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Research Report

Temporal correlation between auditory neurons and thehippocampal theta rhythm induced by novel stimulations inawake guinea pigs

Tamara Libermana,b, Ricardo A. Vellutib, Marisa Pedemontea,⁎aFacultad de Medicina, Centro Latino Americano de Economía Humana Instituto Universitario, CLAEH, Punta del EstebORL Hospital de Clínicas. Facultad de Medicina, Universidad de la República, Montevideo Uruguay

A R T I C L E I N F O

⁎ Corresponding author. Facultad de MedicinE-mail address: marisa.pedemonte@gmaiAbbreviations: EMG, electromyogram; Hipp

histogram; W, wakefulness

0006-8993/$ – see front matter © 2009 Elsevdoi:10.1016/j.brainres.2009.08.061

A B S T R A C T

Article history:Accepted 16 August 2009Available online 27 August 2009

The hippocampal theta rhythm is associatedwith the processing of sensory systems such astouch, smell, vision and hearing, aswell aswithmotor activity, themodulation of autonomicprocesses such as cardiac rhythm, and learning and memory processes. The discovery oftemporal correlation (phase locking) between the theta rhythmand both visual and auditoryneuronal activity has led us to postulate the participation of such rhythm in the temporalprocessing of sensory information. In addition, changes in attention can modify both thetheta rhythm and the auditory and visual sensory activity. The present report tested thehypothesis that the temporal correlation between auditory neuronal discharges in theinferior colliculus central nucleus (ICc) and the hippocampal theta rhythm could beenhanced by changes in sensory stimulation. We presented chronically implanted guineapigs with auditory stimuli that varied over time, and recorded the auditory response duringwakefulness. It was observed that the stimulation shifts were capable of producing thetemporal phase correlations between the theta rhythm and the ICc unit firing, and theydiffered depending on the stimulus change performed. Such correlations disappearedapproximately 6 s after the change presentation. Furthermore, the power of thehippocampaltheta rhythm increased in half of the cases presented with a stimulation change. Based onthese data, we propose that the degree of correlation between the unitary activity and thehippocampal theta rhythm varies with – and therefore may signal – stimulus novelty.

© 2009 Elsevier B.V. All rights reserved.

Keywords:Inferior colliculusUnitary activityHippocampal theta rhythmPhase lockingWakefulnessNovelty

1. Introduction

The processing of auditory sensory information requirestemporal coding and we propose that the hippocampal thetarhythm is involved in this process. The phase and power of thetheta rhythm (4–10 Hz) have been shown to vary in response toattention changes (Grastyan et al., 1959; Kemp and Kaada,

a, CLAEH, Prado & Salt Lal.com (M. Pedemonte)., hippocampal field activi

ier B.V. All rights reserve

1975; Vinogradova, 2001; Pedemonte andVelluti, 2005). Severalstudies have explored the relationship of the theta rhythmwithmotor activity itself (Buño and Velluti, 1977; García-Austt,1984) as well as with the sensory processing of motor activity(Grastyan et al., 1959). This rhythm has even been shown toaffect diverse sensory systems such as touch (Nuñez et al.,1991), pain (Vertes and Kocsis, 1997), vision (Gambini et al.,

ke, Punta del Este, Maldonado, Uruguay. Fax: +1 598 42 496612 13.

ty; ICc, inferior colliculus central nucleus; PSTH, post-stimulus time

d.

Table 1 – Temporal correlations between theta rhythmand ICc spikes, and theta power increases for the differentchanges performed.

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2002) and olfaction (Margrie and Schaefer, 2003). Furthermore,its participation in the modulation of autonomic processessuch as the cardiac rhythm was also ascertained (Pedemonteet al., 1999, 2003).

A number of studies have illustrated the functionalrelationship between the hippocampus and the auditorysystem (Cazard and Buser, 1963; Redding, 1967; Parmeggianiand Rapisarda, 1969; Parmeggianni et al., 1982), leading to thetheory that this rhythm may affect the excitability of distantneurons by inducing membrane potential oscillations (García-Austt, 1984; Kocsis and Vertes, 1992).

The neural activity of the auditory system depends on theinformation arriving from the external world, the body, andthe efferent action of the central nervous system. The brainexerts continuous modulation over sensory processing. Thishas been observed particularly in the auditory system, asystem that never ceases its processing, even during sleep(Velluti, 1997, 2008). Neurons in the central nucleus of theinferior colliculus (ICc) have been shown to exhibit changesin their firing frequency and pattern distribution in correla-tion with an animal's behavioral state (Morales-Cobas et al.,1995).

The hippocampal theta rhythm has been shown tocorrelate with the activity of sensory neurons. Auditorycortical spikes exhibit phase locking with the theta rhythmboth for spontaneous and evoked firing during wakefulness(W), slow wave sleep and paradoxical sleep, although indifferent proportions in each case (Velluti, 2008). The thetapower also showed changes across different behavioral states(Pedemonte et al., 1996, 2001; Gaztelu et al., 1994). Karashimaet al. (2007) observed phase locking between the hippocam-pus theta and paradoxical sleep pontine waves in response tosound. Visual units of the lateral geniculate nucleus were alsostudied in relation to the hippocampal theta rhythm andwere found to exhibit phase locking during W and sleep(Gambini et al., 2002). Pedemonte et al. (2005) found thatfrequency-modulated light stimulation produced a correla-tion during W, which was accompanied by an increase in thetheta power.

The abovementioned observations led us to propose thehypothesis that a temporal correlation between ICc neuronalfiring and hippocampal theta rhythm can occur by changingthe characteristics of the sensory stimulus, thus supportingthe theory that this rhythm plays an important role in sensoryinformation processing, i.e. providing the role of temporallyorganizing and participating in the interpretation of both theauditory signals and any lower rhythms thatmay be providingrelevant information leading to the comprehension of themessage that enters the brain. The ICc has been selected forthis study since it represents critical crossroads of afferent andefferent information.

Temporalcorrelation %

Theta powerincrease %

Increase in sound stimulationrate

44 41

Sound Stimulation onset 26 15Decrease in sound stimulation

rate24 33

Sound stimulation interruption(spontaneous activity)

6 11

2. Results

The unitary activity of 27 ICc neurons was extracellularlyrecorded in response to changes in auditory stimulationduring quiet W, that is those periods of W which exhibit nomovements neither by direct visualization nor in the EMG. Thechanges consisted of increase or decrease of the stimulation

rate within a range of 1 to 10 Hz. Auditory stimuli were 50 mstones at the neuron's best frequency.

Of 149 changes processed, 55 corresponded to pure-tonerate increases, 48 to decreases (both ranging between 1 and 10/s), 26 to stimulation onsets (rhythmical and random stimula-tion) and 20 to interruptions.

The stimulation shift resulted in temporal correlation(phase locking) between ICc neuronal firing and theta rhythmin 36% cases (54 out of 149), and it lasted ∼6 s in most cases.Only one fifth of the cases lasted longer, although neverbeyond 14 s.

Phase locking occurred in different percentages dependingon the stimulation shift. Seventy percent of the correlationswere the result of an increase in stimulation (pure-tone rateincrease and/or onset of stimulation), while 30% of themcorresponded to a decrease in stimulation (pure-tone ratedecrease and interruption of stimulation, see Table 1).

In order to verify the statistical significance of the phaselocking obtained, the number of temporal correlations beforethe shifts, considered as control ones, was ascertained andcontrasted to the number of temporal correlations immedi-ately after shifts, i.e. provoked by the change in stimulus. TheStudent's t test showed that the number of provoked temporalcorrelations was significant (p<0.05). Moreover, it was ob-served that stimulation increases produced a statisticallyhigher significant number of correlations (p< 0.01).

Fig. 1 is an example of a change in the stimuli presentationfrom 9 stimuli/s to 1 stimulus/s. In this particular case, atemporal correlation was evident immediately after thechange (Fig. 1B) but disappeared after a few seconds (Fig. 1C).The spike shuffling was performed to corroborate that thephase locking in B was real. This temporal correlation wasaccompanied by an increase in the hippocampal powerspectrum within the theta range and the theta wavessynchronization, as shown in the autocorrelation.

Among the correlations that responded to stimulationincreases (70%), 44% corresponded to stimuli rate increasesand 26% to stimulation onsets, changing the stimulus ratefrom 0 to 3/s or initiating a random stimulus from silence.

Of the 30% that responded to stimulation decreases, 24%corresponded to rate decreases and 6% to stimulation inter-ruptions (passing fromstimulus-evoked to spontaneous firing).

The temporal correlation was more frequently observedwhen stimulating within the theta range, for example whenchanging from 1 to 6 stimuli/s (64% of cases). Conversely,

Fig. 1 – Example of ICc unit activity and the hippocampal theta rhythm in response to a decrease in the stimuli presentation inawake guinea pig. Top: post-stimulus time histogram (PSTH) before the stimulation shift to characterize the unit as auditory;a series of traces showing from top to bottom: the sound stimulus in which the presentation rate changes from 9/s to 1/s,hippocampal field activity (Hipp), digitized unitary discharge, extracellular ICc unitary discharge and electromyogram (EMG).Vertical lines limit the A, B and C epochs selected for processing. A is immediately prior to the stimulation change, and B and Care successive windows following the stimulus presentation rate change. Bottom: processing of the temporal windows shownat the top. In A, the cross-correlation, calculated by spike-triggered hippocampal electrogram averaging, shows no correlationbetween the hippocampal field activity and the spikes (n=53). In B, the temporal correlation (phase locking) appears when thesound stimulation rate is decreased (spikes, n=12) and in C the phase locking disappears (~6 s later; spikes, n=11). Spikeshuffling of window B validates the phase locking significance (insert). In B the hippocampal theta power spectrum increases(black bars indicating theta frequency range, 4–10 Hz, 57% increment related to window A). Note the predominance of thetheta rhythm in the hippocampal wave autocorrelation in window B (7 Hz).Cals.: Hipp, 0.2 mV; ICc unit, 0.2 mV; EMG, 0.1 mV;time, 1 s.

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when changing from 6 to 1 stimulus/s, only 11% of the casesshowed correlation.

We found that the same neuron could respond differentlyto equivalent stimulation shifts, at different times.Anexampleof this is shown in Fig. 2, where two different responses, only 1min apart, were observed during a shift from1 to 6 stimuli/s. InFig. 2B, the stimulation change resulted in phase locking of thespike to the theta rhythm (verified by spike shuffling), while inFig. 2E the same shift provoked no phase locking. However, thetheta power spectrum showed an increase after the change inboth cases.

In all cases, the correlations present during an interruptedstimulus showed a delay to appear (approximately 6 s after theinterruption).

Stimulation shifts also modified the power of the thetarange, whichwas higher in 49% of the cases (73 out of 149). Thechange in theta power also varied depending on the type ofstimulation change: the power increased in 41% of thestimulation rate increases, 33% of the stimulation ratedecreases, 15% of the stimulation onsets, and 11% of thestimulation interruptions (Table 1). This power increment wasaccompanied by a predominance of such rhythm, as it isshown in the hippocampal autocorrelation of Fig. 1. Althoughthe temporal correlation and the theta power increase were

Fig. 2 – Two different responses of the same ICc neuron provoktraces showing from top to bottom: the sound stimulus presentaseparated by a 1min interval, the hippocampal field activity (Hippdischarge, and the electromyogram (EMG). Vertical lines limit epoperiod of time immediately prior to the stimulus change, and B–CBottom: cross-correlations and power spectra before the shift (Aresults in phase locking of the spike and the theta rhythm, whichincrement related to window A). Spike shuffling validates the sigcross-correlation shows no phase locking although the theta powwindow D). Number of spikes: Epochs A=19, B=54, C=46, D=13,0.2 mV; time, 1 s.

simultaneously provoked in only 17% of the cases, they bothappeared in a higher percentage when the stimulation ratewas increased and in a lower percentagewhen the stimulationwas interrupted (see Table 1).

3. Discussion

The present work investigated the role of the hippocampaltheta rhythm in auditory temporal processing during quiet W.Several studies had previously explored the relation of thetheta rhythmwith diverse sensory systems (Nuñez et al., 1991;Gambini et al., 2002;Margrie andSchaefer, 2003), aswell aswiththe motor activity (Buño and Velluti, 1977; García-Austt, 1984;Grastyan et al., 1959), and autonomic processes (Pedemonteet al., 1999, 2003). Considering the participation of this rhythmin so many systems, it was of great relevance in this work toassure, as soon as possible, a behavioral situation in which noother stimulus than the one required would participate, as it isquiet W. Any presence of movement might modify the resultsin an artifactual fashion, as it is observedwhen the presence ofmovement masks the presence of the theta rhythm.

Changes in auditory stimulation were presented in anattempt to measure the temporal correlation between ICc

ed by the same stimulus change in awake guinea pig. Top:tions, increasing from 1 to 6 stimuli/s, two repetitions), the digitized unitary discharge, the extracellular ICc unitarychs A through F, selected for processing. A and D indicate theand E–F are successive windows after the stimulus change.

and D) and after it (B, C and E, F). The stimulus change in Bis accompanied by an increase in the theta band power (50%nificance of the temporal correlation observed in B. In E, theer spectrum shows an increment (10% increment related toE=55, F= 47. Cals.: Hipp, 0.25 mV; ICc unit, 0.2 mV; EMG,

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neurons and the theta rhythm aswell as changes in the powerof the theta rhythm during unexpected changes in auditorystimulation. Furthermore, we tested whether rate increases ordecreases, and stimulation starts or interruptions induceddifferent responses.

Stimulation shifts in nature would drive attentionchanges that would presumably elicit the same results asin our laboratory setting, thus reflecting the involvement ofthe theta rhythm in the detection and temporal processingof novel information. This is in accordance with the ideathat the hippocampal theta rhythm signals levels ofattention and acts as a novelty detector and comparator(Grossberg and Merrill, 1992; Eichenbaum, 1997; Vinogradova,2001).

These results are consistent with those obtained fromvisual neurons of the lateral geniculate nucleus in guinea pigs,in which stimulation shifts also induced phase locking totheta rhythm, although in different proportions (Pedemonteet al., 2005).

Different percentages of correlation were observed for thedifferent stimulation shifts. Stimulation increases produced ahigher percentage of correlations than stimulation decreases,leading us to speculate that increasing stimulation mayincrease an animal's alertness more effectively than decreas-ing stimulation. Hence, a different level of attention could beinduced by the modification in the stimulus characteristicsand, specifically, a particular processing mode seems to beactivated by acoustic novelty.

The correlations observed during random stimulation, aswell as those present with no stimulation, confirmed that theresponse was evoked by the stimulus shift rather than byperiodic stimulation.

Phase locking and increments in theta power wereproduced immediately after stimulation shifts and persistedfor periods of around 6 s. This is consistent with previousreports showing theta increments and temporal correlationwith the theta rhythm in ICc, the auditory cortex, and thelateral geniculate for 5–10 s (Pedemonte et al., 1996, 2005;Velluti and Pedemonte, 2002). Moreover, Vinogradova (2001)showed inhibitory neuronal responses at the hippocampalCA3 after auditory stimulation, which habituated after 4–6 s.The phase locking to the theta rhythm may be used to spreadthe novel information to different regions of the nervoussystem after stimulation changes, conferring on this rhythmthe novelty detector of the temporal structure of the incomingauditory information.

The different responses observed in a single neuronundergoing equivalent changes, only seconds apart andunder identical recording conditions, suggest that neuronsinvolved in one network could functionally switch functionsdepending on their requirements and the brain state at a givenmoment. The efferent system may dynamically modulate aneuron's function, making it part of a new network and thusexhibiting a different behavior. The presence or absence ofphase correlation with the theta rhythm supports the hypoth-esis of a role of this rhythm in controlling the functionalinteraction between brain structures (Başar and Karakaş, 1998;Bastiaansen and Hagoort, 2003; Pfurtscheller and Lopes daSilva, 1999), such as the specific sensory input and the brainstate at a given moment.

The findings of a temporal correlation between bothactivities may be indicating the participation of such rhythmin different aspects of the involved sensory information. Apartfrom participating in the processing of the incoming sound,i.e. the physical interpretation of sound, this rhythm mayprovide the temporal organization of slower rhythms thatwould also represent relevant information such as naturalanimal call. Those slower rhythms would allow the brain tointerpret the message contained in the entering information,to be finally stored or leading to the animal's reaction as aconsequence.

The theta power exhibits a tendency to increase withstimulation shifts, consistent with the notion that this rhythmprobably signals level of attention. The similarity of resultsin both the auditory and visual sensory systems (Pedemonteet al., 2005) implies that the theta rhythm behavior is a generalattentional mechanism, rather than one specific to the visualsystem. Furthermore, this rhythm canmodulate the firing rateand spike timing of a single neuron (Gambini et al., 2002;Pedemonte et al., 1996, 2001; Velluti, 1997, 2008; Velluti et al.,2000; Siapas et al., 2005; Lee et al., 2005) as well as the gammapower of the intracortical local field potential (Canolty et al.,2006).

While the correlation observed between the theta rhythmand the spike immediately after the change in stimulus wasan observation of a very specific fact, a variation in the thetapower could be due to different situations. The theta powervariationsmay be reflecting awide range of facts and the thetaparticipation in several other processes that cannot becontrolled or measured, such as other sensory processes,motor processes not possible to objectify, autonomic process-es, i.e. it is a more unspecific sign.

It is important to consider that this protocol was performedin awake animals, in which a range of situations taking placemay not be identified and therefore considered. In spite ofthis, those cases in which the theta power showed to increaseimmediately after the stimulation change seem to respond tothe specific processing of the auditory system.

Our results and interpretations also coincide with thoseexpressed by previous reports depicting the auditory systemas a guardian in constant reception of sounds (Velluti andPedemonte, 2002; Velluti, 2005; Pedemonte and Velluti, 2005;Velluti, 2008) to be, in turn, decoded by the nervous system.

Furthermore, the temporal auditory cortex connections toa limbic structure such as the amygdala have been reported(Romansky and Ledoux, 1993). On the other hand, since thehippocampus controls the cingulated gyrus output, theinformation from the septo-hippocampal complex can gainaccess to extended portions of the brain, including the centralgray (Domesick, 1969). Projections from the latter on the IChave also been reported (Radmilovich et al., 1991). Thus,mutual interactionmay exist between hippocampus rhythmicEEG and the auditory IC.

All of the abovementioned results suggest that the thetarhythm participates in sensory auditory information proces-sing in the ICc during W, which is consistent with thehypothesis that this rhythm confers a temporal dimension toauditory information processing (Adey et al., 1960; Pedemonteet al., 1996; Velluti et al., 2000; Velluti, 2008). The need fora temporal control of the incoming information has been

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suggested by different authors (O'Keefe and Recce, 1993;Wallenstein et al., 1998) and the hippocampal theta rhythmcould be accomplishing this function.

One could speculate that certain changes may provokedifferent states of awareness, depending on the relevancethose changes represent. Both the theta phase locking and thetheta band power appear to reflect whether or not the brainhas detected temporal changes in the environment.

In conclusion, it was possible to evoke temporal correla-tions between ICc auditory discharges and the hippocampaltheta rhythm by introducing changes in the sensory stimula-tion of guinea pigs in quiet wakefulness. This demonstratesthe ability of the hippocampus theta rhythm to signal noveltythrough correlated neural activity, thus potentially subservingthe function of analyzing information transfer within thenervous system.

4. Experimental procedure

Adult guinea pigs (Cavia porcellus, n=19) weighing 400–600 gwere recorded after electrode implantation. The anestheticsPentobarbital sodium (30–35 mg/kg i.p.) and xylazine (5 mg/kgi.m.) were used for the surgical procedure. A head-holder wasused to fix the animal's head position according to stereotaxicparameters (Luparello, 1967). A 1 mm diameter craniotomywas made over the ICc contralateral to the ear selected forsound stimulation (A: 0.5, L: 2 mm) in order to insert a glassmicroelectrode for spike recording. Nichrome macroelec-trodes were implanted for the hippocampal electrogramrecordings (A: 6; L: 2; H: −4 mm), which together with theneck electromyogram (EMG) permitted behavioral monitoring.The superior recessus over themiddle ear was opened to placea polyethylene tube of ∼3 mm diameter for subsequent soundpresentation. The electrodes and the tubes were cemented tothe skull, and two metal bars were also cemented to permithead fixation and painless reproduction of the stereotaxicposition during the recording sessions. Recording sessionsstarted after a recovery period of at least a week after surgery(Morales-Cobas et al., 1995, Pedemonte et al., 1996). Allexperimental procedures were conducted in accordance withthe international and national norms for animal research(Committee for Animal Research CHEA, Universidad de laRepública, Montevideo) and with the NIH Guide for the Care andUse of Laboratory Animals.

During the recording sessions the animal was held on acanvas and its head fixated by the two metal bars. A tungstenmicroelectrode (1–3 M Ω) was advanced through the brainusing a micro-manipulator (Narishige MO-8), searching forevoked extracellular units in ICc. The neuronal discharge,hippocampal electrogram and EMG were amplified, acquired,filtered and stored for off-line processing (Spike2, CambridgeElectronic Design).

White noisewas used as the search stimulus. Tones (50ms,5 ms rise-decay time) at the unit's best frequency weresynthesized with a wave generator (WG1 Tucker Davis)synchronized to a stimulator (Grass Instruments, 54GR) toregulate the stimulus presentation rate and permit manualstimulation. An earphone (Beyer dynamic DT 48, 200 Ω) wasattached to the polyethylene tube for sound delivery (70 dB

SPL, 10 dB above threshold; PA4 Tucker Davis) via a closedsound system (Pedemonte et al., 1996; 2001; Pedemonte andVelluti, 2005).

Pure tones were presented in a pattern of increasing anddecreasing rate (range of 1–10 per second). Stimulations onsetand interruption were also performed. Both periodic andrandom stimulations were presented, the latter to avoidcoupling between external periodic stimulation and brainrhythmical activity. Sound stimulation shifts were performedabruptly every 30 s.

All recordings were performed during W, which wasmonitored by the hippocampal electrogram and the EMG.Furthermore, only recordings made during periods of quiet W,in which animals exhibited neither movement nor change inbehavioral state before and after stimulation shifts, wereanalyzed.

Stereotaxic and electrophysiological corroborations of therecording site were always performed. Far field potentials andthe characteristic pattern of discharge observed in the ICc inresponse to pure tones (Morales-Cobas et al., 1995) permittedthe electrophysiological confirmation. Hippocampus and ICrecording loci as well as the electrode positioning wereassessed by visually objectifying the electrodes tracks, oncethe animals were sacrificed and perfused (i/v pentobarbital;10% formalin). When such confirmations were not achieved,the recordings were excluded.

Three contiguous temporal windows of approximately 6 seach were selected to be processed off-line (Spike2), oneimmediately prior to the stimulation change (control) and theother two subsequent to the change. Window duration wasadjusted according to previous reports (Pedemonte et al.,2005). The durations of those windows prior to stimulationonset were individually adjusted in order to include a numberof spontaneous discharges similar to that evoked in subse-quent windows.

The hippocampal electrogram was processed using auto-correlation and power spectrum analysis (Fast Fourier Trans-form) of the theta range (4–10 Hz). The ICc spikes weredigitized with a voltage window discriminator and analyzedwith peri-stimulus time histograms to confirm their auditoryorigin. The cross-correlation between the hippocampal fieldactivity and ICc spikes was assessed by spike-triggeredaveraging, and it was considered positive when it becameflat after “shuffling” the spike series, i.e., interchanging thespike intervals randomly (Fuentes et al., 1981). In order toanalyze the theta band power shifts, the power spectra beforestimulation rate changes were taken as the reference (100%).

The Student's t test was used for statistical validation ofthe observed changes immediately before and after thestimulation shifts. For this purpose, the number of temporalcorrelations present in the windows prior to the stimuluschange, i.e. the spontaneous phase locking, was considered asthe control cases and contrasted to the number of temporalcorrelations provoked by the stimulus changes.

Acknowledgments

We are grateful to ”Programa de Desarrollo de CienciasBásicas“ (PE.DE.CI.BA., Uruguay) for partial support.

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