. Here we focus on the serotonergic system that was shown to be involved in mammalian and insect sensory perception as well as learning and memory. Larval studies suggested that the serotonergic system is involved in the modulation of olfaction, feeding, vision and heart rate regulation. In a dual anatomical and behavioral approach we describe the basic anatomy of the larval serotonergic system, down to the single-cell level. In parallel, by expressing apoptosis-inducing genes during embryonic and larval development, we ablate most of the serotonergic neurons within the larval central nervous system. When testing these animals for naïve odor, sugar, salt and light perception, no profound phenotype was detectable; even appetitive and aversive learning was normal. Our results provide the first comprehensive description of the neuronal network of the larval serotonergic system. Moreover, they suggest that serotonin per se is not necessary for any of the behaviors tested. However, our data do not exclude that this system may modulate or fine-tune a wide set of behaviors, similar to its reported function in other insect species or in mammals. Based on our observations and the availability of a wide variety of genetic tools, this issue can now be addressed. PMID:23082175

The serotonergic central nervous system of the Drosophila larva: anatomy and behavioral function.

PubMed

Huser, Annina; Rohwedder, Astrid; Apostolopoulou, Anthi A; Widmann, Annekathrin; Pfitzenmaier, Johanna E; Maiolo, Elena M; Selcho, Mareike; Pauls, Dennis; von Essen, Alina; Gupta, Tripti; Sprecher, Simon G; Birman, Serge; Riemensperger, Thomas; Stocker, Reinhard F; Thum, Andreas S

2012-01-01

The Drosophila larva has turned into a particularly simple model system for studying the neuronal basis of innate behaviors and higher brain functions. Neuronal networks involved in olfaction, gustation, vision and learning and memory have been described during the last decade, often up to the single-cell level. Thus, most of these sensory networks are substantially defined, from the sensory level up to third-order neurons. This is especially true for the olfactory system of the larva. Given the wealth of genetic tools in Drosophila it is now possible to address the question how modulatory systems interfere with sensory systems and affect learning and memory. Here we focus on the serotonergic system that was shown to be involved in mammalian and insect sensory perception as well as learning and memory. Larval studies suggested that the serotonergic system is involved in the modulation of olfaction, feeding, vision and heart rate regulation. In a dual anatomical and behavioral approach we describe the basic anatomy of the larval serotonergic system, down to the single-cell level. In parallel, by expressing apoptosis-inducing genes during embryonic and larval development, we ablate most of the serotonergic neurons within the larval central nervous system. When testing these animals for naïve odor, sugar, salt and light perception, no profound phenotype was detectable; even appetitive and aversive learning was normal. Our results provide the first comprehensive description of the neuronal network of the larval serotonergic system. Moreover, they suggest that serotonin per se is not necessary for any of the behaviors tested. However, our data do not exclude that this system may modulate or fine-tune a wide set of behaviors, similar to its reported function in other insect species or in mammals. Based on our observations and the availability of a wide variety of genetic tools, this issue can now be addressed.

Single-prolonged stress induces apoptosis in dorsal raphe nucleus in the rat model of posttraumatic stress disorder

PubMed Central

2012-01-01

Introduction Post-traumatic stress disorder (PTSD) is an anxiety disorder that develops after exposure to a life-threatening traumatic experience. Meta-analyses of the brainstem showed that midsagittal area of the pons was significantly reduced in patients with PTSD, suggesting a potential apoptosis in dorsal raphe nucleus after single-prolonged stress (SPS). The aim of this study is to investigate whether SPS induces apoptosis in dorsal raphe nucleus in PTSD rats, which may be a possible mechanism of reduced volume of pons and density of gray matter. Methods In this study, rats were randomly divided into 1d, 7d and 14d groups after SPS along with the control group. The apoptosis rate was determined using annexin V-FITC/PI double-labeled flow cytometry (FCM). Levels of Cytochrome c (Cyt-C) was examined by Western blotting. Expression of Cyt-C on mitochondria in the dorsal raphe nucleus neuron was determined by enzymohistochemistry under transmission electron microscopy (TEM). The change of thiamine monophosphatase (TMP) levels was assessed by enzymohistochemistry under light microscope and TEM. Morphological changes of the ultrastructure of the dorsal raphe nucleus neuron were determined by TEM. Results Apoptotic morphological alterations were observed in dorsal raphe nucleus neuron for all SPS-stimulate groups of rats. The apoptosis rates were significantly increased in dorsal raphe nucleus neuron of SPS rats, along with increased release of cytochrome c from the mitochondria into the cytoplasm, increased expression of Cyt-C and TMP levels in the cytoplasm, which reached to the peak of increase 7 days of SPS. Conclusions The results indicate that SPS induced Cyt-C released from mitochondria into cytosol and apoptosis in dorsal raphe nucleus neuron of rats. Increased TMP in cytoplasm facilitated the clearance of apoptotic cells. We propose that this presents one of the mechanisms that lead to reduced volume of pons and gray matter associated with PTSD. PMID:23181934

Assessing sensory versus optogenetic network activation by combining (o)fMRI with optical Ca2+ recordings.

PubMed

Schmid, Florian; Wachsmuth, Lydia; Schwalm, Miriam; Prouvot, Pierre-Hugues; Jubal, Eduardo Rosales; Fois, Consuelo; Pramanik, Gautam; Zimmer, Claus; Faber, Cornelius; Stroh, Albrecht

2016-11-01

Encoding of sensory inputs in the cortex is characterized by sparse neuronal network activation. Optogenetic stimulation has previously been combined with fMRI (ofMRI) to probe functional networks. However, for a quantitative optogenetic probing of sensory-driven sparse network activation, the level of similarity between sensory and optogenetic network activation needs to be explored. Here, we complement ofMRI with optic fiber-based population Ca 2+ recordings for a region-specific readout of neuronal spiking activity in rat brain. Comparing Ca 2+ responses to the blood oxygenation level-dependent signal upon sensory stimulation with increasing frequencies showed adaptation of Ca 2+ transients contrasted by an increase of blood oxygenation level-dependent responses, indicating that the optical recordings convey complementary information on neuronal network activity to the corresponding hemodynamic response. To study the similarity of optogenetic and sensory activation, we quantified the density of cells expressing channelrhodopsin-2 and modeled light propagation in the tissue. We estimated the effectively illuminated volume and numbers of optogenetically stimulated neurons, being indicative of sparse activation. At the functional level, upon either sensory or optogenetic stimulation we detected single-peak short-latency primary Ca 2+ responses with similar amplitudes and found that blood oxygenation level-dependent responses showed similar time courses. These data suggest that ofMRI can serve as a representative model for functional brain mapping. © The Author(s) 2015.

Scalable control of mounting and attack by Esr1+ neurons in the ventromedial hypothalamus.

PubMed

Lee, Hyosang; Kim, Dong-Wook; Remedios, Ryan; Anthony, Todd E; Chang, Angela; Madisen, Linda; Zeng, Hongkui; Anderson, David J

2014-05-29

Social behaviours, such as aggression or mating, proceed through a series of appetitive and consummatory phases that are associated with increasing levels of arousal. How such escalation is encoded in the brain, and linked to behavioural action selection, remains an unsolved problem in neuroscience. The ventrolateral subdivision of the murine ventromedial hypothalamus (VMHvl) contains neurons whose activity increases during male-male and male-female social encounters. Non-cell-type-specific optogenetic activation of this region elicited attack behaviour, but not mounting. We have identified a subset of VMHvl neurons marked by the oestrogen receptor 1 (Esr1), and investigated their role in male social behaviour. Optogenetic manipulations indicated that Esr1(+) (but not Esr1(-)) neurons are sufficient to initiate attack, and that their activity is continuously required during ongoing agonistic behaviour. Surprisingly, weaker optogenetic activation of these neurons promoted mounting behaviour, rather than attack, towards both males and females, as well as sniffing and close investigation. Increasing photostimulation intensity could promote a transition from close investigation and mounting to attack, within a single social encounter. Importantly, time-resolved optogenetic inhibition experiments revealed requirements for Esr1(+) neurons in both the appetitive (investigative) and the consummatory phases of social interactions. Combined optogenetic activation and calcium imaging experiments in vitro, as well as c-Fos analysis in vivo, indicated that increasing photostimulation intensity increases both the number of active neurons and the average level of activity per neuron. These data suggest that Esr1(+) neurons in VMHvl control the progression of a social encounter from its appetitive through its consummatory phases, in a scalable manner that reflects the number or type of active neurons in the population.

Scalable Control of Mounting and Attack by ESR1+ Neurons in the Ventromedial Hypothalamus

PubMed Central

Lee, Hyosang; Kim, Dong-Wook; Remedios, Ryan; Anthony, Todd E.; Chang, Angela; Madisen, Linda; Zeng, Hongkui; Anderson, David J.

2014-01-01

Social behaviors, such as aggression or mating, proceed through a series of appetitive and consummatory phases1 that are associated with increasing levels of arousal2. How such escalation is encoded in the brain, and linked to behavioral action selection, remains an important unsolved problem in neuroscience. The ventrolateral subdivision of the murine ventromedial hypothalamus (VMHvl) contains neurons whose activity increases during male-male and male-female social encounters. Non-cell type-specific optogenetic activation of this region elicited attack behavior, but not mounting3. We have identified a subset of VMHvl neurons marked by the estrogen receptor 1 (Esr1), and investigated their role in male social behavior. Optogenetic manipulations indicated that Esr1+ (but not Esr1-) neurons are sufficient to initiate attack, and that their activity is continuously required during ongoing agonistic behavior. Surprisingly, weaker optogenetic activation of these neurons promoted mounting behavior, rather than attack, towards both males and females, as well as sniffing and close investigation (CI). Increasing photostimulation intensity could promote a transition from CI and mounting to attack, within a single social encounter. Importantly, time-resolved optogenetic inhibition experiments revealed requirements for Esr1+ neurons in both the appetitive (investigative) and the consummatory phases of social interactions. Combined optogenetic activation and calcium imaging experiments in vitro, as well as c-Fos analysis in vivo, indicated that increasing photostimulation intensity increases both the number of active neurons and the average level of activity per neuron. These data suggest that Esr1+ neurons in VMHvl control the progression of a social encounter from its appetitive through its consummatory phases, in a scalable manner that reflects the number or type of active neurons in the population. PMID:24739975

Single cell gene expression profiling in Alzheimer's disease.

PubMed

Ginsberg, Stephen D; Che, Shaoli; Counts, Scott E; Mufson, Elliott J

2006-07-01

Development and implementation of microarray techniques to quantify expression levels of dozens to hundreds to thousands of transcripts simultaneously within select tissue samples from normal control subjects and neurodegenerative diseased brains has enabled scientists to create molecular fingerprints of vulnerable neuronal populations in Alzheimer's disease (AD) and related disorders. A goal is to sample gene expression from homogeneous cell types within a defined region without potential contamination by expression profiles of adjacent neuronal subpopulations and nonneuronal cells. The precise resolution afforded by single cell and population cell RNA analysis in combination with microarrays and real-time quantitative polymerase chain reaction (qPCR)-based analyses allows for relative gene expression level comparisons across cell types under different experimental conditions and disease progression. The ability to analyze single cells is an important distinction from global and regional assessments of mRNA expression and can be applied to optimally prepared tissues from animal models of neurodegeneration as well as postmortem human brain tissues. Gene expression analysis in postmortem AD brain regions including the hippocampal formation and neocortex reveals selectively vulnerable cell types share putative pathogenetic alterations in common classes of transcripts, for example, markers of glutamatergic neurotransmission, synaptic-related markers, protein phosphatases and kinases, and neurotrophins/neurotrophin receptors. Expression profiles of vulnerable regions and neurons may reveal important clues toward the understanding of the molecular pathogenesis of various neurological diseases and aid in identifying rational targets toward pharmacotherapeutic interventions for progressive, late-onset neurodegenerative disorders such as mild cognitive impairment (MCI) and AD.

Rapid acquisition of novel interface control by small ensembles of arbitrarily selected primary motor cortex neurons

PubMed Central

Law, Andrew J.; Rivlis, Gil

2014-01-01

Pioneering studies demonstrated that novel degrees of freedom could be controlled individually by directly encoding the firing rate of single motor cortex neurons, without regard to each neuron's role in controlling movement of the native limb. In contrast, recent brain-computer interface work has emphasized decoding outputs from large ensembles that include substantially more neurons than the number of degrees of freedom being controlled. To bridge the gap between direct encoding by single neurons and decoding output from large ensembles, we studied monkeys controlling one degree of freedom by comodulating up to four arbitrarily selected motor cortex neurons. Performance typically exceeded random quite early in single sessions and then continued to improve to different degrees in different sessions. We therefore examined factors that might affect performance. Performance improved with larger ensembles. In contrast, other factors that might have reflected preexisting synaptic architecture—such as the similarity of preferred directions—had little if any effect on performance. Patterns of comodulation among ensemble neurons became more consistent across trials as performance improved over single sessions. Compared with the ensemble neurons, other simultaneously recorded neurons showed less modulation. Patterns of voluntarily comodulated firing among small numbers of arbitrarily selected primary motor cortex (M1) neurons thus can be found and improved rapidly, with little constraint based on the normal relationships of the individual neurons to native limb movement. This rapid flexibility in relationships among M1 neurons may in part underlie our ability to learn new movements and improve motor skill. PMID:24920030

morphforge: a toolbox for simulating small networks of biologically detailed neurons in Python

PubMed Central

Hull, Michael J.; Willshaw, David J.

2014-01-01

The broad structure of a modeling study can often be explained over a cup of coffee, but converting this high-level conceptual idea into graphs of the final simulation results may require many weeks of sitting at a computer. Although models themselves can be complex, often many mental resources are wasted working around complexities of the software ecosystem such as fighting to manage files, interfacing between tools and data formats, finding mistakes in code or working out the units of variables. morphforge is a high-level, Python toolbox for building and managing simulations of small populations of multicompartmental biophysical model neurons. An entire in silico experiment, including the definition of neuronal morphologies, channel descriptions, stimuli, visualization and analysis of results can be written within a single short Python script using high-level objects. Multiple independent simulations can be created and run from a single script, allowing parameter spaces to be investigated. Consideration has been given to the reuse of both algorithmic and parameterizable components to allow both specific and stochastic parameter variations. Some other features of the toolbox include: the automatic generation of human-readable documentation (e.g., PDF files) about a simulation; the transparent handling of different biophysical units; a novel mechanism for plotting simulation results based on a system of tags; and an architecture that supports both the use of established formats for defining channels and synapses (e.g., MODL files), and the possibility to support other libraries and standards easily. We hope that this toolbox will allow scientists to quickly build simulations of multicompartmental model neurons for research and serve as a platform for further tool development. PMID:24478690

Correlated variability modifies working memory fidelity in primate prefrontal neuronal ensembles

PubMed Central

Leavitt, Matthew L.; Pieper, Florian; Sachs, Adam J.; Martinez-Trujillo, Julio C.

2017-01-01

Neurons in the primate lateral prefrontal cortex (LPFC) encode working memory (WM) representations via sustained firing, a phenomenon hypothesized to arise from recurrent dynamics within ensembles of interconnected neurons. Here, we tested this hypothesis by using microelectrode arrays to examine spike count correlations (rsc) in LPFC neuronal ensembles during a spatial WM task. We found a pattern of pairwise rsc during WM maintenance indicative of stronger coupling between similarly tuned neurons and increased inhibition between dissimilarly tuned neurons. We then used a linear decoder to quantify the effects of the high-dimensional rsc structure on information coding in the neuronal ensembles. We found that the rsc structure could facilitate or impair coding, depending on the size of the ensemble and tuning properties of its constituent neurons. A simple optimization procedure demonstrated that near-maximum decoding performance could be achieved using a relatively small number of neurons. These WM-optimized subensembles were more signal correlation (rsignal)-diverse and anatomically dispersed than predicted by the statistics of the full recorded population of neurons, and they often contained neurons that were poorly WM-selective, yet enhanced coding fidelity by shaping the ensemble’s rsc structure. We observed a pattern of rsc between LPFC neurons indicative of recurrent dynamics as a mechanism for WM-related activity and that the rsc structure can increase the fidelity of WM representations. Thus, WM coding in LPFC neuronal ensembles arises from a complex synergy between single neuron coding properties and multidimensional, ensemble-level phenomena. PMID:28275096

Compensating Level-Dependent Frequency Representation in Auditory Cortex by Synaptic Integration of Corticocortical Input

PubMed Central

Happel, Max F. K.; Ohl, Frank W.

2017-01-01

Robust perception of auditory objects over a large range of sound intensities is a fundamental feature of the auditory system. However, firing characteristics of single neurons across the entire auditory system, like the frequency tuning, can change significantly with stimulus intensity. Physiological correlates of level-constancy of auditory representations hence should be manifested on the level of larger neuronal assemblies or population patterns. In this study we have investigated how information of frequency and sound level is integrated on the circuit-level in the primary auditory cortex (AI) of the Mongolian gerbil. We used a combination of pharmacological silencing of corticocortically relayed activity and laminar current source density (CSD) analysis. Our data demonstrate that with increasing stimulus intensities progressively lower frequencies lead to the maximal impulse response within cortical input layers at a given cortical site inherited from thalamocortical synaptic inputs. We further identified a temporally precise intercolumnar synaptic convergence of early thalamocortical and horizontal corticocortical inputs. Later tone-evoked activity in upper layers showed a preservation of broad tonotopic tuning across sound levels without shifts towards lower frequencies. Synaptic integration within corticocortical circuits may hence contribute to a level-robust representation of auditory information on a neuronal population level in the auditory cortex. PMID:28046062

Neuronal activity determines distinct gliotransmitter release from a single astrocyte

PubMed Central

Covelo, Ana

2018-01-01

Accumulating evidence indicates that astrocytes are actively involved in brain function by regulating synaptic activity and plasticity. Different gliotransmitters, such as glutamate, ATP, GABA or D-serine, released form astrocytes have been shown to induce different forms of synaptic regulation. However, whether a single astrocyte may release different gliotransmitters is unknown. Here we show that mouse hippocampal astrocytes activated by endogenous (neuron-released endocannabinoids or GABA) or exogenous (single astrocyte Ca2+ uncaging) stimuli modulate putative single CA3-CA1 hippocampal synapses. The astrocyte-mediated synaptic modulation was biphasic and consisted of an initial glutamate-mediated potentiation followed by a purinergic-mediated depression of neurotransmitter release. The temporal dynamic properties of this biphasic synaptic regulation depended on the firing frequency and duration of the neuronal activity that stimulated astrocytes. Present results indicate that single astrocytes can decode neuronal activity and, in response, release distinct gliotransmitters to differentially regulate neurotransmission at putative single synapses. PMID:29380725

Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics.

PubMed

Harris, Kenneth D; Hochgerner, Hannah; Skene, Nathan G; Magno, Lorenza; Katona, Linda; Bengtsson Gonzales, Carolina; Somogyi, Peter; Kessaris, Nicoletta; Linnarsson, Sten; Hjerling-Leffler, Jens

2018-06-18

Understanding any brain circuit will require a categorization of its constituent neurons. In hippocampal area CA1, at least 23 classes of GABAergic neuron have been proposed to date. However, this list may be incomplete; additionally, it is unclear whether discrete classes are sufficient to describe the diversity of cortical inhibitory neurons or whether continuous modes of variability are also required. We studied the transcriptomes of 3,663 CA1 inhibitory cells, revealing 10 major GABAergic groups that divided into 49 fine-scale clusters. All previously described and several novel cell classes were identified, with three previously described classes unexpectedly found to be identical. A division into discrete classes, however, was not sufficient to describe the diversity of these cells, as continuous variation also occurred between and within classes. Latent factor analysis revealed that a single continuous variable could predict the expression levels of several genes, which correlated similarly with it across multiple cell types. Analysis of the genes correlating with this variable suggested it reflects a range from metabolically highly active faster-spiking cells that proximally target pyramidal cells to slower-spiking cells targeting distal dendrites or interneurons. These results elucidate the complexity of inhibitory neurons in one of the simplest cortical structures and show that characterizing these cells requires continuous modes of variation as well as discrete cell classes.

Progranulin levels in status epilepticus as a marker of neuronal recovery and neuroprotection.

PubMed

Huchtemann, T; Körtvélyessy, P; Feistner, H; Heinze, H J; Bittner, D

2015-08-01

Recently, a mouse model showed that progranulin, a mediator in neuroinflammation and a neuronal growth factor, was elevated in the hippocampus after status epilepticus (SE). This elevated level might mirror compensating neuronal mechanisms after SE. Studies concerning neuronal recovery and neuroprotective mechanisms after SE in humans are scarce, so we tested for progranulinin the cerebrospinal fluid (CSF) after various types of SE. We performed a retrospective analysis of progranulin levels in CSF in patients (n = 24) who underwent lumbar puncture as part of diagnostic workup after having SE and in patients after having one single tonic-clonic seizure who comprised the control group (n = 8). In our group with SE, progranulin levels in CSF were not significantly elevated compared to our control group. Furthermore, there was no correlation between progranulin levels and the time interval between lumbar puncture and SE. Additionally, in cases of higher CSF progranulin levels, we found no impact on the clinical outcome after SE. Although our cohort is heterogeneous and not fully sufficient, we conclude that progranulin in CSF is not elevated after SE in our cohort. Therefore, our results do not suggest a change in cerebral progranulin metabolism as a possible neuroregenerative or neuroprotective mechanism in humans after SE in acute and subacute phases. A larger cohort study is needed to further strengthen this result. This article is part of a Special Issue entitled "Status Epilepticus". Copyright © 2015 Elsevier Inc. All rights reserved.

Generating level-dependent models of cervical and thoracic spinal cord injury: Exploring the interplay of neuroanatomy, physiology, and function.

PubMed

Wilcox, Jared T; Satkunendrarajah, Kajana; Nasirzadeh, Yasmin; Laliberte, Alex M; Lip, Alyssa; Cadotte, David W; Foltz, Warren D; Fehlings, Michael G

2017-09-01

The majority of spinal cord injuries (SCI) occur at the cervical level, which results in significant impairment. Neurologic level and severity of injury are primary endpoints in clinical trials; however, how level-specific damages relate to behavioural performance in cervical injury is incompletely understood. We hypothesized that ascending level of injury leads to worsening forelimb performance, and correlates with loss of neural tissue and muscle-specific neuron pools. A direct comparison of multiple models was made with injury realized at the C5, C6, C7 and T7 vertebral levels using clip compression with sham-operated controls. Animals were assessed for 10weeks post-injury with numerous (40) outcome measures, including: classic behavioural tests, CatWalk, non-invasive MRI, electrophysiology, histologic lesion morphometry, neuron counts, and motor compartment quantification, and multivariate statistics on the total dataset. Histologic staining and T1-weighted MR imaging revealed similar structural changes and distinct tissue loss with cystic cavitation across all injuries. Forelimb tests, including grip strength, F-WARP motor scale, Inclined Plane, and forelimb ladder walk, exhibited stratification between all groups and marked impairment with C5 and C6 injuries. Classic hindlimb tests including BBB, hindlimb ladder walk, bladder recovery, and mortality were not different between cervical and thoracic injuries. CatWalk multivariate gait analysis showed reciprocal and progressive changes forelimb and hindlimb function with ascending level of injury. Electrophysiology revealed poor forelimb axonal conduction in cervical C5 and C6 groups alone. The cervical enlargement (C5-T2) showed progressive ventral horn atrophy and loss of specific motor neuron populations with ascending injury. Multivariate statistics revealed a robust dataset, rank-order contribution of outcomes, and allowed prediction of injury level with single-level discrimination using forelimb performance and neuron counts. Level-dependent models were generated using clip-compression SCI, with marked and reliable differences in forelimb performance and specific neuron pool loss. Copyright © 2017 Elsevier Inc. All rights reserved.

Single photon emission computed tomography in motor neuron disease with dementia.

PubMed

Sawada, H; Udaka, F; Kishi, Y; Seriu, N; Mezaki, T; Kameyama, M; Honda, M; Tomonobu, M

1988-01-01

Single photon emission computed tomography with [123 I] isopropylamphetamine was carried out on a patient with motor neuron disease with dementia. [123 I] uptake was decreased in the frontal lobes. This would reflect the histopathological findings such as neuronal loss and gliosis in the frontal lobes.

Neurons as sensors: individual and cascaded chemical sensing.

PubMed

Prasad, Shalini; Zhang, Xuan; Yang, Mo; Ozkan, Cengiz S; Ozkan, Mihrimah

2004-07-15

A single neuron sensor has been developed based on the interaction of gradient electric fields and the cell membrane. Single neurons are rapidly positioned over individual microelectrodes using positive dielectrophoretic traps. This enables the continuous extracellular electrophysiological measurements from individual neurons. The sensor developed using this technique provides the first experimental method for determining single cell sensitivity; the speed of response and the associated physiological changes to a broad spectrum of chemical agents. Binding of specific chemical agents to a specific combination of receptors induces changes to the extracellular membrane potential of a single neuron, which can be translated into unique "signature patterns" (SP), which function as identification tags. Signature patterns are derived using Fast Fourier Transformation (FFT) analysis and Wavelet Transformation (WT) analysis of the modified extracellular action potential. The validity and the sensitivity of the system are demonstrated for a variety of chemical agents ranging from behavior altering chemicals (ethanol), environmentally hazardous agents (hydrogen peroxide, EDTA) to physiologically harmful agents (pyrethroids) at pico- and femto-molar concentrations. The ability of a single neuron to selectively identify specific chemical agents when injected in a serial manner is demonstrated in "cascaded sensing".

Stimulus-specific adaptation and deviance detection in the inferior colliculus

PubMed Central

Ayala, Yaneri A.; Malmierca, Manuel S.

2013-01-01

Deviancy detection in the continuous flow of sensory information into the central nervous system is of vital importance for animals. The task requires neuronal mechanisms that allow for an efficient representation of the environment by removing statistically redundant signals. Recently, the neuronal principles of auditory deviance detection have been approached by studying the phenomenon of stimulus-specific adaptation (SSA). SSA is a reduction in the responsiveness of a neuron to a common or repetitive sound while the neuron remains highly sensitive to rare sounds (Ulanovsky et al., 2003). This phenomenon could enhance the saliency of unexpected, deviant stimuli against a background of repetitive signals. SSA shares many similarities with the evoked potential known as the “mismatch negativity,” (MMN) and it has been linked to cognitive process such as auditory memory and scene analysis (Winkler et al., 2009) as well as to behavioral habituation (Netser et al., 2011). Neurons exhibiting SSA can be found at several levels of the auditory pathway, from the inferior colliculus (IC) up to the auditory cortex (AC). In this review, we offer an account of the state-of-the art of SSA studies in the IC with the aim of contributing to the growing interest in the single-neuron electrophysiology of auditory deviance detection. The dependence of neuronal SSA on various stimulus features, e.g., probability of the deviant stimulus and repetition rate, and the roles of the AC and inhibition in shaping SSA at the level of the IC are addressed. PMID:23335883

Combined histochemical staining, RNA amplification, regional, and single cell cDNA analysis within the hippocampus.

PubMed

Ginsberg, Stephen D; Che, Shaoli

2004-08-01

The use of five histochemical stains (cresyl violet, thionin, hematoxylin & eosin, silver stain, and acridine orange) was evaluated in combination with an expression profiling paradigm that included regional and single cell analyses within the hippocampus of post-mortem human brains and adult mice. Adjacent serial sections of human and mouse hippocampus were labeled by histochemistry or neurofilament immunocytochemistry. These tissue sections were used as starting material for regional and single cell microdissection followed by a newly developed RNA amplification procedure (terminal continuation (TC) RNA amplification) and subsequent hybridization to custom-designed cDNA arrays. Results indicated equivalent levels of global hybridization signal intensity and relative expression levels for individual genes for hippocampi stained by cresyl violet, thionin, and hematoxylin & eosin, and neurofilament immunocytochemistry. Moreover, no significant differences existed between the Nissl stains and neurofilament immunocytochemistry for individual CA1 neurons obtained via laser capture microdissection. In contrast, a marked decrement was observed in adjacent hippocampal sections stained for silver stain and acridine orange, both at the level of the regional dissection and at the CA1 neuron population level. Observations made on the cDNA array platform were validated by real-time qPCR using primers directed against beta-actin and glyceraldehyde-3 phosphate dehydrogenase. Thus, this report demonstrated the utility of using specific Nissl stains, but not stains that bind RNA species directly, in both human and mouse brain tissues at the regional and cellular level for state-of-the-art molecular fingerprinting studies.

Emergence of transformation-tolerant representations of visual objects in rat lateral extrastriate cortex

PubMed Central

Tafazoli, Sina; Safaai, Houman; De Franceschi, Gioia; Rosselli, Federica Bianca; Vanzella, Walter; Riggi, Margherita; Buffolo, Federica; Panzeri, Stefano; Zoccolan, Davide

2017-01-01

Rodents are emerging as increasingly popular models of visual functions. Yet, evidence that rodent visual cortex is capable of advanced visual processing, such as object recognition, is limited. Here we investigate how neurons located along the progression of extrastriate areas that, in the rat brain, run laterally to primary visual cortex, encode object information. We found a progressive functional specialization of neural responses along these areas, with: (1) a sharp reduction of the amount of low-level, energy-related visual information encoded by neuronal firing; and (2) a substantial increase in the ability of both single neurons and neuronal populations to support discrimination of visual objects under identity-preserving transformations (e.g., position and size changes). These findings strongly argue for the existence of a rat object-processing pathway, and point to the rodents as promising models to dissect the neuronal circuitry underlying transformation-tolerant recognition of visual objects. DOI: http://dx.doi.org/10.7554/eLife.22794.001 PMID:28395730

A Neural Signature of Divisive Normalization at the Level of Multisensory Integration in Primate Cortex.

PubMed

Ohshiro, Tomokazu; Angelaki, Dora E; DeAngelis, Gregory C

2017-07-19

Studies of multisensory integration by single neurons have traditionally emphasized empirical principles that describe nonlinear interactions between inputs from two sensory modalities. We previously proposed that many of these empirical principles could be explained by a divisive normalization mechanism operating in brain regions where multisensory integration occurs. This normalization model makes a critical diagnostic prediction: a non-preferred sensory input from one modality, which activates the neuron on its own, should suppress the response to a preferred input from another modality. We tested this prediction by recording from neurons in macaque area MSTd that integrate visual and vestibular cues regarding self-motion. We show that many MSTd neurons exhibit the diagnostic form of cross-modal suppression, whereas unisensory neurons in area MT do not. The normalization model also fits population responses better than a model based on subtractive inhibition. These findings provide strong support for a divisive normalization mechanism in multisensory integration. Copyright © 2017 Elsevier Inc. All rights reserved.

Rapid Integration of Artificial Sensory Feedback during Operant Conditioning of Motor Cortex Neurons.

PubMed

Prsa, Mario; Galiñanes, Gregorio L; Huber, Daniel

2017-02-22

Neuronal motor commands, whether generating real or neuroprosthetic movements, are shaped by ongoing sensory feedback from the displacement being produced. Here we asked if cortical stimulation could provide artificial feedback during operant conditioning of cortical neurons. Simultaneous two-photon imaging and real-time optogenetic stimulation were used to train mice to activate a single neuron in motor cortex (M1), while continuous feedback of its activity level was provided by proportionally stimulating somatosensory cortex. This artificial signal was necessary to rapidly learn to increase the conditioned activity, detect correct performance, and maintain the learned behavior. Population imaging in M1 revealed that learning-related activity changes are observed in the conditioned cell only, which highlights the functional potential of individual neurons in the neocortex. Our findings demonstrate the capacity of animals to use an artificially induced cortical channel in a behaviorally relevant way and reveal the remarkable speed and specificity at which this can occur. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Somatostatin Signaling in Neuronal Cilia Is Criticalfor Object Recognition Memory

PubMed Central

Einstein, Emily B.; Patterson, Carlyn A.; Hon, Beverly J.; Regan, Kathleen A.; Reddi, Jyoti; Melnikoff, David E.; Mateer, Marcus J.; Schulz, Stefan; Johnson, Brian N.

2010-01-01

Most neurons possess a single, nonmotile cilium that projects out from the cell surface. These microtubule-based organelles are important in brain development and neurogenesis; however, their function in mature neurons is unknown. Cilia express a complement of proteins distinct from other neuronal compartments, one of which is the somatostatin receptor subtype SST3. We show here that SST3 is critical for object recognition memory in mice. sst3 knock-out mice are severely impaired in discriminating novel objects, whereas they retain normal memory for object location. Further, systemic injection of an SST3 antagonist (ACQ090) disrupts recall of familiar objects in wild-type mice. To examine mechanisms of SST3, we tested synaptic plasticity in CA1 hippocampus. Electrically evoked long-term potentiation (LTP) was normal in sst3 knock-out mice, while adenylyl cyclase/cAMP-mediated LTP was impaired. The SST3 antagonist also disrupted cAMP-mediated LTP. Basal cAMP levels in hippocampal lysate were reduced in sst3 knock-out mice compared with wild-type mice, while the forskolin-induced increase in cAMP levels was normal. The SST3 antagonist inhibited forskolin-stimulated cAMP increases, whereas the SST3 agonist L-796,778 increased basal cAMP levels in hippocampal slices but not hippocampal lysate. Our results show that somatostatin signaling in neuronal cilia is critical for recognition memory and suggest that the cAMP pathway is a conserved signaling motif in cilia. Neuronal cilia therefore represent a novel nonsynaptic compartment crucial for signaling involved in a specific form of synaptic plasticity and in novelty detection. PMID:20335466

Fast methods for analysis of neurotransmitters from single cell and monitoring their releases in central nervous system by capillary electrophoresis, fluorescence microscopy and luminescence imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Ziqiang

1999-12-10

Fast methods for separation and detection of important neurotransmitters and the releases in central nervous system (CNS) were developed. Enzyme based immunoassay combined with capillary electrophoresis was used to analyze the contents of amino acid neurotransmitters from single neuron cells. The release of amino acid neurotransmitters from neuron cultures was monitored by laser induced fluorescence imaging method. The release and signal transduction of adenosine triphosphate (ATP) in CNS was studied with sensitive luminescence imaging method. A new dual-enzyme on-column reaction method combined with capillary electrophoresis has been developed for determining the glutamate content in single cells. Detection was based onmore » monitoring the laser-induced fluorescence of the reaction product NADH, and the measured fluorescence intensity was related to the concentration of glutamate in each cell. The detection limit of glutamate is down to 10 -8 M level, which is 1 order of magnitude lower than the previously reported detection limit based on similar detection methods. The mass detection limit of a few attomoles is far superior to that of any other reports. Selectivity for glutamate is excellent over most of amino acids. The glutamate content in single human erythrocyte and baby rat brain neurons were determined with this method and results agreed well with literature values.« less

Polarizing the Neuron through Sustained Co-expression of Alternatively Spliced Isoforms.

PubMed

Yap, Karen; Xiao, Yixin; Friedman, Brad A; Je, H Shawn; Makeyev, Eugene V

2016-05-10

Alternative splicing (AS) is an important source of proteome diversity in eukaryotes. However, how this affects protein repertoires at a single-cell level remains an open question. Here, we show that many 3'-terminal exons are persistently co-expressed with their alternatives in mammalian neurons. In an important example of this scenario, cell polarity gene Cdc42, a combination of polypyrimidine tract-binding, protein-dependent, and constitutive splicing mechanisms ensures a halfway switch from the general (E7) to the neuron-specific (E6) alternative 3'-terminal exon during neuronal differentiation. Perturbing the nearly equimolar E6/E7 ratio in neurons results in defects in both axonal and dendritic compartments and suggests that Cdc42E7 is involved in axonogenesis, whereas Cdc42E6 is required for normal development of dendritic spines. Thus, co-expression of a precise blend of functionally distinct splice isoforms rather than a complete switch from one isoform to another underlies proper structural and functional polarization of neurons. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Automatic Fitting of Spiking Neuron Models to Electrophysiological Recordings

PubMed Central

Rossant, Cyrille; Goodman, Dan F. M.; Platkiewicz, Jonathan; Brette, Romain

2010-01-01

Spiking models can accurately predict the spike trains produced by cortical neurons in response to somatically injected currents. Since the specific characteristics of the model depend on the neuron, a computational method is required to fit models to electrophysiological recordings. The fitting procedure can be very time consuming both in terms of computer simulations and in terms of code writing. We present algorithms to fit spiking models to electrophysiological data (time-varying input and spike trains) that can run in parallel on graphics processing units (GPUs). The model fitting library is interfaced with Brian, a neural network simulator in Python. If a GPU is present it uses just-in-time compilation to translate model equations into optimized code. Arbitrary models can then be defined at script level and run on the graphics card. This tool can be used to obtain empirically validated spiking models of neurons in various systems. We demonstrate its use on public data from the INCF Quantitative Single-Neuron Modeling 2009 competition by comparing the performance of a number of neuron spiking models. PMID:20224819

Uniting functional network topology and oscillations in the fronto-parietal single unit network of behaving primates.

PubMed

Dann, Benjamin; Michaels, Jonathan A; Schaffelhofer, Stefan; Scherberger, Hansjörg

2016-08-15

The functional communication of neurons in cortical networks underlies higher cognitive processes. Yet, little is known about the organization of the single neuron network or its relationship to the synchronization processes that are essential for its formation. Here, we show that the functional single neuron network of three fronto-parietal areas during active behavior of macaque monkeys is highly complex. The network was closely connected (small-world) and consisted of functional modules spanning these areas. Surprisingly, the importance of different neurons to the network was highly heterogeneous with a small number of neurons contributing strongly to the network function (hubs), which were in turn strongly inter-connected (rich-club). Examination of the network synchronization revealed that the identified rich-club consisted of neurons that were synchronized in the beta or low frequency range, whereas other neurons were mostly non-oscillatory synchronized. Therefore, oscillatory synchrony may be a central communication mechanism for highly organized functional spiking networks.

Single mechanically-gated cation channel currents can trigger action potentials in neocortical and hippocampal pyramidal neurons.

PubMed

Nikolaev, Yury A; Dosen, Peter J; Laver, Derek R; van Helden, Dirk F; Hamill, Owen P

2015-05-22

The mammalian brain is a mechanosensitive organ that responds to different mechanical forces ranging from intrinsic forces implicated in brain morphogenesis to extrinsic forces that can cause concussion and traumatic brain injury. However, little is known of the mechanosensors that transduce these forces. In this study we use cell-attached patch recording to measure single mechanically-gated (MG) channel currents and their affects on spike activity in identified neurons in neonatal mouse brain slices. We demonstrate that both neocortical and hippocampal pyramidal neurons express stretch-activated MG cation channels that are activated by suctions of ~25mm Hg, have a single channel conductance for inward current of 50-70pS and show weak selectivity for alkali metal cations (i.e., Na(+)

The digastric muscle is less involved in pharyngeal swallowing in rabbits.

PubMed

Tsujimura, Takanori; Yamada, Aki; Nakamura, Yuki; Fukuhara, Takako; Yamamura, Kensuke; Inoue, Makoto

2012-06-01

The swallowing reflex is centrally programmed by the lower brain stem, the so-called swallowing central pattern generator (CPG), and once the reflex is initiated, many muscles in the oral, pharyngeal, laryngeal, and esophageal regions are systematically activated. The mylohyoid (MH) muscle has been considered to be a "leading muscle" according to previous studies, but the functional role of the digastric (DIG) muscle in the swallowing reflex remains unclear. In the present study, therefore, the activities of single units of MH and DIG neurons were recorded extracellularly, and the functional involvement of these neurons in the swallowing reflex was investigated. The experiments were carried out on eight adult male Japanese white rabbits anesthetized with urethane. To identify DIG and MH neurons, the peripheral nerve (either DIG or MH) was stimulated to evoke action potentials of single motoneurons. Motoneurons were identified as such if they either (1) responded to antidromic nerve stimulation of DIG or MH in an all-or-none manner at threshold intensities and (2) followed stimulation frequencies of up to 0.5 kHz. As a result, all 11 MH neurons recorded were synchronously activated during the swallowing reflex, while there was no activity in any of the 7 DIG neurons recorded during the swallowing reflex. All neurons were anatomically localized ventromedially at the level of the caudal portion of the trigeminal motor nucleus, and there were no differences between the MH and DIG neuron sites. The present results strongly suggest that at least in the rabbit, DIG motoneurons are not tightly controlled by the swallowing CPG and, hence, the DIG muscle is less involved in the swallowing reflex.

Phase Locking of Multiple Single Neurons to the Local Field Potential in Cat V1.

PubMed

Martin, Kevan A C; Schröder, Sylvia

2016-02-24

The local field potential (LFP) is thought to reflect a temporal reference for neuronal spiking, which may facilitate information coding and orchestrate the communication between neural populations. To explore this proposed role, we recorded the LFP and simultaneously the spike activity of one to three nearby neurons in V1 of anesthetized cats during the presentation of drifting sinusoidal gratings, binary dense noise stimuli, and natural movies. In all stimulus conditions and during spontaneous activity, the average LFP power at frequencies >20 Hz was higher when neurons were spiking versus not spiking. The spikes were weakly but significantly phase locked to all frequencies of the LFP. The average spike phase of the LFP was stable across high and low levels of LFP power, but the strength of phase locking at low frequencies (≤10 Hz) increased with increasing LFP power. In a next step, we studied how strong stimulus responses of single neurons are reflected in the LFP and the LFP-spike relationship. We found that LFP power was slightly increased and phase locking was slightly stronger during strong compared with weak stimulus-locked responses. In summary, the coupling strength between high frequencies of the LFP and spikes was not strongly modulated by LFP power, which is thought to reflect spiking synchrony, nor was it strongly influenced by how strongly the neuron was driven by the stimulus. Furthermore, a comparison between neighboring neurons showed no clustering of preferred LFP phase. We argue that hypotheses on the relevance of phase locking in their current form are inconsistent with our findings. Copyright © 2016 the authors 0270-6474/16/362494-09$15.00/0.

High-Throughput Mapping of Single-Neuron Projections by Sequencing of Barcoded RNA.

PubMed

Kebschull, Justus M; Garcia da Silva, Pedro; Reid, Ashlan P; Peikon, Ian D; Albeanu, Dinu F; Zador, Anthony M

2016-09-07

Neurons transmit information to distant brain regions via long-range axonal projections. In the mouse, area-to-area connections have only been systematically mapped using bulk labeling techniques, which obscure the diverse projections of intermingled single neurons. Here we describe MAPseq (Multiplexed Analysis of Projections by Sequencing), a technique that can map the projections of thousands or even millions of single neurons by labeling large sets of neurons with random RNA sequences ("barcodes"). Axons are filled with barcode mRNA, each putative projection area is dissected, and the barcode mRNA is extracted and sequenced. Applying MAPseq to the locus coeruleus (LC), we find that individual LC neurons have preferred cortical targets. By recasting neuroanatomy, which is traditionally viewed as a problem of microscopy, as a problem of sequencing, MAPseq harnesses advances in sequencing technology to permit high-throughput interrogation of brain circuits. Copyright © 2016 Elsevier Inc. All rights reserved.

KETONES INHIBIT MITOCHONDRIAL PRODUCTION OF REACTIVE OXYGEN SPECIES PRODUCTION FOLLOWING GLUTAMATE EXCITOTOXICITY BY INCREASING NADH OXIDATION

PubMed Central

Maalouf, Marwan; Sullivan, Patrick G.; Davis, Laurie; Kim, Do Young; Rho, Jong M.

2007-01-01

Dietary protocols that increase serum levels of ketones, such as calorie restriction and the ketogenic diet, offer robust protection against a multitude of acute and chronic neurological diseases. The underlying mechanisms, however, remain unclear. Previous studies have suggested that the ketogenic diet may reduce free radical levels in the brain. Thus, one possibility is that ketones may mediate neuroprotection through antioxidant activity. In the present study, we examined the effects of the ketones β-hydroxybutyrate and acetoacetate on acutely dissociated rat neocortical neurons subjected to glutamate excitotoxicity using cellular electrophysiological and single-cell fluorescence imaging techniques. Further, we explored the effects of ketones on acutely isolated mitochondria exposed to high levels of calcium. A combination of β-hydroxybutyrate and acetoacetate (1 mM each) decreased neuronal death and prevented changes in neuronal membrane properties induced by 10 μM glutamate. Ketones also significantly decreased mitochondrial production of reactive oxygen species and the associated excitotoxic changes by increasing NADH oxidation in the mitochondrial respiratory chain, but did not affect levels of the endogenous antioxidant glutathione. In conclusion, we demonstrate that ketones reduce glutamate-induced free radical formation by increasing the NAD+/NADH ratio and enhancing mitochondrial respiration in neocortical neurons. This mechanism may, in part, contribute to the neuroprotective activity of ketones by restoring normal bioenergetic function in the face of oxidative stress. PMID:17240074

Periodic activation function and a modified learning algorithm for the multivalued neuron.

PubMed

Aizenberg, Igor

2010-12-01

In this paper, we consider a new periodic activation function for the multivalued neuron (MVN). The MVN is a neuron with complex-valued weights and inputs/output, which are located on the unit circle. Although the MVN outperforms many other neurons and MVN-based neural networks have shown their high potential, the MVN still has a limited capability of learning highly nonlinear functions. A periodic activation function, which is introduced in this paper, makes it possible to learn nonlinearly separable problems and non-threshold multiple-valued functions using a single multivalued neuron. We call this neuron a multivalued neuron with a periodic activation function (MVN-P). The MVN-Ps functionality is much higher than that of the regular MVN. The MVN-P is more efficient in solving various classification problems. A learning algorithm based on the error-correction rule for the MVN-P is also presented. It is shown that a single MVN-P can easily learn and solve those benchmark classification problems that were considered unsolvable using a single neuron. It is also shown that a universal binary neuron, which can learn nonlinearly separable Boolean functions, and a regular MVN are particular cases of the MVN-P.

Effects of molindone on central dopaminergic neuronal activity and metabolism: similarity to other neuroleptics.

PubMed

Bunney, B S; Roth, R H; Aghajanian, G K

1975-01-01

The effect of molindone on the activity of dopaminergic (DA) neurons in the rat midbrain and on DA metabolism in the striatum and olfactory tubercles was studied using extracellular single unit recording and biochemical techniques respectively. Molindone in low intravenous doses (0.4-0.8 mg/kg) was found to reverse d-amphetamine and apomorphine induced depression of DA neurons and to block apomorphine induced depression of these cells. Molindone was also found to increase dopamine synthesis and dihydroxyphenylactic acid levels in the striatum and olfacotry tubercles. In all of these respects molindone behaves identically to most classical neuroleptics. However, unlike most antipsychotic drugs previously tested, molindone failed to increase the baseline firing rate of DA cells and blocked haloperidol induced increases in DA neuron activity. In this regard molindone most closely resembles thioridazine and clozapine. Possible mechanisms of action of molindone are discussed based on these findings.

Sensory Coding by Cerebellar Mossy Fibres through Inhibition-Driven Phase Resetting and Synchronisation

PubMed Central

Holtzman, Tahl; Jörntell, Henrik

2011-01-01

Temporal coding of spike-times using oscillatory mechanisms allied to spike-time dependent plasticity could represent a powerful mechanism for neuronal communication. However, it is unclear how temporal coding is constructed at the single neuronal level. Here we investigate a novel class of highly regular, metronome-like neurones in the rat brainstem which form a major source of cerebellar afferents. Stimulation of sensory inputs evoked brief periods of inhibition that interrupted the regular firing of these cells leading to phase-shifted spike-time advancements and delays. Alongside phase-shifting, metronome cells also behaved as band-pass filters during rhythmic sensory stimulation, with maximal spike-stimulus synchronisation at frequencies close to the idiosyncratic firing frequency of each neurone. Phase-shifting and band-pass filtering serve to temporally align ensembles of metronome cells, leading to sustained volleys of near-coincident spike-times, thereby transmitting synchronised sensory information to downstream targets in the cerebellar cortex. PMID:22046297

Neural signal registration and analysis of axons grown in microchannels

NASA Astrophysics Data System (ADS)

Pigareva, Y.; Malishev, E.; Gladkov, A.; Kolpakov, V.; Bukatin, A.; Mukhina, I.; Kazantsev, V.; Pimashkin, A.

2016-08-01

Registration of neuronal bioelectrical signals remains one of the main physical tools to study fundamental mechanisms of signal processing in the brain. Neurons generate spiking patterns which propagate through complex map of neural network connectivity. Extracellular recording of isolated axons grown in microchannels provides amplification of the signal for detailed study of spike propagation. In this study we used neuronal hippocampal cultures grown in microfluidic devices combined with microelectrode arrays to investigate a changes of electrical activity during neural network development. We found that after 5 days in vitro after culture plating the spiking activity appears first in microchannels and on the next 2-3 days appears on the electrodes of overall neural network. We conclude that such approach provides a convenient method to study neural signal processing and functional structure development on a single cell and network level of the neuronal culture.

Single Canonical Model of Reflexive Memory and Spatial Attention

PubMed Central

Patel, Saumil S.; Red, Stuart; Lin, Eric; Sereno, Anne B.

2015-01-01

Many neurons in the dorsal and ventral visual stream have the property that after a brief visual stimulus presentation in their receptive field, the spiking activity in these neurons persists above their baseline levels for several seconds. This maintained activity is not always correlated with the monkey’s task and its origin is unknown. We have previously proposed a simple neural network model, based on shape selective neurons in monkey lateral intraparietal cortex, which predicts the valence and time course of reflexive (bottom-up) spatial attention. In the same simple model, we demonstrate here that passive maintained activity or short-term memory of specific visual events can result without need for an external or top-down modulatory signal. Mutual inhibition and neuronal adaptation play distinct roles in reflexive attention and memory. This modest 4-cell model provides the first simple and unified physiologically plausible mechanism of reflexive spatial attention and passive short-term memory processes. PMID:26493949

Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone

PubMed Central

Zhao, Liangliang; Hadziahmetovic, Majda; Wang, Chenguang; Xu, Xueying; Song, Ying; Jinnah, H.A.; Wodzinska, Jolanta; Iacovelli, Jared; Wolkow, Natalie; Krajacic, Predrag; Weissberger, Alyssa Cwanger; Connelly, John; Spino, Michael; Lee, Michael K.; Connor, James; Giasson, Benoit; Harris, Z. Leah; Dunaief, Joshua L.

2016-01-01

Brain iron accumulates in several neurodegenerative diseases and can cause oxidative damage, but mechanisms of brain iron homeostasis are incompletely understood. Patients with mutations in the cellular iron-exporting ferroxidase ceruloplasmin (Cp) have brain iron accumulation causing neurodegeneration. Here, we assessed the brains of mice with combined mutation of Cp and its homolog hephaestin. Compared to single mutants, brain iron accumulation was accelerated in double mutants in the cerebellum, substantia nigra, and hippocampus. Iron accumulated within glia, while neurons were iron deficient. There was loss of both neurons and glia. Mice developed ataxia and tremor, and most died by 9 months. Treatment with the oral iron chelator deferiprone diminished brain iron levels, protected against neuron loss, and extended lifespan. Ferroxidases play important, partially overlapping roles in brain iron homeostasis by facilitating iron export from glia, making iron available to neurons. PMID:26303407

Neuronal effects of nicotine during auditory selective attention.

PubMed

Smucny, Jason; Olincy, Ann; Eichman, Lindsay S; Tregellas, Jason R

2015-06-01

Although the attention-enhancing effects of nicotine have been behaviorally and neurophysiologically well-documented, its localized functional effects during selective attention are poorly understood. In this study, we examined the neuronal effects of nicotine during auditory selective attention in healthy human nonsmokers. We hypothesized to observe significant effects of nicotine in attention-associated brain areas, driven by nicotine-induced increases in activity as a function of increasing task demands. A single-blind, prospective, randomized crossover design was used to examine neuronal response associated with a go/no-go task after 7 mg nicotine or placebo patch administration in 20 individuals who underwent functional magnetic resonance imaging at 3T. The task design included two levels of difficulty (ordered vs. random stimuli) and two levels of auditory distraction (silence vs. noise). Significant treatment × difficulty × distraction interaction effects on neuronal response were observed in the hippocampus, ventral parietal cortex, and anterior cingulate. In contrast to our hypothesis, U and inverted U-shaped dependencies were observed between the effects of nicotine on response and task demands, depending on the brain area. These results suggest that nicotine may differentially affect neuronal response depending on task conditions. These results have important theoretical implications for understanding how cholinergic tone may influence the neurobiology of selective attention.

Anatomical and Electrophysiological Comparison of CA1 Pyramidal Neurons of the Rat and Mouse

PubMed Central

Routh, Brandy N.; Johnston, Daniel; Harris, Kristen

2009-01-01

The study of learning and memory at the single-neuron level has relied on the use of many animal models, most notably rodents. Although many physiological and anatomical studies have been carried out in rats, the advent of genetically engineered mice has necessitated the comparison of new results in mice to established results from rats. Here we compare fundamental physiological and morphological properties and create three-dimensional compartmental models of identified hippocampal CA1 pyramidal neurons of one strain of rat, Sprague–Dawley, and two strains of mice, C57BL/6 and 129/SvEv. We report several differences in neuronal physiology and anatomy among the three animal groups, the most notable being that neurons of the 129/SvEv mice, but not the C57BL/6 mice, have higher input resistance, lower dendritic surface area, and smaller spines than those of rats. A surprising species-specific difference in membrane resonance indicates that both mouse strains have lower levels of the hyperpolarization-activated nonspecific cation current Ih. Simulations suggest that differences in Ih kinetics rather than maximal conductance account for the lower resonance. Our findings indicate that comparisons of data obtained across strains or species will need to account for these and potentially other physiological and anatomical differences. PMID:19675296

Parameter Estimation of a Spiking Silicon Neuron

PubMed Central

Russell, Alexander; Mazurek, Kevin; Mihalaş, Stefan; Niebur, Ernst; Etienne-Cummings, Ralph

2012-01-01

Spiking neuron models are used in a multitude of tasks ranging from understanding neural behavior at its most basic level to neuroprosthetics. Parameter estimation of a single neuron model, such that the model’s output matches that of a biological neuron is an extremely important task. Hand tuning of parameters to obtain such behaviors is a difficult and time consuming process. This is further complicated when the neuron is instantiated in silicon (an attractive medium in which to implement these models) as fabrication imperfections make the task of parameter configuration more complex. In this paper we show two methods to automate the configuration of a silicon (hardware) neuron’s parameters. First, we show how a Maximum Likelihood method can be applied to a leaky integrate and fire silicon neuron with spike induced currents to fit the neuron’s output to desired spike times. We then show how a distance based method which approximates the negative log likelihood of the lognormal distribution can also be used to tune the neuron’s parameters. We conclude that the distance based method is better suited for parameter configuration of silicon neurons due to its superior optimization speed. PMID:23852978

Genome-wide association study of serum coenzyme Q10 levels identifies susceptibility loci linked to neuronal diseases.

PubMed

Degenhardt, Frauke; Niklowitz, Petra; Szymczak, Silke; Jacobs, Gunnar; Lieb, Wolfgang; Menke, Thomas; Laudes, Matthias; Esko, Tõnu; Weidinger, Stephan; Franke, Andre; Döring, Frank; Onur, Simone

2016-07-01

Coenzyme Q 10 (CoQ 10 ) is a lipophilic redox molecule that is present in membranes of almost all cells in human tissues. CoQ 10 is, amongst other functions, essential for the respiratory transport chain and is a modulator of inflammatory processes and gene expression. Rare monogenetic CoQ 10 deficiencies show noticeable symptoms in tissues (e.g. kidney) and cell types (e.g. neurons) with a high energy demand. To identify common genetic variants influencing serum CoQ 10 levels, we performed a fixed effects meta-analysis in two independent cross-sectional Northern German cohorts comprising 1300 individuals in total. We identified two genome-wide significant susceptibility loci. The best associated single nucleotide polymorphism (SNP) was rs9952641 (P value = 1.31 × 10 - 8 , β = 0.063, CI 0.95 [0.041, 0.085]) within the COLEC12 gene on chromosome 18. The SNP rs933585 within the NRXN-1 gene on chromosome 2 also showed genome wide significance (P value = 3.64 × 10 - 8 , β = -0.034, CI 0.95 [-0.046, -0.022]). Both genes have been previously linked to neuronal diseases like Alzheimer's disease, autism and schizophrenia. Among our 'top-10' associated variants, four additional loci with known neuronal connections showed suggestive associations with CoQ 10 levels. In summary, this study demonstrates that serum CoQ 10 levels are associated with common genetic loci that are linked to neuronal diseases. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Effects of Altered Levels of Extracellular Superoxide Dismutase and Irradiation on Hippocampal Neurogenesis in Female Mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zou, Yani; Leu, David; Palo Alto Institute of Research and Education, Palo Alto, California

Purpose: Altered levels of extracellular superoxide dismutase (EC-SOD) and cranial irradiation have been shown to affect hippocampal neurogenesis. However, previous studies were only conducted in male mice, and it was not clear if there was a difference between males and females. Therefore, female mice were studied and the results compared with those generated in male mice from an earlier study. Methods and Materials: Female wild-type, EC-SOD-null (KO), and EC-SOD bigenic mice with neuronal-specific expression of EC-SOD (OE) were subjected to a single dose of 5-Gy gamma rays to the head at 8 weeks of age. Progenitor cell proliferation, differentiation, andmore » long-term survival of newborn neurons were determined. Results: Similar to results from male mice, EC-SOD deficiency and irradiation both resulted in significant reductions in mature newborn neurons in female mice. EC-SOD deficiency reduced long-term survival of newborn neurons whereas irradiation reduced progenitor cell proliferation. Overexpression of EC-SOD corrected the negative impacts from EC-SOD deficiency and irradiation and normalized the production of newborn neurons in OE mice. Expression of neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 were significantly reduced by irradiation in wild-type mice, but the levels were not changed in KO and OE mice even though both cohorts started out with a lower baseline level. Conclusion: In terms of hippocampal neurogenesis, EC-SOD deficiency and irradiation have the same overall effects in males and females at the age the studies were conducted.« less

Sleep interacts with aβ to modulate intrinsic neuronal excitability.

PubMed

Tabuchi, Masashi; Lone, Shahnaz R; Liu, Sha; Liu, Qili; Zhang, Julia; Spira, Adam P; Wu, Mark N

2015-03-16

Emerging data suggest an important relationship between sleep and Alzheimer's disease (AD), but how poor sleep promotes the development of AD remains unclear. Here, using a Drosophila model of AD, we provide evidence suggesting that changes in neuronal excitability underlie the effects of sleep loss on AD pathogenesis. β-amyloid (Aβ) accumulation leads to reduced and fragmented sleep, while chronic sleep deprivation increases Aβ burden. Moreover, enhancing sleep reduces Aβ deposition. Increasing neuronal excitability phenocopies the effects of reducing sleep on Aβ, and decreasing neuronal activity blocks the elevated Aβ accumulation induced by sleep deprivation. At the single neuron level, we find that chronic sleep deprivation, as well as Aβ expression, enhances intrinsic neuronal excitability. Importantly, these data reveal that sleep loss exacerbates Aβ-induced hyperexcitability and suggest that defects in specific K(+) currents underlie the hyperexcitability caused by sleep loss and Aβ expression. Finally, we show that feeding levetiracetam, an anti-epileptic medication, to Aβ-expressing flies suppresses neuronal excitability and significantly prolongs their lifespan. Our findings directly link sleep loss to changes in neuronal excitability and Aβ accumulation and further suggest that neuronal hyperexcitability is an important mediator of Aβ toxicity. Taken together, these data provide a mechanistic framework for a positive feedback loop, whereby sleep loss and neuronal excitation accelerate the accumulation of Aβ, a key pathogenic step in the development of AD. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sleep Interacts with Aβ to Modulate Intrinsic Neuronal Excitability

PubMed Central

Tabuchi, Masashi; Lone, Shahnaz R.; Liu, Sha; Liu, Qili; Zhang, Julia; Spira, Adam P.; Wu, Mark N.

2015-01-01

SUMMARY Background Emerging data suggest an important relationship between sleep and Alzheimer’s Disease (AD), but how poor sleep promotes the development of AD remains unclear. Results Here, using a Drosophila model of AD, we provide evidence suggesting that changes in neuronal excitability underlie the effects of sleep loss on AD pathogenesis. β-amyloid (Aβ) accumulation leads to reduced and fragmented sleep, while chronic sleep deprivation increases Aβ burden. Moreover, enhancing sleep reduces Aβ deposition. Increasing neuronal excitability phenocopies the effects of reducing sleep on Aβ, and decreasing neuronal activity blocks the elevated Aβ accumulation induced by sleep deprivation. At the single neuron level, we find that chronic sleep deprivation, as well as Aβ expression, enhances intrinsic neuronal excitability. Importantly, these data reveal that sleep loss exacerbates Aβ–induced hyperexcitability and suggest that defects in specific K+ currents underlie the hyperexcitability caused by sleep loss and Aβ expression. Finally, we show that feeding levetiracetam, an anti-epileptic medication, to Aβ-expressing flies suppresses neuronal excitability and significantly prolongs their lifespan. Conclusions Our findings directly link sleep loss to changes in neuronal excitability and Aβ accumulation and further suggest that neuronal hyperexcitability is an important mediator of Aβ toxicity. Taken together, these data provide a mechanistic framework for a positive feedback loop, whereby sleep loss and neuronal excitation accelerate the accumulation of Aβ, a key pathogenic step in the development of AD. PMID:25754641

The effects of prostaglandin E2 on the firing rate activity of thermosensitive and temperature insensitive neurons in the ventromedial preoptic area of the rat hypothalamus.

PubMed

Ranels, Heather J; Griffin, John D

2003-02-21

In response to an immune system challenge with lipopolysaccharide (LPS), recent work has shown that Fos immunoreactivity is displayed by neurons in the ventromedial preoptic area of the hypothalamus (VMPO). In addition, neurons in this region show distinct axonal projections to the anterior perifornical area (APFx) and the paraventricular nucleus (PVN). It has been hypothesized that neurons within the VMPO integrate their local responses to temperature with changes in firing activity that result from LPS induced production of prostaglandin E(2) (PGE(2)). This may be an important mechanism by which the set-point regulation of thermoeffector neurons in the APFx and PVN is altered, resulting in hyperthermia. To characterize the firing rate activity of VMPO neurons, single-unit recordings were made of neuronal extracellular activity in rat hypothalamic tissue slices. Based on the slope of firing rate as a function of tissue temperature, neurons were classified as either warm sensitive or temperature insensitive. Neurons were then treated with PGE(2) (200 nM) while tissue temperature was held at a constant level ( approximately 36 degrees C). The majority of temperature insensitive neurons responded to PGE(2) with an increase in firing rate activity, while warm sensitive neurons showed a reduction in firing rate. This suggests that both warm sensitive and temperature insensitive neurons in the VMPO may play critical and contrasting roles in the production of a fever during an acute phase response to infection.

Development of inhibitory synaptic inputs on layer 2/3 pyramidal neurons in the rat medial prefrontal cortex.

PubMed

Virtanen, Mari A; Lacoh, Claudia Marvine; Fiumelli, Hubert; Kosel, Markus; Tyagarajan, Shiva; de Roo, Mathias; Vutskits, Laszlo

2018-05-01

Inhibitory control of pyramidal neurons plays a major role in governing the excitability in the brain. While spatial mapping of inhibitory inputs onto pyramidal neurons would provide important structural data on neuronal signaling, studying their distribution at the single cell level is difficult due to the lack of easily identifiable anatomical proxies. Here, we describe an approach where in utero electroporation of a plasmid encoding for fluorescently tagged gephyrin into the precursors of pyramidal cells along with ionotophoretic injection of Lucifer Yellow can reliably and specifically detect GABAergic synapses on the dendritic arbour of single pyramidal neurons. Using this technique and focusing on the basal dendritic arbour of layer 2/3 pyramidal cells of the medial prefrontal cortex, we demonstrate an intense development of GABAergic inputs onto these cells between postnatal days 10 and 20. While the spatial distribution of gephyrin clusters was not affected by the distance from the cell body at postnatal day 10, we found that distal dendritic segments appeared to have a higher gephyrin density at later developmental stages. We also show a transient increase around postnatal day 20 in the percentage of spines that are carrying a gephyrin cluster, indicative of innervation by a GABAergic terminal. Since the precise spatial arrangement of synaptic inputs is an important determinant of neuronal responses, we believe that the method described in this work may allow a better understanding of how inhibition settles together with excitation, and serve as basics for further modelling studies focusing on the geometry of dendritic inhibition during development.

A high-throughput method for generating uniform microislands for autaptic neuronal cultures

PubMed Central

Sgro, Allyson E.; Nowak, Amy L.; Austin, Naola S.; Custer, Kenneth L.; Allen, Peter B.; Chiu, Daniel T.; Bajjalieh, Sandra M.

2013-01-01

Generating microislands of culture substrate on coverslips by spray application of poly-D lysine is a commonly used method for culturing isolated neurons that form self (autaptic) synapses. This preparation has multiple advantages for studying synaptic transmission in isolation; however, generating microislands by spraying produces islands of non-uniform size and thus cultures vary widely in the number of islands containing single neurons. To address these problems, we developed a high-throughput method for reliably generating uniformly-shaped microislands of culture substrate. Stamp molds formed of poly(dimethylsiloxane) (PDMS) were fabricated with arrays of circles and used to generate stamps made of 9.2% agarose. The agarose stamps were capable of loading sufficient poly D-lysine and collagen dissolved in acetic acid to rapidly generate coverslips containing at least 64 microislands per coverslip. When hippocampal neurons were cultured on these coverslips, there were significantly more single-neuron islands per coverslip. We noted that single neurons tended to form one of three distinct neurite-arbor morphologies, which varied with island size and the location of the cell body on the island. To our surprise, the number of synapses per autaptic neuron did not correlate with arbor shape or island size, suggesting that other factors regulate the number of synapses formed by isolated neurons. The stamping method we report can be used to increase the number of single-neuron islands per culture and aid in the rapid visualization of microislands. PMID:21515305

Inhibition of propofol on single neuron and neuronal ensemble activity in prefrontal cortex of rats during working memory task.

PubMed

Xu, Xinyu; Tian, Yu; Wang, Guolin; Tian, Xin

2014-08-15

Working memory (WM) refers to the temporary storage and manipulation of information necessary for performance of complex cognitive tasks. There is a growing interest in whether and how propofol anesthesia inhibits WM function. The aim of this study is to investigate the possible inhibition mechanism of propofol anesthesia from the view of single neuron and neuronal ensemble activities. Adult SD rats were randomly divided into two groups: propofol group (0.9 mg kg(-1)min(-1), 2h via a tail vein catheter) and control group. All the rats were tested for working memory performances in a Y-maze-rewarded alternation task (a task of delayed non-matched-to-sample) at 24, 48, 72 h after propofol anesthesia, and the behavior results of WM tasks were recorded at the same time. Spatio-temporal trains of action potentials were obtained from the original signals. Single neuron activity was characterized by peri-event time histograms analysis and neuron ensemble activities were characterized by Granger causality to describe the interactions within the neuron ensemble. The results show that: comparing with the control group, the percentage of neurons excited and related to WM was significantly decreased (p<0.01 in 24h, p<0.05 in 48 h); the interactions within neuron ensemble were significantly weakened (p<0.01 in 24h, p<0.05 in 48 h), whereas no significant difference in 72 h (p>0.05), which were consistent with the behavior results. These findings could lead to improved understanding of the mechanism of anesthesia inhibition on WM functions from the view of single neuron activity and neuron ensemble interactions. Copyright © 2014 Elsevier B.V. All rights reserved.

Population activity statistics dissect subthreshold and spiking variability in V1.

PubMed

Bányai, Mihály; Koman, Zsombor; Orbán, Gergő

2017-07-01

Response variability, as measured by fluctuating responses upon repeated performance of trials, is a major component of neural responses, and its characterization is key to interpret high dimensional population recordings. Response variability and covariability display predictable changes upon changes in stimulus and cognitive or behavioral state, providing an opportunity to test the predictive power of models of neural variability. Still, there is little agreement on which model to use as a building block for population-level analyses, and models of variability are often treated as a subject of choice. We investigate two competing models, the doubly stochastic Poisson (DSP) model assuming stochasticity at spike generation, and the rectified Gaussian (RG) model tracing variability back to membrane potential variance, to analyze stimulus-dependent modulation of both single-neuron and pairwise response statistics. Using a pair of model neurons, we demonstrate that the two models predict similar single-cell statistics. However, DSP and RG models have contradicting predictions on the joint statistics of spiking responses. To test the models against data, we build a population model to simulate stimulus change-related modulations in pairwise response statistics. We use single-unit data from the primary visual cortex (V1) of monkeys to show that while model predictions for variance are qualitatively similar to experimental data, only the RG model's predictions are compatible with joint statistics. These results suggest that models using Poisson-like variability might fail to capture important properties of response statistics. We argue that membrane potential-level modeling of stochasticity provides an efficient strategy to model correlations. NEW & NOTEWORTHY Neural variability and covariability are puzzling aspects of cortical computations. For efficient decoding and prediction, models of information encoding in neural populations hinge on an appropriate model of variability. Our work shows that stimulus-dependent changes in pairwise but not in single-cell statistics can differentiate between two widely used models of neuronal variability. Contrasting model predictions with neuronal data provides hints on the noise sources in spiking and provides constraints on statistical models of population activity. Copyright © 2017 the American Physiological Society.

Shape Selectivity of Middle Superior Temporal Sulcus Body Patch Neurons

PubMed Central

2017-01-01

Abstract Functional MRI studies in primates have demonstrated cortical regions that are strongly activated by visual images of bodies. The presence of such body patches in macaques allows characterization of the stimulus selectivity of their single neurons. Middle superior temporal sulcus body (MSB) patch neurons showed similar stimulus selectivity for natural, shaded, and textured images compared with their silhouettes, suggesting that shape is an important determinant of MSB responses. Here, we examined and modeled the shape selectivity of single MSB neurons. We measured the responses of single MSB neurons to a variety of shapes producing a wide range of responses. We used an adaptive stimulus sampling procedure, selecting and modifying shapes based on the responses of the neuron. Forty percent of shapes that produced the maximal response were rated by humans as animal-like, but the top shape of many MSB neurons was not judged as resembling a body. We fitted the shape selectivity of MSB neurons with a model that parameterizes shapes in terms of curvature and orientation of contour segments, with a pixel-based model, and with layers of units of convolutional neural networks (CNNs). The deep convolutional layers of CNNs provided the best goodness-of-fit, with a median explained explainable variance of the neurons’ responses of 77%. The goodness-of-fit increased along the convolutional layers’ hierarchy but was lower for the fully connected layers. Together with demonstrating the successful modeling of single unit shape selectivity with deep CNNs, the data suggest that semantic or category knowledge determines only slightly the single MSB neuron’s shape selectivity. PMID:28660250

Optical magnetic detection of single-neuron action potentials using quantum defects in diamond

PubMed Central

Barry, John F.; Turner, Matthew J.; Schloss, Jennifer M.; Glenn, David R.; Song, Yuyu; Lukin, Mikhail D.; Park, Hongkun; Walsworth, Ronald L.

2016-01-01

Magnetic fields from neuronal action potentials (APs) pass largely unperturbed through biological tissue, allowing magnetic measurements of AP dynamics to be performed extracellularly or even outside intact organisms. To date, however, magnetic techniques for sensing neuronal activity have either operated at the macroscale with coarse spatial and/or temporal resolution—e.g., magnetic resonance imaging methods and magnetoencephalography—or been restricted to biophysics studies of excised neurons probed with cryogenic or bulky detectors that do not provide single-neuron spatial resolution and are not scalable to functional networks or intact organisms. Here, we show that AP magnetic sensing can be realized with both single-neuron sensitivity and intact organism applicability using optically probed nitrogen-vacancy (NV) quantum defects in diamond, operated under ambient conditions and with the NV diamond sensor in close proximity (∼10 µm) to the biological sample. We demonstrate this method for excised single neurons from marine worm and squid, and then exterior to intact, optically opaque marine worms for extended periods and with no observed adverse effect on the animal. NV diamond magnetometry is noninvasive and label-free and does not cause photodamage. The method provides precise measurement of AP waveforms from individual neurons, as well as magnetic field correlates of the AP conduction velocity, and directly determines the AP propagation direction through the inherent sensitivity of NVs to the associated AP magnetic field vector. PMID:27911765

Optical magnetic detection of single-neuron action potentials using quantum defects in diamond.

PubMed

Barry, John F; Turner, Matthew J; Schloss, Jennifer M; Glenn, David R; Song, Yuyu; Lukin, Mikhail D; Park, Hongkun; Walsworth, Ronald L

2016-12-06

Magnetic fields from neuronal action potentials (APs) pass largely unperturbed through biological tissue, allowing magnetic measurements of AP dynamics to be performed extracellularly or even outside intact organisms. To date, however, magnetic techniques for sensing neuronal activity have either operated at the macroscale with coarse spatial and/or temporal resolution-e.g., magnetic resonance imaging methods and magnetoencephalography-or been restricted to biophysics studies of excised neurons probed with cryogenic or bulky detectors that do not provide single-neuron spatial resolution and are not scalable to functional networks or intact organisms. Here, we show that AP magnetic sensing can be realized with both single-neuron sensitivity and intact organism applicability using optically probed nitrogen-vacancy (NV) quantum defects in diamond, operated under ambient conditions and with the NV diamond sensor in close proximity (∼10 µm) to the biological sample. We demonstrate this method for excised single neurons from marine worm and squid, and then exterior to intact, optically opaque marine worms for extended periods and with no observed adverse effect on the animal. NV diamond magnetometry is noninvasive and label-free and does not cause photodamage. The method provides precise measurement of AP waveforms from individual neurons, as well as magnetic field correlates of the AP conduction velocity, and directly determines the AP propagation direction through the inherent sensitivity of NVs to the associated AP magnetic field vector.

A multiscale method for a robust detection of the default mode network

NASA Astrophysics Data System (ADS)

Baquero, Katherine; Gómez, Francisco; Cifuentes, Christian; Guldenmund, Pieter; Demertzi, Athena; Vanhaudenhuyse, Audrey; Gosseries, Olivia; Tshibanda, Jean-Flory; Noirhomme, Quentin; Laureys, Steven; Soddu, Andrea; Romero, Eduardo

2013-11-01

The Default Mode Network (DMN) is a resting state network widely used for the analysis and diagnosis of mental disorders. It is normally detected in fMRI data, but for its detection in data corrupted by motion artefacts or low neuronal activity, the use of a robust analysis method is mandatory. In fMRI it has been shown that the signal-to-noise ratio (SNR) and the detection sensitivity of neuronal regions is increased with di erent smoothing kernels sizes. Here we propose to use a multiscale decomposition based of a linear scale-space representation for the detection of the DMN. Three main points are proposed in this methodology: rst, the use of fMRI data at di erent smoothing scale-spaces, second, detection of independent neuronal components of the DMN at each scale by using standard preprocessing methods and ICA decomposition at scale-level, and nally, a weighted contribution of each scale by the Goodness of Fit measurement. This method was applied to a group of control subjects and was compared with a standard preprocesing baseline. The detection of the DMN was improved at single subject level and at group level. Based on these results, we suggest to use this methodology to enhance the detection of the DMN in data perturbed with artefacts or applied to subjects with low neuronal activity. Furthermore, the multiscale method could be extended for the detection of other resting state neuronal networks.

Enzymatic properties and localization of motopsin (PRSS12), a protease whose absence causes mental retardation.

PubMed

Mitsui, Shinichi; Yamaguchi, Nozomi; Osako, Yoji; Yuri, Kazunari

2007-03-09

Motopsin (PRSS12) is a mosaic protease expressed in the central nervous system. Truncation of the human motopsin gene causes nonsyndromic mental retardation. Understanding the enzymatic properties and localization of motopsin protein in the central nervous system will help identify the molecular mechanism by which the loss of motopsin function causes mental retardation. Recombinant motopsin showed amidolytic activity against the synthetic substrate benzyloxycarbonyl-l-phenylalanyl-l-arginine 4-methyl-coumaryl-7-amide. Motopsin activated the single-chain tissue plasminogen activator precursor and exhibited gelatinolytic activity. This enzymatic activity was inhibited by typical serine protease inhibitors such as aprotinin, leupeptin, and (4-amidinophenyl) methanesulfonyl fluoride. Immunocytochemistry using anti-motopsin IgG revealed that both human and mouse motopsin proteins were distributed in discrete puncta along the dendrites and soma as well as axons in cultured hippocampal neurons. In the limbic system, including the cingulate and hippocampal pyramidal neurons and piriform cortex, high level of motopsin protein was expressed at postnatal day 10, but a very low level at 10-week-old mice. Motopsin and tissue plasminogen activator were co-expressed in the cingulate pyramidal neurons at postnatal day 10 and were distributed along dendrites of cultured pyramidal neurons. In cranial nuclei, a moderate level of motopsin protein was detected independently on the developmental stage. Our results suggest that motopsin has multiple functions, such as axon outgrowth, arranging perineuronal environment, and maintaining neuronal plasticity, partly in coordination with other proteases including tissue plasminogen activator.

Fast calcium and voltage-sensitive dye imaging in enteric neurones reveal calcium peaks associated with single action potential discharge.

PubMed

Michel, K; Michaelis, M; Mazzuoli, G; Mueller, K; Vanden Berghe, P; Schemann, M

2011-12-15

Slow changes in [Ca(2+)](i) reflect increased neuronal activity. Our study demonstrates that single-trial fast [Ca(2+)](i) imaging (≥200 Hz sampling rate) revealed peaks each of which are associated with single spike discharge recorded by consecutive voltage-sensitive dye (VSD) imaging in enteric neurones and nerve fibres. Fast [Ca(2+)](i) imaging also revealed subthreshold fast excitatory postsynaptic potentials. Nicotine-evoked [Ca(2+)](i) peaks were reduced by -conotoxin and blocked by ruthenium red or tetrodotoxin. Fast [Ca(2+)](i) imaging can be used to directly record single action potentials in enteric neurones. [Ca(2+)](i) peaks required opening of voltage-gated sodium and calcium channels as well as Ca(2+) release from intracellular stores.

Human single-neuron responses at the threshold of conscious recognition

PubMed Central

Quiroga, R. Quian; Mukamel, R.; Isham, E. A.; Malach, R.; Fried, I.

2008-01-01

We studied the responses of single neurons in the human medial temporal lobe while subjects viewed familiar faces, animals, and landmarks. By progressively shortening the duration of stimulus presentation, coupled with backward masking, we show two striking properties of these neurons. (i) Their responses are not statistically different for the 33-ms, 66-ms, and 132-ms stimulus durations, and only for the 264-ms presentations there is a significantly higher firing. (ii) These responses follow conscious perception, as indicated by the subjects' recognition report. Remarkably, when recognized, a single snapshot as brief as 33 ms was sufficient to trigger strong single-unit responses far outlasting stimulus presentation. These results suggest that neurons in the medial temporal lobe can reflect conscious recognition by “all-or-none” responses. PMID:18299568

Single-cell analysis of peptide expression and electrophysiology of right parietal neurons involved in male copulation behavior of a simultaneous hermaphrodite.

PubMed

El Filali, Z; de Boer, P A C M; Pieneman, A W; de Lange, R P J; Jansen, R F; Ter Maat, A; van der Schors, R C; Li, K W; van Straalen, N M; Koene, J M

2015-12-01

Male copulation is a complex behavior that requires coordinated communication between the nervous system and the peripheral reproductive organs involved in mating. In hermaphroditic animals, such as the freshwater snail Lymnaea stagnalis, this complexity increases since the animal can behave both as male and female. The performance of the sexual role as a male is coordinated via a neuronal communication regulated by many peptidergic neurons, clustered in the cerebral and pedal ganglia and dispersed in the pleural and parietal ganglia. By combining single-cell matrix-assisted laser mass spectrometry with retrograde staining and electrophysiology, we analyzed neuropeptide expression of single neurons of the right parietal ganglion and their axonal projections into the penial nerve. Based on the neuropeptide profile of these neurons, we were able to reconstruct a chemical map of the right parietal ganglion revealing a striking correlation with the earlier electrophysiological and neuroanatomical studies. Neurons can be divided into two main groups: (i) neurons that express heptapeptides and (ii) neurons that do not. The neuronal projection of the different neurons into the penial nerve reveals a pattern where (spontaneous) activity is related to branching pattern. This heterogeneity in both neurochemical anatomy and branching pattern of the parietal neurons reflects the complexity of the peptidergic neurotransmission involved in the regulation of male mating behavior in this simultaneous hermaphrodite.

Testing Neuronal Accounts of Anisotropic Motion Perception with Computational Modelling

PubMed Central

Wong, William; Chiang Price, Nicholas Seow

2014-01-01

There is an over-representation of neurons in early visual cortical areas that respond most strongly to cardinal (horizontal and vertical) orientations and directions of visual stimuli, and cardinal- and oblique-preferring neurons are reported to have different tuning curves. Collectively, these neuronal anisotropies can explain two commonly-reported phenomena of motion perception – the oblique effect and reference repulsion – but it remains unclear whether neuronal anisotropies can simultaneously account for both perceptual effects. We show in psychophysical experiments that reference repulsion and the oblique effect do not depend on the duration of a moving stimulus, and that brief adaptation to a single direction simultaneously causes a reference repulsion in the orientation domain, and the inverse of the oblique effect in the direction domain. We attempted to link these results to underlying neuronal anisotropies by implementing a large family of neuronal decoding models with parametrically varied levels of anisotropy in neuronal direction-tuning preferences, tuning bandwidths and spiking rates. Surprisingly, no model instantiation was able to satisfactorily explain our perceptual data. We argue that the oblique effect arises from the anisotropic distribution of preferred directions evident in V1 and MT, but that reference repulsion occurs separately, perhaps reflecting a process of categorisation occurring in higher-order cortical areas. PMID:25409518

Solving Constraint Satisfaction Problems with Networks of Spiking Neurons

PubMed Central

Jonke, Zeno; Habenschuss, Stefan; Maass, Wolfgang

2016-01-01

Network of neurons in the brain apply—unlike processors in our current generation of computer hardware—an event-based processing strategy, where short pulses (spikes) are emitted sparsely by neurons to signal the occurrence of an event at a particular point in time. Such spike-based computations promise to be substantially more power-efficient than traditional clocked processing schemes. However, it turns out to be surprisingly difficult to design networks of spiking neurons that can solve difficult computational problems on the level of single spikes, rather than rates of spikes. We present here a new method for designing networks of spiking neurons via an energy function. Furthermore, we show how the energy function of a network of stochastically firing neurons can be shaped in a transparent manner by composing the networks of simple stereotypical network motifs. We show that this design approach enables networks of spiking neurons to produce approximate solutions to difficult (NP-hard) constraint satisfaction problems from the domains of planning/optimization and verification/logical inference. The resulting networks employ noise as a computational resource. Nevertheless, the timing of spikes plays an essential role in their computations. Furthermore, networks of spiking neurons carry out for the Traveling Salesman Problem a more efficient stochastic search for good solutions compared with stochastic artificial neural networks (Boltzmann machines) and Gibbs sampling. PMID:27065785

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

PubMed Central

Boyd, Penelope J.; Shorrock, Hannah K.; Carter, Roderick N.; Powis, Rachael A.; Thomson, Sophie R.; Thomson, Derek; Graham, Laura C.; Motyl, Anna A. L.; Highley, J. Robin; Becker, Thomas; Becker, Catherina G.; Heath, Paul R.

2017-01-01

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo. PMID:28426667

Phagocytic response of astrocytes to damaged neighboring cells

PubMed Central

Cruz, Gladys Mae S.; Ro, Clarissa C.; Moncada, Emmanuel G.; Khatibzadeh, Nima; Flanagan, Lisa A.; Berns, Michael W.

2018-01-01

This study aims to understand the phagocytic response of astrocytes to the injury of neurons or other astrocytes at the single cell level. Laser nanosurgery was used to damage individual cells in both primary mouse cortical astrocytes and an established astrocyte cell line. In both cases, the release of material/substances from laser-irradiated astrocytes or neurons induced a phagocytic response in near-by astrocytes. Propidium iodide stained DNA originating from irradiated cells was visible in vesicles of neighboring cells, confirming phagocytosis of material from damaged cortical cells. In the presence of an intracellular pH indicator dye, newly formed vesicles correspond to acidic pH fluorescence, thus suggesting lysosome bound degradation of cellular debris. Cells with shared membrane connections prior to laser damage had a significantly higher frequency of induced phagocytosis compared to isolated cells with no shared membrane. The increase in phagocytic response of cells with a shared membrane occurred regardless of the extent of shared membrane (a thin filopodial connection vs. a cell cluster with significant shared membrane). In addition to the presence (or lack) of a membrane connection, variation in phagocytic ability was also observed with differences in injury location within the cell and distance separating isolated astrocytes. These results demonstrate the ability of an astrocyte to respond to the damage of a single cell, be it another astrocyte, or a neuron. This single-cell level of analysis results in a better understanding of the role of astrocytes to maintain homeostasis in the CNS, particularly in the sensing and removal of debris in damaged or pathologic nervous tissue. PMID:29708987

An integrated multi-electrode-optrode array for in vitro optogenetics

PubMed Central

Welkenhuysen, Marleen; Hoffman, Luis; Luo, Zhengxiang; De Proft, Anabel; Van den Haute, Chris; Baekelandt, Veerle; Debyser, Zeger; Gielen, Georges; Puers, Robert; Braeken, Dries

2016-01-01

Modulation of a group of cells or tissue needs to be very precise in order to exercise effective control over the cell population under investigation. Optogenetic tools have already demonstrated to be of great value in the study of neuronal circuits and in neuromodulation. Ideally, they should permit very accurate resolution, preferably down to the single cell level. Further, to address a spatially distributed sample, independently addressable multiple optical outputs should be present. In current techniques, at least one of these requirements is not fulfilled. In addition to this, it is interesting to directly monitor feedback of the modulation by electrical registration of the activity of the stimulated cells. Here, we present the fabrication and characterization of a fully integrated silicon-based multi-electrode-optrode array (MEOA) for in vitro optogenetics. We demonstrate that this device allows for artifact-free electrical recording. Moreover, the MEOA was used to reliably elicit spiking activity from ChR2-transduced neurons. Thanks to the single cell resolution stimulation capability, we could determine spatial and temporal activation patterns and spike latencies of the neuronal network. This integrated approach to multi-site combined optical stimulation and electrical recording significantly advances today’s tool set for neuroscientists in their search to unravel neuronal network dynamics. PMID:26832455

Label-free optical detection of action potential in mammalian neurons (Conference Presentation)

NASA Astrophysics Data System (ADS)

Batabyal, Subrata; Satpathy, Sarmishtha; Bui, Loan; Kim, Young-Tae; Mohanty, Samarendra K.; Davé, Digant P.

2017-02-01

Electrophysiology techniques are the gold standard in neuroscience for studying functionality of a single neuron to a complex neuronal network. However, electrophysiology techniques are not flawless, they are invasive nature, procedures are cumbersome to implement with limited capability of being used as a high-throughput recording system. Also, long term studies of neuronal functionality with aid of electrophysiology is not feasible. Non-invasive stimulation and detection of neuronal electrical activity has been a long standing goal in neuroscience. Introduction of optogenetics has ushered in the era of non-invasive optical stimulation of neurons, which is revolutionizing neuroscience research. Optical detection of neuronal activity that is comparable to electro-physiology is still elusive. A number of optical techniques have been reported recording of neuronal electrical activity but none is capable of reliably measuring action potential spikes that is comparable to electro-physiology. Optical detection of action potential with voltage sensitive fluorescent reporters are potential alternatives to electrophysiology techniques. The heavily rely on secondary reporters, which are often toxic in nature with background fluorescence, with slow response and low SNR making them far from ideal. The detection of one shot (without averaging)-single action potential in a true label-free way has been elusive so far. In this report, we demonstrate the optical detection of single neuronal spike in a cultured mammalian neuronal network without using any exogenous labels. To the best of our knowledge, this is the first demonstration of label free optical detection of single action potentials in a mammalian neuronal network, which was achieved using a high-speed phase sensitive interferometer. We have carried out stimulation and inhibition of neuronal firing using Glutamate and Tetrodotoxin respectively to demonstrate the different outcome (stimulation and inhibition) revealed in optical signal. We hypothesize that the interrogating optical beam is modulated during neuronal firing by electro-motility driven membrane fluctuation in conjunction with electrical wave propagation in cellular system.

Dynamical estimation of neuron and network properties III: network analysis using neuron spike times.

PubMed

Knowlton, Chris; Meliza, C Daniel; Margoliash, Daniel; Abarbanel, Henry D I

2014-06-01

Estimating the behavior of a network of neurons requires accurate models of the individual neurons along with accurate characterizations of the connections among them. Whereas for a single cell, measurements of the intracellular voltage are technically feasible and sufficient to characterize a useful model of its behavior, making sufficient numbers of simultaneous intracellular measurements to characterize even small networks is infeasible. This paper builds on prior work on single neurons to explore whether knowledge of the time of spiking of neurons in a network, once the nodes (neurons) have been characterized biophysically, can provide enough information to usefully constrain the functional architecture of the network: the existence of synaptic links among neurons and their strength. Using standardized voltage and synaptic gating variable waveforms associated with a spike, we demonstrate that the functional architecture of a small network of model neurons can be established.

Fast calcium transients translate the distribution and conduction of neural activity in different regions of a single sensory neuron.

PubMed

Purali, Nuhan

2017-09-01

In the present study, cytosolic calcium concentration changes were recorded in response to various forms of excitations, using the fluorescent calcium indicator dye OG-BAPTA1 together with the current or voltage clamp methods in stretch receptor neurons of crayfish. A single action potential evoked a rise in the resting calcium level in the axon and axonal hillock, whereas an impulse train or a large saturating current injection would be required to evoke an equivalent response in the dendrite region. Under voltage clamp conditions, amplitude differences between axon and dendrite responses vanished completely. The fast activation time and the modulation of the response by extracellular calcium concentration changes indicated that the evoked calcium transients might be mediated by calcium entry into the cytosol through a voltage-gated calcium channel. The decay of the responses was slow and sensitive to extracellular sodium and calcium concentrations as well as exposure to 1-10 mM NiCl 2 and 10-500 µM lanthanum. Thus, a sodium calcium exchanger and a calcium ATPase might be responsible for calcium extrusion from the cytosol. Present results indicate that the calcium indicator OG-BAPTA1 might be an efficient but indirect way of monitoring regional membrane potential differences in a single neuron.

Correlates of a single cortical action potential in the epidural EEG

PubMed Central

Teleńczuk, Bartosz; Baker, Stuart N; Kempter, Richard; Curio, Gabriel

2015-01-01

To identify the correlates of a single cortical action potential in surface EEG, we recorded simultaneously epidural EEG and single-unit activity in the primary somatosensory cortex of awake macaque monkeys. By averaging over EEG segments coincident with more than hundred thousand single spikes, we found short-lived (≈ 0.5 ms) triphasic EEG deflections dominated by high-frequency components > 800 Hz. The peak-to-peak amplitude of the grand-averaged spike correlate was 80 nV, which matched theoretical predictions, while single-neuron amplitudes ranged from 12 to 966 nV. Combining these estimates with post-stimulus-time histograms of single-unit responses to median-nerve stimulation allowed us to predict the shape of the evoked epidural EEG response and to estimate the number of contributing neurons. These findings establish spiking activity of cortical neurons as a primary building block of high-frequency epidural EEG, which thus can serve as a quantitative macroscopic marker of neuronal spikes. PMID:25554430

Modulation of aerial respiratory behaviour in a pond snail.

PubMed

Lukowiak, Ken; Martens, Kara; Orr, Mike; Parvez, Kashif; Rosenegger, David; Sangha, Susan

2006-11-01

Aerial respiratory in Lymnaea is driven by a three-neuron CPG whose sufficiency and necessity has been directly demonstrated. While this CPG is 'hard-wired' it displays a tremendous amount of plasticity. That is, it is possible by employing specific training procedures to alter how it functions in a specific hypoxic environment. Thus, it is possible to study directly the causal mechanisms of long-term memory formation, forgetting, and modulation of the memory at a single cell level. Thus, it is possible to use a relatively simple three-neuron CPG to study not only important questions concerning regulation of important homeostatic mechanisms but to also use it to study how learning and non-declarative memory are mediated at a cellular level.

Probabilistic inference in discrete spaces can be implemented into networks of LIF neurons.

PubMed

Probst, Dimitri; Petrovici, Mihai A; Bytschok, Ilja; Bill, Johannes; Pecevski, Dejan; Schemmel, Johannes; Meier, Karlheinz

2015-01-01

The means by which cortical neural networks are able to efficiently solve inference problems remains an open question in computational neuroscience. Recently, abstract models of Bayesian computation in neural circuits have been proposed, but they lack a mechanistic interpretation at the single-cell level. In this article, we describe a complete theoretical framework for building networks of leaky integrate-and-fire neurons that can sample from arbitrary probability distributions over binary random variables. We test our framework for a model inference task based on a psychophysical phenomenon (the Knill-Kersten optical illusion) and further assess its performance when applied to randomly generated distributions. As the local computations performed by the network strongly depend on the interaction between neurons, we compare several types of couplings mediated by either single synapses or interneuron chains. Due to its robustness to substrate imperfections such as parameter noise and background noise correlations, our model is particularly interesting for implementation on novel, neuro-inspired computing architectures, which can thereby serve as a fast, low-power substrate for solving real-world inference problems.

Probabilistic inference in discrete spaces can be implemented into networks of LIF neurons

PubMed Central

Probst, Dimitri; Petrovici, Mihai A.; Bytschok, Ilja; Bill, Johannes; Pecevski, Dejan; Schemmel, Johannes; Meier, Karlheinz

2015-01-01

The means by which cortical neural networks are able to efficiently solve inference problems remains an open question in computational neuroscience. Recently, abstract models of Bayesian computation in neural circuits have been proposed, but they lack a mechanistic interpretation at the single-cell level. In this article, we describe a complete theoretical framework for building networks of leaky integrate-and-fire neurons that can sample from arbitrary probability distributions over binary random variables. We test our framework for a model inference task based on a psychophysical phenomenon (the Knill-Kersten optical illusion) and further assess its performance when applied to randomly generated distributions. As the local computations performed by the network strongly depend on the interaction between neurons, we compare several types of couplings mediated by either single synapses or interneuron chains. Due to its robustness to substrate imperfections such as parameter noise and background noise correlations, our model is particularly interesting for implementation on novel, neuro-inspired computing architectures, which can thereby serve as a fast, low-power substrate for solving real-world inference problems. PMID:25729361

Neuronal adaptation, novelty detection and regularity encoding in audition

PubMed Central

Malmierca, Manuel S.; Sanchez-Vives, Maria V.; Escera, Carles; Bendixen, Alexandra

2014-01-01

The ability to detect unexpected stimuli in the acoustic environment and determine their behavioral relevance to plan an appropriate reaction is critical for survival. This perspective article brings together several viewpoints and discusses current advances in understanding the mechanisms the auditory system implements to extract relevant information from incoming inputs and to identify unexpected events. This extraordinary sensitivity relies on the capacity to codify acoustic regularities, and is based on encoding properties that are present as early as the auditory midbrain. We review state-of-the-art studies on the processing of stimulus changes using non-invasive methods to record the summed electrical potentials in humans, and those that examine single-neuron responses in animal models. Human data will be based on mismatch negativity (MMN) and enhanced middle latency responses (MLR). Animal data will be based on the activity of single neurons at the cortical and subcortical levels, relating selective responses to novel stimuli to the MMN and to stimulus-specific neural adaptation (SSA). Theoretical models of the neural mechanisms that could create SSA and novelty responses will also be discussed. PMID:25009474

Single Neurons in M1 and Premotor Cortex Directly Reflect Behavioral Interference

PubMed Central

Zach, Neta; Inbar, Dorrit; Grinvald, Yael; Vaadia, Eilon

2012-01-01

Some motor tasks, if learned together, interfere with each other's consolidation and subsequent retention, whereas other tasks do not. Interfering tasks are said to employ the same internal model whereas noninterfering tasks use different models. The division of function among internal models, as well as their possible neural substrates, are not well understood. To investigate these questions, we compared responses of single cells in the primary motor cortex and premotor cortex of primates to interfering and noninterfering tasks. The interfering tasks were visuomotor rotation followed by opposing visuomotor rotation. The noninterfering tasks were visuomotor rotation followed by an arbitrary association task. Learning two noninterfering tasks led to the simultaneous formation of neural activity typical of both tasks, at the level of single neurons. In contrast, and in accordance with behavioral results, after learning two interfering tasks, only the second task was successfully reflected in motor cortical single cell activity. These results support the hypothesis that the representational capacity of motor cortical cells is the basis of behavioral interference and division between internal models. PMID:22427923

Calcium Signaling in Intact Dorsal Root Ganglia

PubMed Central

Gemes, Geza; Rigaud, Marcel; Koopmeiners, Andrew S.; Poroli, Mark J.; Zoga, Vasiliki; Hogan, Quinn H.

2013-01-01

Background Ca2+ is the dominant second messenger in primary sensory neurons. In addition, disrupted Ca2+ signaling is a prominent feature in pain models involving peripheral nerve injury. Standard cytoplasmic Ca2+ recording techniques use high K+ or field stimulation and dissociated neurons. To compare findings in intact dorsal root ganglia, we used a method of simultaneous electrophysiologic and microfluorimetric recording. Methods Dissociated neurons were loaded by bath-applied Fura-2-AM and subjected to field stimulation. Alternatively, we adapted a technique in which neuronal somata of intact ganglia were loaded with Fura-2 through an intracellular microelectrode that provided simultaneous membrane potential recording during activation by action potentials (APs) conducted from attached dorsal roots. Results Field stimulation at levels necessary to activate neurons generated bath pH changes through electrolysis and failed to predictably drive neurons with AP trains. In the intact ganglion technique, single APs produced measurable Ca2+ transients that were fourfold larger in presumed nociceptive C-type neurons than in nonnociceptive Aβ-type neurons. Unitary Ca2+ transients summated during AP trains, forming transients with amplitudes that were highly dependent on stimulation frequency. Each neuron was tuned to a preferred frequency at which transient amplitude was maximal. Transients predominantly exhibited monoexponential recovery and had sustained plateaus during recovery only with trains of more than 100 APs. Nerve injury decreased Ca2+ transients in C-type neurons, but increased transients in Aβ-type neurons. Conclusions Refined observation of Ca2+ signaling is possible through natural activation by conducted APs in undissociated sensory neurons and reveals features distinct to neuronal types and injury state. PMID:20526180

Computing by robust transience: How the fronto-parietal network performs sequential category-based decisions

PubMed Central

Chaisangmongkon, Warasinee; Swaminathan, Sruthi K.; Freedman, David J.; Wang, Xiao-Jing

2017-01-01

Summary Decision making involves dynamic interplay between internal judgements and external perception, which has been investigated in delayed match-to-category (DMC) experiments. Our analysis of neural recordings shows that, during DMC tasks, LIP and PFC neurons demonstrate mixed, time-varying, and heterogeneous selectivity, but previous theoretical work has not established the link between these neural characteristics and population-level computations. We trained a recurrent network model to perform DMC tasks and found that the model can remarkably reproduce key features of neuronal selectivity at the single-neuron and population levels. Analysis of the trained networks elucidates that robust transient trajectories of the neural population are the key driver of sequential categorical decisions. The directions of trajectories are governed by network self-organized connectivity, defining a ‘neural landscape’, consisting of a task-tailored arrangement of slow states and dynamical tunnels. With this model, we can identify functionally-relevant circuit motifs and generalize the framework to solve other categorization tasks. PMID:28334612

Functional identification and reconstitution of an odorant receptor in single olfactory neurons

PubMed Central

Touhara, Kazushige; Sengoku, Shintaro; Inaki, Koichiro; Tsuboi, Akio; Hirono, Junzo; Sato, Takaaki; Sakano, Hitoshi; Haga, Tatsuya

1999-01-01

The olfactory system is remarkable in its capacity to discriminate a wide range of odorants through a series of transduction events initiated in olfactory receptor neurons. Each olfactory neuron is expected to express only a single odorant receptor gene that belongs to the G protein coupled receptor family. The ligand–receptor interaction, however, has not been clearly characterized. This study demonstrates the functional identification of olfactory receptor(s) for specific odorant(s) from single olfactory neurons by a combination of Ca2+-imaging and reverse transcription–coupled PCR analysis. First, a candidate odorant receptor was cloned from a single tissue-printed olfactory neuron that displayed odorant-induced Ca2+ increase. Next, recombinant adenovirus-mediated expression of the isolated receptor gene was established in the olfactory epithelium by using green fluorescent protein as a marker. The infected neurons elicited external Ca2+ entry when exposed to the odorant that originally was used to identify the receptor gene. Experiments performed to determine ligand specificity revealed that the odorant receptor recognized specific structural motifs within odorant molecules. The odorant receptor-mediated signal transduction appears to be reconstituted by this two-step approach: the receptor screening for given odorant(s) from single neurons and the functional expression of the receptor via recombinant adenovirus. The present approach should enable us to examine not only ligand specificity of an odorant receptor but also receptor specificity and diversity for a particular odorant of interest. PMID:10097159

Neural Correlates of Object-Associated Choice Behavior in the Perirhinal Cortex of Rats

PubMed Central

Ahn, Jae-Rong

2015-01-01

The perirhinal cortex (PRC) is reportedly important for object recognition memory, with supporting physiological evidence obtained largely from primate studies. Whether neurons in the rodent PRC also exhibit similar physiological correlates of object recognition, however, remains to be determined. We recorded single units from the PRC in a PRC-dependent, object-cued spatial choice task in which, when cued by an object image, the rat chose the associated spatial target from two identical discs appearing on a touchscreen monitor. The firing rates of PRC neurons were significantly modulated by critical events in the task, such as object sampling and choice response. Neuronal firing in the PRC was correlated primarily with the conjunctive relationships between an object and its associated choice response, although some neurons also responded to the choice response alone. However, we rarely observed a PRC neuron that represented a specific object exclusively regardless of spatial response in rats, although the neurons were influenced by the perceptual ambiguity of the object at the population level. Some PRC neurons fired maximally after a choice response, and this post-choice feedback signal significantly enhanced the neuronal specificity for the choice response in the subsequent trial. Our findings suggest that neurons in the rat PRC may not participate exclusively in object recognition memory but that their activity may be more dynamically modulated in conjunction with other variables, such as choice response and its outcomes. PMID:25632144

Sequence of neuron origin and neocortical laminar fate: relation to cell cycle of origin in the developing murine cerebral wall

NASA Technical Reports Server (NTRS)

Takahashi, T.; Goto, T.; Miyama, S.; Nowakowski, R. S.; Caviness, V. S. Jr

1999-01-01

Neurons destined for each region of the neocortex are known to arise approximately in an "inside-to-outside" sequence from a pseudostratified ventricular epithelium (PVE). This sequence is initiated rostrolaterally and propagates caudomedially. Moreover, independently of location in the PVE, the neuronogenetic sequence in mouse is divisible into 11 cell cycles that occur over a 6 d period. Here we use a novel "birth hour" method that identifies small cohorts of neurons born during a single 2 hr period, i.e., 10-20% of a single cell cycle, which corresponds to approximately 1.5% of the 6 d neuronogenetic period. This method shows that neurons arising with the same cycle of the 11 cycle sequence in mouse have common laminar fates even if they arise from widely separated positions on the PVE (neurons of fields 1 and 40) and therefore arise at different embryonic times. Even at this high level of temporal resolution, simultaneously arising cells occupy more than one cortical layer, and there is substantial overlap in the distributions of cells arising with successive cycles. We demonstrate additionally that the laminar representation of cells arising with a given cycle is little if at all modified over the early postnatal interval of histogenetic cell death. We infer from these findings that cell cycle is a neuronogenetic counting mechanism and that this counting mechanism is integral to subsequent processes that determine cortical laminar fate.

Uniting functional network topology and oscillations in the fronto-parietal single unit network of behaving primates

PubMed Central

Dann, Benjamin; Michaels, Jonathan A; Schaffelhofer, Stefan; Scherberger, Hansjörg

2016-01-01

The functional communication of neurons in cortical networks underlies higher cognitive processes. Yet, little is known about the organization of the single neuron network or its relationship to the synchronization processes that are essential for its formation. Here, we show that the functional single neuron network of three fronto-parietal areas during active behavior of macaque monkeys is highly complex. The network was closely connected (small-world) and consisted of functional modules spanning these areas. Surprisingly, the importance of different neurons to the network was highly heterogeneous with a small number of neurons contributing strongly to the network function (hubs), which were in turn strongly inter-connected (rich-club). Examination of the network synchronization revealed that the identified rich-club consisted of neurons that were synchronized in the beta or low frequency range, whereas other neurons were mostly non-oscillatory synchronized. Therefore, oscillatory synchrony may be a central communication mechanism for highly organized functional spiking networks. DOI: http://dx.doi.org/10.7554/eLife.15719.001 PMID:27525488

Synaptic and nonsynaptic plasticity approximating probabilistic inference

PubMed Central

Tully, Philip J.; Hennig, Matthias H.; Lansner, Anders

2014-01-01

Learning and memory operations in neural circuits are believed to involve molecular cascades of synaptic and nonsynaptic changes that lead to a diverse repertoire of dynamical phenomena at higher levels of processing. Hebbian and homeostatic plasticity, neuromodulation, and intrinsic excitability all conspire to form and maintain memories. But it is still unclear how these seemingly redundant mechanisms could jointly orchestrate learning in a more unified system. To this end, a Hebbian learning rule for spiking neurons inspired by Bayesian statistics is proposed. In this model, synaptic weights and intrinsic currents are adapted on-line upon arrival of single spikes, which initiate a cascade of temporally interacting memory traces that locally estimate probabilities associated with relative neuronal activation levels. Trace dynamics enable synaptic learning to readily demonstrate a spike-timing dependence, stably return to a set-point over long time scales, and remain competitive despite this stability. Beyond unsupervised learning, linking the traces with an external plasticity-modulating signal enables spike-based reinforcement learning. At the postsynaptic neuron, the traces are represented by an activity-dependent ion channel that is shown to regulate the input received by a postsynaptic cell and generate intrinsic graded persistent firing levels. We show how spike-based Hebbian-Bayesian learning can be performed in a simulated inference task using integrate-and-fire (IAF) neurons that are Poisson-firing and background-driven, similar to the preferred regime of cortical neurons. Our results support the view that neurons can represent information in the form of probability distributions, and that probabilistic inference could be a functional by-product of coupled synaptic and nonsynaptic mechanisms operating over several timescales. The model provides a biophysical realization of Bayesian computation by reconciling several observed neural phenomena whose functional effects are only partially understood in concert. PMID:24782758

Two-photon imaging and analysis of neural network dynamics

NASA Astrophysics Data System (ADS)

Lütcke, Henry; Helmchen, Fritjof

2011-08-01

The glow of a starry night sky, the smell of a freshly brewed cup of coffee or the sound of ocean waves breaking on the beach are representations of the physical world that have been created by the dynamic interactions of thousands of neurons in our brains. How the brain mediates perceptions, creates thoughts, stores memories and initiates actions remains one of the most profound puzzles in biology, if not all of science. A key to a mechanistic understanding of how the nervous system works is the ability to measure and analyze the dynamics of neuronal networks in the living organism in the context of sensory stimulation and behavior. Dynamic brain properties have been fairly well characterized on the microscopic level of individual neurons and on the macroscopic level of whole brain areas largely with the help of various electrophysiological techniques. However, our understanding of the mesoscopic level comprising local populations of hundreds to thousands of neurons (so-called 'microcircuits') remains comparably poor. Predominantly, this has been due to the technical difficulties involved in recording from large networks of neurons with single-cell spatial resolution and near-millisecond temporal resolution in the brain of living animals. In recent years, two-photon microscopy has emerged as a technique which meets many of these requirements and thus has become the method of choice for the interrogation of local neural circuits. Here, we review the state-of-research in the field of two-photon imaging of neuronal populations, covering the topics of microscope technology, suitable fluorescent indicator dyes, staining techniques, and in particular analysis techniques for extracting relevant information from the fluorescence data. We expect that functional analysis of neural networks using two-photon imaging will help to decipher fundamental operational principles of neural microcircuits.

Stimulus features coded by single neurons of a macaque body category selective patch.

PubMed

Popivanov, Ivo D; Schyns, Philippe G; Vogels, Rufin

2016-04-26

Body category-selective regions of the primate temporal cortex respond to images of bodies, but it is unclear which fragments of such images drive single neurons' responses in these regions. Here we applied the Bubbles technique to the responses of single macaque middle superior temporal sulcus (midSTS) body patch neurons to reveal the image fragments the neurons respond to. We found that local image fragments such as extremities (limbs), curved boundaries, and parts of the torso drove the large majority of neurons. Bubbles revealed the whole body in only a few neurons. Neurons coded the features in a manner that was tolerant to translation and scale changes. Most image fragments were excitatory but for a few neurons both inhibitory and excitatory fragments (opponent coding) were present in the same image. The fragments we reveal here in the body patch with Bubbles differ from those suggested in previous studies of face-selective neurons in face patches. Together, our data indicate that the majority of body patch neurons respond to local image fragments that occur frequently, but not exclusively, in bodies, with a coding that is tolerant to translation and scale. Overall, the data suggest that the body category selectivity of the midSTS body patch depends more on the feature statistics of bodies (e.g., extensions occur more frequently in bodies) than on semantics (bodies as an abstract category).

Investigating sub-spine actin dynamics in rat hippocampal neurons with super-resolution optical imaging.

PubMed

Tatavarty, Vedakumar; Kim, Eun-Ji; Rodionov, Vladimir; Yu, Ji

2009-11-09

Morphological changes in dendritic spines represent an important mechanism for synaptic plasticity which is postulated to underlie the vital cognitive phenomena of learning and memory. These morphological changes are driven by the dynamic actin cytoskeleton that is present in dendritic spines. The study of actin dynamics in these spines traditionally has been hindered by the small size of the spine. In this study, we utilize a photo-activation localization microscopy (PALM)-based single-molecule tracking technique to analyze F-actin movements with approximately 30-nm resolution in cultured hippocampal neurons. We were able to observe the kinematic (physical motion of actin filaments, i.e., retrograde flow) and kinetic (F-actin turn-over) dynamics of F-actin at the single-filament level in dendritic spines. We found that F-actin in dendritic spines exhibits highly heterogeneous kinematic dynamics at the individual filament level, with simultaneous actin flows in both retrograde and anterograde directions. At the ensemble level, movements of filaments integrate into a net retrograde flow of approximately 138 nm/min. These results suggest a weakly polarized F-actin network that consists of mostly short filaments in dendritic spines.

Chronic multiunit recordings in behaving animals: advantages and limitations.

PubMed

Supèr, Hans; Roelfsema, Pieter R

2005-01-01

By simultaneous recording from neural responses at many different loci at the same time, we can understand the interaction between neurons, and thereby gain insight into the network properties of neural processing, instead of the functioning of individual neurons. Here we will discuss a method for recording in behaving animals that uses chronically implanted micro-electrodes that allow one to track neural responses over a long period of time. In a majority of cases, multiunit activity, which is the aggregate spiking activity of a number of neurons in the vicinity of an electrode tip, is recorded through these electrodes, and occasionally single neurons can be isolated. Here we compare the properties of multiunit responses to the responses of single neurons in the primary visual cortex. We also discuss the advantages and disadvantages of the multiunit signal as opposed to a signal of single neurons. We demonstrate that multiunit recording provides a reliable and useful technique in cases where the neurons at the electrodes have similar response properties. Multiunit recording is therefore especially valuable when task variables have an effect that is consistent across the population of neurons. In the primary visual cortex, this is the case for figure-ground segregation and visual attention. Multiunit recording also has clear advantages for cross-correlation analysis. We show that the cross-correlation function between multiunit signals gives a reliable estimate of the average single-unit cross-correlation function. By the use of multiunit recording, it becomes much easier to detect relatively weak interactions between neurons at different cortical locations.

Brain Connectivity as a DNA Sequencing Problem

NASA Astrophysics Data System (ADS)

Zador, Anthony

The mammalian cortex consists of millions or billions of neurons, each connected to thousands of other neurons. Traditional methods for determining the brain connectivity rely on microscopy to visualize neuronal connections, but such methods are slow, labor-intensive and often lack single neuron resolution. We have recently developed a new method, MAPseq, to recast the determination of brain wiring into a form that can exploit the tremendous recent advances in high-throughput DNA sequencing. DNA sequencing technology has outpaced even Moore's law, so that the cost of sequencing the human genome has dropped from a billion dollars in 2001 to below a thousand dollars today. MAPseq works by introducing random sequences of DNA-``barcodes''-to tag neurons uniquely. With MAPseq, we can determine the connectivity of over 50K single neurons in a single mouse cortex in about a week, an unprecedented throughput, ushering in the era of ``big data'' for brain wiring. We are now developing analytical tools and algorithms to make sense of these novel data sets.

Dynamical state of the network determines the efficacy of single neuron properties in shaping the network activity

PubMed Central

Sahasranamam, Ajith; Vlachos, Ioannis; Aertsen, Ad; Kumar, Arvind

2016-01-01

Spike patterns are among the most common electrophysiological descriptors of neuron types. Surprisingly, it is not clear how the diversity in firing patterns of the neurons in a network affects its activity dynamics. Here, we introduce the state-dependent stochastic bursting neuron model allowing for a change in its firing patterns independent of changes in its input-output firing rate relationship. Using this model, we show that the effect of single neuron spiking on the network dynamics is contingent on the network activity state. While spike bursting can both generate and disrupt oscillations, these patterns are ineffective in large regions of the network state space in changing the network activity qualitatively. Finally, we show that when single-neuron properties are made dependent on the population activity, a hysteresis like dynamics emerges. This novel phenomenon has important implications for determining the network response to time-varying inputs and for the network sensitivity at different operating points. PMID:27212008

Dynamical state of the network determines the efficacy of single neuron properties in shaping the network activity.

PubMed

Sahasranamam, Ajith; Vlachos, Ioannis; Aertsen, Ad; Kumar, Arvind

2016-05-23

Spike patterns are among the most common electrophysiological descriptors of neuron types. Surprisingly, it is not clear how the diversity in firing patterns of the neurons in a network affects its activity dynamics. Here, we introduce the state-dependent stochastic bursting neuron model allowing for a change in its firing patterns independent of changes in its input-output firing rate relationship. Using this model, we show that the effect of single neuron spiking on the network dynamics is contingent on the network activity state. While spike bursting can both generate and disrupt oscillations, these patterns are ineffective in large regions of the network state space in changing the network activity qualitatively. Finally, we show that when single-neuron properties are made dependent on the population activity, a hysteresis like dynamics emerges. This novel phenomenon has important implications for determining the network response to time-varying inputs and for the network sensitivity at different operating points.

Enhanced polychronization in a spiking network with metaplasticity.

PubMed

Guise, Mira; Knott, Alistair; Benuskova, Lubica

2015-01-01

Computational models of metaplasticity have usually focused on the modeling of single synapses (Shouval et al., 2002). In this paper we study the effect of metaplasticity on network behavior. Our guiding assumption is that the primary purpose of metaplasticity is to regulate synaptic plasticity, by increasing it when input is low and decreasing it when input is high. For our experiments we adopt a model of metaplasticity that demonstrably has this effect for a single synapse; our primary interest is in how metaplasticity thus defined affects network-level phenomena. We focus on a network-level phenomenon called polychronicity, that has a potential role in representation and memory. A network with polychronicity has the ability to produce non-synchronous but precisely timed sequences of neural firing events that can arise from strongly connected groups of neurons called polychronous neural groups (Izhikevich et al., 2004). Polychronous groups (PNGs) develop readily when spiking networks are exposed to repeated spatio-temporal stimuli under the influence of spike-timing-dependent plasticity (STDP), but are sensitive to changes in synaptic weight distribution. We use a technique we have recently developed called Response Fingerprinting to show that PNGs formed in the presence of metaplasticity are significantly larger than those with no metaplasticity. A potential mechanism for this enhancement is proposed that links an inherent property of integrator type neurons called spike latency to an increase in the tolerance of PNG neurons to jitter in their inputs.

Color-tuned neurons are spatially clustered according to color preference within alert macaque posterior inferior temporal cortex

PubMed Central

Conway, Bevil R.; Tsao, Doris Y.

2009-01-01

Large islands of extrastriate cortex that are enriched for color-tuned neurons have recently been described in alert macaque using a combination of functional magnetic resonance imaging (fMRI) and single-unit recording. These millimeter-sized islands, dubbed “globs,” are scattered throughout the posterior inferior temporal cortex (PIT), a swath of brain anterior to area V3, including areas V4, PITd, and posterior TEO. We investigated the micro-organization of neurons within the globs. We used fMRI to identify the globs and then used MRI-guided microelectrodes to test the color properties of single glob cells. We used color stimuli that sample the CIELUV perceptual color space at regular intervals to test the color tuning of single units, and make two observations. First, color-tuned neurons of various color preferences were found within single globs. Second, adjacent glob cells tended to have the same color tuning, demonstrating that glob cells are clustered by color preference and suggesting that they are arranged in color columns. Neurons separated by 50 μm, measured parallel to the cortical sheet, had more similar color tuning than neurons separated by 100 μm, suggesting that the scale of the color columns is <100 μm. These results show that color-tuned neurons in PIT are organized by color preference on a finer scale than the scale of single globs. Moreover, the color preferences of neurons recorded sequentially along a given electrode penetration shifted gradually in many penetrations, suggesting that the color columns are arranged according to a chromotopic map reflecting perceptual color space. PMID:19805195

Afferent and motoneuron activity in response to single neuromast stimulation in the posterior lateral line of larval zebrafish

PubMed Central

Haehnel-Taguchi, Melanie; Akanyeti, Otar

2014-01-01

The lateral line system of fishes contains mechanosensory receptors along the body surface called neuromasts, which can detect water motion relative to the body. The ability to sense flow informs many behaviors, such as schooling, predator avoidance, and rheotaxis. Here, we developed a new approach to stimulate individual neuromasts while either recording primary sensory afferent neuron activity or swimming motoneuron activity in larval zebrafish (Danio rerio). Our results allowed us to characterize the transfer functions between a controlled lateral line stimulus, its representation by primary sensory neurons, and its subsequent behavioral output. When we deflected the cupula of a neuromast with a ramp command, we found that the connected afferent neuron exhibited an adapting response which was proportional in strength to deflection velocity. The maximum spike rate of afferent neurons increased sigmoidally with deflection velocity, with a linear range between 0.1 and 1.0 μm/ms. However, spike rate did not change when the cupula was deflected below 8 μm, regardless of deflection velocity. Our findings also reveal an unexpected sensitivity in the larval lateral line system: stimulation of a single neuromast could elicit a swimming response which increased in reliability with increasing deflection velocities. At high deflection velocities, we observed that lateral line evoked swimming has intermediate values of burst frequency and duty cycle that fall between electrically evoked and spontaneous swimming. An understanding of the sensory capabilities of a single neuromast will help to build a better picture of how stimuli are encoded at the systems level and ultimately translated into behavior. PMID:24966296

Large-scale recording of neuronal ensembles.

PubMed

Buzsáki, György

2004-05-01

How does the brain orchestrate perceptions, thoughts and actions from the spiking activity of its neurons? Early single-neuron recording research treated spike pattern variability as noise that needed to be averaged out to reveal the brain's representation of invariant input. Another view is that variability of spikes is centrally coordinated and that this brain-generated ensemble pattern in cortical structures is itself a potential source of cognition. Large-scale recordings from neuronal ensembles now offer the opportunity to test these competing theoretical frameworks. Currently, wire and micro-machined silicon electrode arrays can record from large numbers of neurons and monitor local neural circuits at work. Achieving the full potential of massively parallel neuronal recordings, however, will require further development of the neuron-electrode interface, automated and efficient spike-sorting algorithms for effective isolation and identification of single neurons, and new mathematical insights for the analysis of network properties.

Multiscale modeling of brain dynamics: from single neurons and networks to mathematical tools.

PubMed

Siettos, Constantinos; Starke, Jens

2016-09-01

The extreme complexity of the brain naturally requires mathematical modeling approaches on a large variety of scales; the spectrum ranges from single neuron dynamics over the behavior of groups of neurons to neuronal network activity. Thus, the connection between the microscopic scale (single neuron activity) to macroscopic behavior (emergent behavior of the collective dynamics) and vice versa is a key to understand the brain in its complexity. In this work, we attempt a review of a wide range of approaches, ranging from the modeling of single neuron dynamics to machine learning. The models include biophysical as well as data-driven phenomenological models. The discussed models include Hodgkin-Huxley, FitzHugh-Nagumo, coupled oscillators (Kuramoto oscillators, Rössler oscillators, and the Hindmarsh-Rose neuron), Integrate and Fire, networks of neurons, and neural field equations. In addition to the mathematical models, important mathematical methods in multiscale modeling and reconstruction of the causal connectivity are sketched. The methods include linear and nonlinear tools from statistics, data analysis, and time series analysis up to differential equations, dynamical systems, and bifurcation theory, including Granger causal connectivity analysis, phase synchronization connectivity analysis, principal component analysis (PCA), independent component analysis (ICA), and manifold learning algorithms such as ISOMAP, and diffusion maps and equation-free techniques. WIREs Syst Biol Med 2016, 8:438-458. doi: 10.1002/wsbm.1348 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.

Stimulus encoding and feature extraction by multiple sensory neurons.

PubMed

Krahe, Rüdiger; Kreiman, Gabriel; Gabbiani, Fabrizio; Koch, Christof; Metzner, Walter

2002-03-15

Neighboring cells in topographical sensory maps may transmit similar information to the next higher level of processing. How information transmission by groups of nearby neurons compares with the performance of single cells is a very important question for understanding the functioning of the nervous system. To tackle this problem, we quantified stimulus-encoding and feature extraction performance by pairs of simultaneously recorded electrosensory pyramidal cells in the hindbrain of weakly electric fish. These cells constitute the output neurons of the first central nervous stage of electrosensory processing. Using random amplitude modulations (RAMs) of a mimic of the fish's own electric field within behaviorally relevant frequency bands, we found that pyramidal cells with overlapping receptive fields exhibit strong stimulus-induced correlations. To quantify the encoding of the RAM time course, we estimated the stimuli from simultaneously recorded spike trains and found significant improvements over single spike trains. The quality of stimulus reconstruction, however, was still inferior to the one measured for single primary sensory afferents. In an analysis of feature extraction, we found that spikes of pyramidal cell pairs coinciding within a time window of a few milliseconds performed significantly better at detecting upstrokes and downstrokes of the stimulus compared with isolated spikes and even spike bursts of single cells. Coincident spikes can thus be considered "distributed bursts." Our results suggest that stimulus encoding by primary sensory afferents is transformed into feature extraction at the next processing stage. There, stimulus-induced coincident activity can improve the extraction of behaviorally relevant features from the stimulus.

Time-lapse imaging of p65 and IκBα translocation kinetics following Ca2+-induced neuronal injury reveals biphasic translocation kinetics in surviving neurons.

PubMed

Schwamborn, Robert; Düssmann, Heiko; König, Hans-Georg; Prehn, Jochen H M

2017-04-01

The transcription factor nuclear factor-κB (NF-κB) regulates neuronal differentiation, plasticity and survival. It is well established that excitatory neurotransmitters such as glutamate control NF-κB activity. Glutamate receptor overactivation is also involved in ischemic- and seizure-induced neuronal injury and neurodegeneration. However, little is known at the single cell-level how NF-κB signaling relates to neuronal survival during excitotoxic injury. We found that silencing of p65/NF-κB delayed N-methyl-d-aspartate (NMDA)-induced excitotoxic injury in hippocampal neurons, suggesting a functional role of p65 in excitotoxicity. Time-lapse imaging of p65 and its inhibitor IκBα using GFP and Cerulean fusion proteins revealed specific patterns of excitotoxic NF-κB activation. Nuclear translocation of p65 began on average 8±3min following 15min of NMDA treatment and was observed in up to two thirds of hippocampal neurons. Nuclear translocation of IκBα preceded that of p65 suggesting independent translocation processes. In surviving neurons, the onset of p65 nuclear export correlated with mitochondrial membrane potential recovery. Dying neurons exhibited persistent nuclear accumulation of p65-eGFP until plasma membrane permeabilization. Our data demonstrate an important role for p65 activation kinetics in neuronal cell death decisions following excitotoxic injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Involvement of Infralimbic Prefrontal Cortex but not Lateral Habenula in Dopamine Attenuation After Chronic Mild Stress.

PubMed

Moreines, Jared L; Owrutsky, Zoe L; Grace, Anthony A

2017-03-01

Emerging evidence supports a role for dopamine in major depressive disorder (MDD). We recently reported fewer spontaneously active ventral tegmental area (VTA) dopamine neurons (ie, reduced dopamine neuron population activity) in the chronic mild stress (CMS) rodent model of MDD. In this study, we examined the role of two brain regions that have been implicated in MDD in humans, the infralimbic prefrontal cortex (ILPFC)-that is, rodent homolog of Brodmann area 25 (BA25), and the lateral habenula (LHb) in the CMS-induced attenuation of dopamine neuron activity. The impact of activating the ILPFC or LHb was evaluated using single-unit extracellular recordings of identified VTA dopamine neurons. The involvement of each region in dopamine neuron attenuation following 5-7 weeks of CMS was then evaluated by selective inactivation. Activation of either ILPFC or LHb in normal rats potently suppressed dopamine neuron population activity, but in unique patterns. ILPFC activation selectively inhibited dopamine neurons in medial VTA, which were most impacted by CMS. Conversely, LHb activation selectively inhibited dopamine neurons in lateral VTA, which were unaffected by CMS. Moreover, only ILPFC inactivation restored dopamine neuron population activity to normal levels following CMS; LHb inactivation had no restorative effect. These data suggest that, in the CMS model of MDD, the ILPFC is the primary driver of diminished dopamine neuron responses. These findings support a neural substrate for ILPFC/BA25 linking affective and motivational circuitry dysfunction in MDD.

A Unifying Mechanistic Model of Selective Attention in Spiking Neurons

PubMed Central

Bobier, Bruce; Stewart, Terrence C.; Eliasmith, Chris

2014-01-01

Visuospatial attention produces myriad effects on the activity and selectivity of cortical neurons. Spiking neuron models capable of reproducing a wide variety of these effects remain elusive. We present a model called the Attentional Routing Circuit (ARC) that provides a mechanistic description of selective attentional processing in cortex. The model is described mathematically and implemented at the level of individual spiking neurons, with the computations for performing selective attentional processing being mapped to specific neuron types and laminar circuitry. The model is used to simulate three studies of attention in macaque, and is shown to quantitatively match several observed forms of attentional modulation. Specifically, ARC demonstrates that with shifts of spatial attention, neurons may exhibit shifting and shrinking of receptive fields; increases in responses without changes in selectivity for non-spatial features (i.e. response gain), and; that the effect on contrast-response functions is better explained as a response-gain effect than as contrast-gain. Unlike past models, ARC embodies a single mechanism that unifies the above forms of attentional modulation, is consistent with a wide array of available data, and makes several specific and quantifiable predictions. PMID:24921249

Endogenous Sequential Cortical Activity Evoked by Visual Stimuli

PubMed Central

Miller, Jae-eun Kang; Hamm, Jordan P.; Jackson, Jesse; Yuste, Rafael

2015-01-01

Although the functional properties of individual neurons in primary visual cortex have been studied intensely, little is known about how neuronal groups could encode changing visual stimuli using temporal activity patterns. To explore this, we used in vivo two-photon calcium imaging to record the activity of neuronal populations in primary visual cortex of awake mice in the presence and absence of visual stimulation. Multidimensional analysis of the network activity allowed us to identify neuronal ensembles defined as groups of cells firing in synchrony. These synchronous groups of neurons were themselves activated in sequential temporal patterns, which repeated at much higher proportions than chance and were triggered by specific visual stimuli such as natural visual scenes. Interestingly, sequential patterns were also present in recordings of spontaneous activity without any sensory stimulation and were accompanied by precise firing sequences at the single-cell level. Moreover, intrinsic dynamics could be used to predict the occurrence of future neuronal ensembles. Our data demonstrate that visual stimuli recruit similar sequential patterns to the ones observed spontaneously, consistent with the hypothesis that already existing Hebbian cell assemblies firing in predefined temporal sequences could be the microcircuit substrate that encodes visual percepts changing in time. PMID:26063915

Short- and long-term memory in Drosophila require cAMP signaling in distinct neuron types.

PubMed

Blum, Allison L; Li, Wanhe; Cressy, Mike; Dubnau, Josh

2009-08-25

A common feature of memory and its underlying synaptic plasticity is that each can be dissected into short-lived forms involving modification or trafficking of existing proteins and long-term forms that require new gene expression. An underlying assumption of this cellular view of memory consolidation is that these different mechanisms occur within a single neuron. At the neuroanatomical level, however, different temporal stages of memory can engage distinct neural circuits, a notion that has not been conceptually integrated with the cellular view. Here, we investigated this issue in the context of aversive Pavlovian olfactory memory in Drosophila. Previous studies have demonstrated a central role for cAMP signaling in the mushroom body (MB). The Ca(2+)-responsive adenylyl cyclase RUTABAGA is believed to be a coincidence detector in gamma neurons, one of the three principle classes of MB Kenyon cells. We were able to separately restore short-term or long-term memory to a rutabaga mutant with expression of rutabaga in different subsets of MB neurons. Our findings suggest a model in which the learning experience initiates two parallel associations: a short-lived trace in MB gamma neurons, and a long-lived trace in alpha/beta neurons.

Segmental neuropathic pain does not develop in male rats with complete spinal transections.

PubMed

Hubscher, Charles H; Kaddumi, Ezidin G; Johnson, Richard D

2008-10-01

In a previous study using male rats, a correlation was found between the development of "at-level" allodynia in T6-7 dermatomes following severe T8 spinal contusion injury and the sparing of some myelinated axons within the core of the lesion epicenter. To further test our hypothesis that this sparing is important for the expression of allodynia and the supraspinal plasticity that ensues, an injury that severs all axons (i.e., a complete spinal cord transection) was made in 15 male rats. Behavioral assessments were done at level throughout the 30-day recovery period followed by terminal electrophysiological recordings (urethane anesthesia) from single medullary reticular formation (MRF) neurons receiving convergent nociceptive inputs from receptive fields above, at, and below the lesion level. None of the rats developed signs of at-level allodynia (versus 18 of 26 male rats following severe contusion). However, the terminal recording (206 MRF neurons) data resembled those obtained previously post-contusion. That is, there was evidence of neuronal hyper-excitability (relative to previous data from intact controls) to high- and low-threshold mechanical stimulation for "at-level" (dorsal trunk) and "above-level" (eyelids and face) cutaneous territories. These results, when combined with prior data on intact controls and severe/moderate contusions, indicate that (1) an anatomically incomplete injury (some lesion epicenter axonal sparing) following severe contusion is likely important for the development of allodynia and (2) the neuronal hyper-excitability at the level of the medulla is likely involved in nociceptive processes that are not directly related to the conscious expression of pain-like avoidance behaviors that are being used as evidence of allodynia.

Molecular determinants of magnesium-dependent synaptic plasticity at electrical synapses formed by connexin36

NASA Astrophysics Data System (ADS)

Palacios-Prado, Nicolás; Chapuis, Sandrine; Panjkovich, Alejandro; Fregeac, Julien; Nagy, James I.; Bukauskas, Feliksas F.

2014-08-01

Neuronal gap junction (GJ) channels composed of connexin36 (Cx36) play an important role in neuronal synchronization and network dynamics. Here we show that Cx36-containing electrical synapses between inhibitory neurons of the thalamic reticular nucleus are bidirectionally modulated by changes in intracellular free magnesium concentration ([Mg2+]i). Chimeragenesis demonstrates that the first extracellular loop of Cx36 contains a Mg2+-sensitive domain, and site-directed mutagenesis shows that the pore-lining residue D47 is critical in determining high Mg2+-sensitivity. Single-channel analysis of Mg2+-sensitive chimeras and mutants reveals that [Mg2+]i controls the strength of electrical coupling mostly via gating mechanisms. In addition, asymmetric transjunctional [Mg2+]i induces strong instantaneous rectification, providing a novel mechanism for electrical rectification in homotypic Cx36 GJs. We suggest that Mg2+-dependent synaptic plasticity of Cx36-containing electrical synapses could underlie neuronal circuit reconfiguration via changes in brain energy metabolism that affects neuronal levels of intracellular ATP and [Mg2+]i.

Cortical pyramidal cells as non-linear oscillators: experiment and spike-generation theory.

PubMed

Brumberg, Joshua C; Gutkin, Boris S

2007-09-26

Cortical neurons are capable of generating trains of action potentials in response to current injections. These discharges can take different forms, e.g., repetitive firing that adapts during the period of current injection or bursting behaviors. We have used a combined experimental and computational approach to characterize the dynamics leading to action potential responses in single neurons. Specifically we investigated the origin of complex firing patterns in response to sinusoidal current injections. Using a reduced model, the theta-neuron, alongside recordings from cortical pyramidal cells we show that both real and simulated neurons show phase-locking to sine wave stimuli up to a critical frequency, above which period skipping and 1-to-x phase-locking occurs. The locking behavior follows a complex "devil's staircase" phenomena, where locked modes are interleaved with irregular firing. We further show that the critical frequency depends on the time scale of spike generation and on the level of spike frequency adaptation. These results suggest that phase-locking of neuronal responses to complex input patterns can be explained by basic properties of the spike-generating machinery.

Genetically encoded proton sensors reveal activity-dependent pH changes in neurons.

PubMed

Raimondo, Joseph V; Irkle, Agnese; Wefelmeyer, Winnie; Newey, Sarah E; Akerman, Colin J

2012-01-01

The regulation of hydrogen ion concentration (pH) is fundamental to cell viability, metabolism, and enzymatic function. Within the nervous system, the control of pH is also involved in diverse and dynamic processes including development, synaptic transmission, and the control of network excitability. As pH affects neuronal activity, and can also itself be altered by neuronal activity, the existence of tools to accurately measure hydrogen ion fluctuations is important for understanding the role pH plays under physiological and pathological conditions. Outside of their use as a marker of synaptic release, genetically encoded pH sensors have not been utilized to study hydrogen ion fluxes associated with network activity. By combining whole-cell patch clamp with simultaneous two-photon or confocal imaging, we quantified the amplitude and time course of neuronal, intracellular, acidic transients evoked by epileptiform activity in two separate in vitro models of temporal lobe epilepsy. In doing so, we demonstrate the suitability of three genetically encoded pH sensors: deGFP4, E(2)GFP, and Cl-sensor for investigating activity-dependent pH changes at the level of single neurons.

Molecular Determinants of Magnesium-Dependent Synaptic Plasticity at Electrical Synapses Formed by Connexin36

PubMed Central

Palacios-Prado, Nicolás; Chapuis, Sandrine; Panjkovich, Alejandro; Fregeac, Julien; Nagy, James I.; Bukauskas, Feliksas F.

2014-01-01

Neuronal gap junction (GJ) channels composed of connexin36 (Cx36) play an important role in neuronal synchronization and network dynamics. Here we show that Cx36-containing electrical synapses between inhibitory neurons of the thalamic reticular nucleus are bi-directionally modulated by changes in intracellular free magnesium concentration ([Mg2+]i). Chimeragenesis demonstrates that the first extracellular loop of Cx36 contains a Mg2+-sensitive domain, and site-directed mutagenesis shows that the pore-lining residue D47 is critical in determining high Mg2+-sensitivity. Single channel analysis of Mg2+-sensitive chimeras and mutants reveals that [Mg2+]i controls the strength of electrical coupling mostly via gating mechanisms. In addition, asymmetric transjunctional [Mg2+]i induces strong instantaneous rectification, providing a novel mechanism for electrical rectification in homotypic Cx36 GJs. We suggest that Mg2+-dependent synaptic plasticity of Cx36-containing electrical synapses could underlie neuronal circuit reconfiguration via changes in brain energy metabolism that affects neuronal levels of intracellular ATP and [Mg2+]i. PMID:25135336

I-123 iomazenil single photon emission computed tomography for detecting loss of neuronal integrity in patients with traumatic brain injury.

PubMed

Abiko, Kagari; Ikoma, Katsunori; Shiga, Tohru; Katoh, Chietsugu; Hirata, Kenji; Kuge, Yuji; Kobayashi, Kentaro; Tamaki, Nagara

2017-12-01

Traumatic brain injury (TBI) causes brain dysfunction in many patients. Using C-11 flumazenil (FMZ) positron emission tomography (PET), we have detected and reported the loss of neuronal integrity, leading to brain dysfunction in TBI patients. Similarly to FMZ PET, I-123 iomazenil (IMZ) single photon emission computed tomography (SPECT) is widely used to determine the distribution of the benzodiazepine receptor (BZR) in the brain cortex. The purpose of this study is to examine whether IMZ SPECT is as useful as FMZ PET for evaluating the loss of neuronal integrity in TBI patients. The subjects of this study were seven patients who suffered from neurobehavioral disability. They underwent IMZ SPECT and FMZ PET. Nondisplaceable binding potential (BP ND ) was calculated from FMZ PET images. The uptake of IMZ was evaluated on the basis of lesion-to-pons ratio (LPR). The locations of low uptake levels were visually evaluated both in IMZ SPECT and FMZ PET images. We compared FMZ BP ND and (LPR-1) of IMZ SPECT. In the visual assessment, FMZ BP ND decreased in 11 regions. In IMZ SPECT, low uptake levels were observed in eight of the 11 regions. The rate of concordance between FMZ PET and IMZ SPECT was 72.7%. The mean values IMZ (LPR-1) (1.95 ± 1.01) was significantly lower than that of FMZ BP ND (2.95 ± 0.80 mL/mL). There was good correlation between FMZ BP ND and IMZ (LPR-1) (r = 0.80). IMZ SPECT findings were almost the same as FMZ PET findings in TBI patients. The results indicated that IMZ SPECT is useful for evaluating the loss of neuronal integrity. Because IMZ SPECT can be performed in various facilities, IMZ SPECT may become widely adopted for evaluating the loss of neuronal integrity.

Sensation in a single neuron pair represses male behavior in hermaphrodites

PubMed Central

White, Jamie Q.; Jorgensen, Erik M.

2012-01-01

Summary Pheromones elicit innate sex-specific mating behaviors in many species. We demonstrate that in C. elegans, male-specific sexual attraction behavior is programmed in both sexes but repressed in hermaphrodites. Repression requires a single sensory neuron pair, the ASIs. To represses attraction in adults, the ASIs must be present, active, and capable of sensing the environment during development. The ASIs release TGF-β, and ASI function can be bypassed by experimental activation of TGF-β signaling. Sexual attraction in de-repressed hermaphrodites requires the same sensory neurons as in males. The sexual identity of both these sensory neurons and a distinct subset of interneurons must be male to relieve repression and release attraction. TGF-β may therefore act to change connections between sensory- and interneurons during development to engage repression. Thus, sensation in a single sensory neuron pair during development reprograms a common neural circuit from male to female behavior. PMID:22920252

Astrocytes express specific variants of CaM KII delta and gamma, but not alpha and beta, that determine their cellular localizations.

PubMed

Vallano, M L; Beaman-Hall, C M; Mathur, A; Chen, Q

2000-04-01

Multiple isoforms of type II Ca(2+)-calmodulin-dependent kinase (CaM KII) are composed of two major neuron-specific subunits, designated alpha and beta, and two less well-characterized subunits that are also expressed in non-neuronal tissues, designated delta and gamma. Regulated expression of these 4 gene products, and several variants produced by alternative splicing, shows temporal and regional specificity and influences intracellular targeting. We used immunoblotting and RT-PCR to analyze subunit and variant expression and distribution in cultured cerebellar astrocytes and neurons, and whole cerebellar cortex from rodent brain. The data indicate that: (i) astrocytes express a single splice variant of delta, namely delta(2); (ii) like neurons, astrocytes express two forms of CaM KII gamma; gamma(B) and gamma(A); (iii) these CaM KII variants are enriched in the supernate fraction in astrocytes, and the particulate fraction in neurons; (iv) unlike neurons, astrocytes do not express detectable levels of alpha or beta subunits or their respective splice variants. The results indicate that neurons and astrocytes express distinct CaM KII subunits and variants that localize to distinct subcellular compartments and, by inference, exert distinct cellular functions. Copyright 2000 Wiley-Liss, Inc.

Multiple functional attributes of glucose-monitoring neurons in the medial orbitofrontal (ventrolateral prefrontal) cortex.

PubMed

Szabó, István; Hormay, Edina; Csetényi, Bettina; Nagy, Bernadett; Lénárd, László; Karádi, Zoltán

2018-02-01

Multiple functional attributes of glucose-monitoring neurons in the medial orbitofrontal (ventrolateral prefrontal) cortex. NEUROSCI BIOBEHAV REV 73(1) XXX-XXX, 2017.- Special chemosensory cells, the glucose-monitoring (GM) neurons, reportedly involved in the central feeding control, exist in the medial orbitofrontal (ventrolateral prefrontal) cortex (mVLPFC). Electrophysiological, metabolic and behavioral studies reveal complex functional attributes of these cells and raise their homeostatic significance. Single neuron recordings, by means of the multibarreled microelectrophoretic technique, elucidate differential sensitivities of limbic forebrain neurons in the rat and the rhesus monkey to glucose and other chemicals, whereas gustatory stimulations demonstrate their distinct taste responsiveness. Metabolic examinations provide evidence for alteration of blood glucose level in glucose tolerance test and elevation of plasma triglyceride concentration after destruction of the local GM cells by streptozotocin (STZ). In behavioral studies, STZ microinjection into the mVLPFC fails to interfere with the acquisition of saccharin conditioned taste avoidance, does cause, however, taste perception deficit in taste reactivity tests. Multiple functional attributes of GM neurons in the mVLPFC, within the frame of the hierarchically organized central GM neuronal network, appear to play important role in the maintenance of the homeostatic balance. Copyright © 2017 Elsevier Ltd. All rights reserved.

Differential Activation of Fast-Spiking and Regular-Firing Neuron Populations During Movement and Reward in the Dorsal Medial Frontal Cortex

PubMed Central

Insel, Nathan; Barnes, Carol A.

2015-01-01

The medial prefrontal cortex is thought to be important for guiding behavior according to an animal's expectations. Efforts to decode the region have focused not only on the question of what information it computes, but also how distinct circuit components become engaged during behavior. We find that the activity of regular-firing, putative projection neurons contains rich information about behavioral context and firing fields cluster around reward sites, while activity among putative inhibitory and fast-spiking neurons is most associated with movement and accompanying sensory stimulation. These dissociations were observed even between adjacent neurons with apparently reciprocal, inhibitory–excitatory connections. A smaller population of projection neurons with burst-firing patterns did not show clustered firing fields around rewards; these neurons, although heterogeneous, were generally less selective for behavioral context than regular-firing cells. The data suggest a network that tracks an animal's behavioral situation while, at the same time, regulating excitation levels to emphasize high valued positions. In this scenario, the function of fast-spiking inhibitory neurons is to constrain network output relative to incoming sensory flow. This scheme could serve as a bridge between abstract sensorimotor information and single-dimensional codes for value, providing a neural framework to generate expectations from behavioral state. PMID:24700585

Fuzzy decoupling controller based on multimode control algorithm of PI-single neuron and its application

NASA Astrophysics Data System (ADS)

Zhang, Xianxia; Wang, Jian; Qin, Tinggao

2003-09-01

Intelligent control algorithms are introduced into the control system of temperature and humidity. A multi-mode control algorithm of PI-Single Neuron is proposed for single loop control of temperature and humidity. In order to remove the coupling between temperature and humidity, a new decoupling method is presented, which is called fuzzy decoupling. The decoupling is achieved by using a fuzzy controller that dynamically modifies the static decoupling coefficient. Taking the control algorithm of PI-Single Neuron as the single loop control of temperature and humidity, the paper provides the simulated output response curves with no decoupling control, static decoupling control and fuzzy decoupling control. Those control algorithms are easily implemented in singlechip-based hardware systems.

Reward-timing-dependent bidirectional modulation of cortical microcircuits during optical single-neuron operant conditioning.

PubMed

Hira, Riichiro; Ohkubo, Fuki; Masamizu, Yoshito; Ohkura, Masamichi; Nakai, Junichi; Okada, Takashi; Matsuzaki, Masanori

2014-11-24

Animals rapidly adapt to environmental change. To reveal how cortical microcircuits are rapidly reorganized when an animal recognizes novel reward contingency, we conduct two-photon calcium imaging of layer 2/3 motor cortex neurons in mice and simultaneously reinforce the activity of a single cortical neuron with water delivery. Here we show that when the target neuron is not relevant to a pre-trained forelimb movement, the mouse increases the target neuron activity and the number of rewards delivered during 15-min operant conditioning without changing forelimb movement behaviour. The reinforcement bidirectionally modulates the activity of subsets of non-target neurons, independent of distance from the target neuron. The bidirectional modulation depends on the relative timing between the reward delivery and the neuronal activity, and is recreated by pairing reward delivery and photoactivation of a subset of neurons. Reward-timing-dependent bidirectional modulation may be one of the fundamental processes in microcircuit reorganization for rapid adaptation.

Localized electrical stimulation of in vitro neurons using an array of sub-cellular sized electrodes.

PubMed

Braeken, Dries; Huys, Roeland; Loo, Josine; Bartic, Carmen; Borghs, Gustaaf; Callewaert, Geert; Eberle, Wolfgang

2010-12-15

The investigation of single-neuron parameters is of great interest because many aspects in the behavior and communication of neuronal networks still remain unidentified. However, the present available techniques for single-cell measurements are slow and do not allow for a high-throughput approach. We present here a CMOS compatible microelectrode array with 84 electrodes (with diameters ranging from 1.2 to 4.2 μm) that are smaller than the size of cell, thereby supporting single-cell addressability. We show controllable electroporation of a single cell by an underlying electrode while monitoring changes in the intracellular membrane potential. Further, by applying a localized electrical field between two electrodes close to a neuron while recording changes in the intracellular calcium concentration, we demonstrate activation of a single cell (∼270%, DF/F(0)), followed by a network response of the neighboring cells. The technology can be easily scaled up to larger electrode arrays (theoretically up to 137,000 electrodes/mm(2)) with active CMOS electronics integration able to perform high-throughput measurements on single cells. Copyright © 2010 Elsevier B.V. All rights reserved.

Neuromorphic neural interfaces: from neurophysiological inspiration to biohybrid coupling with nervous systems

NASA Astrophysics Data System (ADS)

Broccard, Frédéric D.; Joshi, Siddharth; Wang, Jun; Cauwenberghs, Gert

2017-08-01

Objective. Computation in nervous systems operates with different computational primitives, and on different hardware, than traditional digital computation and is thus subjected to different constraints from its digital counterpart regarding the use of physical resources such as time, space and energy. In an effort to better understand neural computation on a physical medium with similar spatiotemporal and energetic constraints, the field of neuromorphic engineering aims to design and implement electronic systems that emulate in very large-scale integration (VLSI) hardware the organization and functions of neural systems at multiple levels of biological organization, from individual neurons up to large circuits and networks. Mixed analog/digital neuromorphic VLSI systems are compact, consume little power and operate in real time independently of the size and complexity of the model. Approach. This article highlights the current efforts to interface neuromorphic systems with neural systems at multiple levels of biological organization, from the synaptic to the system level, and discusses the prospects for future biohybrid systems with neuromorphic circuits of greater complexity. Main results. Single silicon neurons have been interfaced successfully with invertebrate and vertebrate neural networks. This approach allowed the investigation of neural properties that are inaccessible with traditional techniques while providing a realistic biological context not achievable with traditional numerical modeling methods. At the network level, populations of neurons are envisioned to communicate bidirectionally with neuromorphic processors of hundreds or thousands of silicon neurons. Recent work on brain-machine interfaces suggests that this is feasible with current neuromorphic technology. Significance. Biohybrid interfaces between biological neurons and VLSI neuromorphic systems of varying complexity have started to emerge in the literature. Primarily intended as a computational tool for investigating fundamental questions related to neural dynamics, the sophistication of current neuromorphic systems now allows direct interfaces with large neuronal networks and circuits, resulting in potentially interesting clinical applications for neuroengineering systems, neuroprosthetics and neurorehabilitation.

1D-3D hybrid modeling-from multi-compartment models to full resolution models in space and time.

PubMed

Grein, Stephan; Stepniewski, Martin; Reiter, Sebastian; Knodel, Markus M; Queisser, Gillian

2014-01-01

Investigation of cellular and network dynamics in the brain by means of modeling and simulation has evolved into a highly interdisciplinary field, that uses sophisticated modeling and simulation approaches to understand distinct areas of brain function. Depending on the underlying complexity, these models vary in their level of detail, in order to cope with the attached computational cost. Hence for large network simulations, single neurons are typically reduced to time-dependent signal processors, dismissing the spatial aspect of each cell. For single cell or networks with relatively small numbers of neurons, general purpose simulators allow for space and time-dependent simulations of electrical signal processing, based on the cable equation theory. An emerging field in Computational Neuroscience encompasses a new level of detail by incorporating the full three-dimensional morphology of cells and organelles into three-dimensional, space and time-dependent, simulations. While every approach has its advantages and limitations, such as computational cost, integrated and methods-spanning simulation approaches, depending on the network size could establish new ways to investigate the brain. In this paper we present a hybrid simulation approach, that makes use of reduced 1D-models using e.g., the NEURON simulator-which couples to fully resolved models for simulating cellular and sub-cellular dynamics, including the detailed three-dimensional morphology of neurons and organelles. In order to couple 1D- and 3D-simulations, we present a geometry-, membrane potential- and intracellular concentration mapping framework, with which graph- based morphologies, e.g., in the swc- or hoc-format, are mapped to full surface and volume representations of the neuron and computational data from 1D-simulations can be used as boundary conditions for full 3D simulations and vice versa. Thus, established models and data, based on general purpose 1D-simulators, can be directly coupled to the emerging field of fully resolved, highly detailed 3D-modeling approaches. We present the developed general framework for 1D/3D hybrid modeling and apply it to investigate electrically active neurons and their intracellular spatio-temporal calcium dynamics.

1D-3D hybrid modeling—from multi-compartment models to full resolution models in space and time

PubMed Central

Grein, Stephan; Stepniewski, Martin; Reiter, Sebastian; Knodel, Markus M.; Queisser, Gillian

2014-01-01

Investigation of cellular and network dynamics in the brain by means of modeling and simulation has evolved into a highly interdisciplinary field, that uses sophisticated modeling and simulation approaches to understand distinct areas of brain function. Depending on the underlying complexity, these models vary in their level of detail, in order to cope with the attached computational cost. Hence for large network simulations, single neurons are typically reduced to time-dependent signal processors, dismissing the spatial aspect of each cell. For single cell or networks with relatively small numbers of neurons, general purpose simulators allow for space and time-dependent simulations of electrical signal processing, based on the cable equation theory. An emerging field in Computational Neuroscience encompasses a new level of detail by incorporating the full three-dimensional morphology of cells and organelles into three-dimensional, space and time-dependent, simulations. While every approach has its advantages and limitations, such as computational cost, integrated and methods-spanning simulation approaches, depending on the network size could establish new ways to investigate the brain. In this paper we present a hybrid simulation approach, that makes use of reduced 1D-models using e.g., the NEURON simulator—which couples to fully resolved models for simulating cellular and sub-cellular dynamics, including the detailed three-dimensional morphology of neurons and organelles. In order to couple 1D- and 3D-simulations, we present a geometry-, membrane potential- and intracellular concentration mapping framework, with which graph- based morphologies, e.g., in the swc- or hoc-format, are mapped to full surface and volume representations of the neuron and computational data from 1D-simulations can be used as boundary conditions for full 3D simulations and vice versa. Thus, established models and data, based on general purpose 1D-simulators, can be directly coupled to the emerging field of fully resolved, highly detailed 3D-modeling approaches. We present the developed general framework for 1D/3D hybrid modeling and apply it to investigate electrically active neurons and their intracellular spatio-temporal calcium dynamics. PMID:25120463

Multiple fMRI system-level baseline connectivity is disrupted in patients with consciousness alterations.

PubMed

Demertzi, Athena; Gómez, Francisco; Crone, Julia Sophia; Vanhaudenhuyse, Audrey; Tshibanda, Luaba; Noirhomme, Quentin; Thonnard, Marie; Charland-Verville, Vanessa; Kirsch, Murielle; Laureys, Steven; Soddu, Andrea

2014-03-01

In healthy conditions, group-level fMRI resting state analyses identify ten resting state networks (RSNs) of cognitive relevance. Here, we aim to assess the ten-network model in severely brain-injured patients suffering from disorders of consciousness and to identify those networks which will be most relevant to discriminate between patients and healthy subjects. 300 fMRI volumes were obtained in 27 healthy controls and 53 patients in minimally conscious state (MCS), vegetative state/unresponsive wakefulness syndrome (VS/UWS) and coma. Independent component analysis (ICA) reduced data dimensionality. The ten networks were identified by means of a multiple template-matching procedure and were tested on neuronality properties (neuronal vs non-neuronal) in a data-driven way. Univariate analyses detected between-group differences in networks' neuronal properties and estimated voxel-wise functional connectivity in the networks, which were significantly less identifiable in patients. A nearest-neighbor "clinical" classifier was used to determine the networks with high between-group discriminative accuracy. Healthy controls were characterized by more neuronal components compared to patients in VS/UWS and in coma. Compared to healthy controls, fewer patients in MCS and VS/UWS showed components of neuronal origin for the left executive control network, default mode network (DMN), auditory, and right executive control network. The "clinical" classifier indicated the DMN and auditory network with the highest accuracy (85.3%) in discriminating patients from healthy subjects. FMRI multiple-network resting state connectivity is disrupted in severely brain-injured patients suffering from disorders of consciousness. When performing ICA, multiple-network testing and control for neuronal properties of the identified RSNs can advance fMRI system-level characterization. Automatic data-driven patient classification is the first step towards future single-subject objective diagnostics based on fMRI resting state acquisitions. Copyright © 2013 Elsevier Ltd. All rights reserved.

Deciphering neuronal population codes for acute thermal pain

NASA Astrophysics Data System (ADS)

Chen, Zhe; Zhang, Qiaosheng; Phuong Sieu Tong, Ai; Manders, Toby R.; Wang, Jing

2017-06-01

Objective. Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Current pain research mostly focuses on molecular and synaptic changes at the spinal and peripheral levels. However, a complete understanding of pain mechanisms requires the physiological study of the neocortex. Our goal is to apply a neural decoding approach to read out the onset of acute thermal pain signals, which can be used for brain-machine interface. Approach. We used micro wire arrays to record ensemble neuronal activities from the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC) in freely behaving rats. We further investigated neural codes for acute thermal pain at both single-cell and population levels. To detect the onset of acute thermal pain signals, we developed a novel latent state-space framework to decipher the sorted or unsorted S1 and ACC ensemble spike activities, which reveal information about the onset of pain signals. Main results. The state space analysis allows us to uncover a latent state process that drives the observed ensemble spike activity, and to further detect the ‘neuronal threshold’ for acute thermal pain on a single-trial basis. Our method achieved good detection performance in sensitivity and specificity. In addition, our results suggested that an optimal strategy for detecting the onset of acute thermal pain signals may be based on combined evidence from S1 and ACC population codes. Significance. Our study is the first to detect the onset of acute pain signals based on neuronal ensemble spike activity. It is important from a mechanistic viewpoint as it relates to the significance of S1 and ACC activities in the regulation of the acute pain onset.

Is GABA neurotransmission enhanced in auditory thalamus relative to inferior colliculus?

PubMed Central

Cai, Rui; Kalappa, Bopanna I.; Brozoski, Thomas J.; Ling, Lynne L.

2013-01-01

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central auditory system. Sensory thalamic structures show high levels of non-desensitizing extrasynaptic GABAA receptors (GABAARs) and a reduction in the redundancy of coded information. The present study compared the inhibitory potency of GABA acting at GABAARs between the inferior colliculus (IC) and the medial geniculate body (MGB) using quantitative in vivo, in vitro, and ex vivo experimental approaches. In vivo single unit studies compared the ability of half maximal inhibitory concentrations of GABA to inhibit sound-evoked temporal responses, and found that GABA was two to three times (P < 0.01) more potent at suppressing MGB single unit responses than IC unit responses. In vitro whole cell patch-clamp slice recordings were used to demonstrate that gaboxadol, a δ-subunit selective GABAAR agonist, was significantly more potent at evoking tonic inhibitory currents from MGB neurons than IC neurons (P < 0.01). These electrophysiological findings were supported by an in vitro receptor binding assay which used the picrotoxin analog [3H]TBOB to assess binding in the GABAAR chloride channel. MGB GABAARs had significantly greater total open chloride channel capacity relative to GABAARs in IC (P < 0.05) as shown by increased total [3H]TBOB binding. Finally, a comparative ex vivo measurement compared endogenous GABA levels and suggested a trend towards higher GABA concentrations in MGB than in IC. Collectively, these studies suggest that, per unit GABA, high affinity extrasynaptic and synaptic GABAARs confer a significant inhibitory GABAAR advantage to MGB neurons relative to IC neurons. This increased GABA sensitivity likely underpins the vital filtering role of auditory thalamus. PMID:24155003

Decoding sound level in the marmoset primary auditory cortex.

PubMed

Sun, Wensheng; Marongelli, Ellisha N; Watkins, Paul V; Barbour, Dennis L

2017-10-01

Neurons that respond favorably to a particular sound level have been observed throughout the central auditory system, becoming steadily more common at higher processing areas. One theory about the role of these level-tuned or nonmonotonic neurons is the level-invariant encoding of sounds. To investigate this theory, we simulated various subpopulations of neurons by drawing from real primary auditory cortex (A1) neuron responses and surveyed their performance in forming different sound level representations. Pure nonmonotonic subpopulations did not provide the best level-invariant decoding; instead, mixtures of monotonic and nonmonotonic neurons provided the most accurate decoding. For level-fidelity decoding, the inclusion of nonmonotonic neurons slightly improved or did not change decoding accuracy until they constituted a high proportion. These results indicate that nonmonotonic neurons fill an encoding role complementary to, rather than alternate to, monotonic neurons. NEW & NOTEWORTHY Neurons with nonmonotonic rate-level functions are unique to the central auditory system. These level-tuned neurons have been proposed to account for invariant sound perception across sound levels. Through systematic simulations based on real neuron responses, this study shows that neuron populations perform sound encoding optimally when containing both monotonic and nonmonotonic neurons. The results indicate that instead of working independently, nonmonotonic neurons complement the function of monotonic neurons in different sound-encoding contexts. Copyright © 2017 the American Physiological Society.

Single neuron computation: from dynamical system to feature detector.

PubMed

Hong, Sungho; Agüera y Arcas, Blaise; Fairhall, Adrienne L

2007-12-01

White noise methods are a powerful tool for characterizing the computation performed by neural systems. These methods allow one to identify the feature or features that a neural system extracts from a complex input and to determine how these features are combined to drive the system's spiking response. These methods have also been applied to characterize the input-output relations of single neurons driven by synaptic inputs, simulated by direct current injection. To interpret the results of white noise analysis of single neurons, we would like to understand how the obtained feature space of a single neuron maps onto the biophysical properties of the membrane, in particular, the dynamics of ion channels. Here, through analysis of a simple dynamical model neuron, we draw explicit connections between the output of a white noise analysis and the underlying dynamical system. We find that under certain assumptions, the form of the relevant features is well defined by the parameters of the dynamical system. Further, we show that under some conditions, the feature space is spanned by the spike-triggered average and its successive order time derivatives.

Neural Population Dynamics during Reaching Are Better Explained by a Dynamical System than Representational Tuning

PubMed Central

Dann, Benjamin

2016-01-01

Recent models of movement generation in motor cortex have sought to explain neural activity not as a function of movement parameters, known as representational models, but as a dynamical system acting at the level of the population. Despite evidence supporting this framework, the evaluation of representational models and their integration with dynamical systems is incomplete in the literature. Using a representational velocity-tuning based simulation of center-out reaching, we show that incorporating variable latency offsets between neural activity and kinematics is sufficient to generate rotational dynamics at the level of neural populations, a phenomenon observed in motor cortex. However, we developed a covariance-matched permutation test (CMPT) that reassigns neural data between task conditions independently for each neuron while maintaining overall neuron-to-neuron relationships, revealing that rotations based on the representational model did not uniquely depend on the underlying condition structure. In contrast, rotations based on either a dynamical model or motor cortex data depend on this relationship, providing evidence that the dynamical model more readily explains motor cortex activity. Importantly, implementing a recurrent neural network we demonstrate that both representational tuning properties and rotational dynamics emerge, providing evidence that a dynamical system can reproduce previous findings of representational tuning. Finally, using motor cortex data in combination with the CMPT, we show that results based on small numbers of neurons or conditions should be interpreted cautiously, potentially informing future experimental design. Together, our findings reinforce the view that representational models lack the explanatory power to describe complex aspects of single neuron and population level activity. PMID:27814352

Neural Population Dynamics during Reaching Are Better Explained by a Dynamical System than Representational Tuning.

PubMed

Michaels, Jonathan A; Dann, Benjamin; Scherberger, Hansjörg

2016-11-01

Recent models of movement generation in motor cortex have sought to explain neural activity not as a function of movement parameters, known as representational models, but as a dynamical system acting at the level of the population. Despite evidence supporting this framework, the evaluation of representational models and their integration with dynamical systems is incomplete in the literature. Using a representational velocity-tuning based simulation of center-out reaching, we show that incorporating variable latency offsets between neural activity and kinematics is sufficient to generate rotational dynamics at the level of neural populations, a phenomenon observed in motor cortex. However, we developed a covariance-matched permutation test (CMPT) that reassigns neural data between task conditions independently for each neuron while maintaining overall neuron-to-neuron relationships, revealing that rotations based on the representational model did not uniquely depend on the underlying condition structure. In contrast, rotations based on either a dynamical model or motor cortex data depend on this relationship, providing evidence that the dynamical model more readily explains motor cortex activity. Importantly, implementing a recurrent neural network we demonstrate that both representational tuning properties and rotational dynamics emerge, providing evidence that a dynamical system can reproduce previous findings of representational tuning. Finally, using motor cortex data in combination with the CMPT, we show that results based on small numbers of neurons or conditions should be interpreted cautiously, potentially informing future experimental design. Together, our findings reinforce the view that representational models lack the explanatory power to describe complex aspects of single neuron and population level activity.

Stimulus features coded by single neurons of a macaque body category selective patch

PubMed Central

Popivanov, Ivo D.; Schyns, Philippe G.; Vogels, Rufin

2016-01-01

Body category-selective regions of the primate temporal cortex respond to images of bodies, but it is unclear which fragments of such images drive single neurons’ responses in these regions. Here we applied the Bubbles technique to the responses of single macaque middle superior temporal sulcus (midSTS) body patch neurons to reveal the image fragments the neurons respond to. We found that local image fragments such as extremities (limbs), curved boundaries, and parts of the torso drove the large majority of neurons. Bubbles revealed the whole body in only a few neurons. Neurons coded the features in a manner that was tolerant to translation and scale changes. Most image fragments were excitatory but for a few neurons both inhibitory and excitatory fragments (opponent coding) were present in the same image. The fragments we reveal here in the body patch with Bubbles differ from those suggested in previous studies of face-selective neurons in face patches. Together, our data indicate that the majority of body patch neurons respond to local image fragments that occur frequently, but not exclusively, in bodies, with a coding that is tolerant to translation and scale. Overall, the data suggest that the body category selectivity of the midSTS body patch depends more on the feature statistics of bodies (e.g., extensions occur more frequently in bodies) than on semantics (bodies as an abstract category). PMID:27071095

Optogenetic Stimulation of Arcuate Nucleus Kiss1 Neurons Reveals a Steroid-Dependent Glutamatergic Input to POMC and AgRP Neurons in Male Mice

PubMed Central

Nestor, Casey C; Qiu, Jian; Padilla, Stephanie L.; Zhang, Chunguang; Bosch, Martha A.; Fan, Wei; Aicher, Sue A.; Palmiter, Richard D.

2016-01-01

Kisspeptin (Kiss1) neurons are essential for reproduction, but their role in the control of energy balance and other homeostatic functions remains unclear. Proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons, located in the arcuate nucleus (ARC) of the hypothalamus, integrate numerous excitatory and inhibitory inputs to ultimately regulate energy homeostasis. Given that POMC and AgRP neurons are contacted by Kiss1 neurons in the ARC (Kiss1ARC) and they express androgen receptors, Kiss1ARC neurons may mediate the orexigenic action of testosterone via POMC and/or AgRP neurons. Quantitative PCR analysis of pooled Kiss1ARC neurons revealed that mRNA levels for Kiss1 and vesicular glutamate transporter 2 were higher in castrated male mice compared with gonad-intact males. Single-cell RT-PCR analysis of yellow fluorescent protein (YFP) ARC neurons harvested from males injected with AAV1-EF1α-DIO-ChR2:YFP revealed that 100% and 88% expressed mRNAs for Kiss1 and vesicular glutamate transporter 2, respectively. Whole-cell, voltage-clamp recordings from nonfluorescent postsynaptic ARC neurons showed that low frequency photo-stimulation (0.5 Hz) of Kiss1-ChR2:YFP neurons elicited a fast glutamatergic inward current in POMC and AgRP neurons. Paired-pulse, photo-stimulation revealed paired-pulse depression, which is indicative of greater glutamate release, in the castrated male mice compared with gonad-intact male mice. Group I and group II metabotropic glutamate receptor agonists depolarized and hyperpolarized POMC and AgRP neurons, respectively, which was mimicked by high frequency photo-stimulation (20 Hz) of Kiss1ARC neurons. Therefore, POMC and AgRP neurons receive direct steroid- and frequency-dependent glutamatergic synaptic input from Kiss1ARC neurons in male mice, which may be a critical pathway for Kiss1 neurons to help coordinate energy homeostasis and reproduction. PMID:27093227

Single neuron firing properties impact correlation-based population coding

PubMed Central

Hong, Sungho; Ratté, Stéphanie; Prescott, Steven A.; De Schutter, Erik

2012-01-01

Correlated spiking has been widely observed but its impact on neural coding remains controversial. Correlation arising from co-modulation of rates across neurons has been shown to vary with the firing rates of individual neurons. This translates into rate and correlation being equivalently tuned to the stimulus; under those conditions, correlated spiking does not provide information beyond that already available from individual neuron firing rates. Such correlations are irrelevant and can reduce coding efficiency by introducing redundancy. Using simulations and experiments in rat hippocampal neurons, we show here that pairs of neurons receiving correlated input also exhibit correlations arising from precise spike-time synchronization. Contrary to rate co-modulation, spike-time synchronization is unaffected by firing rate, thus enabling synchrony- and rate-based coding to operate independently. The type of output correlation depends on whether intrinsic neuron properties promote integration or coincidence detection: “ideal” integrators (with spike generation sensitive to stimulus mean) exhibit rate co-modulation whereas “ideal” coincidence detectors (with spike generation sensitive to stimulus variance) exhibit precise spike-time synchronization. Pyramidal neurons are sensitive to both stimulus mean and variance, and thus exhibit both types of output correlation proportioned according to which operating mode is dominant. Our results explain how different types of correlations arise based on how individual neurons generate spikes, and why spike-time synchronization and rate co-modulation can encode different stimulus properties. Our results also highlight the importance of neuronal properties for population-level coding insofar as neural networks can employ different coding schemes depending on the dominant operating mode of their constituent neurons. PMID:22279226

Mapping chromatic pathways in the Drosophila visual system.

PubMed

Lin, Tzu-Yang; Luo, Jiangnan; Shinomiya, Kazunori; Ting, Chun-Yuan; Lu, Zhiyuan; Meinertzhagen, Ian A; Lee, Chi-Hon

2016-02-01

In Drosophila, color vision and wavelength-selective behaviors are mediated by the compound eye's narrow-spectrum photoreceptors R7 and R8 and their downstream medulla projection (Tm) neurons Tm5a, Tm5b, Tm5c, and Tm20 in the second optic neuropil or medulla. These chromatic Tm neurons project axons to a deeper optic neuropil, the lobula, which in insects has been implicated in processing and relaying color information to the central brain. The synaptic targets of the chromatic Tm neurons in the lobula are not known, however. Using a modified GFP reconstitution across synaptic partners (GRASP) method to probe connections between the chromatic Tm neurons and 28 known and novel types of lobula neurons, we identify anatomically the visual projection neurons LT11 and LC14 and the lobula intrinsic neurons Li3 and Li4 as synaptic targets of the chromatic Tm neurons. Single-cell GRASP analyses reveal that Li4 receives synaptic contacts from over 90% of all four types of chromatic Tm neurons, whereas LT11 is postsynaptic to the chromatic Tm neurons, with only modest selectivity and at a lower frequency and density. To visualize synaptic contacts at the ultrastructural level, we develop and apply a "two-tag" double-labeling method to label LT11's dendrites and the mitochondria in Tm5c's presynaptic terminals. Serial electron microscopic reconstruction confirms that LT11 receives direct contacts from Tm5c. This method would be generally applicable to map the connections of large complex neurons in Drosophila and other animals. © 2015 Wiley Periodicals, Inc.

Neuronal Ensemble Synchrony during Human Focal Seizures

PubMed Central

Ahmed, Omar J.; Harrison, Matthew T.; Eskandar, Emad N.; Cosgrove, G. Rees; Madsen, Joseph R.; Blum, Andrew S.; Potter, N. Stevenson; Hochberg, Leigh R.; Cash, Sydney S.

2014-01-01

Seizures are classically characterized as the expression of hypersynchronous neural activity, yet the true degree of synchrony in neuronal spiking (action potentials) during human seizures remains a fundamental question. We quantified the temporal precision of spike synchrony in ensembles of neocortical neurons during seizures in people with pharmacologically intractable epilepsy. Two seizure types were analyzed: those characterized by sustained gamma (∼40–60 Hz) local field potential (LFP) oscillations or by spike-wave complexes (SWCs; ∼3 Hz). Fine (<10 ms) temporal synchrony was rarely present during gamma-band seizures, where neuronal spiking remained highly irregular and asynchronous. In SWC seizures, phase locking of neuronal spiking to the SWC spike phase induced synchrony at a coarse 50–100 ms level. In addition, transient fine synchrony occurred primarily during the initial ∼20 ms period of the SWC spike phase and varied across subjects and seizures. Sporadic coherence events between neuronal population spike counts and LFPs were observed during SWC seizures in high (∼80 Hz) gamma-band and during high-frequency oscillations (∼130 Hz). Maximum entropy models of the joint neuronal spiking probability, constrained only on single neurons' nonstationary coarse spiking rates and local network activation, explained most of the fine synchrony in both seizure types. Our findings indicate that fine neuronal ensemble synchrony occurs mostly during SWC, not gamma-band, seizures, and primarily during the initial phase of SWC spikes. Furthermore, these fine synchrony events result mostly from transient increases in overall neuronal network spiking rates, rather than changes in precise spiking correlations between specific pairs of neurons. PMID:25057195

Multimodal integration in rostral fastigial nucleus provides an estimate of body movement

PubMed Central

Brooks, Jessica X.; Cullen, Kathleen E.

2012-01-01

The ability to accurately control posture and perceive self motion and spatial orientation requires knowledge of both the motion of the head and body. However, while the vestibular sensors and nuclei directly encode head motion, no sensors directly encode body motion. Instead, the convergence of vestibular and neck proprioceptive inputs during self-motion is generally believed to underlie the ability to compute body motion. Here, we provide evidence that the brain explicitly computes an internal estimate of body motion at the level of single cerebellar neurons. Neuronal responses were recorded from the rostral fastigial nucleus, the most medial of the deep cerebellar nuclei, during whole-body, body-under-head, and head-on-body rotations. We found that approximately half of the neurons encoded the motion of the body-in-space, while the other half encoded the motion of the head-in-space in a manner similar to neurons in the vestibular nuclei. Notably, neurons encoding body motion responded to both vestibular and proprioceptive stimulation (accordingly termed bimodal neurons). In contrast, neurons encoding head motion were only sensitive to vestibular inputs (accordingly termed unimodal neurons). Comparison of the proprioceptive and vestibular responses of bimodal neurons further revealed similar tuning in response to changes in head-on-body position. We propose that the similarity in nonlinear processing of vestibular and proprioceptive signals underlies the accurate computation of body motion. Furthermore, the same neurons that encode body motion (i.e., bimodal neurons) most likely encode vestibular signals in a body referenced coordinate frame, since the integration of proprioceptive and vestibular information is required for both computations. PMID:19710303

Action Potential Waveform Variability Limits Multi-Unit Separation in Freely Behaving Rats

PubMed Central

Stratton, Peter; Cheung, Allen; Wiles, Janet; Kiyatkin, Eugene; Sah, Pankaj; Windels, François

2012-01-01

Extracellular multi-unit recording is a widely used technique to study spontaneous and evoked neuronal activity in awake behaving animals. These recordings are done using either single-wire or mulitwire electrodes such as tetrodes. In this study we have tested the ability of single-wire electrodes to discriminate activity from multiple neurons under conditions of varying noise and neuronal cell density. Using extracellular single-unit recording, coupled with iontophoresis to drive cell activity across a wide dynamic range, we studied spike waveform variability, and explored systematic differences in single-unit spike waveform within and between brain regions as well as the influence of signal-to-noise ratio (SNR) on the similarity of spike waveforms. We also modelled spike misclassification for a range of cell densities based on neuronal recordings obtained at different SNRs. Modelling predictions were confirmed by classifying spike waveforms from multiple cells with various SNRs using a leading commercial spike-sorting system. Our results show that for single-wire recordings, multiple units can only be reliably distinguished under conditions of high recording SNR (≥4) and low neuronal density (≈20,000/ mm3). Physiological and behavioural changes, as well as technical limitations typical of awake animal preparations, reduce the accuracy of single-channel spike classification, resulting in serious classification errors. For SNR <4, the probability of misclassifying spikes approaches 100% in many cases. Our results suggest that in studies where the SNR is low or neuronal density is high, separation of distinct units needs to be evaluated with great caution. PMID:22719894

[Single and Network Neuron Activity of Subthalamic Nucleus at Impulsive and Delayed (Self-Control) Reactions in Choice Behavior].

PubMed

Sidorina, V V; Gerasimova, Yu A; Kuleshova, E P; Merzhanova, G Kh

2015-01-01

During our experiments on cats was investigated the subthalamic neuron activity at different types of behavior in case of reinforcement choice depending on its value and availability. In chronic experiences the multiunit activity in subthalamic nucleus (STN) and orbitofrontal cortex (FC) has been recorded. Multiunit activity was analyzed over frequency and network properties of spikes. It was shown, that STN neurons reaction to different reinforcements and conditional stimulus at short- or long-delay reactions was represented by increasing or decreasing of frequency of single neurons. However the same STN neu- rons responded with increasing of frequency of single neuron during expectation of mix-bread-meat and decreasing--during the meat expectation. It has been revealed, that the number of STN interneuron interactions was authentic more at impulsive behavior than at self-control choice of behavior. The number of interactions between FC and STN neurons within intervals of 0-30 Ms was authentic more at display impulsive than during self-control behavior. These results suppose that FC and STN neurons participate in integration of reinforcement estimation; and distinctions in a choice of behavior are defined by the local and distributed interneuron interactions of STN and FC.

Evaluating the potential of using quantum dots for monitoring electrical signals in neurons

NASA Astrophysics Data System (ADS)

Efros, Alexander L.; Delehanty, James B.; Huston, Alan L.; Medintz, Igor L.; Barbic, Mladen; Harris, Timothy D.

2018-04-01

Success in the projects aimed at providing an advanced understanding of the brain is directly predicated on making critical advances in nanotechnology. This Perspective addresses the unique interface of neuroscience and nanomaterials by considering the foundational problem of sensing neuron membrane voltage and offers a potential solution that may be facilitated by a prototypical nanomaterial. Despite substantial improvements, the visualization of instantaneous voltage changes within individual neurons, whether in cell culture or in vivo, at both the single-cell and network level at high speed remains complex and problematic. The unique properties of semiconductor quantum dots (QDs) have made them powerful fluorophores for bioimaging. What is not widely appreciated, however, is that QD photoluminescence is exquisitely sensitive to proximal electric fields. This property should be suitable for sensing voltage changes that occur in the active neuronal membrane. Here, we examine the potential role of QDs in addressing the important challenge of real-time optical voltage imaging.

Programmable logic construction kits for hyper-real-time neuronal modeling.

PubMed

Guerrero-Rivera, Ruben; Morrison, Abigail; Diesmann, Markus; Pearce, Tim C

2006-11-01

Programmable logic designs are presented that achieve exact integration of leaky integrate-and-fire soma and dynamical synapse neuronal models and incorporate spike-time dependent plasticity and axonal delays. Highly accurate numerical performance has been achieved by modifying simpler forward-Euler-based circuitry requiring minimal circuit allocation, which, as we show, behaves equivalently to exact integration. These designs have been implemented and simulated at the behavioral and physical device levels, demonstrating close agreement with both numerical and analytical results. By exploiting finely grained parallelism and single clock cycle numerical iteration, these designs achieve simulation speeds at least five orders of magnitude faster than the nervous system, termed here hyper-real-time operation, when deployed on commercially available field-programmable gate array (FPGA) devices. Taken together, our designs form a programmable logic construction kit of commonly used neuronal model elements that supports the building of large and complex architectures of spiking neuron networks for real-time neuromorphic implementation, neurophysiological interfacing, or efficient parameter space investigations.

Two pairs of mushroom body efferent neurons are required for appetitive long-term memory retrieval in Drosophila.

PubMed

Plaçais, Pierre-Yves; Trannoy, Séverine; Friedrich, Anja B; Tanimoto, Hiromu; Preat, Thomas

2013-11-14

One of the challenges facing memory research is to combine network- and cellular-level descriptions of memory encoding. In this context, Drosophila offers the opportunity to decipher, down to single-cell resolution, memory-relevant circuits in connection with the mushroom bodies (MBs), prominent structures for olfactory learning and memory. Although the MB-afferent circuits involved in appetitive learning were recently described, the circuits underlying appetitive memory retrieval remain unknown. We identified two pairs of cholinergic neurons efferent from the MB α vertical lobes, named MB-V3, that are necessary for the retrieval of appetitive long-term memory (LTM). Furthermore, LTM retrieval was correlated to an enhanced response to the rewarded odor in these neurons. Strikingly, though, silencing the MB-V3 neurons did not affect short-term memory (STM) retrieval. This finding supports a scheme of parallel appetitive STM and LTM processing. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Neurons with hysteresis form a network that can learn without any changes in synaptic connection strengths

NASA Astrophysics Data System (ADS)

Hoffmann, Geoffrey W.; Benson, Maurice W.

1986-08-01

A neural network concept derived from an analogy between the immune system and the central nerous system is outlined. The theory is based on a nervous that is slightly more complicated than the conventional McCullogh-Pitts type of neuron, in that it exhibits hysteresis at the single cell level. This added complication is compensated by the fact that a network of such neurons is able to learn without the necessity for any changes in synaptic connection strengths. The learning occurs as a natural consequence of interactions between the network and its enviornment, with environmental stimuli moving the system around in an N-dimensional phase space, until a point in phase space is reached such that the system's responses are appropriate for dealing with the stimuli. Due to the hysteresis associated with each neuron, the system tends to stay in the region of phase space where it is located. The theory includes a role for sleep in learning.

A Single Pair of Serotonergic Neurons Counteracts Serotonergic Inhibition of Ethanol Attraction in Drosophila

PubMed Central

Kaiser, Andrea; Gräber, Nikolas; Schläger, Laura; Ritze, Yvonne; Scholz, Henrike

2016-01-01

Attraction to ethanol is common in both flies and humans, but the neuromodulatory mechanisms underlying this innate attraction are not well understood. Here, we dissect the function of the key regulator of serotonin signaling—the serotonin transporter–in innate olfactory attraction to ethanol in Drosophila melanogaster. We generated a mutated version of the serotonin transporter that prolongs serotonin signaling in the synaptic cleft and is targeted via the Gal4 system to different sets of serotonergic neurons. We identified four serotonergic neurons that inhibit the olfactory attraction to ethanol and two additional neurons that counteract this inhibition by strengthening olfactory information. Our results reveal that compensation can occur on the circuit level and that serotonin has a bidirectional function in modulating the innate attraction to ethanol. Given the evolutionarily conserved nature of the serotonin transporter and serotonin, the bidirectional serotonergic mechanisms delineate a basic principle for how random behavior is switched into targeted approach behavior. PMID:27936023

A Single Pair of Serotonergic Neurons Counteracts Serotonergic Inhibition of Ethanol Attraction in Drosophila.

PubMed

Xu, Li; He, Jianzheng; Kaiser, Andrea; Gräber, Nikolas; Schläger, Laura; Ritze, Yvonne; Scholz, Henrike

2016-01-01

Attraction to ethanol is common in both flies and humans, but the neuromodulatory mechanisms underlying this innate attraction are not well understood. Here, we dissect the function of the key regulator of serotonin signaling-the serotonin transporter-in innate olfactory attraction to ethanol in Drosophila melanogaster. We generated a mutated version of the serotonin transporter that prolongs serotonin signaling in the synaptic cleft and is targeted via the Gal4 system to different sets of serotonergic neurons. We identified four serotonergic neurons that inhibit the olfactory attraction to ethanol and two additional neurons that counteract this inhibition by strengthening olfactory information. Our results reveal that compensation can occur on the circuit level and that serotonin has a bidirectional function in modulating the innate attraction to ethanol. Given the evolutionarily conserved nature of the serotonin transporter and serotonin, the bidirectional serotonergic mechanisms delineate a basic principle for how random behavior is switched into targeted approach behavior.

A plural role for lipids in motor neuron diseases: energy, signaling and structure

PubMed Central

Schmitt, Florent; Hussain, Ghulam; Dupuis, Luc; Loeffler, Jean-Philippe; Henriques, Alexandre

2013-01-01

Motor neuron diseases (MNDs) are characterized by selective death of motor neurons and include mainly adult-onset amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Neurodegeneration is not the single pathogenic event occurring during disease progression. There are multiple lines of evidence for the existence of defects in lipid metabolism at peripheral level. For instance, hypermetabolism is well characterized in ALS, and dyslipidemia correlates with better prognosis in patients. Lipid metabolism plays also a role in other MNDs. In SMA, misuse of lipids as energetic nutrients is described in patients and in related animal models. The composition of structural lipids in the central nervous system is modified, with repercussion on membrane fluidity and on cell signaling mediated by bioactive lipids. Here, we review the main epidemiologic and mechanistic findings that link alterations of lipid metabolism and motor neuron degeneration, and we discuss the rationale of targeting these modifications for therapeutic management of MNDs. PMID:24600344

Dynamic range in small-world networks of Hodgkin-Huxley neurons with chemical synapses

NASA Astrophysics Data System (ADS)

Batista, C. A. S.; Viana, R. L.; Lopes, S. R.; Batista, A. M.

2014-09-01

According to Stevens' law the relationship between stimulus and response is a power-law within an interval called the dynamic range. The dynamic range of sensory organs is found to be larger than that of a single neuron, suggesting that the network structure plays a key role in the behavior of both the scaling exponent and the dynamic range of neuron assemblies. In order to verify computationally the relationships between stimulus and response for spiking neurons, we investigate small-world networks of neurons described by the Hodgkin-Huxley equations connected by chemical synapses. We found that the dynamic range increases with the network size, suggesting that the enhancement of the dynamic range observed in sensory organs, with respect to single neurons, is an emergent property of complex network dynamics.

Rapid learning in visual cortical networks.

PubMed

Wang, Ye; Dragoi, Valentin

2015-08-26

Although changes in brain activity during learning have been extensively examined at the single neuron level, the coding strategies employed by cell populations remain mysterious. We examined cell populations in macaque area V4 during a rapid form of perceptual learning that emerges within tens of minutes. Multiple single units and LFP responses were recorded as monkeys improved their performance in an image discrimination task. We show that the increase in behavioral performance during learning is predicted by a tight coordination of spike timing with local population activity. More spike-LFP theta synchronization is correlated with higher learning performance, while high-frequency synchronization is unrelated with changes in performance, but these changes were absent once learning had stabilized and stimuli became familiar, or in the absence of learning. These findings reveal a novel mechanism of plasticity in visual cortex by which elevated low-frequency synchronization between individual neurons and local population activity accompanies the improvement in performance during learning.

Linking macroscopic with microscopic neuroanatomy using synthetic neuronal populations.

PubMed

Schneider, Calvin J; Cuntz, Hermann; Soltesz, Ivan

2014-10-01

Dendritic morphology has been shown to have a dramatic impact on neuronal function. However, population features such as the inherent variability in dendritic morphology between cells belonging to the same neuronal type are often overlooked when studying computation in neural networks. While detailed models for morphology and electrophysiology exist for many types of single neurons, the role of detailed single cell morphology in the population has not been studied quantitatively or computationally. Here we use the structural context of the neural tissue in which dendritic trees exist to drive their generation in silico. We synthesize the entire population of dentate gyrus granule cells, the most numerous cell type in the hippocampus, by growing their dendritic trees within their characteristic dendritic fields bounded by the realistic structural context of (1) the granule cell layer that contains all somata and (2) the molecular layer that contains the dendritic forest. This process enables branching statistics to be linked to larger scale neuroanatomical features. We find large differences in dendritic total length and individual path length measures as a function of location in the dentate gyrus and of somatic depth in the granule cell layer. We also predict the number of unique granule cell dendrites invading a given volume in the molecular layer. This work enables the complete population-level study of morphological properties and provides a framework to develop complex and realistic neural network models.

Linking Macroscopic with Microscopic Neuroanatomy Using Synthetic Neuronal Populations

PubMed Central

Schneider, Calvin J.; Cuntz, Hermann; Soltesz, Ivan

2014-01-01

Dendritic morphology has been shown to have a dramatic impact on neuronal function. However, population features such as the inherent variability in dendritic morphology between cells belonging to the same neuronal type are often overlooked when studying computation in neural networks. While detailed models for morphology and electrophysiology exist for many types of single neurons, the role of detailed single cell morphology in the population has not been studied quantitatively or computationally. Here we use the structural context of the neural tissue in which dendritic trees exist to drive their generation in silico. We synthesize the entire population of dentate gyrus granule cells, the most numerous cell type in the hippocampus, by growing their dendritic trees within their characteristic dendritic fields bounded by the realistic structural context of (1) the granule cell layer that contains all somata and (2) the molecular layer that contains the dendritic forest. This process enables branching statistics to be linked to larger scale neuroanatomical features. We find large differences in dendritic total length and individual path length measures as a function of location in the dentate gyrus and of somatic depth in the granule cell layer. We also predict the number of unique granule cell dendrites invading a given volume in the molecular layer. This work enables the complete population-level study of morphological properties and provides a framework to develop complex and realistic neural network models. PMID:25340814

Alkaloids from piper longum protect dopaminergic neurons against inflammation-mediated damage induced by intranigral injection of lipopolysaccharide.

PubMed

He, Huan; Guo, Wei-Wei; Xu, Rong-Rong; Chen, Xiao-Qing; Zhang, Nan; Wu, Xia; Wang, Xiao-Min

2016-10-24

Alkaloids from Piper longum (PLA), extracted from P. longum, have potent anti-inflammatory effects. The aim of this study was to investigate whether PLA could protect dopaminergic neurons against inflammation-mediated damage by inhibiting microglial activation using a lipopolysaccharide (LPS)-induced dopaminergic neuronal damage rat model. The animal behaviors of rotational behavior, rotarod test and open-field test were investigated. The survival ratio of dopaminergic neurons and microglial activation were examined. The dopamine (DA) and its metabolite were detected by high performance liquid chromatography (HPLC). The effects of PLA on the expression of interleukin (IL)-6, interleukin (IL)-1β and tumor necrosis factor (TNF)-α were detected by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) and nitric oxide (NO) were also estimated. We showed that the survival ratio of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra pars compacta (SNpc) and DA content in the striatum were reduced after a single intranigral dose of LPS (10 μg) treatment. The survival rate of TH-ir neurons in the SNpc and DA levels in the striatum were significantly improved after treatment with PLA for 6 weeks. The over-activated microglial cells were suppressed by PLA treatment. We also observed that the levels of inflammatory cytokines, including TNF-α, IL-6 and IL-1β were decreased and the excessive production of ROS and NO were abolished after PLA treatment. Therefore, the behavioral dysfunctions induced by LPS were improved after PLA treatment. This study suggests that PLA plays a significant role in protecting dopaminergic neurons against inflammatory reaction induced damage.

The response of cortical neurons to in vivo-like input current: theory and experiment: II. Time-varying and spatially distributed inputs.

PubMed

Giugliano, Michele; La Camera, Giancarlo; Fusi, Stefano; Senn, Walter

2008-11-01

The response of a population of neurons to time-varying synaptic inputs can show a rich phenomenology, hardly predictable from the dynamical properties of the membrane's inherent time constants. For example, a network of neurons in a state of spontaneous activity can respond significantly more rapidly than each single neuron taken individually. Under the assumption that the statistics of the synaptic input is the same for a population of similarly behaving neurons (mean field approximation), it is possible to greatly simplify the study of neural circuits, both in the case in which the statistics of the input are stationary (reviewed in La Camera et al. in Biol Cybern, 2008) and in the case in which they are time varying and unevenly distributed over the dendritic tree. Here, we review theoretical and experimental results on the single-neuron properties that are relevant for the dynamical collective behavior of a population of neurons. We focus on the response of integrate-and-fire neurons and real cortical neurons to long-lasting, noisy, in vivo-like stationary inputs and show how the theory can predict the observed rhythmic activity of cultures of neurons. We then show how cortical neurons adapt on multiple time scales in response to input with stationary statistics in vitro. Next, we review how it is possible to study the general response properties of a neural circuit to time-varying inputs by estimating the response of single neurons to noisy sinusoidal currents. Finally, we address the dendrite-soma interactions in cortical neurons leading to gain modulation and spike bursts, and show how these effects can be captured by a two-compartment integrate-and-fire neuron. Most of the experimental results reviewed in this article have been successfully reproduced by simple integrate-and-fire model neurons.

Internally generated preactivation of single neurons in human medial frontal cortex predicts volition

PubMed Central

Fried, Itzhak; Mukamel, Roy; Kreiman, Gabriel

2011-01-01

Understanding how self-initiated behavior is encoded by neuronal circuits in the human brain remains elusive. We recorded the activity of 1019 neurons while twelve subjects performed self-initiated finger movement. We report progressive neuronal recruitment over ~1500 ms before subjects report making the decision to move. We observed progressive increase or decrease in neuronal firing rate, particularly in the supplementary motor area (SMA), as the reported time of decision was approached. A population of 256 SMA neurons is sufficient to predict in single trials the impending decision to move with accuracy greater than 80% already 700 ms prior to subjects’ awareness. Furthermore, we predict, with a precision of a few hundred ms, the actual time point of this voluntary decision to move. We implement a computational model whereby volition emerges once a change in internally generated firing rate of neuronal assemblies crosses a threshold. PMID:21315264

Multithreaded Stochastic PDES for Reactions and Diffusions in Neurons.

PubMed

Lin, Zhongwei; Tropper, Carl; Mcdougal, Robert A; Patoary, Mohammand Nazrul Ishlam; Lytton, William W; Yao, Yiping; Hines, Michael L

2017-07-01

Cells exhibit stochastic behavior when the number of molecules is small. Hence a stochastic reaction-diffusion simulator capable of working at scale can provide a more accurate view of molecular dynamics within the cell. This paper describes a parallel discrete event simulator, Neuron Time Warp-Multi Thread (NTW-MT), developed for the simulation of reaction diffusion models of neurons. To the best of our knowledge, this is the first parallel discrete event simulator oriented towards stochastic simulation of chemical reactions in a neuron. The simulator was developed as part of the NEURON project. NTW-MT is optimistic and thread-based, which attempts to capitalize on multi-core architectures used in high performance machines. It makes use of a multi-level queue for the pending event set and a single roll-back message in place of individual anti-messages to disperse contention and decrease the overhead of processing rollbacks. Global Virtual Time is computed asynchronously both within and among processes to get rid of the overhead for synchronizing threads. Memory usage is managed in order to avoid locking and unlocking when allocating and de-allocating memory and to maximize cache locality. We verified our simulator on a calcium buffer model. We examined its performance on a calcium wave model, comparing it to the performance of a process based optimistic simulator and a threaded simulator which uses a single priority queue for each thread. Our multi-threaded simulator is shown to achieve superior performance to these simulators. Finally, we demonstrated the scalability of our simulator on a larger CICR model and a more detailed CICR model.

Spatial heterogeneity of cortical receptive fields and its impact on multisensory interactions.

PubMed

Carriere, Brian N; Royal, David W; Wallace, Mark T

2008-05-01

Investigations of multisensory processing at the level of the single neuron have illustrated the importance of the spatial and temporal relationship of the paired stimuli and their relative effectiveness in determining the product of the resultant interaction. Although these principles provide a good first-order description of the interactive process, they were derived by treating space, time, and effectiveness as independent factors. In the anterior ectosylvian sulcus (AES) of the cat, previous work hinted that the spatial receptive field (SRF) architecture of multisensory neurons might play an important role in multisensory processing due to differences in the vigor of responses to identical stimuli placed at different locations within the SRF. In this study the impact of SRF architecture on cortical multisensory processing was investigated using semichronic single-unit electrophysiological experiments targeting a multisensory domain of the cat AES. The visual and auditory SRFs of AES multisensory neurons exhibited striking response heterogeneity, with SRF architecture appearing to play a major role in the multisensory interactions. The deterministic role of SRF architecture was tightly coupled to the manner in which stimulus location modulated the responsiveness of the neuron. Thus multisensory stimulus combinations at weakly effective locations within the SRF resulted in large (often superadditive) response enhancements, whereas combinations at more effective spatial locations resulted in smaller (additive/subadditive) interactions. These results provide important insights into the spatial organization and processing capabilities of cortical multisensory neurons, features that may provide important clues as to the functional roles played by this area in spatially directed perceptual processes.

I h and HCN channels in murine spiral ganglion neurons: tonotopic variation, local heterogeneity, and kinetic model.

PubMed

Liu, Qing; Manis, Paul B; Davis, Robin L

2014-08-01

One of the major contributors to the response profile of neurons in the auditory pathways is the I h current. Its properties such as magnitude, activation, and kinetics not only vary among different types of neurons (Banks et al., J Neurophysiol 70:1420-1432, 1993; Fu et al., J Neurophysiol 78:2235-2245, 1997; Bal and Oertel, J Neurophysiol 84:806-817, 2000; Cao and Oertel, J Neurophysiol 94:821-832, 2005; Rodrigues and Oertel, J Neurophysiol 95:76-87, 2006; Yi et al., J Neurophysiol 103:2532-2543, 2010), but they also display notable diversity in a single population of spiral ganglion neurons (Mo and Davis, J Neurophysiol 78:3019-3027, 1997), the first neural element in the auditory periphery. In this study, we found from somatic recordings that part of the heterogeneity can be attributed to variation along the tonotopic axis because I h in the apical neurons have more positive half-activation voltage levels than basal neurons. Even within a single cochlear region, however, I h current properties are not uniform. To account for this heterogeneity, we provide immunocytochemical evidence for variance in the intracellular density of the hyperpolarization-activated cyclic nucleotide-gated channel α-subunit 1 (HCN1), which mediates I h current. We also observed different combinations of HCN1 and HCN4 α-subunits from cell to cell. Lastly, based on the physiological data, we performed kinetic analysis for the I h current and generated a mathematical model to better understand varied I h on spiral ganglion function. Regardless of whether I h currents are recorded at the nerve terminals (Yi et al., J Neurophysiol 103:2532-2543, 2010) or at the somata of spiral ganglion neurons, they have comparable mean half-activation voltage and induce similar resting membrane potential changes, and thus our model may also provide insights into the impact of I h on synaptic physiology.

Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5 – implications for dementia with Lewy bodies

PubMed Central

2014-01-01

Background In dementia with Lewy bodies (DLB) abnormal interactions between α-synuclein (α-syn) and beta amyloid (Aβ) result in selective degeneration of neurons in the neocortex, limbic system and striatum. However, factors rendering these neurons selectively vulnerable have not been fully investigated. The metabotropic glutamate receptor 5 (mGluR5) has been shown to be up regulated in DLB and might play a role as a mediator of the neurotoxic effects of Aβ and α-syn in vulnerable neuronal populations. In this context, the main objective of the present study was to investigate the role of mGluR5 as a mediator of the neurotoxic effects of α-syn and Aβ in the hippocampus. Results We generated double transgenic mice over-expressing amyloid precursor protein (APP) and α-syn under the mThy1 cassette and investigated the relationship between α-syn cleavage, Aβ, mGluR5 and neurodegeneration in the hippocampus. We found that compared to the single tg mice, the α-syn/APP tg mice displayed greater accumulation of α-syn and mGluR5 in the CA3 region of the hippocampus compared to the CA1 and other regions. This was accompanied by loss of CA3 (but not CA1) neurons in the single and α-syn/APP tg mice and greater loss of MAP 2 and synaptophysin in the CA3 in the α-syn/APP tg. mGluR5 gene transfer using a lentiviral vector into the hippocampus CA1 region resulted in greater α-syn accumulation and neurodegeneration in the single and α-syn/APP tg mice. In contrast, silencing mGluR5 with a lenti-shRNA protected neurons in the CA3 region of tg mice. In vitro, greater toxicity was observed in primary hippocampal neuronal cultures treated with Aβ oligomers and over-expressing α-syn; this effect was attenuated by down-regulating mGluR5 with an shRNA lentiviral vector. In α-syn-expressing neuronal cells lines, Aβ oligomers promoted increased intracellular calcium levels, calpain activation and α-syn cleavage resulting in caspase-3-dependent cell death. Treatment with pharmacological mGluR5 inhibitors such as 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) attenuated the toxic effects of Aβ in α-syn-expressing neuronal cells. Conclusions Together, these results support the possibility that vulnerability of hippocampal neurons to α-syn and Aβ might be mediated via mGluR5. Moreover, therapeutical interventions targeting mGluR5 might have a role in DLB. PMID:24885390

A dynamic code for economic object valuation in prefrontal cortex neurons

PubMed Central

Tsutsui, Ken-Ichiro; Grabenhorst, Fabian; Kobayashi, Shunsuke; Schultz, Wolfram

2016-01-01

Neuronal reward valuations provide the physiological basis for economic behaviour. Yet, how such valuations are converted to economic decisions remains unclear. Here we show that the dorsolateral prefrontal cortex (DLPFC) implements a flexible value code based on object-specific valuations by single neurons. As monkeys perform a reward-based foraging task, individual DLPFC neurons signal the value of specific choice objects derived from recent experience. These neuronal object values satisfy principles of competitive choice mechanisms, track performance fluctuations and follow predictions of a classical behavioural model (Herrnstein’s matching law). Individual neurons dynamically encode both, the updating of object values from recently experienced rewards, and their subsequent conversion to object choices during decision-making. Decoding from unselected populations enables a read-out of motivational and decision variables not emphasized by individual neurons. These findings suggest a dynamic single-neuron and population value code in DLPFC that advances from reward experiences to economic object values and future choices. PMID:27618960

Dynamic SERS nanosensor for neurotransmitter sensing near neurons.

PubMed

Lussier, Félix; Brulé, Thibault; Bourque, Marie-Josée; Ducrot, Charles; Trudeau, Louis-Éric; Masson, Jean-François

2017-12-04

Current electrophysiology and electrochemistry techniques have provided unprecedented understanding of neuronal activity. However, these techniques are suited to a small, albeit important, panel of neurotransmitters such as glutamate, GABA and dopamine, and these constitute only a subset of the broader range of neurotransmitters involved in brain chemistry. Surface-enhanced Raman scattering (SERS) provides a unique opportunity to detect a broader range of neurotransmitters in close proximity to neurons. Dynamic SERS (D-SERS) nanosensors based on patch-clamp-like nanopipettes decorated with gold nanoraspberries can be located accurately under a microscope using techniques analogous to those used in current electrophysiology or electrochemistry experiments. In this manuscript, we demonstrate that D-SERS can measure in a single experiment ATP, glutamate (glu), acetylcholine (ACh), GABA and dopamine (DA), among other neurotransmitters, with the potential for detecting a greater number of neurotransmitters. The SERS spectra of these neurotransmitters were identified with a barcoding data processing method and time series of the neurotransmitter levels were constructed. The D-SERS nanosensor was then located near cultured mouse dopaminergic neurons. The detection of neurotransmitters was performed in response to a series of K + depolarisations, and allowed the detection of elevated levels of both ATP and dopamine. Control experiments were also performed near glial cells, showing only very low basal detection neurotransmitter events. This paper demonstrates the potential of D-SERS to detect neurotransmitter secretion events near living neurons, but also constitutes a strong proof-of-concept for the broad application of SERS to the detection of secretion events by neurons or other cell types in order to study normal or pathological cell functions.

Prospective Coding by Spiking Neurons

PubMed Central

Brea, Johanni; Gaál, Alexisz Tamás; Senn, Walter

2016-01-01

Animals learn to make predictions, such as associating the sound of a bell with upcoming feeding or predicting a movement that a motor command is eliciting. How predictions are realized on the neuronal level and what plasticity rule underlies their learning is not well understood. Here we propose a biologically plausible synaptic plasticity rule to learn predictions on a single neuron level on a timescale of seconds. The learning rule allows a spiking two-compartment neuron to match its current firing rate to its own expected future discounted firing rate. For instance, if an originally neutral event is repeatedly followed by an event that elevates the firing rate of a neuron, the originally neutral event will eventually also elevate the neuron’s firing rate. The plasticity rule is a form of spike timing dependent plasticity in which a presynaptic spike followed by a postsynaptic spike leads to potentiation. Even if the plasticity window has a width of 20 milliseconds, associations on the time scale of seconds can be learned. We illustrate prospective coding with three examples: learning to predict a time varying input, learning to predict the next stimulus in a delayed paired-associate task and learning with a recurrent network to reproduce a temporally compressed version of a sequence. We discuss the potential role of the learning mechanism in classical trace conditioning. In the special case that the signal to be predicted encodes reward, the neuron learns to predict the discounted future reward and learning is closely related to the temporal difference learning algorithm TD(λ). PMID:27341100

Towards a magnetoresistive platform for neural signal recording

NASA Astrophysics Data System (ADS)

Sharma, P. P.; Gervasoni, G.; Albisetti, E.; D'Ercoli, F.; Monticelli, M.; Moretti, D.; Forte, N.; Rocchi, A.; Ferrari, G.; Baldelli, P.; Sampietro, M.; Benfenati, F.; Bertacco, R.; Petti, D.

2017-05-01

A promising strategy to get deeper insight on brain functionalities relies on the investigation of neural activities at the cellular and sub-cellular level. In this framework, methods for recording neuron electrical activity have gained interest over the years. Main technological challenges are associated to finding highly sensitive detection schemes, providing considerable spatial and temporal resolution. Moreover, the possibility to perform non-invasive assays would constitute a noteworthy benefit. In this work, we present a magnetoresistive platform for the detection of the action potential propagation in neural cells. Such platform allows, in perspective, the in vitro recording of neural signals arising from single neurons, neural networks and brain slices.

High-resolution simultaneous voltage and Ca2+ imaging

PubMed Central

Vogt, Kaspar E; Gerharz, Stephan; Graham, Jeremy; Canepari, Marco

2011-01-01

Combining voltage and Ca2+ imaging allows the correlation of electrical and chemical activity at sub-cellular level. Here we describe a novel apparatus designed to obtain simultaneous voltage and Ca2+ measurements with single-trial resolution from sites as small as a few microns. These measurements can be obtained with negligible optical cross-talk between the two signals and negligible photo-damage of the preparation. The capability of the technique was assessed recording either from individual neurons in brain slices or from networks of cultured neurons. The present achievements open the gate to many novel physiological investigations requiring simultaneous measurement of voltage and Ca2+ signals. PMID:21115640

Optical Imaging of Neuronal Activity and Visualization of Fine Neural Structures in Non-Desheathed Nervous Systems

PubMed Central

Stein, Wolfgang

2014-01-01

Locating circuit neurons and recording from them with single-cell resolution is a prerequisite for studying neural circuits. Determining neuron location can be challenging even in small nervous systems because neurons are densely packed, found in different layers, and are often covered by ganglion and nerve sheaths that impede access for recording electrodes and neuronal markers. We revisited the voltage-sensitive dye RH795 for its ability to stain and record neurons through the ganglion sheath. Bath-application of RH795 stained neuronal membranes in cricket, earthworm and crab ganglia without removing the ganglion sheath, revealing neuron cell body locations in different ganglion layers. Using the pyloric and gastric mill central pattern generating neurons in the stomatogastric ganglion (STG) of the crab, Cancer borealis, we found that RH795 permeated the ganglion without major residue in the sheath and brightly stained somatic, axonal and dendritic membranes. Visibility improved significantly in comparison to unstained ganglia, allowing the identification of somata location and number of most STG neurons. RH795 also stained axons and varicosities in non-desheathed nerves, and it revealed the location of sensory cell bodies in peripheral nerves. Importantly, the spike activity of the sensory neuron AGR, which influences the STG motor patterns, remained unaffected by RH795, while desheathing caused significant changes in AGR activity. With respect to recording neural activity, RH795 allowed us to optically record membrane potential changes of sub-sheath neuronal membranes without impairing sensory activity. The signal-to-noise ratio was comparable with that previously observed in desheathed preparations and sufficiently high to identify neurons in single-sweep recordings and synaptic events after spike-triggered averaging. In conclusion, RH795 enabled staining and optical recording of neurons through the ganglion sheath and is therefore both a good anatomical marker for living neural tissue and a promising tool for studying neural activity of an entire network with single-cell resolution. PMID:25062029

Quantitative RT-PCR and immunoblot analyses reveal acclimated A2 noradrenergic neuron substrate fuel transporter, glucokinase, phospho-AMPK, and dopamine-β-hydroxylase responses to hypoglycemia.

PubMed

Cherian, Ajeesh Koshy; Briski, Karen P

2011-07-01

Cellular metabolic stasis is monitored in discrete brain sites, including the dorsal vagal complex (DVC), where A2 noradrenergic neurons perform this sensory function. Single-cell qPCR and high-sensitivity immunoblotting were used to determine if A2 neurons adapt to chronic hypoglycemia by increasing substrate fuel transporter expression, and whether such adjustments coincide with decreased cellular energy instability during this systemic metabolic stress. Tyrosine hydroxylase-immunolabeled neurons were laser-microdissected from the caudal DVC 2 hr after single or serial neutral protamine Hagedorn insulin (NPH) dosing. Preceding hypoglycemia suppressed basal A2 MCT2, GLUT3, and GLUT4 profiles and diminished MCT2, GLUT4, and glucokinase responses to recurring hypoglycemia. Acute NPH caused a robust increase in A2 phospho-AMPK protein levels; baseline phospho-AMPK expression was elevated after 3 days of insulin treatment but only slight augmented after a fourth NPH injection. Transcripts encoding the catecholamine biosynthetic enzyme dopamine-β-hydroxylase were unaffected by acute NPH but were diminished by serial insulin dosing. This evidence for diminished basal A2 glucose and lactate uptake and attenuated phospho-AMPK-mediated detection of hypoglycemia-associated energy deficits suggests that these cells acclimate to chronic hypoglycemia by adopting a new metabolic steady state characterized by energy paucity and reduced sensitivity to hypoglycemia. Because dopamine-β-hydroxylase mRNA was reduced after serial, but not single NPH dosing, A2 neurotransmitter biosynthesis may be impervious to acute hypoglycemia but inhibited when posthypoglycemic metabolic deficiency is exacerbated by recurring hypoglycemia. This research suggests that chronic hypoglycemia-associated adjustments in A2-sensory neurotransmission may reflect cellular energetic debilitation rather than adaptive attenuation of cellular metabolic imbalance. Copyright © 2011 Wiley-Liss, Inc.

CFTR mediates noradrenaline-induced ATP efflux from DRG neurons.

PubMed

Kanno, Takeshi; Nishizaki, Tomoyuki

2011-09-24

In our earlier study, noradrenaline (NA) stimulated ATP release from dorsal root ganglion (DRG) neurons as mediated via β(3) adrenoceptors linked to G(s) protein involving protein kinase A (PKA) activation, to cause allodynia. The present study was conducted to understand how ATP is released from DRG neurons. In an outside-out patch-clamp configuration from acutely dissociated rat DRG neurons, single-channel currents, sensitive to the P2X receptor inhibitor PPADS, were evoked by approaching the patch-electrode tip close to a neuron, indicating that ATP is released from DRG neurons, to activate P2X receptor. NA increased the frequency of the single-channel events, but such NA effect was not found for DRG neurons transfected with the siRNA to silence the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In the immunocytochemical study using acutely dissociated rat DRG cells, CFTR was expressed in neurons alone, but not satellite cells, fibroblasts, or Schwann cells. It is concluded from these results that CFTR mediates NA-induced ATP efflux from DRG neurons as an ATP channel.

Analysis of neuronal cells of dissociated primary culture on high-density CMOS electrode array

PubMed Central

Matsuda, Eiko; Mita, Takeshi; Hubert, Julien; Bakkum, Douglas; Frey, Urs; Hierlemann, Andreas; Takahashi, Hirokazu; Ikegami, Takashi

2017-01-01

Spontaneous development of neuronal cells was recorded around 4–34 days in vitro (DIV) with high-density CMOS array, which enables detailed study of the spatio-temporal activity of neuronal culture. We used the CMOS array to characterize the evolution of the inter-spike interval (ISI) distribution from putative single neurons, and estimate the network structure based on transfer entropy analysis, where each node corresponds to a single neuron. We observed that the ISI distributions gradually obeyed the power law with maturation of the network. The amount of information transferred between neurons increased at the early stage of development, but decreased as the network matured. These results suggest that both ISI and transfer entropy were very useful for characterizing the dynamic development of cultured neural cells over a few weeks. PMID:24109870

Effects of Different Modes of Hypobaric Hypoxia on the Content of Epigenetic Factors in the Rat in Neurons of Rat Neocortex.

PubMed

Samoilov, M O; Churilova, A V; Glushchenko, T S; Rybnikova, E A

2017-04-01

We studied the effects of different modes of hypobaric hypoxia on the content of epigenetic factors acH3K24, meH3K9, and meDNA modulating conformational characteristics of chromatin and gene expression in neurons of associative complex of rat parietal neocortex. Severe destructive hypoxia dramatically reduced the level of acH3K24 in 3 h after the end of exposure and increased meH3K9 and meDNA content. By contrast, 3-fold (but not single) adaptive exposure to moderate hypobaric hypoxia that produced a neuroprotective effect enhanced neuronal acH3K24 expression and decreased both meH3K9 and meDNA levels. Elevated acH3K24 content facilitates, while increased content of meH3K9 hampers binding of transcription factors to the target genes. At the same time, increased expression of meDNA suppresses transcription. The role of modification of epigenetic mechanisms in the regulation of proadaptive genes under the effects of hypoxic exposure according to various protocols is discussed.

Fast targeted gene transfection and optogenetic modification of single neurons using femtosecond laser irradiation

PubMed Central

Antkowiak, Maciej; Torres-Mapa, Maria Leilani; Witts, Emily C.; Miles, Gareth B.; Dholakia, Kishan; Gunn-Moore, Frank J.

2013-01-01

A prevailing problem in neuroscience is the fast and targeted delivery of DNA into selected neurons. The development of an appropriate methodology would enable the transfection of multiple genes into the same cell or different genes into different neighboring cells as well as rapid cell selective functionalization of neurons. Here, we show that optimized femtosecond optical transfection fulfills these requirements. We also demonstrate successful optical transfection of channelrhodopsin-2 in single selected neurons. We extend the functionality of this technique for wider uptake by neuroscientists by using fast three-dimensional laser beam steering enabling an image-guided “point-and-transfect” user-friendly transfection of selected cells. A sub-second transfection timescale per cell makes this method more rapid by at least two orders of magnitude when compared to alternative single-cell transfection techniques. This novel technology provides the ability to carry out large-scale cell selective genetic studies on neuronal ensembles and perform rapid genetic programming of neural circuits. PMID:24257461

Fast targeted gene transfection and optogenetic modification of single neurons using femtosecond laser irradiation.

PubMed

Antkowiak, Maciej; Torres-Mapa, Maria Leilani; Witts, Emily C; Miles, Gareth B; Dholakia, Kishan; Gunn-Moore, Frank J

2013-11-21

A prevailing problem in neuroscience is the fast and targeted delivery of DNA into selected neurons. The development of an appropriate methodology would enable the transfection of multiple genes into the same cell or different genes into different neighboring cells as well as rapid cell selective functionalization of neurons. Here, we show that optimized femtosecond optical transfection fulfills these requirements. We also demonstrate successful optical transfection of channelrhodopsin-2 in single selected neurons. We extend the functionality of this technique for wider uptake by neuroscientists by using fast three-dimensional laser beam steering enabling an image-guided "point-and-transfect" user-friendly transfection of selected cells. A sub-second transfection timescale per cell makes this method more rapid by at least two orders of magnitude when compared to alternative single-cell transfection techniques. This novel technology provides the ability to carry out large-scale cell selective genetic studies on neuronal ensembles and perform rapid genetic programming of neural circuits.

Simple and effective graphene laser processing for neuron patterning application

NASA Astrophysics Data System (ADS)

Lorenzoni, Matteo; Brandi, Fernando; Dante, Silvia; Giugni, Andrea; Torre, Bruno

2013-06-01

A straightforward fabrication technique to obtain patterned substrates promoting ordered neuron growth is presented. Chemical vapor deposition (CVD) single layer graphene (SLG) was machined by means of single pulse UV laser ablation technique at the lowest effective laser fluence in order to minimize laser damage effects. Patterned substrates were then coated with poly-D-lysine by means of a simple immersion in solution. Primary embryonic hippocampal neurons were cultured on our substrate, demonstrating an ordered interconnected neuron pattern mimicking the pattern design. Surprisingly, the functionalization is more effective on the SLG, resulting in notably higher alignment for neuron adhesion and growth. Therefore the proposed technique should be considered a valuable candidate to realize a new generation of highly specialized biosensors.

Simple and effective graphene laser processing for neuron patterning application

PubMed Central

Lorenzoni, Matteo; Brandi, Fernando; Dante, Silvia; Giugni, Andrea; Torre, Bruno

2013-01-01

A straightforward fabrication technique to obtain patterned substrates promoting ordered neuron growth is presented. Chemical vapor deposition (CVD) single layer graphene (SLG) was machined by means of single pulse UV laser ablation technique at the lowest effective laser fluence in order to minimize laser damage effects. Patterned substrates were then coated with poly-D-lysine by means of a simple immersion in solution. Primary embryonic hippocampal neurons were cultured on our substrate, demonstrating an ordered interconnected neuron pattern mimicking the pattern design. Surprisingly, the functionalization is more effective on the SLG, resulting in notably higher alignment for neuron adhesion and growth. Therefore the proposed technique should be considered a valuable candidate to realize a new generation of highly specialized biosensors. PMID:23739674

Effects of Aloe Vera on Spinal Cord Ischemia-Reperfusion Injury of Rats.

PubMed

Yuksel, Yasemin; Guven, Mustafa; Kaymaz, Burak; Sehitoglu, Muserref Hilal; Aras, Adem Bozkurt; Akman, Tarik; Tosun, Murat; Cosar, Murat

2016-12-01

The purpose of this study was to evaluate the possible protective/therapeutic effects of aloe vera (AV) on ischemia-reperfusion injury (I/R) of spinal cord in rats. A total of 28 Wistar Albino rats were divided into four random groups of equal number (n = 7). Group I (control) had no medication or surgery; Group II underwent spinal cord ischemia and was given no medication; Group III was administered AV by gastric gavage for 30 days as pre-treatment; Group IV was administered single dose intraperitoneal methylprednisolone (MP) after the ischemia. Nuclear respiratory factor-1 (NRF1), malondialdehyde (MDA) and superoxide dismutase (SOD) levels were evaluated. Tissue samples were examined histopathologically and neuronal nitric oxide synthase (nNOS) and nuclear factor-kappa B (NF-κB) protein expressions were assessed by immunohistochemical staining. NRF1 and SOD levels of ischemia group were found to be lower compared to the other groups. MDA levels significantly increased after I/R. Treatment with AV and MP resulted in reduced MDA levels and also alleviated hemorrhage, edema, inflammatory cell migration and neurons were partially protected from ischemic injury. When AV treatment was compared with MP, there was no statistical difference between them in terms of reduction of neuronal damage. I/R injury increased NF-κB and nNOS expressions. AV and MP treatments decreased NF-κB and nNOS expressions. It was observed that aloe vera attenuated neuronal damage histopathologically and biochemically as pretreatment. Further studies may provide more evidence to determine the additional role of aloe vera in spinal cord ischemia reperfusion injury.

A computational model of pattern separation efficiency in the dentate gyrus with implications in schizophrenia

PubMed Central

Faghihi, Faramarz; Moustafa, Ahmed A.

2015-01-01

Information processing in the hippocampus begins by transferring spiking activity of the entorhinal cortex (EC) into the dentate gyrus (DG). Activity pattern in the EC is separated by the DG such that it plays an important role in hippocampal functions including memory. The structural and physiological parameters of these neural networks enable the hippocampus to be efficient in encoding a large number of inputs that animals receive and process in their life time. The neural encoding capacity of the DG depends on its single neurons encoding and pattern separation efficiency. In this study, encoding by the DG is modeled such that single neurons and pattern separation efficiency are measured using simulations of different parameter values. For this purpose, a probabilistic model of single neurons efficiency is presented to study the role of structural and physiological parameters. Known neurons number of the EC and the DG is used to construct a neural network by electrophysiological features of granule cells of the DG. Separated inputs as activated neurons in the EC with different firing probabilities are presented into the DG. For different connectivity rates between the EC and DG, pattern separation efficiency of the DG is measured. The results show that in the absence of feedback inhibition on the DG neurons, the DG demonstrates low separation efficiency and high firing frequency. Feedback inhibition can increase separation efficiency while resulting in very low single neuron’s encoding efficiency in the DG and very low firing frequency of neurons in the DG (sparse spiking). This work presents a mechanistic explanation for experimental observations in the hippocampus, in combination with theoretical measures. Moreover, the model predicts a critical role for impaired inhibitory neurons in schizophrenia where deficiency in pattern separation of the DG has been observed. PMID:25859189

Parvalbumin-expressing interneurons can act solo while somatostatin-expressing interneurons act in chorus in most cases on cortical pyramidal cells.

PubMed

Safari, Mir-Shahram; Mirnajafi-Zadeh, Javad; Hioki, Hiroyuki; Tsumoto, Tadaharu

2017-10-06

Neural circuits in the cerebral cortex consist primarily of excitatory pyramidal (Pyr) cells and inhibitory interneurons. Interneurons are divided into several subtypes, in which the two major groups are those expressing parvalbumin (PV) or somatostatin (SOM). These subtypes of interneurons are reported to play distinct roles in tuning and/or gain of visual response of pyramidal cells in the visual cortex. It remains unclear whether there is any quantitative and functional difference between the PV → Pyr and SOM → Pyr connections. We compared unitary inhibitory postsynaptic currents (uIPSCs) evoked by electrophysiological activation of single presynaptic interneurons with population IPSCs evoked by photo-activation of a mass of interneurons in vivo and in vitro in transgenic mice in which PV or SOM neurons expressed channelrhodopsin-2, and found that at least about 14 PV neurons made strong connections with a postsynaptic Pyr cell while a much larger number of SOM neurons made weak connections. Activation or suppression of single PV neurons modified visual responses of postsynaptic Pyr cells in 6 of 7 pairs whereas that of single SOM neurons showed no significant modification in 8 of 11 pairs, suggesting that PV neurons can act solo whereas most of SOM neurons may act in chorus on Pyr cells.

Identification of a Drosophila glucose receptor using Ca2+ imaging of single chemosensory neurons.

PubMed

Miyamoto, Tetsuya; Chen, Yan; Slone, Jesse; Amrein, Hubert

2013-01-01

Evaluation of food compounds by chemosensory cells is essential for animals to make appropriate feeding decisions. In the fruit fly Drosophila melanogaster, structurally diverse chemicals are detected by multimeric receptors composed of members of a large family of Gustatory receptor (Gr) proteins. Putative sugar and bitter receptors are expressed in distinct subsets of Gustatory Receptor Neurons (GRN) of taste sensilla, thereby assigning distinct taste qualities to sugars and bitter tasting compounds, respectively. Here we report a Ca(2+) imaging method that allows association of ligand-mediated responses to a single GRN. We find that different sweet neurons exhibit distinct response profiles when stimulated with various sugars, and likewise, different bitter neurons exhibit distinct response profiles when stimulated with a set of bitter chemicals. These observations suggest that individual neurons within a taste modality are represented by distinct repertoires of sweet and bitter taste receptors, respectively. Furthermore, we employed this novel method to identify glucose as the primary ligand for the sugar receptor Gr61a, which is not only expressed in sweet sensing neurons of classical chemosensory sensilla, but also in two supersensitive neurons of atypical taste sensilla. Thus, single cell Ca(2+) imaging can be employed as a powerful tool to identify ligands for orphan Gr proteins.

Ghrelin Induces Leptin Resistance by Activation of Suppressor of Cytokine Signaling 3 Expression in Male Rats: Implications in Satiety Regulation

PubMed Central

Heldsinger, Andrea; Grabauskas, Gintautas; Wu, Xiaoyin; Zhou, ShiYi; Lu, Yuanxu; Song, Il

2014-01-01

The anorexigenic adipocyte-derived hormone leptin and the orexigenic hormone ghrelin act in opposition to regulate feeding behavior via the vagal afferent pathways. The mechanisms by which ghrelin exerts its inhibitory effects on leptin are unknown. We hypothesized that ghrelin activates the exchange protein activated by cAMP (Epac), inducing increased SOCS3 expression, which negatively affects leptin signal transduction and neuronal firing in nodose ganglia (NG) neurons. We showed that 91 ± 3% of leptin receptor (LRb) –bearing neurons contained ghrelin receptors (GHS-R1a) and that ghrelin significantly inhibited leptin-stimulated STAT3 phosphorylation in rat NG neurons. Studies of the signaling cascades used by ghrelin showed that ghrelin caused a significant increase in Epac and suppressor of cytokine signaling 3 (SOCS3) expression in cultured rat NG neurons. Transient transfection of cultured NG neurons to silence SOCS3 and Epac genes reversed the inhibitory effects of ghrelin on leptin-stimulated STAT3 phosphorylation. Patch-clamp studies and recordings of single neuronal discharges of vagal primary afferent neurons showed that ghrelin markedly inhibited leptin-stimulated neuronal firing, an action abolished by silencing SOCS3 expression in NG. Plasma ghrelin levels increased significantly during fasting. This was accompanied by enhanced SOCS3 expression in the NG and prevented by treatment with a ghrelin antagonist. Feeding studies showed that silencing SOCS3 expression in the NG reduced food intake evoked by endogenous leptin. We conclude that ghrelin exerts its inhibitory effects on leptin-stimulated neuronal firing by increasing SOCS3 expression. The SOCS3 signaling pathway plays a pivotal role in ghrelin's inhibitory effect on STAT3 phosphorylation, neuronal firing, and feeding behavior. PMID:25060362

Representation of Dynamic Interaural Phase Difference in Auditory Cortex of Awake Rhesus Macaques

PubMed Central

Scott, Brian H.; Malone, Brian J.; Semple, Malcolm N.

2009-01-01

Neurons in auditory cortex of awake primates are selective for the spatial location of a sound source, yet the neural representation of the binaural cues that underlie this tuning remains undefined. We examined this representation in 283 single neurons across the low-frequency auditory core in alert macaques, trained to discriminate binaural cues for sound azimuth. In response to binaural beat stimuli, which mimic acoustic motion by modulating the relative phase of a tone at the two ears, these neurons robustly modulate their discharge rate in response to this directional cue. In accordance with prior studies, the preferred interaural phase difference (IPD) of these neurons typically corresponds to azimuthal locations contralateral to the recorded hemisphere. Whereas binaural beats evoke only transient discharges in anesthetized cortex, neurons in awake cortex respond throughout the IPD cycle. In this regard, responses are consistent with observations at earlier stations of the auditory pathway. Discharge rate is a band-pass function of the frequency of IPD modulation in most neurons (73%), but both discharge rate and temporal synchrony are independent of the direction of phase modulation. When subjected to a receiver operator characteristic analysis, the responses of individual neurons are insufficient to account for the perceptual acuity of these macaques in an IPD discrimination task, suggesting the need for neural pooling at the cortical level. PMID:19164111

Representation of dynamic interaural phase difference in auditory cortex of awake rhesus macaques.

PubMed

Scott, Brian H; Malone, Brian J; Semple, Malcolm N

2009-04-01

Neurons in auditory cortex of awake primates are selective for the spatial location of a sound source, yet the neural representation of the binaural cues that underlie this tuning remains undefined. We examined this representation in 283 single neurons across the low-frequency auditory core in alert macaques, trained to discriminate binaural cues for sound azimuth. In response to binaural beat stimuli, which mimic acoustic motion by modulating the relative phase of a tone at the two ears, these neurons robustly modulate their discharge rate in response to this directional cue. In accordance with prior studies, the preferred interaural phase difference (IPD) of these neurons typically corresponds to azimuthal locations contralateral to the recorded hemisphere. Whereas binaural beats evoke only transient discharges in anesthetized cortex, neurons in awake cortex respond throughout the IPD cycle. In this regard, responses are consistent with observations at earlier stations of the auditory pathway. Discharge rate is a band-pass function of the frequency of IPD modulation in most neurons (73%), but both discharge rate and temporal synchrony are independent of the direction of phase modulation. When subjected to a receiver operator characteristic analysis, the responses of individual neurons are insufficient to account for the perceptual acuity of these macaques in an IPD discrimination task, suggesting the need for neural pooling at the cortical level.

Pheromone modulates plant odor responses in the antennal lobe of a moth.

PubMed

Chaffiol, Antoine; Dupuy, Fabienne; Barrozo, Romina B; Kropf, Jan; Renou, Michel; Rospars, Jean-Pierre; Anton, Sylvia

2014-06-01

In nature, male moths are exposed to a complex plant odorant environment when they fly upwind to a sex pheromone source in their search for mates. Plant odors have been shown to affect responses to pheromone at various levels but how does pheromone affects plant odor perception? We recorded responses from neurons within the non-pheromonal "ordinary glome ruli" of the primary olfactory center, the antennal lobe (AL), to single and pulsed stimulations with the plant odorant heptanal, the pheromone, and their mixture in the male moth Agrotis ipsilon. We identified 3 physiological types of neurons according to their activity patterns combining excitatory and inhibitory phases. Both local and projection neurons were identified in each physiological type. Neurons with excitatory responses to heptanal responded also frequently to the pheromone and showed additive responses to the mixture. Moreover, the neuron's ability of resolving successive pulses generally improved with the mixture. Only some neurons with combined excitatory/inhibitory, or purely inhibitory responses to heptanal, also responded to the pheromone. Although individual mixture responses were not significantly different from heptanal responses in these neurons, pulse resolution was improved with the mixture as compared with heptanal alone. These results demonstrate that the pheromone and the general odorant subsystems interact more intensely in the moth AL than previously thought. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Excitatory innervation of caudal hypoglossal nucleus from nucleus reticularis gigantocellularis in the rat.

PubMed

Yang, C C; Chan, J Y; Chan, S H

1995-03-01

We examined the possible innervation of the caudal hypoglossal nucleus by the nucleus reticularis gigantocellularis of the medulla oblongata, based on single-neuron recording and retrograde tracing experiments in Sprague-Dawley rats. Under pentobarbital sodium (50 mg/kg, i.p.) anesthesia, electrical stimulation of the caudal portion of the nucleus reticularis gigantocellularis with repetitive 0.5-ms rectangular pulses increased (46 of 51 neurons) the basal discharge frequency of spontaneously active cells, or evoked spike activity in silent, hypoglossal neurons located at the level of the obex. This excitatory effect was related to the intensity (25-100 microA) and/or frequency (0.5-20 Hz) of the stimulating pulses to the nucleus reticularis gigantocellularis. Perikaryal activation of neurons by microinjection of L-glutamate (0.5 nmol, 25 nl) into the caudal portion of the nucleus reticularis gigantocellularis similarly produced an excitatory action on eight of 14 hypoglossal neurons. Retrogradely labeled neurons were found bilaterally within the confines of the nucleus reticularis gigantocellularis following unilateral microinjection of wheatgerm agglutinin-conjugated horseradish peroxidase or Fast Blue into the corresponding hypoglossal recording sites. Furthermore, the distribution of labeled neurons in the nucleus reticularis gigantocellularis substantially overlapped with the loci of electrical or chemical stimulation. These complementary electrophysiological and neuroanatomical results support the conclusion that an excitatory link exists between the nucleus reticularis gigantocellularis and at least the caudal portion of the hypoglossal nucleus in the rat.

Relationship between inter-stimulus-intervals and intervals of autonomous activities in a neuronal network.

PubMed

Ito, Hidekatsu; Minoshima, Wataru; Kudoh, Suguru N

2015-08-01

To investigate relationships between neuronal network activity and electrical stimulus, we analyzed autonomous activity before and after electrical stimulus. Recordings of autonomous activity were performed using dissociated culture of rat hippocampal neurons on a multi-electrodes array (MEA) dish. Single stimulus and pared stimuli were applied to a cultured neuronal network. Single stimulus was applied every 1 min, and paired stimuli was performed by two sequential stimuli every 1 min. As a result, the patterns of synchronized activities of a neuronal network were changed after stimulus. Especially, long range synchronous activities were induced by paired stimuli. When 1 s inter-stimulus-intervals (ISI) and 1.5 s ISI paired stimuli are applied to a neuronal network, relatively long range synchronous activities expressed in case of 1.5 s ISI. Temporal synchronous activity of neuronal network is changed according to inter-stimulus-intervals (ISI) of electrical stimulus. In other words, dissociated neuronal network can maintain given information in temporal pattern and a certain type of an information maintenance mechanism was considered to be implemented in a semi-artificial dissociated neuronal network. The result is useful toward manipulation technology of neuronal activity in a brain system.

Seeing a straight line on a curved surface: decoupling of patterns from surfaces by single IT neurons

PubMed Central

Ratan Murty, N. Apurva

2016-01-01

We have no difficulty seeing a straight line drawn on a paper even when the paper is bent, but this inference is in fact nontrivial. Doing so requires either matching local features or representing the pattern after factoring out the surface shape. Here we show that single neurons in the monkey inferior temporal (IT) cortex show invariant responses to patterns across rigid and nonrigid changes of surfaces. We recorded neuronal responses to stimuli in which the pattern and the surrounding surface were varied independently. In a subset of neurons, we found pattern-surface interactions that produced similar responses to stimuli across congruent pattern and surface transformations. These interactions produced systematic shifts in curvature tuning of patterns when overlaid on convex and flat surfaces. Our results show that surfaces are factored out of patterns by single neurons, thereby enabling complex perceptual inferences. NEW & NOTEWORTHY We have no difficulty seeing a straight line on a curved piece of paper, but in fact, doing so requires decoupling the shape of the surface from the pattern itself. Here we report a novel form of invariance in the visual cortex: single neurons in monkey inferior temporal cortex respond similarly to congruent transformations of patterns and surfaces, in effect decoupling patterns from the surface on which they are overlaid. PMID:27733595

Single Cell Transcriptomics of Hypothalamic Warm Sensitive Neurons that Control Core Body Temperature and Fever Response

PubMed Central

Eberwine, James; Bartfai, Tamas

2011-01-01

We report on an ‘unbiased’ molecular characterization of individual, adult neurons, active in a central, anterior hypothalamic neuronal circuit, by establishing cDNA libraries from each individual, electrophysiologically identified warm sensitive neuron (WSN). The cDNA libraries were analyzed by Affymetrix microarray. The presence and frequency of cDNAs was confirmed and enhanced with Illumina sequencing of each single cell cDNA library. cDNAs encoding the GABA biosynthetic enzyme. GAD1 and of adrenomedullin, galanin, prodynorphin, somatostatin, and tachykinin were found in the WSNs. The functional cellular and in vivo studies on dozens of the more than 500 neurotransmitter -, hormone- receptors and ion channels, whose cDNA was identified and sequence confirmed, suggest little or no discrepancy between the transcriptional and functional data in WSNs; whenever agonists were available for a receptor whose cDNA was identified, a functional response was found.. Sequencing single neuron libraries permitted identification of rarely expressed receptors like the insulin receptor, adiponectin receptor2 and of receptor heterodimers; information that is lost when pooling cells leads to dilution of signals and mixing signals. Despite the common electrophysiological phenotype and uniform GAD1 expression, WSN- transcriptomes show heterogenity, suggesting strong epigenetic influence on the transcriptome. Our study suggests that it is well-worth interrogating the cDNA libraries of single neurons by sequencing and chipping. PMID:20970451

Predictive Coding of Dynamical Variables in Balanced Spiking Networks

PubMed Central

Boerlin, Martin; Machens, Christian K.; Denève, Sophie

2013-01-01

Two observations about the cortex have puzzled neuroscientists for a long time. First, neural responses are highly variable. Second, the level of excitation and inhibition received by each neuron is tightly balanced at all times. Here, we demonstrate that both properties are necessary consequences of neural networks that represent information efficiently in their spikes. We illustrate this insight with spiking networks that represent dynamical variables. Our approach is based on two assumptions: We assume that information about dynamical variables can be read out linearly from neural spike trains, and we assume that neurons only fire a spike if that improves the representation of the dynamical variables. Based on these assumptions, we derive a network of leaky integrate-and-fire neurons that is able to implement arbitrary linear dynamical systems. We show that the membrane voltage of the neurons is equivalent to a prediction error about a common population-level signal. Among other things, our approach allows us to construct an integrator network of spiking neurons that is robust against many perturbations. Most importantly, neural variability in our networks cannot be equated to noise. Despite exhibiting the same single unit properties as widely used population code models (e.g. tuning curves, Poisson distributed spike trains), balanced networks are orders of magnitudes more reliable. Our approach suggests that spikes do matter when considering how the brain computes, and that the reliability of cortical representations could have been strongly underestimated. PMID:24244113

Exaggerated phosphorylation of brain tau protein in CRH KO mice exposed to repeated immobilization stress.

PubMed

Kvetnansky, Richard; Novak, Petr; Vargovic, Peter; Lejavova, Katarina; Horvathova, Lubica; Ondicova, Katarina; Manz, George; Filipcik, Peter; Novak, Michal; Mravec, Boris

2016-07-01

Neuroendocrine and behavioral stress responses are orchestrated by corticotropin-releasing hormone (CRH) and norepinephrine (NE) synthesizing neurons. Recent findings indicate that stress may promote development of neurofibrillary pathology in Alzheimer's disease. Therefore, we investigated relationships among stress, tau protein phosphorylation, and brain NE using wild-type (WT) and CRH-knockout (CRH KO) mice. We assessed expression of phosphorylated tau (p-tau) at the PHF-1 epitope and NE concentrations in the locus coeruleus (LC), A1/C1 and A2/C2 catecholaminergic cell groups, hippocampus, amygdala, nucleus basalis magnocellularis, and frontal cortex of unstressed, singly stressed or repeatedly stressed mice. Moreover, gene expression and protein levels of tyrosine hydroxylase (TH) and CRH receptor mRNA were determined in the LC. Plasma corticosterone levels were also measured. Exposure to a single stress increases tau phosphorylation throughout the brain in WT mice when compared to singly stressed CRH KO animals. In contrast, repeatedly stressed CRH KO mice showed exaggerated tau phosphorylation relative to WT controls. We also observed differences in extent of tau phosphorylation between investigated structures, e.g. the LC and hippocampus. Moreover, CRH deficiency leads to different responses to stress in gene expression of TH, NE concentrations, CRH receptor mRNA, and plasma corticosterone levels. Our data indicate that CRH effects on tau phosphorylation are dependent on whether stress is single or repeated, and differs between brain regions. Our findings indicate that CRH attenuates mechanisms responsible for development of stress-induced tau neuropathology, particularly in conditions of chronic stress. However, the involvement of central catecholaminergic neurons in these mechanisms remains unclear and is in need of further investigation.

Processing of Intraoral Olfactory and Gustatory Signals in the Gustatory Cortex of Awake Rats

PubMed Central

Fontanini, Alfredo

2017-01-01

The integration of gustatory and olfactory information is essential to the perception of flavor. Human neuroimaging experiments have pointed to the gustatory cortex (GC) as one of the areas involved in mediating flavor perception. Although GC's involvement in encoding the chemical identity and hedonic value of taste stimuli is well studied, it is unknown how single GC neurons process olfactory stimuli emanating from the mouth. In this study, we relied on multielectrode recordings to investigate how single GC neurons respond to intraorally delivered tastants and tasteless odorants dissolved in water and whether/how these two modalities converge in the same neurons. We found that GC neurons could either be unimodal, responding exclusively to taste (taste-only) or odor (odor-only), or bimodal, responding to both gustatory and olfactory stimuli. Odor responses were confirmed to result from retronasal olfaction: monitoring respiration revealed that exhalation preceded odor-evoked activity and reversible inactivation of olfactory receptors in the nasal epithelium significantly reduced responses to intraoral odorants but not to tastants. Analysis of bimodal neurons revealed that they encode palatability significantly better than the unimodal taste-only group. Bimodal neurons exhibited similar responses to palatable tastants and odorants dissolved in water. This result suggested that odorized water could be palatable. This interpretation was further supported with a brief access task, where rats avoided consuming aversive taste stimuli and consumed the palatable tastants and dissolved odorants. These results demonstrate the convergence of the chemosensory components of flavor onto single GC neurons and provide evidence for the integration of flavor with palatability coding. SIGNIFICANCE STATEMENT Food perception and choice depend upon the concurrent processing of olfactory and gustatory signals from the mouth. The primary gustatory cortex has been proposed to integrate chemosensory stimuli; however, no study has examined the single-unit responses to intraoral odorant presentation. Here we found that neurons in gustatory cortex can respond either exclusively to tastants, exclusively to odorants, or to both (bimodal). Several differences exist between these groups' responses; notably, bimodal neurons code palatability significantly better than unimodal neurons. This group of neurons might represent a substrate for how odorants gain the quality of tastants. PMID:28077705

The granularity of grasping. Comment on "Grasping synergies: A motor-control approach to the mirror neuron mechanism" by A. D'Ausilio et al.

NASA Astrophysics Data System (ADS)

Hamilton, Antonia F. de C.

2015-03-01

The idea that mirror neuron systems in the human and the macaque monkey could provide a link between perceiving an action and performing it has spurred intense research [1,2]. Hundreds of papers now examine if this link exists and what it might contribute to human behaviour. The review article from D'Ausilio et al. [3] highlights how relatively few papers have considered the granularity of coding with mirror neuron systems, and even fewer have directly tested different possibilities. Granularity refers to the critical question of what actually is encoded within the mirror system - are neurons selective for low level kinematic features such as joint angle, or for postural synergies, or for action goals? Focusing on studies of single neurons in macaques and on studies measuring the excitability of primary motor cortex with TMS, the review suggests that it is very hard to distinguish low-level kinematic from goal representations. Furthermore, these two levels are often highly correlated in real-life contexts - the kinematics needed to grasp an apple are defined by the shape of the goal (an apple tends to be a large sphere) and these kinematics differ for other possible goals (a pencil which is a narrow cylinder). In some cases, kinematics may be enough to define a goal [4]. The review suggests that it is therefore arbitrary to distinguish these levels, and that a synergy level might be a better way to understand the mirror system. Synergies are a form of coding based on commonly used hand-shapes or hand postures, which take into account the fact that some joint angles are more likely to co-occur than others. Evidence that different grasp shapes are represented separately in premotor cortex has been found [5]. These could provide an intermediate level of representation between muscle activity and goals. The review proposes that a synergy level of granularity provides the best way to consider both the motor system and the role of the mirror system in understanding actions.

Modeling schizophrenia using hiPSC neurons

PubMed Central

Brennand, Kristen; Simone, Anthony; Jou, Jessica; Gelboin-Burkhart, Chelsea; Tran, Ngoc; Sangar, Sarah; Li, Yan; Mu, Yangling; Chen, Gong; Yu, Diana; McCarthy, Shane; Sebat, Jonathan; Gage, Fred H.

2012-01-01

SUMMARY Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80–85%1. Though postmortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue2 and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD3, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (SI Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cAMP and WNT signaling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic Loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood4–6. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder (SI Table 1). PMID:21490598

Membrane Properties and the Balance between Excitation and Inhibition Control Gamma-Frequency Oscillations Arising from Feedback Inhibition

PubMed Central

Economo, Michael N.; White, John A.

2012-01-01

Computational studies as well as in vivo and in vitro results have shown that many cortical neurons fire in a highly irregular manner and at low average firing rates. These patterns seem to persist even when highly rhythmic signals are recorded by local field potential electrodes or other methods that quantify the summed behavior of a local population. Models of the 30–80 Hz gamma rhythm in which network oscillations arise through ‘stochastic synchrony’ capture the variability observed in the spike output of single cells while preserving network-level organization. We extend upon these results by constructing model networks constrained by experimental measurements and using them to probe the effect of biophysical parameters on network-level activity. We find in simulations that gamma-frequency oscillations are enabled by a high level of incoherent synaptic conductance input, similar to the barrage of noisy synaptic input that cortical neurons have been shown to receive in vivo. This incoherent synaptic input increases the emergent network frequency by shortening the time scale of the membrane in excitatory neurons and by reducing the temporal separation between excitation and inhibition due to decreased spike latency in inhibitory neurons. These mechanisms are demonstrated in simulations and in vitro current-clamp and dynamic-clamp experiments. Simulation results further indicate that the membrane potential noise amplitude has a large impact on network frequency and that the balance between excitatory and inhibitory currents controls network stability and sensitivity to external inputs. PMID:22275859

Effect of raclopride on dopamine D2 receptor mRNA expression in rat brain.

PubMed

Kopp, J; Lindefors, N; Brené, S; Hall, H; Persson, H; Sedvall, G

1992-01-01

Prolonged treatment with dopamine D2 receptor antagonists is known to elevate the density of dopamine D2 receptor binding sites in caudate-putamen and nucleus accumbens in rat and human brain. In this study we used the dopamine D2 receptor antagonist raclopride (3 mumol/kg, s.c.) to determine if a single injection or daily administration of this drug for up to 18 days changed the expression of dopamine D2 receptor mRNA in rat caudate-putamen and accumbens as measured by in situ hybridization. A single injection of raclopride did not significantly change the numerical density of dopamine D2 receptor mRNA-expressing neurons in any of the regions examined. A daily administration of raclopride for 18 days resulted in a 31% increase in the number of cells expressing detectable amounts of dopamine D2 receptor mRNA in dorsolateral caudate-putamen and in a 20% increase in the area of silver grains over individual hybridization-positive neurons in this brain region measured on emulsion-dipped slides. The region-specific increase in the D2 receptor mRNA level in dorsolateral caudate-putamen was confirmed by measurement of the hybridization signal on X-ray film autoradiograms. The levels of D2 receptor mRNA remained unchanged in medial caudate-putamen and accumbens after 18 days' treatment. The region-selective increase in dopamine D2 receptor mRNA expression in dorsolateral caudate-putamen indicates a differential regulation of dopamine D2 receptor mRNA expression in a subpopulation of caudate-putamen neurons by this neuroleptic. We suggest that the increase in dopamine D2 receptor density in caudate-putamen known to follow prolonged dopamine D2 receptor blockade to some extent is regulated at the level of gene expression.

Extensive excitatory network interactions shape temporal processing of communication signals in a model sensory system.

PubMed

Ma, Xiaofeng; Kohashi, Tsunehiko; Carlson, Bruce A

2013-07-01

Many sensory brain regions are characterized by extensive local network interactions. However, we know relatively little about the contribution of this microcircuitry to sensory coding. Detailed analyses of neuronal microcircuitry are usually performed in vitro, whereas sensory processing is typically studied by recording from individual neurons in vivo. The electrosensory pathway of mormyrid fish provides a unique opportunity to link in vitro studies of synaptic physiology with in vivo studies of sensory processing. These fish communicate by actively varying the intervals between pulses of electricity. Within the midbrain posterior exterolateral nucleus (ELp), the temporal filtering of afferent spike trains establishes interval tuning by single neurons. We characterized pairwise neuronal connectivity among ELp neurons with dual whole cell recording in an in vitro whole brain preparation. We found a densely connected network in which single neurons influenced the responses of other neurons throughout the network. Similarly tuned neurons were more likely to share an excitatory synaptic connection than differently tuned neurons, and synaptic connections between similarly tuned neurons were stronger than connections between differently tuned neurons. We propose a general model for excitatory network interactions in which strong excitatory connections both reinforce and adjust tuning and weak excitatory connections make smaller modifications to tuning. The diversity of interval tuning observed among this population of neurons can be explained, in part, by each individual neuron receiving a different complement of local excitatory inputs.

Spatial Tuning Shifts Increase the Discriminability and Fidelity of Population Codes in Visual Cortex

PubMed Central

2017-01-01

Selective visual attention enables organisms to enhance the representation of behaviorally relevant stimuli by altering the encoding properties of single receptive fields (RFs). Yet we know little about how the attentional modulations of single RFs contribute to the encoding of an entire visual scene. Addressing this issue requires (1) measuring a group of RFs that tile a continuous portion of visual space, (2) constructing a population-level measurement of spatial representations based on these RFs, and (3) linking how different types of RF attentional modulations change the population-level representation. To accomplish these aims, we used fMRI to characterize the responses of thousands of voxels in retinotopically organized human cortex. First, we found that the response modulations of voxel RFs (vRFs) depend on the spatial relationship between the RF center and the visual location of the attended target. Second, we used two analyses to assess the spatial encoding quality of a population of voxels. We found that attention increased fine spatial discriminability and representational fidelity near the attended target. Third, we linked these findings by manipulating the observed vRF attentional modulations and recomputing our measures of the fidelity of population codes. Surprisingly, we discovered that attentional enhancements of population-level representations largely depend on position shifts of vRFs, rather than changes in size or gain. Our data suggest that position shifts of single RFs are a principal mechanism by which attention enhances population-level representations in visual cortex. SIGNIFICANCE STATEMENT Although changes in the gain and size of RFs have dominated our view of how attention modulates visual information codes, such hypotheses have largely relied on the extrapolation of single-cell responses to population responses. Here we use fMRI to relate changes in single voxel receptive fields (vRFs) to changes in population-level representations. We find that vRF position shifts contribute more to population-level enhancements of visual information than changes in vRF size or gain. This finding suggests that position shifts are a principal mechanism by which spatial attention enhances population codes for relevant visual information. This poses challenges for labeled line theories of information processing, suggesting that downstream regions likely rely on distributed inputs rather than single neuron-to-neuron mappings. PMID:28242794

Transcriptomic correlates of neuron electrophysiological diversity

PubMed Central

Li, Brenna; Crichlow, Cindy-Lee; Mancarci, B. Ogan; Pavlidis, Paul

2017-01-01

How neuronal diversity emerges from complex patterns of gene expression remains poorly understood. Here we present an approach to understand electrophysiological diversity through gene expression by integrating pooled- and single-cell transcriptomics with intracellular electrophysiology. Using neuroinformatics methods, we compiled a brain-wide dataset of 34 neuron types with paired gene expression and intrinsic electrophysiological features from publically accessible sources, the largest such collection to date. We identified 420 genes whose expression levels significantly correlated with variability in one or more of 11 physiological parameters. We next trained statistical models to infer cellular features from multivariate gene expression patterns. Such models were predictive of gene-electrophysiological relationships in an independent collection of 12 visual cortex cell types from the Allen Institute, suggesting that these correlations might reflect general principles relating expression patterns to phenotypic diversity across very different cell types. Many associations reported here have the potential to provide new insights into how neurons generate functional diversity, and correlations of ion channel genes like Gabrd and Scn1a (Nav1.1) with resting potential and spiking frequency are consistent with known causal mechanisms. Our work highlights the promise and inherent challenges in using cell type-specific transcriptomics to understand the mechanistic origins of neuronal diversity. PMID:29069078

The AMPA receptor subunit GluR1 regulates dendritic architecture of motor neurons

NASA Technical Reports Server (NTRS)

Inglis, Fiona M.; Crockett, Richard; Korada, Sailaja; Abraham, Wickliffe C.; Hollmann, Michael; Kalb, Robert G.

2002-01-01

The morphology of the mature motor neuron dendritic arbor is determined by activity-dependent processes occurring during a critical period in early postnatal life. The abundance of the AMPA receptor subunit GluR1 in motor neurons is very high during this period and subsequently falls to a negligible level. To test the role of GluR1 in dendrite morphogenesis, we reintroduced GluR1 into rat motor neurons at the end of the critical period and quantitatively studied the effects on dendrite architecture. Two versions of GluR1 were studied that differed by the amino acid in the "Q/R" editing site. The amino acid occupying this site determines single-channel conductance, ionic permeability, and other essential electrophysiologic properties of the resulting receptor channels. We found large-scale remodeling of dendritic architectures in a manner depending on the amino acid occupying the Q/R editing site. Alterations in the distribution of dendritic arbor were not prevented by blocking NMDA receptors. These observations suggest that the expression of GluR1 in motor neurons modulates a component of the molecular substrate of activity-dependent dendrite morphogenesis. The control of these events relies on subunit-specific properties of AMPA receptors.

Brain-state invariant thalamo-cortical coordination revealed by non-linear encoders.

PubMed

Viejo, Guillaume; Cortier, Thomas; Peyrache, Adrien

2018-03-01

Understanding how neurons cooperate to integrate sensory inputs and guide behavior is a fundamental problem in neuroscience. A large body of methods have been developed to study neuronal firing at the single cell and population levels, generally seeking interpretability as well as predictivity. However, these methods are usually confronted with the lack of ground-truth necessary to validate the approach. Here, using neuronal data from the head-direction (HD) system, we present evidence demonstrating how gradient boosted trees, a non-linear and supervised Machine Learning tool, can learn the relationship between behavioral parameters and neuronal responses with high accuracy by optimizing the information rate. Interestingly, and unlike other classes of Machine Learning methods, the intrinsic structure of the trees can be interpreted in relation to behavior (e.g. to recover the tuning curves) or to study how neurons cooperate with their peers in the network. We show how the method, unlike linear analysis, reveals that the coordination in thalamo-cortical circuits is qualitatively the same during wakefulness and sleep, indicating a brain-state independent feed-forward circuit. Machine Learning tools thus open new avenues for benchmarking model-based characterization of spike trains.

Brain-state invariant thalamo-cortical coordination revealed by non-linear encoders

PubMed Central

Cortier, Thomas; Peyrache, Adrien

2018-01-01

Understanding how neurons cooperate to integrate sensory inputs and guide behavior is a fundamental problem in neuroscience. A large body of methods have been developed to study neuronal firing at the single cell and population levels, generally seeking interpretability as well as predictivity. However, these methods are usually confronted with the lack of ground-truth necessary to validate the approach. Here, using neuronal data from the head-direction (HD) system, we present evidence demonstrating how gradient boosted trees, a non-linear and supervised Machine Learning tool, can learn the relationship between behavioral parameters and neuronal responses with high accuracy by optimizing the information rate. Interestingly, and unlike other classes of Machine Learning methods, the intrinsic structure of the trees can be interpreted in relation to behavior (e.g. to recover the tuning curves) or to study how neurons cooperate with their peers in the network. We show how the method, unlike linear analysis, reveals that the coordination in thalamo-cortical circuits is qualitatively the same during wakefulness and sleep, indicating a brain-state independent feed-forward circuit. Machine Learning tools thus open new avenues for benchmarking model-based characterization of spike trains. PMID:29565979

Optimization Methods for Spiking Neurons and Networks

PubMed Central

Russell, Alexander; Orchard, Garrick; Dong, Yi; Mihalaş, Ştefan; Niebur, Ernst; Tapson, Jonathan; Etienne-Cummings, Ralph

2011-01-01

Spiking neurons and spiking neural circuits are finding uses in a multitude of tasks such as robotic locomotion control, neuroprosthetics, visual sensory processing, and audition. The desired neural output is achieved through the use of complex neuron models, or by combining multiple simple neurons into a network. In either case, a means for configuring the neuron or neural circuit is required. Manual manipulation of parameters is both time consuming and non-intuitive due to the nonlinear relationship between parameters and the neuron’s output. The complexity rises even further as the neurons are networked and the systems often become mathematically intractable. In large circuits, the desired behavior and timing of action potential trains may be known but the timing of the individual action potentials is unknown and unimportant, whereas in single neuron systems the timing of individual action potentials is critical. In this paper, we automate the process of finding parameters. To configure a single neuron we derive a maximum likelihood method for configuring a neuron model, specifically the Mihalas–Niebur Neuron. Similarly, to configure neural circuits, we show how we use genetic algorithms (GAs) to configure parameters for a network of simple integrate and fire with adaptation neurons. The GA approach is demonstrated both in software simulation and hardware implementation on a reconfigurable custom very large scale integration chip. PMID:20959265

Elevated correlations in neuronal ensembles of mouse auditory cortex following parturition.

PubMed

Rothschild, Gideon; Cohen, Lior; Mizrahi, Adi; Nelken, Israel

2013-07-31

The auditory cortex is malleable by experience. Previous studies of auditory plasticity have described experience-dependent changes in response profiles of single neurons or changes in global tonotopic organization. However, experience-dependent changes in the dynamics of local neural populations have remained unexplored. In this study, we examined the influence of a dramatic yet natural experience in the life of female mice, giving birth and becoming a mother on single neurons and neuronal ensembles in the primary auditory cortex (A1). Using in vivo two-photon calcium imaging and electrophysiological recordings from layer 2/3 in A1 of mothers and age-matched virgin mice, we monitored changes in the responses to a set of artificial and natural sounds. Population dynamics underwent large changes as measured by pairwise and higher-order correlations, with noise correlations increasing as much as twofold in lactating mothers. Concomitantly, changes in response properties of single neurons were modest and selective. Remarkably, despite the large changes in correlations, information about stimulus identity remained essentially the same in the two groups. Our results demonstrate changes in the correlation structure of neuronal activity as a result of a natural life event.

Automated quantification of neuronal networks and single-cell calcium dynamics using calcium imaging

PubMed Central

Patel, Tapan P.; Man, Karen; Firestein, Bonnie L.; Meaney, David F.

2017-01-01

Background Recent advances in genetically engineered calcium and membrane potential indicators provide the potential to estimate the activation dynamics of individual neurons within larger, mesoscale networks (100s–1000 +neurons). However, a fully integrated automated workflow for the analysis and visualization of neural microcircuits from high speed fluorescence imaging data is lacking. New method Here we introduce FluoroSNNAP, Fluorescence Single Neuron and Network Analysis Package. FluoroSNNAP is an open-source, interactive software developed in MATLAB for automated quantification of numerous biologically relevant features of both the calcium dynamics of single-cells and network activity patterns. FluoroSNNAP integrates and improves upon existing tools for spike detection, synchronization analysis, and inference of functional connectivity, making it most useful to experimentalists with little or no programming knowledge. Results We apply FluoroSNNAP to characterize the activity patterns of neuronal microcircuits undergoing developmental maturation in vitro. Separately, we highlight the utility of single-cell analysis for phenotyping a mixed population of neurons expressing a human mutant variant of the microtubule associated protein tau and wild-type tau. Comparison with existing method(s) We show the performance of semi-automated cell segmentation using spatiotemporal independent component analysis and significant improvement in detecting calcium transients using a template-based algorithm in comparison to peak-based or wavelet-based detection methods. Our software further enables automated analysis of microcircuits, which is an improvement over existing methods. Conclusions We expect the dissemination of this software will facilitate a comprehensive analysis of neuronal networks, promoting the rapid interrogation of circuits in health and disease. PMID:25629800

Analysis of fault-tolerant neurocontrol architectures

NASA Technical Reports Server (NTRS)

Troudet, T.; Merrill, W.

1992-01-01

The fault-tolerance of analog parallel distributed implementations of a multivariable aircraft neurocontroller is analyzed by simulating weight and neuron failures in a simplified scheme of analog processing based on the functional architecture of the ETANN chip (Electrically Trainable Artificial Neural Network). The neural information processing is found to be only partially distributed throughout the set of weights of the neurocontroller synthesized with the backpropagation algorithm. Although the degree of distribution of the neural processing, and consequently the fault-tolerance of the neurocontroller, could be enhanced using Locally Distributed Weight and Neuron Approaches, a satisfactory level of fault-tolerance could only be obtained by retraining the degrated VLSI neurocontroller. The possibility of maintaining neurocontrol performance and stability in the presence of single weight of neuron failures was demonstrated through an automated retraining procedure of the neurocontroller based on a pre-programmed choice and sequence of the training parameters.

Brain-wide neuronal dynamics during motor adaptation in zebrafish.

PubMed

Ahrens, Misha B; Li, Jennifer M; Orger, Michael B; Robson, Drew N; Schier, Alexander F; Engert, Florian; Portugues, Ruben

2012-05-09

A fundamental question in neuroscience is how entire neural circuits generate behaviour and adapt it to changes in sensory feedback. Here we use two-photon calcium imaging to record the activity of large populations of neurons at the cellular level, throughout the brain of larval zebrafish expressing a genetically encoded calcium sensor, while the paralysed animals interact fictively with a virtual environment and rapidly adapt their motor output to changes in visual feedback. We decompose the network dynamics involved in adaptive locomotion into four types of neuronal response properties, and provide anatomical maps of the corresponding sites. A subset of these signals occurred during behavioural adjustments and are candidates for the functional elements that drive motor learning. Lesions to the inferior olive indicate a specific functional role for olivocerebellar circuitry in adaptive locomotion. This study enables the analysis of brain-wide dynamics at single-cell resolution during behaviour.

A mini-overview of single muscle fibre mechanics: the effects of age, inactivity and exercise in animals and humans.

PubMed

Jee, Hyunseok; Kim, Jong-Hee

2017-09-05

Many basic movements of living organisms are dependent on muscle function. Muscle function allows for the coordination and harmonious integrity of movement that is necessary for various biological processes. Gross and fine motor skills are both regulated at the micro-level (single muscle fibre level), controlled by neuronal regulation, and it is therefore important to understand muscle function at both micro- and macro-levels to understand the overall movement of living organisms. Single muscle mechanics and the cellular environment of muscles fundamentally allow for the harmonious movement of our bodies. Indeed, a clear understanding of the functionality of muscle at the micro-level is indispensable for explaining muscular function at the macro-(whole gross muscle) level. By investigating single muscle fibre mechanics, we can also learn how other factors such Ca2+ kinetics, enzyme activity and contractile proteins can contribute to muscle mechanics at the micro- and macro-levels. Further, we can also describe how aging affects the capacity of skeletal muscle cells, as well as how exercise can prevent aging-based sarcopenia and frailty. The purpose of this review is to introduce and summarise the current knowledge of single muscle fibre mechanics in light of aging and inactivity. We then describe how exercise mitigates negative muscle adaptations that occur under those circumstances. In addition, single muscle fibre mechanics in both animal and human models are discussed.

Hox repertoires for motor neuron diversity and connectivity gated by a single accessory factor, FoxP1.

PubMed

Dasen, Jeremy S; De Camilli, Alessandro; Wang, Bin; Tucker, Philip W; Jessell, Thomas M

2008-07-25

The precision with which motor neurons innervate target muscles depends on a regulatory network of Hox transcription factors that translates neuronal identity into patterns of connectivity. We show that a single transcription factor, FoxP1, coordinates motor neuron subtype identity and connectivity through its activity as a Hox accessory factor. FoxP1 is expressed in Hox-sensitive motor columns and acts as a dose-dependent determinant of columnar fate. Inactivation of Foxp1 abolishes the output of the motor neuron Hox network, reverting the spinal motor system to an ancestral state. The loss of FoxP1 also changes the pattern of motor neuron connectivity, and in the limb motor axons appear to select their trajectories and muscle targets at random. Our findings show that FoxP1 is a crucial determinant of motor neuron diversification and connectivity, and clarify how this Hox regulatory network controls the formation of a topographic neural map.

Brains are not just neurons. Comment on “Toward a computational framework for cognitive biology: Unifying approaches from cognitive neuroscience and comparative cognition” by Fitch

NASA Astrophysics Data System (ADS)

Huber, Ludwig

2014-09-01

This comment addresses the first component of Fitch's framework: the computational power of single neurons [3]. Although I agree that traditional models of neural computation have vastly underestimated the computational power of single neurons, I am hesitant to follow him completely. The exclusive focus on neurons is likely to underestimate the importance of other cells in the brain. In the last years, two such cell types have received appropriate attention by neuroscientists: interneurons and glia. Interneurons are small, tightly packed cells involved in the control of information processing in learning and memory. Rather than transmitting externally (like motor or sensory neurons), these neurons process information within internal circuits of the brain (therefore also called 'relay neurons'). Some specialized interneuron subtypes temporally regulate the flow of information in a given cortical circuit during relevant behavioral events [4]. In the human brain approx. 100 billion interneurons control information processing and are implicated in disorders such as epilepsy and Parkinson's.

Multifractal analysis of information processing in hippocampal neural ensembles during working memory under Δ9-tetrahydrocannabinol administration

PubMed Central

Fetterhoff, Dustin; Opris, Ioan; Simpson, Sean L.; Deadwyler, Sam A.; Hampson, Robert E.; Kraft, Robert A.

2014-01-01

Background Multifractal analysis quantifies the time-scale-invariant properties in data by describing the structure of variability over time. By applying this analysis to hippocampal interspike interval sequences recorded during performance of a working memory task, a measure of long-range temporal correlations and multifractal dynamics can reveal single neuron correlates of information processing. New method Wavelet leaders-based multifractal analysis (WLMA) was applied to hippocampal interspike intervals recorded during a working memory task. WLMA can be used to identify neurons likely to exhibit information processing relevant to operation of brain–computer interfaces and nonlinear neuronal models. Results Neurons involved in memory processing (“Functional Cell Types” or FCTs) showed a greater degree of multifractal firing properties than neurons without task-relevant firing characteristics. In addition, previously unidentified FCTs were revealed because multifractal analysis suggested further functional classification. The cannabinoid-type 1 receptor partial agonist, tetrahydrocannabinol (THC), selectively reduced multifractal dynamics in FCT neurons compared to non-FCT neurons. Comparison with existing methods WLMA is an objective tool for quantifying the memory-correlated complexity represented by FCTs that reveals additional information compared to classification of FCTs using traditional z-scores to identify neuronal correlates of behavioral events. Conclusion z-Score-based FCT classification provides limited information about the dynamical range of neuronal activity characterized by WLMA. Increased complexity, as measured with multifractal analysis, may be a marker of functional involvement in memory processing. The level of multifractal attributes can be used to differentially emphasize neural signals to improve computational models and algorithms underlying brain–computer interfaces. PMID:25086297

The Neural Substrate for Binaural Masking Level Differences in the Auditory Cortex

PubMed Central

Gilbert, Heather J.; Krumbholz, Katrin; Palmer, Alan R.

2015-01-01

The binaural masking level difference (BMLD) is a phenomenon whereby a signal that is identical at each ear (S0), masked by a noise that is identical at each ear (N0), can be made 12–15 dB more detectable by inverting the waveform of either the tone or noise at one ear (Sπ, Nπ). Single-cell responses to BMLD stimuli were measured in the primary auditory cortex of urethane-anesthetized guinea pigs. Firing rate was measured as a function of signal level of a 500 Hz pure tone masked by low-passed white noise. Responses were similar to those reported in the inferior colliculus. At low signal levels, the response was dominated by the masker. At higher signal levels, firing rate either increased or decreased. Detection thresholds for each neuron were determined using signal detection theory. Few neurons yielded measurable detection thresholds for all stimulus conditions, with a wide range in thresholds. However, across the entire population, the lowest thresholds were consistent with human psychophysical BMLDs. As in the inferior colliculus, the shape of the firing-rate versus signal-level functions depended on the neurons' selectivity for interaural time difference. Our results suggest that, in cortex, BMLD signals are detected from increases or decreases in the firing rate, consistent with predictions of cross-correlation models of binaural processing and that the psychophysical detection threshold is based on the lowest neural thresholds across the population. PMID:25568115

Gli function is essential for motor neuron induction in zebrafish.

PubMed

Vanderlaan, Gary; Tyurina, Oksana V; Karlstrom, Rolf O; Chandrasekhar, Anand

2005-06-15

The Gli family of zinc-finger transcription factors mediates Hedgehog (Hh) signaling in all vertebrates. However, their roles in ventral neural tube patterning, in particular motor neuron induction, appear to have diverged across species. For instance, cranial motor neurons are essentially lost in zebrafish detour (gli1(-)) mutants, whereas motor neuron development is unaffected in mouse single gli and some double gli knockouts. Interestingly, the expression of some Hh-regulated genes (ptc1, net1a, gli1) is mostly unaffected in the detour mutant hindbrain, suggesting that other Gli transcriptional activators may be involved. To better define the roles of the zebrafish gli genes in motor neuron induction and in Hh-regulated gene expression, we examined these processes in you-too (yot) mutants, which encode dominant repressor forms of Gli2 (Gli2(DR)), and following morpholino-mediated knockdown of gli1, gli2, and gli3 function. Motor neuron induction at all axial levels was reduced in yot (gli2(DR)) mutant embryos. In addition, Hh target gene expression at all axial levels except in rhombomere 4 was also reduced, suggesting an interference with the function of other Glis. Indeed, morpholino-mediated knockdown of Gli2(DR) protein in yot mutants led to a suppression of the defective motor neuron phenotype. However, gli2 knockdown in wild-type embryos generated no discernable motor neuron phenotype, while gli3 knockdown reduced motor neuron induction in the hindbrain and spinal cord. Significantly, gli2 or gli3 knockdown in detour (gli1(-)) mutants revealed roles for Gli2 and Gli3 activator functions in ptc1 expression and spinal motor neuron induction. Similarly, gli1 or gli3 knockdown in yot (gli2(DR)) mutants resulted in severe or complete loss of motor neurons, and of ptc1 and net1a expression, in the hindbrain and spinal cord. In addition, gli1 expression was greatly reduced in yot mutants following gli3, but not gli1, knockdown, suggesting that Gli3 activator function is specifically required for gli1 expression. These observations demonstrate that Gli activator function (encoded by gli1, gli2, and gli3) is essential for motor neuron induction and Hh-regulated gene expression in zebrafish.

Creation of defined single cell resolution neuronal circuits on microelectrode arrays

NASA Astrophysics Data System (ADS)

Pirlo, Russell Kirk

2009-12-01

The way cell-cell organization of neuronal networks influences activity and facilitates function is not well understood. Microelectrode arrays (MEAs) and advancing cell patterning technologies have enabled access to and control of in vitro neuronal networks spawning much new research in neuroscience and neuroengineering. We propose that small, simple networks of neurons with defined circuitry may serve as valuable research models where every connection can be analyzed, controlled and manipulated. Towards the goal of creating such neuronal networks we have applied microfabricated elastomeric membranes, surface modification and our unique laser cell patterning system to create defined neuronal circuits with single-cell precision on MEAs. Definition of synaptic connectivity was imposed by the 3D physical constraints of polydimethylsiloxane elastomeric membranes. The membranes had 20mum clear-through holes and 2-3mum deep channels which when applied to the surface of the MEA formed microwells to confine neurons to electrodes connected via shallow tunnels to direct neurite outgrowth. Tapering and turning of channels was used to influence neurite polarity. Biocompatibility of the membranes was increased by vacuum baking, oligomer extraction, and autoclaving. Membranes were bound to the MEA by oxygen plasma treatment and heated pressure. The MEA/membrane surface was treated with oxygen plasma, poly-D-lysine and laminin to improve neuron attachment, survival and neurite outgrowth. Prior to cell patterning the outer edge of culture area was seeded with 5x10 5 cells per cm and incubated for 2 days. Single embryonic day 7 chick forebrain neurons were then patterned into the microwells and onto the electrodes using our laser cell patterning system. Patterned neurons successfully attached to and were confined to the electrodes. Neurites extended through the interconnecting channels and connected with adjacent neurons. These results demonstrate that neuronal circuits can be created with clearly defined circuitry and a one-to-one neuron-electrode ratio. The techniques and processes described here may be used in future research to create defined neuronal circuits to model in vivo circuits and study neuronal network processing.

Patterns of fast synaptic cholinergic activation of neurons in the celiac ganglia of cats.

PubMed

Niel, J P; Clerc, N; Jule, Y

1988-12-01

Fast nicotinic transmission was studied in vitro in neurons of isolated cat celiac ganglia. In the absence of nerve stimulation, neurons could be classified into three types: silent neurons, synaptically activated neurons, and spontaneously discharging neurons. In all three types, fast synaptic activation could be obtained in single neurons by stimulating with a single pulse both the splanchnic nerves or one of the peripheral nerves connected to the ganglia. During repetitive nerve stimulation, a gradual depression of the central and peripheral fast nicotinic activation occurred, which was not affected by phentolamine plus propranolol, domperidone, atropine, or naloxone. Repetitive nerve stimulation was followed by a long lasting discharge of excitatory postsynaptic potentials and action potentials that decreased gradually with time. This discharge, which was probably due to presynaptic or prejunctional facilitation of acetylcholine release from cholinergic terminals, was reduced by the application of phentolamine plus propranolol, domperidone, or atropine and increased with naloxone. The existence of the mechanisms described in this study reflects the complexity of the integrative processes at work in neurons of the cat celiac ganglia that involve fast synaptic cholinergic activation.

Single-Neuron NMDA Receptor Phenotype Influences Neuronal Rewiring and Reintegration following Traumatic Injury

PubMed Central

Patel, Tapan P.; Ventre, Scott C.; Geddes-Klein, Donna; Singh, Pallab K.

2014-01-01

Alterations in the activity of neural circuits are a common consequence of traumatic brain injury (TBI), but the relationship between single-neuron properties and the aggregate network behavior is not well understood. We recently reported that the GluN2B-containing NMDA receptors (NMDARs) are key in mediating mechanical forces during TBI, and that TBI produces a complex change in the functional connectivity of neuronal networks. Here, we evaluated whether cell-to-cell heterogeneity in the connectivity and aggregate contribution of GluN2B receptors to [Ca2+]i before injury influenced the functional rewiring, spontaneous activity, and network plasticity following injury using primary rat cortical dissociated neurons. We found that the functional connectivity of a neuron to its neighbors, combined with the relative influx of calcium through distinct NMDAR subtypes, together contributed to the individual neuronal response to trauma. Specifically, individual neurons whose [Ca2+]i oscillations were largely due to GluN2B NMDAR activation lost many of their functional targets 1 h following injury. In comparison, neurons with large GluN2A contribution or neurons with high functional connectivity both independently protected against injury-induced loss in connectivity. Mechanistically, we found that traumatic injury resulted in increased uncorrelated network activity, an effect linked to reduction of the voltage-sensitive Mg2+ block of GluN2B-containing NMDARs. This uncorrelated activation of GluN2B subtypes after injury significantly limited the potential for network remodeling in response to a plasticity stimulus. Together, our data suggest that two single-cell characteristics, the aggregate contribution of NMDAR subtypes and the number of functional connections, influence network structure following traumatic injury. PMID:24647941

A new model of strabismic amblyopia: Loss of spatial acuity due to increased temporal dispersion of geniculate X-cell afferents on to cortical neurons.

PubMed

Crewther, D P; Crewther, S G

2015-09-01

Although the neural locus of strabismic amblyopia has been shown to lie at the first site of binocular integration, first in cat and then in primate, an adequate mechanism is still lacking. Here we hypothesise that increased temporal dispersion of LGN X-cell afferents driven by the deviating eye onto single cortical neurons may provide a neural mechanism for strabismic amblyopia. This idea was investigated via single cell extracellular recordings of 93 X and 50 Y type LGN neurons from strabismic and normal cats. Both X and Y neurons driven by the non-deviating eye showed shorter latencies than those driven by either the strabismic or normal eyes. Also the mean latency difference between X and Y neurons was much greater for the strabismic cells compared with the other two groups. The incidence of lagged X-cells driven by the deviating eye of the strabismic cats was higher than that of LGN X-cells from normal animals. Remarkably, none of the cells recorded from the laminae driven by the non-deviating eye were of the lagged class. A simple computational model was constructed in which a mixture of lagged and non-lagged afferents converge on to single cortical neurons. Model cut-off spatial frequencies to a moving grating stimulus were sensitive to the temporal dispersion of the geniculate afferents. Thus strabismic amblyopia could be viewed as a lack of developmental tuning of geniculate lags for neurons driven by the amblyopic eye. Monocular control of fixation by the non-deviating eye is associated with reduced incidence of lagged neurons, suggesting that in normal vision, lagged neurons might play a role in maintaining binocular connections for cortical neurons. Copyright © 2014 Elsevier Ltd. All rights reserved.

Reagents that block neuronal death from Huntington's disease also curb oxidative stress.

PubMed

Valencia, Antonio; Sapp, Ellen; Reeves, Patrick B; Alexander, Jonathan; Masso, Nicholas; Li, Xueyi; Kegel, Kimberly B; DiFiglia, Marian

2012-01-04

Patients with Huntington's disease suffer severe neuronal loss and signs of oxidative damage in the brain. Previously we found that primary neurons from embryonic cortex of mice bearing the Huntington's disease mutation (140 glutamines inserted into exon 1 of huntingtin) showed higher levels of reactive oxygen species before cell death. Here, we treated mutant neurons with known neuroprotective agents and determined the effects on neuronal survival and levels of reactive oxygen species. Primary neurons were exposed to the neurotrophin, brain derived neurotrophic factor, the antioxidant N-acetyl-cysteine or a specific inhibitor of glycogen synthase kinase 3-β, SB216763. Each reagent increased the survival of the mutant neurons compared with untreated mutant neurons and also reduced the levels of reactive oxygen species to levels of wild-type neurons. These results suggest that reducing the levels of reactive oxygen species may be necessary to protect neurons with the Huntington's disease mutation from cell death.

A new approach to spike sorting for multi-neuronal activities recorded with a tetrode--how ICA can be practical.

PubMed

Takahashi, Susumu; Anzai, Yuichiro; Sakurai, Yoshio

2003-07-01

Multi-neuronal recording with a tetrode is a powerful technique to reveal neuronal interactions in local circuits. However, it is difficult to detect precise spike timings among closely neighboring neurons because the spike waveforms of individual neurons overlap on the electrode when more than two neurons fire simultaneously. In addition, the spike waveforms of single neurons, especially in the presence of complex spikes, are often non-stationary. These problems limit the ability of ordinary spike sorting to sort multi-neuronal activities recorded using tetrodes into their single-neuron components. Though sorting with independent component analysis (ICA) can solve these problems, it has one serious limitation that the number of separated neurons must be less than the number of electrodes. Using a combination of ICA and the efficiency of ordinary spike sorting technique (k-means clustering), we developed an automatic procedure to solve the spike-overlapping and the non-stationarity problems with no limitation on the number of separated neurons. The results for the procedure applied to real multi-neuronal data demonstrated that some outliers which may be assigned to distinct clusters if ordinary spike-sorting methods were used can be identified as overlapping spikes, and that there are functional connections between a putative pyramidal neuron and its putative dendrite. These findings suggest that the combination of ICA and k-means clustering can provide insights into the precise nature of functional circuits among neurons, i.e. cell assemblies.

Divisive normalization and neuronal oscillations in a single hierarchical framework of selective visual attention.

PubMed

Montijn, Jorrit Steven; Klink, P Christaan; van Wezel, Richard J A

2012-01-01

Divisive normalization models of covert attention commonly use spike rate modulations as indicators of the effect of top-down attention. In addition, an increasing number of studies have shown that top-down attention increases the synchronization of neuronal oscillations as well, particularly in gamma-band frequencies (25-100 Hz). Although modulations of spike rate and synchronous oscillations are not mutually exclusive as mechanisms of attention, there has thus far been little effort to integrate these concepts into a single framework of attention. Here, we aim to provide such a unified framework by expanding the normalization model of attention with a multi-level hierarchical structure and a time dimension; allowing the simulation of a recently reported backward progression of attentional effects along the visual cortical hierarchy. A simple cascade of normalization models simulating different cortical areas is shown to cause signal degradation and a loss of stimulus discriminability over time. To negate this degradation and ensure stable neuronal stimulus representations, we incorporate a kind of oscillatory phase entrainment into our model that has previously been proposed as the "communication-through-coherence" (CTC) hypothesis. Our analysis shows that divisive normalization and oscillation models can complement each other in a unified account of the neural mechanisms of selective visual attention. The resulting hierarchical normalization and oscillation (HNO) model reproduces several additional spatial and temporal aspects of attentional modulation and predicts a latency effect on neuronal responses as a result of cued attention.

Divisive Normalization and Neuronal Oscillations in a Single Hierarchical Framework of Selective Visual Attention

PubMed Central

Montijn, Jorrit Steven; Klink, P. Christaan; van Wezel, Richard J. A.

2012-01-01

Divisive normalization models of covert attention commonly use spike rate modulations as indicators of the effect of top-down attention. In addition, an increasing number of studies have shown that top-down attention increases the synchronization of neuronal oscillations as well, particularly in gamma-band frequencies (25–100 Hz). Although modulations of spike rate and synchronous oscillations are not mutually exclusive as mechanisms of attention, there has thus far been little effort to integrate these concepts into a single framework of attention. Here, we aim to provide such a unified framework by expanding the normalization model of attention with a multi-level hierarchical structure and a time dimension; allowing the simulation of a recently reported backward progression of attentional effects along the visual cortical hierarchy. A simple cascade of normalization models simulating different cortical areas is shown to cause signal degradation and a loss of stimulus discriminability over time. To negate this degradation and ensure stable neuronal stimulus representations, we incorporate a kind of oscillatory phase entrainment into our model that has previously been proposed as the “communication-through-coherence” (CTC) hypothesis. Our analysis shows that divisive normalization and oscillation models can complement each other in a unified account of the neural mechanisms of selective visual attention. The resulting hierarchical normalization and oscillation (HNO) model reproduces several additional spatial and temporal aspects of attentional modulation and predicts a latency effect on neuronal responses as a result of cued attention. PMID:22586372

Modulation of Temporal Precision in Thalamic Population Responses to Natural Visual Stimuli

PubMed Central

Desbordes, Gaëlle; Jin, Jianzhong; Alonso, Jose-Manuel; Stanley, Garrett B.

2010-01-01

Natural visual stimuli have highly structured spatial and temporal properties which influence the way visual information is encoded in the visual pathway. In response to natural scene stimuli, neurons in the lateral geniculate nucleus (LGN) are temporally precise – on a time scale of 10–25 ms – both within single cells and across cells within a population. This time scale, established by non stimulus-driven elements of neuronal firing, is significantly shorter than that of natural scenes, yet is critical for the neural representation of the spatial and temporal structure of the scene. Here, a generalized linear model (GLM) that combines stimulus-driven elements with spike-history dependence associated with intrinsic cellular dynamics is shown to predict the fine timing precision of LGN responses to natural scene stimuli, the corresponding correlation structure across nearby neurons in the population, and the continuous modulation of spike timing precision and latency across neurons. A single model captured the experimentally observed neural response, across different levels of contrasts and different classes of visual stimuli, through interactions between the stimulus correlation structure and the nonlinearity in spike generation and spike history dependence. Given the sensitivity of the thalamocortical synapse to closely timed spikes and the importance of fine timing precision for the faithful representation of natural scenes, the modulation of thalamic population timing over these time scales is likely important for cortical representations of the dynamic natural visual environment. PMID:21151356

Dissecting Cell-Type Composition and Activity-Dependent Transcriptional State in Mammalian Brains by Massively Parallel Single-Nucleus RNA-Seq.

PubMed

Hu, Peng; Fabyanic, Emily; Kwon, Deborah Y; Tang, Sheng; Zhou, Zhaolan; Wu, Hao

2017-12-07

Massively parallel single-cell RNA sequencing can precisely resolve cellular diversity in a high-throughput manner at low cost, but unbiased isolation of intact single cells from complex tissues such as adult mammalian brains is challenging. Here, we integrate sucrose-gradient-assisted purification of nuclei with droplet microfluidics to develop a highly scalable single-nucleus RNA-seq approach (sNucDrop-seq), which is free of enzymatic dissociation and nucleus sorting. By profiling ∼18,000 nuclei isolated from cortical tissues of adult mice, we demonstrate that sNucDrop-seq not only accurately reveals neuronal and non-neuronal subtype composition with high sensitivity but also enables in-depth analysis of transient transcriptional states driven by neuronal activity, at single-cell resolution, in vivo. Copyright © 2017 Elsevier Inc. All rights reserved.

Recording large-scale neuronal ensembles with silicon probes in the anesthetized rat.

PubMed

Schjetnan, Andrea Gomez Palacio; Luczak, Artur

2011-10-19

Large scale electrophysiological recordings from neuronal ensembles offer the opportunity to investigate how the brain orchestrates the wide variety of behaviors from the spiking activity of its neurons. One of the most effective methods to monitor spiking activity from a large number of neurons in multiple local neuronal circuits simultaneously is by using silicon electrode arrays. Action potentials produce large transmembrane voltage changes in the vicinity of cell somata. These output signals can be measured by placing a conductor in close proximity of a neuron. If there are many active (spiking) neurons in the vicinity of the tip, the electrode records combined signal from all of them, where contribution of a single neuron is weighted by its 'electrical distance'. Silicon probes are ideal recording electrodes to monitor multiple neurons because of a large number of recording sites (+64) and a small volume. Furthermore, multiple sites can be arranged over a distance of millimeters, thus allowing for the simultaneous recordings of neuronal activity in the various cortical layers or in multiple cortical columns (Fig. 1). Importantly, the geometrically precise distribution of the recording sites also allows for the determination of the spatial relationship of the isolated single neurons. Here, we describe an acute, large-scale neuronal recording from the left and right forelimb somatosensory cortex simultaneously in an anesthetized rat with silicon probes (Fig. 2).

Recording Large-scale Neuronal Ensembles with Silicon Probes in the Anesthetized Rat

PubMed Central

Schjetnan, Andrea Gomez Palacio; Luczak, Artur

2011-01-01

Large scale electrophysiological recordings from neuronal ensembles offer the opportunity to investigate how the brain orchestrates the wide variety of behaviors from the spiking activity of its neurons. One of the most effective methods to monitor spiking activity from a large number of neurons in multiple local neuronal circuits simultaneously is by using silicon electrode arrays1-3. Action potentials produce large transmembrane voltage changes in the vicinity of cell somata. These output signals can be measured by placing a conductor in close proximity of a neuron. If there are many active (spiking) neurons in the vicinity of the tip, the electrode records combined signal from all of them, where contribution of a single neuron is weighted by its 'electrical distance'. Silicon probes are ideal recording electrodes to monitor multiple neurons because of a large number of recording sites (+64) and a small volume. Furthermore, multiple sites can be arranged over a distance of millimeters, thus allowing for the simultaneous recordings of neuronal activity in the various cortical layers or in multiple cortical columns (Fig. 1). Importantly, the geometrically precise distribution of the recording sites also allows for the determination of the spatial relationship of the isolated single neurons4. Here, we describe an acute, large-scale neuronal recording from the left and right forelimb somatosensory cortex simultaneously in an anesthetized rat with silicon probes (Fig. 2). PMID:22042361

Neuron-Type-Specific Utility in a Brain-Machine Interface: a Pilot Study.

PubMed

Garcia-Garcia, Martha G; Bergquist, Austin J; Vargas-Perez, Hector; Nagai, Mary K; Zariffa, Jose; Marquez-Chin, Cesar; Popovic, Milos R

2017-11-01

Firing rates of single cortical neurons can be volitionally modulated through biofeedback (i.e. operant conditioning), and this information can be transformed to control external devices (i.e. brain-machine interfaces; BMIs). However, not all neurons respond to operant conditioning in BMI implementation. Establishing criteria that predict neuron utility will assist translation of BMI research to clinical applications. Single cortical neurons (n=7) were recorded extracellularly from primary motor cortex of a Long-Evans rat. Recordings were incorporated into a BMI involving up-regulation of firing rate to control the brightness of a light-emitting-diode and subsequent reward. Neurons were classified as 'fast-spiking', 'bursting' or 'regular-spiking' according to waveform-width and intrinsic firing patterns. Fast-spiking and bursting neurons were found to up-regulate firing rate by a factor of 2.43±1.16, demonstrating high utility, while regular-spiking neurons decreased firing rates on average by a factor of 0.73±0.23, demonstrating low utility. The ability to select neurons with high utility will be important to minimize training times and maximize information yield in future clinical BMI applications. The highly contrasting utility observed between fast-spiking and bursting neurons versus regular-spiking neurons allows for the hypothesis to be advanced that intrinsic electrophysiological properties may be useful criteria that predict neuron utility in BMI implementation.

Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons.

PubMed

Webb, Alexis B; Angelo, Nikhil; Huettner, James E; Herzog, Erik D

2009-09-22

Circadian rhythms are modeled as reliable and self-sustained oscillations generated by single cells. The mammalian suprachiasmatic nucleus (SCN) keeps near 24-h time in vivo and in vitro, but the identity of the individual cellular pacemakers is unknown. We tested the hypothesis that circadian cycling is intrinsic to a unique class of SCN neurons by measuring firing rate or Period2 gene expression in single neurons. We found that fully isolated SCN neurons can sustain circadian cycling for at least 1 week. Plating SCN neurons at <100 cells/mm(2) eliminated synaptic inputs and revealed circadian neurons that contained arginine vasopressin (AVP) or vasoactive intestinal polypeptide (VIP) or neither. Surprisingly, arrhythmic neurons (nearly 80% of recorded neurons) also expressed these neuropeptides. Furthermore, neurons were observed to lose or gain circadian rhythmicity in these dispersed cell cultures, both spontaneously and in response to forskolin stimulation. In SCN explants treated with tetrodotoxin to block spike-dependent signaling, neurons gained or lost circadian cycling over many days. The rate of PERIOD2 protein accumulation on the previous cycle reliably predicted the spontaneous onset of arrhythmicity. We conclude that individual SCN neurons can generate circadian oscillations; however, there is no evidence for a specialized or anatomically localized class of cell-autonomous pacemakers. Instead, these results indicate that AVP, VIP, and other SCN neurons are intrinsic but unstable circadian oscillators that rely on network interactions to stabilize their otherwise noisy cycling.

Behavioral and Single-Neuron Sensitivity to Millisecond Variations in Temporally Patterned Communication Signals

PubMed Central

Baker, Christa A.; Ma, Lisa; Casareale, Chelsea R.

2016-01-01

In many sensory pathways, central neurons serve as temporal filters for timing patterns in communication signals. However, how a population of neurons with diverse temporal filtering properties codes for natural variation in communication signals is unknown. Here we addressed this question in the weakly electric fish Brienomyrus brachyistius, which varies the time intervals between successive electric organ discharges to communicate. These fish produce an individually stereotyped signal called a scallop, which consists of a distinctive temporal pattern of ∼8–12 electric pulses. We manipulated the temporal structure of natural scallops during behavioral playback and in vivo electrophysiology experiments to probe the temporal sensitivity of scallop encoding and recognition. We found that presenting time-reversed, randomized, or jittered scallops increased behavioral response thresholds, demonstrating that fish's electric signaling behavior was sensitive to the precise temporal structure of scallops. Next, using in vivo intracellular recordings and discriminant function analysis, we found that the responses of interval-selective midbrain neurons were also sensitive to the precise temporal structure of scallops. Subthreshold changes in membrane potential recorded from single neurons discriminated natural scallops from time-reversed, randomized, and jittered sequences. Pooling the responses of multiple neurons improved the discriminability of natural sequences from temporally manipulated sequences. Finally, we found that single-neuron responses were sensitive to interindividual variation in scallop sequences, raising the question of whether fish may analyze scallop structure to gain information about the sender. Collectively, these results demonstrate that a population of interval-selective neurons can encode behaviorally relevant temporal patterns with millisecond precision. SIGNIFICANCE STATEMENT The timing patterns of action potentials, or spikes, play important roles in representing information in the nervous system. However, how these temporal patterns are recognized by downstream neurons is not well understood. Here we use the electrosensory system of mormyrid weakly electric fish to investigate how a population of neurons with diverse temporal filtering properties encodes behaviorally relevant input timing patterns, and how this relates to behavioral sensitivity. We show that fish are behaviorally sensitive to millisecond variations in natural, temporally patterned communication signals, and that the responses of individual midbrain neurons are also sensitive to variation in these patterns. In fact, the output of single neurons contains enough information to discriminate stereotyped communication signals produced by different individuals. PMID:27559179

Behavioral and Single-Neuron Sensitivity to Millisecond Variations in Temporally Patterned Communication Signals.

PubMed

Baker, Christa A; Ma, Lisa; Casareale, Chelsea R; Carlson, Bruce A

2016-08-24

In many sensory pathways, central neurons serve as temporal filters for timing patterns in communication signals. However, how a population of neurons with diverse temporal filtering properties codes for natural variation in communication signals is unknown. Here we addressed this question in the weakly electric fish Brienomyrus brachyistius, which varies the time intervals between successive electric organ discharges to communicate. These fish produce an individually stereotyped signal called a scallop, which consists of a distinctive temporal pattern of ∼8-12 electric pulses. We manipulated the temporal structure of natural scallops during behavioral playback and in vivo electrophysiology experiments to probe the temporal sensitivity of scallop encoding and recognition. We found that presenting time-reversed, randomized, or jittered scallops increased behavioral response thresholds, demonstrating that fish's electric signaling behavior was sensitive to the precise temporal structure of scallops. Next, using in vivo intracellular recordings and discriminant function analysis, we found that the responses of interval-selective midbrain neurons were also sensitive to the precise temporal structure of scallops. Subthreshold changes in membrane potential recorded from single neurons discriminated natural scallops from time-reversed, randomized, and jittered sequences. Pooling the responses of multiple neurons improved the discriminability of natural sequences from temporally manipulated sequences. Finally, we found that single-neuron responses were sensitive to interindividual variation in scallop sequences, raising the question of whether fish may analyze scallop structure to gain information about the sender. Collectively, these results demonstrate that a population of interval-selective neurons can encode behaviorally relevant temporal patterns with millisecond precision. The timing patterns of action potentials, or spikes, play important roles in representing information in the nervous system. However, how these temporal patterns are recognized by downstream neurons is not well understood. Here we use the electrosensory system of mormyrid weakly electric fish to investigate how a population of neurons with diverse temporal filtering properties encodes behaviorally relevant input timing patterns, and how this relates to behavioral sensitivity. We show that fish are behaviorally sensitive to millisecond variations in natural, temporally patterned communication signals, and that the responses of individual midbrain neurons are also sensitive to variation in these patterns. In fact, the output of single neurons contains enough information to discriminate stereotyped communication signals produced by different individuals. Copyright © 2016 the authors 0270-6474/16/368985-16$15.00/0.

IRE1α pathway of endoplasmic reticulum stress induces neuronal apoptosis in the locus coeruleus of rats under single prolonged stress.

PubMed

Zhao, Wei; Han, Fang; Shi, Yuxiu

2016-08-01

Our previous studies have shown evidence of endoplasmic reticulum (ER) stress-induced apoptosis in the hippocampus and mPFC in an animal model of post- traumatic stress disorder (PTSD). Inositol-requiring enzyme 1α (IRE1α) and its downstream molecule X-box binding protein 1 (XBP1) play key roles in the ER-related apoptosis pathway. Dysregulation of the locus coeruleus (LC) has been reported to contribute to cognitive and/or arousal impairments associated with PTSD. The aim of the present study was to explore the role of IRE1α pathway in neuronal apoptosis in the LC of rat models of PTSD. We used an acute exposure to prolonged stress (single prolonged stress, SPS) to model PTSD in rats and examined the effects related to the IRE1α pathway. Neuronal apoptosis in LC was detected by transmission electron microscopy and TUNEL staining. The results showed that the level of LC neuronal apoptosis was markedly increased after SPS. SPS exposure triggered IRE1α pathway, as evidenced by the increased activity of IRE1α, specific splicing of XBP1, and up-regulated expression of binding immunoglobulin protein/78kDa glucose-regulated protein (BiP/GRP78), and C/EBP-homologous protein (CHOP). Treatment with STF-083010, an IRE1α RNase-specific inhibitor, successfully attenuated the above changes. These results indicate that excessive activation of the ER stress-associated IRE1α pathway is involved in LC neuronal apoptosis induced by SPS exposure; this may be a crucial mechanism of the pathogenesis of PTSD. Copyright © 2016 Elsevier Inc. All rights reserved.

Mean-field equations for neuronal networks with arbitrary degree distributions.

PubMed

Nykamp, Duane Q; Friedman, Daniel; Shaker, Sammy; Shinn, Maxwell; Vella, Michael; Compte, Albert; Roxin, Alex

2017-04-01

The emergent dynamics in networks of recurrently coupled spiking neurons depends on the interplay between single-cell dynamics and network topology. Most theoretical studies on network dynamics have assumed simple topologies, such as connections that are made randomly and independently with a fixed probability (Erdös-Rényi network) (ER) or all-to-all connected networks. However, recent findings from slice experiments suggest that the actual patterns of connectivity between cortical neurons are more structured than in the ER random network. Here we explore how introducing additional higher-order statistical structure into the connectivity can affect the dynamics in neuronal networks. Specifically, we consider networks in which the number of presynaptic and postsynaptic contacts for each neuron, the degrees, are drawn from a joint degree distribution. We derive mean-field equations for a single population of homogeneous neurons and for a network of excitatory and inhibitory neurons, where the neurons can have arbitrary degree distributions. Through analysis of the mean-field equations and simulation of networks of integrate-and-fire neurons, we show that such networks have potentially much richer dynamics than an equivalent ER network. Finally, we relate the degree distributions to so-called cortical motifs.

Mean-field equations for neuronal networks with arbitrary degree distributions

NASA Astrophysics Data System (ADS)

Nykamp, Duane Q.; Friedman, Daniel; Shaker, Sammy; Shinn, Maxwell; Vella, Michael; Compte, Albert; Roxin, Alex

2017-04-01

The emergent dynamics in networks of recurrently coupled spiking neurons depends on the interplay between single-cell dynamics and network topology. Most theoretical studies on network dynamics have assumed simple topologies, such as connections that are made randomly and independently with a fixed probability (Erdös-Rényi network) (ER) or all-to-all connected networks. However, recent findings from slice experiments suggest that the actual patterns of connectivity between cortical neurons are more structured than in the ER random network. Here we explore how introducing additional higher-order statistical structure into the connectivity can affect the dynamics in neuronal networks. Specifically, we consider networks in which the number of presynaptic and postsynaptic contacts for each neuron, the degrees, are drawn from a joint degree distribution. We derive mean-field equations for a single population of homogeneous neurons and for a network of excitatory and inhibitory neurons, where the neurons can have arbitrary degree distributions. Through analysis of the mean-field equations and simulation of networks of integrate-and-fire neurons, we show that such networks have potentially much richer dynamics than an equivalent ER network. Finally, we relate the degree distributions to so-called cortical motifs.

Inferring Single Neuron Properties in Conductance Based Balanced Networks

PubMed Central

Pool, Román Rossi; Mato, Germán

2011-01-01

Balanced states in large networks are a usual hypothesis for explaining the variability of neural activity in cortical systems. In this regime the statistics of the inputs is characterized by static and dynamic fluctuations. The dynamic fluctuations have a Gaussian distribution. Such statistics allows to use reverse correlation methods, by recording synaptic inputs and the spike trains of ongoing spontaneous activity without any additional input. By using this method, properties of the single neuron dynamics that are masked by the balanced state can be quantified. To show the feasibility of this approach we apply it to large networks of conductance based neurons. The networks are classified as Type I or Type II according to the bifurcations which neurons of the different populations undergo near the firing onset. We also analyze mixed networks, in which each population has a mixture of different neuronal types. We determine under which conditions the intrinsic noise generated by the network can be used to apply reverse correlation methods. We find that under realistic conditions we can ascertain with low error the types of neurons present in the network. We also find that data from neurons with similar firing rates can be combined to perform covariance analysis. We compare the results of these methods (that do not requite any external input) to the standard procedure (that requires the injection of Gaussian noise into a single neuron). We find a good agreement between the two procedures. PMID:22016730

Coding of auditory temporal and pitch information by hippocampal individual cells and cell assemblies in the rat.

PubMed

Sakurai, Y

2002-01-01

This study reports how hippocampal individual cells and cell assemblies cooperate for neural coding of pitch and temporal information in memory processes for auditory stimuli. Each rat performed two tasks, one requiring discrimination of auditory pitch (high or low) and the other requiring discrimination of their duration (long or short). Some CA1 and CA3 complex-spike neurons showed task-related differential activity between the high and low tones in only the pitch-discrimination task. However, without exception, neurons which showed task-related differential activity between the long and short tones in the duration-discrimination task were always task-related neurons in the pitch-discrimination task. These results suggest that temporal information (long or short), in contrast to pitch information (high or low), cannot be coded independently by specific neurons. The results also indicate that the two different behavioral tasks cannot be fully differentiated by the task-related single neurons alone and suggest a model of cell-assembly coding of the tasks. Cross-correlation analysis among activities of simultaneously recorded multiple neurons supported the suggested cell-assembly model.Considering those results, this study concludes that dual coding by hippocampal single neurons and cell assemblies is working in memory processing of pitch and temporal information of auditory stimuli. The single neurons encode both auditory pitches and their temporal lengths and the cell assemblies encode types of tasks (contexts or situations) in which the pitch and the temporal information are processed.

Ethanol Reversal of Oxycodone Tolerance in Dorsal Root Ganglia Neurons.

PubMed

Jacob, Joanna C; Sakakibara, Kensuke; Mischel, Ryan A; Henderson, Graeme; Dewey, William L; Akbarali, Hamid I

2018-05-01

Oxycodone is a semisynthetic opioid compound that is widely prescribed, used, and abused today, and has a well-established role in shaping the current opioid epidemic. Previously, we have shown that tolerance develops to the antinociceptive and respiratory depressive effects of oxycodone in mice, and that a moderate dose of acute ethanol or a protein kinase C (PKC) inhibitor reversed that tolerance. To investigate further if tolerance was occurring through neuronal mechanisms, our aims for this study were to assess the effects of acute and prolonged oxycodone in isolated dorsal root ganglia (DRG) neurons and to determine if this tolerance was reversed by either ethanol or a PKC inhibitor. We found that an acute exposure to 3 μ M oxycodone reduced neuronal excitability, as measured by increased threshold potentials and reduced action potential amplitude, without eliciting measurable changes in resting membrane potential. Exposure to 10 μ M oxycodone for 18-24 hours prevented oxycodone's effect on neuronal excitability, indicative of tolerance development. The development of opioid tolerance was mitigated in DRG neurons from β -arrestin 2 knockout mice. Oxycodone tolerance was reversed in isolated DRG neurons by the acute application of either ethanol (20 mM) or the PKC inhibitor, bisindolylmaleimide XI hydrochloride (Bis XI), when a challenge of 3 µ M oxycodone significantly reduced neuronal excitability following prolonged exposure. Through these studies, we concluded that oxycodone acutely reduced neuronal excitability, tolerance developed to this effect, and reversal of that tolerance occurred at the level of a single neuron, suggesting that reversal of oxycodone tolerance by either ethanol or Bis XI involves cellular mechanisms. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Hippocampal and amygdalar cell-specific translation is similar soon after stress but diverge over time.

PubMed

Madan, Jesvin S; Gupta, Kanika; Chattarji, Sumantra; Bhattacharya, Aditi

2018-06-01

Stress is known to cause contrasting patterns of morphological and physiological plasticity in the hippocampus and amygdala. An obligatory cellular process underlying such neural changes is de novo translation and alterations in protein expression. Yet the nature of the translational response to stress in neurons remains largely unexplored. Even less is known about how glia are affected. Using a click-chemistry-based method to label the de novo proteome in live brain slices, we monitored translation in neurons and astrocytes of the basolateral amygdala (BLA) and dorsal hippocampal area CA3 (dCA3) in rats at different time-points after a single 2-hr exposure to immobilization stress. We observed enhancements in neuronal translation in both brain regions 1 hour after stress. This initial increase persisted in the BLA up to 10 days afterwards. In contrast, dCA3 neuronal translation gradually decreased to below control levels 10 days later. Translation profiles of dCA3 astrocytes followed timelines similar to neurons, but in BLA astrocytes translation peaked 1 day later and remained elevated 10 days later. Together our results demonstrate that stress causes an immediate upregulation of protein synthesis in both amygdalar and hippocampal neurons and astrocytes. However, these two areas eventually exhibit opposite temporal profiles of protein expression well after the end of stress. These findings identify new metrics of stress-induced plasticity at the level of cell-type specific proteomic landscape that may provide important insights into the molecular basis of the divergent temporal effects of stress across brain regions and biological scales. © 2018 Wiley Periodicals, Inc.

Simultaneous multi-patch-clamp and extracellular-array recordings: Single neuron reflects network activity

NASA Astrophysics Data System (ADS)

Vardi, Roni; Goldental, Amir; Sardi, Shira; Sheinin, Anton; Kanter, Ido

2016-11-01

The increasing number of recording electrodes enhances the capability of capturing the network’s cooperative activity, however, using too many monitors might alter the properties of the measured neural network and induce noise. Using a technique that merges simultaneous multi-patch-clamp and multi-electrode array recordings of neural networks in-vitro, we show that the membrane potential of a single neuron is a reliable and super-sensitive probe for monitoring such cooperative activities and their detailed rhythms. Specifically, the membrane potential and the spiking activity of a single neuron are either highly correlated or highly anti-correlated with the time-dependent macroscopic activity of the entire network. This surprising observation also sheds light on the cooperative origin of neuronal burst in cultured networks. Our findings present an alternative flexible approach to the technique based on a massive tiling of networks by large-scale arrays of electrodes to monitor their activity.

Simultaneous multi-patch-clamp and extracellular-array recordings: Single neuron reflects network activity.

PubMed

Vardi, Roni; Goldental, Amir; Sardi, Shira; Sheinin, Anton; Kanter, Ido

2016-11-08

The increasing number of recording electrodes enhances the capability of capturing the network's cooperative activity, however, using too many monitors might alter the properties of the measured neural network and induce noise. Using a technique that merges simultaneous multi-patch-clamp and multi-electrode array recordings of neural networks in-vitro, we show that the membrane potential of a single neuron is a reliable and super-sensitive probe for monitoring such cooperative activities and their detailed rhythms. Specifically, the membrane potential and the spiking activity of a single neuron are either highly correlated or highly anti-correlated with the time-dependent macroscopic activity of the entire network. This surprising observation also sheds light on the cooperative origin of neuronal burst in cultured networks. Our findings present an alternative flexible approach to the technique based on a massive tiling of networks by large-scale arrays of electrodes to monitor their activity.

Simultaneous multi-patch-clamp and extracellular-array recordings: Single neuron reflects network activity

PubMed Central

Vardi, Roni; Goldental, Amir; Sardi, Shira; Sheinin, Anton; Kanter, Ido

2016-01-01

The increasing number of recording electrodes enhances the capability of capturing the network’s cooperative activity, however, using too many monitors might alter the properties of the measured neural network and induce noise. Using a technique that merges simultaneous multi-patch-clamp and multi-electrode array recordings of neural networks in-vitro, we show that the membrane potential of a single neuron is a reliable and super-sensitive probe for monitoring such cooperative activities and their detailed rhythms. Specifically, the membrane potential and the spiking activity of a single neuron are either highly correlated or highly anti-correlated with the time-dependent macroscopic activity of the entire network. This surprising observation also sheds light on the cooperative origin of neuronal burst in cultured networks. Our findings present an alternative flexible approach to the technique based on a massive tiling of networks by large-scale arrays of electrodes to monitor their activity. PMID:27824075

A wireless neural recording system with a precision motorized microdrive for freely behaving animals

PubMed Central

Hasegawa, Taku; Fujimoto, Hisataka; Tashiro, Koichiro; Nonomura, Mayu; Tsuchiya, Akira; Watanabe, Dai

2015-01-01

The brain is composed of many different types of neurons. Therefore, analysis of brain activity with single-cell resolution could provide fundamental insights into brain mechanisms. However, the electrical signal of an individual neuron is very small, and precise isolation of single neuronal activity from moving subjects is still challenging. To measure single-unit signals in actively behaving states, establishment of technologies that enable fine control of electrode positioning and strict spike sorting is essential. To further apply such a single-cell recording approach to small brain areas in naturally behaving animals in large spaces or during social interaction, we developed a compact wireless recording system with a motorized microdrive. Wireless control of electrode placement facilitates the exploration of single neuronal activity without affecting animal behaviors. Because the system is equipped with a newly developed data-encoding program, the recorded data are readily compressed almost to theoretical limits and securely transmitted to a host computer. Brain activity can thereby be stably monitored in real time and further analyzed using online or offline spike sorting. Our wireless recording approach using a precision motorized microdrive will become a powerful tool for studying brain mechanisms underlying natural or social behaviors. PMID:25597933

Fto colocalizes with a satiety mediator oxytocin in the brain and upregulates oxytocin gene expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olszewski, Pawel K., E-mail: olsze005@umn.edu; Minnesota Obesity Center, Saint Paul, MN 55108; Fredriksson, Robert

2011-05-13

Highlights: {yields} The majority of neurons synthesizing a satiety mediator, oxytocin, coexpress Fto. {yields} The level of colocalization is similar in the male and female brain. {yields} Fto overexpression in hypothalamic neurons increases oxytocin mRNA levels by 50%. {yields} Oxytocin does not affect Fto expression through negative feedback mechanisms. -- Abstract: Single nucleotide polymorphisms in the fat mass and obesity-associated (FTO) gene have been associated with obesity in humans. Alterations in Fto expression in transgenic animals affect body weight, energy expenditure and food intake. Fto, a nuclear protein and proposed transcription co-factor, has been speculated to affect energy balance throughmore » a functional relationship with specific genes encoding feeding-related peptides. Herein, we employed double immunohistochemistry and showed that the majority of neurons synthesizing a satiety mediator, oxytocin, coexpress Fto in the brain of male and female mice. We then overexpressed Fto in a murine hypothalamic cell line and, using qPCR, detected a 50% increase in the level of oxytocin mRNA. Expression levels of several other feeding-related genes, including neuropeptide Y (NPY) and Agouti-related protein (AgRP), were unaffected by the FTO transfection. Addition of 10 and 100 nmol oxytocin to the cell culture medium did not affect Fto expression in hypothalamic cells. We conclude that Fto, a proposed transcription co-factor, influences expression of the gene encoding a satiety mediator, oxytocin.« less

Cognitive Control Signals in Posterior Cingulate Cortex

PubMed Central

Hayden, Benjamin Y.; Smith, David V.; Platt, Michael L.

2010-01-01

Efficiently shifting between tasks is a central function of cognitive control. The role of the default network – a constellation of areas with high baseline activity that declines during task performance – in cognitive control remains poorly understood. We hypothesized that task switching demands cognitive control to shift the balance of processing toward the external world, and therefore predicted that switching between the two tasks would require suppression of activity of neurons within the posterior cingulate cortex (CGp). To test this idea, we recorded the activity of single neurons in CGp, a central node in the default network, in monkeys performing two interleaved tasks. As predicted, we found that basal levels of neuronal activity were reduced following a switch from one task to another and gradually returned to pre-switch baseline on subsequent trials. We failed to observe these effects in lateral intraparietal cortex, part of the dorsal fronto-parietal cortical attention network directly connected to CGp. These findings indicate that suppression of neuronal activity in CGp facilitates cognitive control, and suggest that activity in the default network reflects processes that directly compete with control processes elsewhere in the brain. PMID:21160560

Sparse bursts optimize information transmission in a multiplexed neural code.

PubMed

Naud, Richard; Sprekeler, Henning

2018-06-22

Many cortical neurons combine the information ascending and descending the cortical hierarchy. In the classical view, this information is combined nonlinearly to give rise to a single firing-rate output, which collapses all input streams into one. We analyze the extent to which neurons can simultaneously represent multiple input streams by using a code that distinguishes spike timing patterns at the level of a neural ensemble. Using computational simulations constrained by experimental data, we show that cortical neurons are well suited to generate such multiplexing. Interestingly, this neural code maximizes information for short and sparse bursts, a regime consistent with in vivo recordings. Neurons can also demultiplex this information, using specific connectivity patterns. The anatomy of the adult mammalian cortex suggests that these connectivity patterns are used by the nervous system to maintain sparse bursting and optimal multiplexing. Contrary to firing-rate coding, our findings indicate that the physiology and anatomy of the cortex may be interpreted as optimizing the transmission of multiple independent signals to different targets. Copyright © 2018 the Author(s). Published by PNAS.

Factoring neurotrophins into a neurite-based pathophysiological model of schizophrenia.

PubMed

Bellon, Alfredo; Krebs, Marie-Odile; Jay, Thérèse M

2011-06-01

Neurotrophins are growth factors that, through variations in concentration and changes in receptor expression, regulate the formation of axons and dendrites during development and throughout adult life. Here we review these growth factors, particularly in the context of schizophrenia, a psychiatric disorder characterized by neurodevelopmental abnormalities. We first discuss emerging information derived from physiologically relevant organotypic cultures and in vivo studies regarding the effects of neurotrophins on the neuronal structure including pruning and GABAergic neurons. We then review postmortem studies of neurotrophin levels and their receptors in brains of individuals with schizophrenia, and compare them with what is known about neurotrophin effects on neuronal structure. This comparison indicates that only some neuropathological defects encountered in patients with schizophrenia can be explained by the single action of neurotrophins on dendrites and axons. However, we propose that a number of inconsistent findings and apparently unrelated results in the schizophrenia field can be reconciled if neurons are considered structurally plastic cells capable of extending and retracting dendrites and axons throughout life. Copyright © 2011 Elsevier Ltd. All rights reserved.

Electrical excitability: a spectrum of properties in the progeny of a single embryonic neuroblast.

PubMed Central

Goodman, C S; Pearson, K G; Spitzer, N C

1980-01-01

We have examined the range of some properties of the progeny of a single embryonic precursor cell in the grasshopper. The approximately 100 progeny of this single neuroblast share certain features such as their transmitter and some aspects of their morphology; at the same time, however, they demonstrate a broad spectrum of electrical properties, from spiking to non-spiking neurons. The first-born progeny are spiking neurons with peripheral axons. Many of the progeny, including all of the last-born, do not generate action potentials. The nonspiking progeny are local intraganglionic neurons and appear to compose a major proportion of the progeny of this neuroblast. All of the nonspiking neurons have calcium inward current channels and can make action potentials when outward current channels are blocked. We propose a model for grasshopper neurogenesis based on cell lineage such that (i) certain features (e.g., transmitter) are shared by the progeny of all cell divisions from a single neuroblast, and (ii) other features (e.g., electrical properties) are shared by the progeny of a given birth position (e.g., first versus last born) from all of the neuroblasts. According to this model, the first-born progeny from all neuroblasts are spiking neurons, whereas the last-born are nonspiking. Images PMID:6246499

Racing to learn: statistical inference and learning in a single spiking neuron with adaptive kernels

PubMed Central

Afshar, Saeed; George, Libin; Tapson, Jonathan; van Schaik, André; Hamilton, Tara J.

2014-01-01

This paper describes the Synapto-dendritic Kernel Adapting Neuron (SKAN), a simple spiking neuron model that performs statistical inference and unsupervised learning of spatiotemporal spike patterns. SKAN is the first proposed neuron model to investigate the effects of dynamic synapto-dendritic kernels and demonstrate their computational power even at the single neuron scale. The rule-set defining the neuron is simple: there are no complex mathematical operations such as normalization, exponentiation or even multiplication. The functionalities of SKAN emerge from the real-time interaction of simple additive and binary processes. Like a biological neuron, SKAN is robust to signal and parameter noise, and can utilize both in its operations. At the network scale neurons are locked in a race with each other with the fastest neuron to spike effectively “hiding” its learnt pattern from its neighbors. The robustness to noise, high speed, and simple building blocks not only make SKAN an interesting neuron model in computational neuroscience, but also make it ideal for implementation in digital and analog neuromorphic systems which is demonstrated through an implementation in a Field Programmable Gate Array (FPGA). Matlab, Python, and Verilog implementations of SKAN are available at: http://www.uws.edu.au/bioelectronics_neuroscience/bens/reproducible_research. PMID:25505378

Racing to learn: statistical inference and learning in a single spiking neuron with adaptive kernels.

PubMed

Afshar, Saeed; George, Libin; Tapson, Jonathan; van Schaik, André; Hamilton, Tara J

2014-01-01

This paper describes the Synapto-dendritic Kernel Adapting Neuron (SKAN), a simple spiking neuron model that performs statistical inference and unsupervised learning of spatiotemporal spike patterns. SKAN is the first proposed neuron model to investigate the effects of dynamic synapto-dendritic kernels and demonstrate their computational power even at the single neuron scale. The rule-set defining the neuron is simple: there are no complex mathematical operations such as normalization, exponentiation or even multiplication. The functionalities of SKAN emerge from the real-time interaction of simple additive and binary processes. Like a biological neuron, SKAN is robust to signal and parameter noise, and can utilize both in its operations. At the network scale neurons are locked in a race with each other with the fastest neuron to spike effectively "hiding" its learnt pattern from its neighbors. The robustness to noise, high speed, and simple building blocks not only make SKAN an interesting neuron model in computational neuroscience, but also make it ideal for implementation in digital and analog neuromorphic systems which is demonstrated through an implementation in a Field Programmable Gate Array (FPGA). Matlab, Python, and Verilog implementations of SKAN are available at: http://www.uws.edu.au/bioelectronics_neuroscience/bens/reproducible_research.

Neural plasticity explored by correlative two-photon and electron/SPIM microscopy

NASA Astrophysics Data System (ADS)

Allegra Mascaro, A. L.; Silvestri, L.; Costantini, I.; Sacconi, L.; Maco, B.; Knott, G. W.; Pavone, F. S.

2013-06-01

Plasticity of the central nervous system is a complex process which involves the remodeling of neuronal processes and synaptic contacts. However, a single imaging technique can reveal only a small part of this complex machinery. To obtain a more complete view, complementary approaches should be combined. Two-photon fluorescence microscopy, combined with multi-photon laser nanosurgery, allow following the real-time dynamics of single neuronal processes in the cerebral cortex of living mice. The structural rearrangement elicited by this highly confined paradigm of injury can be imaged in vivo first, and then the same neuron could be retrieved ex-vivo and characterized in terms of ultrastructural features of the damaged neuronal branch by means of electron microscopy. Afterwards, we describe a method to integrate data from in vivo two-photon fluorescence imaging and ex vivo light sheet microscopy, based on the use of major blood vessels as reference chart. We show how the apical dendritic arbor of a single cortical pyramidal neuron imaged in living mice can be found in the large-scale brain reconstruction obtained with light sheet microscopy. Starting from its apical portion, the whole pyramidal neuron can then be segmented and located in the correct cortical layer. With the correlative approach presented here, researchers will be able to place in a three-dimensional anatomic context the neurons whose dynamics have been observed with high detail in vivo.

Functional magnetic resonance microscopy at single-cell resolution in Aplysia californica

PubMed Central

Radecki, Guillaume; Nargeot, Romuald; Jelescu, Ileana Ozana; Le Bihan, Denis; Ciobanu, Luisa

2014-01-01

In this work, we show the feasibility of performing functional MRI studies with single-cell resolution. At ultrahigh magnetic field, manganese-enhanced magnetic resonance microscopy allows the identification of most motor neurons in the buccal network of Aplysia at low, nontoxic Mn2+ concentrations. We establish that Mn2+ accumulates intracellularly on injection into the living Aplysia and that its concentration increases when the animals are presented with a sensory stimulus. We also show that we can distinguish between neuronal activities elicited by different types of stimuli. This method opens up a new avenue into probing the functional organization and plasticity of neuronal networks involved in goal-directed behaviors with single-cell resolution. PMID:24872449

Dynamics of Multistable States during Ongoing and Evoked Cortical Activity

PubMed Central

Mazzucato, Luca

2015-01-01

Single-trial analyses of ensemble activity in alert animals demonstrate that cortical circuits dynamics evolve through temporal sequences of metastable states. Metastability has been studied for its potential role in sensory coding, memory, and decision-making. Yet, very little is known about the network mechanisms responsible for its genesis. It is often assumed that the onset of state sequences is triggered by an external stimulus. Here we show that state sequences can be observed also in the absence of overt sensory stimulation. Analysis of multielectrode recordings from the gustatory cortex of alert rats revealed ongoing sequences of states, where single neurons spontaneously attain several firing rates across different states. This single-neuron multistability represents a challenge to existing spiking network models, where typically each neuron is at most bistable. We present a recurrent spiking network model that accounts for both the spontaneous generation of state sequences and the multistability in single-neuron firing rates. Each state results from the activation of neural clusters with potentiated intracluster connections, with the firing rate in each cluster depending on the number of active clusters. Simulations show that the model's ensemble activity hops among the different states, reproducing the ongoing dynamics observed in the data. When probed with external stimuli, the model predicts the quenching of single-neuron multistability into bistability and the reduction of trial-by-trial variability. Both predictions were confirmed in the data. Together, these results provide a theoretical framework that captures both ongoing and evoked network dynamics in a single mechanistic model. PMID:26019337

Single cell transcriptomics of hypothalamic warm sensitive neurons that control core body temperature and fever response Signaling asymmetry and an extension of chemical neuroanatomy.

PubMed

Eberwine, James; Bartfai, Tamas

2011-03-01

We report on an 'unbiased' molecular characterization of individual, adult neurons, active in a central, anterior hypothalamic neuronal circuit, by establishing cDNA libraries from each individual, electrophysiologically identified warm sensitive neuron (WSN). The cDNA libraries were analyzed by Affymetrix microarray. The presence and frequency of cDNAs were confirmed and enhanced with Illumina sequencing of each single cell cDNA library. cDNAs encoding the GABA biosynthetic enzyme Gad1 and of adrenomedullin, galanin, prodynorphin, somatostatin, and tachykinin were found in the WSNs. The functional cellular and in vivo studies on dozens of the more than 500 neurotransmitters, hormone receptors and ion channels, whose cDNA was identified and sequence confirmed, suggest little or no discrepancy between the transcriptional and functional data in WSNs; whenever agonists were available for a receptor whose cDNA was identified, a functional response was found. Sequencing single neuron libraries permitted identification of rarely expressed receptors like the insulin receptor, adiponectin receptor 2 and of receptor heterodimers; information that is lost when pooling cells leads to dilution of signals and mixing signals. Despite the common electrophysiological phenotype and uniform Gad1 expression, WSN transcriptomes show heterogeneity, suggesting strong epigenetic influence on the transcriptome. Our study suggests that it is well-worth interrogating the cDNA libraries of single neurons by sequencing and chipping. Copyright © 2010 Elsevier Inc. All rights reserved.

Different cortical projections from three subdivisions of the rat lateral posterior thalamic nucleus: a single-neuron tracing study with viral vectors.

PubMed

Nakamura, Hisashi; Hioki, Hiroyuki; Furuta, Takahiro; Kaneko, Takeshi

2015-05-01

The lateral posterior thalamic nucleus (LP) is one of the components of the extrageniculate pathway in the rat visual system, and is cytoarchitecturally divided into three subdivisions--lateral (LPl), rostromedial (LPrm), and caudomedial (LPcm) portions. To clarify the differences in the dendritic fields and axonal arborisations among the three subdivisions, we applied a single-neuron labeling technique with viral vectors to LP neurons. The proximal dendrites of LPl neurons were more numerous than those of LPrm and LPcm neurons, and LPrm neurons tended to have wider dendritic fields than LPl neurons. We then analysed the axonal arborisations of LP neurons by reconstructing the axon fibers in the cortex. The LPl, LPrm and LPcm were different from one another in terms of the projection targets--the main target cortical regions of LPl and LPrm neurons were the secondary and primary visual areas, whereas those of LPcm neurons were the postrhinal and temporal association areas. Furthermore, the principal target cortical layers of LPl neurons in the visual areas were middle layers, but that of LPrm neurons was layer 1. This indicates that LPl and LPrm neurons can be categorised into the core and matrix types of thalamic neurons, respectively, in the visual areas. In addition, LPl neurons formed multiple axonal clusters within the visual areas, whereas the fibers of LPrm neurons were widely and diffusely distributed. It is therefore presumed that these two types of neurons play different roles in visual information processing by dual thalamocortical innervation of the visual areas. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

An NV-Diamond Magnetic Imager for Neuroscience

NASA Astrophysics Data System (ADS)

Turner, Matthew; Schloss, Jennifer; Bauch, Erik; Hart, Connor; Walsworth, Ronald

2017-04-01

We present recent progress towards imaging time-varying magnetic fields from neurons using nitrogen-vacancy centers in diamond. The diamond neuron imager is noninvasive, label-free, and achieves single-cell resolution and state-of-the-art broadband sensitivity. By imaging magnetic fields from injected currents in mammalian neurons, we will map functional neuronal network connections and illuminate biophysical properties of neurons invisible to traditional electrophysiology. Furthermore, through enhancing magnetometer sensitivity, we aim to demonstrate real-time imaging of action potentials from networks of mammalian neurons.

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

PubMed Central

Coffee, R. Lane; Tessier, Charles R.; Woodruff, Elvin A.; Broadie, Kendal

2010-01-01

SUMMARY Fragile X syndrome (FXS), resulting solely from the loss of function of the human fragile X mental retardation 1 (hFMR1) gene, is the most common heritable cause of mental retardation and autism disorders, with syndromic defects also in non-neuronal tissues. In addition, the human genome encodes two closely related hFMR1 paralogs: hFXR1 and hFXR2. The Drosophila genome, by contrast, encodes a single dFMR1 gene with close sequence homology to all three human genes. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) recapitulate FXS-associated molecular, cellular and behavioral phenotypes, suggesting that FMR1 function has been conserved, albeit with specific functions possibly sub-served by the expanded human gene family. To test evolutionary conservation, we used tissue-targeted transgenic expression of all three human genes in the Drosophila disease model to investigate function at (1) molecular, (2) neuronal and (3) non-neuronal levels. In neurons, dfmr1 null mutants exhibit elevated protein levels that alter the central brain and neuromuscular junction (NMJ) synaptic architecture, including an increase in synapse area, branching and bouton numbers. Importantly, hFMR1 can, comparably to dFMR1, fully rescue both the molecular and cellular defects in neurons, whereas hFXR1 and hFXR2 provide absolutely no rescue. For non-neuronal requirements, we assayed male fecundity and testes function. dfmr1 null mutants are effectively sterile owing to disruption of the 9+2 microtubule organization in the sperm tail. Importantly, all three human genes fully and equally rescue mutant fecundity and spermatogenesis defects. These results indicate that FMR1 gene function is evolutionarily conserved in neural mechanisms and cannot be compensated by either FXR1 or FXR2, but that all three proteins can substitute for each other in non-neuronal requirements. We conclude that FMR1 has a neural-specific function that is distinct from its paralogs, and that the unique FMR1 function is responsible for regulating neuronal protein expression and synaptic connectivity. PMID:20442204

Spatial Correlations in Natural Scenes Modulate Response Reliability in Mouse Visual Cortex

PubMed Central

Rikhye, Rajeev V.

2015-01-01

Intrinsic neuronal variability significantly limits information encoding in the primary visual cortex (V1). Certain stimuli can suppress this intertrial variability to increase the reliability of neuronal responses. In particular, responses to natural scenes, which have broadband spatiotemporal statistics, are more reliable than responses to stimuli such as gratings. However, very little is known about which stimulus statistics modulate reliable coding and how this occurs at the neural ensemble level. Here, we sought to elucidate the role that spatial correlations in natural scenes play in reliable coding. We developed a novel noise-masking method to systematically alter spatial correlations in natural movies, without altering their edge structure. Using high-speed two-photon calcium imaging in vivo, we found that responses in mouse V1 were much less reliable at both the single neuron and population level when spatial correlations were removed from the image. This change in reliability was due to a reorganization of between-neuron correlations. Strongly correlated neurons formed ensembles that reliably and accurately encoded visual stimuli, whereas reducing spatial correlations reduced the activation of these ensembles, leading to an unreliable code. Together with an ensemble-specific normalization model, these results suggest that the coordinated activation of specific subsets of neurons underlies the reliable coding of natural scenes. SIGNIFICANCE STATEMENT The natural environment is rich with information. To process this information with high fidelity, V1 neurons have to be robust to noise and, consequentially, must generate responses that are reliable from trial to trial. While several studies have hinted that both stimulus attributes and population coding may reduce noise, the details remain unclear. Specifically, what features of natural scenes are important and how do they modulate reliability? This study is the first to investigate the role of spatial correlations, which are a fundamental attribute of natural scenes, in shaping stimulus coding by V1 neurons. Our results provide new insights into how stimulus spatial correlations reorganize the correlated activation of specific ensembles of neurons to ensure accurate information processing in V1. PMID:26511254

Age-Related Phasic Patterns of Mitochondrial Maintenance in Adult Caenorhabditis elegans Neurons

PubMed Central

Morsci, Natalia S.; Hall, David H.

2016-01-01

Aging is associated with cognitive decline and increasing risk of neurodegeneration. Perturbation of mitochondrial function, dynamics, and trafficking are implicated in the pathogenesis of several age-associated neurodegenerative diseases. Despite this fundamental importance, the critical understanding of how organismal aging affects lifetime neuronal mitochondrial maintenance remains unknown, particularly in a physiologically relevant context. To address this issue, we performed a comprehensive in vivo analysis of age-associated changes in mitochondrial morphology, density, trafficking, and stress resistance in individual Caenorhabditis elegans neurons throughout adult life. Adult neurons display three distinct stages of increase, maintenance, and decrease in mitochondrial size and density during adulthood. Mitochondrial trafficking in the distal neuronal processes declines progressively with age starting from early adulthood. In contrast, long-lived daf-2 mutants exhibit delayed age-associated changes in mitochondrial morphology, constant mitochondrial density, and maintained trafficking rates during adulthood. Reduced mitochondrial load at late adulthood correlates with decreased mitochondrial resistance to oxidative stress. Revealing aging-associated changes in neuronal mitochondria in vivo is an essential precedent that will allow future elucidation of the mechanistic causes of mitochondrial aging. Thus, our study establishes the critical foundation for the future analysis of cellular pathways and genetic and pharmacological factors regulating mitochondrial maintenance in aging- and disease-relevant conditions. SIGNIFICANCE STATEMENT Using Caenorhabditis elegans as a model, we address long-standing questions: How does aging affect neuronal mitochondrial morphology, density, trafficking, and oxidative stress resistance? Are these age-related changes amenable to genetic manipulations that slow down the aging process? Our study illustrates that mitochondrial trafficking declines progressively from the first day of adulthood, whereas mitochondrial size, density, and resistance to oxidative stress undergo three distinct stages: increase in early adulthood, maintenance at high levels during mid-adulthood, and decline during late adulthood. Thus, our study characterizes mitochondrial aging profile at the level of a single neuron in its native environment and establishes the critical foundation for the future genetic and pharmacological dissection of factors that influence long-term mitochondrial maintenance in neurons. PMID:26818523

Optimal Detection of a Localized Perturbation in Random Networks of Integrate-and-Fire Neurons.

PubMed

Bernardi, Davide; Lindner, Benjamin

2017-06-30

Experimental and theoretical studies suggest that cortical networks are chaotic and coding relies on averages over large populations. However, there is evidence that rats can respond to the short stimulation of a single cortical cell, a theoretically unexplained fact. We study effects of single-cell stimulation on a large recurrent network of integrate-and-fire neurons and propose a simple way to detect the perturbation. Detection rates obtained from simulations and analytical estimates are similar to experimental response rates if the readout is slightly biased towards specific neurons. Near-optimal detection is attained for a broad range of intermediate values of the mean coupling between neurons.

Optimal Detection of a Localized Perturbation in Random Networks of Integrate-and-Fire Neurons

NASA Astrophysics Data System (ADS)

Bernardi, Davide; Lindner, Benjamin

2017-06-01

Experimental and theoretical studies suggest that cortical networks are chaotic and coding relies on averages over large populations. However, there is evidence that rats can respond to the short stimulation of a single cortical cell, a theoretically unexplained fact. We study effects of single-cell stimulation on a large recurrent network of integrate-and-fire neurons and propose a simple way to detect the perturbation. Detection rates obtained from simulations and analytical estimates are similar to experimental response rates if the readout is slightly biased towards specific neurons. Near-optimal detection is attained for a broad range of intermediate values of the mean coupling between neurons.

Single neuronal recordings using surface micromachined polysilicon microelectrodes.

PubMed

Muthuswamy, Jit; Okandan, Murat; Jackson, Nathan

2005-03-15

Bulk micromachining techniques of silicon have been used successfully in the past several years to microfabricate microelectrodes for monitoring single neurons in acute and chronic experiments. In this study we report for the first time a novel surface micromachining technique to microfabricate a very thin polysilicon microelectrode that can be used for monitoring single-unit activity in the central nervous system. The microelectrodes are 3 mm long and 50 microm x 3.75 microm in cross-section. Excellent signal to noise ratios in the order of 25-35 dB were obtained while recording neuronal action potentials. The microelectrodes successfully penetrated the brains after a microincision of the dura mater. Chronic implantation of the microprobe for up to 33 days produced only minor gliosis. Since the polysilicon shank acts as a conductor, additional processing steps involved in laying conductor lines on silicon substrates are avoided. Further, surface micromachining allows for fabricating extremely thin microelectrodes which could result in decreased inflammatory responses. We conclude that the polysilicon microelectrode reported here could be a complementary approach to bulk-micromachined silicon microelectrodes for chronic monitoring of single neurons in the central nervous system.

Resolving rates of mutation in the brain using single-neuron genomics

PubMed Central

Evrony, Gilad D; Lee, Eunjung; Park, Peter J; Walsh, Christopher A

2016-01-01

Whether somatic mutations contribute functional diversity to brain cells is a long-standing question. Single-neuron genomics enables direct measurement of somatic mutation rates in human brain and promises to answer this question. A recent study (Upton et al., 2015) reported high rates of somatic LINE-1 element (L1) retrotransposition in the hippocampus and cerebral cortex that would have major implications for normal brain function, and suggested that these events preferentially impact genes important for neuronal function. We identify aspects of the single-cell sequencing approach, bioinformatic analysis, and validation methods that led to thousands of artifacts being interpreted as somatic mutation events. Our reanalysis supports a mutation frequency of approximately 0.2 events per cell, which is about fifty-fold lower than reported, confirming that L1 elements mobilize in some human neurons but indicating that L1 mosaicism is not ubiquitous. Through consideration of the challenges identified, we provide a foundation and framework for designing single-cell genomics studies. DOI: http://dx.doi.org/10.7554/eLife.12966.001 PMID:26901440

Mathematical modeling in chronobiology.

PubMed

Bordyugov, G; Westermark, P O; Korenčič, A; Bernard, S; Herzel, H

2013-01-01

Circadian clocks are autonomous oscillators entrained by external Zeitgebers such as light-dark and temperature cycles. On the cellular level, rhythms are generated by negative transcriptional feedback loops. In mammals, the suprachiasmatic nucleus (SCN) in the anterior part of the hypothalamus plays the role of the central circadian pacemaker. Coupling between individual neurons in the SCN leads to precise self-sustained oscillations even in the absence of external signals. These neuronal rhythms orchestrate the phasing of circadian oscillations in peripheral organs. Altogether, the mammalian circadian system can be regarded as a network of coupled oscillators. In order to understand the dynamic complexity of these rhythms, mathematical models successfully complement experimental investigations. Here we discuss basic ideas of modeling on three different levels (1) rhythm generation in single cells by delayed negative feedbacks, (2) synchronization of cells via external stimuli or cell-cell coupling, and (3) optimization of chronotherapy.

Imaging mitochondrial flux in single cells with a FRET sensor for pyruvate.

PubMed

San Martín, Alejandro; Ceballo, Sebastián; Baeza-Lehnert, Felipe; Lerchundi, Rodrigo; Valdebenito, Rocío; Contreras-Baeza, Yasna; Alegría, Karin; Barros, L Felipe

2014-01-01

Mitochondrial flux is currently accessible at low resolution. Here we introduce a genetically-encoded FRET sensor for pyruvate, and methods for quantitative measurement of pyruvate transport, pyruvate production and mitochondrial pyruvate consumption in intact individual cells at high temporal resolution. In HEK293 cells, neurons and astrocytes, mitochondrial pyruvate uptake was saturated at physiological levels, showing that the metabolic rate is determined by intrinsic properties of the organelle and not by substrate availability. The potential of the sensor was further demonstrated in neurons, where mitochondrial flux was found to rise by 300% within seconds of a calcium transient triggered by a short theta burst, while glucose levels remained unaltered. In contrast, astrocytic mitochondria were insensitive to a similar calcium transient elicited by extracellular ATP. We expect the improved resolution provided by the pyruvate sensor will be of practical interest for basic and applied researchers interested in mitochondrial function.

Imaging Mitochondrial Flux in Single Cells with a FRET Sensor for Pyruvate

PubMed Central

Baeza-Lehnert, Felipe; Lerchundi, Rodrigo; Valdebenito, Rocío; Contreras-Baeza, Yasna; Alegría, Karin; Barros, L. Felipe

2014-01-01

Mitochondrial flux is currently accessible at low resolution. Here we introduce a genetically-encoded FRET sensor for pyruvate, and methods for quantitative measurement of pyruvate transport, pyruvate production and mitochondrial pyruvate consumption in intact individual cells at high temporal resolution. In HEK293 cells, neurons and astrocytes, mitochondrial pyruvate uptake was saturated at physiological levels, showing that the metabolic rate is determined by intrinsic properties of the organelle and not by substrate availability. The potential of the sensor was further demonstrated in neurons, where mitochondrial flux was found to rise by 300% within seconds of a calcium transient triggered by a short theta burst, while glucose levels remained unaltered. In contrast, astrocytic mitochondria were insensitive to a similar calcium transient elicited by extracellular ATP. We expect the improved resolution provided by the pyruvate sensor will be of practical interest for basic and applied researchers interested in mitochondrial function. PMID:24465702

Shunting inhibition improves robustness of gamma oscillations in hippocampal interneuron networks by homogenizing firing rates.

PubMed

Vida, Imre; Bartos, Marlene; Jonas, Peter

2006-01-05

Networks of GABAergic neurons are key elements in the generation of gamma oscillations in the brain. Computational studies suggested that the emergence of coherent oscillations requires hyperpolarizing inhibition. Here, we show that GABA(A) receptor-mediated inhibition in mature interneurons of the hippocampal dentate gyrus is shunting rather than hyperpolarizing. Unexpectedly, when shunting inhibition is incorporated into a structured interneuron network model with fast and strong synapses, coherent oscillations emerge. In comparison to hyperpolarizing inhibition, networks with shunting inhibition show several advantages. First, oscillations are generated with smaller tonic excitatory drive. Second, network frequencies are tuned to the gamma band. Finally, robustness against heterogeneity in the excitatory drive is markedly improved. In single interneurons, shunting inhibition shortens the interspike interval for low levels of drive but prolongs it for high levels, leading to homogenization of neuronal firing rates. Thus, shunting inhibition may confer increased robustness to gamma oscillations in the brain.

Cholinergic Plasticity of Oscillating Neuronal Assemblies in Mouse Hippocampal Slices

PubMed Central

Zylla, Maura M.; Zhang, Xiaomin; Reichinnek, Susanne; Draguhn, Andreas; Both, Martin

2013-01-01

The mammalian hippocampus expresses several types of network oscillations which entrain neurons into transiently stable assemblies. These groups of co-active neurons are believed to support the formation, consolidation and recall of context-dependent memories. Formation of new assemblies occurs during theta- and gamma-oscillations under conditions of high cholinergic activity. Memory consolidation is linked to sharp wave-ripple oscillations (SPW-R) during decreased cholinergic tone. We hypothesized that increased cholinergic tone supports plastic changes of assemblies while low cholinergic tone favors their stability. Coherent spatiotemporal network patterns were measured during SPW-R activity in mouse hippocampal slices. We compared neuronal activity within the oscillating assemblies before and after a transient phase of carbachol-induced gamma oscillations. Single units maintained their coupling to SPW-R throughout the experiment and could be re-identified after the transient phase of gamma oscillations. However, the frequency of SPW-R-related unit firing was enhanced after muscarinic stimulation. At the network level, these changes resulted in altered patterns of extracellularly recorded SPW-R waveforms. In contrast, recording of ongoing SPW-R activity without intermittent cholinergic stimulation revealed remarkably stable repetitive activation of assemblies. These results show that activation of cholinergic receptors induces plasticity at the level of oscillating hippocampal assemblies, in line with the different role of gamma- and SPW-R network activity for memory formation and –consolidation, respectively. PMID:24260462

Cnidarian Cell Type Diversity and Regulation Revealed by Whole-Organism Single-Cell RNA-Seq.

PubMed

Sebé-Pedrós, Arnau; Saudemont, Baptiste; Chomsky, Elad; Plessier, Flora; Mailhé, Marie-Pierre; Renno, Justine; Loe-Mie, Yann; Lifshitz, Aviezer; Mukamel, Zohar; Schmutz, Sandrine; Novault, Sophie; Steinmetz, Patrick R H; Spitz, François; Tanay, Amos; Marlow, Heather

2018-05-31

The emergence and diversification of cell types is a leading factor in animal evolution. So far, systematic characterization of the gene regulatory programs associated with cell type specificity was limited to few cell types and few species. Here, we perform whole-organism single-cell transcriptomics to map adult and larval cell types in the cnidarian Nematostella vectensis, a non-bilaterian animal with complex tissue-level body-plan organization. We uncover eight broad cell classes in Nematostella, including neurons, cnidocytes, and digestive cells. Each class comprises different subtypes defined by the expression of multiple specific markers. In particular, we characterize a surprisingly diverse repertoire of neurons, which comparative analysis suggests are the result of lineage-specific diversification. By integrating transcription factor expression, chromatin profiling, and sequence motif analysis, we identify the regulatory codes that underlie Nematostella cell-specific expression. Our study reveals cnidarian cell type complexity and provides insights into the evolution of animal cell-specific genomic regulation. Copyright © 2018 Elsevier Inc. All rights reserved.

Nogo-receptor 1 antagonization in combination with neurotrophin-4/5 is not superior to single factor treatment in promoting survival and morphological complexity of cultured dopaminergic neurons.

PubMed

Seiler, Stefanie; Di Santo, Stefano; Sahli, Sebastian; Andereggen, Lukas; Widmer, Hans Rudolf

2017-08-01

Cell transplantation using ventral mesencephalic tissue is an experimental approach to treat Parkinson's disease. This approach is limited by poor survival of the transplants and the high number of dopaminergic neurons needed for grafting. Increasing the yield of dopaminergic neurons in donor tissue is of great importance. We have previously shown that antagonization of the Nogo-receptor 1 by NEP1-40 promoted survival of cultured dopaminergic neurons and exposure to neurotrophin-4/5 increased dopaminergic cell densities in organotypic midbrain cultures. We investigated whether a combination of both treatments offers a novel tool to further improve dopaminergic neuron survival. Rat embryonic ventral mesencephalic neurons grown as organotypic free-floating roller tube or primary dissociated cultures were exposed to neurotrophin-4/5 and NEP1-40. The combined and single factor treatment resulted in significantly higher numbers of tyrosine hydroxylase positive neurons compared to controls. Significantly stronger tyrosine hydroxylase signal intensity was detected by Western blotting in the combination-treated cultures compared to controls but not compared to single factor treatments. Neurotrophin-4/5 and the combined treatment showed significantly higher signals for the neuronal marker microtubule-associated protein 2 in Western blots compared to control while no effects were observed for the astroglial marker glial fibrillary acidic protein between groups, suggesting that neurotrophin-4/5 targets mainly neuronal cells. Finally, NEP1-40 and the combined treatment significantly augmented tyrosine hydroxylase positive neurite length. Summarizing, our findings substantiate that antagonization of the Nogo-receptor 1 promotes dopaminergic neurons but does not further increase the yield of dopaminergic neurons and their morphological complexity when combined with neurotrophin-4/5 hinting to the idea that these treatments might exert their effects by activating common downstream pathways. Copyright © 2017 Elsevier B.V. All rights reserved.

Self-Consistent Scheme for Spike-Train Power Spectra in Heterogeneous Sparse Networks.

PubMed

Pena, Rodrigo F O; Vellmer, Sebastian; Bernardi, Davide; Roque, Antonio C; Lindner, Benjamin

2018-01-01

Recurrent networks of spiking neurons can be in an asynchronous state characterized by low or absent cross-correlations and spike statistics which resemble those of cortical neurons. Although spatial correlations are negligible in this state, neurons can show pronounced temporal correlations in their spike trains that can be quantified by the autocorrelation function or the spike-train power spectrum. Depending on cellular and network parameters, correlations display diverse patterns (ranging from simple refractory-period effects and stochastic oscillations to slow fluctuations) and it is generally not well-understood how these dependencies come about. Previous work has explored how the single-cell correlations in a homogeneous network (excitatory and inhibitory integrate-and-fire neurons with nearly balanced mean recurrent input) can be determined numerically from an iterative single-neuron simulation. Such a scheme is based on the fact that every neuron is driven by the network noise (i.e., the input currents from all its presynaptic partners) but also contributes to the network noise, leading to a self-consistency condition for the input and output spectra. Here we first extend this scheme to homogeneous networks with strong recurrent inhibition and a synaptic filter, in which instabilities of the previous scheme are avoided by an averaging procedure. We then extend the scheme to heterogeneous networks in which (i) different neural subpopulations (e.g., excitatory and inhibitory neurons) have different cellular or connectivity parameters; (ii) the number and strength of the input connections are random (Erdős-Rényi topology) and thus different among neurons. In all heterogeneous cases, neurons are lumped in different classes each of which is represented by a single neuron in the iterative scheme; in addition, we make a Gaussian approximation of the input current to the neuron. These approximations seem to be justified over a broad range of parameters as indicated by comparison with simulation results of large recurrent networks. Our method can help to elucidate how network heterogeneity shapes the asynchronous state in recurrent neural networks.

Executive Control Over Cognition: Stronger and Earlier Rule-Based Modulation of Spatial Category Signals in Prefrontal Cortex Relative to Parietal Cortex

PubMed Central

Goodwin, Shikha J.; Blackman, Rachael K.; Sakellaridi, Sofia

2012-01-01

Human cognition is characterized by flexibility, the ability to select not only which action but which cognitive process to engage to best achieve the current behavioral objective. The ability to tailor information processing in the brain to rules, goals, or context is typically referred to as executive control, and although there is consensus that prefrontal cortex is importantly involved, at present we have an incomplete understanding of how computational flexibility is implemented at the level of prefrontal neurons and networks. To better understand the neural mechanisms of computational flexibility, we simultaneously recorded the electrical activity of groups of single neurons within prefrontal and posterior parietal cortex of monkeys performing a task that required executive control of spatial cognitive processing. In this task, monkeys applied different spatial categorization rules to reassign the same set of visual stimuli to alternative categories on a trial-by-trial basis. We found that single neurons were activated to represent spatially defined categories in a manner that was rule dependent, providing a physiological signature of a cognitive process that was implemented under executive control. We found also that neural signals coding rule-dependent categories were distributed between the parietal and prefrontal cortex—however, not equally. Rule-dependent category signals were stronger, more powerfully modulated by the rule, and earlier to emerge in prefrontal cortex relative to parietal cortex. This suggests that prefrontal cortex may initiate the switch in neural representation at a network level that is important for computational flexibility. PMID:22399773

Figure-ground segregation at contours: a neural mechanism in the visual cortex of the alert monkey.

PubMed

Baumann, R; van der Zwan, R; Peterhans, E

1997-06-01

An important task of vision is the segregation of figure and ground in situations of spatial occlusion. Psychophysical evidence suggests that the depth order at contours is defined early in visual processing. We have analysed this process in the visual cortex of the alert monkey. The animals were trained on a visual fixation task which reinforced foveal viewing. During periods of active visual fixation, we recorded the responses of single neurons in striate and prestriate cortex (areas V1, V2, and V3/V3A). The stimuli mimicked situations of spatial occlusion, usually a uniform light (or dark) rectangle overlaying a grating texture of opposite contrast. The direction of figure and ground at the borders of these rectangles was defined by the direction of the terminating grating lines (occlusion cues). Neuronal responses were analysed with respect to figure-ground direction and contrast polarity at such contours. Striate neurons often failed to respond to such stimuli, or were selective for contrast polarity; others were non-selective. Some neurons preferred a certain combination of figure-ground direction and contrast polarity. These neurons were rare both in striate and prestriate cortex. The majority of neurons signalled figure-ground direction independent of contrast polarity. These neurons were only found in prestriate cortex. We explain these responses in terms of a model which also explains neuronal signals of illusory contours. These results suggest that occlusion cues are used at an early level of processing to segregate figure and ground at contours.

Neuronal avalanches and learning

NASA Astrophysics Data System (ADS)

de Arcangelis, Lucilla

2011-05-01

Networks of living neurons represent one of the most fascinating systems of biology. If the physical and chemical mechanisms at the basis of the functioning of a single neuron are quite well understood, the collective behaviour of a system of many neurons is an extremely intriguing subject. Crucial ingredient of this complex behaviour is the plasticity property of the network, namely the capacity to adapt and evolve depending on the level of activity. This plastic ability is believed, nowadays, to be at the basis of learning and memory in real brains. Spontaneous neuronal activity has recently shown features in common to other complex systems. Experimental data have, in fact, shown that electrical information propagates in a cortex slice via an avalanche mode. These avalanches are characterized by a power law distribution for the size and duration, features found in other problems in the context of the physics of complex systems and successful models have been developed to describe their behaviour. In this contribution we discuss a statistical mechanical model for the complex activity in a neuronal network. The model implements the main physiological properties of living neurons and is able to reproduce recent experimental results. Then, we discuss the learning abilities of this neuronal network. Learning occurs via plastic adaptation of synaptic strengths by a non-uniform negative feedback mechanism. The system is able to learn all the tested rules, in particular the exclusive OR (XOR) and a random rule with three inputs. The learning dynamics exhibits universal features as function of the strength of plastic adaptation. Any rule could be learned provided that the plastic adaptation is sufficiently slow.

Burst firing and modulation of functional connectivity in cat striate cortex.

PubMed

Snider, R K; Kabara, J F; Roig, B R; Bonds, A B

1998-08-01

We studied the influences of the temporal firing patterns of presynaptic cat visual cortical cells on spike generation by postsynaptic cells. Multiunit recordings were dissected into the activity of individual neurons within the recorded group. Cross-correlation analysis was then used to identify directly coupled neuron pairs. The 22 multiunit groups recorded typically showed activity from two to six neurons, each containing between 1 and 15 neuron pairs. From a total of 241 neuron pairs, 91 (38%) had a shifted cross-correlation peak, which indicated a possible direct connection. Only two multiunit groups contained no shifted peaks. Burst activity, defined by groups of two or more spikes with intervals of

Cocaine disinhibits dopamine neurons in the ventral tegmental area via use-dependent blockade of GABA neuron voltage-sensitive sodium channels

PubMed Central

Steffensen, Scott C.; Taylor, Seth R.; Horton, Malia L.; Barber, Elise N.; Lyle, Laura T.; Stobbs, Sarah H.; Allison, David W.

2010-01-01

The aim of this study was to evaluate the effects of cocaine on γ-aminobutyric acid (GABA) and dopamine (DA) neurons in the ventral tegmental area (VTA). Utilizing single-unit recordings in vivo, microelectrophoretic administration of DA enhanced the firing rate of VTA GABA neurons via D2/D3 DA receptor activation. Lower doses of intravenous cocaine (0.25–0.5 mg/kg), or the DA transporter (DAT) blocker methamphetamine, enhanced VTA GABA neuron firing rate via D2/D3 receptor activation. Higher doses of cocaine (1.0–2.0 mg/kg) inhibited their firing rate, which was not sensitive to the D2/D3 antagonist eticlopride. The voltage-sensitive sodium channel (VSSC) blocker lidocaine inhibited the firing rate of VTA GABA neurons at all doses tested (0.25–2.0 mg/kg). Cocaine or lidocaine reduced VTA GABA neuron spike discharges induced by stimulation of the internal capsule (ICPSDs) at dose levels 0.25–2 mg/kg (IC50 1.2 mg/kg). There was no effect of DA or methamphetamine on ICPSDs, or of DA antagonists on cocaine inhibition of ICPSDs. In VTA GABA neurons in vitro, cocaine reduced (IC50 13 μm) current-evoked spikes and TTX-sensitive sodium currents in a use-dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC50 13 μm), increased IPSC paired-pulse facilitation and decreased spontaneous IPSC frequency, without affecting miniature IPSC frequency or amplitude. These findings suggest that cocaine acts on GABA neurons to reduce activity-dependent GABA release on DA neurons in the VTA, and that cocaine's use-dependent blockade of VTA GABA neuron VSSCs may synergize with its DAT inhibiting properties to enhance mesolimbic DA transmission implicated in cocaine reinforcement. PMID:19046384

Processing of Intraoral Olfactory and Gustatory Signals in the Gustatory Cortex of Awake Rats.

PubMed

Samuelsen, Chad L; Fontanini, Alfredo

2017-01-11

The integration of gustatory and olfactory information is essential to the perception of flavor. Human neuroimaging experiments have pointed to the gustatory cortex (GC) as one of the areas involved in mediating flavor perception. Although GC's involvement in encoding the chemical identity and hedonic value of taste stimuli is well studied, it is unknown how single GC neurons process olfactory stimuli emanating from the mouth. In this study, we relied on multielectrode recordings to investigate how single GC neurons respond to intraorally delivered tastants and tasteless odorants dissolved in water and whether/how these two modalities converge in the same neurons. We found that GC neurons could either be unimodal, responding exclusively to taste (taste-only) or odor (odor-only), or bimodal, responding to both gustatory and olfactory stimuli. Odor responses were confirmed to result from retronasal olfaction: monitoring respiration revealed that exhalation preceded odor-evoked activity and reversible inactivation of olfactory receptors in the nasal epithelium significantly reduced responses to intraoral odorants but not to tastants. Analysis of bimodal neurons revealed that they encode palatability significantly better than the unimodal taste-only group. Bimodal neurons exhibited similar responses to palatable tastants and odorants dissolved in water. This result suggested that odorized water could be palatable. This interpretation was further supported with a brief access task, where rats avoided consuming aversive taste stimuli and consumed the palatable tastants and dissolved odorants. These results demonstrate the convergence of the chemosensory components of flavor onto single GC neurons and provide evidence for the integration of flavor with palatability coding. Food perception and choice depend upon the concurrent processing of olfactory and gustatory signals from the mouth. The primary gustatory cortex has been proposed to integrate chemosensory stimuli; however, no study has examined the single-unit responses to intraoral odorant presentation. Here we found that neurons in gustatory cortex can respond either exclusively to tastants, exclusively to odorants, or to both (bimodal). Several differences exist between these groups' responses; notably, bimodal neurons code palatability significantly better than unimodal neurons. This group of neurons might represent a substrate for how odorants gain the quality of tastants. Copyright © 2017 the authors 0270-6474/17/370244-14$15.00/0.

Behavioral aging is associated with reduced sensory neuron excitability in Aplysia californica.

PubMed

Kempsell, Andrew T; Fieber, Lynne A

2014-01-01

Invertebrate models have advantages for understanding the basis of behavioral aging due to their simple nervous systems and short lifespans. The potential usefulness of Aplysia californica in aging research is apparent from its long history of neurobiological research, but it has been underexploited in this model use. Aging of simple reflexes at both single sensory neuron and neural circuit levels was studied to connect behavioral aging to neurophysiological aging. The tail withdrawal reflex (TWR), righting reflex, and biting response were measured throughout sexual maturity in 3 cohorts of hatchery-reared animals of known age. Reflex times increased and reflex amplitudes decreased significantly during aging. Aging in sensory neurons of animals with deficits in measures of the TWR and biting response resulted in significantly reduced excitability in old animals compared to their younger siblings. The threshold for firing increased while the number of action potentials in response to depolarizing current injection decreased during aging in sensory neurons, but not in tail motoneurons. Glutamate receptor-activated responses in sensory neurons also decreased with aging. In old tail motoneurons, the amplitude of evoked EPSPs following tail shock decreased, presumably due to reduced sensory neuron excitability during aging. The results were used to develop stages of aging relevant to both hatchery-reared and wild-caught Aplysia. Aplysia is a viable aging model in which the contributions of differential aging of components of neural circuits may be assessed.

Behavioral aging is associated with reduced sensory neuron excitability in Aplysia californica

PubMed Central

Kempsell, Andrew T.; Fieber, Lynne A.

2014-01-01

Invertebrate models have advantages for understanding the basis of behavioral aging due to their simple nervous systems and short lifespans. The potential usefulness of Aplysia californica in aging research is apparent from its long history of neurobiological research, but it has been underexploited in this model use. Aging of simple reflexes at both single sensory neuron and neural circuit levels was studied to connect behavioral aging to neurophysiological aging. The tail withdrawal reflex (TWR), righting reflex, and biting response were measured throughout sexual maturity in 3 cohorts of hatchery-reared animals of known age. Reflex times increased and reflex amplitudes decreased significantly during aging. Aging in sensory neurons of animals with deficits in measures of the TWR and biting response resulted in significantly reduced excitability in old animals compared to their younger siblings. The threshold for firing increased while the number of action potentials in response to depolarizing current injection decreased during aging in sensory neurons, but not in tail motoneurons. Glutamate receptor-activated responses in sensory neurons also decreased with aging. In old tail motoneurons, the amplitude of evoked EPSPs following tail shock decreased, presumably due to reduced sensory neuron excitability during aging. The results were used to develop stages of aging relevant to both hatchery-reared and wild-caught Aplysia. Aplysia is a viable aging model in which the contributions of differential aging of components of neural circuits may be assessed. PMID:24847260

Histamine influences body temperature by acting at H1 and H3 receptors on distinct populations of preoptic neurons

PubMed Central

Lundius, Ebba Gregorsson; Sanchez-Alavez, Manuel; Ghochani, Yasmin; Klaus, Joseph; Tabarean, Iustin V.

2010-01-01

The preoptic area/anterior hypothalamus (PO/AH), a region that contains neurons that control thermoregulation, is the main locus at which histamine affects body temperature. Here we report that histamine reduced the spontaneous firing rate of GABAergic preoptic neurons by activating H3 subtype histamine receptors. This effect involved a decrease in the level of phosphorylation of the extracellular signal-regulated kinase (ERK) and was not dependent on synaptic activity. Furthermore, a population of nonGABAergic neurons was depolarized and their firing rate was enhanced by histamine acting at H1 subtype receptors. In our experiments, activation of the H1R receptors was linked to the PLC pathway and Ca2+ release from intracellular stores. This depolarization persisted in TTX or when fast synaptic potentials were blocked indicating that it represents a postsynaptic effect. Single-cell reverse transcription –PCR analysis revealed expression of H3 receptors in a population of GABAergic neurons while H1 receptors were expressed in nonGABAergic cells. Histamine applied in the median preoptic nucleus induced a robust, long lasting hyperthermia effect that was mimicked by either H1 or H3 histamine receptor subtype specific agonists. Our data indicate that histamine modulates the core body temperature by acting at two distinct populations of preoptic neurons which express H1 and H3 receptor subtypes, respectively. PMID:20335473

Histamine influences body temperature by acting at H1 and H3 receptors on distinct populations of preoptic neurons.

PubMed

Lundius, Ebba Gregorsson; Sanchez-Alavez, Manuel; Ghochani, Yasmin; Klaus, Joseph; Tabarean, Iustin V

2010-03-24

The preoptic area/anterior hypothalamus, a region that contains neurons that control thermoregulation, is the main locus at which histamine affects body temperature. Here we report that histamine reduced the spontaneous firing rate of GABAergic preoptic neurons by activating H3 subtype histamine receptors. This effect involved a decrease in the level of phosphorylation of the extracellular signal-regulated kinase and was not dependent on synaptic activity. Furthermore, a population of non-GABAergic neurons was depolarized, and their firing rate was enhanced by histamine acting at H1 subtype receptors. In our experiments, activation of the H1R receptors was linked to the PLC pathway and Ca(2+) release from intracellular stores. This depolarization persisted in TTX or when fast synaptic potentials were blocked, indicating that it represents a postsynaptic effect. Single-cell reverse transcription-PCR analysis revealed expression of H3 receptors in a population of GABAergic neurons, while H1 receptors were expressed in non-GABAergic cells. Histamine applied in the median preoptic nucleus induced a robust, long-lasting hyperthermia effect that was mimicked by either H1 or H3 histamine receptor subtype-specific agonists. Our data indicate that histamine modulates the core body temperature by acting at two distinct populations of preoptic neurons that express H1 and H3 receptor subtypes, respectively.

Complex-learning Induced Modifications in Synaptic Inhibition: Mechanisms and Functional Significance.

PubMed

Reuveni, Iris; Lin, Longnian; Barkai, Edi

2018-06-15

Following training in a difficult olfactory-discrimination (OD) task rats acquire the capability to perform the task easily, with little effort. This new acquired skill, of 'learning how to learn' is termed 'rule learning'. At the single-cell level, rule learning is manifested in long-term enhancement of intrinsic neuronal excitability of piriform cortex (PC) pyramidal neurons, and in excitatory synaptic connections between these neurons to maintain cortical stability, such long-lasting increase in excitability must be accompanied by paralleled increase in inhibitory processes that would prevent hyper-excitable activation. In this review we describe the cellular and molecular mechanisms underlying complex-learning-induced long-lasting modifications in GABA A -receptors and GABA B -receptor-mediated synaptic inhibition. Subsequently we discuss how such modifications support the induction and preservation of long-term memories in the in the mammalian brain. Based on experimental results, computational analysis and modeling, we propose that rule learning is maintained by doubling the strength of synaptic inputs, excitatory as well as inhibitory, in a sub-group of neurons. This enhanced synaptic transmission, which occurs in all (or almost all) synaptic inputs onto these neurons, activates specific stored memories. At the molecular level, such rule-learning-relevant synaptic strengthening is mediated by doubling the conductance of synaptic channels, but not their numbers. This post synaptic process is controlled by a whole-cell mechanism via particular second messenger systems. This whole-cell mechanism enables memory amplification when required and memory extinction when not relevant. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

The Role of Ventral Tegmental Area Gamma-Aminobutyric Acid in Chronic Neuropathic Pain after Spinal Cord Injury in Rats.

PubMed

Ko, Moon Yi; Jang, Eun Young; Lee, June Yeon; Kim, Soo Phil; Whang, Sung Hun; Lee, Bong Hyo; Kim, Hee Young; Yang, Chae Ha; Cho, Hee Jung; Gwak, Young S

2018-04-20

Spinal cord injury (SCI) frequently results in chronic neuropathic pain (CNP). However, the understanding of brain neural circuits in CNP modulation is unclear. The present study examined the changes of ventral tegmental area (VTA) putative GABAergic and dopaminergic neuronal activity with CNP attenuation in rats. SCI was established by T10 clip compression injury (35 g, 1 min) in rats, and neuropathic pain behaviors, in vivo extracellular single-cell recording of putative VTA gamma-aminobutyric acid (GABA)/dopamine neurons, extracellular GABA level, glutamic acid decarboxylase (GAD), and vesicular GABA transporters (VGATs) were measured in the VTA, respectively. The results revealed that extracellular GABA level was significantly increased in the CNP group (50.5 ± 18.9 nM) compared to the sham control group (10.2 ± 1.7 nM). In addition, expression of GAD 65/67 , c-Fos, and VGAT exhibited significant increases in the SCI groups compared to the sham control group. With regard to neuropathic pain behaviors, spontaneous pain measured by ultrasound vocalizations (USVs) and evoked pain measured by paw withdrawal thresholds showed significant alteration, which was reversed by intravenous (i.v.) administration of morphine (0.5-5.0 mg/kg). With regard to in vivo electrophysiology, VTA putative GABAergic neuronal activity (13.6 ± 1.7 spikes/sec) and putative dopaminergic neuronal activity (2.4 ± 0.8 spikes/sec) were increased and decreased, respectively, in the SCI group compared to the sham control group. These neuronal activities were reversed by i.v. administration of morphine. The present study suggests that chronic increase of GABAergic neuronal activity suppresses dopaminergic neuronal activity in the VTA and is responsible for negative emotion and motivation for attenuation of SCI-induced CNP.

Molecular hierarchy in neurons differentiated from mouse ES cells containing a single human chromosome 21.

PubMed

Wang, Chi Chiu; Kadota, Mitsutaka; Nishigaki, Ryuichi; Kazuki, Yasuhiro; Shirayoshi, Yasuaki; Rogers, Michael Scott; Gojobori, Takashi; Ikeo, Kazuho; Oshimura, Mitsuo

2004-02-06

Defects in neurogenesis and neuronal differentiation in the fetal brain of Down syndrome (DS) patients lead to the apparent neuropathological abnormalities and contribute to the phenotypic characters of mental retardation, and premature development of Alzheimer's disease, those being the most common phenotype in DS. In order to understand the molecular mechanism underlying the cause of phenotypic abnormalities in the DS brain, we have utilized an in vitro model of TT2F mouse embryonic stem cells containing a single human chromosome 21 (hChr21) to study neuron development and neuronal differentiation by microarray containing 15K developmentally expressed cDNAs. Defective neuronal differentiation in the presence of extra hChr21 manifested primarily the post-transcriptional and translational modification, such as Mrpl10, SNAPC3, Srprb, SF3a60 in the early neuronal stem cell stage, and Mrps18a, Eef1g, and Ubce8 in the late differentiated stage. Hierarchical clustering patterned specific expression of hChr21 gene dosage effects on neuron outgrowth, migration, and differentiation, such as Syngr2, Dncic2, Eif3sf, and Peg3.

Single neuron modeling and data assimilation in BNST neurons

NASA Astrophysics Data System (ADS)

Farsian, Reza

Neurons, although tiny in size, are vastly complicated systems, which are responsible for the most basic yet essential functions of any nervous system. Even the most simple models of single neurons are usually high dimensional, nonlinear, and contain many parameters and states which are unobservable in a typical neurophysiological experiment. One of the most fundamental problems in experimental neurophysiology is the estimation of these parameters and states, since knowing their values is essential in identification, model construction, and forward prediction of biological neurons. Common methods of parameter and state estimation do not perform well for neural models due to their high dimensionality and nonlinearity. In this dissertation, two alternative approaches for parameters and state estimation of biological neurons have been demonstrated: dynamical parameter estimation (DPE) and a Markov Chain Monte Carlo (MCMC) method. The first method uses elements of chaos control and synchronization theory for parameter and state estimation. MCMC is a statistical approach which uses a path integral formulation to evaluate a mean and an error bound for these unobserved parameters and states. These methods have been applied to biological system of neurons in Bed Nucleus of Stria Termialis neurons (BNST) of rats. State and parameters of neurons in both systems were estimated, and their value were used for recreating a realistic model and predicting the behavior of the neurons successfully. The knowledge of biological parameters can ultimately provide a better understanding of the internal dynamics of a neuron in order to build robust models of neuron networks.

Absence of NEFL in patient-specific neurons in early-onset Charcot-Marie-Tooth neuropathy.

PubMed

Sainio, Markus T; Ylikallio, Emil; Mäenpää, Laura; Lahtela, Jenni; Mattila, Pirkko; Auranen, Mari; Palmio, Johanna; Tyynismaa, Henna

2018-06-01

We used patient-specific neuronal cultures to characterize the molecular genetic mechanism of recessive nonsense mutations in neurofilament light ( NEFL ) underlying early-onset Charcot-Marie-Tooth (CMT) disease. Motor neurons were differentiated from induced pluripotent stem cells of a patient with early-onset CMT carrying a novel homozygous nonsense mutation in NEFL . Quantitative PCR, protein analytics, immunocytochemistry, electron microscopy, and single-cell transcriptomics were used to investigate patient and control neurons. We show that the recessive nonsense mutation causes a nearly total loss of NEFL messenger RNA (mRNA), leading to the complete absence of NEFL protein in patient's cultured neurons. Yet the cultured neurons were able to differentiate and form neuronal networks and neurofilaments. Single-neuron gene expression fingerprinting pinpointed NEFL as the most downregulated gene in the patient neurons and provided data of intermediate filament transcript abundancy and dynamics in cultured neurons. Blocking of nonsense-mediated decay partially rescued the loss of NEFL mRNA. The strict neuronal specificity of neurofilament has hindered the mechanistic studies of recessive NEFL nonsense mutations. Here, we show that such mutation leads to the absence of NEFL, causing childhood-onset neuropathy through a loss-of-function mechanism. We propose that the neurofilament accumulation, a common feature of many neurodegenerative diseases, mimics the absence of NEFL seen in recessive CMT if aggregation prevents the proper localization of wild-type NEFL in neurons. Our results suggest that the removal of NEFL as a proposed treatment option is harmful in humans.

Single-cell transcriptional analysis of taste sensory neuron pair in Caenorhabditis elegans.

PubMed

Takayama, Jun; Faumont, Serge; Kunitomo, Hirofumi; Lockery, Shawn R; Iino, Yuichi

2010-01-01

The nervous system is composed of a wide variety of neurons. A description of the transcriptional profiles of each neuron would yield enormous information about the molecular mechanisms that define morphological or functional characteristics. Here we show that RNA isolation from single neurons is feasible by using an optimized mRNA tagging method. This method extracts transcripts in the target cells by co-immunoprecipitation of the complexes of RNA and epitope-tagged poly(A) binding protein expressed specifically in the cells. With this method and genome-wide microarray, we compared the transcriptional profiles of two functionally different neurons in the main C. elegans gustatory neuron class ASE. Eight of the 13 known subtype-specific genes were successfully detected. Additionally, we identified nine novel genes including a receptor guanylyl cyclase, secreted proteins, a TRPC channel and uncharacterized genes conserved among nematodes, suggesting the two neurons are substantially different than previously thought. The expression of these novel genes was controlled by the previously known regulatory network for subtype differentiation. We also describe unique motif organization within individual gene groups classified by the expression patterns in ASE. Our study paves the way to the complete catalog of the expression profiles of individual C. elegans neurons.

Transcriptional responses of the rat vasopressin gene to acute and repeated acute osmotic stress.

PubMed

Zemo, David A; McCabe, Joseph T

2002-09-01

To determine the impact of hypertonic saline administration upon rat arginine vasopressin (AVP) gene transcription in supraoptic nucleus neurons, a probe complementary to the first intron (AVP1) of AVP was used to measure changes in AVP heteronuclear RNA (hnRNA) levels. Animals that received hypertonic saline had increases in AVP1 after 15 and 30 min, with a return to baseline levels by 180 min. In a double injection paradigm, animals were given an injection of normal or hypertonic saline followed 180 min later by a second injection of normal or hypertonic saline and sacrificed 30 min later. When both injections were hypertonic saline (H-H), AVP1 levels were greater than levels seen after a single hypertonic saline injection, or after an injection of normal saline followed by a second injection of hypertonic saline (N-H). This study shows acute, repeated exposure to hypertonic saline causes a robust increase in vasopressin gene transcription. Since a second hyperosmotic stimulus is known to increase neuronal firing rate and activity, our results suggest that a correlation exists with intracellular mechanisms regulating vasopressin gene transcription.

HCS-Neurons: identifying phenotypic changes in multi-neuron images upon drug treatments of high-content screening.

PubMed

Charoenkwan, Phasit; Hwang, Eric; Cutler, Robert W; Lee, Hua-Chin; Ko, Li-Wei; Huang, Hui-Ling; Ho, Shinn-Ying

2013-01-01

High-content screening (HCS) has become a powerful tool for drug discovery. However, the discovery of drugs targeting neurons is still hampered by the inability to accurately identify and quantify the phenotypic changes of multiple neurons in a single image (named multi-neuron image) of a high-content screen. Therefore, it is desirable to develop an automated image analysis method for analyzing multi-neuron images. We propose an automated analysis method with novel descriptors of neuromorphology features for analyzing HCS-based multi-neuron images, called HCS-neurons. To observe multiple phenotypic changes of neurons, we propose two kinds of descriptors which are neuron feature descriptor (NFD) of 13 neuromorphology features, e.g., neurite length, and generic feature descriptors (GFDs), e.g., Haralick texture. HCS-neurons can 1) automatically extract all quantitative phenotype features in both NFD and GFDs, 2) identify statistically significant phenotypic changes upon drug treatments using ANOVA and regression analysis, and 3) generate an accurate classifier to group neurons treated by different drug concentrations using support vector machine and an intelligent feature selection method. To evaluate HCS-neurons, we treated P19 neurons with nocodazole (a microtubule depolymerizing drug which has been shown to impair neurite development) at six concentrations ranging from 0 to 1000 ng/mL. The experimental results show that all the 13 features of NFD have statistically significant difference with respect to changes in various levels of nocodazole drug concentrations (NDC) and the phenotypic changes of neurites were consistent to the known effect of nocodazole in promoting neurite retraction. Three identified features, total neurite length, average neurite length, and average neurite area were able to achieve an independent test accuracy of 90.28% for the six-dosage classification problem. This NFD module and neuron image datasets are provided as a freely downloadable MatLab project at http://iclab.life.nctu.edu.tw/HCS-Neurons. Few automatic methods focus on analyzing multi-neuron images collected from HCS used in drug discovery. We provided an automatic HCS-based method for generating accurate classifiers to classify neurons based on their phenotypic changes upon drug treatments. The proposed HCS-neurons method is helpful in identifying and classifying chemical or biological molecules that alter the morphology of a group of neurons in HCS.

Optical recording from respiratory pattern generator of fetal mouse brainstem reveals a distributed network.

PubMed

Eugenin, J; Nicholls, J G; Cohen, L B; Muller, K J

2006-01-01

Unfailing respiration depends on neural mechanisms already present in mammals before birth. Experiments were made to determine how inspiratory and expiratory neurons are grouped in the brainstem of fetal mice. A further aim was to assess whether rhythmicity arises from a single pacemaker or is generated by multiple sites in the brainstem. To measure neuronal firing, a fluorescent calcium indicator dye was applied to embryonic central nervous systems isolated from mice. While respiratory commands were monitored electrically from third to fifth cervical ventral roots, activity was measured optically over areas containing groups of respiratory neurones, or single neurones, along the medulla from the facial nucleus to the pre-Bötzinger complex. Large optical signals allowed recordings to be made during individual respiratory cycles. Inspiratory and expiratory neurones were intermingled. A novel finding was that bursts of activity arose in a discrete area intermittently, occurring during some breaths, but failing in others. Raised CO2 partial pressure or lowered pH increased the frequency of respiration; neurons then fired reliably with every cycle. Movies of activity revealed patterns of activation of inspiratory and expiratory neurones during successive respiratory cycles; there was no evidence for waves spreading systematically from region to region. Our results suggest that firing of neurons in immature respiratory circuits is a stochastic process, and that the rhythm does not depend on a single pacemaker. Respiratory circuits in fetal mouse brainstem appear to possess a high safety factor for generating rhythmicity, which may or may not persist as development proceeds.

Structural basis for serotonergic regulation of neural circuits in the mouse olfactory bulb.

PubMed

Suzuki, Yoshinori; Kiyokage, Emi; Sohn, Jaerin; Hioki, Hiroyuki; Toida, Kazunori

2015-02-01

Olfactory processing is well known to be regulated by centrifugal afferents from other brain regions, such as noradrenergic, acetylcholinergic, and serotonergic neurons. Serotonergic neurons widely innervate and regulate the functions of various brain regions. In the present study, we focused on serotonergic regulation of the olfactory bulb (OB), one of the most structurally and functionally well-defined brain regions. Visualization of a single neuron among abundant and dense fibers is essential to characterize and understand neuronal circuits. We accomplished this visualization by successfully labeling and reconstructing serotonin (5-hydroxytryptamine: 5-HT) neurons by infection with sindbis and adeno-associated virus into dorsal raphe nuclei (DRN) of mice. 5-HT synapses were analyzed by correlative confocal laser microscopy and serial-electron microscopy (EM) study. To further characterize 5-HT neuronal and network function, we analyzed whether glutamate was released from 5-HT synaptic terminals using immuno-EM. Our results are the first visualizations of complete 5-HT neurons and fibers projecting from DRN to the OB with bifurcations. We found that a single 5-HT axon can form synaptic contacts to both type 1 and 2 periglomerular cells within a single glomerulus. Through immunolabeling, we also identified vesicular glutamate transporter 3 in 5-HT neurons terminals, indicating possible glutamatergic transmission. Our present study strongly implicates the involvement of brain regions such as the DRN in regulation of the elaborate mechanisms of olfactory processing. We further provide a structure basis of the network for coordinating or linking olfactory encoding with other neural systems, with special attention to serotonergic regulation. © 2014 Wiley Periodicals, Inc.

Internally Generated Reactivation of Single Neurons in Human Hippocampus During Free Recall

PubMed Central

Gelbard-Sagiv, Hagar; Mukamel, Roy; Harel, Michal; Malach, Rafael; Fried, Itzhak

2009-01-01

The emergence of memory, a trace of things past, into human consciousness is one of the greatest mysteries of the human mind. Whereas the neuronal basis of recognition memory can be probed experimentally in human and nonhuman primates, the study of free recall requires that the mind declare the occurrence of a recalled memory (an event intrinsic to the organism and invisible to an observer). Here, we report the activity of single neurons in the human hippocampus and surrounding areas when subjects first view cinematic episodes consisting of audiovisual sequences and again later when they freely recall these episodes. A subset of these neurons exhibited selective firing, which often persisted throughout and following specific episodes for as long as 12 seconds. Verbal reports of memories of these specific episodes at the time of free recall were preceded by selective reactivation of the same hippocampal and entorhinal cortex neurons. We suggest that this reactivation is an internally generated neuronal correlate for the subjective experience of spontaneous emergence of human recollection. PMID:18772395

VAV-1 acts in a single interneuron to inhibit motor circuit activity in Caenorhabditis elegans.

PubMed

Fry, Amanda L; Laboy, Jocelyn T; Norman, Kenneth R

2014-11-21

The complex molecular and cellular mechanisms underlying neuronal control of animal movement are not well understood. Locomotion of Caenorhabditis elegans is mediated by a neuronal circuit that produces coordinated sinusoidal movement. Here we utilize this simple, yet elegant, behaviour to show that VAV-1, a conserved guanine nucleotide exchange factor for Rho-family GTPases, negatively regulates motor circuit activity and the rate of locomotion. While vav-1 is expressed in a small subset of neurons, we find that VAV-1 function is required in a single interneuron, ALA, to regulate motor neuron circuit activity. Furthermore, we show by genetic and optogenetic manipulation of ALA that VAV-1 is required for the excitation and activation of this neuron. We find that ALA signalling inhibits command interneuron activity by abrogating excitatory signalling in the command interneurons, which is responsible for promoting motor neuron circuit activity. Together, our data describe a novel neuromodulatory role for VAV-1-dependent signalling in the regulation of motor circuit activity and locomotion.

A single cell high content assay detects mitochondrial dysfunction in iPSC-derived neurons with mutations in SNCA.

PubMed

Little, Daniel; Luft, Christin; Mosaku, Olukunbi; Lorvellec, Maëlle; Yao, Zhi; Paillusson, Sébastien; Kriston-Vizi, Janos; Gandhi, Sonia; Abramov, Andrey Y; Ketteler, Robin; Devine, Michael J; Gissen, Paul

2018-06-13

Mitochondrial dysfunction is implicated in many neurodegenerative diseases including Parkinson's disease (PD). Induced pluripotent stem cells (iPSCs) provide a unique cell model for studying neurological diseases. We have established a high-content assay that can simultaneously measure mitochondrial function, morphology and cell viability in iPSC-derived dopaminergic neurons. iPSCs from PD patients with mutations in SNCA and unaffected controls were differentiated into dopaminergic neurons, seeded in 384-well plates and stained with the mitochondrial membrane potential dependent dye TMRM, alongside Hoechst-33342 and Calcein-AM. Images were acquired using an automated confocal screening microscope and single cells were analysed using automated image analysis software. PD neurons displayed reduced mitochondrial membrane potential and altered mitochondrial morphology compared to control neurons. This assay demonstrates that high content screening techniques can be applied to the analysis of mitochondria in iPSC-derived neurons. This technique could form part of a drug discovery platform to test potential new therapeutics for PD and other neurodegenerative diseases.

Neural signatures of attention: insights from decoding population activity patterns.

PubMed

Sapountzis, Panagiotis; Gregoriou, Georgia G

2018-01-01

Understanding brain function and the computations that individual neurons and neuronal ensembles carry out during cognitive functions is one of the biggest challenges in neuroscientific research. To this end, invasive electrophysiological studies have provided important insights by recording the activity of single neurons in behaving animals. To average out noise, responses are typically averaged across repetitions and across neurons that are usually recorded on different days. However, the brain makes decisions on short time scales based on limited exposure to sensory stimulation by interpreting responses of populations of neurons on a moment to moment basis. Recent studies have employed machine-learning algorithms in attention and other cognitive tasks to decode the information content of distributed activity patterns across neuronal ensembles on a single trial basis. Here, we review results from studies that have used pattern-classification decoding approaches to explore the population representation of cognitive functions. These studies have offered significant insights into population coding mechanisms. Moreover, we discuss how such advances can aid the development of cognitive brain-computer interfaces.

[A modified intracellular labelling technique for high-resolution staining of neuron in 500 microm-thickness brain slice].

PubMed

Zhao, Ming-liang; Liu, Guo-long; Sui, Jian-feng; Ruan, Huai-zhen; Xiong, Ying

2007-05-01

To develop simple but reliable intracellular labelling method for high-resolution visualization of the fine structure of single neurons in brain slice with thickness of 500 microm. Biocytin was introduced into neurons in 500 microm-thickness brain slices while blind whole cell recording. Following processed for histochemistry using the avidin-biotin-complex method, stained slices were mounted in glycerol on special glass slides. Labelled cells were digital photomicrographed every 30 microm and reconstructed with Adobe Photoshop software. After histochemistry, limited background staining was produced. The resolution was so high that fine structure, including branching, termination of individual axons and even spines of neurons could be identified in exquisite detail with optic microscope. With the help of software, the neurons of interest could be reconstructed from a stack of photomicrographs. The modified method provides an easy and reliable approach to revealing the detailed morphological properties of single neurons in 500 microm-thickness brain slice. Without requisition of special equipment, it is suited to be broadly applied.

Modulation and detection of single neuron activity using spin transfer nano-oscillators

NASA Astrophysics Data System (ADS)

Algarin, Jose Miguel; Ramaswamy, Bharath; Venuti, Lucy; Swierzbinski, Matthew; Villar, Pablo; Chen, Yu-Jin; Krivorotov, Ilya; Weinberg, Irving N.; Herberholz, Jens; Araneda, Ricardo; Shapiro, Benjamin; Waks, Edo

2017-09-01

The brain is a complex network of interconnected circuits that exchange electrical signals with each other. These electrical signals provide insight on how neural circuits code information, and give rise to sensations, thoughts, emotions and actions. Currents methods to detect and modulate these electrical signals use implanted electrodes or optical fields with light sensitive dyes in the brain. These techniques require complex surgeries or suffer low resolution. In this talk we explore a new method to both image and stimulate single neurons using spintronics. We propose using a Spin Transfer Nano-Oscillators (STNOs) as a nanoscale sensor that converts neuronal action potentials to microwave field oscillations that can be detected wirelessly by magnetic induction. We will describe our recent proof-of-concept demonstration of both detection and wireless modulation of neuronal activity using STNOs. For detection we use electrodes to connect a STNO to a lateral giant crayfish neuron. When we stimulate the neuron, the STNO responds to the neuronal activity with a corresponding microwave signal. For modulation, we stimulate the STNOs wirelessly using an inductively coupled solenoid. The STNO rectifies the induced microwave signal to produce a direct voltage. This direct voltage from the STNO, when applied in the vicinity of a mammalian neuron, changes the frequency of electrical signals produced by the neuron.

Automatically tracking neurons in a moving and deforming brain

PubMed Central

Nguyen, Jeffrey P.; Linder, Ashley N.; Plummer, George S.; Shaevitz, Joshua W.

2017-01-01

Advances in optical neuroimaging techniques now allow neural activity to be recorded with cellular resolution in awake and behaving animals. Brain motion in these recordings pose a unique challenge. The location of individual neurons must be tracked in 3D over time to accurately extract single neuron activity traces. Recordings from small invertebrates like C. elegans are especially challenging because they undergo very large brain motion and deformation during animal movement. Here we present an automated computer vision pipeline to reliably track populations of neurons with single neuron resolution in the brain of a freely moving C. elegans undergoing large motion and deformation. 3D volumetric fluorescent images of the animal’s brain are straightened, aligned and registered, and the locations of neurons in the images are found via segmentation. Each neuron is then assigned an identity using a new time-independent machine-learning approach we call Neuron Registration Vector Encoding. In this approach, non-rigid point-set registration is used to match each segmented neuron in each volume with a set of reference volumes taken from throughout the recording. The way each neuron matches with the references defines a feature vector which is clustered to assign an identity to each neuron in each volume. Finally, thin-plate spline interpolation is used to correct errors in segmentation and check consistency of assigned identities. The Neuron Registration Vector Encoding approach proposed here is uniquely well suited for tracking neurons in brains undergoing large deformations. When applied to whole-brain calcium imaging recordings in freely moving C. elegans, this analysis pipeline located 156 neurons for the duration of an 8 minute recording and consistently found more neurons more quickly than manual or semi-automated approaches. PMID:28545068

Automatically tracking neurons in a moving and deforming brain.

PubMed

Nguyen, Jeffrey P; Linder, Ashley N; Plummer, George S; Shaevitz, Joshua W; Leifer, Andrew M

2017-05-01

Advances in optical neuroimaging techniques now allow neural activity to be recorded with cellular resolution in awake and behaving animals. Brain motion in these recordings pose a unique challenge. The location of individual neurons must be tracked in 3D over time to accurately extract single neuron activity traces. Recordings from small invertebrates like C. elegans are especially challenging because they undergo very large brain motion and deformation during animal movement. Here we present an automated computer vision pipeline to reliably track populations of neurons with single neuron resolution in the brain of a freely moving C. elegans undergoing large motion and deformation. 3D volumetric fluorescent images of the animal's brain are straightened, aligned and registered, and the locations of neurons in the images are found via segmentation. Each neuron is then assigned an identity using a new time-independent machine-learning approach we call Neuron Registration Vector Encoding. In this approach, non-rigid point-set registration is used to match each segmented neuron in each volume with a set of reference volumes taken from throughout the recording. The way each neuron matches with the references defines a feature vector which is clustered to assign an identity to each neuron in each volume. Finally, thin-plate spline interpolation is used to correct errors in segmentation and check consistency of assigned identities. The Neuron Registration Vector Encoding approach proposed here is uniquely well suited for tracking neurons in brains undergoing large deformations. When applied to whole-brain calcium imaging recordings in freely moving C. elegans, this analysis pipeline located 156 neurons for the duration of an 8 minute recording and consistently found more neurons more quickly than manual or semi-automated approaches.

Octylphenol (OP) alters the expression of members of the amyloid protein family in the hypothalamus of the snapping turtle, Chelydra serpentina serpentina.

PubMed Central

Trudeau, Vance L; Chiu, Suzanne; Kennedy, Sean W; Brooks, Ronald J

2002-01-01

The gonadal estrogen estradiol-17beta (E(2)) is important for developing and regulating hypothalamic function and many aspects of reproduction in vertebrates. Pollutants such as octylphenol (OP) that mimic the actions of estrogens are therefore candidate endocrine-disrupting chemicals. We used a differential display strategy (RNA-arbitrarily primed polymerase chain reaction) to isolate partial cDNA sequences of neurotransmitter, developmental, and disease-related genes that may be regulated by OP or E(2) in the snapping turtle Chelydra serpentina serpentina hypothalamus. Hatchling and year-old male snapping turtles were exposed to a 10 ng/mL nominal concentration of waterborne OP or E(2) for 17 days. One transcript [421 base pairs (bp)] regulated by OP and E(2) was 93% identical to human APLP-2. APLP-2 and the amyloid precursor protein (APP) regulate neuronal differentiation and are also implicated in the genesis of Alzheimer disease in humans. Northern blot analysis determined that the turtle hypothalamus contains a single APLP-2 transcript of 3.75 kb in length. Exposure to OP upregulated hypothalamic APLP-2 mRNA levels 2-fold (p < 0.05) in month-old and yearling turtles. E(2) did not affect APLP-2 mRNA levels in hatchlings but stimulated a 2-fold increase (p < 0.05) in APLP-2 mRNA levels in yearling males. The protein beta-amyloid, a selectively processed peptide derived from APP, is also involved in neuronal differentiation, and accumulation of this neurotoxic peptide causes neuronal degeneration in the brains of patients with Alzheimer disease. Therefore, we also sought to determine the effects of estrogens on the expression of beta-amyloid. Using homology cloning based on known sequences, we isolated a cDNA fragment (474 bp) from turtle brain with 88% identity to human APP. Northern blot analysis determined that a single 3.5-kb transcript was expressed in the turtle hypothalamus. Waterborne OP also increased the expression of hypothalamic APP after 35 days of exposure. Our results indicate that low levels of OP are bioactive and can alter the expression of APLP-2 and APP. Because members of the APP gene family are involved in neuronal development, we hypothesize that OP exposure may disrupt hypothalamic development in young turtles. PMID:11882478

Octylphenol (OP) alters the expression of members of the amyloid protein family in the hypothalamus of the snapping turtle, Chelydra serpentina serpentina.

PubMed

Trudeau, Vance L; Chiu, Suzanne; Kennedy, Sean W; Brooks, Ronald J

2002-03-01

The gonadal estrogen estradiol-17beta (E(2)) is important for developing and regulating hypothalamic function and many aspects of reproduction in vertebrates. Pollutants such as octylphenol (OP) that mimic the actions of estrogens are therefore candidate endocrine-disrupting chemicals. We used a differential display strategy (RNA-arbitrarily primed polymerase chain reaction) to isolate partial cDNA sequences of neurotransmitter, developmental, and disease-related genes that may be regulated by OP or E(2) in the snapping turtle Chelydra serpentina serpentina hypothalamus. Hatchling and year-old male snapping turtles were exposed to a 10 ng/mL nominal concentration of waterborne OP or E(2) for 17 days. One transcript [421 base pairs (bp)] regulated by OP and E(2) was 93% identical to human APLP-2. APLP-2 and the amyloid precursor protein (APP) regulate neuronal differentiation and are also implicated in the genesis of Alzheimer disease in humans. Northern blot analysis determined that the turtle hypothalamus contains a single APLP-2 transcript of 3.75 kb in length. Exposure to OP upregulated hypothalamic APLP-2 mRNA levels 2-fold (p < 0.05) in month-old and yearling turtles. E(2) did not affect APLP-2 mRNA levels in hatchlings but stimulated a 2-fold increase (p < 0.05) in APLP-2 mRNA levels in yearling males. The protein beta-amyloid, a selectively processed peptide derived from APP, is also involved in neuronal differentiation, and accumulation of this neurotoxic peptide causes neuronal degeneration in the brains of patients with Alzheimer disease. Therefore, we also sought to determine the effects of estrogens on the expression of beta-amyloid. Using homology cloning based on known sequences, we isolated a cDNA fragment (474 bp) from turtle brain with 88% identity to human APP. Northern blot analysis determined that a single 3.5-kb transcript was expressed in the turtle hypothalamus. Waterborne OP also increased the expression of hypothalamic APP after 35 days of exposure. Our results indicate that low levels of OP are bioactive and can alter the expression of APLP-2 and APP. Because members of the APP gene family are involved in neuronal development, we hypothesize that OP exposure may disrupt hypothalamic development in young turtles.

Two-photon microscope for multisite microphotolysis of caged neurotransmitters in acute brain slices

PubMed Central

Losavio, Bradley E.; Iyer, Vijay; Saggau, Peter

2009-01-01

We developed a two-photon microscope optimized for physiologically manipulating single neurons through their postsynaptic receptors. The optical layout fulfills the stringent design criteria required for high-speed, high-resolution imaging in scattering brain tissue with minimal photodamage. We detail the practical compensation of spectral and temporal dispersion inherent in fast laser beam scanning with acousto-optic deflectors, as well as a set of biological protocols for visualizing nearly diffraction-limited structures and delivering physiological synaptic stimuli. The microscope clearly resolves dendritic spines and evokes electrophysiological transients in single neurons that are similar to endogenous responses. This system enables the study of multisynaptic integration and will assist our understanding of single neuron function and dendritic computation. PMID:20059271

Photodynamic therapy-induced nitric oxide production in neuronal and glial cells

NASA Astrophysics Data System (ADS)

Kovaleva, Vera D.; Uzdensky, Anatoly B.

2016-10-01

Nitric oxide (NO) has been recently demonstrated to enhance apoptosis of glial cells induced by photodynamic therapy (PDT), but to protect glial cells from PDT-induced necrosis in the crayfish stretch receptor, a simple neuroglial preparation that consists of a single mechanosensory neuron enveloped by satellite glial cells. We used the NO-sensitive fluorescent probe 4,5-diaminofluorescein diacetate to study the distribution and dynamics of PDT-induced NO production in the mechanosensory neuron and surrounding glial cells. The NO production in the glial envelope was higher than in the neuronal soma axon and dendrites both in control and in experimental conditions. In dark NO generator, DEA NONOate or NO synthase substrate L-arginine hydrochloride significantly increased the NO level in glial cells, whereas NO scavenger 2-Phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO) or inhibitors of NO synthase L-NG-nitro arginine methyl ester and Nω-nitro-L-arginine decreased it. PDT induced the transient increase in NO production with a maximum at 4 to 7 min after the irradiation start followed by its inhibition at 10 to 40 min. We suggested that PDT stimulated neuronal rather than inducible NO synthase isoform in glial cells, and the produced NO could mediate PDT-induced apoptosis.

Reconstruction of neuronal input through modeling single-neuron dynamics and computations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qin, Qing; Wang, Jiang; Yu, Haitao

Mathematical models provide a mathematical description of neuron activity, which can better understand and quantify neural computations and corresponding biophysical mechanisms evoked by stimulus. In this paper, based on the output spike train evoked by the acupuncture mechanical stimulus, we present two different levels of models to describe the input-output system to achieve the reconstruction of neuronal input. The reconstruction process is divided into two steps: First, considering the neuronal spiking event as a Gamma stochastic process. The scale parameter and the shape parameter of Gamma process are, respectively, defined as two spiking characteristics, which are estimated by a state-spacemore » method. Then, leaky integrate-and-fire (LIF) model is used to mimic the response system and the estimated spiking characteristics are transformed into two temporal input parameters of LIF model, through two conversion formulas. We test this reconstruction method by three different groups of simulation data. All three groups of estimates reconstruct input parameters with fairly high accuracy. We then use this reconstruction method to estimate the non-measurable acupuncture input parameters. Results show that under three different frequencies of acupuncture stimulus conditions, estimated input parameters have an obvious difference. The higher the frequency of the acupuncture stimulus is, the higher the accuracy of reconstruction is.« less

Dual Anterograde and Retrograde Viral Tracing of Reciprocal Connectivity.

PubMed

Haberl, Matthias G; Ginger, Melanie; Frick, Andreas

2017-01-01

Current large-scale approaches in neuroscience aim to unravel the complete connectivity map of specific neuronal circuits, or even the entire brain. This emerging research discipline has been termed connectomics. Recombinant glycoprotein-deleted rabies virus (RABV ∆G) has become an important tool for the investigation of neuronal connectivity in the brains of a variety of species. Neuronal infection with even a single RABV ∆G particle results in high-level transgene expression, revealing the fine-detailed morphology of all neuronal features-including dendritic spines, axonal processes, and boutons-on a brain-wide scale. This labeling is eminently suitable for subsequent post-hoc morphological analysis, such as semiautomated reconstruction in 3D. Here we describe the use of a recently developed anterograde RABV ∆G variant together with a retrograde RABV ∆G for the investigation of projections both to, and from, a particular brain region. In addition to the automated reconstruction of a dendritic tree, we also give as an example the volume measurements of axonal boutons following RABV ∆G-mediated fluorescent marker expression. In conclusion RABV ∆G variants expressing a combination of markers and/or tools for stimulating/monitoring neuronal activity, used together with genetic or behavioral animal models, promise important insights in the structure-function relationship of neural circuits.

Cracking the barcode of fullerene-like cortical microcolumns.

PubMed

Tozzi, Arturo; Peters, James F; Ori, Ottorino

2017-03-22

Artificial neural systems and nervous graph theoretical analysis rely upon the stance that the neural code is embodied in logic circuits, e.g., spatio-temporal sequences of ON/OFF spiking neurons. Nevertheless, this assumption does not fully explain complex brain functions. Here we show how nervous activity, other than logic circuits, could instead depend on topological transformations and symmetry constraints occurring at the micro-level of the cortical microcolumn, i.e., the embryological, anatomical and functional basic unit of the brain. Tubular microcolumns can be flattened in fullerene-like two-dimensional lattices, equipped with about 80 nodes standing for pyramidal neurons where neural computations take place. We show how the countless possible combinations of activated neurons embedded in the lattice resemble a barcode. Despite the fact that further experimental verification is required in order to validate our claim, different assemblies of firing neurons might have the appearance of diverse codes, each one responsible for a single mental activity. A two-dimensional fullerene-like lattice, grounded on simple topological changes standing for pyramidal neurons' activation, not just displays analogies with the real microcolumn's microcircuitry and the neural connectome, but also the potential for the manufacture of plastic, robust and fast artificial networks in robotic forms of full-fledged neural systems. Copyright © 2017 Elsevier B.V. All rights reserved.

Reconstruction of neuronal input through modeling single-neuron dynamics and computations

NASA Astrophysics Data System (ADS)

Qin, Qing; Wang, Jiang; Yu, Haitao; Deng, Bin; Chan, Wai-lok

2016-06-01

Mathematical models provide a mathematical description of neuron activity, which can better understand and quantify neural computations and corresponding biophysical mechanisms evoked by stimulus. In this paper, based on the output spike train evoked by the acupuncture mechanical stimulus, we present two different levels of models to describe the input-output system to achieve the reconstruction of neuronal input. The reconstruction process is divided into two steps: First, considering the neuronal spiking event as a Gamma stochastic process. The scale parameter and the shape parameter of Gamma process are, respectively, defined as two spiking characteristics, which are estimated by a state-space method. Then, leaky integrate-and-fire (LIF) model is used to mimic the response system and the estimated spiking characteristics are transformed into two temporal input parameters of LIF model, through two conversion formulas. We test this reconstruction method by three different groups of simulation data. All three groups of estimates reconstruct input parameters with fairly high accuracy. We then use this reconstruction method to estimate the non-measurable acupuncture input parameters. Results show that under three different frequencies of acupuncture stimulus conditions, estimated input parameters have an obvious difference. The higher the frequency of the acupuncture stimulus is, the higher the accuracy of reconstruction is.

Macroscopic phase-resetting curves for spiking neural networks

NASA Astrophysics Data System (ADS)

Dumont, Grégory; Ermentrout, G. Bard; Gutkin, Boris

2017-10-01

The study of brain rhythms is an open-ended, and challenging, subject of interest in neuroscience. One of the best tools for the understanding of oscillations at the single neuron level is the phase-resetting curve (PRC). Synchronization in networks of neurons, effects of noise on the rhythms, effects of transient stimuli on the ongoing rhythmic activity, and many other features can be understood by the PRC. However, most macroscopic brain rhythms are generated by large populations of neurons, and so far it has been unclear how the PRC formulation can be extended to these more common rhythms. In this paper, we describe a framework to determine a macroscopic PRC (mPRC) for a network of spiking excitatory and inhibitory neurons that generate a macroscopic rhythm. We take advantage of a thermodynamic approach combined with a reduction method to simplify the network description to a small number of ordinary differential equations. From this simplified but exact reduction, we can compute the mPRC via the standard adjoint method. Our theoretical findings are illustrated with and supported by numerical simulations of the full spiking network. Notably our mPRC framework allows us to predict the difference between effects of transient inputs to the excitatory versus the inhibitory neurons in the network.

Biophysical synaptic dynamics in an analog VLSI network of Hodgkin-Huxley neurons.

PubMed

Yu, Theodore; Cauwenberghs, Gert

2009-01-01

We study synaptic dynamics in a biophysical network of four coupled spiking neurons implemented in an analog VLSI silicon microchip. The four neurons implement a generalized Hodgkin-Huxley model with individually configurable rate-based kinetics of opening and closing of Na+ and K+ ion channels. The twelve synapses implement a rate-based first-order kinetic model of neurotransmitter and receptor dynamics, accounting for NMDA and non-NMDA type chemical synapses. The implemented models on the chip are fully configurable by 384 parameters accounting for conductances, reversal potentials, and pre/post-synaptic voltage-dependence of the channel kinetics. We describe the models and present experimental results from the chip characterizing single neuron dynamics, single synapse dynamics, and multi-neuron network dynamics showing phase-locking behavior as a function of synaptic coupling strength. The 3mm x 3mm microchip consumes 1.29 mW power making it promising for applications including neuromorphic modeling and neural prostheses.

Mitochondria localize to injured axons to support regeneration

PubMed Central

Han, Sung Min; Baig, Huma S.; Hammarlund, Marc

2016-01-01

SUMMARY Axon regeneration is essential to restore the nervous system after axon injury. However, the neuronal cell biology that underlies axon regeneration is incompletely understood. Here we use in vivo single-neuron analysis to investigate the relationship between nerve injury, mitochondrial localization, and axon regeneration. Mitochondria translocate into injured axons, so that average mitochondria density increases after injury. Moreover, single-neuron analysis reveals that axons that fail to increase mitochondria have poor regeneration. Experimental alterations to axonal mitochondrial distribution or mitochondrial respiratory chain function result in corresponding changes to regeneration outcomes. Axonal mitochondria are specifically required for growth cone migration, identifying a key energy challenge for injured neurons. Finally, mitochondrial localization to the axon after injury is regulated in part by dual-leucine zipper kinase-1 (DLK-1), a conserved regulator of axon regeneration. These data identify regulation of axonal mitochondria as a new cell biological mechanism that helps determine the regenerative response of injured neurons. PMID:28009276

Neural noise and movement-related codes in the macaque supplementary motor area.

PubMed

Averbeck, Bruno B; Lee, Daeyeol

2003-08-20

We analyzed the variability of spike counts and the coding capacity of simultaneously recorded pairs of neurons in the macaque supplementary motor area (SMA). We analyzed the mean-variance functions for single neurons, as well as signal and noise correlations between pairs of neurons. All three statistics showed a strong dependence on the bin width chosen for analysis. Changes in the correlation structure of single neuron spike trains over different bin sizes affected the mean-variance function, and signal and noise correlations between pairs of neurons were much smaller at small bin widths, increasing monotonically with the width of the bin. Analyses in the frequency domain showed that the noise between pairs of neurons, on average, was most strongly correlated at low frequencies, which explained the increase in noise correlation with increasing bin width. The coding performance was analyzed to determine whether the temporal precision of spike arrival times and the interactions within and between neurons could improve the prediction of the upcoming movement. We found that in approximately 62% of neuron pairs, the arrival times of spikes at a resolution between 66 and 40 msec carried more information than spike counts in a 200 msec bin. In addition, in 19% of neuron pairs, inclusion of within (11%)- or between-neuron (8%) correlations in spike trains improved decoding accuracy. These results suggest that in some SMA neurons elements of the spatiotemporal pattern of activity may be relevant for neural coding.

Coding of vocalizations by single neurons in ventrolateral prefrontal cortex.

PubMed

Plakke, Bethany; Diltz, Mark D; Romanski, Lizabeth M

2013-11-01

Neuronal activity in single prefrontal neurons has been correlated with behavioral responses, rules, task variables and stimulus features. In the non-human primate, neurons recorded in ventrolateral prefrontal cortex (VLPFC) have been found to respond to species-specific vocalizations. Previous studies have found multisensory neurons which respond to simultaneously presented faces and vocalizations in this region. Behavioral data suggests that face and vocal information are inextricably linked in animals and humans and therefore may also be tightly linked in the coding of communication calls in prefrontal neurons. In this study we therefore examined the role of VLPFC in encoding vocalization call type information. Specifically, we examined previously recorded single unit responses from the VLPFC in awake, behaving rhesus macaques in response to 3 types of species-specific vocalizations made by 3 individual callers. Analysis of responses by vocalization call type and caller identity showed that ∼19% of cells had a main effect of call type with fewer cells encoding caller. Classification performance of VLPFC neurons was ∼42% averaged across the population. When assessed at discrete time bins, classification performance reached 70 percent for coos in the first 300 ms and remained above chance for the duration of the response period, though performance was lower for other call types. In light of the sub-optimal classification performance of the majority of VLPFC neurons when only vocal information is present, and the recent evidence that most VLPFC neurons are multisensory, the potential enhancement of classification with the addition of accompanying face information is discussed and additional studies recommended. Behavioral and neuronal evidence has shown a considerable benefit in recognition and memory performance when faces and voices are presented simultaneously. In the natural environment both facial and vocalization information is present simultaneously and neural systems no doubt evolved to integrate multisensory stimuli during recognition. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives". Copyright © 2013 Elsevier B.V. All rights reserved.

Auditory and audio-vocal responses of single neurons in the monkey ventral premotor cortex.

PubMed

Hage, Steffen R

2018-03-20

Monkey vocalization is a complex behavioral pattern, which is flexibly used in audio-vocal communication. A recently proposed dual neural network model suggests that cognitive control might be involved in this behavior, originating from a frontal cortical network in the prefrontal cortex and mediated via projections from the rostral portion of the ventral premotor cortex (PMvr) and motor cortex to the primary vocal motor network in the brainstem. For the rapid adjustment of vocal output to external acoustic events, strong interconnections between vocal motor and auditory sites are needed, which are present at cortical and subcortical levels. However, the role of the PMvr in audio-vocal integration processes remains unclear. In the present study, single neurons in the PMvr were recorded in rhesus monkeys (Macaca mulatta) while volitionally producing vocalizations in a visual detection task or passively listening to monkey vocalizations. Ten percent of randomly selected neurons in the PMvr modulated their discharge rate in response to acoustic stimulation with species-specific calls. More than four-fifths of these auditory neurons showed an additional modulation of their discharge rates either before and/or during the monkeys' motor production of the vocalization. Based on these audio-vocal interactions, the PMvr might be well positioned to mediate higher order auditory processing with cognitive control of the vocal motor output to the primary vocal motor network. Such audio-vocal integration processes in the premotor cortex might constitute a precursor for the evolution of complex learned audio-vocal integration systems, ultimately giving rise to human speech. Copyright © 2018 Elsevier B.V. All rights reserved.

Emergence of Adaptive Computation by Single Neurons in the Developing Cortex

PubMed Central

Famulare, Michael; Gjorgjieva, Julijana; Moody, William J.

2013-01-01

Adaptation is a fundamental computational motif in neural processing. To maintain stable perception in the face of rapidly shifting input, neural systems must extract relevant information from background fluctuations under many different contexts. Many neural systems are able to adjust their input–output properties such that an input's ability to trigger a response depends on the size of that input relative to its local statistical context. This “gain-scaling” strategy has been shown to be an efficient coding strategy. We report here that this property emerges during early development as an intrinsic property of single neurons in mouse sensorimotor cortex, coinciding with the disappearance of spontaneous waves of network activity, and can be modulated by changing the balance of spike-generating currents. Simultaneously, developing neurons move toward a common intrinsic operating point and a stable ratio of spike-generating currents. This developmental trajectory occurs in the absence of sensory input or spontaneous network activity. Through a combination of electrophysiology and modeling, we demonstrate that developing cortical neurons develop the ability to perform nearly perfect gain scaling by virtue of the maturing spike-generating currents alone. We use reduced single neuron models to identify the conditions for this property to hold. PMID:23884925

Spatial dynamics of action potentials estimated by dendritic Ca(2+) signals in insect projection neurons.

PubMed

Ogawa, Hiroto; Mitani, Ruriko

2015-11-13

The spatial dynamics of action potentials, including their propagation and the location of spike initiation zone (SIZ), are crucial for the computation of a single neuron. Compared with mammalian central neurons, the spike dynamics of invertebrate neurons remain relatively unknown. Thus, we examined the spike dynamics based on single spike-induced Ca(2+) signals in the dendrites of cricket mechanosensory projection neurons, known as giant interneurons (GIs). The Ca(2+) transients induced by a synaptically evoked single spike were larger than those induced by an antidromic spike, whereas subthreshold synaptic potentials caused no elevation of Ca(2+). These results indicate that synaptic activity enhances the dendritic Ca(2+) influx through voltage-gated Ca(2+) channels. Stimulation of the presynaptic sensory afferents ipsilateral to the recording site evoked a dendritic spike with higher amplitude than contralateral stimulation, thereby suggesting that alteration of the spike waveform resulted in synaptic enhancement of the dendritic Ca(2+) transients. The SIZ estimated from the spatial distribution of the difference in the Ca(2+) amplitude was distributed throughout the right and left dendritic branches across the primary neurite connecting them in GIs. Copyright © 2015 Elsevier Inc. All rights reserved.

Two-Photon Functional Imaging of the Auditory Cortex in Behaving Mice: From Neural Networks to Single Spines.

PubMed

Li, Ruijie; Wang, Meng; Yao, Jiwei; Liang, Shanshan; Liao, Xiang; Yang, Mengke; Zhang, Jianxiong; Yan, Junan; Jia, Hongbo; Chen, Xiaowei; Li, Xingyi

2018-01-01

In vivo two-photon Ca 2+ imaging is a powerful tool for recording neuronal activities during perceptual tasks and has been increasingly applied to behaving animals for acute or chronic experiments. However, the auditory cortex is not easily accessible to imaging because of the abundant temporal muscles, arteries around the ears and their lateral locations. Here, we report a protocol for two-photon Ca 2+ imaging in the auditory cortex of head-fixed behaving mice. By using a custom-made head fixation apparatus and a head-rotated fixation procedure, we achieved two-photon imaging and in combination with targeted cell-attached recordings of auditory cortical neurons in behaving mice. Using synthetic Ca 2+ indicators, we recorded the Ca 2+ transients at multiple scales, including neuronal populations, single neurons, dendrites and single spines, in auditory cortex during behavior. Furthermore, using genetically encoded Ca 2+ indicators (GECIs), we monitored the neuronal dynamics over days throughout the process of associative learning. Therefore, we achieved two-photon functional imaging at multiple scales in auditory cortex of behaving mice, which extends the tool box for investigating the neural basis of audition-related behaviors.

Effect of Morphologic Features of Neurons on the Extracellular Electric Potential: A Simulation Study Using Cable Theory and Electro-Quasi-Static Equations.

PubMed

Bestel, R; Appali, R; van Rienen, U; Thielemann, C

2017-11-01

Microelectrode arrays serve as an indispensable tool in electro-physiological research to study the electrical activity of neural cells, enabling measurements of single cell as well as network communication analysis. Recent experimental studies have reported that the neuronal geometry has an influence on electrical signaling and extracellular recordings. However, the corresponding mechanisms are not yet fully understood and require further investigation. Allowing systematic parameter studies, computational modeling provides the opportunity to examine the underlying effects that influence extracellular potentials. In this letter, we present an in silico single cell model to analyze the effect of geometrical variability on the extracellular electric potentials. We describe finite element models of a single neuron with varying geometric complexity in three-dimensional space. The electric potential generation of the neuron is modeled using Hodgkin-Huxley equations. The signal propagation is described with electro-quasi-static equations, and results are compared with corresponding cable equation descriptions. Our results show that both the geometric dimensions and the distribution of ion channels of a neuron are critical factors that significantly influence both the amplitude and shape of extracellular potentials.

Two-Photon Functional Imaging of the Auditory Cortex in Behaving Mice: From Neural Networks to Single Spines

PubMed Central

Li, Ruijie; Wang, Meng; Yao, Jiwei; Liang, Shanshan; Liao, Xiang; Yang, Mengke; Zhang, Jianxiong; Yan, Junan; Jia, Hongbo; Chen, Xiaowei; Li, Xingyi

2018-01-01

In vivo two-photon Ca2+ imaging is a powerful tool for recording neuronal activities during perceptual tasks and has been increasingly applied to behaving animals for acute or chronic experiments. However, the auditory cortex is not easily accessible to imaging because of the abundant temporal muscles, arteries around the ears and their lateral locations. Here, we report a protocol for two-photon Ca2+ imaging in the auditory cortex of head-fixed behaving mice. By using a custom-made head fixation apparatus and a head-rotated fixation procedure, we achieved two-photon imaging and in combination with targeted cell-attached recordings of auditory cortical neurons in behaving mice. Using synthetic Ca2+ indicators, we recorded the Ca2+ transients at multiple scales, including neuronal populations, single neurons, dendrites and single spines, in auditory cortex during behavior. Furthermore, using genetically encoded Ca2+ indicators (GECIs), we monitored the neuronal dynamics over days throughout the process of associative learning. Therefore, we achieved two-photon functional imaging at multiple scales in auditory cortex of behaving mice, which extends the tool box for investigating the neural basis of audition-related behaviors. PMID:29740289

Simple Learned Weighted Sums of Inferior Temporal Neuronal Firing Rates Accurately Predict Human Core Object Recognition Performance

PubMed Central

Hong, Ha; Solomon, Ethan A.; DiCarlo, James J.

2015-01-01

To go beyond qualitative models of the biological substrate of object recognition, we ask: can a single ventral stream neuronal linking hypothesis quantitatively account for core object recognition performance over a broad range of tasks? We measured human performance in 64 object recognition tests using thousands of challenging images that explore shape similarity and identity preserving object variation. We then used multielectrode arrays to measure neuronal population responses to those same images in visual areas V4 and inferior temporal (IT) cortex of monkeys and simulated V1 population responses. We tested leading candidate linking hypotheses and control hypotheses, each postulating how ventral stream neuronal responses underlie object recognition behavior. Specifically, for each hypothesis, we computed the predicted performance on the 64 tests and compared it with the measured pattern of human performance. All tested hypotheses based on low- and mid-level visually evoked activity (pixels, V1, and V4) were very poor predictors of the human behavioral pattern. However, simple learned weighted sums of distributed average IT firing rates exactly predicted the behavioral pattern. More elaborate linking hypotheses relying on IT trial-by-trial correlational structure, finer IT temporal codes, or ones that strictly respect the known spatial substructures of IT (“face patches”) did not improve predictive power. Although these results do not reject those more elaborate hypotheses, they suggest a simple, sufficient quantitative model: each object recognition task is learned from the spatially distributed mean firing rates (100 ms) of ∼60,000 IT neurons and is executed as a simple weighted sum of those firing rates. SIGNIFICANCE STATEMENT We sought to go beyond qualitative models of visual object recognition and determine whether a single neuronal linking hypothesis can quantitatively account for core object recognition behavior. To achieve this, we designed a database of images for evaluating object recognition performance. We used multielectrode arrays to characterize hundreds of neurons in the visual ventral stream of nonhuman primates and measured the object recognition performance of >100 human observers. Remarkably, we found that simple learned weighted sums of firing rates of neurons in monkey inferior temporal (IT) cortex accurately predicted human performance. Although previous work led us to expect that IT would outperform V4, we were surprised by the quantitative precision with which simple IT-based linking hypotheses accounted for human behavior. PMID:26424887

Laser Stimulation of Single Auditory Nerve Fibers

PubMed Central

Littlefield, Philip D.; Vujanovic, Irena; Mundi, Jagmeet; Matic, Agnella Izzo; Richter, Claus-Peter

2011-01-01

Objectives/Hypothesis One limitation with cochlear implants is the difficulty stimulating spatially discrete spiral ganglion cell groups because of electrode interactions. Multipolar electrodes have improved on this some, but also at the cost of much higher device power consumption. Recently, it has been shown that spatially selective stimulation of the auditory nerve is possible with a mid-infrared laser aimed at the spiral ganglion via the round window. However, these neurons must be driven at adequate rates for optical radiation to be useful in cochlear implants. We herein use single-fiber recordings to characterize the responses of auditory neurons to optical radiation. Study Design In vivo study using normal-hearing adult gerbils. Methods Two diode lasers were used for stimulation of the auditory nerve. They operated between 1.844 μm and 1.873 μm, with pulse durations of 35 μs to 1,000 μs, and at repetition rates up to 1,000 pulses per second (pps). The laser outputs were coupled to a 200-μm-diameter optical fiber placed against the round window membrane and oriented toward the spiral ganglion. The auditory nerve was exposed through a craniotomy, and recordings were taken from single fibers during acoustic and laser stimulation. Results Action potentials occurred 2.5 ms to 4.0 ms after the laser pulse. The latency jitter was up to 3 ms. Maximum rates of discharge averaged 97 ± 52.5 action potentials per second. The neurons did not strictly respond to the laser at stimulation rates over 100 pps. Conclusions Auditory neurons can be stimulated by a laser beam passing through the round window membrane and driven at rates sufficient for useful auditory information. Optical stimulation and electrical stimulation have different characteristics; which could be selectively exploited in future cochlear implants. Level of Evidence Not applicable. PMID:20830761

Evaluation of mRNA expression levels and electrophysiological function of neuron-like cells derived from canine bone marrow stromal cells.

PubMed

Nakano, Rei; Edamura, Kazuya; Sugiya, Hiroshi; Narita, Takanori; Okabayashi, Ken; Moritomo, Tadaaki; Teshima, Kenji; Asano, Kazushi; Nakayama, Tomohiro

2013-10-01

To investigate the in vitro differentiation of canine bone marrow stromal cells (BMSCs) into functional, mature neurons. Bone marrow from 6 adult dogs. BMSCs were isolated from bone marrow and chemically induced to develop into neurons. The morphology of the BMSCs during neuronal induction was monitored, and immunocytochemical analyses for neuron markers were performed after the induction. Real-time PCR methods were used to evaluate the mRNA expression levels of markers for neural stem or progenitor cells, neurons, and ion channels, and western blotting was used to assess the expression of neuronal proteins before and after neuronal induction. The electrophysiological properties of the neuron-like cells induced from canine BMSCs were evaluated with fluorescent dye to monitor Ca(2)+ influx. Canine BMSCs developed a neuron-like morphology after neuronal induction. Immunocytochemical analysis revealed that these neuron-like cells were positive for neuron markers. After induction, the cells' mRNA expression levels of almost all neuron and ion channel markers increased, and the protein expression levels of nestin and neurofilament-L increased significantly. However, the neuron-like cells derived from canine BMSCs did not have the Ca(2)+ influx characteristic of spiking neurons. Although canine BMSCs had neuron-like morphological and biochemical properties after induction, they did not develop the electrophysiological characteristics of neurons. Thus, these results have suggested that canine BMSCs could have the capacity to differentiate into a neuronal lineage, but the differentiation protocol used may have been insufficient to induce development into functional neurons.