Behavioural Brain Research 160 (2005) 236–249

Research report

Hippocampal theta activity related to elicitation andinhibition of approach locomotion

Harry M. Sinnamon∗

Neuroscience and Behavior Program, Wesleyan University, Judd Hall, 207 High Street, Middletown, CT 06459-0408, USA

Received 22 September 2004; received in revised form 4 December 2004; accepted 6 December 2004

Abstract

This study determined if the hippocampal theta rhythm showed phase relationships or changes in amplitude and frequency with the onsetof stimuli and locomotion in a task in which auditory cues initiated and suppressed approach locomotion. Rats with electrodes in the dorsalhippocampus lapped at a milk dipper and were presented a tone which predicted the delivery of a food pellet. In some trials the pellet cue tonewas negated by 60-Hz clicks beginning 0.3 s after onset, and no pellet was delivered. A video capture system (20-ms sampling) synchronizedto the hippocampal recording system (10-ms sampling) was used to determine the onset of locomotor approach to the pellet area. The findingsf on. Neithert lk lapping,t hen a non-n quency bya to processt©

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ailed to support proposals that phase-related mechanisms play a role in encoding and retrieval of movement-related informatihe pellet cue nor the negating cue reset the theta rhythm, and they did not produce differential evoked potentials. During miheta amplitude increased in the 1/2 s prior to all pellet cues regardless of their locomotor effect. Frequency also rose but only wegated pellet elicited short-latency locomotion. During locomotor execution, theta peak amplitude peaked earlier than theta frepproximately one period. In general during performance of this task, increasing theta amplitude reflected a general preparation

he cue and increasing theta frequency reflected the readiness to respond to the cue with locomotion.2004 Elsevier B.V. All rights reserved.

eywords:Theta; Hippocampus; Approach; Locomotion; Inhibition; Reward; Attention

There is general agreement that behavioral states char-cterized by prominent hippocampal theta activity are asso-iated with increased levels of information processing relatedo the control of behavior[4,14,38–40]. However, the mech-nisms used by the processes, the types of information pro-essed, and the circuitry implementing behavioral control allemain elusive. Particular interest has developed in the tem-oral and phase dynamics of the theta rhythm because of

he correspondence between theta frequencies and optimalarameters for long term potentiation[19,20,24]. Proposalsave been made for theta phase-related mechanisms both for

he encoding[21] and for the retrieval of movement-relatednformation [19]. If the theta rhythm does operate in thisay, it would be expected that phase-related patterns in theta

∗ Tel.: +1 860 685 2955; fax: +1 860 685 2761.E-mail address:hsinnamon@wesleyan.edu.

would be present for stimuli that are being encoded, orinitiate retrieval of conditioned movements. Consistentthis idea, resetting of the theta rhythm was found in scases with the presentation of an auditory cue that eliapproach behavior in a classical conditioning situation[9].Consistent resetting has been found for auditory cuesrequired processing in working memory and that controdifferential instrumental behavior[16].

The general relationship between theta activity and mment is well-established. Theta activity is prominent duthe performance of locomotor and orienting behaviorsis minimal during immobility and performance of repetitconsummatory and instrumental behaviors[5,15,36,41]inthe absence of postural adjustments[36]. Theta activity of alower frequency also appears during fear-related immobin the rat[30]. Synchronization of theta to movements corepresent either dependency on either the motor act o

166-4328/$ – see front matter © 2004 Elsevier B.V. All rights reserved.oi:10.1016/j.bbr.2004.12.006

H.M. Sinnamon / Behavioural Brain Research 160 (2005) 236–249 237

implicit sensory events related to it. Such movement-relatedphasing has been reported for sniffing[14,22,23]; and instru-mental bar pressing behavior[8,31]. Synchronization of thetarhythm to the onset of locomotion has not been reported, butless time-locked modulations of theta activity prior to loco-motion have been found. Theta frequency increases prior tothe rapid onset of locomotor behaviors in the behaving rat[25,37,41]. In the anesthetized rat, low frequency theta ac-tivity increases prior to the initiation of locomotion[32,34].It also appears prior to the initiation of a locomotor aversivemovement in competitive feeding situation[26].

The purpose of the present study was to specify the tem-poral dynamics of the relationship between theta activity andsensory and locomotor events in a task in which auditory cuesinitiate and inhibit approach. Specifically, the question waswhether a theta response to a cue was time-locked and couldbe described as rhythm resetting or synchronization, or alter-nately had a more graded modulated pattern. An analogousquestion was asked of theta patterns related to the onset ofapproach locomotion. The focus of the study was the thetaresponse to cues that inhibit approach locomotion. Althoughthe hippocampus appears to be involved in the processing ofsimple appetitive cues eliciting approach locomotion[7], a re-cent study[33] found no phase-related responses to auditorycues that elicited spatially directed locomotor approach. Oneof the earliest proposed functions[12] for the hippocampusi thisi tion[ oi ll-e s ofi ap-p odinga t thet werep e ana uer tion.N rim-p Thisp stop-s g.B edt wase h lo-c

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of 15–20 g up to a weight of 400 g. After preliminary training inthe test chamber, the rats were anesthetized by intraperitoneal in-jections of Nembutal (40 mg/kg). During surgery, anesthesia wassupplemented as needed by 10 mg/kg intraperitoneal injections ofNembutal. Eight 1-mm holes were drilled into the skull to receiveanchor screws and electrodes. The electrodes were twisted pairs ofTeflon-insulated stainless steel wires (125-�m diameter) with a ver-tical tip separations of 1.5 mm. They were placed bilaterally in thedorsal hippocampus at approximately 4.0 mm posterior to bregma,3.0 mm lateral to the midline, and at various depths but with the su-perficial pole always dorsal to CA1 cell layer. An uninsulated copperwire was wrapped around the anchor screws to serve as ground con-nection. The electrode wire terminated in Amphenol pins that wereinserted into a plastic strip secured to the skull with dental cement.The incision was infiltrated with Marcaine (0.5%), treated with top-ical antibiotics, and closed with a wound clip. The rat was returnedto ad libitum feeding for 5 days before resuming training.

1.2. Apparatus

1.2.1. Test chamberThe test chamber, illustrated inFig. 1, had a floor 61 cm× 25 cm

and sidewalls 35 cm high that slanted outward 15◦. The front wall(panel B) contained an acrylic window for the video camera (Hi-tachi Denshi KP-M2U, 6-mm lens). A stainless steel tube protrudedfrom a lower corner of the window to deliver a 45-mg food pelletto a circular tray recessed in the floor. The rat initiated the trial byuc . Int , anda f thet ccessh lk andw a 4-k abovet elletd e pre-s rials,t 0 Hz)b ; nop d thet ar ofs A).

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s the inhibition of behavior. Recent considerations ofdea have implicated the hippocampus in latent inhibi18], pre-pulse inhibition[3], the inhibition of attention tnterfering stimuli[10,29], and have reinterpreted the westablished spatial function of the hippocampus in term

nhibition[11]. Therefore, a cue suppressing well-learnedroach locomotion would be expected to engage the encnd control mechanisms of the hippocampus, and affec

heta generation processes related to locomotion. Ratsre-trained in a classical conditioning task to associatuditory cue with the delivery of a food pellet until the celiably produced approach locomotion to the pellet locaext, in certain trials a delayed negating cue was supeosed on the pellet cue, and the pellet was withheld.resentation procedure is a challenging variant of theignal paradigm[13] intended to maximize active encodinecause of its difficulty, the inhibition procedure allow

he comparison of trials in which the same negating cueither effective or not effective in suppressing approacomotion.

. Methods and materials

.1. Subjects and surgery

All surgical and testing procedures were approved by theeyan Animal Welfare Committee. Five Male Sprague–Dawleyred at Wesleyan University were housed on a 12:12 reversedycle in individual cages with ad libitum access to water. They wrovided a daily food pellet ration to produce a weekly weight

sing its forepaw to depress a clear acrylic treadle (3.5 cm× 24 cm)entered in the floor 24 cm in front of the front wall (panel A)he up position, the treadle protruded 1.3 cm above the floorn embedded light emitting diode (LED) was lit. Depression o

readle extinguished the LED, and raised a dipper through an aole in the floor to present 0.1 cc of sweetened condensed miater (1:1 by volume) for 1.36 s. When the dipper retracted,Hz tone at 65 dB was produced for 0.7 s by a speaker locatedhe camera window (panel B). On pellet trials (panel C), the pispenser was activated at the offset of the tone resulting in thentation of the pellet approximately 0.7 s later. On negation the speaker above the pellet cue speaker produced clicks (6eginning 0.3 s after the onset and continuing for its durationellet was delivered on these trials (panel D). The rat restarte

rial by turning away from the pellet area and entering the retall formed by two acrylic walls that lead to the treadle (panel

.2.2. Video recordingA frame grabber board (Data Translation 3152) capt

ingle monochrome video fields of 200× 148 pixels at ratf 50 fields/s. The video acquisition and storage was

rolled by a custom program (BEProbe) running on a sard PC (Dell Optiplex GT110). The program is availa

n binary executable and Visual Basic 6 source codet http://hsinnamon.web.wesleyan.edu/BEProbe.html. Each 5.12-

rial was associated with 256 frames.

.2.3. Analog recordingsA cable equipped with two dual operational amplifiers (LM

482) configured as voltage followers was connected to then the rat’s head. The other end terminated at a 9-channel sliounted on a counterbalanced arm. The paired outputs of thrational amplifiers were led to Grass P15 differential ampli

238 H.M. Sinnamon / Behavioural Brain Research 160 (2005) 236–249

Fig. 1. Schematic illustration of the test apparatus. In the self-paced trial, the rat entered the stall to depress an illuminated treadle and lapped at a milk dipperpresented for 1.36 s at a hole in the floor. On pellet trials (panel C), the retraction of the dipper was simultaneous with the onset of a 0.7-s, 4-kHz tone from thelower speaker. At the offset of the tone, a dispenser was activated and a food pellet exited the delivery tube to rest in the recessed tray approximately0.7 s later.The rat could initiate locomotor approach to the pellet either during or after the pellet cue. After obtaining the pellet, the rat entered the rear of the stall to startanother trial. On approximately half of the trials, a negating cue (clicks from the upper speaker) was superimposed on the pellet cue starting at 0.3 (panel D)and no pellet was dispensed. Correct behavior on these trials was suppression of locomotor approach to the pellet area and a direct turn to the rear of the stall.The depression of the treadle triggered two synchronized computers to acquire the data. One stored the current 64 video frames in a circulating bufferand thenstored the subsequent 192 frames; the other acquired the parallel analog measures at a sampling rate of 1 kHz, and stored them at a sampling interval of 100 ms.

and low and high half-amplitude filter settings at 1 and 30 Hz. AMicrostar DAP 2400 A/D board mounted in a separate computersampled these signals at 1 kHz, and to reduce the data storage de-mands, the digitized values were averaged over 10 samples to yieldan effective sampling rate of 100 Hz. An Analog Devices ADXL05accelerometer was mounted near the rat end of the recording cable.The single axis was oriented so that forward and upward move-ments produced upward deflections. Two force transducers (WPInstruments) mounted under a movable section of the floor in thestall registered the rat’s presence in the stall. These signals and the

various event markers were sampled similarly to the hippocampalactivity.

The video and A/D recording acquisition systems used contin-uously updated buffers containing 1.28 s of data. When the rat de-pressed the treadle, the two acquisition systems stored the data fromtheir buffers and then stored the next 3.84 s of their respective data.For each 20-ms video frame there were two values for each recordingchannel. Each was the mean of 101-kHz samples, one correspondedto the first 10-ms period and the other corresponded to the second10-ms period.

H.M. Sinnamon / Behavioural Brain Research 160 (2005) 236–249 239

1.3. Procedure

After surgery, the rats were pre-trained in multiple (range 9–19),20-min sessions, each approximately 40 trials, to enter the stall,depress the treadle, lap the milk, and approach the pellet area onpellet cue trials. To strengthen the association between the pelletcue and the pellet presentation, a portion of the trials were double-dipper trials in which the pellet cue was omitted, and instead ofa pellet delivery, the dipper was presented again. The number anddensity of double dipper trials was customized for each rat. Pre-training was complete when the rats consistently approached thepellet area on trials with the pellet cues and consistently remained atthe dipper during its absence on the double dipper trials. Subsequentrecording sessions (range 12–19) of trials with both pellet cues andnegated pellet cues provided the data for the study. The rats found itdifficult to withhold approach to the pellet area on negated trials. Tofacilitate training, trials with negated pellet cues after the first sessionwere presented consecutively until locomotion to the pellet area wassuppressed. Negated cue trials were limited to approximately 1/3of the total trials in a session to avoid generally extinguishing theapproach behavior to the pellet cue. Recordings from approximately24 trials were stored for each session; half were from negated cuetrials and included trials in which the rat both incorrectly approachedthe pellet area and correctly suppressed locomotion.

1.4. Histology

ought ev-e ans-v erev esw tson[

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wave activity were considered to show phasing relationships or syn-chronization if the peaks of the average exceeded 2 standard errorsof the mean (S.E.M.). Because averages of non-synchronous signalsapproach 0, plots of the average along with±2S.E.M. provides agraphic approximation of consecutive 1-sidedt-tests of the null hy-pothesis of no synchrony at a significance level <0.05. Averages ofpeak-by-peak measures were evaluated for trends around locomotorinitiation by repeated measures analysis of variance comparing val-ues at−400,−200 ms, and the values at +200 and +400 to the valuesat 0 ms. For trends around the onset of the cues where more reso-lution was needed, comparisons were made at intervals of 100 ms.Comparisons at specific time points were made by pairedt tests.

2. Results

2.1. Overview

Each of the five rats had bilateral electrodes which hada superficial pole dorsal to the CA1 cell layer of the dorsalhippocampus, and a deeper pole at variable depths, includ-ing the hippocampal fissure, CA4, CA3 dendritic area, anddendritic region of the dentate gyrus. The analysis here wasbased on one bipolar electrode selected for each rat as themost consistent theta through the trial. Representative hip-pocampal activity is shown in panel A ofFig. 2 which alsoshows the key behavioral and stimulus events in a pellet cuet ) ofh atedi nter-p triali ames pres-s ch tot imb( ntedt Thep per.T up-w n thes rom-e tedi fewf earedi es-o tely2 me1 pellet(

elletc area.I e, ap cting( panelE andt p att gating

The rat was given a lethal dose of Nembutal and perfused thrhe heart with normal saline followed by 10% Formalin. After sral weeks of additional fixation, the brain was sectioned trersely every 100�m with a vibratome. Unstained sections wiewed with a microscope at 40× magnification. Recording sitere localized with reference to the atlas of Paxinos and Wa

28].

.5. Analysis of hippocampal activity

Peak-by-peak measures of amplitude and frequency wereo relate theta activity to the onset of locomotor and stimulus evhe hippocampal record was transformed into standard scoresass filtered without phase lag between 4 and 14 Hz, andmoothed with a period 3 running average.

Filtering, without phase lag, was implemented on acquiredals by performing Fourier transforms on the records for eachtrial, setting the appropriate coefficients to 0, and performin

nverse transform. Positive peaks (relative positivity at the delectrode) above a selectable threshold were detected and thelitudes determined. Detection accuracy was checked visuallorrected manually.

The peak amplitude and inter-peak interval values were apend to make these records compatible with 10-ms sampling pf the analog records, they were interpolated. For the interpola

he amplitude and interval values of a peak were replicated for0-ms sampling period up to the next peak.

The onsets and offsets of behavioral events were determtime marked) primarily by inspecting replays of video frameuences, and as needed by inspecting the trajectories of maigitized points representing the nose, eyes and forepaws of thhe onset times provided indexes for excerpting the analog rend generating peri-event averages. Averages of hippocampa

-

rial. Positive peaks (deeper electrode relatively positiveippocampal activity filtered in the theta band are indic

n panel B, and the interpolated peak amplitudes and ieak intervals are shown in panels C and D. The 5.12-s

ncluded 256 frames each of 20-ms duration. In the first frhown (50) the rat entered the rear of the stall (note deion in force plate record, panel J), and began the approahe treadle to start a trial. At frame 62, the rat’s right forelRt FL) contacted the treadle (panel K) and the rat orieo begin lapping (panel E) at the milk dipper (panel N).ellet cue occurred (panel M) at the retraction of the diphe rat initiated locomotor approach to the pellet with anard head movement (frame 152) that was apparent iingle frame inspection and well reflected in the acceleter record (panel F). The initiation was not well reflec

n the horizontal movement (panels G and H). Withinrames, the accelerating rightward head movement appn the horizontal velocity (panel H) and later in the lower rlution horizontal displacement (panel G). Approxima00 ms later, the rat lifted the left forelimb (arrow, fra62) to begin the stepping phase of the approach to theframe 167).

Fig. 3 shows a representative trial with a negated pue in which the rat suppressed locomotion to the pelletn addition the rat showed withdrawal from the treadlattern appearing only in negated cue trials. After contaframe 60) and depressing the treadle, the rat lapped () at the milk dipper (panel N). After the dipper retracted

he pellet cue occurred (panel M), the rat continued to lahe access hole (panel E). The rat responded to the ne

240 H.M. Sinnamon / Behavioural Brain Research 160 (2005) 236–249

Fig. 2. Representative pellet trial showing behavioral measures, hippocampal activity measures, and stimulus events. Five video frames selected from the 256frames in the 5.12-s trial show behaviors leading to the approach to the pellet (Rt FL, right forelimb). (Panel A) Hippocampal activity high pass filtered at 4 Hz.(Panel B) positive peaks in smoothed band pass (4–14 Hz) activity. (Panels C and D) Peak-by-peak amplitude of positive peaks and inter-peak interval,valuesinterpolated from left to right. (Panel E) Manually digitized record of tongue protrusions at the milk dipper. (Panel F) Accelerometer trace, upwardand forwardmovements produce upward deflections. (Panels G and H) Manually digitized trajectory and velocity of the left eye on the horizontal plane. (Panel J) Forceplate in stall, note the depression when the rat enters the stall prior to frame 50 and the elevation when the rat has left to approach the pellet around frame 167.(Panels K–P) Stimulus event markers.

cue (panel P) by making a rightward head movement (HM,frame 158), followed by a succession of steps (frames 187,199, 220) back into the stall reflected in the depression in theforce plate record (panel J).

Suppressing locomotion to the pellet area on the negatedpellet cue trials was difficult, and no rat showed completemastery of the task. In pretraining the rats had been presentedwith pellet cues exclusively associated with the pellets, andin the negated cue recording sessions, the majority of trialsinvolved non-negated pellet cues followed by pellet delivery.Despite the difficulty, all rats showed indications that theywere attending to the negating cue and responding appro-

priately with suppression of approach locomotion on sometrials. Fig. 4, panel A shows the proportion of trials withnegated pellet cues in which the rats approached the pelletarea. In the first session, the rats were generally unrespon-sive to the negating cue, persisting in approach, but by thelast three sessions, all had increased the proportion of trialswithout approach (median = 0.51, range: 0.50–0.73). Whenthe pellet cue was not negated, all rats continued to approachthe pellet area on virtually every trial. Panel B shows thatfour of the five rats showed an increase in backward loco-motion from the treadle on negated cue trials. Withdrawalbehavior never occurred on non-negated trials. It persisted

H.M. Sinnamon / Behavioural Brain Research 160 (2005) 236–249 241

Fig. 3. Representative negated cue trial. The selected video frames show suppression of locomotor approach to the pellet and withdrawal from the treadleduring the negating cue (Rt FL, right forelimb; HM, head movement, Lt FL, left forelimb). Other panels as inFig. 2except panel (P) which indicates a negatingcue.

despite the delay it caused in the starting of the next trial,as the rat could enable the treadle only by returning to thefront of the stall, locomoting around the stall, and entering itfrom the rear. Panel C shows redirected locomotion, anotherbehavior that only appeared on negated pellet cue trials. Itwas a short-latency approach that veered away from the pel-let area during the negating cue. Redirected locomotion in-creased in frequency for all rats with continued experiencewith the negating cue. The absence of complete locomotorsuppression with the negated cue was useful because it pro-vided trials in which the negating cue was not effective forcomparison to trials in which the cue suppressed locomotion.The qualitative indexes illustrated inFig. 4were more effec-tive in showing the development of locomotor suppressionby the negating cue than was the latency of locomotor initi-

ation. It was anticipated that after pretraining with the pelletcue alone, the rats would initiate locomotion within 0.3 msof the cue and then after experience with the negating cue,they would progressively delay locomotion until the negatingperiod had passed. Contrary to expectation, all rats showed avariety of latencies throughout the training with the negatingcue.

2.2. Hippocampal activity related to pellet and negatingcues

To relate hippocampal activity to locomotion and cues inthis task, trials with similar locomotor behaviors were com-bined across sessions. Thus, pellet cues were classified interms of the time that the locomotion to the pellet occurred.

242 H.M. Sinnamon / Behavioural Brain Research 160 (2005) 236–249

Fig. 4. Increase in behaviors related to locomotor suppression in five subjectswith experience with a negating cue superposed on a pellet cue. Comparisonto behavior in the first session with the negating cue to the mean of the lastthree sessions. (A) Approach locomotion to the pellet area. (B) Backwardlocomotion from the treadle (withdrawal). (C) Redirected locomotion, short-latency approach that veered away from the pellet area during the negatingcue.

Locomotion initiated within 0.3 s of the onset of the pelletcue, i.e., prior to the time that the negating cue could haveoccurred, represents maximal locomotor activation by thepellet cue. InFig. 5, pellet cues with this short latency lo-comotion are represented by the thick lines. In panels E andF, the accelerometer (Accel) (thick lines) show the rise asso-ciated with the locomotor head movement first appearing dur-ing the period before negation period (arrow) and becomingmore prominent during the negation period. The force platetraces rose later as the subsequent stepping of the hindlimbsmoved the rat out of the stall. The short latency trials werecompared to trials in which locomotion appeared at longerlatencies, i.e., during the negation period (panels A and C),and after the negation period (panels B and D). Locomotionoccurring during the negation period (in the absence of thenegating cue) reflects weaker activation of locomotor initia-tion; it is represented on the left side ofFig. 5. Locomotionafter the offset of the pellet cue reflects the weakest activa-tion of locomotor activation; it is represented on the rightside of Fig. 5. The values at 100-ms intervals for each ofthe slower locomotion conditions were compared to the fastlocomotion condition by two-way analysis of variance, withrepeated measures over time, followed by individual pairedt tests.

Theta amplitude progressively rose within the 0.5 s pe-riod prior to all pellet cues. During this time, the dipper wasp n inF gat-i intot withr wasi ntin-u was

initiated after the pellet cue, the rise in amplitude stoppedand maintained a lower level throughout the pellet cue(panel B).

Inter-peak intervals decreased prior to onset of the cuesthat elicited shorter latency locomotion either before or dur-ing the negation period (Fig. 5, panel C). The pre-onset de-cline was not present when the locomotion occurred after thecue offset (panel D). The inter-peak intervals prior to cueswhich elicited locomotion during the negation period (panelC) were generally lower but the differences were small andnot significant for any of the individual comparisons.

After the onset of the pellet cue, inter-peak interval de-creased according to the elicited locomotor patterns. Whenlocomotion started prior to the negating period (panel C), thedecline that begun prior to cue onset continued. When lo-comotion started during the negating period, the decline re-versed and then resumed (panel C). When locomotion startedafter the pellet cue offset, the decline was not apparent duringthe pellet cue. These patterns indicate that theta amplitudegenerally, and theta frequency more selectively, increasedprior to an expected cue that elicited locomotion. After onsetof the cue, the time course of theta amplitude and frequencytracked the execution of locomotion.

For negated pellet cues, trials in which locomotion to thepellet area was absent reflects maximal suppression of lo-comotor initiation. They provide the reference and are rep-rs sup-pa flectl e lefts tedp or tot sup-p panelA sed,t levelt cor-r imi-l ega-t reda ed al thes a re-v litudea

r tot n lo-c itudeo ualc nseti com-p t la-tp n ofl

resent and the rats continued to lap the milk. As showig. 5, panel A, when locomotion started prior to the ne

ng period, the pre-cue amplitude rise continued steeplyhe pellet cue period to reach a maximum associatedapid phase of the locomotion. When the locomotionnitiated during the negation period, the pre-cue rise coed more slowly (panel A), and when the locomotion

esented by heavy lines inFig. 6. Trials with locomotiontarting after the negating cue reflects lesser locomotorression and are represented on the right side ofFig. 6. Tri-ls with locomotion starting during the negating cue re

east locomotor suppression and are represented on thide ofFig. 6. Similar to the pattern found for non-negaellet cues, amplitude rose during the 0.5-s period pri

he negated cues regardless of whether locomotion wasressed, or whether it started during the negating cue () or after it (panel B). When locomotion was suppres

he rise stopped prior to the negating cue and remainedhroughout the negating cue. When locomotion was inectly initiated during the negating cue, the pattern was sar but there was small continuation of the rise into the nion period (panel A). When incorrect locomotion occurfter the offset of the negating cue, amplitude maintain

evel throughout the negation cue that was lower thanuppressed locomotion case. Note that this pattern iserse of the general positive association between ampnd locomotion.

Inter-peak interval did not show pre-onset trends priohe negated pellet cues, but it was generally lower wheomotion was suppressed (panels C and D). The magnf the difference was small, with only one of the individomparisons significant (panel D). However, the pre-onter-peak intervals on suppressed trials were also lowared to the trials with non-negated cues eliciting shor

ency locomotion (F(1,76) = 17.70,P< 0.001;Fig. 6). Thisattern is a reversal of the general positive associatio

ower inter-peak intervals with locomotion.

H.M. Sinnamon / Behavioural Brain Research 160 (2005) 236–249 243

Fig. 5. Theta peak amplitude and inter-peak interval averaged around the onset of non-negated pellet cues that elicited locomotion at different latencies. Meansof five rats. The reference condition, represented by thick lines in each panel, is the cue eliciting locomotion within 0.3 s of onset, i.e., prior to thenegatingperiod. Circles and triangles, 100-ms points of comparison. Filled, significant difference (pairedt-test,P< 0.05) from the corresponding mean for the referencecondition. The dashed vertical lines represent, respectively, the onset of the pellet cue, and the onset and offset of the negation period. (A) Thin line, meantheta amplitude around a pellet cue eliciting locomotion within the potential negation period at latencies (0.3–0.7 s). Pre-onset increase over time for both cueswas significant (F(9,76) = 4.21,P< 0.001) and similar in pattern (F(9,76) = 0.51,P= 0.87). Post-onset time course of two conditions differed (F(9,76) = 9.67,P< 0.001), (B) Thin line, mean theta amplitude for trials in which locomotion to the pellet area appeared after the offset of the pellet cue (after the potentialnegating cue). Pre-onset increase over time for both cues was significant (F(9,76) = 2.61,P= 0.01) and similar in pattern (F(9,76) = 1.06,P= 0.40). Post-onsettime course of two conditions differed (F(9,76) = 4.35,P< 0.001). (C) Mean theta inter-peak intervals for cues eliciting locomotion during the negation period(thin line) compared to cues eliciting locomotion earlier (thick line). Pre-onset, the cue eliciting locomotion during the negation period was generally lower(F(1, 76) = 21.22,P< 0.001) but none of the individual differences were significant. Both cues showed a decrease leading up to onset (F(9,76) = 2.45,P= 0.01)that was similar (F(9,76) = 0.54,P= 0.83). Post-onset, the time course for the two cues differed (F(9,76) = 9.67,P< 0.001). (D) Mean inter-peak intervals forcues eliciting post-offset locomotion compared to earlier locomotion. Pre-onset, no differences between cues (F(1,76) = 0.68,P< 0.41), and no trend over time(F(9,76) = 1.60,P= 0.13). Post-onset, time course for the two cues differed (F(9,76) = 3.21,P= 0.002). (E and F) Mean accelerometer (Accel) and force platemeasures for a representative rat for the three cue conditions. Arrows indicate start of rise of accelerometer trace associated with the onset of locomotion.

Hippocampal slow wave activity was averaged to deter-mine if cues which controlled locomotion produced differ-ential evoked responses or synchronization of theta activity.Fig. 7shows the averages for the five recording sites aroundthe onset of pellet cues eliciting short latency locomotion(left panels) and pellet cues with a superimposed negatingcue which suppressed locomotion (right panels). The verti-cal dashed lines indicate the pellet cue onset and the bound-aries of the negating period. Consistent evoked responses tothe onset of any cue were infrequent and none differentiatedthe cues with different locomotor responses. For example,

one site (vt 52-2, panels C and D) in which the deep elec-trode was located in the dendritic region of the dentate gyrusshowed a prominent evoked response to the onset of the pelletcue. It showed similar waveforms in response to non-negatedpellet cues that elicited locomotion at various latencies andto effective and non-effective negated pellet cues.

Averages for effective negating cues are shown in the rightpanels ofFig. 7. Synchronization of theta activity, indicatedby peaks exceeding the 2S.E.M. limits, was found but re-lations to the properties of the cues showed no consistentpattern among the sites. Of particular interest, there were no

244 H.M. Sinnamon / Behavioural Brain Research 160 (2005) 236–249

Fig. 6. Theta peak amplitude and inter-peak interval averaged around the onset of a pellet cue with a superimposed negating cue. Means of five rats, formatsimilar toFig. 5.The reference condition represented by the thick lines includes trials in which the negating cue effectively suppressed locomotion to the pelletarea. (A) Averaged peak amplitude around cues in which incorrect locomotion occurred during the negating cue (thin line) compared to cues with correctlysuppressed locomotion (thick line). Pre-onset, cues did not differ (F(1,76) = 0.62,P= 0.43), and showed increasing trends (F(9,76) = 2.47,P= 0.01) that weresimilar (F(9,76) = 1.48,P= 0.17). Post-onset, overall differences between cues not significant (F(1,76) = 0.07,P= 0.80), and the trend over time (F(9,76) = 2.47,P= 0.01) was similar (F(9,76) = 1.48,P= 0.17). (B) Averaged peak amplitude averaged around cues in which incorrect locomotion occurred after the offsetof the negated cue (thin line) compared to cues with correctly suppressed locomotion (thick line). Pre-onset, cues did not differ (F(1,76) = 0.44,P= 0.51),and showed increasing trends (F(9,76) = 8.47,P< 0.001) that were similar (F(9,76) = 0.35,P= 0.96). Post-onset, amplitude generally lower when locomotionoccurred after the cue (F(1,76) = 21.15,P< 0.001), and no significant trend over time (F(9,76) = 1.53,P= 0.15). (C) Averaged inter-peak interval for cues withincorrect locomotion during the negating cue (thin line). Pre-onset, inter-peak interval generally lower when locomotion was suppressed (F(1,76) = 12.95,P< 0.001) and neither cue showed significant trend (F(9,76) = 1.52,P= 0.16). Post-onset, the trend over time for two conditions differed (F(9,76) = 4.93,P< 0.001). (D) Averaged inter-peak interval for cues with incorrect locomotion after the negated cue (thin line). Pre-onset, inter-peak interval generally lowerwhen locomotion was suppressed (F(1,76) = 5.38,P= 0.02) and neither cue showed significant trend (F(9,76) = 0.65,P= 0.75). Post-onset, inter-peak intervalgenerally lower when locomotion was suppressed (F(1,76) = 7.04,P= 0.009), and both conditions showed a decline (F(9,76) = 2.35,P= 0.02) that was similar(F(9,76) = 0.42,P= 0.92). (E and F) Averaged accelerometer (Accel) and force plate traces for one rat. Arrows indicate start of rise of accelerometer tracesassociated with the onset of locomotion.

indications that the onset of the effective negating cue pro-duced a resetting or synchronization of the theta pattern. Theright panels ofFig. 7show these averages. One site (vt62-1,panel K) showed synchronization during the locomotor sup-pression by the negating cue. However, the synchronizationstarted prior to the onset of the negating cue, and also ap-peared prior to correct and incorrect locomotion. Finally, av-erages around the negating cues producing withdrawal fromthe treadle, arguably the most extreme suppressive response,showed no indication of phase relations. These patterns indi-

cate that the cues controlling the initiation and suppressionof locomotion in this task did not produce differential evokedresponses or synchronization of theta activity.

2.3. Hippocampal activity related to locomotor initiation

Locomotor approaches to the pellet area were classifiedaccording the type of cue (non-negated and negated) and ac-cording to latency (prior to, during and following the negat-ing period). The various locomotor bouts produced simi-

H.M. Sinnamon / Behavioural Brain Research 160 (2005) 236–249 245

Fig. 7. Averaged hippocampal activity (high pass filtered 4 Hz) around theonset of pellet cues eliciting short latency locomotion (left panels) andpellet cues with a superimposed negating cue that suppressed locomotion(right panels). The points above and below the averages indicate 2 stan-dard errors of the mean (S.E.M.) above and below 0. (A–K) Each rowrepresents averages for one recording site for the two conditions. (L andM) Accelerometer (Accel) and force plate averages for rat vt62. The ver-tical dashed lines indicate the onset of the pellet cue, and the negatingperiod.

lar accelerometer and force plate recordings (Fig. 8, panelsL–Q). The leftmost panels ofFig. 8 show theta amplitudeand inter-peak intervals around the shortest latency locomo-tion which was initiated prior to the negating period. Thetaamplitude increased (panel A) and inter-peak interval de-

creased (panel F) in the 0.5 s period prior to the onset ofthis rapid onset locomotion, and the trends continued dur-ing the execution. All types of locomotion showed the gen-eral pattern of an increase in amplitude (panels B–E) and adecrease in inter-peak interval (panels G–K) during execu-tion. These patterns indicate that amplitude and frequencyof theta activity did not differentiate between correct and in-correct locomotion in this task. The pre-locomotor decreasein inter-peak interval was found for only the short-latencylocomotion elicited prior to the negation period. Note thatthe period prior to this short-latency locomotion overlappedthe period prior to the onset of the pellet cue. As shown inFig. 5, the amplitude rise and inter-peak interval decline priorto this type of approach began in the period prior to the pelletcue.

In Fig. 8, the time courses of the changes in amplitudeand inter-peak interval were similar for the various typesof locomotion. Amplitude peaked closely in time with themaximal acceleration of the locomotor approach and inter-peak interval reached a minimum at a later point. This lag ofinter-peak interval relative to amplitude was tested by com-paring the times of the peaks in the accelerometer record,theta amplitude, and theta inter-peak interval. For each rat,the three values were averaged for the five types of loco-motor bouts.Fig. 9 shows that the maximum in the ac-celerometer record appeared at approximately 150 ms aftert ituder nots r-v starto ax-i m( r allo

on-s e ex-a n orr oo geste anelsA nseto anelE therc d inF inga ioni ngesi siteso mo-t

3

re-l oth

he onset of the locomotor head movement. Theta ampleached its maximum less than 50 ms later which wasignificantly longer (t(4) = 1.19,P= 0.30). Inter-peak inteal reached a minimum approximately 300 ms after thef locomotion which was later than the accelerometer m

mum (t(4) = 6.97,P= 0.002) and the amplitude maximut(4) = 2.62,P= 0.06). The differences were consistent fof the recording sites.

Hippocampal slow wave activity averaged around theets of the various classes of locomotor approach wermined for indications of phase relations, synchronizatioesetting of theta activity.Fig. 10provides examples for twf the recording sites. Site vt52-2 which displayed the larvoked response to the pellet cue onset is illustrated in p–E. It showed a synchronized pattern following the of correct approach (panel D) and incorrect approach (p) to the pellet area but no sustained pattern in the oonditions. Site vt62-1 which had theta records illustrateigs. 1 and 2showed no indication of synchronization durny of the locomotor types. Overall, initiation of locomot

n this task was not associated with phase-related chan theta activity that were consistent across recordingr consistently differentiated between the classes of loco

ion.

. Discussion

This study determined how hippocampal theta activityated to cue events and locomotion in a task involving b

246 H.M. Sinnamon / Behavioural Brain Research 160 (2005) 236–249

Fig. 8. Theta peak amplitude and inter-peak interval averaged around onset of the onset of the locomotor head movement initiating the approach to the pelletarea. Mean of five recording sites. The left panels (A, F, and L) represent short-latency (<0.3 s) locomotion initiated prior to the potential negatingcue.Panels B, G, and M: locomotion on pellet trials initiated correctly during the period when the negating cue could have occurred but did not. Panels C, H,and N: incorrect locomotion initiated during the negating cue. Panels D, J and P: locomotion correctly initiated after the offset of non-negated pellet cue.Panels E, K, and Q: incorrect locomotion initiated after a negated pellet cue. The average traces are bracketed by±1 standard error traces. Filled circlesindicate significant differences before or after the onset tested by analysis of variance at 200-ms intervals. (A) Pre-onset:F(2,8) = 8.50,P= 0.01; (B) pre-onset:F(2,8) = 5.84,P= 0.03; (C) pre-onset:F(2,8) = 8.46,P= 0.01; (D) pre-onset:F(2,8) = 11.82,P= 0.004; (E) pre-onset:F(2,8) = 6.21,P= 0.024; (F) pre-onset:F(2,8) = 4.38,P= 0.05; post-onset,F(2,8) = 20.95,P= 0.001; (G) post-onset:F(2,8) = 134.69,P< 0.001; (H) post-onset:F(2,8) = 24.28,P< 0.001; (J) post-onset:F(2,8) = 30.36,P< 0.001; (K) Post-onset:F(2,8) = 21.58,P= 0.001. (Panels L–Q) Accelerometer and force plate records averaged for one rat (vt62). Numberof trials for the five rats in each condition: (A and F) 47, 73, 59, 108, 37; (B and G) 95, 45, 57, 21, 39; (C and H) 47, 56, 35, 19, 55; (D and J) 34, 25, 13, 11,24; (E and K) 23, 40, 29, 14, 21.

Fig. 9. Comparison of times following the onset of locomotion for the maxi-mum in the accelerometer record, the maximum in theta peak amplitude andthe minimum in the theta inter-peak interval. Each data point is the mean(±1S.E.M.) of five rats. The value for each rat was the mean collapsed overthe five types of locomotor bouts. The number of trials for each case is givenin the caption forFig. 8.

the initiation and suppression of well-learned approach lo-comotion. The absence of specific responses to the cue con-sistently associated with a food pellet was not surprising.However, the putative role of the hippocampus in behav-ioral inhibition suggested that theta activity would selec-tively respond if the pellet cue was negated by a delayedsuperimposed cue never associated with the pellet. The thetarhythm did not synchronize either to the pellet cue whenit could be negated or to the negating cue itself. Theta ac-tivity was present throughout the trial although amplitudeand frequency were relatively low during milk lapping. Dur-ing milk lapping, starting at approximately 0.5 s prior to theonset of pellet cues, theta amplitude and frequency showedanticipatory changes. Average amplitude increased prior toall cue conditions but frequency increased only when a non-negated pellet elicited locomotion at shorter latencies. Fol-lowing the onset of the cues, both theta peak amplitude andfrequency depended on whether and when locomotion wasexecuted or suppressed. Both amplitude and frequency in-creased with the execution of locomotion, but increases in

H.M. Sinnamon / Behavioural Brain Research 160 (2005) 236–249 247

Fig. 10. Averaged hippocampal activity (high pass filtered 4 Hz) around the onset of locomotion. Locomotion conditions same asFig. 8. Recording sites andformat same asFig. 7.

theta peak amplitude peaked earlier. These results indicatethat changes in theta patterns in this inhibition task werenot closely time-locked to the stimulus or behavioral events.Rather, they appeared to be graded modulations in amplitudeand frequency related to the preparation for, and execution of,movement.

Consistent with related work[33], theta activity was nearlycontinuous throughout the trial with modulations of ampli-tude and frequency during the various behavioral sequencesin the trial, which included approach to the treadle, lappingof the milk, orientation and locomotor approach to the pelletarea. Although the theta rhythm did not reset or consistentlysynchronize with any of the stimulus or locomotor events,amplitude and frequency changed prior to the cue onsets,and therefore theta activity was sensitive to the features of thetask. A recent study[42] that found changes in theta powercorresponding to transitions in instrumental behavior gener-ally similar to the present patterns also did not report cuerelated phasic changes in theta activity. The factors requiredfor a cue to reset or synchronize theta activity appear not tobe present in this situation even though it incorporated sev-eral of the information processing functions proposed for thehippocampus. When optimally performing the task, the ratwithheld approach at the onset of the pellet cue, waited fora possible negating cue, and selected either an approach oran alternative to it. Performance would seem to involve at-t nses f thisd ma-t ions.

It seems that these factors are not sufficient for an approachcue or a negating cue to reset or synchronize the theta rhythm.The specification of factors that differentiate tasks in whichcues produce resetting ([16,17,24]and tasks in which cues donot [33,42] will further understanding the function of thetaactivity.

The negating cue used here was behaviorally effectiveand the absence of resetting can not be due to its lack ofsalience. Other types of inhibitory cues, perhaps those re-quiring working memory[17], would produce a resetting oftheta activity. A factor that could work against producingtheta resetting tendency to develop response predispositions.The rats frequently appeared to enter a trial with a move-ment program pre-selected on the basis of the outcomes ofrecent trials. Tasks structured to minimize the opportunity topre-program responses might minimize theta activity priorto the cue onset and accordingly increase the likelihood ofresetting. Vinogradova[39] has proposed that sustained thetaassociated with focused attention is resistant to resetting andrepresents the filtering out of distracting information. An-other factor possibly working against resetting is that a risein theta amplitude (and in some trials frequency) occurredprior to the onset of the predictable pellet cue. If cue on-set were unpredictable, the increase in theta amplitude orfrequency might be sufficiently abrupt to be characterizedas resetting. Until research supports these conjectures, thea tivityd od-u tion.A the

ention, working memory, inhibitory control, and respoelection. Moreover, the absence of complete mastery oifficult task makes it reasonable to infer that active infor

ion processing occurred throughout the recording sess

vailable evidence leads to the conclusion that theta acuring performance of a behavioral inhibition task is mlated by processes that have relatively low time resolut least in this task, theta activity did not seem to reflect

248 H.M. Sinnamon / Behavioural Brain Research 160 (2005) 236–249

processing of higher time resolution phasic events like cueonset.

Theta amplitude rose prior to the onset of the pellet cuesthat elicited locomotion at short and long latencies and priorto negated pellet cues which suppressed locomotion. There-fore, the pre-onset amplitude trends did not predict the behav-ior evoked by the cue. The rise in amplitude appeared duringcontinuous milk lapping, and appears to reflect expectancyof cue onset rather than specific movements.

The half-second period in which it occurred correspondsto approximately two to three theta cycles at the frequencytypical during lapping of milk. This finding is consistent withthe idea that the theta rhythm is involved in the coding ofsensory information that is relevant to preparation for move-ment. In cats tested in an omitted stimulus paradigm, ris-ing expectancy was associated with an amplitude increasein the theta components of the response to a cue that pre-dicted the onset of a significant period[2]. In rats, thetapower increases appeared prior to a bar press which initi-ated discriminatory cues to which the rats were uncertain ofthe appropriate response but not when the cues were welllearned[42]. In the present study, theta frequency also roseduring the pre-onset period but only in trials in which a non-negated pellet elicited locomotion at shorter latencies. Fre-quency did not rise prior to the cue onset in trials in whichthe cue elicited locomotion at longer latencies or when then here-f ulda thatt ationt re-fl otion[

t ap-p h thes truc-t theo tivei itht theo cue.T thatc cili-t ing.I torc ntingb ighert

peaka otionw encyi ncyw e be-g tionw r on-s pli-

tude was maintained at a higher level on trials with locomotorsuppression compared to trials with incorrect locomotion af-ter the offset of the cue. With the inhibition of conditioned ap-proach, various search behaviors emerge[35], and it is likelythat these alternatives to locomotion also would be associatedwith theta activity. Further studies of locomotor suppression,should differentiate the suppression of approach locomotionassociated with immobility versus that associated with alter-native active behaviors such as orienting and the redirectedlocomotion which restarts the trial.

With the execution of locomotor approach, the timecourses of increases in theta peak amplitude and forwardacceleration were similar whereas the increase in theta fre-quency peaked later. The lag of frequency relative to ampli-tude corresponded to approximately one theta cycle. Differ-ent sensitivity and recovery time courses for theta amplitudeand frequency after reversible lesions have been described[6,27]. Differences in the short-term time courses of the twotheta parameters apparently has not been explicitly reported,but a similar pattern is apparent in the time course of thetaactivity with locomotor onset described in the cat[1]. Sev-eral features of the amplitude–frequency difference need tobe clarified. One is the degree to which the times of the peaksare determined by the kinematics of the locomotion. In thisstudy, the locomotor episodes were of short duration, in-volving only a few steps to reach the pellet, and thereforet eaters ilityi t theg r-t thee am-p gard-l easesi om-b deo estsd ion.C tfi on-s denti withtc ssingm back,a uggestt longa

A

ant.T man,B ntri-b

egating cue effectively suppressed approach. It may tore reflect the activation of initiation processes that wontagonize suppression. Overall, the patterns indicate

he rise in theta amplitude reflected a general preparo process the cue[42], and the rise in theta frequencyected the readiness to respond to the cue with locom4].

The changes in theta amplitude and frequency thaeared prior to the onset of the pellet cue reflected bottructure and the ordering of the trials. The trials were sured so that a fixed period of milk lapping precedednset of the pellet cue. It was effective in producing rela

mmobility and a low baseline level of theta activity. Whe dipper fixed in duration and always terminating withnset a pellet cue, the rats could predict the onset of thehe detection of rises in theta amplitude and frequencyorrelated with the anticipation of the cue onset was faated by the low baseline theta activity during milk lappn a related study[33] that also used predictable locomoues but did not find these pre-onset trends, overt orieehavior was present and baseline theta activity was h

han the present study.Following the onset of the cues, the patterns of theta

mplitude and frequency depended on whether locomas executed or suppressed. Both amplitude and frequ

ncreased with the execution of locomotion. When the lateas short, the locomotor-related trends continued thosun prior to the onset of the pellet cue. When the locomoas delayed, the pre-onset trends leveled until locomotoet. One finding did not fit this straightforward pattern: am

he apparent earlier peak in amplitude could reflect a grensitivity of amplitude to deceleration. Another possibs that amplitude reduction corresponds to the arrival aoal of the approach[42]. A fundamental question for fu

her work is how amplitude and frequency covary duringxecution of a range of behavior patterns. In this study,litude increases appeared prior to the onset of cues re

ess of their behavioral effects, whereas pre-onset incrn frequency were related to the subsequent behavior. Cined with this finding, the temporal priority of amplituver frequency with the execution of locomotion suggifferent functions for amplitude and frequency modulatonsistent with sensory-oriented theories[29,39]and recenndings[42], the anticipatory changes in amplitude are cistent with a role in attention and in processing antecenformation such as feed-forward signals. Consistenthe sensorimotor theory of Bland and Oddie[4], the lagginghanges in frequency are consistent with a role in proceovement-related information such as reafference, feednd consequences. In general, the patterns observed s

hat theta amplitude and frequency might differentiate acognitive-motor dimension.

cknowledgements

Supported by a Wesleyan University Program grhanks to Esther Schlegel, Leah Pransky, Seth Shipruce Strickland, David Boule, and Greg Pare for coutions to this work.

H.M. Sinnamon / Behavioural Brain Research 160 (2005) 236–249 249

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