Current Source Density Analysis Research Articles

Abstract TP142: Post-Ischemic Cortical Excitability and Gene Expression are Modulated by Transplanted Human Neural Stem Cells

Human neural stem cell (hNSC) transplantation improves recovery in preclinical stroke models. However their effects on surviving sensorimotor circuits are not well understood. Here we performed a comprehensive electrophysiological assessment and RNA-seq analysis of the stroke-injured rat cortex after transplantation of two hNSC lines, G010 (fetal-derived) and NR1 (hES-derived). Vehicle, G010, or NR1 cells were transplanted into the ischemic cortex of Nude rats 1 wk after distal middle cerebral artery occlusion. Neurological recovery was accessed by the Whisker-paw test. Acute brain slices were prepared 1 wk post-transplantation for electrophysiological recording. A linear multichannel recording probe was placed in the peri-infarct motor cortex and local field potentials (LFPs) recorded simultaneously from all cortical layers following circuit activation in layer 2/3. For RNA-seq analysis, the transplantation area was dissected, RNA extracted and cDNA libraries prepared for RNA-seq. G010 and NR1 cells enhanced post-stroke behavioral recovery starting 1 or 3 wks post-transplantation, respectively. Current source density (CSD) analysis of evoked LFPs, a method used to more accurately localize synaptic currents, revealed that both G010 and NR1 cells restored circuit excitability in layer 2/3, through reduction in inhibitory/excitatory (I/E) balance. However, the mechanisms driving the I/E balance shift were different, with NR1 cells enhancing excitation while G010 cells reduced inhibition. RNA-seq analysis of the cortex revealed that stem cell- versus vehicle-treated animals had different gene expression patterns in all cortical layers. Moreover, NR1 and G010 cells affected different genes. Layer 2/3-specific genes significantly affected by G010 grafts include Arpp21, Enpp2, Gbe1, Mylk, Pea15, Pkig, Rcn1, Slit3, Uchl1 and Wfs1; while NR1 grafts altered expression of Hapln4, Kcnc1, Ppp1r1b, Scn1a, Slit3 and Slitrk1. GO analysis revealed that both stem cell treatments activated critical canonical pathways e.g. Actin Cytoskeleton Signaling and Synaptic Long Term Depression. Stem cell transplantation modulates host gene expression and this is associated with increased circuit excitability and motor-sensory function.

Automated Source Estimation of Scalp EEG Epileptic Activity Using eLORETA Kurtosis Analysis

Objectives: eLORETA (exact low-resolution brain electromagnetic tomography) is a technique created by Pascual-Marqui et al. [Int J Psychophysiol. 1994 Oct; 18(1): 49–65] for the 3-dimensional representation of current source density in the brain by electroencephalography (EEG) data. Kurtosis analysis allows for the identification of spiky activity in the brain. In this study, we focused on the evaluation of the reliability of eLORETA kurtosis analysis. For this purpose, the results of eLORETA kurtosis source localization of paroxysmal activity in EEG were compared with those of eLORETA current source density (CSD) analysis of EEG data in 3 epilepsy patients with partial seizures. Methods: EEG was measured using a digital EEG system with 19 channels. We set the bandpass filter at traditional frequency band settings (1–4, 4–8, 8–15, 15–30, and 30–60 Hz) and 5–10 and 20–70 Hz and performed eLORETA kurtosis to compare the source localization of paroxysmal activity with that of visual interpretation of EEG data and CSD analysis of eLORETA in focal epilepsy patients. Results: The eLORETA kurtosis analysis of EEG data preprocessed by bandpass filtering from 20 to 70 Hz and traditional frequency band settings did not show any discrete paroxysmal source activity compatible with the results of CSD analysis of eLORETA. In all 3 cases, eLORETA kurtosis analysis filtered at 5–10 Hz showed paroxysmal activities in the theta band, which were all consistent with the visual inspection results and the CSD analysis results. Discussion: Our findings suggested that eLORETA kurtosis analysis of EEG data might be useful for the identification of spiky paroxysmal activity sources in epilepsy patients. Since EEG is widely used in the clinical practice of epilepsy, eLORETA kurtosis analysis is a promising method that can be applied to epileptic activity mapping.

Current Source Density Analysis of Electroantennogram Recordings: A Tool for Mapping the Olfactory Response in an Insect Antenna.

The set of chemosensory receptors expressed by the olfactory receptor neurons lying in an insect's antennae and maxillary palps define the ability of this insect to perceive the volatile chemicals of its environment. The main two electrophysiological methods of antennal recordings for studying the range of chemicals that activate chemosensory receptors have limitations. Single-sensillum recording (SSR) samples a subset of olfactory receptor neurons and therefore does not reveal the full capacity of an insect to perceive an odor. Electroantennography (EAG), even if less resolutive than SSRs, is sometimes preferred since it samples the activity of a large number of the olfactory receptor neurons. But, at least in flies, the amplitude of the EAG signal is not directly correlated with the degree of sensitivity of the insect to the olfactory compound. Such dual methodology was also used to study mammalian brains, and the current source density (CSD) analysis was developed to bridge the gap between the cellular and the population recordings. This paper details the use of a similar approach adapted to the study of olfactory responses within insects with bulbous antennae. The EAG was recorded at multiple antennal positions and the CSD that generates the EAG potentials were estimated. The method measures the activation of olfactory receptor neurons (ORNs) across the antennae and thus it quantifies the olfactory sensitivity of the insect. It allows a rapid mapping of olfactory responses and thus can be used to guide further SSRs or to determine that two chemicals are detected by independent ORNs. This study further explored biases resulting from a limited number of recording positions or from an approximation of the antennal geometry that should be considered for interpreting the CSD maps. It also shows that the CSD analysis of EAGs is compatible with a gas chromatograph stimulator for analyzing the response to complex odors. Finally, I discuss the origin of the EAG signal in light of the CSD theory.

The olfactory bulb is a source of high-frequency oscillations (130\u2013180\u2009Hz) associated with a subanesthetic dose of ketamine in rodents

High-frequency neuronal population oscillations (HFO, 130–180 Hz) are robustly potentiated by subanesthetic doses of ketamine. This frequency band has been recorded in functionally and neuroanatomically diverse cortical and subcortical regions, notably ventral striatal areas. However, the locus of generation remains largely unknown. There is compelling evidence that olfactory regions can drive oscillations in distant areas. Here we tested the hypothesis that the olfactory bulb (OB) is a locus for the generation of HFO following a subanesthetic dose of ketamine. The effect of ketamine on the electrophysiological activity of the OB and ventral striatum of male Wistar rats was examined using field potential and unit recordings, local inhibition, naris blockade, current source density and causality estimates. Ketamine-HFO was of larger magnitude and was phase-advanced in the OB relative to ventral striatum. Granger causality analysis was consistent with the OB as the source of HFO. Unilateral local inhibition of the OB and naris blockade both attenuated HFO recorded locally and in the ventral striatum. Within the OB, current source density analysis revealed HFO current dipoles close to the mitral layer and unit firing of mitral/tufted cells was phase locked to HFO. Our results reveal the OB as a source of ketamine-HFO which can contribute to HFO in the ventral striatum, known to project diffusely to many other brain regions. These findings provide a new conceptual understanding on how changes in olfactory system function may have implications for neurological disorders involving NMDA receptor dysfunction such as schizophrenia and depression.

WaveCSD: A method for estimating transmembrane currents originated from propagating neuronal activity in the neocortex: Application to study cortical spreading depression

BackgroundRecent years have witnessed an upsurge in the development of methods for estimating current source densities (CSDs) in the neocortical tissue from their recorded local field potential (LFP) reflections using microelectrode arrays. Among these, methods utilizing linear arrays work under the assumption that CSDs vary as a function of cortical depth; whereas they are constant in the tangential direction, infinitely or in a confined cylinder. This assumption is violated in the analysis of neuronal activity propagating along the neocortical sheet, e.g. propagation of alpha waves or cortical spreading depression. New methodHere, we developed a novel mathematical method (waveCSD) for CSD analysis of LFPs associated with a planar wave of neocortical neuronal activity propagating at a constant velocity towards a linear probe. ResultsResults show that the algorithm is robust to the presence of noise in LFP data and uncertainties in knowledge of propagation velocity. Also, results show high level of accuracy of the method in a wide range of electrode resolutions. Using in vivo experimental recordings from the rat neocortex, we employed waveCSD to characterize transmembrane currents associated with cortical spreading depressions. Comparison with existing method(s)Simulation results indicate that waveCSD has a significantly higher reconstruction accuracy compared to the widely-used inverse CSD method (iCSD), and the regularized kernel CSD method (kCSD), in the analysis of CSDs originating from propagating neuronal activity. ConclusionsThe waveCSD method provides a theoretical platform for estimation of transmembrane currents from their LFPs in experimental paradigms involving wave propagation.

Recording Spatially Restricted Oscillations in the Hippocampus of Behaving Mice.

The local field potential (LFP) emerges from ion movements across neural membranes. Since the voltage recorded by LFP electrodes reflects the summed electrical field of a large volume of brain tissue, extracting information about local activity is challenging. Studying neuronal microcircuits, however, requires a reliable distinction between truly local events and volume-conducted signals originating in distant brain areas. Current source density (CSD) analysis offers a solution for this problem by providing information about current sinks and sources in the vicinity of the electrodes. In brain areas with laminar cytoarchitecture such as the hippocampus, one-dimensional CSD can be obtained by estimating the second spatial derivative of the LFP. Here, we describe a method to record multilaminar LFPs using linear silicon probes implanted into the dorsal hippocampus. CSD traces are computed along individual shanks of the probe. This protocol thus describes a procedure to resolve spatially restricted neuronal network oscillations in the hippocampus of freely moving mice.

Adult-Onset Hearing Impairment Induces Layer-Specific Cortical Reorganization: Evidence of Crossmodal Plasticity and Central Gain Enhancement.

Adult-onset hearing impairment can lead to hyperactivity in the auditory pathway (i.e., central gain enhancement) as well as increased cortical responsiveness to nonauditory stimuli (i.e., crossmodal plasticity). However, it remained unclear to what extent hearing loss-induced hyperactivity is relayed beyond the auditory cortex, and thus, whether central gain enhancement competes or coexists with crossmodal plasticity throughout the distinct layers of the audiovisual cortex. To that end, we investigated the effects of partial hearing loss on laminar processing in the auditory, visual and audiovisual cortices of adult rats using extracellular electrophysiological recordings performed 2 weeks after loud noise exposure. Current-source density analyses revealed that central gain enhancement was not relayed to the audiovisual cortex (V2L), and was instead restricted to the granular layer of the higher order auditory area, AuD. In contrast, crossmodal plasticity was evident across multiple cortical layers within V2L, and also manifested in AuD. Surprisingly, despite this coexistence of central gain enhancement and crossmodal plasticity, noise exposure did not disrupt the responsiveness of these neighboring cortical regions to combined audiovisual stimuli. Overall, we have shown for the first time that adult-onset hearing impairment causes a complex assortment of intramodal and crossmodal changes across the layers of higher order sensory cortices.

Interhemispheric Transfer Time Asymmetry of Visual Information Depends on Eye Dominance: An Electrophysiological Study.

The interhemispheric transfer of information is a fundamental process in the human brain. When a visual stimulus appears eccentrically in one visual-hemifield, it will first activate the contralateral hemisphere but also the ipsilateral one with a slight delay due to the interhemispheric transfer. This interhemispheric transfer of visual information is believed to be faster from the right to the left hemisphere in right-handers. Such an asymmetry is considered as a relevant fact in the context of the lateralization of the human brain. We show here using current source density (CSD) analyses of visually evoked potential (VEP) that, in right-handers and, to a lesser extent in left-handers, this asymmetry is in fact dependent on the sighting eye dominance, the tendency we have to prefer one eye for monocular tasks. Indeed, in right-handers, a faster interhemispheric transfer of visual information from the right to left hemisphere was observed only in participants with a right dominant eye (DE). Right-handers with a left DE showed the opposite pattern, with a faster transfer from the left to the right hemisphere. In left-handers, albeit a smaller number of participants has been tested and hence confirmation is required, only those with a right DE showed an asymmetrical interhemispheric transfer with a faster transfer from the right to the left hemisphere. As a whole these results demonstrate that eye dominance is a fundamental determinant of asymmetries in interhemispheric transfer of visual information and suggest that it is an important factor of brain lateralization.

Heterogeneous Origins of Human Sleep Spindles in Different Cortical Layers.

Sleep spindles are a cardinal feature in human NREM sleep and may be important for memory consolidation. We studied the intracortical organization of spindles in men and women by recording spontaneous sleep spindles from different cortical layers using linear microelectrode arrays. Two patterns of spindle generation were identified using visual inspection, and confirmed with factor analysis. Spindles (10-16 Hz) were largest and most common in upper and middle channels, with limited involvement of deep channels. Many spindles were observed in only upper or only middle channels, but approximately half occurred in both. In spindles involving both middle and upper channels, the spindle envelope onset in middle channels led upper by ∼25-50 ms on average. The phase relationship between spindle waves in upper and middle channels varied dynamically within spindle epochs, and across individuals. Current source density analysis demonstrated that upper and middle channel spindles were both generated by an excitatory supragranular current sink while an additional deep source was present for middle channel spindles only. Only middle channel spindles were accompanied by deep low (25-50 Hz) and high (70-170 Hz) gamma activity. These results suggest that upper channel spindles are generated by supragranular pyramids, and middle channel by infragranular. Possibly, middle channel spindles are generated by core thalamocortical afferents, and upper channel by matrix. The concurrence of these patterns could reflect engagement of cortical circuits in the integration of more focal (core) and distributed (matrix) aspects of memory. These results demonstrate that at least two distinct intracortical systems generate human sleep spindles.SIGNIFICANCE STATEMENT Bursts of ∼14 Hz oscillations, lasting ∼1 s, have been recognized for over 80 years as cardinal features of mammalian sleep. Recent findings suggest that they play a key role in organizing cortical activity during memory consolidation. We used linear microelectrode arrays to study their intracortical organization in humans. We found that spindles could be divided into two types. One mainly engages upper layers of the cortex, which are considered to be specialized for associative activity. The other engages both upper and middle layers, including those devoted to sensory input. The interaction of these two spindle types may help organize the interaction of sensory and associative aspects of memory consolidation.

Sleep deprivation decreases neuronal excitability and responsiveness in rats both in vivo and ex vivo

Sleep deprivation has severe consequences for higher nervous functions. Its effects on neuronal excitability may be one of the most important factors underlying functional deterioration caused by sleep loss. In the present work, excitability changes were studied using two complementary in vivo and ex vivo models. Auditory evoked potentials were recorded from freely-moving animals in vivo. Amplitude of evoked responses showed a near-continuous decrease during deprivation. Prevention of sleep also reduced synaptic efficacy ex vivo, measured from brain slices derived from rats that underwent sleep deprivation. While seizure susceptibility was not affected significantly by sleep deprivation in these preparations, the pattern of spontaneous seizure activity was altered. If seizures developed, they lasted longer and tended to contain more spikes in slices obtained from sleep-deprived than from control rats. Current-source density analysis revealed that location and sequence of activation of local cortical networks recruited by seizures did not change by sleep deprivation. Moderate differences seen in the amplitude of individual sinks and sources might be explained by smaller net transmembrane currents as a consequence of decreased excitability. These findings contradict the widely accepted conception of synaptic homeostasis suggesting gradual increase of excitability during wakefulness. Our results also indicate that decreased neuronal excitability caused by sleep deprivation is preserved in slices prepared from rats immediately after deprivation. This observation might mean new opportunities to explore the effects of sleep deprivation in ex vivo preparations that allow a wider range of experimental manipulations and more sophisticated methods of analysis than in vivo preparations.

Current source density mapping of antennal sensory selectivity reveals conserved olfactory systems between tephritids and Drosophila

Ecological specialization of insects involves the functional and morphological reshaping of olfactory systems. Little is known about the degree to which insect sensitivity to odorant compounds is conserved between genera, tribes, or families. Here we compared the olfactory systems of six tephritid fruit fly species spanning two tribes and the distantly related Drosophila melanogaster at molecular, functional, and morphological levels. Olfaction in these flies is mediated by a set of olfactory receptors (ORs) expressed in different functional classes of neurons located in distinct antennal regions. We performed a phylogenetic analysis that revealed both family-specific OR genes and putative orthologous OR genes between tephritids and Drosophila. With respect to function, we then used a current source density (CSD) analysis to map activity across antennae. Functional maps mirrored the intrinsic structure of antennae observed with scanning electron microscopy. Together, the results revealed partial conservation of the olfactory systems between tephritids and Drosophila. We also demonstrate that the mapping of olfactory responses is necessary to decipher antennal sensory selectivity to olfactory compounds. CSD analysis can be easily applied to map antennae of other species and therefore enables the rapid deriving of olfactory maps and the reconstructing of the target organisms’ history of evolution.

Primary Generators of Visually Evoked Field Potentials Recorded in the Macaque Auditory Cortex.

Prior studies have reported "local" field potential (LFP) responses to faces in the macaque auditory cortex and have suggested that such face-LFPs may be substrates of audiovisual integration. However, although field potentials (FPs) may reflect the synaptic currents of neurons near the recording electrode, due to the use of a distant reference electrode, they often reflect those of synaptic activity occurring in distant sites as well. Thus, FP recordings within a given brain region (e.g., auditory cortex) may be "contaminated" by activity generated elsewhere in the brain. To determine whether face responses are indeed generated within macaque auditory cortex, we recorded FPs and concomitant multiunit activity with linear array multielectrodes across auditory cortex in three macaques (one female), and applied current source density (CSD) analysis to the laminar FP profile. CSD analysis revealed no appreciable local generator contribution to the visual FP in auditory cortex, although we did note an increase in the amplitude of visual FP with cortical depth, suggesting that their generators are located below auditory cortex. In the underlying inferotemporal cortex, we found polarity inversions of the main visual FP components accompanied by robust CSD responses and large-amplitude multiunit activity. These results indicate that face-evoked FP responses in auditory cortex are not generated locally but are volume-conducted from other face-responsive regions. In broader terms, our results underscore the caution that, unless far-field contamination is removed, LFPs in general may reflect such "far-field" activity, in addition to, or in absence of, local synaptic responses.SIGNIFICANCE STATEMENT Field potentials (FPs) can index neuronal population activity that is not evident in action potentials. However, due to volume conduction, FPs may reflect activity in distant neurons superimposed upon that of neurons close to the recording electrode. This is problematic as the default assumption is that FPs originate from local activity, and thus are termed "local" (LFP). We examine this general problem in the context of previously reported face-evoked FPs in macaque auditory cortex. Our findings suggest that face-FPs are indeed generated in the underlying inferotemporal cortex and volume-conducted to the auditory cortex. The note of caution raised by these findings is of particular importance for studies that seek to assign FP/LFP recordings to specific cortical layers.

(Invited) Multimodal Microelectrode Failure Analysis Reveals Complex Relationship at the Neural Interface

Penetrating microelectrode arrays that can record extracellular action potentials from small, targeted groups of neurons are critical for basic neuroscience research and emerging clinical applications. However, these electrode devices suffer from reliability and variability issues which impact their performance on the order of months to years. The failure mechanisms of these electrodes are understood to be a complex combination of the biotic and abiotic failure modes. The breaching of the blood–brain barrier (BBB) to insert devices triggers a cascade of biochemical pathways resulting in complex molecular and cellular responses to implanted devices. Molecular and cellular changes in the microenvironment surrounding an implant include the introduction of mechanical strain, BBB leakage, activation of glial cells, loss of perfusion, secondary metabolic injury, and neuronal degeneration. The resulting inflammation is a key hypothesized cause of neural recording failure. However, previous attempt so directly correlate recording performance, to impedance, and to histological outcomes have led counter-intuitive and sometimes conflicting outcomes. One reason is that many neurons remain quiescent during anesthetized or resting-state conditions. We previously demonstrated this by visually evoked stimulation paradigms of the contralateral eye in order to evaluate chronic recording performance of linear silicon electrode in the primary visual cortex. Additional, multiphoton analysis using GCaMP6 transgenic animals further confirmed these results. More recently, there has been a growing interesting recording during awake free-roaming conditions in the primary motor cortex in order to avoid resting-state related quiescent activity. However, this in turn leads to increases in Lenz’s Law related artefacts that have the same time constants and waveform shapes as action potentials in rodents, but not NHP. While behaviorally training animals to remain immobile could improve outcomes, it also introduces the potential for Experimenter Expectancy Effect bias on the outcomes. The visual stimulation paradigm enable the use of current source density analysis to electrophysiologically identify Layer II/III, IV, and V in the cortex. This, in turn, allowed correlation of electrophysiological layers to the histological layers based on section depth and the differences in neural morphology and density. Our findings from electrophysiology, impedance spectroscopy, and post-mortem histology demonstrate a very poor relationship between histology and impedance to electrophysiology. For example, tissue with low-levels of glial encapsulation, healthy neuronal proximity, and low impedance can still have poor recording performance, even with neural activity is behaviorally driven. Even when histology confirms a perfect tissue interface, cracking or delamination of insulation on the microelectrode has been linked to a drop in impedance and a loss of recording failure. In contrast, cracking of the electrical trace and delamination of the recording site has been linked to recording failure through a jump in electrical impedance. As such, several modes of mechanical failure of chronically implanted planar silicon electrodes were found that result in degradation and/or loss of recording. Our findings highlight the importance of strains and material properties of various subcomponents within an electrode array and the poor reliability of determining electrode viability through electrochemical impedance spectroscopy. Interestingly, we discovered in a number of situations that even with good neural density, uncompromised electrode material, and good impedances, recording performance can sometimes completely degrade. New multimodal analysis demonstrates the importance of capturing dynamic information, such as with in vivo multiphoton study, and that the presence of neurons does not guarantee functional neural activity over time. We further demonstrate that the foundation of assumptions and simplification made in the field for neural interface research are not true or incomplete. To solve the longstanding chronic neural interface problem, we need to first understand the complexity of the problem.

Gamma Oscillations in the Rat Ventral Striatum Originate in the Piriform Cortex.

Local field potentials (LFPs) recorded from the human and rodent ventral striatum (vStr) exhibit prominent, behaviorally relevant gamma-band oscillations. These oscillations are related to local spiking activity and transiently synchronize with anatomically related areas, suggesting a possible role in organizing vStr activity. However, the origin of vStr gamma is unknown. We recorded vStr gamma oscillations across a 1.4 mm2 grid spanned by 64 recording electrodes as male rats rested and foraged for rewards, revealing a highly consistent power gradient originating in the adjacent piriform cortex. Phase differences across the vStr were consistently small (<15°) and current source density analysis further confirmed the absence of local sink-source pairs in the vStr. Reversible occlusions of the ipsilateral (but not contralateral) nostril, known to abolish gamma oscillations in the piriform cortex, strongly reduced vStr gamma power and the occurrence of transient gamma-band events. These results imply that local circuitry is not a major contributor to gamma oscillations in the vStr LFP and that piriform cortex is an important driver of gamma-band oscillations in the vStr and associated limbic areas.SIGNIFICANCE STATEMENT The ventral striatum (vStr) is an area of anatomical convergence in circuits underlying motivated behavior, but it remains unclear how its inputs from different sources interact. A major proposal about how neural circuits may switch dynamically between convergent inputs is through temporal organization reflected in local field potential (LFP) oscillations. Our results show that, in the rat, the mechanisms controlling gamma-band oscillations in the vStr LFP are primarily located in the in the adjacent piriform cortex rather than in the vStr itself, providing a novel interpretation of previous rodent work on gamma oscillations in the vStr and related circuits and an important consideration for future work seeking to use oscillations in these areas as biomarkers for behavioral and neurological disorders.

Systemic Nicotine Increases Gain and Narrows Receptive Fields in A1 via Integrated Cortical and Subcortical Actions.

Nicotine enhances sensory and cognitive processing via actions at nicotinic acetylcholine receptors (nAChRs), yet the precise circuit- and systems-level mechanisms remain unclear. In sensory cortex, nicotinic modulation of receptive fields (RFs) provides a model to probe mechanisms by which nAChRs regulate cortical circuits. Here, we examine RF modulation in mouse primary auditory cortex (A1) using a novel electrophysiological approach: current-source density (CSD) analysis of responses to tone-in-notched-noise (TINN) acoustic stimuli. TINN stimuli consist of a tone at the characteristic frequency (CF) of the recording site embedded within a white noise stimulus filtered to create a spectral “notch” of variable width centered on CF. Systemic nicotine (2.1 mg/kg) enhanced responses to the CF tone and to narrow-notch stimuli, yet reduced the response to wider-notch stimuli, indicating increased response gain within a narrowed RF. Subsequent manipulations showed that modulation of cortical RFs by systemic nicotine reflected effects at several levels in the auditory pathway: nicotine suppressed responses in the auditory midbrain and thalamus, with suppression increasing with spectral distance from CF so that RFs became narrower, and facilitated responses in the thalamocortical pathway, while nicotinic actions within A1 further contributed to both suppression and facilitation. Thus, multiple effects of systemic nicotine integrate along the ascending auditory pathway. These actions at nAChRs in cortical and subcortical circuits, which mimic effects of auditory attention, likely contribute to nicotinic enhancement of sensory and cognitive processing.

Temporal and spatial dynamics of peripheral afferent-evoked activity in the dorsal horn recorded in rat spinal cord slices.

In the present study, multi-electrode array recording was used to examine dorsal horn activity following stimulation of primary afferents in a rat dorsal root attached-spinal cord slice preparation. The multi-electrode array probe was placed under the dorsal horn slice and local field potentials evoked by stimulation on the dorsal root were analyzed. Three kinds of dorsal root-evoked responses were identified. In lamina IIo, local field potentials exhibited P1 (peak latency 1.46±0.08ms), N1 (2.77±0.18ms, n=12), N2 (7.31±0.48ms), N3 (12.12±0.73ms) and P2(18.30±0.80ms) waves. In lamina IIi local field potentials exhibited P (1.99±0.10ms), N1 (3.35±0.17ms) and N2 (8.58±0.44ms) waves. In laminae III-VI, local field potentials exhibited P1 (3.01±0.07ms), P2 (7.02±0.21ms) and N waves (22.57±0.79ms). Sweep spread was calculated by two dimensional current source density (2D-CSD) analysis. Both α-amino-3-hydroxy-5-methylisoxazole-4-propionic a/kainate and N-methyl-d-aspartate-type glutamate receptors participated in this neuronal circuitry. Morphine diminished local field potentials. Gabapentin diminished the negative components in lamina II and P2 component in lamina IIo, but increased the positive components in lamina IIi and laminae III-VI. The present study revealed that functional dorsal horn activity was preserved in the spinal cord slice preparation. Glutamatergic synapses were crucially involved in information processing. Opioid interneurons and gabapentin may play a modulatory role in regulating signal flows in the dorsal horn. Taken together, these results identify a spatio-temporal profile of dorsal horn activity evoked by dorsal root stimulation, and implicate glutamatergic and opioidergic receptors and gabapentin in this activity.

Ion diffusion may introduce spurious current sources in current-source density (CSD) analysis

Current-source density (CSD) analysis is a well-established method for analyzing recorded local field potentials (LFPs), that is, the low-frequency part of extracellular potentials. Standard CSD theory is based on the assumption that all extracellular currents are purely ohmic, and thus neglects the possible impact from ionic diffusion on recorded potentials. However, it has previously been shown that in physiological conditions with large ion-concentration gradients, diffusive currents can evoke slow shifts in extracellular potentials. Using computer simulations, we here show that diffusion-evoked potential shifts can introduce errors in standard CSD analysis, and can lead to prediction of spurious current sources. Further, we here show that the diffusion-evoked prediction errors can be removed by using an improved CSD estimator which accounts for concentration-dependent effects.NEW & NOTEWORTHY Standard CSD analysis does not account for ionic diffusion. Using biophysically realistic computer simulations, we show that unaccounted-for diffusive currents can lead to the prediction of spurious current sources. This finding may be of strong interest for in vivo electrophysiologists doing extracellular recordings in general, and CSD analysis in particular.

An analysis of current source density profiles activated by local stimulation in the mouse auditory cortex in vitro

To examine local network properties of the mouse auditory cortex in vitro, we recorded extracellular spatiotemporal laminar profiles driven by short electric local stimulation on a planar multielectrode array substrate. The recorded local field potentials were subsequently evaluated using current source density (CSD) analysis to identify sources and sinks. Current sinks are thought to be an indicator of net synaptic current in the small volume of cortex surrounding the recording site. Thus, CSD analysis combined with multielectrode arrays enabled us to compare mean synaptic activity in response to small current stimuli on a layer-by-layer basis. We also used senescence-accelerated mice (SAM), some strains of which show earlier onset of age-related hearing loss, to examine the characteristic spatiotemporal CSD profiles stimulated by electrodes in specific cortical layers. Thus, the CSD patterns were classified into several clusters based on stimulation sites in the cortical layers. We also found some differences in CSD patterns between the two SAM strains in terms of aging according to principle component analysis with dimension reduction. For simultaneous two-site stimulation, we modeled the obtained CSD profiles as a linear superposition of the CSD profiles to individual single-site stimulation. The model analysis indicated the nonlinearity of spatiotemporal integration over stimulus-driven activity in a layer-specific manner. Finally, on the basis of these results, we discuss the auditory cortex local network properties and the effects of aging on these mouse strains.

Layer-specificity in the effects of attention and working memory on activity in primary visual cortex

Neuronal activity in early visual cortex depends on attention shifts but the contribution to working memory has remained unclear. Here, we examine neuronal activity in the different layers of the primary visual cortex (V1) in an attention-demanding and a working memory task. A current-source density analysis reveales top-down inputs in the superficial layers and layer 5, and an increase in neuronal firing rates most pronounced in the superficial and deep layers and weaker in input layer 4. This increased activity is strongest in the attention task but it is also highly reliable during working memory delays. A visual mask erases the V1 memory activity, but it reappeares at a later point in time. These results provide new insights in the laminar circuits involved in the top-down modulation of activity in early visual cortex in the presence and absence of visual stimuli.

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

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.