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1

Nasal respiration is critical for ketamine induced high frequency oscillations and hyperactivity

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Wrobel J. J., Sredniawa W., Wojcik D. K., Hunt M. J.
Acta Neurobiologiae Experimentalis
|
2019
|
tom 79
|
nr Suppl.1
INTRODUCTION: Ketamine, at subanesthetic doses, produces psychotomimetic effects. In rodents, ketamine produces characteristic changes in oscillatory activity that can be recorded in local field potentials (LFP). One effect after systemic injection of ketamine is the emergence of abnormal high frequency oscillations (HFO) 130 ‑180 Hz that have been described in many rodent brain areas. Recently, we have shown that the olfactory bulb (OB) plays an important role in the generation of HFO after ketamine. AIM(S): The aim of the present study was to examine the extent to which nasal respiration may drive abnormal HFO after ketamine, in freely‑moving rats. METHOD(S): LFPs (from the OB) and nasal respiration (thermocouples implanted in the nares) were recorded before and after injection (saline or ketamine 20 mg/kg) from male Wistar rats. A separate group of rats was used to study nares blockade. To block the nares, rats were anesthetised and a silicon occluder was inserted into one or both nares. Controls were exposed to initial isoflurane for a comparable amount of time but without blockade. Rats were given recovery and then injected with ketamine. RESULTS: Ketamine immediately increased exploratory fast sniffing (4‑10 Hz), which correlated with increases in locomotor activity and HFO power. Saline injection did not substantially alter these measures. Nasal respiration entrained bursts of ketamine HFO recorded in the OB on a cycle‑by‑cycle basis. Further, ketamine-induced HFO was attenuated unilaterally by naris blockade on the same side. Bilateral naris blockade reduced power and frequency of HFO and also reduced hyperactivity produced by ketamine. CONCLUSIONS: Our results suggest that nasal respiration is a powerful drive of HFO after injection of ketamine in the OB. These findings may explain previous observations that ketamine-HFO couples to slower frequencies. Functional nasal respiration appears to be critical for the emergence of both HFO and hyperactivity produced by ketamine.
2

Reliable estimation of current sources from multielectrode LFP recordings with kernel CSD and L-curve

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Sredniawa W., Hunt M. J., Wojcik D. K.
Acta Neurobiologiae Experimentalis
|
2018
|
tom 78
|
nr Suppl.1
Passive propagation of electric fields can induce ap‑ parent coherence in local field potentials (LFP) record‑ ed over distances of several millimetres hindering their analysis. This issue can be overcome with current source density analysis (CSD). Mathematically, CSD reconstruc‑ tion is an ill‑posed problem which means that many dif‑ ferent possible current source distributions fit the mea‑ sured LFP and the challenge is to find the most probable one. Furthermore, LFP recordings are always noisy, par‑ ticularly in data obtained from freely moving animals, which may affect CSD estimation. Previously, we pro‑ posed the kernel CSD (kCSD) method for reconstruction of the spatial distribution of sources and sinks in biologi‑ cal tissue from noisy data. Here we show how the method parameters can be estimated quickly and reliably using an L‑curve approach. We demonstrated the feasibility of this approach on model data and illustrated its power in the analysis of LFP recordings from linear probes im‑ planted in the olfactory bulb (OB) of freely moving rats. We focused on ketamine‑induced high frequency oscilla‑ tions (HFO, 120‑200 Hz) since, to date, the locus of gen‑ eration of HFO remains unclear. kCSD is a model‑based CSD estimation method which assumes a flexible model of CSD and estimates its parameters from data. L‑curve is a technique for finding the optimal way of weighting the complexity of the model against the difference between model predictions and the actual set of measurements. The LFPs we analysed were recorded from freely moving rats implanted with a 32‑channel linear probe targeted to the OB. Recordings were made at baseline and post in‑ jection of 25 mg/kg ketamine (i.p.). To examine the faith‑ fulness of kCSD reconstruction we tested this method on model LFPs from ground truth data. We showed that the L‑curve provides reliable and practical estimation of regularization parameters for robust kCSD estimation of sources from noisy LFPs. After validating this method, we estimated the current sources from recordings in the rat OB. We found HFO dipoles close to the mitral layer, whereas above it there was little evidence of any phase reversal. kCSD with L‑curve is a robust method for esti‑ mation of current sources from noisy data. It facilitates localization of the sources of abnormal HFO activity to a specific layer within olfactory bulb which is consistent with histology.
3

HFO under ketamine xylazine anesthesia are coupled to large current sources and nasal respiration: a proposed mechanism for the generation of HFO after NMDAR blockade

88%
Sredniawa W., Wrobel J. J., Whittington M., Wojcik D. K., Hunt M. J.
Acta Neurobiologiae Experimentalis
|
2019
|
tom 79
|
nr Suppl.1
INTRODUCTION: Over the past decade, we and other groups have shown that ketamine and other NMDA receptor antagonists evoke high‑frequency oscillations (HFO; 130‑180 Hz) in a variety of rodent cortical and subcortical regions. AIM(S): Our recent studies show that the olfactory bulb (OB) appears to be particularly important for the generation of this activity. To date, this activity has mainly been recorded in awake rats; however, there is some evidence that fast oscillation can be recorded in the OB of rodents under ketamine xylazine anesthesia. METHOD(S): LFPs in the OB were recorded using twisted stainless-steel electrodes in rats under ketamine 100 mg/kg + xylazine 10 mg/kg anesthesia (KX) or a subanesthetic dose of ketamine 20 mg/kg. In a second study, rats were implanted with thermocouples for simultaneous recording of nasal respiration and LFPs in the OB. In a third study, 32 channel silicon probes were used to record LFPs under KX. KX was associated with the emergence of a fast oscillations, around 120 Hz (which we termed KX-HFO) that occurred in bursts nested on slower oscillations. This is similar to HFO that occurs in awake rats following subanesthetic doses of ketamine. KX‑HFO were attenuated by unilateral naris blockade and reversed phase close to the mitral layer – also similar to the awake state. RESULTS: Simultaneous recordings from the nasal cavity (with thermocouples) and LFPs showed that KX-HFO was tightly coupled to nasal respiration, around 2 Hz. Spatial profile of LFPs recorded across the OB revealed strong HFO current sources close to the mitral layer that was preceded by a large current sink (around 2 Hz) more ventrally (in the extraplexiform/glomerular layers). CONCLUSIONS: Nasal respiration drives afferent input to the OB that produces corresponding large current sinks (local depolarization) in the OB which under KX anesthesia (and more generally NMDAR blockade) leads to the emergence of HFO by stimulating mitral/ tufted neurons at their apical dendrites.
4

Kernel current source density and connectivity estimation methods for the analysis of local field potentials

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Sredniawa W., Jablonka J., Sadowska M., Bebas P., Wojcik D. K.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Extracellular potentials, such as the Local Field Potentials (LFPs), are routinely measured in numerous electrophysiological experiments. LFP can carry valuable information about the electric properties of the tissue, however analysis of the recorded signal is usually a complex task. Apart from basic preparation, such as bandpass filtering and artifact removal, many other analytic methods have been proposed for the LFP study. Here we discuss methods for estimation of electric sources and sinks in brain tissue (Current Source Density, CSD) and methods to estimate connectivity in small networks, and their utility in analysis of cortical recordings in rats. AIM(S): Comparison of the effective connectivity and the structure of sinks and sources in cortical columns during whisker stimulations. METHOD(S): Analytic methods: kernel Current Source Density and Modular Connectivity Factorization (MCF) applied to LFP recordings and simulated data from cortical column. Experimental methods: Simultaneous multielectrode in vivo recordings from both hemispheres of the rats brain. RESULTS: Preliminary studies show different distribution of the current sources in contralateral to ipsilateral hemisphere during whisker stimulation in rats. Comparison of the hemispheres from deprived rats shows an extension of the whisker representation in the barrel cortex receptive field. CONCLUSIONS: KCSD method showssignificant differences in current sources localization in contralateral to ipsilateral hemisphere. Modular Connectivity Factorization method applied to LFP recordings from simulated data separates cortical column layers into interpretable modules. Physiological interpretation of the results needs further validation on the cortical column model. FINANCIAL SUPPORT: Instytut Biologii Doświadczalnej im. Marcelego Nenckiego Polska Akademia Nauk, Warsaw, Poland, Uniwersytet Warszawski, Warsaw, Poland
5

The olfactory bulb generates and imposes ketamine-associated high frequency oscillations in the ventral striatum of rodents

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Hunt M. J., Adams N. E., Sredniawa W., Wojcik D. K., Simon A., Kasicki S., Whittington M. A.
Acta Neurobiologiae Experimentalis
|
2018
|
tom 78
|
nr Suppl.1
Over the past decade, high frequency oscillations (HFO, 130‑180 Hz) recorded in field potentials have been shown to be robustly potentiated by ketamine adminis‑ tration. This rhythm has been recorded in functionally and neuroanatomically diverse cortical and subcortical regions, most notably in the ventral striatum. Howev‑ er, the precise locus of generation remains largely un‑ known. There is compelling evidence that olfactory regions can drive oscillations in distant areas. Here, we tested the hypothesis that the olfactory bulb (OB) exerts a top‑down role in the generation of ketamine‑HFO. We examined the effect of ketamine on electrophysiologi‑ cal activity of the OB and ventral striatum in vivo. Field potential recordings, local inhibition, naris blockade, current source density and unit recordings were used. Ketamine‑HFO in the OB was larger and preceded HFO recorded in the ventral striatum. Granger causality anal‑ ysis was consistent with directional flow from the OB. Unilateral local inhibition of the OB, and naris blockade, attenuated HFO recorded locally and in the ventral stri‑ atum. 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 demonstrate a hierarchical top‑down relationship between ketamine‑HFO in the OB and the ventral striatum. The OB plays a primary role in the gen‑ eration of ketamine‑HFO and orchestrates this activity in a distant region. These findings provide a new con‑ ceptual understanding on how ketamine influences fun‑ damental brain activity which may have implications for schizophrenia.
6

Kernel current source density revisited

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Chintaluri C., Kowalska M., Czerwinski M. B., Sredniawa W., Jedrzejewska-Szmek J., Dzik J. M., Wojcik D. K.
Acta Neurobiologiae Experimentalis
|
2019
|
tom 79
|
nr Suppl.1
INTRODUCTION: Extracellular recordings reflect transmembrane currents of neural and glial cells and thus have long been the foundation of measurements of neural activity. Recorded potential reflects activity of the underlying neural network and is directly related to the distribution of current sources along the active cells (current source density, CSD). The long‑range of the electric field leads to significant correlations between recordings at distant sites, which complicates the analysis. However, data interpretation can be facilitated by reconstruction of current sources. AIM(S): Facilitate reconstruction of sources of brain activity with open software. METHOD(S): The Kernel Current Source Density method (KCSD) is a general non-parametric framework for CSD estimation based on kernel techniques, which are widely used in machine‑learning. KCSD allows for current source estimation from potentials recorded by arbitrarily distributed electrodes. Overfitting is prevented by constraining complexity of the inferred CSD model. RESULTS: Here, we revisit KCSD to present a new, open-source implementation in the form of a package, which includes new functionality and several additional tools for kCSD analysis and for validation of the results of analysis accompanied by extensive tutorials implemented in Jupyter notebook. Specifically, we have added 1) analysis of spectral properties of the method; 2) error map generation for assessment of reconstruction accuracy; and 3) L‑curve, a method for estimation of optimum reconstruction parameters. The new implementation allows for CSD reconstruction from potentials measured by 1D, 2D, and 3D experimental setups for a) sources distributed in the entire tissue, b) in a slice, or c) in a single cell with known morphology, provided that the potential is generated by that cell. CONCLUSIONS: New Python implementation of kCSD facilitates CSD analysis and allows for estimation of errors. The toolbox and tutorials are available at https:// github.com/Neuroinflab/kCSD‑python.
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