Publications by authors named "Bernat Kocsis"

44 Publications

The effect of ketamine on delta-range coupling between prefrontal cortex and hippocampus supported by respiratory rhythmic input from the olfactory bulb.

Brain Res 2022 09 30;1791:147996. Epub 2022 Jun 30.

Dept Psychiatry at BIDMC, Harvard Medical School, USA. Electronic address:

Respiratory rhythm plays an important role in cognitive functions in rodents, as well as in humans. Respiratory related oscillation (RRO), generated in the olfactory bulb (OB), is an extrinsic rhythm imposed on brain networks. In rats, RRO can couple with intrinsic brain oscillations at theta frequency during sniffing and in the delta range outside of such episodes. Disruption of gamma synchronization in cortical networks by ketamine is well established whereas its effects on slow rhythms are poorly understood. We found in this study, that RRO in prefrontal cortex (PFC) and hippocampus (HC) remains present after ketamine injection, even on the background of highly unstable respiratory rate, co-incident with "psychotic-like" behavior and abnormal cortical gamma activity. Guided by the timing of ketamine-induced gamma reaction, pairwise coherences between structures exhibiting RRO and their correlation structure was statistically tested in 5-min segments post-injection (0-25 min) and during recovery (1, 5, 10 h). As in control, RRO in the OB was firmly followed by cortical-bound OB exits directed toward PFC but not to HC. RRO between these structures, however, significantly correlated with OB-HC but not with OB-PFC. The only exception to this general observation was observed during a short transitional period, immediately after injection. Ketamine has a remarkable history in psychiatric research. Modeling chronic NMDA-hypofunction using acute NMDA-receptor blockade shifted the primary focus of schizophrenia research to dysfunctional cortical microcircuitry and the recent discovery of ketamine's antidepressant actions extended investigations to neurophysiology of anxiety and depression. Cortical oscillations are relevant for understanding their pathomechanism.
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http://dx.doi.org/10.1016/j.brainres.2022.147996DOI Listing
September 2022

Rhythmic firing of neurons in the medulla of conscious freely behaving rats: rhythmic coupling with baroreceptor input.

Pflugers Arch 2022 Apr 9. Epub 2022 Apr 9.

Department of Neuroscience and Experimental Therapeutics, Albany Medical Center, 43 New Scotland Ave, Albany, NY, 12208, USA.

Recent investigations emphasized the importance of neural control of cardiovascular adjustments in complex behaviors, including stress, exercise, arousal, sleep-wake states, and different tasks. Baroreceptor feedback is an essential component of this system acting on different time scales from maintaining stable levels of cardiovascular parameters on the long-term to rapid alterations according to behavior. The baroreceptor input is essentially rhythmic, reflecting periodic fluctuations in arterial blood pressure. Cardiac rhythm is a prominent feature of the autonomic control system, present on different levels, including neuron activity in central circuits. The mechanism of rhythmic entrainment of neuron firing by the baroreceptor input was studied in great detail under anesthesia, but recordings of sympathetic-related neuron firing in freely moving animals remain extremely scarce. In this study, we recorded multiple single neuron activity in the reticular formation of the medulla in freely moving rats during natural behavior. Neurons firing in synchrony with the cardiac rhythm were detected in each experiment (n = 4). In agreement with prior observations in anesthetized cats, we found that neurons in this area exhibited high neuron-to-neuron variability and temporal flexibility in their coupling to cardiac rhythm in freely moving rats, as well. This included firing in bursts at multiples of cardiac cycles, but not directly coupled to the heartbeat, supporting the concept of baroreceptor input entraining intrinsic neural oscillations rather than imposing a rhythm of solely external origin on these networks. It may also point to a mechanism of maintaining the basic characteristics of sympathetic neuron activity, i.e., burst discharge and cardiac-related rhythmicity, on the background of behavior-related adjustments in their firing rate.
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http://dx.doi.org/10.1007/s00424-022-02687-7DOI Listing
April 2022

Respiratory coupling between prefrontal cortex and hippocampus of rats anaesthetized with urethane in theta and non-theta states.

Eur J Neurosci 2021 08 16;54(4):5507-5517. Epub 2021 Jul 16.

Department of Psychiatry at BIDMC, Harvard Medical School, Boston, Massachusetts, USA.

Respiratory modulation of forebrain activity, long considered hard to reliably separate from breathing artefacts, has been firmly established in recent years using a variety of advanced techniques. Respiratory-related oscillation (RRO) is derived from rhythmic nasal airflow in the olfactory bulb (OB) and is conveyed to higher order brain networks, including the prefrontal cortex (PFC) and hippocampus (HC), where it may potentially contribute to communication between these structures by synchronizing their activities at the respiratory rate. RRO was shown to change with sleep-wake states; it is strongest in quiet waking, somewhat less in active waking, characterized with theta activity in the HC, and absent in sleep. The goal of this study was to test RRO synchronization between PFC and HC under urethane anaesthesia where theta and non-theta states spontaneously alternate. We found that in theta states, PFC-HC coherences significantly correlated with OB-HC but not with OB-PFC, even though RRO was stronger in PFC than in HC. In non-theta states, PFC-HC synchrony correlated with coherences connecting OB to either PFC or HC. Thus, similar to freely behaving rats, PFC-HC synchrony at RRO was primarily dependent on the response of HC to the common rhythmic drive, but only in theta state. The findings help outlining the value and the limits of applications in which urethane-anaesthetized rats can be used for modelling the neural mechanisms of RRO in behaving animals.
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http://dx.doi.org/10.1111/ejn.15384DOI Listing
August 2021

Delta-range coupling between prefrontal cortex and hippocampus supported by respiratory rhythmic input from the olfactory bulb in freely behaving rats.

Sci Rep 2021 04 14;11(1):8100. Epub 2021 Apr 14.

Department Psychiatry at BIDMC, Harvard Medical School, 3 Blackfan Circle, Boston, MA, 02215, USA.

Respiratory rhythm (RR) during sniffing is known to couple with hippocampal theta rhythm. However, outside of the short sniffing bouts, a more stable ~ 2 Hz RR was recently shown to rhythmically modulate non-olfactory cognitive processes, as well. The underlying RR coupling with wide-spread forebrain activity was confirmed using advanced techniques, creating solid premise for investigating how higher networks use this mechanism in their communication. Here we show essential differences in the way prefrontal cortex (PFC) and hippocampus (HC) process the RR signal from the olfactory bulb (OB) that may support dynamic, flexible PFC-HC coupling utilizing this input. We used inter-regional coherences and their correlations in rats, breathing at low rate (~ 2 Hz), outside of the short sniffing bouts. We found strong and stable OB-PFC coherence in wake states, contrasting OB-HC coherence which was low but highly variable. Importantly, this variability was essential for establishing PFC-HC synchrony at RR, whereas variations of RRO in OB and PFC had no significant effect. The findings help to understand the mechanism of rhythmic modulation of non-olfactory cognitive processes by the on-going regular respiration, reported in rodents as well as humans. These mechanisms may be impaired when nasal breathing is limited or in OB-pathology, including malfunctions of the olfactory epithelium due to infections, such as in Covid-19.
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http://dx.doi.org/10.1038/s41598-021-87562-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046996PMC
April 2021

Delta-range coupling between prefrontal cortex and hippocampus supported by respiratory rhythmic input from the olfactory bulb in freely behaving rats.

bioRxiv 2021 Feb 3. Epub 2021 Feb 3.

Dept Psychiatry at BIDMC, Harvard Medical School.

An explosion of recent findings firmly demonstrated that brain activity and cognitive function in rodents and humans are modulated synchronously with nasal respiration. Rhythmic respiratory (RR) coupling of wide-spread forebrain activity was confirmed using advanced techniques, including current source density analysis, single unit firing, and phase modulation of local gamma activity, creating solid premise for investigating how higher networks use this mechanism in their communication. Here we show essential differences in the way prefrontal cortex (PFC) and hippocampus (HC) process the RR signal from the olfactory bulb (OB) allowing dynamic PFC-HC coupling utilizing this input. We used inter-regional coherences and their correlations in rats, breathing at low rate (∼2 Hz) at rest, outside of the short sniffing bouts. We found strong and stable OB-PFC coherence, contrasting OB-HC coherence which was low but highly variable. PFC-HC coupling, however, primarily correlated with the latter, indicating that HC access to the PFC output is dynamically regulated by the responsiveness of HC to the common rhythmic drive. This pattern was present in both theta and non-theta states of waking, whereas PFC-HC communication appeared protected from RR synchronization in sleep states. The findings help to understand the mechanism of rhythmic modulation of non-olfactory cognitive processes by the on-going regular respiration, reported in rodents as well as humans. These mechanisms may be impaired when nasal breathing is limited or in OB-pathology, including malfunctions of the OB epithelium due to infections, such as in COVID-19.
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http://dx.doi.org/10.1101/2020.05.04.077461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872353PMC
February 2021

Effect of a 5-HT7 Receptor Antagonist on Reversal Learning in the Rat Attentional Set-Shifting Test.

ACS Chem Neurosci 2021 01 18;12(1):42-48. Epub 2020 Dec 18.

Department of Psychiatry, BIDMC, Harvard Medical School, Boston, Massachussetts 02215, United States.

5-HT7 receptor antagonism has been shown to ameliorate ketamine-induced schizophrenia-like deficits in extradimensional set-shifting using the attentional set-shifting task (ASST). However, this rodent paradigm distinguishes between several types of cognitive rigidity associated with neuropsychiatric conditions. The goal of this study was to test 5-HT7 receptor involvement in the reversal learning component of the ASST because this ability depends primarily on the orbito-frontal cortex, which shows strong 5-HT7 receptor expression. We found that impaired performance on the ASST induced by NMDA receptor blockade (MK-801, 0.2 mg/kg) in 14 rats was reversed by coadministration of the 5-HT7 receptor antagonist SB-269970. The strongest effect was found on the reversal phases of ASST, whereas injection of SB-269970 alone had no effect. These results indicate that 5-HT7 receptor mechanisms may have a specific contribution to the complex cognitive deficits, increasing perseverative responding, in psychiatric diseases, including schizophrenia, depression, and anorexia nervosa, which express different forms of cognitive inflexibility.
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http://dx.doi.org/10.1021/acschemneuro.0c00554DOI Listing
January 2021

Inferring the direction of rhythmic neural transmission via inter-regional phase-amplitude coupling (ir-PAC).

Sci Rep 2019 05 6;9(1):6933. Epub 2019 May 6.

J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL, USA.

Phase-amplitude coupling (PAC) estimates the statistical dependence between the phase of a low-frequency component and the amplitude of a high-frequency component of local field potentials (LFP). To date PAC has been mainly applied to one signal. In this work, we introduce a new application of PAC to two LFPs and suggest that it can be used to infer the direction and strength of rhythmic neural transmission between distinct brain networks. This hypothesis is based on the accumulating evidence that transmembrane currents related to action potentials contribute a broad-band component to LFP in the high-gamma band, and PAC calculated between the amplitude of high-gamma (>60 Hz) in one LFP and the phase of a low-frequency oscillation (e.g., theta) in another would therefore relate the output (spiking) of one area to the input (somatic/dendritic postsynaptic potentials) of the other. We tested the hypothesis on theta-band long range communications between hippocampus and prefrontal cortex (PFC) and theta-band short range communications between dentate gyrus (DG) and the Ammon's horn (CA1) within the hippocampus. The ground truth was provided by the known anatomical connections predicting hippocampus → PFC and DG → CA1, i.e., theta transmission is unidirectional in both cases: from hippocampus to PFC and from DG to CA1 along the tri-synaptic pathway within hippocampus. We found that (1) hippocampal high-gamma amplitude was significantly coupled to PFC theta phase, but not vice versa; (2) similarly, DG high-gamma amplitude was significantly coupled to CA1 theta phase, but not vice versa, and (3) the DG high-gamma-CA1 theta PAC was significantly correlated with DG → CA1 Granger causality, a well-established analytical measure of directional neural transmission. These results support the hypothesis that inter-regional PAC (ir-PAC) can be used to relate the output of a rhythmic "driver" network (i.e., high gamma) to the input of a rhythmic "receiver" network (i.e., theta) and thereby establish the direction and strength of rhythmic neural transmission.
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http://dx.doi.org/10.1038/s41598-019-43272-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502832PMC
May 2019

Optogenetic stimulation of basal forebrain parvalbumin neurons modulates the cortical topography of auditory steady-state responses.

Brain Struct Funct 2019 May 2;224(4):1505-1518. Epub 2019 Mar 2.

Center for Neuroscience, Korea Institute of Science and Technology (KIST), Hwarang-ro 14-gil 5, Seongbuk-gu, Seoul, 02792, South Korea.

High-density electroencephalographic (hdEEG) recordings are widely used in human studies to determine spatio-temporal patterns of cortical electrical activity. How these patterns of activity are modulated by subcortical arousal systems is poorly understood. Here, we couple selective optogenetic stimulation of a defined subcortical cell-type, basal forebrain (BF) parvalbumin (PV) neurons, with hdEEG recordings in mice (Opto-hdEEG). Stimulation of BF PV projection neurons preferentially generated time-locked gamma oscillations in frontal cortices. BF PV gamma-frequency stimulation potently modulated an auditory sensory paradigm used to probe cortical function in neuropsychiatric disorders, the auditory steady-state response (ASSR). Phase-locked excitation of BF PV neurons in advance of 40 Hz auditory stimuli enhanced the power, precision and reliability of cortical responses, and the relationship between responses in frontal and auditory cortices. Furthermore, synchronization within a frontal hub and long-range cortical interactions were enhanced. Thus, phasic discharge of BF PV neurons changes cortical processing in a manner reminiscent of global workspace models of attention and consciousness.
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http://dx.doi.org/10.1007/s00429-019-01845-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532347PMC
May 2019

Subunit-specific NMDAR antagonism dissociates schizophrenia subtype-relevant oscillopathies associated with frontal hypofunction and hippocampal hyperfunction.

Sci Rep 2018 08 2;8(1):11588. Epub 2018 Aug 2.

Harvard Medical School, Boston, MA, USA.

NMDAR antagonism alters mesolimbic, hippocampal, and cortical function, acutely reproducing the positive, cognitive, and negative symptoms of schizophrenia. These physiological and behavioral effects may depend differentially on NMDAR subtype- and region-specific effects. The dramatic electrophysiological signatures of NMDAR blockade in rodents include potentiated high frequency oscillations (HFOs, ∼140 Hz), likely generated in mesolimbic structures, and increased HFO phase-amplitude coupling (PAC), a phenomenon related to goal-directed behavior and dopaminergic tone. This study examined the impact of subtype-specific NMDAR antagonism on HFOs and PAC. We found that positive-symptom-associated NR2A-preferring antagonism (NVP-AAM077), but not NR2B-specific antagonism (Ro25-6985) or saline control, replicated increases in HFO power seen with nonspecific antagonism (MK-801). However, PAC following NR2A-preferring antagonism was distinct from all other conditions. While θ-HFO PAC was prominent or potentiated in other conditions, NVP-AAM077 increased δ-HFO PAC and decreased θ-HFO PAC. Furthermore, active wake epochs exhibiting narrowband frontal δ oscillations, and not broadband sleep-associated δ, selectively exhibited δ-HFO coupling, while paradoxical sleep epochs having a high CA1 θ to frontal δ ratio selectively exhibited θ-HFO coupling. Our results suggest: (1) NR2A-preferring antagonism induces oscillopathies reflecting frontal hyperfunction and hippocampal hypofunction; and (2) HFO PAC indexes cortical vs. hippocampal control of mesolimbic circuits.
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http://dx.doi.org/10.1038/s41598-018-29331-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072790PMC
August 2018

Reciprocal Interactions between Medial Septum and Hippocampus in Theta Generation: Granger Causality Decomposition of Mixed Spike-Field Recordings.

Front Neuroanat 2017 12;11:120. Epub 2017 Dec 12.

Department of Psychiatry, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Harvard University, Boston, MA, United States.

The medial septum (MS) plays an essential role in rhythmogenesis in the hippocampus (HIPP); theta-rhythmic bursts of MS neurons are believed to drive theta oscillations in rats' HIPP. The MS theta pacemaker hypothesis has solid foundation but the MS-hippocampal interactions during different behavioral states are poorly understood. The MS and the HIPP have reciprocal connections and it is not clear in particular what role, if any, the strong HIPP to MS projection plays in theta generation. To study the functional interactions between MS and HIPP during different behavioral states, this study investigated the relationship between MS single-unit activity and HIPP field potential oscillations during theta states of active waking and REM sleep and non-theta states of slow wave sleep (SWS) and quiet waking (QW), i.e., sleep-wake states that comprise the full behavioral repertoire of undisturbed, freely moving rats. We used non-parametric Granger causality (GC) to decompose the MS-HIPP synchrony into its directional components, MS→HIPP and HIPP→MS, and to examine the causal interactions between them within the theta frequency band. We found a significant unidirectional MS→HIPP influence in non-theta states which switches to bidirectional theta drive during theta states with MS→HIPP and HIPP→MS GC being of equal magnitude. In non-theta states, unidirectional MS→HIPP influence was accompanied by significant MS-HIPP coherence, but no signs of theta oscillations in the HIPP. In theta states of active waking and REM sleep, sharp theta coherence and strong theta power in both structures was associated with a rise in HIPP→MS to the level of the MS→HIPP drive. Thus, striking differences between waking and REM sleep theta states and non-theta states of SWS and QW were primarily observed in activation of theta influence carried by the descending HIPP→MS pathway associated with more regular rhythmic bursts in the MS and sharper MS→HIPP GC spectra without a significant increase in MS→HIPP GC magnitude. The results of this study suggest an essential role of descending HIPP to MS projections in theta generation.
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http://dx.doi.org/10.3389/fnana.2017.00120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733038PMC
December 2017

Respiration-coupled rhythms in prefrontal cortex: beyond if, to when, how, and why.

Brain Struct Funct 2018 01 8;223(1):11-16. Epub 2017 Dec 8.

Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1007/s00429-017-1587-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794025PMC
January 2018

Impaired reversal learning in an animal model of anorexia nervosa.

Physiol Behav 2017 Oct 24;179:313-318. Epub 2017 Jun 24.

Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02135, USA. Electronic address:

Background: Clinical investigations indicate that anorexia nervosa (AN) is associated with impaired cognitive flexibility. Activity-based anorexia (ABA), a rodent behavioral model of AN, is characterized by compulsive wheel running associated with voluntary food restriction and progressive weight loss. The goal of this study was to test whether ABA is associated with impaired cognitive flexibility.

Methods: Female Sprague-Dawley rats were trained to perform the attentional set-shifting test (ASST) to assess cognitive flexibility, including capacity for set-shifting and reversal learning. Rats were assigned to ABA or weight-loss paired control (WPC) conditions. Following baseline testing, the ABA group had access to food for 1h/d and access to running wheels 23h/d until 20% weight loss was voluntarily achieved. For the WPC group, running wheels were locked and access to food was restricted to reduce body weight at the same rate as the ABA group. ASST performance was assessed after weight loss, and again following weight recovery.

Results: Compared to baseline, the ABA group (but not the WPC group) showed a significant decrement in reversal learning at low weight, with return to baseline performance following weight restoration. The other components of ASST were not affected.

Conclusions: Impaired reversal learning, indicative of increased perseverative responding, in the ABA model reveals its potential to recapitulate selective components of cortical dysfunction in AN. This finding supports the utility of the ABA model for investigations of the neural mechanisms underlying such deficits. Reversal learning relies on neural circuits involving the orbitofrontal cortex and thus the results implicate orbitofrontal abnormalities in AN-like state.
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http://dx.doi.org/10.1016/j.physbeh.2017.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041414PMC
October 2017

Prefrontal-hippocampal coupling by theta rhythm and by 2-5 Hz oscillation in the delta band: The role of the nucleus reuniens of the thalamus.

Brain Struct Funct 2017 Aug 16;222(6):2819-2830. Epub 2017 Feb 16.

Department of Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, USA.

Rhythmic synchronizations of hippocampus (HC) and prefrontal cortex (PFC) at theta frequencies (4-8 Hz) are thought to mediate key cognitive functions, and disruptions of HC-PFC coupling were implicated in psychiatric diseases. Theta coupling is thought to represent a HC-to-PFC drive transmitted via the well-described unidirectional HC projection to PFC. In comparison, communication in the PFC-to-HC direction is less understood, partly because no known direct anatomical connection exists. Two recent findings, i.e., reciprocal projections between the thalamic nucleus reuniens (nRE) with both PFC and HC and a unique 2-5 Hz rhythm reported in the PFC, indicate, however, that a second low-frequency oscillation may provide a synchronizing signal from PFC to HC via nRE. Thus, in this study, we recorded local field potentials in the PFC, HC, and nRE to investigate the role of nRE in PFC-HC coupling established by the two low-frequency oscillations. Using urethane-anesthetized rats and stimulation of pontine reticular formation to experimentally control the parameters of both forebrain rhythms, we found that theta and 2-5 Hz rhythm were dominant in HC and PFC, respectively, but were present and correlated in all three signals. Removal of nRE influence, either statistically (by partialization of PFC-HC correlation when controlling for the nRE signal) or pharmacologically (by lidocaine microinjection in nRE), resulted in decreased coherence between the PFC and HC 2-5-Hz oscillations, but had minimal effect on theta coupling. This study proposes a novel thalamo-cortical network by which PFC-to-HC coupling occurs via a 2-5 Hz oscillation and is mediated through the nRe.
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http://dx.doi.org/10.1007/s00429-017-1374-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542875PMC
August 2017

Differential modulation of global and local neural oscillations in REM sleep by homeostatic sleep regulation.

Proc Natl Acad Sci U S A 2017 02 13;114(9):E1727-E1736. Epub 2017 Feb 13.

Center for Neuroscience, Korea Institute of Science and Technology, Seoul 02792, South Korea;

Homeostatic rebound in rapid eye movement (REM) sleep normally occurs after acute sleep deprivation, but REM sleep rebound settles on a persistently elevated level despite continued accumulation of REM sleep debt during chronic sleep restriction (CSR). Using high-density EEG in mice, we studied how this pattern of global regulation is implemented in cortical regions with different functions and network architectures. We found that across all areas, slow oscillations repeated the behavioral pattern of persistent enhancement during CSR, whereas high-frequency oscillations showed progressive increases. This pattern followed a common rule despite marked topographic differences. The findings suggest that REM sleep slow oscillations may translate top-down homeostatic control to widely separated brain regions whereas fast oscillations synchronizing local neuronal ensembles escape this global command. These patterns of EEG oscillation changes are interpreted to reconcile two prevailing theories of the function of sleep, synaptic homeostasis and sleep dependent memory consolidation.
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http://dx.doi.org/10.1073/pnas.1615230114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338556PMC
February 2017

NEUROSCIENCE. REMembering what you learned.

Authors:
Bernat Kocsis

Science 2016 May;352(6287):770-1

Harvard Medical School, Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

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http://dx.doi.org/10.1126/science.aaf9117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316141PMC
May 2016

Assessing Granger Causality in Electrophysiological Data: Removing the Adverse Effects of Common Signals via Bipolar Derivations.

Front Syst Neurosci 2015 20;9:189. Epub 2016 Jan 20.

J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida Gainesville, FL, USA.

Multielectrode voltage data are usually recorded against a common reference. Such data are frequently used without further treatment to assess patterns of functional connectivity between neuronal populations and between brain areas. It is important to note from the outset that such an approach is valid only when the reference electrode is nearly electrically silent. In practice, however, the reference electrode is generally not electrically silent, thereby adding a common signal to the recorded data. Volume conduction further complicates the problem. In this study we demonstrate the adverse effects of common signals on the estimation of Granger causality, which is a statistical measure used to infer synaptic transmission and information flow in neural circuits from multielectrode data. We further test the hypothesis that the problem can be overcome by utilizing bipolar derivations where the difference between two nearby electrodes is taken and treated as a representation of local neural activity. Simulated data generated by a neuronal network model where the connectivity pattern is known were considered first. This was followed by analyzing data from three experimental preparations where a priori predictions regarding the patterns of causal interactions can be made: (1) laminar recordings from the hippocampus of an anesthetized rat during theta rhythm, (2) laminar recordings from V4 of an awake-behaving macaque monkey during alpha rhythm, and (3) ECoG recordings from electrode arrays implanted in the middle temporal lobe and prefrontal cortex of an epilepsy patient during fixation. For both simulation and experimental analysis the results show that bipolar derivations yield the expected connectivity patterns whereas the untreated data (referred to as unipolar signals) do not. In addition, current source density signals, where applicable, yield results that are close to the expected connectivity patterns, whereas the commonly practiced average re-reference method leads to erroneous results.
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http://dx.doi.org/10.3389/fnsys.2015.00189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718991PMC
February 2016

Brain rhythms connect impaired inhibition to altered cognition in schizophrenia.

Biol Psychiatry 2015 Jun 14;77(12):1020-30. Epub 2015 Feb 14.

Cognitive Rhythms Collaborative , Boston University; Department of Mathematics & Statistics, Boston University.

In recent years, schizophrenia research has focused on inhibitory interneuron dysfunction at the level of neurobiology and on cognitive impairments at the psychological level. Reviewing both experimental and computational findings, we show how the temporal structure of the activity of neuronal populations, exemplified by brain rhythms, can begin to bridge these levels of complexity. Oscillations in neuronal activity tie the pathophysiology of schizophrenia to alterations in local processing and large-scale coordination, and these alterations in turn can lead to the cognitive and perceptual disturbances observed in schizophrenia.
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http://dx.doi.org/10.1016/j.biopsych.2015.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444389PMC
June 2015

Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations.

Proc Natl Acad Sci U S A 2015 Mar 2;112(11):3535-40. Epub 2015 Mar 2.

Department of Psychiatry, VA Boston Healthcare System, Brockton, MA 02301; Department of Psychiatry, Harvard Medical School, Boston, MA 02115;

Cortical gamma band oscillations (GBO, 30-80 Hz, typically ∼40 Hz) are involved in higher cognitive functions such as feature binding, attention, and working memory. GBO abnormalities are a feature of several neuropsychiatric disorders associated with dysfunction of cortical fast-spiking interneurons containing the calcium-binding protein parvalbumin (PV). GBO vary according to the state of arousal, are modulated by attention, and are correlated with conscious awareness. However, the subcortical cell types underlying the state-dependent control of GBO are not well understood. Here we tested the role of one cell type in the wakefulness-promoting basal forebrain (BF) region, cortically projecting GABAergic neurons containing PV, whose virally transduced fibers we found apposed cortical PV interneurons involved in generating GBO. Optogenetic stimulation of BF PV neurons in mice preferentially increased cortical GBO power by entraining a cortical oscillator with a resonant frequency of ∼40 Hz, as revealed by analysis of both rhythmic and nonrhythmic BF PV stimulation. Selective saporin lesions of BF cholinergic neurons did not alter the enhancement of cortical GBO power induced by BF PV stimulation. Importantly, bilateral optogenetic inhibition of BF PV neurons decreased the power of the 40-Hz auditory steady-state response, a read-out of the ability of the cortex to generate GBO used in clinical studies. Our results are surprising and novel in indicating that this presumptively inhibitory BF PV input controls cortical GBO, likely by synchronizing the activity of cortical PV interneurons. BF PV neurons may represent a previously unidentified therapeutic target to treat disorders involving abnormal GBO, such as schizophrenia.
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http://dx.doi.org/10.1073/pnas.1413625112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371918PMC
March 2015

Enhancement of gamma activity after selective activation of dopamine D4 receptors in freely moving rats and in a neurodevelopmental model of schizophrenia.

Brain Struct Funct 2014 Nov 10;219(6):2173-80. Epub 2013 Jul 10.

Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA,

Dopamine D4 receptor (D4R) mechanisms have been implicated in several psychiatric diseases, including schizophrenia, attention-deficit hyperactivity disorder (ADHD), and autism, which are characterized by cognitive deficits. The cellular mechanisms are poorly understood but impaired neuronal synchronization within cortical networks in the gamma frequency band has been proposed to contribute to these deficits. A D4R polymorphism was recently linked to variations in gamma power in both normal and ADHD subjects, and D4R activation was shown to enhance kainate-induced gamma oscillations in brain slices in vitro. The goal of this study was to investigate the effect of D4R activation on gamma oscillations in freely moving rats during natural behavior. Field potentials were recorded in the frontal, prefrontal, parietal, and occipital cortex and hippocampus. Gamma power was assessed before and after subcutaneous injection of a D4R agonist, A-412997, in several doses between 0.3 and 10.0 mg/kg. The experiments were also repeated in a neurodevelopmental model of schizophrenia, in which rats are prenatally treated with methylazoxymethanol (MAM). We found that the D4R agonist increased gamma power in all regions at short latency and lasted for ~2 h, both in normal and MAM-treated rats. The effect was dose dependent indicated by the significant difference between the effects after 3 and 10 mg/kg in pair-wise comparison, whereas 0.3 and 1.0 mg/kg injections were ineffective. This study demonstrates the involvement of D4R in cortical gamma oscillations in vivo and identifies this receptor as potential target for pharmacological treatment of cognitive deficits.
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http://dx.doi.org/10.1007/s00429-013-0607-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859720PMC
November 2014

Aberrant cortical neuroplasticity in the OSA patient (Commentary on Opie et al.).

Eur J Neurosci 2013 Jun;37(11):1843

Department of Psychiatry, VA Boston Healthcare System/Harvard Medical School, Brockton, MA 02301, USA.

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http://dx.doi.org/10.1111/ejn.12221DOI Listing
June 2013

Impact of ketamine on neuronal network dynamics: translational modeling of schizophrenia-relevant deficits.

CNS Neurosci Ther 2013 Jun 24;19(6):437-47. Epub 2013 Apr 24.

Laboratory of Neurophysiology, Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Subanesthetic doses of the psychomimetic, ketamine, have been used for many years to elicit behavioral effects reminiscent of schizophrenia in both healthy humans and in animal models of the disease. More recently, there has been a move toward the use of simple neurophysiological measures (event-related potentials, brain oscillations) to assay the functional integrity of neuronal circuits in schizophrenia as these measures can be assessed in patients, healthy controls, intact animals, and even in brain slices. Furthermore, alterations of these measures are correlated with basic information processing deficits that are now considered central to the disease. Thus, here we review recent studies that determine the effect of ketamine on these measures and discuss to what extent they recapitulate findings in patients with schizophrenia. In particular, we examine methodological differences between human and animal studies and compare in vivo and in vitro effects of ketamine. Ketamine acts on multiple cortical and subcortical sites, as well as on receptors other than the N-methyl-d-aspartate receptor. Acute ketamine models' changes correlated with psychotic states (e.g. increased baseline gamma-band oscillations), whereas chronic ketamine causes cortical circuit changes and neurophysiological deficits (e.g. impaired event-related gamma-band oscillations) correlated with cognitive impairments in schizophrenia.
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http://dx.doi.org/10.1111/cns.12081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663928PMC
June 2013

Activation of 5-HT6 receptors modulates sleep-wake activity and hippocampal theta oscillation.

ACS Chem Neurosci 2013 Jan 10;4(1):191-9. Epub 2012 Dec 10.

Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States.

The modulatory role of 5-HT neurons and a number of different 5-HT receptor subtypes has been well documented in the regulation of sleep-wake cycles and hippocampal activity. A high level of 5-HT(6) receptor expression is present in the rat hippocampus. Further, hippocampal function has been shown to be modulated by both 5-HT(6) agonists and antagonists. In the current study, the potential involvement of 5-HT(6) receptors in the control of hippocampal theta rhythms and sleep-wake cycles has been investigated. Hippocampal activity was recorded by intracranial hippocampal electrodes both in anesthetized (n = 22) and in freely moving rats (n = 9). Theta rhythm was monitored in different sleep-wake states in freely moving rats and was elicited by stimulation of the brainstem reticular formation under anesthesia. Changes in theta frequency and power were analyzed before and after injection of the 5-HT(6) antagonist (SAM-531) and the 5-HT(6) agonist (EMD386088). In freely moving rats, EMD386088 suppressed sleep for several hours and significantly decreased theta peak frequency, while, in anesthetized rats, EMD386088 had no effect on theta power but significantly decreased theta frequency, which could be blocked by coadministration of SAM-531. SAM-531 alone did not change sleep-wake patterns and had no effect on theta parameters in both unanesthetized and anesthetized rats. Decreases in theta frequency induced by the 5-HT(6) receptor agonist correspond to previously described electrophysiological patterns shared by all anxiolytic drugs, and it is in line with its behavioral anxiolytic profile. The 5-HT(6) antagonist, however, failed to potentiate theta power, which is characteristic of many pro-cognitive substances, indicating that 5-HT(6) receptors might not tonically modulate hippocampal oscillations and sleep-wake patterns.
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http://dx.doi.org/10.1021/cn300184tDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547479PMC
January 2013

State-dependent increase of cortical gamma activity during REM sleep after selective blockade of NR2B subunit containing NMDA receptors.

Authors:
Bernat Kocsis

Sleep 2012 Jul 1;35(7):1011-6. Epub 2012 Jul 1.

Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Study Objectives: Sub-anesthetic doses of NMDA receptor antagonists suppress sleep and elicit continuous high-power gamma oscillations lasting for hours. This effect is subunit-specific, as it was also seen after preferential blockade of the NR2A but not of the NR2B subunit-containing receptors. The objective of this study was to test whether NR2B receptor antagonists that do not induce lasting aberrant gamma elevation affect gamma activity during specific behaviors and states, including REM sleep, when gamma normally occurs.

Design: Gamma oscillations in cortical EEG were assessed in different vigilance states in rats and were compared before and after injection of nonselective (ketamine, 10 mg/kg, and MK801, 0.2 mg/kg), as well as NR2A-preferring (NVP-AAM077, 20 mg/kg), and NR2B-selective NMDA receptor antagonists (Ro25-6985, 10 mg), and vehicle.

Measurements And Results: In contrast to nonselective and NR2A-preferring antagonists, Ro25-6985 did not disrupt sleep and had no effect on gamma activity during waking and slow wave sleep. It significantly increased, however, gamma power in the frontal (but not in occipital) cortex during REM sleep (by 37% ± 10%, average in the first 4 h). The effect had a short onset; enhanced gamma activity appeared as early as in the first REM sleep episode post-injection and lasted over 8 hours. Increased gamma power induced by MK-801 (46% ± 5%) and NVP-AAM077 (100% ± 8%) during REM sleep could also be detected several hours after injection when periodic alternation of sleep-wake states returned.

Conclusions: By acting on gamma oscillations in a state-dependent manner, NMDA receptors might have subunit-specific role in REM sleep-associated cognitive processes.
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http://dx.doi.org/10.5665/sleep.1972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369220PMC
July 2012

Differential role of NR2A and NR2B subunits in N-methyl-D-aspartate receptor antagonist-induced aberrant cortical gamma oscillations.

Authors:
Bernat Kocsis

Biol Psychiatry 2012 Jun 4;71(11):987-95. Epub 2011 Nov 4.

Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts MA02215, USA.

Background: N-methyl-D-aspartate receptor (NMDA-R) hypofunction plays an important role in cognitive impairment in schizophrenia. NMDA-R antagonists elicit psychotic symptoms in humans and schizophrenia-relevant signs in rodents, including a strong increase in cortical gamma activity. NMDA-Rs are composed of different subunits, and accumulating evidence indicates that neuronal damage due to NMDA-R antagonists depends on their action on a specific type of the receptor containing the NR2A subunit. In human schizophrenics, NR2A is selectively reduced in fast-firing interneurons. These neurons are critical for gamma oscillations, indicating that pathological changes in gamma activity may depend on subunit-specific NMDA-R deficit. The present study tested this hypothesis.

Methods: Cortical electroencephalograms were recorded in freely moving rats and the changes in gamma power were measured after administration of NMDA-R antagonists with different subunit selectivity, including NR2A-preferring (PEAQX, n = 5; NVP-AAM077, n = 18), NR2B-selective (ifenprodil, n = 6; threo-ifenprodil, n = 4; Ro25-6985, n = 13), and NR2C/D-selective (n = 8) antagonists, along with vehicle and nonselective NMDA-R antagonists (ketamine, n = 10; MK801, n = 12). Changes in prepulse inhibition of startle was tested after MK-801 (n = 6), NVP-AAM077, and Ro-6891 (n = 5) injection.

Results: Strong increase in gamma power was induced by nonselective NMDA-R antagonists and by blockade of NMDA-Rs containing the NR2A subunit, with co-occurring gating deficits and diminished low-frequency modulation of gamma oscillations. In contrast, selective blockade of NR2B, C, or D subunit-containing receptors had minor effects.

Conclusions: Major subtype-specific differences in the role of NMDA-Rs in cortical gamma oscillation may have implications for the pathomechanism and treatment of cognitive impairment in schizophrenia.
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http://dx.doi.org/10.1016/j.biopsych.2011.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276718PMC
June 2012

Comparison of the effects of acute and chronic administration of ketamine on hippocampal oscillations: relevance for the NMDA receptor hypofunction model of schizophrenia.

Brain Struct Funct 2012 Apr 7;217(2):395-409. Epub 2011 Oct 7.

Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA.

The proper organization and function of GABAergic interneuron networks is essential for many cognitive processes and abnormalities in these systems have been documented in schizophrenic patients. The memory function of the hippocampus depends on two major patterns of oscillations in the theta and gamma ranges, both requiring the intact functioning of the network of fast-firing interneurons expressing parvalbumin. We examined the ability of acute and chronic administration of NMDA receptor (NMDA-R) antagonists to recapitulate the oscillatory dysfunctions observed in schizophrenia. In freely moving rats, acute injection of MK801 or ketamine increased gamma power in both CA1 and dentate gyrus of the hippocampus. Theta peak shifted to higher frequencies whereas the average 5-10 Hz theta power decreased by 24% in CA1 and remained high in the dentate gyrus. Strong increase in CA1 gamma and decrease in theta power triggered by brainstem stimulation were found under urethane anesthesia. In contrast to acute experiments, chronic administration of ketamine caused a steady decline in both gamma and theta oscillations, 2-4 weeks after treatment. A further important difference between the two models was that the effects of acute injection were more robust than the changes after chronic treatment. Chronic administration of ketamine also leads to decrease in the number of detectable parvalbumin interneurons. Histological examination of interindividual differences indicated, however, that within the ketamine treated group a further decrease in parvalbumin neurons correlated with strengthening of oscillations. The findings are consistent with abnormalities of oscillations in human schizophrenia and further validate the NMDA-R hypofunction hypothesis.
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http://dx.doi.org/10.1007/s00429-011-0351-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288729PMC
April 2012

Comparative analysis of the neurophysiological profile of group II metabotropic glutamate receptor activators and diazepam: effects on hippocampal and cortical EEG patterns in rats.

Neuropharmacology 2012 Jan 26;62(1):226-36. Epub 2011 Jul 26.

Department of Neuroscience, Pfizer Global Research and Development, Eastern Point Road, MS 8220-4366, Groton, CT 06340, USA.

Selective activation of the Group II metabotropic glutamate receptors 2/3 (mGlu2/3) by either full agonists or positive allosteric modulators (PAMs) show anxiolytic activity. In the present study the anxiolytic profile of mGlu2/3 receptor agonists LY-354740 and LY-404039 and the mGlu2 receptor PAM 1-methyl-2-((cis-3-methyl-4-(4-trifluoromethyl-2-methoxy)-phenyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyridine (MTFIP) were evaluated using neurophysiology-based assays. Activation of mGlu2/3 receptors by these compounds, as well as the positive control diazepam, significantly decreased the frequency of hippocampal theta oscillation elicited by stimulation of the brainstem nucleus pontis oralis (nPO), a characteristic action of anxiolytic compounds. Since the nPO is a critical region involved in regulation of rapid eye movement sleep, mGlu2/3 receptor activators were also tested on sleep parameters, as well as on cortical and hippocampal encephalography (EEG) activity. Both mGlu2/3 agonists and the mGlu2 PAM significantly prolonged REM sleep latency and reduced total REM sleep duration while during the active awake state all compounds lowered hippocampal peak theta frequency. However, diazepam and mGlu2/3 agonists/PAM elicited opposite changes in cortical EEG delta and beta bands. Delta power significantly increased after any of the mGlu2/3 compounds but decreased after diazepam. In the beta band, mGlu2/3 receptor agonists dose-dependently decreased beta power in contrast to the well-known beta activation by diazepam. These effects lasted 3-4h and could not be explained by modest, transient changes (<1h) in waking and slow wave sleep. The current observations support the role of mGlu2/3 receptor activators as potential anxiolytic compounds, but indicate a distinct action on cortical EEG activity which is different from the effects of GABA(A) PAMs. This article is part of a Special Issue entitled 'Anxiety and Depression'.
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http://dx.doi.org/10.1016/j.neuropharm.2011.07.011DOI Listing
January 2012

Control of hippocampal theta rhythm by serotonin: role of 5-HT2c receptors.

Neuropharmacology 2011 Sep 31;61(3):489-94. Epub 2011 Jan 31.

Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA.

The hippocampus plays an important role in learning and memory and has been implicated in a number of diseases, including epilepsy, anxiety and schizophrenia. A prominent feature of the hippocampal network is the capability to generate rhythmic oscillations. Serotonergic modulation is known to play an important role in the regulation of theta rhythm. 5-HT2c receptors represent a specific target of psychopharmacology and, in particular, the behavioral effects of the 5-HT2c receptor agonist mCPP have been thoroughly tested. The present study used this compound and the selective 5-HT2c receptor antagonist SB-242084 to elucidate the role of 5-HT2c receptors in the generation of hippocampal oscillations. Hippocampal EEG was recorded and the power in the theta frequency range was monitored in different behaviors in freely-moving rats and after brainstem stimulation in anesthetized animals. We found that in freely-moving rats, mCPP suppressed hippocampal theta rhythm and the effect was stronger during REM sleep than during waking theta states. Under urethane anesthesia, mCPP decreased the power for both spontaneous and elicited theta rhythm in a dose-dependent manner and the 5-HT2c antagonist reversed this effect. The results of this study demonstrate that 5-HT2c receptors are important element of the serotonergic modulation of hippocampal theta oscillations and thus pharmacological interactions with these receptors can modulate physiological and pathological processes associated with limbic theta activity.
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http://dx.doi.org/10.1016/j.neuropharm.2011.01.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110562PMC
September 2011

Hippocampal oscillations in the rodent model of schizophrenia induced by amygdala GABA receptor blockade.

Front Psychiatry 2010 1;1:132. Epub 2010 Sep 1.

Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Brain oscillations are critical for cognitive processes, and their alterations in schizophrenia have been proposed to contribute to cognitive impairments. Network oscillations rely upon GABAergic interneurons, which also show characteristic changes in schizophrenia. The aim of this study was to examine the capability of hippocampal networks to generate oscillations in a rat model previously shown to reproduce the stereotypic structural alterations of the hippocampal interneuron circuit seen in schizophrenic patients. This model uses injection of GABA-A receptor antagonist picrotoxin into the basolateral amygdala which causes cell-type specific disruption of interneuron signaling in the hippocampus. We found that after such treatment, hippocampal theta rhythm was still present during REM sleep, locomotion, and exploration of novel environment and could be elicited under urethane anesthesia. Subtle changes in theta and gamma parameters were observed in both preparations; specifically in the stimulus intensity-theta frequency relationship under urethane and in divergent reactions of oscillations at the two major theta dipoles in freely moving rats. Thus, theta power in the CA1 region was generally enhanced as compared with deep theta dipole which decreased or did not change. The results indicate that pathologic reorganization of interneurons that follows the over-activation of the amygdala-hippocampal pathway, as shown for this model of schizophrenia, does not lead to destruction of the oscillatory circuit but changes the normal balance of rhythmic activity in its various compartments.
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http://dx.doi.org/10.3389/fpsyt.2010.00132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034149PMC
April 2011

Activation of cannabinoid-1 receptors disrupts sensory gating and neuronal oscillation: relevance to schizophrenia.

Biol Psychiatry 2008 Jun 7;63(11):1075-83. Epub 2008 Feb 7.

Department of Neuroscience, Pfizer Global Research and Development, Groton, CT 06340, USA.

Background: Impaired auditory gating and abnormal neuronal synchrony are indicators of dysfunctional information processing in schizophrenia patients and possible underlying mechanisms of their impaired sensory and cognitive functions. Because cannabinoid receptors and endocannabinoids have been linked to psychiatric disorders, including schizophrenia, the aim of this study was to evaluate the effects of cannabinoid-1 (CB1) receptor activation on sensory gating and neuronal oscillations in rats.

Methods: Auditory sensory gating has been recorded from the hippocampus and entorhinal cortex (EC) in anesthetized rats. Neuronal network oscillations were recorded from the hippocampus, medial septum, EC, and medial prefrontal cortex in anesthetized and freely moving rats. Effects of systemic administration of CB1 receptor agonist CP-55940 were evaluated on these parameters.

Results: CP-55940 significantly disrupted auditory gating both in the hippocampus and EC in anesthetized rats. Theta field potential oscillations were disrupted in the hippocampus and EC, with simultaneous interruption of theta-band oscillations of septal neurons. Administration of the CB1 receptor antagonist AM-251 reversed both the agonist-induced gating deficit and the diminished oscillations. In freely moving rats, CP-55940 significantly reduced theta and gamma power in the hippocampus, whereas in the EC, only gamma power was attenuated. However, novelty-induced theta and gamma activities were significantly diminished by CP-55940 in both the hippocampus and EC.

Conclusions: Our data indicate that activation of CB1 receptors interferes with neuronal network oscillations and impairs sensory gating function in the limbic circuitry, further supporting the connection between cannabis abuse and increased susceptibility of developing schizophrenia spectrum disorders.
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http://dx.doi.org/10.1016/j.biopsych.2007.12.005DOI Listing
June 2008

Elicited hippocampal theta rhythm: a screen for anxiolytic and procognitive drugs through changes in hippocampal function?

Behav Pharmacol 2007 Sep;18(5-6):329-46

Department of Psychology, University of Otago, Dunedin, New Zealand.

Hippocampal damage produces cognitive deficits similar to dementia and changes in emotional and motivated reactions similar to anxiolytic drugs. The gross electrical activity of the hippocampus contains a marked 'theta rhythm'. This is a relatively high voltage sinusoidal waveform, resulting from synchronous phasic firing of cells, variation in which correlates with behavioural state. Like the hippocampus, theta has been linked to both cognitive and emotional functions. Critically, it has recently been shown that restoration of theta-like rhythmicity can restore lost cognitive function. We review the effects of systemic administration of drugs on hippocampal theta elicited by stimulation of the reticular formation. We conclude that reductions in the frequency of reticular-elicited theta provide what is currently the best in-vivo means of detecting antianxiety drugs. We also suggest that increases in the power of reticular-elicited theta could detect drugs useful in the treatment of disorders, such as dementia, that involve memory loss. We argue that these functionally distinct effects should be seen as indirect and that each results from a change in a single form of cognitive-emotional processing that particularly involves the hippocampus.
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http://dx.doi.org/10.1097/FBP.0b013e3282ee82e3DOI Listing
September 2007
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