Theta Rhythm of the Hippocampus: Subcortical Control and ... › 1786 › 3d91e8a50037... · thalamocortical/cortical systems. The temporal convergence of activity of these two systems

10.1177/1534582304273594BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWSVertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS

Theta Rhythm of the Hippocampus:Subcortical Control and Functional Significance

Robert P. VertesWalter B. HooverGonzalo Viana Di PriscoFlorida Atlantic University

The theta rhythm is the largest extracellular synchronous signalthat can be recorded from the mammalian brain and has beenstrongly implicated in mnemonic processes of the hippocampus.We describe (a) ascending brain stem–forebrain systemsinvolved in controlling theta and nontheta (desynchronization)states of the hippocampal electroencephalogram; (b) theta rhyth-mically discharging cells in several structures of Papez’s circuitand their possible functional significance, specifically withrespect to head direction cells in this same circuit; and (c) the roleof nucleus reuniens of the thalamus as a major interface betweenthe medial prefrontal cortex and hippocampus and as a promi-nent source of afferent limbic information to the hippocampus.We suggest that the hippocampus receives two main types ofinput: theta rhythm from ascending brain stem–diencephalo-septal systems and information bearing mainly fromthalamocortical/cortical systems. The temporal convergence ofactivity of these two systems results in the encoding of informa-tion in the hippocampus, primarily reaching it from theentorhinal cortex and nucleus reuniens.

Key Words: supramammillary nucleus, median raphenucleus, medial prefrontal cortex, Papez’s circuit, nu-cleus reuniens, LTP, memory

The theta rhythm of the hippocampus is a large-amplitude (1-2 mV) nearly sinusoidal oscillation of 5 to12 Hz in the behaving rat (Bland, 1986; Vertes & Kocsis,1997). It is the largest extracellular synchronous signalthat can be recorded in the mammalian brain. Theta isselectively present during two behavioral states: wakingbehaviors that are thought to be critical for the survivalof the species and throughout rapid eye movement(REM) sleep (Vanderwolf, 1969; Winson, 1972). Thetaof waking is present in rats during exploratory motorbehavior (Vanderwolf, 1969). The theta rhythm hasattracted significant attention based on its reported

involvement in memory processing functions of the hip-pocampus.

The present review will focus on the following maintopics: (a) subcortical circuitry controlling theta andnontheta (desynchronized) states of the hippocampalelectroencephalogram (EEG), (b) theta rhythmical sig-nals exiting the hippocampus through structures ofPapez’s circuit and their functional significance, (c) thenucleus reuniens (RE) of the thalamus as a prominentsource of limbic information to the hippocampus, and(d) the role of theta in mnemonic functions.

ASCENDING BRAIN STEM–DIENCEPHALICSYSTEMS CONTROLLING THE THETA RHYTHMAND DESYNCHRONIZED (NONTHETA) STATESOF THE HIPPOCAMPAL EEG

Theta Rhythm

It is well documented that rhythmically dischargingcells of the medial septum/vertical limb of the diagonalband nucleus (MS/DBv) that fire synchronously withtheta are responsible for its generation in hippocampalformation (Brazhnik & Fox, 1997; Brazhnik &Vinogradova, 1986; Gogolak, Stumpf, Petsche, & Sterc,1968; Lamour, Dutar, & Jobert, 1984; Leung & Shen,2004; Petsche, Gogolak, & Van Zwieten, 1965; Petsche,Stumpf, & Gogolak, 1962; Stewart & Fox, 1989; Vertes &Kocsis, 1997; Vinogradova, 1995). Low-frequency MS/DBv stimulation drives theta (James, McNaughton,

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Authors’ Note: This work was supported by National Institute of Men-tal Health Grants MH63519 and MH01476 to R.P.V.

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Rawlins, Feldon, & Gray, 1977; Kramis & Vanderwolf,1980; McNaughton, Azmitia, Williams, Buchan, & Gray,1980; McNaughton et al., 1977), and reversible or irre-versible MS/DBv lesions, or the disruption of the rhyth-mical discharge of MS/DBv cells, eliminates the thetarhythm in the hippocampus as well as in parahip-pocampal structures such as the entorhinal andcingulate cortices (Donovick, 1968; Gray, 1971; Leung &Borst, 1987; Mitchell, Rawlins, Steward, & Olton, 1982;Sainsbury & Bland, 1981). The MS/DBv has been desig-nated the “pacemaker” for the hippocampal thetarhythm (Leung & Shen, 2004; Numan, 2000; Vertes &Kocsis, 1997; Vinogradova, 1995).

It is also well established that the brain stem reticularformation (RF), through actions on the MS/DBv, servesa direct role in the generation of theta. In their originalreport that identified the theta rhythm in the curarizedrabbit, Green and Arduini (1954) showed that thetacould be elicited by natural sensory stimuli or by electri-cal stimulation of the brain stem RF. Shortly thereafter,Petsche and colleagues (1962, 1965) demonstrated thatseptal pacemaking cells could be driven by input arisingfrom the brain stem RF, leading them (Petsche et al.,1965) to conclude that the septum transforms “thesteady flow of pulses from the RF into a discontinuouspattern of discharges” that are then transferred “to thepyramidal cells of the hippocampus thus inducing thetheta rhythm.”

Although these early studies indicated a role for thebrain stem RF in elicitation of theta, they did not identifyspecific RF locations responsible for this effect. Stimula-tion was generally delivered to the midbrain RF (forreview, see Vertes, 1982). In a series of reports, weshowed that the nucleus pontis oralis (RPO) of therostral pontine RF was critical for the generation oftheta. We found that cells of RPO in the behaving rat dis-charge at high tonic rates (50-75 Hz) selectively duringwaking motor behavior and REM sleep (theta-associatedstates in the rat; Vertes, 1977, 1979) and that electricalstimulation of pontis oralis, but not that of surroundingregions of the brain stem, generates theta (Vertes, 1980,1981). Other studies have similarly shown that RF stimu-lation, centered in RPO, both activates septalpacemaking cells and elicits theta (Bland, Oddie,Colom, & Vertes, 1994; Brazhnik, Vinogradova, &Karanov, 1985; Macadar, Chalupa, & Lindsley, 1974;McNaughton, Richardson, & Gore, 1986; Oddie, Bland,Colom, & Vertes, 1994).

In line with the proposal of Petsche et al. (1965), theforegoing suggested, then, that RPO is the primarysource of tonic drive to the septal pacemaking cells inthe elicitation of theta. To further assess this, we exam-ined anatomical connections of RPO with the medial

septum. Specifically, we made injections of the retro-grade tracer, WGA-HRP, into the MS/DBv and analyzedpatterns of labeled neurons in the brain stem (Vertes,1988). Although labeled cells were identified in severalregions of the brain stem, prominently includingmonoaminergic nuclei, exceedingly few were found inRPO or other reticular nuclei of the brain stem (Vertes,1988). This suggested that the influence of RPO on theMS/DBv in the generation of theta was mediated by anintervening nucleus (or nuclei) or di- or polysynapticpathways between RPO and the MS/DBv.

Although retrograde tracer injections in MS/DBvfailed to produce labeling in RPO, interestingly, theygave rise to pronounced cell labeling in thesupramammillary nucleus (SUM), dorsal to themammillary bodies (Vertes, 1988). Approximately 150to 200 labeled neurons per 50-µm section were seenthrough the heart of SUM. This suggested that the SUMmay be a link between the brain stem and septuminvolved in the generation of theta. As discussed below,this has subsequently been confirmed by several lines ofevidence: (a) SUM receives projections from RPO and,in turn, projects significantly to the septum and hippo-campus; (b) SUM cells fire rhythmically with theta; (c)electrical stimulation-induced or pharmacological acti-vation of SUM drives theta; and (d) the suppression ofSUM disrupts the rhythmical discharge of septalpacemaking cells and eliminates theta in thehippocampus.

Using autoradiographic techniques, we demon-strated that RPO projects to SUM (Vertes, 1990; Vertes &Martin, 1988) and, confirming our retrograde findings(Vertes, 1988), showed that injections of theanterograde tracer PHA-L into SUM produced denselabeling in the medial and lateral septum as well as in thehippocampus (Vertes, 1992). Within the hippocampus,SUM fibers distribute selectively to the dentate gyrus andto CA2/CA3a of Ammon’s horn (Vertes, 1992; Vertes &McKenna, 2000). There are essentially no SUM projec-tions to the CA1 region of Ammon’s horn. These pat-terns of projections are consistent with those describedin other reports and across species (Borhegyi,Magloczky, Acsady, & Freund, 1998; Haglund, Swanson,& Kohler, 1984; Kiss, Csaki, Bokor, Shanabrough, &Leranth, 2000; Leranth & Kiss, 1996; Magloczky, Acsady,& Freund, 1994; Veazey, Amaral, & Cowan, 1982; Wyss,Swanson, & Cowan, 1979a).

In an initial study recording multiunit activity in anes-thetized rats, Kirk and McNaughton (1991) identified apopulation of cells of the SUM that fired rhythmicallywith the hippocampal theta rhythm. They furthershowed that this activity did not depend on the MS/DBv;procaine injections in the MS/DBv that abolished

174 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS



hippocampal theta did not alter the rhythmical firing ofSUM neurons. In subsequent examinations (Kocsis &Vertes, 1994, 1997) of the activity of SUM cells as well asthose in surrounding regions of the caudaldiencephalon, we found that 29 of 170 neurons dis-charged rhythmically, synchronous with theta (Kocsis &Vertes, 1994). All 29 theta-related cells were localized toSUM or to the mammillary bodies, ventral to SUM; noneof 141 neurons located outside of the SUM/MB firedsynchronously with theta. Bland, Konopacki, Kirk,Oddie, and Dickson (1995) similarly reported that 16 of16 SUM cells and 19 of 23 MB cells discharged rhythmi-cally with theta—phasic theta-on cells in their terminol-ogy (Colom & Bland, 1987; Ford, Colom, & Bland,1989).

Finally, the activation or suppression of SUM drives orblocks theta, respectively. Specifically, electrical stimula-tion or carbachol injections in SUM activate theta burstneurons of the septum and hippocampus and producetheta (Bland, Colom, & Ford, 1990; Bland et al., 1994;Bocian & Konopacki, 2004; Oddie et al., 1994; Smythe,Christie, Colom, Lawson, & Bland, 1991), whereas thereversible suppression of SUM with procaine injectionsin anesthetized rats disrupts the spontaneous as well asthe RPO-elicited bursting discharge of septalpacemaking cells and eliminates hippocampal theta(Bland et al., 1994; Oddie et al., 1994). Procaine injec-tions into SUM in awake (nonanesthetized) rats signifi-cantly reduces the frequency of theta but does not totallyeliminate it (Kirk & McNaughton, 1993; Pan &McNaughton, 1997, 2002).

McNaughton and colleagues (Kirk & McNaughton,1993; see also Gray & McNaughton, 2000; Kirk, 1998;Woodnorth, Kyd, Logan, Long, & McNaughton, 2003)have proposed that SUM codes the frequency of thetheta rhythm and the medial septum the amplitude oftheta. Specifically, they showed that procaine injectionscaudal to SUM (blocking RPO actions on SUM) orwithin SUM significantly reduced the frequency of theta,whereas procaine injections in the MS/DBv reduced theamplitude but not frequency of theta (Kirk &McNaughton, 1993). They concluded that

the most parsimonious explanation of this result is thattransduction of the intensity of reticular activation to thefrequency of the resultant RSA (rhythmical slow activityor theta) takes place in the supramammillary regionrather than in the septal area. It is likely thattransduction occurs in the SuM itself. The frequencycoded (i.e., phasic) information is then fed, probablyvia the MFB, to the MS/DB. (Kirk & McNaughton,1993, p. 520)

In addition to rhythmically firing neurons of SUM,cells of the posterior nucleus of the hypothalamus (PH)

have been shown to discharge tonically with theta(Bland et al., 1995; Bland & Oddie, 1998). Specifically,Bland et al. (1995) reported that 43 of 54 neurons of PHfired at high tonic rates selectively during theta—theirtonic theta-on cells. With respect to the possible PHinfluence on the hippocampus, PH does not project tothe hippocampus (Vertes, Crane, Colom, & Bland,1995) but distributes strongly to several structures withpronounced input to the hippocampus, prominentlyincluding the medial septum, RE of the thalamus (seebelow), and SUM. Bursting SUM neurons and the toni-cally firing PH cells may act synergistically to relayascending reticular activity to the MS/DBv in the controlof theta (Bland & Oddie, 1998; Vertes & Kocsis, 1997).

In summary, several lines of evidence indicate that thetheta rhythm is controlled by a network of cells extend-ing from the brain stem to the forebrain, that is, fromRPO to the SUM to the septum/hippocampus. Asdepicted in Figure 1, during theta, tonically firing cells ofthe RPO activate putative glutamatergic neurons ofSUM, which convert the steady barrage into a rhythmicalpattern of discharge that is relayed to cholinergic andgamma-aminobutyric acid (GABA)-ergic pacemakingcells of the MS/DBv. Septal cholinergic neurons exciteprincipal cells and interneurons of the hippocampus(Dutar, Bassant, Senut, & Lamour, 1995; Frotscher &Leranth, 1985; Leranth & Frotscher, 1989; Vertes &Kocsis, 1997), whereas septal GABAergic cells inhibitGABAergic interneurons of the hippocampus (Freund& Antal, 1988; Gulyas et al., 1991) in the generation oftheta. Although septohippocampal cholinergic neuronsfire rhythmically with theta, they may not rhythmicallydrive (or entrain) hippocampal neurons at theta fre-quencies. Rather, acetylcholine may exert “tonic” excit-atory actions on hippocampal pyramidal cells, depolariz-ing them to threshold for the activation of intrinsiccurrents sufficient to produce membrane potentialoscillations at theta frequencies (Vertes & Kocsis, 1997).This is supported by the demonstration thatcholinomimetics produce a theta-like rhythm in the iso-lated hippocampal slice (Bland & Colom, 1993; Bland,Colom, Konopacki, & Roth, 1988; Konopacki, 1998;Konopacki, MacIver, Bland, & Roth, 1987).

Nontheta States of the Hippocampal EEG(Hippocampal EEG Desynchronization):Role of the Median Raphe Nucleus (MR)

The MR is a major serotonin-containing cell group ofthe midbrain with extensive projections to the forebrain(Aznar, Qian, & Knudsen, 2004; Leranth & Vertes, 1999;McKenna & Vertes, 2001; Morin & Meyer-Bernstein,1999; Vertes, Fortin, & Crane, 1999; Vertes & Martin,1988). An extensive body of evidence indicates that theMR is directly involved in the desynchronization of the

Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 175



hippocampal EEG, or the blockade of theta. It was dem-onstrated early on that MR stimulation desynchronized

the hippocampal EEG (Assaf & Miller, 1978; Macadaret al., 1974; Vertes, 1981; Yamamoto, Watanabe, Oishi, &Ueki, 1979) and that MR lesions produced continuouslyrunning theta, independent of behavior (Maru,Takahashi, & Iwahara, 1979; Yamamoto et al., 1979).These effects reportedly involved serotonergic (5-HT)cells of MR. Assaf and Miller (1978) demonstrated thatthe disruptive effect of MR stimulation on septalpacemaking cells and the hippocampal EEG wasblocked by pretreatment with the 5-HT synthesis inhibi-tor p-chlorophenylalanine, which produced a 60% to80% depletion of forebrain serotonin. Yamamoto et al.(1979) reported that ongoing theta produced by MRlesions could be temporari ly interrupted byintraperitoneal injections of the serotonin precursor L-5-hydroxytryptophan (L-5-HTP), and McNaughtonet al. (1980) showed in behaving rats that the effective-ness of driving theta with septal stimulation was signifi-cantly enhanced following destruction of ascendingserotonergic fibers.

More recently, we showed (Kinney, Kocsis, & Vertes,1994, 1995, 1996; Vertes, Kinney, Kocsis, & Fortin, 1994)that injections of various substances into the MR in anes-thetized rats that either suppressed 5-HT MR neurons(5-HT1A autoreceptor agonists or GABA agonists) orreduced excitatory drive to them (excitatory amino acidantagonists) produced theta at short latencies (1-2 min-utes) and for long durations (20-80 minutes). In likemanner, Varga, Sik, Freund, and Kocsis (2002) reportedthat GABAB receptors are selectively present onserotonergic neurons of MR and that infusions of theGABAB agonist, baclofen, into MR in anesthetized ratsproduced long-lasting theta. They concluded (Vargaet al., 2002) that the effects of baclofen on theta“resulted from suppression of the serotonergic outputfrom the median raphe.”

In examinations of the effects of manipulations of MRon the septum and hippocampus in awake rabbits,Vinogradova and colleagues (Kitchigina, Kudina,Kutyreva, & Vinogradova, 1999; Vinogradova,Kitchigina, Kudina, & Zenchenko, 1999) similarlyshowed that low-amplitude median raphe stimulationdisrupted the bursting discharge of medial septal cellsand abolished theta in the hippocampus and that thereversible suppression of MR with injections of lidocaineincreased the frequency and regularity of discharge oftheta-bursting neurons of the septum and hippocampusand produced continuous theta in the hippocampus.They concluded that “the median raphe nucleus can beregarded as a functional antagonist of the RF, powerfullysuppressing theta bursts of the medial septal area neu-rons and the hippocampal theta rhythm” (Kitchiginaet al., 1999, p. 453).


Medial Septum

SUM

Median Raphe Pontis Oralis

HippocampalFormation

Ch

G

S

G

Glu

Glu

GGlu

G

G

S

+

-

Figure 1: Schematic Diagram Showing the Major Interconnections ofAscending Systems Controlling Theta and Nontheta(Desynchronization) States of the Hippocampal Electroen-cephalogram.

NOTE: During theta, tonically firing cells of nucleus pontis oralis acti-vate putative glutamatergic neurons of the supramammillary nucleus(SUM) which, in turn, convert this steady barrage into a rhythmicalpattern of discharge that is relayed to cholinergic and gamma-aminobutyric acid (GABA)-ergic pacemaking cells of the medial sep-tum. Medial septal GABAergic neurons connect with and inhibitGABAergic cells of the hippocampus, thereby exerting a disinhibitoryaction on pyramidal cells of the hippocampus. Medial septalGABAergic cells receive intraseptal excitatory input from both septalcholinergic and glutamatergic (Hajszan, Alreja, & Leranth, 2004) neu-rons. Cholinergic septohippocampal pacemaking cells terminate onboth interneurons and principal cells of the hippocampus. Duringstates of hippocampal desynchronization (nontheta), a subset ofserotonergic septal-projecting cells of the median raphe nucleus (MR)discharge at enhanced rates and activate GABAergic cells of the medialseptum, which in turn inhibit GABAergic/cholinergic pacemakingcells of the medial septum in the desynchronization of thehippocampal EEG. Serotonergic neurons of the MR also project di-rectly to the SUM and to the hippocampus and could also exertdesynchronizing actions on the hippocampal EEG through these con-nections. See the text for further description of this circuitry. Thedashed line signifies presently undetermined SUM glutamatergic pro-jections to glutamatergic cells of the septum. Arrows (at the end oflines) indicate excitatory connections; straight lines indicate inhibi-tory connections. Ch = acetylcholine; G = GABA; Glu = glutamate; S =serotonin.




Figure 2: The Discharge Characteristics of a Theta-Off Neuron of the Median Raphe Nucleus.SOURCE: Reprinted from Viana Di Prisco, Albo, Vertes, and Kocsis (2002), p. 386, with permission of Springer-Verlag.NOTE: The cell showed an abrupt cessation of firing at the onset and for the duration of hippocampal theta elicited with either tail pinch (TP) (A)or with electrical stimulation of the tail (DC) (B). (C) Superimposed action potentials of the cell showing a wide spike of ~2 ms. (D) ISI histogram ofthe cell demonstrating a sharp peak at 110 ms, indicating that the cell fired at very regular rates during control (nontheta) conditions. (E)Autocorrelogram depicting the steady rate of discharge of the cell at ~9 Hz (peaks in E). (F) Cross-correlogram (spike-triggered averaging) showingthat the cell did not discharge rhythmically synchronous theta as indicated by the flat unit-electroencephalogram cross-correlogram.



In addition to 5-HT cells, the MR contains significantnumbers of GABAergic neurons (Jacobs & Azmitia,1992; Mugnaini & Oertel, 1985; Maloney, Mainville, &Jones, 1999), which have been shown to contact andinhibit 5-HT MR cells (Forchetti & Meek, 1981;Nishikawa & Scatton, 1985a, 1985b). As discussed, injec-tions of GABAA (Kinney et al., 1995) or GABAB agonists(Varga et al., 2002) into MR generate persistent theta.This suggests a GABAergic MR influence on 5-HT cellsof MR in the modulation of the hippocampal EEG. Inrecent examinations of the discharge properties of MRneurons in anesthetized rats (Kocsis & Vertes, 1996;Viana Di Prisco, Albo, Vertes, & Kocsis, 2002), we identi-fied two major populations of cells, putatively 5-HT andGABAergic neurons, with activity related to thehippocampal EEG. Specifically, we demonstrated that avery large percentage of MR cells showed changes inactivity associated with changes in the hippocampal EEG(Viana Di Prisco et al., 2002). Approximately 80% (145/181) of MR neurons fired at increased or decreased ratesof activity with theta and were termed theta-on and theta-off cells, respectively. These cells were further dividedinto slow (~ 1 Hz), moderate (5-11 Hz) and fast-firing(>12 Hz) theta-on or theta-off cells. The slow-firingtheta-on and theta-off cells, as well as a subpopulation ofthe moderately firing cells, exhibited characteristics ofclassic 5-HT raphe neurons (Aghajanian, Foote, &Sheard, 1968, 1970; Jacobs, Heym, & Steinfels, 1984; Ras-mussen, Heym, & Jacobs, 1984; Sprouse & Aghajanian,1987; Jacobs & Azmitia, 1992) and were thought to beserotonergic cells. All fast-firing cells were theta-on cells;no fast-firing theta-off cells were observed. Fast-firingcells showed either tonic or phasic (rhythmical)increases in activity with theta.

The discharge profile of a moderately firing, putativeserotonergic, theta-off cell is shown in Figure 2. Asdepicted, the cell discharged at very regular rates duringcontrol (nontheta) conditions (Figure 2A) and abruptlyceased firing with the onset, and essentially for the dura-tion, of theta elicited with tail pinch (TP; Figure 2A) orby electrical stimulation of the tail (Figure 2B). For a fewneurons tested, cells that were strongly inhibited duringTP-elicited theta were also completely suppressed fol-lowing the intravenous administration of the 5-HT1A ago-nist, 8-OH-DPAT, further indicating that they wereserotonergic neurons.

We suggested, then, that (a) the slow-firing cells(theta-on and theta-off) and a subset of the moderatelydischarging cells were serotonergic neurons and thephasic and tonic fast-firing cells were mainly GABAergicneurons, (b) the 5-HT theta-off (or desynchronization-on) cells were projection neurons and the 5-HT theta-onand GABAergic cells were primarily interneurons, and(c) these populations of cells mutually interact in the

modulation of the hippocampal EEG (Viana Di Priscoet al., 2002). In effect, the activation of local 5-HT theta-on cells as well as the GABAergic theta-on cells wouldinhibit 5-HT theta-off projection cells to release or gen-erate theta, whereas suppression of 5-HT theta-on and/or GABAergic theta-on activity would disinhibit 5-HTtheta-off (desynchronization-on) cells resulting in ablockade of theta or a desynchronization of thehippocampal EEG (see Figure 1).

In one of the few studies examining the activity of MRcells in behaving animals, Jacobs and colleagues(Marrosu, Fornal, Metzler, & Jacobs, 1996) showed inawake cats that putative 5-HT cells of MR exhibited prop-erties indicative of a role in the desynchronization of thehippocampal EEG. These cells fire at highest rates dur-ing automatic behaviors of waking and slow wave sleep(desynchronized states of the hippocampus) and at low-est rates during the exploration of waking and REMsleep (theta states; Jacobs & Azmitia, 1992; Marrosuet al., 1996).

Although not fully determined, the desynchronizingactions of MR on the hippocampus appear to be primar-ily mediated by the medial septum. The MR projectsstrongly to the medial septum (Aznar et al., 2004; Morin& Meyer-Bernstein, 1999; Vertes et al., 1999; Vertes &Martin, 1988), and MR fibers predominantly terminateon GABAergic cells of the MS/DBv (Leranth & Vertes,1999, 2000), forming asymmetric (excitatory) connec-tions with them. Alreja and colleagues (Alreja, 1996; Liu& Alreja, 1997) demonstrated that 5-HT excites localGABAergic cells of the MS/DBv, which in turn inhibitsubsets of septal pacemaking GABAergic andcholinergic septohippocampal neurons, possibly in thecontrol of the hippocampal EEG. Supporting this,Kinney et al. (1996) showed that injections of 8-OH-DPAT into MR (which inhibits 5-HT neurons) rhythmi-cally activated septal pacemaking cells and generatedtheta.

The MR could also exert desynchronizing influenceson the hippocampus via actions on other targets, such asthe RPO, SUM, or directly on the hippocampus (Figure1). With respect to MR-RPO (reticular) interactions inthe control of theta, Vinogradova et al. (1999) proposedthat a suppression of MR activity could result in the“elimination of the MR inhibitory influences on thereticular formation” and thereby “stimulate the genera-tion of theta rhythm and increase of its frequency in thesepto-hippocampal system” (p. 750).

In summary, two brain stem–originating systems exertpronounced (and opposing) actions on the electricalactivity of the hippocampus, that is, hippocampal syn-chronizing (theta) and desynchronizing (non-theta) sys-tems, originating from the RPO and MR, respectively.During theta, tonically firing cells of RPO activate neu-




rons of the SUM, which in turn convert this steady bar-rage into a rhythmical pattern of discharge that isrelayed to pacemaking cells of the MS/DBv to generatetheta. During states of hippocampal desynchronization,a subset of 5-HT, septal-projecting MR cells discharge atenhanced rates and activate local GABAergic cells of theMS/DBv, which in turn inhibit cholinergic/GABAergicpacemaking cells of the MS/DBv in the desynchroni-zation of the hippocampal EEG (see Figure 1; Vertes &Kocsis, 1997; Bland & Oddie, 1998).

THETA-RHYTHMIC SIGNALS EXITING THEHIPPOCAMPUS THROUGH STRUCTURES OFPAPEZ’S CIRCUIT AND POSSIBLEFUNCTIONAL SIGNIFICANCE

As discussed, we described theta rhythmically firingneurons in SUM as well as in the mammillary bodies(MB), ventral to SUM (Kocsis & Vertes, 1994, 1997). Oth-ers studies have similarly demonstrated theta-rhythmiccells in MB (Bland et al., 1995; Kirk, Oddie, Konopacki,& Bland, 1996). Although SUM and MB cells fire rhyth-mically with theta, they bear different relationships totheta, that is, influencing theta (SUM) or influenced byit (MB). For instance, it has been shown that procaineinjections in the MS/DBv (which abolish theta) disruptthe rhythmical discharge of MB cells but not that of SUMcells (Bland et al., 1995; Kirk et al., 1996; Kirk &McNaughton, 1991). This suggests that MB is part of adescending system driven from the septum/hippocam-pus, whereas SUM is a part of an ascending system gener-ating theta. This is consistent with anatomical findingsshowing that MB receives major descending projectionsfrom the hippocampus via the postcommissural fornix(Amaral & Witter, 1995; Swanson & Cowan, 1977; Witter,Ostendorf, & Groenewegen, 1990) but does not projectto the hippocampus, whereas the SUM receives fewfibers from the hippocampus but is the source of denseprojections to the septum and hippocampus (Borhegyiet al., 1998; Haglund et al., 1984; Kiss et al., 2000;Leranth & Kiss, 1996; Magloczky et al., 1994; Vertes,1992; Vertes & McKenna, 2000).

The MB represents a major output of the hippocam-pus (Amaral & Witter, 1995) and are a principal compo-nent of Papez’s circuit, an anatomical circuit (a loop)beginning and ending in the hippocampus. As originallydefined by Papez (1937), the projections of the circuitare hippocampal formation → mammillary bodies → ante-rior thalamus → cingulate cortex → parahippocampalgyrus → hippocampal formation. Although the circuithas been refined based on subsequent anatomical find-ings (Amaral & Witter, 1995; Shibata, 1992; van Groen &Wyss, 1995), the major links of the circuit unquestion-ably represent a prominent system of connections in the

mammalian brain. Hence, the enduring nature ofPapez’s circuit. Unlike, however, its persistence as ana-tomical entity, the proposed functional role for the cir-cuit has been less resilient. The early notion that Papez’scircuit subserves emotional experience/expression(LeDoux, 1993) has been replaced by the proposal thatit is primarily involved in mnemonic functions(Aggleton & Brown, 1999). Lesions of each of the majorstructures of Papez’s circuit have been shown to disruptmemory (Aggleton & Brown, 1999; Byatt & Dalrymple-Alford, 1996; Gabriel et al., 1995; Sutherland, Whishaw,& Kolb, 1988; Sziklas & Pertides, 1993, 1999; Tulving &Markowitsch, 1997; van Groen, Kadish, & Wyss, 2002;Warburton, Baird, & Aggleton, 1997).

The findings that MB cells fire rhythmically withtheta, coupled with the demonstration that MB pro-jects massively to the anterior thalamus via themammillothalamic tract (Seki & Zho, 1984; Shibata,1992), suggest that MB may exert a theta-rhythmic influ-ence on the anterior thalamus, much like the hippocam-pus on MB. To assess this, we examined the activity ofcells of the three divisions of the anterior thalamus(anteroventral [AV], anterodorsal [AD], anteromedialnuclei) with respect to the hippocampal EEG and foundthat neurons in all divisions fired rhythmically with theta(Vertes, Albo, & Viana Di Prisco, 2001; Albo, Viana DiPrisco, & Vertes, 2003), with the highest percentage inthe AV nucleus.

We found (Vertes et al., 2001) that approximately75% of AV neurons fired rhythmically with theta and theactivity of about half of them (46%) was highly corre-lated with theta, as exemplified by the AV neuron of Fig-ure 3. As depicted, with the onset of theta (elicited by tailpinch), the activity of the cell changed from an irregularpattern to a highly rhythmical pattern, synchronous withtheta (Figure 3A). This change from nonrhythmical(control) to rhythmical (theta) activity is exemplified bythe rhythmical peaks in the autocorrelogram (Figure3B), unit-theta locked EEG oscillations (spike-triggeredaveraging) in the cross-correlogram (Figure 3C), andthe pronounced coherence between unit discharge andthe hippocampal EEG at theta frequency (about 3.3 Hz;Figure 3D). By comparison with the large percentage oftheta-rhythmic neurons in AV (~75%), approximately12% of AD cells and 6% of anteromedial nucleus cellswere found to discharge rhythmically, stronglysynchronous with theta (Albo et al., 2003).

As discussed, the MB distributes massively to the ante-rior thalamus and appear to exert a theta-rhythmic influ-ence on the anterior thalamus, mainly on AV. The MBalso projects strongly to, and receive pronounced projec-tions from, the tegmental nuclei of the brain stem (thedorsal and ventral tegmental nuclei of Gudden; Allen &Hopkins, 1989, 1990; Hayakawa & Zyo, 1990, 1991), sug-




gesting a similar MB rhythmical influence on thesenuclei.

In a recent examination of the activity of cells of theventral tegmental nucleus (VTg) and its rostral exten-sion, the anterior tegmental nucleus (ATg), in anesthe-tized rats, we found that all cells of the VTg/ATg (n = 37)fired rhythmically in bursts with theta (Kocsis, Viana DiPrisco, & Vertes, 2001). Furthermore, the discharge ofVTg and ATg cells was highly coherent with the thetarhythm; that is, for segments of the record, coherences(spectral covariance) often exceeded 0.90. The theta-associated activity of VTg cells was often so intense that itcould be readily identified as the electrode justapproached the nucleus, that is, before single spikescould be clearly identified.

Figure 4 shows a strongly theta rhythmically firingVTg neuron (Kocsis et al., 2001). As depicted, the neu-ron discharged in rhythmic bursts with theta (Figure

4C), as demonstrated by rhythmical peaks in theautocorrelogram (Figure 4E) and a dominant rhythmiccomponent at 3.7 Hz in the VTg-hippocampal cross-correlogram (Figure 4G). By contrast, during nonthetastates (desynchronization), the neuron fired irregularly(Figure 4D) with no significant peaks in theautocorrelogram (Figure 4F) or in the spike-triggeredaverage (Figure 4H).

Consistent with these findings, Bassant andPoindessous-Jazat (2001) demonstrated that the activityof VTg cells in behaving rats was highly correlated withtheta during both waking and REM sleep. They furtherdrew attention to the marked similarity of the rhythmicfiring of VTg and MS/DBv cells, stating, “Interestingly,the characteristics of the rhythmic discharges in VTn areclose to those observed in MS/DB, a region crucialfor the generation of the hippocampal theta rhythm”(p. 810).

MB projections to VTg are mainly excitatory(Hayakawa & Zyo, 1990), and return VTg to MB projec-tions are predominantly inhibitory (GABAergiclHayakawa&Zyo,1991), thus formingarecurrentexcitatory-inhibitory network. This MB-VTg network exhibits anumber of similarities with other excitatory-inhibitoryrecurrent systems known to generate rhythmic oscilla-tions at low frequencies (Contreras & Steriade, 1996;Ritz & Sejnowski, 1997; Plenz & Kital, 1999). We suggestthat VTg-MB connections may be an important subloopgrafted onto Papez’s circuit, involved in maintainingtheta rhythmical activity in MB and hence throughoutPapez’s circuit.

Theta-Rhythmic Cells andHead Direction (HD) Cells

There is a remarkable correspondence in ratsbetween structures containing theta-rhythmic neuronsand those containing HD cells (Taube, 1998; Vann &Aggleton, 2004). HD cells fire selectively when a rat isfacing or oriented in a particular direction (e.g., north-east) irrespective of its location in its environment(Taube, 1998). Both HD and theta-rhythmic cellshave been described in the tegmental nuclei ofGudden, the MB, the anterior thalamus, posteriorcingulate (retrosplenial) cortex, and the subiculum/hippocampus.

In addition (and importantly), theta and HD cellshave been localized to separate subnuclei of structures(of Papez’s circuit) containing them. For example, HDcells are present in the dorsal tegmental nucleus (Bassett& Taube, 2001; Sharp, Tinkelman, & Cho, 2001), the lat-eral MB (Blair, Cho, & Sharp, 1998, 1999; Stackman &Taube, 1998), the AD nucleus of the thalamus (Blairet al., 1999; Blair, Lipscomb, & Sharp, 1997; Blair &Sharp, 1995; Goodridge & Taube, 1997; Taube & Muller,


Figure 3: Discharge Characteristics of a Neuron of the Anterior Ven-tral Nucleus of the Thalamus That Fired Rhythmically inBursts Synchronous With the Theta Rhythm.

SOURCE: Reprinted from Vertes, Albo, and Viana Di Prisco (2001), p.621, with permission of Elsevier.NOTE: (A) Upper traces: recordings of the hippocampal electroen-cephalogram (EEG) and unit activity before and during theta elicitedwith tail pinch (horizontal bar). Lower traces: expanded record (fromA) showing that the cell continued to discharge in bursts, strongly syn-chronous with theta after termination of tail pinch. (B,C)Autocorrelograms and cross-correlograms (spike-triggered averaging)depicting the rhythmical discharge of the cell (B) locked to the thetarhythm [C]) during theta but not control conditions. (D) Spectral andcross-spectral (coherence) plots showing peaks in the EEG and unitsignals at theta frequency and significant coherence between EEG andunit signals at theta frequency during theta (solid lines) but not duringcontrol conditions (dotted lines).




Figure 4: Neuron of the Ventral Tegmental Nucleus of Gudden (VTg) That Fired Rhythmically in Bursts Synchronous With the HippocampalTheta Rhythm.

SOURCE: Reprinted from Kocsis, Viana Di Prisco, and Vertes (2001), p. 383, with permission of Blackwell Publishing, Oxford.NOTE: (A) Schematic representation of Papez’s circuit and anatomical interconnections of the tegmental nuclei (of Gudden) with Papez’s circuit.(B) Histological section localizing the recording site in VTg of the cell depicted below. (C,D) The discharge characteristics of a VTg neuron (lowertraces) together with the simultaneously recorded hippocampal electroencephalogram (upper traces) showing a change from an irregular patternof activity during nontheta states (D) to a rhythmical bursting pattern during theta (C) elicited with sensory stimulation. Autocorrelograms (E, F)and cross-correlograms (G, H) showing that the VTg neuron fired rhythmically, phased locked to the theta rhythm during theta (E, G) but not dur-ing control (nontheta) conditions (F, H). AT = anterior thalamus; DR = dorsal raphe nucleus; HF = hippocampal formation; MB = mammillarybody; MR = median raphe nucleus.



1998; Zugaro, Tabuchi, Fouquier, Berthoz, & Wiener,2001), the anterior retrosplenial cortex (Chen, Lin,Green, Barnes, & McNaughton, 1994; Cho & Sharp,2001), and the postsubiculum (Golob, Wolk, & Taube,1998; Taube & Muller, 1998; Taube, Muller, & Ranck,1990). By contrast, theta cells are present in the VTg(Bassant & Poindessous-Jazat, 2001; Kocsis et al., 2001),the medial MB (Bland et al., 1995; Kirk et al., 1996;Kocsis & Vertes, 1994, 1997), the AV nucleus of thethalamus (Albo et al., 2003; Vertes et al., 2001), the poste-rior retrosplenial cortex (Albo, Viana Di Prisco,Truccolo, Vertes, & Ding, 2001; Talk, Kang, & Gabriel,2004), and the hippocampus/entorhinal cortex (EC;Alonso & Garcia-Austt, 1987; Brazhnik, Vinogradova,Stafekhina, & Kitchigina, 1993; Colom & Bland, 1987;Dickson, Kirk, Oddie, & Bland, 1995; Fox & Ranck, 1981;Stewart, Quirk, Barry, & Fox, 1992). Finally, the varioussubnuclei comprising these parallel, but segregated,theta and HD systems are themselves anatomically inter-connected, with little crossover between systems.

Vann and Aggleton (2004) recently designated thesetwo systems as the medial and lateral mammillary sys-tems (and associated structures): the medial being thetaand the lateral HD. As depicted in Figure 5 (from Vann& Aggleton, 2004), the medial system (theta) consists ofVTg, the medial MB, AV, and the subiculum/EC; the lat-eral system (HD) consists of the dorsal tegmentalnucleus, lateral MB, AD and the pre-, para-, andpostsubiculum.

Vann and Aggleton (2004) suggested that the recentdemonstration that the MB contains two (theta and HD)functionally segregated systems (or in their terms, twomemory systems in one) may be a key to understandingthe role of MB in memory, which has remained elusivedespite the fact that “the mammillary bodies have beenimplicated in amnesia perhaps for longer than any othersingle brain region” (p. 35). Regarding these two systemsand their possible interaction in memory processing,they stated,

At the same time it is assumed that the medial and lateralmammillary systems function in a synergistic way, asreflected by their common connections with the hippo-campus, tegmentum and anterior thalamus. This coop-erative activity raises the question of where the functionsof these two systems might interact. Anatomically, themost plausible candidate regions are the retrosplenialcortex and the hippocampal formation, although thishas not been formally examined. There is, in addition,the functional question of why head direction and thetamight have a special relationship. The answer to this pre-sumably lies in the hippocampus, as so many of theeffects of mammillary body damage mimic those ofhippocampal damage, but to a lesser degree. (p. 42)

The question of “why head direction and theta mighthave a special relationship” is an intriguing one and mayinvolve the special properties of bursting neurons(Lisman, 1997). For instance, in a review comparing thecharacteristics of single spikes to bursts, Lisman (1997)concluded that, relative to single spikes, bursts representa much more effective (or reliable) mode of communi-cation between neurons. Specifically, Lisman pointedout that there is a very low probability that singlepresynaptic spikes can generate action potentials inpostsynaptic cells (unreliable synapses), compared to ahigh probability that presynaptic bursts would drivepostsynaptic neurons (reliable synapses). Hence, burstsconvert unreliable to reliable synapses (Lisman, 1997).Although various factors undoubtedly contribute to theefficacy of bursts, presumably one of the most importantis the steady accumulation of intracellular calcium inpresynaptic terminals with successive spikes of bursts,eventually leading to the release of sufficient amounts oftransmitter to fire postsynaptic cells (Tank, Regehr, &Delaney, 1995; Wu & Saggau, 1994).

A number of recent studies have shown that relay neu-rons of the thalamus fire tonically or in bursts, with dif-fering characteristics in the two modes of discharge(Guido, Lu, & Sherman, 1992; Guido & Weyand, 1995;Ramcharan, Gnadt, & Sherman, 2000; Sherman, 1996;Weyand, Boudreaux, & Guido, 2001). For example,Guido and Weyand (1995) demonstrated in behavingcats that a large percentage (71%) of cells of the lateralgeniculate nucleus of thalamus discharged in bursts to agradient passed through the visual field and concludedthat bursting “provides a form of visual amplification”serving to detect salient visual stimuli. In like manner,


SeptumSupramammillary nucleiTuberomammilary nuclei

Anterior medialand anteriorventral nuclei

Subiculum Medialentorhinalcortex

Ventraltegmentalnucleus

Medial mammillary nucleus Lateral mammillary nucleus

Anterior dorsalnucleus

Thalamus

Dorsaltegmentalnucleus

Gudden's tegmental nuclei

PresubiculumPostsubiculumParasubiculum

Hippocampal formation Hippocampal formation

Figure 5: Schematic Representation of the Main Nuclei and Their In-terconnections Associated With the Medial MammillaryTheta System and the Lateral Mammillary Head DirectionSystem.

SOURCE: Reprinted from Vann and Aggleton (2004), p. 38, with per-mission of the authors.



Fanselow, Sameshima, Baccala, and Nicolelis (2001)reported that cells of the ventrobasal thalamus, when fir-ing in bursts during whisker movements/twitches, aremaximally sensitive to somatosensory stimulation in theperiods immediately (120 ms) following the burst. Theyindicated that bursts “generate a period during whichneurons are highly sensitive to incoming stimuli.”Finally, Swadlow and Gusev (2001) demonstrated inawake rabbits that ventrobasal thalamic neurons pro-duce significantly stronger postsynaptic actions on cellsof the somatosensory cortex when firing in bursts thantonically.

In a manner similar, then, to relay cells of thethalamus, the burst firing of neurons of Papez’s circuit attheta frequency could selectively modify the activity ofpostsynaptic targets, rendering them more responsive toother inputs. For example, the theta burst discharge ofneurons of the AV nucleus of the thalamus could modifythe activity of target cells of the hippocampus and/or theretrosplenial cortex, increasing their responsiveness toother inputs, such as from HD cells of the AD thalamus,thereby magnifying the influence of anterodorsal HDcells on hippocampal/retrosplenial neurons.

It would appear that directional information is verycritical for a rat (and other species) when engaged inlocomotor/exploratory behaviors (theta states) and lessso during nonlocomotor activities such as grooming orconsumatory acts (nontheta states). Accordingly, thetamay serve as an important signal involved in the differen-tial processing of HD activity under the two conditions(e.g., locomotion and grooming); that is, only when HDactivity is coupled with theta-rhythmic discharge is HDactivity processed and used to guide spatial behaviors.

In summary, recent evidence indicates that a theta-rhythmical signal exits the hippocampus and reverber-ates through structures of Papez’s circuit, possiblyinvolved in memory processing functions of this circuit.Two parallel, and anatomically segregated, systemswithin Papez’s circuit have been identified: theta andHD circuits. The two systems may functionally interact atmultiple levels of the circuit to process HD informationused for spatial learning/navigation.

THE NUCLEUS REUNIENS (RE) OF THETHALAMUS: A MAJOR SOURCE OFMULITMODAL LIMBIC INFORMATIONTO THE HIPPOCAMPUS

Although the hippocampus receives a diverse array ofinformation, there are few direct inputs to the hippo-campus. Excluding monoaminergic afferents, few struc-tures project directly to the hippocampus, essentiallyonly the EC, medial septum, basal nucleus of amygdala,

the SUM, and the RE of the thalamus (Witter & Amaral,2004). Of these, the RE has been the least examined.

The RE lies ventrally on the midline, dorsal to thethird ventricle and ventral to the rhomboid nucleus ofthe thalamus, and extends longitudinally, virtuallythroughout the thalamus (see Swanson, 1998). The RE isthe largest of the midline nuclei of the thalamus. The REis the major source of thalamic afferents to the hippo-campus and parahippocampal structures (Bokor, Csaki,Kocsis, & Kiss, 2002; Dolleman-Van der Weel & Witter,1996; Herkenham, 1978; Riley & Moore, 1981; Room &Groenewegen, 1986; Su & Bentivoglio, 1990;Wouterlood, 1991; Wouterlood, Saldana, & Witter, 1990;Wyss, Swanson, & Cowan, 1979b; Yanagihara, Niimi, &Ono, 1987). RE distributes densely to CA1 of Ammon’shorn, the ventral subiculum, and the medial EC, as wellas moderately to the dorsal subiculum, theparasubiculum, and the lateral EC (Bokor et al., 2002; Su& Bentivoglio, 1990; Wouterlood, 1991; Wouterloodet al., 1990). There are essentially no RE projections tothe dentate gyrus. RE fibers form asymmetric (excit-atory) contacts predominantly on distal dendrites ofpyramidal cells in stratum lacunosum-moleculare ofCA1 (Wouterlood et al., 1990).

Based on the relationship of RE to the hippocampus,we were interested in sources of afferent projections tothe RE. In an initial report (Vertes, 2002), we examinedprojections from the medial prefrontal cortex (mPFC)to the thalamus, with a concentration on RE. Injectionsof the anterograde tracer, PHA-L, were made in the fourdivisions of the mPFC (medial agranular, anteriorcingulate, prelimbic cortex, and infralimbic cortex) andpatterns of labeling determined. In brief, we showed that(a) the infralimbic (IL), prelimbic (PL), and anteriorcingulate cortices distribute heavily and selectively tomidline/medial structures of the thalamus, includingthe paratenial, paraventricular, interanteromedial,anteromedial, intermediodorsal, mediodorsal,reuniens, and central medial nuclei; (b) the medialagranular cortex distributes strongly to the rostralintralaminar nuclei (central lateral, paracentral, centralmedial nuclei) and to the ventromedial andventrolateral nuclei of thalamus; and (c) importantly, allfour divisions of the mPFC project densely (or massively)to the RE.

The pattern of distribution of infralimbic fibers to thethalamus is schematically illustrated in Figure 6. Asdepicted, labeling is restricted to the midline nuclei ofthe thalamus, and within the midline thalamus is verydense in the mediodorsal nucleus and RE. At therostral thalamus (Figure 6A-6C), labeling spreadsdorsoventrally throughout the midline, whereas at thecaudal thalamus (Figure 6D-6G), labeling is essentiallyconfined to the paraventricular and mediodorsal nuclei,




dorsally, and RE, ventrally. This latter pattern is illus-trated in the photomicrograph of Figure 7. As depicted,labeled fibers virtually outline RE and are very abundantin the lateral wings of RE, ipsilaterally (left side).

Several reports in various species have describedprominent projections from the hippocampus to theprefrontal cortex (Carr & Sesack, 1996; Cavada, Llamas,

& Reinoso-Suarez, 1983; Ferino, Thierry, & Glowinski,1987; Irle & Markowitsch, 1982; Jay, Glowinski, &Thierry, 1989; Jay & Witter, 1991; Swanson, 1981; vanGroen & Wyss, 1990). In rats, hippocampal projectionsto the mPFC arise from temporal aspects of CA1 and thesubiculum and terminate in a fairly restricted region ofthe ventral mPFC, including the medial orbital area, IL,and PL (Jay et al., 1989; Jay & Witter, 1991). Despite well-documented hippocampal to mPFC projections, thereare essentially no direct projections from the mPFCto the hippocampus (Beckstead, 1979; Buchanan,Thompson, Maxwell, & Powell, 1994; Hurley, Herbert,Moga, & Saper, 1991; Reep, Corwin, Hashimoto, & Wat-son, 1987; Room, Russchen, Groenewegen, & Lohman,1985; Sesack, Deutch, Roth, & Bunney, 1989; Takagishi& Chiba, 1991).

In the absence of prefrontal projections to the hippo-campus, the findings that the mPFC projects strongly tothe RE (Vertes, 2002, 2004), coupled with the demon-stration that RE is a major source of afferents to the hip-pocampus, suggests that RE is an important relay in thetransfer of information from the mPFC to the hippocam-pus. This system of connections (mPFC-RE-hippocampus)would appear to be the major route from the prefrontalcortex to the hippocampus and accordingly would com-plete an important functional loop between the hippo-campus and mPFC.

In a continuing analysis of RE, we recently examinedother afferents to the RE, or the totality of inputs to theRE (McKenna & Vertes, 2004). Injections of the retro-grade tracer Fluorogold were made into various regionsof RE and patterns of retrogradely labeled cells deter-mined. We showed that RE receives a very diverse andwidely distributed set of afferent projections. Figure 8schematically depicts patterns of projections to therostromedial RE. As illustrated, the RE receives pro-nounced projections from several cortical andsubcortical sites. They include (a) the orbitomedial (seealso above), insular, ectorhinal, perirhinal, andretrosplenial cortices; (b) the CA1/subiculum of hippo-campus; (c) the claustrum, lateral septum, substantiainnominata, and lateral preoptic nucleus of the basalforebrain; (d) the medial nucleus of amygdala (MEA);(e) the paraventricular and lateral geniculate nuclei ofthalamus; (f) the zona incerta; (g) the anterior,ventromedial, lateral, posterior, supramammillary, anddorsal premammillary nuclei of the hypothalamus; and(h) the ventral tegmental area, periaqueductal gray,medial and posterior pretectal nuclei, superiorcolliculus, precommissural nucleus, parabrachialnucleus, laterodorsal and pedunculopontine tegmentalnuclei, nucleus incertus, and the dorsal and medianraphe nuclei of the brainstem.


IC

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PF FR

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PO

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LHLGNdCL

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Figure 6: Schematic Representation of Selected Sections Throughthe Diencephalon Depicting Labeling Present in theThalamus Produced by a PHA-L Injection in theInfralimbic Cortex.

SOURCE: Reprinted from Vertes (2002), p. 168, with permission ofWiley-Liss, Inc.NOTE: Sections aligned rostral to caudal (A-H). AD = anterodorsal nu-cleus; AM = anteromedial nucleus; AMy = AM, ventral part; AV =anteroventral nucleus; CA3 = CA3 field of Ammon’s horn; CEM = cen-tral medial nucleus; CL = central lateral nucleus; F = fornix; FI = fimbriaof hippocampal formation; FR = fasciculus retroflexus; IAM =interanteromedial nucleus; IC = internal capsule; IMD =intermediodorsal nucleus; LGNd,v = lateral geniculate nucleus, dorsaland ventral divisions; LH = lateral habenula; LD = lateral dorsal nu-cleus; LP = lateral posterior nucleus; LV = lateral ventricle; MD,l =mediodorsal nucleus, lateral division; MH = medial habenula; ML =medial lemniscus; MT = mammillothalamic tract; PC = paracentral nu-cleus; PF = parafascicular nucleus; PH = posterior nucleus of hypothala-mus; PO, posterior nucleus; PT, paratenial nucleus; PVa,p,paraventricular nucleus; anterior and posterior divisions; RE = nucleusreuniens; RH = rhomboid nucleus; RT = reticular nucleus; SM = striamedullaris, SME = submedial nucleus; ST = stria terminalis; VAL = ven-tral anterior-lateral complex; VB = ventrobasal complex; VM =ventromedial nucleus; ZI = zona incerta; 3V = third ventricle.




Figure 7: Darkfield Photomicrograph of a Transverse Section Through the Rostral Diencephalon Showing Patterns of Labeling at the RostralThalamus Produced by a PHA-L Injection in the Infralimbic Cortex.

SOURCE: Reprinted from Vertes (2002), p. 171, with permission of Wiley-Liss, Inc.NOTE: Note pronounced labeling in the paraventricular, mediodorsal (MD), and intermediodorsal nuclei, dorsally, and the nucleus reuniens(RE), ventrally. SM = stria medullaris Scale bar = 450 µm.




Figure 8: Series of Representative Rostrocaudally Aligned Schematic Transverse Sections (A-P) Depicting the Location of Retrogradely LabeledCells in the Brain Produced by a Fluorogold Injection in the Rostromedial Part of Nucleus Reuniens (G).

SOURCE: Reprinted from McKenna and Vertes (2004), pp. 120-121, with permission of Wiley-Liss, Inc.NOTE: Circles = 10 cells; triangles = 5 cells; stars = 2 cells. AC,d = anterior cingulate cortex, dorsal division; ACB = nucleus accumbens; AGm = medialagranular (prefrontal) cortex; AGl = lateral agranular (prefrontal) cortex; AHN = anterior hypothalamic nucleus, AI,d,p,v = agranular insular cor-tex, dorsal, posterior, ventral divisions; AM = anteromedial nucleus of thalamus; APN = anterior pretectal nucleus; BST = bed nucleus of striaterminalis; CA1, CA3 = field CA1, CA3 of Ammon’s horn; CEA = central nucleus of amygdala; CLA = claustrum; COA = cortical nucleus of amygdala;COM = commissural nucleus of PAG; CP = caudate/putamen; DBh = nucleus of the diagonal band, horizontal limb; DG = dentate gyrus of hippo-campus; DMH = dorsomedial nucleus of hypothalamus; DR = dorsal raphe nucleus; EC = entorhinal cortex; ECT = ectorhinal cortex; EN =endopiriform nucleus; FF = fields of Forel; IC = inferior colliculus; IL = infralimbic cortex; IP = interpeduncular nucleus; LD = lateral dorsal nucleusof thalamus; LDT = laterodorsal tegmental nucleus; LG,d,v = lateral geniculate nucleus, dorsal, ventral divisions; LH = lateral habenula; LHy = lat-eral hypothalamic area; LS = lateral septal nucleus; MA = magnocellular preoptic nucleus; MB = mammillary bodies; MD = mediodorsal nucleus ofthalamus; MgRe = magnocellular reticular nucleus; MO5 = motor nucleus of trigeminal nerve; MPN = medial preoptic nucleus; MPO = medialpreoptic area; MR = median raphe nucleus; MRF = mesencephalic reticular formation; MS = medial septum; NGC = nucleus gigantocellularis; NTS= nucleus of solitary tract; N7 = facial nucleus; OC = occipital cortex; OT = olfactory tubercle; PAG = periaqueductal gray; PARA = parasubiculum ofhippocampus; PBm = parabrachial nucleus, medial division; PCO = precommissural nucleus of PAG; PERI = perirhinal cortex; PH = posterior nu-cleus of hypothalamus; PIR = piriform cortex; PL = prelimbic cortex; PN = nucleus of pons; PGC = nucleus paragigantocellularis; POST =postsubiculum of hippocampus; PPN = pedunculopontine tegmental nucleus; PRE = presubiculum of hippocampus; PV = paraventricular nucleusof thalamus; PVR = parvocellular reticular nucleus; RE = nucleus reuniens of thalamus; RM = raphe magnus; RPC = nucleus reticularis pontis

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Figure 9 depicts patterns of retrograde labeling in thesubiculum (of hippocampus) following the RE injectionof Figure 8. As shown, the entire dorsoventral extent ofthe ventral subiculum (postsubiculum, dorsal/ventralsubiculum) was densely labeled. These pronouncedsubicular-RE projections complement equally densereturn RE projections to the hippocampus (Bokor et al.,2002; Dolleman-Van der Weel & Witter, 1996;Wouterlood, 1991; Wouterlood et al., 1990), indicatingstrong reciprocal connections between these structures.Figure 10 shows prominent cell labeling in the amygdalafollowing a rostrolateral RE injection, mainly within theMEA and to a lesser extent in the anterior cortical andbasomedial nuclei. An early report by Canteras, Simerly,and Swanson (1995) also described strong projectionsfrom the MEA to the RE, leading them to conclude that“another potentially significant way for the MEA toaccess the hippocampal formation is by way of inputsfrom the nucleus reuniens” (p. 238).

In summary, the RE receives pronounced projectionsfrom diverse regions of the brain involved in a host offunctions. To our knowledge, no other nucleus of thethalamus, and certainly none outside of the midlinethalamus, receives a comparable degree and diversity ofinputs. Although RE receives projections from severalstructures of the brain, the output of RE is quite limited.RE essentially distributes only to the hippocampal for-mation, EC, and orbital/medial prefrontal cortices(Bokor et al., 2002; Conde, Maire-Lepoivre, Audinat, &Crepe, 1995; Herkenham, 1978; Ohtake & Yamada,1989; Reep & Corwin, 1999; Reep, Corwin, & King, 1996;Risold, Thompson, & Swanson, 1997; Van der Werf,Witter, & Groenewegen, 2002; Vertes, Hoover, &Sherman, 2002; Vertes, McKenna, do Valle, Sherman, &Hoover, 2003; Wouterlood, 1991; Wouterlood et al.,1990; Zhang & Bertram, 2002). The RE appears to be acritical site for the convergence of information from var-ious sources (mainly from limbic/limbic-related struc-tures) and its transfer to the hippocampus andprefrontal cortex.

RE Actions on the Hippocampus and mPFC

Although it has been know for some time that the REis a major input to the hippocampus (Herkenham,1978), few studies have examined the physiologicaleffects of the RE on the hippocampus. Two recent

reports have shown, however, that the RE exerts signifi-cant actions at the CA1 of the hippocampus (Bertram &Zhang, 1999; Dollemann-Van der Weel, Lopes da Silva,& Witter, 1997).

Dollemann-Van der Weel et al. (1997) demonstratedthat RE stimulation produced large negative-going fieldpotentials at the stratum lacunosum-moleculare of CA1of the hippocampus, indicative of prominent depolariz-ing actions on distal apical dendrites of CA1 pyramidalcells, as well as a marked facilitation of evoked responsesat CA1 using a paired-pulse paradigm. They proposedthat the RE may “exert a persistent influence on the stateof pyramidal cell excitability,” depolarizing cells to closeto threshold for activation by other excitatory inputs (p.5684).

Consistent with this, Bertram and Zhang (1999)recently compared the effects of stimulation of the REwith stimulation of the CA3 region of the hippocampuson population responses (field excitatory postsynapticpotentials and spikes) at CA1 and reported that REactions on CA1 were equivalent to, and in some cases con-siderably greater than, those of CA3 on CA1. They con-cluded that the RE projection to the hippocampus “allowsfor the direct and powerful excitation of the CA1 region.This thalamohippocampal connection bypasses thetrisynaptic/commissural pathway that has been thoughtto be the exclusive excitatory drive to CA1” (p. 15).

As briefly discussed above, in addition to the hippo-campus/EC, the RE also distributes strongly to theorbitomedial prefrontal cortex (see Vertes et al., 2003).In a manner shown for the hippocampus (Bertram &Zhang, 1999; Dollemann-Van der Weel et al., 1997), werecently demonstrated that RE stimulation producedmarked excitatory actions on the mPFC. As depicted inFigure 11, RE stimulation gave rise to short-latency (~20ms), large-amplitude (1-2 mV) evoked responses in themPFC. The typical response consisted of a small positivedeflection (P1) at about 7 ms, followed by a large nega-tive deflection (N2) at 20 to 40 ms, and then a large posi-tive wave at 60 to 80 ms. Although effects were observedthroughout the dorsoventral extent of the mPFC withRE stimulation, they were most pronounced (i.e., largestamplitude) in the prelimbic and infralimbic cortices ofthe ventral mPFC (Figure 11).

The hippocampus and prefrontal cortex serve well-recognized roles in memory processing. In an interest-


(continued)

caudalis; RPO = nucleus reticularis pontis oralis; RR = retrorubral area; RSC = retrosplenial cortex; RTG = reticular tegmental nucleus; SC,i = supe-rior colliculus, intermediate layer; SI = substantia innominata; SO = superior olivary nucleus; SSI = primary somatosensory cortex; SSII = secondarysomatosensory cortex; SN,c,r = substantia nigra, pars compacta, pars reticulata; SN5 = spinal nucleus of trigeminal nerve; SV = superior vestibularnucleus; SUB,d,v = subiculum, dorsal, ventral parts; SUM = supramammillary nucleus; TE = temporal cortex; TTd = taenia tecta, dorsal part; VAL =ventral anterior-lateral complex of thalamus; VB = ventrobasal complex of thalamus; VTA = ventral tegmental area; ZI = zona incerta; 4V = fourthventricle.




Figure 9: Low- (A) and High-Magnification (B, C) Light-Field Photomicrographs Depicting Retrograde Cell Labeling in the Ventral SubicularComplex Produced by a Fluorogold Injection in the Rostromedial Part of the Nucleus Reuniens.

SOURCE: Reprinted from McKenna and Vertes (2004), p. 123, with permission of Wiley-Liss, Inc.NOTE: As shown, pronounced numbers of labeled cells extended dorsal-ventrally throughout the subiculum within the postsubiculum and dorsaland ventral subiculum. (B, C) Clusters of labeled cells of the dorsal subiculum shown at high levels of magnification (see arrows). Scale bar for (A) =325 µm; for (B) = 130 µm; for (C) = 65 µm.



ing variant on the role of the mPFC in memory (via inter-actions with the hippocampus), Buckner, Kelley, andPeterson (1999) suggested that the prefrontal cortexmay promote memory formation without being directlyinvolved in “intentional memorization.” According tothe authors, the prefrontal cortex uses information inshort-term (working) memory to deal with impendingtask demands, and its long-term storage may simply be aby-product of its use in meeting immediate demands. As

such, the conversion from working memory to long-termstores involves the transfer of information from themPFC to the hippocampus and adjacent structures ofthe temporal lobe. They stated,

One speculation would be that the critical cascade driv-ing human memory formation occurs only when frontalactivity provides information to medial temporal lobestructures. The medial temporal lobe may then functionto bind together from frontal and other cortical regionsto form lasting, recollectable memory traces. Thus, bothregions would be critical to the conception of a memory,and lack of participation of either brain region woulddisrupt memory formation. (p. 313)

The demonstration that the RE is strongly reciprocallylinked to the hippocampus and to the mPFC, and exertspronounced excitatory actions on both structures, sug-gests that the RE may represent a critical interface be-tween the hippocampus and orbitomedial prefrontalcortex in memory processing.

THE ROLE OF THE THETA RHYTHM OFTHE HIPPOCAMPUS IN MEMORY

Although theta has been implicated in several func-tions including arousal (Green & Arduini, 1954) andrecently sensorimotor integration (Bland & Colom,1993; Bland & Oddie, 2001), the prevailing view is thattheta serves a critical role in mnemonic functions of thehippocampus (N. Burgess, Maguire, & O’Keefe, 2002;Hasselmo, 2000; Hasselmo, Bodelon, & Wyble, 2002;Kahana, Seelig, & Masden, 2001; Kirk & Mackay, 2003;Vertes & Kocsis, 1997). In an early report, Winson (1978)described the important findings that small medialseptal lesions that eliminated theta in the hippocampusproduced severe spatial memory deficits in rats. Subse-quent studies similarly reported that the loss of thetawith reversible or irreversible lesions of the medial sep-tum significantly altered performance on spatial(Leutgeb & Mizumori, 1999; M’Harzi & Jarrard, 1992;Mizumori, Perez, Alvarado, Barnes, & McNaughton,1990) as well as nonspatial tasks (Asaka, Griffin, & Berry,2002; Mizumori et al., 1990) in rats and rabbits.

In an early review (Vertes, 1986) we proposed thattheta may promote memory in a manner comparable tothe long-term changes produced by tetanic stimulationin long-term potentiation (LTP) experiments. Specifi-cally, we stated that “theta rhythm, which involves thesynchronous activation of large numbers ofseptohippocampal neurons, may act as a ‘naturaltetanizer’ producing synaptic modifications at specifichippocampal sites supportive of long term changes atthese sites” (p. 65). In effect, Vertes suggested that thetamay potentiate the actions of other inputs to the hippo-


Figure 10: Low- (A) and High-Magnification (B) Light-Field Photomi-crographs Depicting Labeled Neurons in the AmygdalaProduced by Fluorogold Injection in the Rostrolateral Partof the Nucleus Reuniens.

SOURCE: Reprinted from McKenna and Vertes (2004), p. 130, withpermission of Wiley-Liss, Inc.NOTE: Note pronounced numbers of labeled cells in the medial(MEA), anterior cortical (COA), and basomedial nuclei of theamygdala (BMA). (B) High-magnification photomicrograph of a smallcluster of labeled cells in the cortical nucleus of amygdala (arrow in A).Scale bar for (A) = 350 µm; for (B) = 70 µm.



campus, possibly to encode information arriving viathese afferents. This was supported by the early demon-stration that septal stimulation, mimicking theta,significantly enhanced population responses in thehippocampus.

For instance, Krnjevic and Robert (1982) showed thatsingle-pulse or tetanic stimulation of the medial septumsignificantly potentiated commissurally-elicited popula-tion spikes at CA1 and likened the process to what occursnaturally with theta. They stated,

The fact that the septal facilitatory action is evoked mosteffectively by brief tetanic volleys at 50-100 Hz seems sig-nificant in view of previous observations that many septalunits fire in 50-100 Hz bursts and that theta waves areespecially readily evoked by septal stimulation in brief,high frequency trains. (p. 2181)

In like manner, Buzsaki, Grastyan, Czopf, Kellenyi,and Prohaska (1981) described significantly larger

amplitude population spikes at CA1 (to commissuralstimulation) during theta-associated behaviors (e.g.,running) than during nontheta associated behaviors(e.g., grooming and drinking) in freely moving rats andconcluded that the medial septum, through its role ingenerating theta, “exerts a potent biasing effect on theefficacy of other afferents to the hippocampus” (p. 235).

Perhaps the strongest support, however, for the viewthat theta may act as “natural tetanizer” in the long-termmodification of hippocampal activity is the demonstra-tion that LTP is optimally elicited in the hippocampuswith stimulation at theta frequency (for review, seeVertes & Kocsis, 1997). In an initial report, using thehippocampal slice preparation, Larson, Wong, andLynch (1986) showed that LTP was most effectivelyinduced in the CA1 area of rats by trains of stimulationthat were separated by 200 ms (i.e., 5 Hz). Intervalsshorter or longer than 200 ms produced significantlyless, or no, potentiation. In a follow-up study, Staubli andLynch (1987) showed that stimulation at theta fre-


Figure 11: Evoked Field Potentials in the Infralimbic/Prelimbic Cortex of the Medial Prefrontal Cortex (Left Side) to Stimulation (300 A) at 250m Steps Dorsal-Ventrally Through the Midline Thalamus.

NOTE: As depicted, evoked responses were elicited with stimulation dorsally and ventrally in the midline thalamus, centered in the paraventricularnucleus and nucleus reuniens, respectively. There was a null zone between them. The highest amplitude evoked potentials were produced withstimulation of the nucleus reuniens. AGm = medial agranular (prefrontal) cortex; AGl = lateral agranular (prefrontal) cortex; AHN = anterior hy-pothalamic nucleus; AM = anteromedial nucleus of thalamus; CLA = claustrum; IAM = interanteromedial nucleus of thalamus; IL = infralimbic cor-tex; LHA = lateral hypothalamic area; PV = paraventricular nucleus of thalamus; RE = nucleus reuniens of thalamus.



quency also very effectively produced LTP at CA1 in thebehaving rat, and it remained stable for 1 to 5 weeks oruntil the preparation deteriorated. The authors com-mented that it seemed remarkable that a brief period ofstimulation (at theta frequency), which in total lastedabout 300 ms, produced effects that persisted for severalweeks but indicated that this would be expected of a pro-cess subserving memory. They stated that their findings“point to a possible link between the naturally occurringtheta rhythm and the development of synaptic changesof the type needed for memory storage” (p. 233).

Diamond, Dunwiddie, and Rose (1988) subsequentlyexamined various parameters of this effect in thehippocampal slice and behaving rat. Stimulation con-sisted of a single priming pulse followed 140 to 170 mslater by a high-frequency (100 Hz) burst ranging from 2to 10 pulses. This was termed, and is now commonlyreferred to as, primed burst (PB) stimulation and the LTPelicited by it as primed burst potentiation. The authorsshowed that (a) priming intervals of 140 to 170 ms (i.e.,between the priming pulse and bursts) produced LTPand shorter or longer intervals were ineffective; (b) 5 or10 pulses that were not preceded by a priming pulsefailed to elicit LTP; (c) significant PB potentiation wasobtained with as few as 3 pulses (a single priming pulsefollowed 170 ms later by a 2-pulse burst); (d) PBpotentiation could be elicited both homo- andheterosynaptically, that is, with the priming pulse andbursts delivered to the same or separate sets of afferentsto CA1, respectively; (e) LTP elicited with PB and con-ventional stimulation parameters were not additive, sug-gesting common underlying mechanisms for the twoforms of LTP; and (f) the magnitude and duration of PBpotentiation at CA1 was virtually the same for the sliceand awake preparation.

Rose and Dunwiddie (1986) pointed out that prior tothe demonstration of PB potentiation, a major problemin viewing LTP as an endogenous substrate for memorywas that the stimulation parameters commonly used toinduce it (e.g., 100 Hz for 1 second) were verynonphysiological. This problem has seemingly been cir-cumvented with the demonstration that LTP can beinduced in the hippocampus with as few three to fivepulses, when pulses are delivered at theta frequencies.

The findings that LTP can be optimally induced in thehippocampus with stimuli mimicking theta suggest arole for the naturally occurring theta rhythm in LTP/LTP-like effects. In this regard, it has been shown in thehippocampal slice (Huerta & Lisman, 1993, 1995, 1996)and intact preparation (Bramham & Srebro, 1989;Holscher, Anwyl, & Rowan, 1997; Pavlides, Greenstein,Grudman, & Winson, 1988) that stimulation delivered inthe presence, but not in the absence, of theta generates

LTP and that effects are most pronounced when stimula-tion is given on the positive phase of the theta rhythm(Holsher et al., 1997; Huerta & Lisman, 1993, 1995,1996; Pavlides et al., 1988). Pavlides et al. (1988) showedin urethane anesthetized rats that PB stimulation of theperforant path delivered on the positive phase of thetheta rhythm induced LTP, whereas that given on thenegative phase of theta resulted in a decrease in popula-tion spike amplitudes or was without effect. Huerta andLisman (1995, 1996) similarly reported that a singleburst of four pulses at the peaks of carbachol-elicitedtheta in the hippocampal slice produced long-lastingLTP at CA1, whereas stimulation of the trough of thetaproduced a suppression (depotentiation) of previouslypotentiated synapses.

In accord with the foregoing, Kandel and colleagues(Bach, Hawkins, Osman, Kandel, & Mayford, 1995;Mayford et al., 1996; Mayford, Wang, Kandel, & Odell,1995; Rotenberg, Mayford, Hawkins, Kandel, & Muller,1996) recently examined several hippocampal-relatedfunctions in transgenic mice in which calcium-calmodulin-dependent kinase II (CaMKII) was ren-dered persistently active by replacing threonine286 withan aspartate group (CaMKII-Asp286). The geneticallyaltered mice (CaMKII-Asp286) showed (a) a loss of LTPelicited with stimulation at theta frequency but not thatelicited with high-frequency stimulation, (b) a disrup-tion of place cell activity, and (c) severe deficits in spatiallearning. Based on these findings, Kandel and associates(Bach et al., 1995)proposed that the endogenous thetarhythm may exert LTP-like effects, synaptically strength-ening place cells leading to the formation of spatial mapsnecessary for spatial learning/memory. They stated,

There are, however, several reasons to believe that fre-quencies of about 5 Hz may be particularly important forspatial memory, because these frequencies stimulateendogenous firing patterns that seem important for spa-tial memory. When a rodent explores a new environ-ment, it displays a 4-12 Hz theta rhythm in the hippocam-pus driven by cholinergic synaptic inputs from themedial septum. Cholinergic activation in turn leads to adepolarizing oscillation at the theta frequency in themembrane potential of the CA3 pyramidal neurons. Atthe peak of these depolarizations, the CA3 cells fire oneor more action potentials that, in turn, might inducetheta frequency LTP in the CA1 neurons. Thus, thelearning impairment seen in CaMKII-Asp-286 trans-genic mice may be due to the lost capacity to form LTP inresponse to the synaptic activation patterns that occurduring learning. (p. 913)

Finally, in line with the demonstration that LTP canbe effectively elicited in the presence but not in theabsence of theta, Berry and colleagues (Griffin, Asaka,




Darling, & Berry, 2004; Seager, Johnson, Chabot, Asaka,& Berry, 2002) recently reported that the rate of acquisi-tion of a classically conditioned eye-blink response inrabbits was significantly accelerated when conditioningtrials were given in the presence than in the absence oftheta. Essentially, rabbits reached criteria responding inapproximately half the time (or with 50% few trials)when trials were timed to occur with theta than withoutit. The researchers concluded that “naturally occurringtheta activity plays a facilitatory role in the establishmentof a neural representation of the CS-US contingency”(Griffin et al., 2004, p. 408).

Theta and Human Memory

Several recent studies have directly linked theta tomemory-processing functions in humans (for review, seeBasar, Schurmann, & Sakowitz, 2001; Bastiaansen &Hagoort, 2003; Klimesch, 1999). In an initial report,Klimesch, Doppelmayr, Russegger, and Pachinger(1996) described significant increases in the power oftheta (4-7 Hz) during the encoding of words that weresubsequently successfully recalled compared to thosenot recalled. In a follow-up study, they demonstratedequivalent increases in theta during the successfulretrieval of lists of words, more pronounced in goodthan poor performers (Doppelmayr, Klimesch,Schwaiger, Auinger, & Winkler, 1998).

Similar changes in the percentage and/or power oftheta have been described for the encoding/retrieval ofvisual (e.g., pictures; Klimesch et al., 2001), auditory(Krause, Sillanmaki, Haggqvist, & Heino, 2001), and tac-tile (Grunwald et al., 1999, 2001) information, as well asfor tasks involving declarative memory, recognitionmemory, working memory, and spatial memory inhumans (see below).

With respect to recognition memory, A. P. Burgessand Gruzelier (1997) described a greater than 2-foldincrease in the power of theta during the presentation ofa previously viewed (or repeated) list of words, com-pared to a new list of words. In an early report on work-ing memory, Gevins, Smith, McEvoy, and Yu (1997) dem-onstrated significant increases in theta in the anteriorcingulate cortex during performance of a working mem-ory dual n-back task. Specifically, participants were pre-sented with a short list of 1 of 12 letters in 1 of 12 loca-tions on a video monitor and were required to match aprobe letter with a letter n-back on the list (e.g., threeback)—the letter or its location. Theta increased as afunction of increased (working) memory load on thetask, with additional changes occurring with improvedperformance on the task. These basic findings have beenconfirmed in several subsequent studies involving work-ing memory tasks (Fell et al., 2003; Jensen & Tesche,2002; Raghavachari et al., 2001; Sarnthein, Petsche,

Rappelsberger, Shaw, & von Stein, 1998; Tesche &Karhu, 2000; Weiss, Muller, & Rappelsberger, 2000).

Recording EEG activity with depth (or subdural) elec-trodes in epileptic patients (as opposed to conventionalscalp recordings), Kahana, Sekuler, Caplan, Kirschen,and Madsen (1999) demonstrated task-dependentchanges in theta in various regions of the cortex duringthe navigation of virtual mazes. They showed that thetaactivity (a) was not continuously present but occurredduring distinct well-defined episodes associated with thelearning/recall of virtual mazes, (b) was visible in theraw EEG traces, and (c) was significantly more pro-nounced with the learning of complex 12-choice com-pared to simpler 6-choice mazes. They concluded that “itis likely that theta oscillations are important in humanspatial navigation” (p. 783).

These investigators (Raghavachari et al., 2001) subse-quently described similar findings using a nonspatial,verbal working memory task: the Sternberg task. Similarto the n-back task (see above), participants were pre-sented with a list of one to four letters (consonants) andwere required to determine whether a “probe” matchedletters on the list. They showed that theta activity dramat-ically increased at the start of the trial, continuedthrough the trial, and abruptly ended at the terminationof the trial, a phenomena termed gating. They furtherreported that increases in theta were dependent onworking memory components of the task and not onsensory or motor aspects of the task.

In contrast to (or in addition to) overall changes inlevels of theta during memory-associated tasks, recentreports have described changes in degrees of coherence(spectral covariance) of theta between regions of thecortex (or between cortex and hippocampus) duringworking memory tasks. Sarnthein et al. (1998) reportedstrong theta coherence between the prefrontal and pos-terior association cortices during the acquisition of ver-bal and visuospatial working memory tasks. Participantswere shown either a short sequence of (keyboard) char-acters or abstract line drawings and, following a 4-seconddelay, were required to reproduce them. Coherence washigh during the 4-second working memory interval,leading the authors to conclude that “low frequencyinteractions between the prefrontal cortex and posteriorassociation areas mediate working memory processes”(p. 7096).

In like manner, Fell et al. (2003) demonstrated thattheta activity was highly coherent between the hippo-campus and rhinal cortex during the encoding of suc-cessfully versus nonsuccessfully recalled words. Theauthors stated that this coupling of theta between thehippocampus and rhinal cortex “supports the hypothe-sis of a specific function of theta oscillations in declara-tive memory formation” (p. 1086).




Summary

Several lines of evidence indicate that the thetarhythm is critically involved in memory processing func-tions, as follows: (a) LTP in the hippocampus is optimallyelicited with stimulation at theta frequency, (b) stimula-tion delivered in the presence but not in the absence oftheta potentiates population responses in the hippocam-pus, (c) discrete medial septal lesions that abolish thetaproduce severe learning/memory deficits, (d) the lossof LTP with PB (or theta) stimulation in mutant mice isassociated with a pronounced disruption of place cellactivity and spatial memory, and (e) task-dependentincreases in the percentage and/or power of theta havebeen described in the cortex and hippocampus ofhumans during performance of various episodic/declarative, recognition, spatial, and working memorytasks.

CONCLUSIONS

As reviewed above, theta promotes memory, and thequestion that begs answering is “by what mecha-

nism(s)?” Insights into the process may be gained by ref-erence to factors associated with LTP (see also above). Ina recent review of LTP, Malenka and Nicoll (1999)described what they termed triggering mechanisms for LTP.According to the authors, LTP is triggered by the com-bined actions of high-frequency (e.g., tetanic stimula-tion) and low-frequency (normal synaptic) inputs to N-methyl-D-aspartate (NMDA )receptor–containing cells.The high-frequency (or strong) signal drivespostsynaptic neurons to threshold for the opening ofNMDA receptor channels, which become activated bythe simultaneous release of glutamate from synapticinputs to these neurons. This was referred to as the “pair-ing protocol.” As further pointed out, the opening ofNMDA receptor channels results in a massive influx ofcalcium, which initiates a series of events that leads to arestructuring of the postsynaptic membrane and aneventual strengthening of connections between pre- andpostsynaptic cells (Malenka & Nicoll, 1999).

By analogy, we suggest that the theta rhythm repre-sents the strong depolarizing drive to the hippocampus,whereas other inputs (mainly cortical) constitute the


Figure 12: Schematic Diagram Showing the Two Major Types of Input to the Hippocampal Formation: A Theta System Involving Ascending BrainStem–Diencephalo-Septal Projections (RPO SUM MS/DBv) and Direct SUM Projections to the Hippocampus and an Informa-tion-Bearing System Ultimately Reaching the Hippocampus Through the Entorhinal Cortex and Nucleus Reuniens of Thalamus.

NOTE: As described (see text), we propose that the temporal convergence of activity of these two systems would result in the encoding of informa-tion in the hippocampus from its main afferent sources. MS/DBv = medial septum/vertical limb of the diagonal band nucleus; mPFC = medialprefrontal cortex; RE = nucleus reuniens; RPO = nucleus pontis oralis; SUM = supramammillary nucleus.



information-carrying synaptic input to the hippocampusand, when coupled, produce lasting changes. Specifi-cally, during theta-associated states, theta would drivelarge populations of hippocampal neurons to thresholdfor the activation of NMDA receptor channels, which,when coupled with the release of glutamate from otherinputs to these cells, would result in the opening ofNMDA channels and consequent cellular changes.Accordingly, events occurring coincident with thetawould have greater (or selective) access to the hippo-campus. In effect, theta would serve as a significance sig-nal to the hippocampus; that is, information arrivingwith theta would be stored (at least temporarily) in thehippocampus, whereas information arriving in theabsence of theta would not be encoded—or not to thesame degree as that reaching the hippocampusconcurrently with theta.

To conclude, the hippocampus receives two maintypes of input: theta from ascending brain stem–diencephalo-septohippocampal systems (Figure 12) andinformation bearing mainly from thalamocortical/cortical systems (Figure 12). The temporal convergenceof activity from these two systems would result in theencoding of information in the hippocampus mainlyreaching it from the EC and RE (Figure 12).

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