Beta2 oscillations (23 30 Hz) in the mouse hippocampus ... · Beta2 oscillations (23–30 Hz) in the mouse hippocampus during novel object recognition Arthur S. C. Franc a,1,2 George

Beta2 oscillations (23–30 Hz) in the mouse hippocampusduring novel object recognition

Arthur S. C. Franc�a,1,2 George C. do Nascimento,3 V�ıtor Lopes-dos-Santos,1 Larissa Muratori,1 Sidarta Ribeiro,1

Bruno Lob~ao-Soares4 and Adriano B. L. Tort11Brain Institute, Federal University of Rio Grande do Norte, Natal, RN 59056-450, Brazil2Edmond and Lily Safra International Institute of Neuroscience of Natal, Natal, Brazil3Department of Biomedical Engineering, Federal University of Rio Grande do Norte, Natal, Brazil4Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, Brazil

Keywords: brain rhythms, in vivo electrophysiology, local field potential, novelty, spectral analysis

Abstract

The oscillatory activity of hippocampal neuronal networks is believed to play a role in memory acquisition and consolidation. Particu-lar focus has been given to characterising theta (4–12 Hz), gamma (40–100 Hz) and ripple (150–250 Hz) oscillations. Beyond thesewell-described network states, few studies have investigated hippocampal beta2 (23–30 Hz) activity in vivo and its link to behaviour.A previous sudy showed that the exploration of novel environments may lead to the appearance of beta2 oscillations in the mousehippocampus. In the present study we characterised hippocampal beta2 oscillations in mice during an object recognition task. Wefound prominent bursts of beta2 oscillations in the beginning of novel exploration sessions (four new objects), which could be readilyobserved by spectral analysis and visual inspection of local field potentials. Beta2 modulated hippocampal but not neocortical neu-rons and its power decreased along the session. We also found increased beta2 power in the beginning of a second exploration ses-sion performed 24 h later in a slightly modified environment (two new, two familiar objects), but to a lesser extent than in the firstsession. However, the increase in beta2 power in the second exploration session became similar to the first session when we phar-macologically impaired object recognition in a new set of experiments performed 1 week later. Our results suggest that hippocampalbeta2 activity is associated with a dynamic network state tuned for novelty detection and which may allow new learning to occur.

Introduction

The relation between neuronal oscillations and behaviour has beenthe focus of many studies over recent decades. Although alsodetected at the single-neuron level (Kamondi et al., 1998), neuronaloscillations are typically studied at the mesoscopic scale of localfield potentials (LFPs; Buzsaki & Draguhn, 2004; Buzsaki, 2006),which represent the activity of an ensemble of nearby neurons (Buz-saki, 2004; Linden et al., 2011; Buzsaki et al., 2012; Reimannet al., 2013). In the hippocampus, many studies have focused on therole of theta (4–12 Hz; Vanderwolf, 1969; Winson, 1978; Buzsaki,2002), gamma (30–100 Hz; Csicsvari et al., 2003; Montgomery &Buzsaki, 2007; Colgin et al., 2009), high-frequency (110–160 Hz;Scheffer-Teixeira et al., 2012; Tort et al., 2013) oscillations, andsharp-wave associated ripples (150–250 Hz; Buzsaki et al., 1992;Girardeau et al., 2009; Ego-Stengel & Wilson, 2010), in differentbehaviours and cognitive states. In addition, Berke et al. (2008)have called attention to prominent bursts of 23- to 30-Hz oscilla-tions that appear in CA1 and CA3 when mice explore novel envi-ronments. This rhythm, referred to as beta2 oscillations, has beenshown to modulate hippocampal neurons and to depend on NMDA

transmission (Berke et al., 2008), which is known to be importantfor rapid learning (Nakazawa et al., 2003). Grossberg (2009) sug-gested that beta2 oscillations provide a transient plasticity signalable to solve the stability–plasticity dilemma, by which the abilityof a neuronal network to learn rapidly must be compatible with sta-ble memory representations without catastrophic forgetting (Gross-berg, 1980, 1999, 2009).The beta2 oscillations reported in Berke et al. (2008) are visible

in unfiltered LFPs and, actually, may have amplitude similar to thatof theta oscillations. This is by itself a remarkable finding consider-ing that hippocampal oscillations constitute a major focus ofresearch: why have such large-amplitude oscillations not beendescribed before? And, to the best of our knowledge, why has therenot been a second report showing similar hippocampal oscillations?Would the putative appearance of beta2 only during specific behav-iours account for the fact that these oscillations remained undetectedfor so long? If so, what kinds of behaviours elicit beta2 oscillations?Are they specific to novel spatial experiences? Can amnesic inter-ventions modulate beta2 appearance in the hippocampus?In the present study we sought to confirm and extend the original

findings of Berke et al. (2008). By recording from freely movingmice, we found that the exploration of novel objects leads to thetransient appearance of prominent beta2 oscillations; no such activ-ity occurred when animals were recorded in the home cage before

Correspondence: Adriano B. L. Tort, as above.E-mail: [email protected]

Received 26 June 2014, revised 26 August 2014, accepted 1 September 2014

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd

European Journal of Neuroscience, pp. 1–11, 2014 doi:10.1111/ejn.12739

and after the exploration session. Furthermore, beta2 powerdepended on the numbert of novel objects present in the arena, andpharmacologically blocking object memory consolidation was asso-ciated with higher beta2 power than when animals showed normalrecognition of familiar objects. These results provide support to theproposal that hippocampal beta2 oscillations could play a role innovelty detection and may constitute a signal for new learning tooccur (Berke et al., 2008; Grossberg, 2009).

Materials and Methods

Animals

Five C57BL/6 mice were used in this study. Animals were housedindividually, with a 12-h cycle of light and dark (lights on at06.00 h), and no food or water restriction. All procedures followedguidelines of the National Institutes of Health and were approved bythe Edmond and Lily Safra International Institute of Neuroscienceof Natal Ethics Committee (protocol number 08/2010).

Task design

Animals were submitted to a novel object recognition task. Eachexperiment (saline or haloperidol protocol; see below) consisted oftwo sessions 24 h apart with three periods each: pre-exploration

(home cage), object exploration (open field), and post-exploration(home cage; Fig. 1A).In the first session, four objects (A, B, C and D) were presented

for 10 min during the exploration period in a circular arena (50 cmdiameter and 30 cm high). Immediately after, animals were sub-jected to intraperitoneal (i.p.) injection of saline (saline protocol)before returning to the home cage. Twenty-four hours later (i.e., inthe second session), animals explored two familiar objects (A and Bfrom the first session) and two novel objects (E and F).One week after the first experiment, four of the animals were sub-

jected to a similar behavioural task but with different objects andwith injection of haloperidol (0.3 mg/kg) immediately after the firstexploration session (haloperidol protocol), which impairs object rec-ognition in the second session (Lob~ao-Soares et al., 2009). As inexperiment 1, objects are also referred to as A, B, C, D, E and Ffor computing the novelty index (see below). Animals were video-recorded throughout the experiments.

Surgery

Animals were implanted with multielectrode arrays (dimensions0.9 9 2.1 mm) composed of 50-lm-diameter tungsten wires, 1.5 mmin length; four electrodes targeted the primary motor cortex (M1), fourelectrodes targeted the somatosensory cortex (S1) and five electrodestargeted the CA1 region of the dorsal hippocampus. The arrays were

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Fig. 1. Experimental design. (A) Novel object recognition task. Each experiment (performed 1 week apart) consisted of two sessions spaced by 24 h. Withineach session, animals were recorded for 10 min before, during and after the exploration of four objects in an open field. In session 2, animals were exposed totwo novel and two familiar objects. Animals received saline (experiment 1) or haloperidol 0.3 mg/kg (experiment 2) i.p. after the object exploration insession 1. (B) Cresyl Violet staining showing electrode tracks (right) and estimated electrode positions (left; adapted from Franklin & Paxinos, 2007).

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons LtdEuropean Journal of Neuroscience, 1–11

2 A. S. C. Franc�a et al.

implanted through a rectangular opening in the skull (coordinates frombegma, 0.55 and 1.65 mm mediolateral and 0.0 and �2.2 mm antero-posterior). Electrode placement was confirmed by inspecting histolog-ical brain sections stained with Cresyl Violet (Fig. 1B).

Recordings

Electrophysiological recordings were made using a multichannelacquisition processor (Plexon Inc., Dallas, TX, USA). LFPs werepreamplified (10009), filtered (1–500 Hz) and sampled at 1000 Hz.A high-impedance homemade headstage and a PBX preamplifier(Plexon Inc., Dallas) model were used. Spikes from multiunit activ-ity were obtained by amplifying (10009), filtering at 500–8000 Hz,and sampling at 40 kHz.

Data analysis

Data analyses were performed using built-in and custom-written rou-tines in Matlab (MathWorks, Natick, MA, USA). The raw signalwas first visually inspected and electrodes with prominent noisewere discarded from further analysis.

Filter settings

Filtering was achieved with the eegfilt.m routine from the EEGLABMatlab toolbox (http://sccn.ucsd.edu/eeglab/). This routine uses alinear finite response filter and applies the filter forward and thenbackwards to eliminate phase distortions. The instantaneous phaseand amplitude of a filtered signal were obtained from the analyticalrepresentation of the signal using the hilbert.m routine from the Sig-nal Processing Toolbox. Theta and beta2 oscillations were obtainedby bandpass filtering at 4–12 Hz and 23–30 Hz, respectively.

Spectral analyses

The power spectrum density was computed by the pwelch.mroutine from the Signal Processing Toolbox (50% overlapping

Hamming window of 4 s). Band power was defined as the meanover power values in the analysed frequency range. The time–fre-quency representation shown in Fig. 3A was obtained by the spec-trogram.m routine from the Signal Processing Toolbox. Thelatency to peak beta2 activity was estimated from the mean ampli-tude of beta2-filtered signals in 10-s sliding windows with 50%overlap. To detect beta2 bursts, for each electrode we first com-puted the mean amplitude of the beta2-filtered signal. A burstevent was defined as occurring when the instantaneous amplitudewas > 2 SD from the mean. Burst duration was defined as the per-iod > 1 SD from the mean. For the burst analysis shown in Fig. 7,each animal contributed with a single LFP, selected as the hippo-campal electrode with the highest number of beta2 bursts (elec-trodes in any individual animal had similar numbers of beta2bursts; not shown).

Behavioural analysis

Object exploration time was considered to be the time animals spentwith the whiskers or both front paws in contact with objects. Micehave a natural tendency to explore novel objects (Hughes, 1997,2007; Dere et al., 2007; Heyser & Chemero, 2012), and spendroughly the same amount of time exploring each of the four objectsif they are all novel. On the other hand, if only two objects arenovel, animals spend less time exploring the familiar objects, givingrise to unequal exploration time between novel and familiar objects(Dere et al., 2007). Therefore, we defined the novelty index as theratio of the time spent exploring the two objects that were the samein sessions 1 and 2 (objects A and B) divided by the time exploringthe other two objects (objects C and D in session 1 and E and F insession 2). Notice that, under normal conditions, the novelty indexshould be lower in session 2 than 1 because objects A and Bbecome familiar and are less explored.The correlation between beta2 and the time spent in locomotion

or exploring objects was obtained by first computing the mean (overelectrodes) normalised beta2 power per animal, and then by pooling

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Hippocampal beta2 oscillations 3

values among animals. We used 1-min non-overlapping windows;beta2 power in each window was normalised to the power value inthe last window.

Results

Transient hippocampal beta2 oscillations appear during theexploration of novel objects

Each experiment consisted of two sessions separated by 24 h, inwhich animals were allowed to explore four objects in an open fieldfor 10 min (Fig. 1A). The four objects were novel in session 1,while only two objects were novel in session 2 (the other twoobjects were the same as in session 1). Behavioural analysis showedthat animals explored the objects in sessions 1 and 2 ofexperiment 1 (saline injection after session 1; see Materials andMethods). In session 1, animals spent roughly the same amount oftime exploring the four novel objects, while in session 2 animalsspent more time exploring the only two novel objects (paired t-test,t4 = 3.83, P = 0.0186; Fig. 2), which shows that animals recognisedthe two familiar objects.We started the electrophysiological analyses by first characteris-

ing the oscillatory content of hippocampal LFPs during the explora-tion of the four novel objects in session 1 of experiment 1. Asexpected, spectral analyses revealed robust theta oscillationsthroughout the 10-min exploration period (see Figs 3A and 4B).Interestingly, and consistent with Berke et al. (2008), we foundprominent beta2 activity mostly during the beginning of session 1(Fig. 3B). The mean latency to peak beta2 activity among animalswas 55 � 9 s (range 35–80 s; Fig. 3B inset). Beta2 power in thefirst 100 s of object exploration was 2.30 � 0.24 times higher thanin the last 100 s (paired t-test compared to 1, t16 = 5.41,P < 0.0001; Fig. 4A). The power of other frequency bands such astheta and gamma was also higher in the beginning of the explora-tion session (Fig. 4), but to a much lower extent than that observedfor beta2 [maximum power ratio of 1.31 � 0.07 (first 100 s/last100 s) for theta oscillations]; indeed, the increase in power seen atthe beginning of session 1 was statistically significantly larger forbeta2 than for four other analysed frequency bands (F4,80 = 15.44,

P < 0.0001, one-way ANOVA; Fig. 4). As shown in Fig. 5, thedecrease in beta2 power along the session correlated with thedecrease in locomotion (r = 0.49, P < 0.01), but not with the timeanimals spent exploring objects (P = 0.35; compare Figs 2A and3B).We next confirmed the results above by visual inspection of raw

LFPs. To that end, we first filtered the LFP into the beta2 band andlocalised the periods of high beta2 amplitude (which, consistent withthe power analysis, occurred mostly at the beginning of the session;Figs 6A and 7A). We then examined the unfiltered LFP at theseperiods and found that both sustained theta oscillations and bursts ofbeta2 activity could be directly observed; the latter was characterisedby high-amplitude, sharp LFP deflections (Figs 6B and 7B inset).The mean duration of beta2 bursts was 167 � 42 ms (Fig. 7B).Therefore, beta2 oscillations are a genuine LFP activity and not har-monics or artifacts of the spectral analysis. In all, these results showthat beta2 has a unique dynamics along the first object explorationsession, with most beta2 bursts occurring at the beginning of thesession.

Beta2 power is lower when animals explore two familiar andtwo novel objects

We next examined LFP power content in the second explorationsession of experiment 1, as well as performed spectral analysesduring the pre- and post-exploration periods in the home cage. Asshown in Fig. 8A, we found that the transient increase in beta2power occurred only during the object exploration period in boththe first and second sessions (repeated-measures ANOVA,F2,462 = 25.19, P < 0.0001 and F2,393 = 24.26, P < 0.0001, for thefirst and second sessions, respectively), but not when animals wererecorded in their home cage. Interestingly, when power values werenormalised by dividing by the mean power in the last minute ofexploration, we found that the transient increase in normalised beta2power was larger in the first than in the second object explorationsession (repeated-measures ANOVA, F1,283 = 5325.16, P < 0.0001;Fig. 8B). These results suggest that a greater level of novelty in thefirst session compared to the second (four vs two novel objects,respectively) is associated with higher beta2 activity.

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Fig. 3. The hippocampus exhibits transient beta2 oscillations during the exploration of novel objects. (A) Top panel, time–frequency decomposition of a repre-sentative hippocampal LFP signal during the first object exploration session (four novel objects). The bottom panel highlights the transient increase in beta2power. (B) Normalised hippocampal beta2 power along the first object exploration session of experiment 1 in non-overlapping 1-min windows (mean � SEM).Power values were normalised to the last window (*P < 0.01, t-test against 1, Bonferroni-corrected for ten comparisons). Inset shows mean latency (�SEM) topeak beta2 activity (see Materials and Methods).



Beta2 oscillations modulate hippocampal but not S1 and M1neurons

We next analysed LFP signals simultaneously recorded from S1 andM1. In contrast to hippocampal signals, S1 and M1 LFPs exhibitedno power peak in the beta2 range (Fig. 9A). We then investigatedwhether spiking activity was coupled to beta2. Fig. 9B shows anexample of multiunit activity in CA1, which was highly modulatedby both theta and beta2 oscillations (see also Berke et al., 2008). Atthe group level, while hippocampal beta2 modulated CA1 neurons(Rayleigh test, P < 0.0001), population activity recorded at neocorti-cal regions was not coupled to beta2 phase (Fig. 9C). Thus, nov-elty-related beta2 oscillations seem to occur and modulate spikingactivity in the hippocampus but not in S1 or M1 (see Discussion).

Impairing object recognition is associated with resurgence ofprominent beta2 activity

One week after the first set of recordings (experiment 1) we sub-jected animals to a similar protocol, but using different objects(experiment 2). In addition, in experiment 2 animals were treated

with haloperidol (0.3 mg/kg i.p.) instead of saline immediately afterthe first object exploration session; haloperidol is amnesic in thisparadigm (Lob~ao-Soares et al., 2009; A.S.C. Franc�a, B. Lob~ao-Soares, L. Muratori, G.C. do Nascimento, J. Winne, C.M. Pereira,S.M.B. Jeronimo, S. Ribeiro, unpublished observations). While ani-mals treated with saline after the first session of experiment 1showed lower preference for the two familiar objects (A and B) inthe second session (paired t-test, t4 = 4.759, P = 0.0089; Fig. 10Aleft panel), haloperidol injected after the first session of experi-ment 2 led animals to display no object preference in the secondsession (Fig. 10B left panel). Thus, in the saline protocol the nov-elty index in the second exploration session was lower than in thefirst session (paired t-test, t4 = 4.262, P = 0.0130; Fig. 10C, leftbars), while in the haloperidol protocol the novelty index was notdifferent between sessions 1 and 2 (Fig. 10C, right bars), suggestingthat amnesic animals perceived the four objects as equally novel inthe second session.Interestingly, while animals displayed a lower increase in beta2

power in the beginning of the second exploration session of experi-ment 1 (c.f. Fig. 8), animals treated with haloperidol exhibited

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Fig. 4. Beta2 oscillations increase more in power than other hippocampal oscillations at the beginning of the exploration session. (A) Power ratios for five fre-quency ranges, as labeled. The power ratio is defined as the mean power in the analysed frequency band in the first 100 s of the session divided by the meanband power in the last 100 s. Bars denote mean � SEM; *P < 0.05, t-test against 1, Bonferroni-corrected for five comparisons; #P < 0.0001 compared to allother spectral bands, one-way ANOVA followed by Tukey’s post hoc test. (B) Power spectrum density for the first (light gray) and last (dark gray) 100 s of objectexploration in three representative animals. Insets show the beta2 range.

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Fig. 5. Beta2 power is not correlated with object exploration time. Shown are scatterplots between normalised beta2 power and time spent in locomotion (left)and exploring objects (right) in 1-min time windows (pooled data from all five animals).



prominent beta2 activity in both the first and second sessions ofexperiment 2 (see Fig. 10A and B, right panels, for representativeexamples). Thus, the beta2 power ratio (first 100 s/last 100 s)decreased from 2.3 in the first session of experiment 1 to � 1.2 inthe second session (t-test, t31 = 4.011, P < 0.001; Fig. 10D, leftbars), while it was close to 1.8 in both the first and second explora-tion sessions of experiment 2 (Fig. 10D, right bars). In all, theseresults suggest that changes in beta2 power within sessions parallel

changes in behaviour (compare Fig. 10C and D), with greater beta2activity in sessions associated with a greater number of novelobjects as putatively perceived by the animals.

Discussion

We have characterised hippocampal beta2 oscillations through extra-cellular recordings, pharmacological intervention and behavioural

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analysis in a novel-object recognition task. We found prominentbursts of beta2 oscillations when mice were allowed to explore fournovel objects in an open field. The occurrence of beta2 bursts wastransient and concentrated at the beginning of the explorationsession. Compared to basal levels, beta2 activity was also higher inthe beginning of a second session in which animals explored twonovel and two familiar objects, but to a lower extent than in the firstexploration session with four novel objects. Interestingly, however,the transient increase in beta2 activity was higher in the second ses-sion of experiment 2, when animals putatively perceived familiarobjects as novel due to the injection of an amnesic drug immedi-ately after the first exploration session. Taken together, our resultssuggest that the appearance of beta2 activity in the hippocampus isassociated with novel experience.The hippocampus plays a key role in memory formation

(Squire, 1992; Eichenbaum, 2004), spatial navigation (O’Keefe &Dostrovsky, 1971; O’Keefe & Nadel, 1978), context discrimination(Frankland et al., 1998; Mizumori et al., 2007; Tort et al., 2011),‘match–mismatch’ operations and novelty detection (Knight, 1996;Lisman & Otmakhova, 2001; Kumaran & Maguire, 2007; Duncanet al., 2012). Growing evidence indicates that network oscillationsare important for the hippocampus to execute its functions (Mont-gomery & Buzsaki, 2007; Tort et al., 2009; Jutras et al., 2013).Given the large amplitude of the beta2 oscillations observed here,

which allow their direct observation by visual inspection of rawfield potentials, it is quite surprising that (to the best of our knowl-edge) these hippocampal oscillations have only been reported in vivoonce (Berke et al., 2008). This could be due to a selective appear-ance of beta2 in specific behavioural states of mice. In contrast,theta and gamma oscillations always accompany exploratory activ-ity, while ripple oscillations are common during consummatorybehaviour such as drinking and grooming (Buzsaki et al., 2003).Our results corroborate several of the beta2 characteristics first

reported in Berke et al. (2008), such as their large amplitude, transientappearance in the beginning of a novel exploration session, and modu-lation of hippocampal units. Interestingly, in both studies peak beta2activity was not at the onset of the novel experience but occurred aftera latency period. This latency period may reflect the time animals taketo perceive the experience as novel (or to generate a mismatch fromprevious expectations; Grossberg, 2009), and/or for stable place fieldrepresentations to emerge. It should be noted that, while we found apositive correlation between beta2 power and locomotion activity (asboth decreased along the session), we believe there is no causal rela-tionship between them: peak locomotion tended to occur at the veryonset of the exploration session and did not coincide with peak beta2activity. Moreover, Berke et al. (2008) reported the disappearance ofbeta2 activity after a couple laps in a novel rectangular arena, despitethe fact that animals continued to run. The decrease in beta2 activity

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Fig. 8. The transient increase in beta2 power is lower in the second exploration session with two familiar and two novel objects. (A) Beta2 power time-coursebefore (black), during (gray) and after (white) object exploration for the first (left) and second (right) sessions of experiment 1. (B) Comparison of normalisedbeta2 power between session 1 and session 2. Notice in the middle panel that the transient increase in beta2 power is higher in the first object exploration ses-sion (P < 0.05, repeated-measures ANOVA). In A and B, power was computed using non-overlapping windows of 1-min length; power values were normalisedto the last window in B.



with time, along with no changes in spatial context or animals’ behav-iour, reported in Berke et al. (2008) is consistent with our findingsshowing no correlation between beta2 and the time animals spentexploring the objects.It should be mentioned that Berke et al. (2008) and the present

study obtained results from different mouse strains. Specifically,Berke et al. (2008) observed beta2 bursts in a genetically modifiedmouse strain (‘fNR1 mouse’; Tsien et al., 1996) and pointed to theimportance of examining whether their findings would hold true forwild-type animals. Here we show that this is indeed the case.However, whether similar hippocampal beta2 activity exists in otherspecies such as rats remains to be demonstrated. In addition to cor-roborating previous findings, here we went on to demonstrate thatblocking familiar object recognition is associated with the reappear-ance of prominent of beta2 oscillations as in the first explorationsession. This result goes well with previous theoretical accounts(Grossberg, 2009) and further supports a role for hippocampal beta2oscillations in novel experience.We found that hippocampal but not S1 or M1 recordings exhib-

ited beta2 oscillations, and, moreover, beta2 phase-modulated onlyCA1 but neither M1 nor S1 neurons. These results suggest a certainspecificity of novelty-related beta2 activity to the hippocampus.Nevertheless, beta2 oscillations were also recently reported in thebasal forebrain of rats during an associative learning task (Quinnet al., 2010). In this study, beta2 power was higher in the first day

of learning in which the object–reward pairs were novel than in sub-sequent days when pairings became familiar (Quinn et al., 2010).Moreover, within the first day of learning, beta2 power was lowestin the first trials but increased with later encounters with the objects(Quinn et al., 2010), akin to the latency period for maximal beta2power observed here. In contrast, however, Quinn et al. (2010) didnot observe a disappearance of beta2 activity after objects becamefamiliar. The basal forebrain possesses cholinergic, glutamatergicand GABAergic neurons that project to widespread regions of thecortex, including the hippocampus (McKinney et al., 1983; Mesu-lam et al., 1983; Gritti et al., 1997; Manns et al., 2003). Basal fore-brain projections modulate synaptic plasticity in the cortex (Kilgard& Merzenich, 1998; Conner et al., 2005) and are involved in atten-tional processes at the behavioural level (Muir et al., 1993; Voytkoet al., 1994; Chiba et al., 1995). Beta2 oscillations could be thusinvolved in modulating the saliency of novel stimuli in downstreamareas; nevertheless, whether the beta2 oscillations described inQuinn et al. (2010) are related to the beta2 in the hippocampusremains to be determined.Several types of oscillatory activity can be obtained in the hippo-

campus in vitro, and many believe that these would correspond totheir in vivo counterparts (Traub et al., 1996; Whittington & Traub,2003). Previous work has shown that the internal circuits of the hip-pocampus are able to produce theta, gamma and ripple frequencyoscillations (Whittington et al., 2000; Maier et al., 2003; Whitting-

0 180 360 540 7200

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Fig. 9. Beta2 modulates hippocampal but not S1 and M1 neurons. (A) Mean power spectra for CA1 (black), S1 (red) and M1 (blue) LFPs during the first100 s of object exploration. Shaded area represents �SEM. Notice beta2 activity only in CA1. (B) Spike-phase histograms for an example CA1 unit coupled totheta and beta2 oscillations. (C) Firing probability as a function of hippocampal beta2 phase for multiunit activity recorded from CA1, M1 and S1 (groupresults). Only CA1 spikes were significantly modulated by beta2 phase (P < 0.05, Rayleigh test).



ton & Traub, 2003; Colgin et al., 2004, 2005; Gloveli et al., 2005;Goutagny et al., 2009). For instance, the cholinergic agonist carba-chol generates � 25–40 Hz oscillations in hippocampal slices andthese are considered to be related to hippocampal gammaoscillations observed in vivo (Fisahn et al., 1998; Traub et al.,2000; Dickinson et al., 2003; Palhalmi et al., 2004). However, ourresults prompt the speculation that the ‘gamma’ oscillationsobserved in hippocampal slices during cholinergic activation wouldactually correspond to a faster version (due to the experimentalpreparation) of in vivo beta2 oscillations, and not to in vivo gammaoscillations as previously suggested. Consistent with this hypothesis,the sharp wave shape of ‘gamma’ in the slice as well as its narrowpower peak (Fisahn et al., 1998; Gloveli et al., 2005; Le~ao et al.,

2009) resemble in vivo beta2 oscillations more than in vivo gamma.Moreover, in vivo hippocampal beta2 oscillations seem to dependon CA3 (Berke et al., 2008), similarly to ‘gamma’ in the slice (Fis-ahn et al., 1998). Acetylcholine release has been linked to noveltyand saliency detection (Acquas et al., 1996), which is putativelyassociated with beta2 bursts, whereas gamma oscillations exist evenin the absence of salient or novel stimuli. Furthermore, as men-tioned above, the basal forebrain is a major source of acetylcholineand also produces beta2 oscillations in vivo (Quinn et al., 2010).Finally, it should be noted that oscillations in the beta2 frequencyrange have actually been observed in hippocampal slices under cho-linergic activation in similar protocols as used for generating‘gamma’ (Shimono et al., 2000; Colgin, 2006), but they probably

Experiment 1 - SalineA

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Fig. 10. Blocking object recognition in the second exploration session leads to a resurgence of beta2 activity. (A) Left, percentage of time exploring objects inthe first and second sessions of experiment 1. Objects A and B were present in both sessions. Animals received saline injection after the first object explorationsession (see Fig. 1A). Notice that animals explored less the familiar objects (A and B) in session 2. Right, power spectra in the beta2 range for the first (lightgray) and last (dark gray) 100 s of object exploration in a representative animal. Note prominent difference in beta2 power levels only for session 1. (B) Asabove, but for experiment 2, in which animals were treated with haloperidol after session 1. Notice that animals did not display preference for the new objects(E and F) in session 2 and that there was a prominent power difference in the beta2 range between the beginning and end of both session 1 and session 2. (C)Novelty index, defined in session 1 (white) as the exploration time of objects A and B divided by the exploration time of objects C and D, and in session 2(gray) as (A and B)/(E and F). Notice that saline injection after session 1 allowed animals to recognise objects A and B in session 2, which led to a lower nov-elty index; on the other hand, animals treated with haloperidol after session 1 did not display object preference in session 2, and had equal levels of noveltyindex in sessions 1 and 2. (D) Beta2 power ratio (first 100 s/last 100 s) for sessions 1 (white) and 2 (gray) of the two experimental protocols. Results areexpressed as mean � SEM; *P < 0.01, t-test; n.s., nonsignificant.



received less attention than gamma due to the lack of its in vivocorrespondent. Further work combining in vitro and in vivo tech-niques should test whether ‘gamma’ in hippocampal slice prepara-tions might in reality correspond to the novelty-related beta2activity reported here.An influential model proposes that the hippocampus and the ven-

tral tegmental area (VTA) form a loop that controls the formation oflong-term memory (Lisman & Grace, 2005). Accordingly, the hip-pocampus would be responsible for detecting new information andsending novelty signals to the VTA, which would integrate thisinformation with others (such as saliency) and in turn release dopa-mine in the hippocampus, enhancing LTP and learning. Such amodel is consistent with electrophysiological, molecular and behav-ioural findings (Gasbarri et al., 1996; Otmakhova & Lisman, 1996;Lemon & Manahan-Vaughan, 2006; Morice et al., 2007; Terryet al., 2007; Rossato et al., 2009). However, there is not much liter-ature about the influence of D2 antagonists on the novel object rec-ognition task used here. We have recently found that haloperidolblocks object memory consolidation (A.S.C. Franc�a, B. Lob~ao-Soares, L. Muratori, G.C. do Nascimento, J. Winne, C.M. Pereira,S.M.B. Jeronimo, S. Ribeiro, unpublished observations), as observedin the present study. These findings are consistent with a role ofdopaminergic projections to the hippocampus in controlling the for-mation of long-term memory (Lisman & Grace, 2005; Rossatoet al., 2009). Whether hippocampal beta2 oscillations would takepart in the communication between the hippocampus and VTAremains to be established.In summary, our results demonstrate the appearance of transient

beta2 oscillations in the hippocampus during exploration of novelobjects. As hypothesised by Grossberg (1999), these findings suggestthat beta2 may be involved in signaling specific time periods for newplasticity to occur. However, much yet should be done to characterisetheir biophysical mechanisms of generation, regions of occurrence, aswell as cognitive roles. In particular, it would be interesting to knowwhether disruption of beta2 activity during memory acquisitionaffects behaviour and LFP spectral content when testing memoryretrieval. Most importantly, the field would benefit from independentlabs reporting a similar pattern of organised electrical activity; weconcur with many others (Button et al., 2013) in the belief that repli-cation is key for constructing solid knowledge.

Acknowledgments

Supported by grants of Conselho Nacional de Desenvolvimento Cient�ıfico eTecnol�ogico (CNPq)/Minist�erio da Ciencia e Tecnologia (MCT), Coorde-nac�~ao de Aperfeic�oamento de Pessoal de N�ıvel Superior (CAPES), Fundac�~aode Apoio �a Pesquisa do Estado do Rio Grande do Norte (FAPERN), Financi-adora de Estudos e Projetos (FINEP), Pr�o-Reitoria de P�os-Graduac�~ao da Uni-versidade Federal do Rio Grande do Norte (UFRN), Programa de Apoio aN�ucleos Emergentes (PRONEM 003/2011 FAPERN/CNPq), and Pew LatinAmerican Fellows Program in the Biomedical Sciences. The authors thankCesar Renn�o-Costa, Richardson Le~ao and Jurij Brankack for helpful discus-sions. The authors declare no competing financial interests.

Abbreviations

LFP, local field potential; M1, primary motor cortex; S1, primary somatosen-sory cortex.

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Beta2 oscillations (23 30 Hz) in the mouse hippocampus ... · Beta2 oscillations (23–30 Hz) in the mouse hippocampus during novel object recognition Arthur S. C. Franc a,1,2 George