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Phase-amplitude cross-frequency coupling in rats olfactory bulb after injection of ketamine

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Jurkiewicz G., Hunt M. J., Zygierewicz J.

Acta Neurobiologiae Experimentalis

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2019

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tom 79

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nr Suppl.1

INTRODUCTION: The injection of ketamine is an animal model of schizophrenia. It leads to behavioral changes such as hyperlocomotion and accelerated breath and electrophysiological changes such as the appearance of high‑frequency oscillations (HFO). Previous studies reported that the amplitude of HFO in the striatum is coupled with a phase of respiratory rhythm. However, recent studies suggest that the olfactory bulb is an important generator of HFO which can impose this activity in ventral striatal areas. AIM(S): The purpose of this study was to examine the LFP recording from olfactory bulb after injection of ketamine with a novel method of phase-amplitude coupling detection. METHOD(S): The proposed novel method of PAC detection is based on analysis of time‑frequency representation of signals aligned to a given phase in the low‑frequency band. Low‑frequency wave is obtained with the Matching Pursuit algorithm by selecting waveforms of interest. The time‑frequency representation of the signal’s energy density is derived from continuous wavelet transform and normalized at each frequency relative to its average value in the baseline period. Next, the representation is thresholded at values obtained from surrogate data. The resulting maps are used to compute comodulograms. The effects presented in the comodulograms are validated with extreme values statistics. RESULTS: We found statistically significant coupling between the amplitude of high‑frequency oscillation (around 150 Hz) and phase of low‑frequency oscillation (around 7 Hz) in most of the examined rats. The temporal pattern of PAC shows dependence on injection of ketamine. CONCLUSIONS: The HFO in olfactory bulb display the property of phase-amplitude coupling with low-frequency oscillation. The additional conclusion is that the proposed novel method is adequate to detect coupling in real LFP data.

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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

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2019

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tom 79

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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.

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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

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2018

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tom 78

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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.

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Scientific writing for the biomedical sciences

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Hunt M. J., Ochmanska M., Cilulko-Dolega J.

Medical Science Pulse

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2018

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tom 12

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nr 1

Scientific writing is an essential part of a research scientist’s career and is usually the end process of many years’ hard bench work generating the data for publication. Clear communication of your research findings, the aims and potential importance of your work are the foundation of all good scientific manuscripts. Writing a scientific manuscript in English, especially if English is not your first language, can make an already challenging task even more difficult. The purpose of this article is to assist authors in the preparation of manuscripts intended for submission to peer-reviewed journals. The article mainly focusses on the biomedical sciences, but researchers of other scientific disciplines can also benefit from the content. We provide useful advice on all the main subsections of a standard research manuscript, from selecting an appropriate title, through to preparing a properly organized discussion. Advice on how each section should be arranged as well as points to be avoided can be found in the guide. As a general guide the most important point of a manuscript is that the research findings contained are presented clearly and accurately without excessive repetition or embellishment. Finally, this article closes with a section which contains language mistakes which are frequently made by authors whose first language is not English.

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How to write an effective response letter to reviewers

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Hunt M. J., Ochmanska M., Cilulko-Dolega J.

Medical Science Pulse

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2019

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tom 13

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nr 1

The review process is intended to provide an objective assessment of the suitability of a submission to the target journal. When authors receive the decision letter from the editor it is almost always accompanied with the reviews, which at times can be quite critical. Writing a well-constructed response letter to the reviewers, with well-reasoned arguments, is a key part of the reviewing process. Although the manuscript is the main focus of the submission, the content and tone of the response letter can have a surprisingly large impact on the eventual recommendation given by the reviewers. The importance of writing a clear response letter is often overlooked by authors. This prompted us to prepare a short article addressing the main points that can help authors prepare their response to reviewer letter to the reviewers. Although each review is unique, here, we outline ten points which are aimed at helping authors respond effectively and clearly to reviewers’ comments. The points are based on the authors’ collective experiences which includes publishing and reviewing for international peer-reviewed journals. The tone of the letter should always be professional, organized and objective. Each point raised by the reviewers needs to be replied to in a precise way, with clear evidence that the major concerns have been considered in a serious way. This article also covers what information should be included, when it is appropriate to disagree with a reviewer, and how to present appropriate rebuttals.

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Involvement of the ventral tegmental area in the eneration of high frequency oscillations in the NMDAr hypofunction model of schizophrenia

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Piasecka J., Olszrwski M., Whittington M. A., Kasicki S., Hunt M. J.

Acta Neurobiologiae Experimentalis

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2015

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tom 75

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nr Supl.

BACKGROUND AND AIMS: NMDA receptor hypofunction is widely considered to contribute to the symptoms of schizophrenia. Although the pathophysiology of this disease remains unclear the nucleus accumbens (NAc) is one of the brain regions that has been widely implicated. Abnormal high frequency oscillations (HFO, 130–180 Hz) can be recorded in the rat NAc after injection of NMDA receptor antagonists. We have shown previously that reversible inhibition of the NAc by local infusion of tetrodotoxin reduces the amplitude of MK801-enhanced HFO indicating that this oscillation is generated by the intrinsic NAc network. Afferent regions powerfully modulate the activity of NAc neurons. However, it is not known to what extent HFO in the NAc may be driven by its afferent projections (ventral hippocampus, basolateral amygdala, prefrontal cortex and the vental tegmental area). METHODS: To address this issue, rats were implanted with electrodes in the NAc and guides targeted at these afferent sites. RESULTS: We found that infusion of TTX to the ventral tegmental area reduced the power of MK801-enhanced HFO on the ipsilateral but not contralateral side. In contrast infusion of TTX to the prefrontal cortex or ventral hippocampus had negligible effect MK801-enhanced HFO, although TTX infusion to the amygdala was found to produce a much weaker reduction in HFO power. CONCLUSIONS: These findings indicate that projections from the ventral tegmental area are capable of driving abnormal HFO in the NAc after injection of NMDA receptor antagonist. Further it suggests a loop involving these regions are required for the generation of HFO in rodent NAc. Project funded by the National Center of Science DEC-2011/03/B/ NZ4/03053.

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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

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Sredniawa W., Wrobel J. J., Whittington M., Wojcik D. K., Hunt M. J.

Acta Neurobiologiae Experimentalis

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2019

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tom 79

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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.

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How to write a good abstract for a biomedical paper

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Hunt M. J., Raflik K., Wesolowski D., Sibilska-Wozniacka A., Sakowska-Hunt D. E.

Medical Science Pulse

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2020

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tom 14

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nr 1

Although a relatively short text, the abstract of a paper summarizes the most important issues raised in the main text. The abstract is, at least initially, the key text on which journal editors, reviewers and eventually readers form their initial judgement on the overall quality of the full manuscript. Therefore, it is essential to execute this step of the writing process well. In this article, we discuss the purpose of an abstract, why it is important, and how to write a good abstract. Increasingly, journal abstracts are structured to follow the IMRAD format (Introduction, Methods, Results, and Discussion). We provide examples of well written and badly written abstracts, with explanatory notes, to help readers understand the key points that need to be addressed and mistakes that should be avoided. Since international abstracts are generally written in English, preparing an abstract can be especially challenging for researchers who are not native speakers of English. We close this article with general linguistic advice, paying particular attention to key terms and word choice than can meaningfully express an author’s intention in a concise way. The points raised in this article will help authors improve their scientific writing and enable their findings to be expressed with clarity.

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Clozapine, glycine and NMDA all reduce the frequency of high frequency oscillations in the nucleus accumbens of freely moving mice

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Olszewski M., Piasecka J., Whittington M. A., Kasicki S., Hunt M. J.

Acta Neurobiologiae Experimentalis

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2015

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tom 75

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nr Supl.

BACKGROUND AND AIMS: To examine the effect of NMDA receptor antagonists and antipsychotics on high frequency oscillations (HFO, 130–180 Hz) recorded in local field potentials from the nucleus accumbens (NAc) of freely moving mice. To identify the receptors that may underlie clozapine-induced reductions in HFO frequency. METHODS: Freely moving mice, with electrodes implanted in the NAc, received systemic injection of NMDAR antagonists (ketamine and MK801); antipsychotic compounds (clozapine and haloperidol) were administered to MK801-pretreated mice. We attempted to identify the receptors mediating clozapine-induced reductions in HFO frequency using a pharmacological agents targeting 5HT1A, 5HT2A, histamine H3 and NMDA receptors. RESULTS: Ketamine and MK801 dose dependently increased the power of HFO and produced small increases in their frequency. Clozapine, dose dependently reduced the frequency of HFO whereas haloperidol had little effect on HFO. Systemic injection of glycine, which has antipsychotic properties, and allosterically modulates NMDAR, reduced the frequency of HFO to values comparable after injection of clozapine. Systemic administration of NMDA produced a short-lasting reduction in MK801-enhanced HFO frequency. Other receptors known to be targets for clozapine, namely 5-HT2A, 5-HT7 and histamine H3 receptors had no effect on MK801-enhanced HFO, although we did find a reduction in HFO frequency after injection of 5HT1A agonist. CONCLUSIONS: These results show that NMDAR antagonists and antipsychotics produce broadly similar fundamental effects on HFO in mice and rats. Stimulation of NMDAR (directly, or through the glycine site) as well as activation of 5HT1A receptors, reduces the frequency of MK801-enhanced HFO suggesting that atypical antipsychotic drugs may alter HFO by interacting with NMDA and 5HT1A receptors. Project funded by the National Center of Science DEC-2011/03/B/ NZ4/03053.

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Local blockade of NMDA receptors in the rat prefrontal cortex increases c_Fos expression in multiple subcortical regions

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Nowak K., Meyza K., Nikolaev E., Hunt M. J., Kasicki S.

Acta Neurobiologiae Experimentalis

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2012

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tom 72

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nr 3

Ketamine, phencyclidine and MK801 are uncompetitive NMDA receptor (NMDAR) antagonists which are used widely to model certain features of schizophrenia in rats. Systemic administration of NMDAR antagonists, in addition to provoking an increase in c-Fos expression, leads to important neurochemical and electrophysiological changes within the medial prefrontal cortex (mPFC). Since the mPFC is considered to exert a top-down regulatory control of subcortical brain regions, we examined the effects of local infusion of the NMDAR antagonist, MK801, into the mPFC on the expression of c-Fos protein (widely used marker of neuronal activation) in several subcortical structures. The experiment was performed on freely moving rats, bilaterally implanted with guide cannulae in the prelimbic mPFC, infused with MK801 or saline. Bilateral administration of MK801 to the mPFC produced changes in the behavior (increased stereotypy and decreased sleep-like behavior) and complex changes in c-Fos protein expression with significant increases observed in the nucleus accumbens (core and shell), amygdala (basolateral and central nuclei), the CA1 field of the hippocampus, and mediodorsal and paraventricular thalamic nuclei, as compared to the saline group. Together, we demonstrate that blockade of NMDA receptors in the mPFC is sufficient to lead to behavioral abnormalities and increased c-Fos expression in many, but not all, of the subcortical structures examined. Our findings suggest that some of the behavioral abnormalities produced by uncompetitive NMDAR antagonists may result from aberrant activity in cortico-subcortical pathways. These data support an increasing body of literature, suggesting that the mPFC is an important site mediating the effects of NMDAR antagonists.

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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

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2018

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tom 78

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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.

Ograniczanie wyników

Phase-amplitude cross-frequency coupling in rats olfactory bulb after injection of ketamine

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

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

Scientific writing for the biomedical sciences

How to write an effective response letter to reviewers

Involvement of the ventral tegmental area in the eneration of high frequency oscillations in the NMDAr hypofunction model of schizophrenia

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

How to write a good abstract for a biomedical paper

Clozapine, glycine and NMDA all reduce the frequency of high frequency oscillations in the nucleus accumbens of freely moving mice

Local blockade of NMDA receptors in the rat prefrontal cortex increases c_Fos expression in multiple subcortical regions

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