Theta Rhythm of the Hippocampus: Subcortical Control and Functional Significance

Abstract

The theta rhythm is the largest extracellular synchronous signal that can be recorded from the mammalian brain and has been strongly implicated in mnemonic processes of the hippocampus. We describe (a) ascending brain stem-forebrain systems involved in controlling theta and nontheta (desynchronization) states of the hippocampal electroencephalogram; (b) theta rhythmically discharging cells in several structures of Papez's circuit and their possible functional significance, specifically with respect to head direction cells in this same circuit; and (c) the role of nucleus reuniens of the thalamus as a major interface between the medial prefrontal cortex and hippocampus and as a prominent source of afferent limbic information to the hippocampus. We suggest that the hippocampus receives two main types of input: theta rhythm from ascending brain stem- diencephaloseptal systems and information bearing mainly from thalamocortical/cortical systems. The temporal convergence of activity of these two systems results in the encoding of information in the hippocampus, primarily reaching it from the entorhinal cortex and nucleus reuniens.

Full text

10.1177/1534582304273594
BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS
Theta Rhythm of the Hippocampus:
Subcortical Control and Functional Significance
Robert P. Vertes
Walter B. Hoover
Gonzalo Viana Di Prisco
Florida Atlantic University
The theta rhythm is the largest extracellular synchronous signal
that can be recorded from the mammalian brain and has been
strongly implicated in mnemonic processes of the hippocampus.
We describe (a) ascending brain stem–forebrain systems
involved in controlling theta and nontheta (desynchronization)
states of the hippocampal electroencephalogram; (b) theta rhyth-
mically discharging cells in several structures of Papez’s circuit
and their possible functional significance, specifically with
respect to head direction cells in this same circuit; and (c) the role
of nucleus reuniens of the thalamus as a major interface between
the 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 of
input: theta rhythm from ascending brain stem–diencephalo-
septal systems and information bearing mainly from
thalamocortical/cortical systems. The temporal convergence of
activity of these two systems results in the encoding of informa
-
tion in the hippocampus, primarily reaching it from the
entorhinal cortex and nucleus reuniens.
Key Words: supramammillary nucleus, median raphe
nucleus, 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 to
12 Hz in the behaving rat (Bland, 1986; Vertes & Kocsis,
1997). It is the largest extracellular synchronous signal
that can be recorded in the mammalian brain. Theta is
selectively present during two behavioral states: waking
behaviors that are thought to be critical for the survival
of the species and throughout rapid eye movement
(REM) sleep (Vanderwolf, 1969; Winson, 1972). Theta
of waking is present in rats during exploratory motor
behavior (Vanderwolf, 1969). The theta rhythm has
attracted significant attention based on its reported
involvement in memory processing functions of the hip
-
pocampus.
The present review will focus on the following main
topics: (a) subcortical circuitry controlling theta and
nontheta (desynchronized) states of the hippocampal
electroencephalogram (EEG), (b) theta rhythmical sig-
nals exiting the hippocampus through structures of
Papez’s circuit and their functional significance, (c) the
nucleus reuniens (RE) of the thalamus as a prominent
source of limbic information to the hippocampus, and
(d) the role of theta in mnemonic functions.
ASCENDING BRAIN STEM–DIENCEPHALIC
SYSTEMS CONTROLLING THE THETA RHYTHM
AND DESYNCHRONIZED (NONTHETA) STATES
OF THE HIPPOCAMPAL EEG
Theta Rhythm
It is well documented that rhythmically discharging
cells of the medial septum/vertical limb of the diagonal
band nucleus (MS/DBv) that fire synchronously with
theta are responsible for its generation in hippocampal
formation (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,
173
Authors’ Note: This work was supported by National Institute of Men
-
tal Health Grants MH63519 and MH01476 to R.P.V.
Behavioral and Cognitive Neuroscience Reviews
Volume 3 Number 3, September 2004 173-200
DOI: 10.1177/1534582304273594
© 2004 Sage Publications
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

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 theta
rhythm in the hippocampus as well as in parahip-
pocampal structures such as the entorhinal and
cingulate 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 theta
rhythm (Leung & Shen, 2004; Numan, 2000; Vertes &
Kocsis, 1997; Vinogradova, 1995).
It is also well established that the brain stem reticular
formation (RF), through actions on the MS/DBv, serves
a direct role in the generation of theta. In their original
report that identified the theta rhythm in the curarized
rabbit, Green and Arduini (1954) showed that theta
could be elicited by natural sensory stimuli or by electri
-
cal stimulation of the brain stem RF. Shortly thereafter,
Petsche and colleagues (1962, 1965) demonstrated that
septal pacemaking cells could be driven by input arising
from the brain stem RF, leading them (Petsche et al.,
1965) to conclude that the septum transforms “the
steady flow of pulses from the RF into a discontinuous
pattern of discharges” that are then transferred “to the
pyramidal cells of the hippocampus thus inducing the
theta rhythm.”
Although these early studies indicated a role for the
brain stem RF in elicitation of theta, they did not identify
specific RF locations responsible for this effect. Stimula-
tion was generally delivered to the midbrain RF (for
review, see Vertes, 1982). In a series of reports, we
showed that the nucleus pontis oralis (RPO) of the
rostral pontine RF was critical for the generation of
theta. We found that cells of RPO in the behaving rat dis
-
charge at high tonic rates (50-75 Hz) selectively during
waking motor behavior and REM sleep (theta-associated
states in the rat; Vertes, 1977, 1979) and that electrical
stimulation of pontis oralis, but not that of surrounding
regions of the brain stem, generates theta (Vertes, 1980,
1981). Other studies have similarly shown that RF stimu
-
lation, centered in RPO, both activates septal
pacemaking 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), the
foregoing suggested, then, that RPO is the primary
source of tonic drive to the septal pacemaking cells in
the 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 analyzed
patterns of labeled neurons in the brain stem (Vertes,
1988). Although labeled cells were identified in several
regions of the brain stem, prominently including
monoaminergic nuclei, exceedingly few were found in
RPO or other reticular nuclei of the brain stem (Vertes,
1988). This suggested that the influence of RPO on the
MS/DBv in the generation of theta was mediated by an
intervening nucleus (or nuclei) or di- or polysynaptic
pathways between RPO and the MS/DBv.
Although retrograde tracer injections in MS/DBv
failed to produce labeling in RPO, interestingly, they
gave rise to pronounced cell labeling in the
supramammillary nucleus (SUM), dorsal to the
mammillary bodies (Vertes, 1988). Approximately 150
to 200 labeled neurons per 50-µm section were seen
through the heart of SUM. This suggested that the SUM
may be a link between the brain stem and septum
involved in the generation of theta. As discussed below,
this has subsequently been confirmed by several lines of
evidence: (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 of
SUM disrupts the rhythmical discharge of septal
pacemaking cells and eliminates theta in the
hippocampus.
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 the
anterograde tracer PHA-L into SUM produced dense
labeling in the medial and lateral septum as well as in the
hippocampus (Vertes, 1992). Within the hippocampus,
SUM fibers distribute selectively to the dentate gyrus and
to 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 described
in 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 a
population of cells of the SUM that fired rhythmically
with the hippocampal theta rhythm. They further
showed that this activity did not depend on the MS/DBv;
procaine injections in the MS/DBv that abolished
174 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

hippocampal theta did not alter the rhythmical firing of
SUM neurons. In subsequent examinations (Kocsis &
Vertes, 1994, 1997) of the activity of SUM cells as well as
those in surrounding regions of the caudal
diencephalon, we found that 29 of 170 neurons dis
-
charged rhythmically, synchronous with theta (Kocsis &
Vertes, 1994). All 29 theta-related cells were localized to
SUM or to the mammillary bodies, ventral to SUM; none
of 141 neurons located outside of the SUM/MB fired
synchronously with theta. Bland, Konopacki, Kirk,
Oddie, and Dickson (1995) similarly reported that 16 of
16 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 or
blocks theta, respectively. Specifically, electrical stimula
-
tion or carbachol injections in SUM activate theta burst
neurons of the septum and hippocampus and produce
theta (Bland, Colom, & Ford, 1990; Bland et al., 1994;
Bocian & Konopacki, 2004; Oddie et al., 1994; Smythe,
Christie, Colom, Lawson, & Bland, 1991), whereas the
reversible suppression of SUM with procaine injections
in anesthetized rats disrupts the spontaneous as well as
the RPO-elicited bursting discharge of septal
pacemaking 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 totally
eliminate 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 the
theta rhythm and the medial septum the amplitude of
theta. Specifically, they showed that procaine injections
caudal to SUM (blocking RPO actions on SUM) or
within SUM significantly reduced the frequency of theta,
whereas procaine injections in the MS/DBv reduced the
amplitude but not frequency of theta (Kirk &
McNaughton, 1993). They concluded that
the most parsimonious explanation of this result is that
transduction of the intensity of reticular activation to the
frequency of the resultant RSA (rhythmical slow activity
or theta) takes place in the supramammillary region
rather than in the septal area. It is likely that
transduction occurs in the SuM itself. The frequency
coded (i.e., phasic) information is then fed, probably
via 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 PH
fired at high tonic rates selectively during theta—their
tonic theta-on cells. With respect to the possible PH
influence on the hippocampus, PH does not project to
the hippocampus (Vertes, Crane, Colom, & Bland,
1995) but distributes strongly to several structures with
pronounced input to the hippocampus, prominently
including the medial septum, RE of the thalamus (see
below), and SUM. Bursting SUM neurons and the toni
-
cally firing PH cells may act synergistically to relay
ascending reticular activity to the MS/DBv in the control
of theta (Bland & Oddie, 1998; Vertes & Kocsis, 1997).
In summary, several lines of evidence indicate that the
theta rhythm is controlled by a network of cells extend
-
ing from the brain stem to the forebrain, that is, from
RPO to the SUM to the septum/hippocampus. As
depicted in Figure 1, during theta, tonically firing cells of
the RPO activate putative glutamatergic neurons of
SUM, which convert the steady barrage into a rhythmical
pattern of discharge that is relayed to cholinergic and
gamma-aminobutyric acid (GABA)-ergic pacemaking
cells of the MS/DBv. Septal cholinergic neurons excite
principal cells and interneurons of the hippocampus
(Dutar, Bassant, Senut, & Lamour, 1995; Frotscher &
Leranth, 1985; Leranth & Frotscher, 1989; Vertes &
Kocsis, 1997), whereas septal GABAergic cells inhibit
GABAergic interneurons of the hippocampus (Freund
& Antal, 1988; Gulyas et al., 1991) in the generation of
theta. Although septohippocampal cholinergic neurons
fire rhythmically with theta, they may not rhythmically
drive (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 intrinsic
currents sufficient to produce membrane potential
oscillations at theta frequencies (Vertes & Kocsis, 1997).
This is supported by the demonstration that
cholinomimetics 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 of
the 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 the
MR is directly involved in the desynchronization of the
Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 175
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

hippocampal EEG, or the blockade of theta. It was dem
-
onstrated early on that MR stimulation desynchronized
the hippocampal EEG (Assaf & Miller, 1978; Macadar
et al., 1974; Vertes, 1981; Yamamoto, Watanabe, Oishi, &
Ueki, 1979) and that MR lesions produced continuously
running 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 that
the disruptive effect of MR stimulation on septal
pacemaking cells and the hippocampal EEG was
blocked by pretreatment with the 5-HT synthesis inhibi
-
tor p-chlorophenylalanine, which produced a 60% to
80% depletion of forebrain serotonin. Yamamoto et al.
(1979) reported that ongoing theta produced by MR
lesions could be temporarily interrupted by
intraperitoneal injections of the serotonin precursor L-
5-hydroxytryptophan (L-5-HTP), and McNaughton
et al. (1980) showed in behaving rats that the effective
-
ness of driving theta with septal stimulation was signifi
-
cantly enhanced following destruction of ascending
serotonergic 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-HT
1A
autoreceptor agonists or GABA agonists) or
reduced excitatory drive to them (excitatory amino acid
antagonists) produced theta at short latencies (1-2 min-
utes) and for long durations (20-80 minutes). In like
manner, Varga, Sik, Freund, and Kocsis (2002) reported
that GABA
B
receptors are selectively present on
serotonergic neurons of MR and that infusions of the
GABA
B
agonist, baclofen, into MR in anesthetized rats
produced long-lasting theta. They concluded (Varga
et al., 2002) that the effects of baclofen on theta
“resulted from suppression of the serotonergic output
from the median raphe.”
In examinations of the effects of manipulations of MR
on the septum and hippocampus in awake rabbits,
Vinogradova and colleagues (Kitchigina, Kudina,
Kutyreva, & Vinogradova, 1999; Vinogradova,
Kitchigina, Kudina, & Zenchenko, 1999) similarly
showed that low-amplitude median raphe stimulation
disrupted the bursting discharge of medial septal cells
and abolished theta in the hippocampus and that the
reversible suppression of MR with injections of lidocaine
increased the frequency and regularity of discharge of
theta-bursting neurons of the septum and hippocampus
and produced continuous theta in the hippocampus.
They concluded that “the median raphe nucleus can be
regarded as a functional antagonist of the RF, powerfully
suppressing theta bursts of the medial septal area neu
-
rons and the hippocampal theta rhythm” (Kitchigina
et al., 1999, p. 453).
176 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
Medial Septum
SUM
Median Raphe Pontis Oralis
Hippocampal
Formation
Ch
G
S
G
Glu
Glu
G
Glu
G
G
S
+
-
Figure 1: Schematic Diagram Showing the Major Interconnections of
Ascending 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 rhythmical
pattern 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 inhibit
GABAergic cells of the hippocampus, thereby exerting a disinhibitory
action on pyramidal cells of the hippocampus. Medial septal
GABAergic cells receive intraseptal excitatory input from both septal
cholinergic and glutamatergic (Hajszan, Alreja, & Leranth, 2004) neu
-
rons. Cholinergic septohippocampal pacemaking cells terminate on
both interneurons and principal cells of the hippocampus. During
states of hippocampal desynchronization (nontheta), a subset of
serotonergic septal-projecting cells of the median raphe nucleus (MR)
discharge at enhanced rates and activate GABAergic cells of the medial
septum, which in turn inhibit GABAergic/cholinergic pacemaking
cells of the medial septum in the desynchronization of the
hippocampal EEG. Serotonergic neurons of the MR also project di
-
rectly to the SUM and to the hippocampus and could also exert
desynchronizing actions on the hippocampal EEG through these con
-
nections. See the text for further description of this circuitry. The
dashed line signifies presently undetermined SUM glutamatergic pro
-
jections to glutamatergic cells of the septum. Arrows (at the end of
lines) indicate excitatory connections; straight lines indicate inhibi
-
tory connections. Ch = acetylcholine; G = GABA; Glu = glutamate; S =
serotonin.
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 177
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 of
the 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) showing
that the cell did not discharge rhythmically synchronous theta as indicated by the flat unit-electroencephalogram cross-correlogram.
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

In addition to 5-HT cells, the MR contains significant
numbers of GABAergic neurons (Jacobs & Azmitia,
1992; Mugnaini & Oertel, 1985; Maloney, Mainville, &
Jones, 1999), which have been shown to contact and
inhibit 5-HT MR cells (Forchetti & Meek, 1981;
Nishikawa & Scatton, 1985a, 1985b). As discussed, injec
-
tions of GABA
A
(Kinney et al., 1995) or GABA
B
agonists
(Varga et al., 2002) into MR generate persistent theta.
This suggests a GABAergic MR influence on 5-HT cells
of MR in the modulation of the hippocampal EEG. In
recent examinations of the discharge properties of MR
neurons in anesthetized rats (Kocsis & Vertes, 1996;
Viana Di Prisco, Albo, Vertes, & Kocsis, 2002), we identi
-
fied two major populations of cells, putatively 5-HT and
GABAergic neurons, with activity related to the
hippocampal EEG. Specifically, we demonstrated that a
very large percentage of MR cells showed changes in
activity 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 rates
of activity with theta and were termed theta-on and theta-
off cells, respectively. These cells were further divided
into slow (~ 1 Hz), moderate (5-11 Hz) and fast-firing
(>12 Hz) theta-on or theta-off cells. The slow-firing
theta-on and theta-off cells, as well as a subpopulation of
the moderately firing cells, exhibited characteristics of
classic 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 be
serotonergic cells. All fast-firing cells were theta-on cells;
no fast-firing theta-off cells were observed. Fast-firing
cells showed either tonic or phasic (rhythmical)
increases in activity with theta.
The discharge profile of a moderately firing, putative
serotonergic, theta-off cell is shown in Figure 2. As
depicted, the cell discharged at very regular rates during
control (nontheta) conditions (Figure 2A) and abruptly
ceased firing with the onset, and essentially for the dura
-
tion, of theta elicited with tail pinch (TP; Figure 2A) or
by electrical stimulation of the tail (Figure 2B). For a few
neurons tested, cells that were strongly inhibited during
TP-elicited theta were also completely suppressed fol
-
lowing the intravenous administration of the 5-HT
1A
ago
-
nist, 8-OH-DPAT, further indicating that they were
serotonergic neurons.
We suggested, then, that (a) the slow-firing cells
(theta-on and theta-off) and a subset of the moderately
discharging cells were serotonergic neurons and the
phasic and tonic fast-firing cells were mainly GABAergic
neurons, (b) the 5-HT theta-off (or desynchronization-
on) cells were projection neurons and the 5-HT theta-on
and GABAergic cells were primarily interneurons, and
(c) these populations of cells mutually interact in the
modulation of the hippocampal EEG (Viana Di Prisco
et al., 2002). In effect, the activation of local 5-HT theta-
on cells as well as the GABAergic theta-on cells would
inhibit 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-HT
theta-off (desynchronization-on) cells resulting in a
blockade of theta or a desynchronization of the
hippocampal EEG (see Figure 1).
In one of the few studies examining the activity of MR
cells in behaving animals, Jacobs and colleagues
(Marrosu, Fornal, Metzler, & Jacobs, 1996) showed in
awake cats that putative 5-HT cells of MR exhibited prop
-
erties indicative of a role in the desynchronization of the
hippocampal 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 REM
sleep (theta states; Jacobs & Azmitia, 1992; Marrosu
et al., 1996).
Although not fully determined, the desynchronizing
actions of MR on the hippocampus appear to be primar-
ily mediated by the medial septum. The MR projects
strongly to the medial septum (Aznar et al., 2004; Morin
& Meyer-Bernstein, 1999; Vertes et al., 1999; Vertes &
Martin, 1988), and MR fibers predominantly terminate
on 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 local
GABAergic cells of the MS/DBv, which in turn inhibit
subsets of septal pacemaking GABAergic and
cholinergic septohippocampal neurons, possibly in the
control 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 generated
theta.
The MR could also exert desynchronizing influences
on the hippocampus via actions on other targets, such as
the RPO, SUM, or directly on the hippocampus (Figure
1). With respect to MR-RPO (reticular) interactions in
the control of theta, Vinogradova et al. (1999) proposed
that a suppression of MR activity could result in the
“elimination of the MR inhibitory influences on the
reticular formation” and thereby “stimulate the genera
-
tion of theta rhythm and increase of its frequency in the
septo-hippocampal system” (p. 750).
In summary, two brain stem–originating systems exert
pronounced (and opposing) actions on the electrical
activity 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
-
178 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

rons of the SUM, which in turn convert this steady bar
-
rage into a rhythmical pattern of discharge that is
relayed to pacemaking cells of the MS/DBv to generate
theta. During states of hippocampal desynchronization,
a subset of 5-HT, septal-projecting MR cells discharge at
enhanced rates and activate local GABAergic cells of the
MS/DBv, which in turn inhibit cholinergic/GABAergic
pacemaking 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 THE
HIPPOCAMPUS THROUGH STRUCTURES OF
PAPEZ’S CIRCUIT AND POSSIBLE
FUNCTIONAL SIGNIFICANCE
As discussed, we described theta rhythmically firing
neurons in SUM as well as in the mammillary bodies
(MB), ventral to SUM (Kocsis & Vertes, 1994, 1997). Oth
-
ers studies have similarly demonstrated theta-rhythmic
cells 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 to
theta, that is, influencing theta (SUM) or influenced by
it (MB). For instance, it has been shown that procaine
injections in the MS/DBv (which abolish theta) disrupt
the rhythmical discharge of MB cells but not that of SUM
cells (Bland et al., 1995; Kirk et al., 1996; Kirk &
McNaughton, 1991). This suggests that MB is part of a
descending system driven from the septum/hippocam-
pus, whereas SUM is a part of an ascending system gener-
ating theta. This is consistent with anatomical findings
showing that MB receives major descending projections
from the hippocampus via the postcommissural fornix
(Amaral & Witter, 1995; Swanson & Cowan, 1977; Witter,
Ostendorf, & Groenewegen, 1990) but does not project
to the hippocampus, whereas the SUM receives few
fibers from the hippocampus but is the source of dense
projections to the septum and hippocampus (Borhegyi
et 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 originally
defined by Papez (1937), the projections of the circuit
are hippocampal formation → mammillary bodies → ante-
rior thalamus → cingulate cortex → parahippocampal
gyrus → hippocampal formation. Although the circuit
has 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 of
Papez’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’s
circuit subserves emotional experience/expression
(LeDoux, 1993) has been replaced by the proposal that
it is primarily involved in mnemonic functions
(Aggleton & Brown, 1999). Lesions of each of the major
structures of Papez’s circuit have been shown to disrupt
memory (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 with
theta, coupled with the demonstration that MB pro
-
jects massively to the anterior thalamus via the
mammillothalamic 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 of
cells of the three divisions of the anterior thalamus
(anteroventral [AV], anterodorsal [AD], anteromedial
nuclei) with respect to the hippocampal EEG and found
that neurons in all divisions fired rhythmically with theta
(Vertes, Albo, & Viana Di Prisco, 2001; Albo, Viana Di
Prisco, & Vertes, 2003), with the highest percentage in
the AV nucleus.
We found (Vertes et al., 2001) that approximately
75% of AV neurons fired rhythmically with theta and the
activity 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 tail
pinch), the activity of the cell changed from an irregular
pattern to a highly rhythmical pattern, synchronous with
theta (Figure 3A). This change from nonrhythmical
(control) to rhythmical (theta) activity is exemplified by
the rhythmical peaks in the autocorrelogram (Figure
3B), unit-theta locked EEG oscillations (spike-triggered
averaging) in the cross-correlogram (Figure 3C), and
the pronounced coherence between unit discharge and
the hippocampal EEG at theta frequency (about 3.3 Hz;
Figure 3D). By comparison with the large percentage of
theta-rhythmic neurons in AV (~75%), approximately
12% of AD cells and 6% of anteromedial nucleus cells
were found to discharge rhythmically, strongly
synchronous 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 MB
also projects strongly to, and receive pronounced projec
-
tions from, the tegmental nuclei of the brain stem (the
dorsal and ventral tegmental nuclei of Gudden; Allen &
Hopkins, 1989, 1990; Hayakawa & Zyo, 1990, 1991), sug
-
Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 179
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

gesting a similar MB rhythmical influence on these
nuclei.
In a recent examination of the activity of cells of the
ventral 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 Di
Prisco, & Vertes, 2001). Furthermore, the discharge of
VTg and ATg cells was highly coherent with the theta
rhythm; 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 it
could be readily identified as the electrode just
approached the nucleus, that is, before single spikes
could be clearly identified.
Figure 4 shows a strongly theta rhythmically firing
VTg neuron (Kocsis et al., 2001). As depicted, the neu
-
ron discharged in rhythmic bursts with theta (Figure
4C), as demonstrated by rhythmical peaks in the
autocorrelogram (Figure 4E) and a dominant rhythmic
component at 3.7 Hz in the VTg-hippocampal cross-
correlogram (Figure 4G). By contrast, during nontheta
states (desynchronization), the neuron fired irregularly
(Figure 4D) with no significant peaks in the
autocorrelogram (Figure 4F) or in the spike-triggered
average (Figure 4H).
Consistent with these findings, Bassant and
Poindessous-Jazat (2001) demonstrated that the activity
of VTg cells in behaving rats was highly correlated with
theta during both waking and REM sleep. They further
drew attention to the marked similarity of the rhythmic
firing of VTg and MS/DBv cells, stating, “Interestingly,
the characteristics of the rhythmic discharges in VTn are
close to those observed in MS/DB, a region crucial
for 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 (GABAergicl
Hayakawa & Zyo, 1991), thus forming a recurrent excitatory-
inhibitory network. This MB-VTg network exhibits a
number of similarities with other excitatory-inhibitory
recurrent systems known to generate rhythmic oscilla-
tions at low frequencies (Contreras & Steriade, 1996;
Ritz & Sejnowski, 1997; Plenz & Kital, 1999). We suggest
that VTg-MB connections may be an important subloop
grafted onto Papez’s circuit, involved in maintaining
theta rhythmical activity in MB and hence throughout
Papez’s circuit.
Theta-Rhythmic Cells and
Head Direction (HD) Cells
There is a remarkable correspondence in rats
between structures containing theta-rhythmic neurons
and those containing HD cells (Taube, 1998; Vann &
Aggleton, 2004). HD cells fire selectively when a rat is
facing or oriented in a particular direction (e.g., north
-
east) irrespective of its location in its environment
(Taube, 1998). Both HD and theta-rhythmic cells
have been described in the tegmental nuclei of
Gudden, the MB, the anterior thalamus, posterior
cingulate (retrosplenial) cortex, and the subiculum/
hippocampus.
In addition (and importantly), theta and HD cells
have been localized to separate subnuclei of structures
(of Papez’s circuit) containing them. For example, HD
cells 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 (Blair
et al., 1999; Blair, Lipscomb, & Sharp, 1997; Blair &
Sharp, 1995; Goodridge & Taube, 1997; Taube & Muller,
180 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
Figure 3: Discharge Characteristics of a Neuron of the Anterior Ven-
tral Nucleus of the Thalamus That Fired Rhythmically in
Bursts 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 elicited
with tail pinch (horizontal bar). Lower traces: expanded record (from
A) 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 theta
rhythm [C]) during theta but not control conditions. (D) Spectral and
cross-spectral (coherence) plots showing peaks in the EEG and unit
signals at theta frequency and significant coherence between EEG and
unit signals at theta frequency during theta (solid lines) but not during
control conditions (dotted lines).
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 181
Figure 4: Neuron of the Ventral Tegmental Nucleus of Gudden (VTg) That Fired Rhythmically in Bursts Synchronous With the Hippocampal
Theta 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 (lower
traces) together with the simultaneously recorded hippocampal electroencephalogram (upper traces) showing a change from an irregular pattern
of 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 = mammillary
body; MR = median raphe nucleus.
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

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 the
thalamus (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 various
subnuclei 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 these
two systems as the medial and lateral mammillary sys-
tems (and associated structures): the medial being theta
and the lateral HD. As depicted in Figure 5 (from Vann
& Aggleton, 2004), the medial system (theta) consists of
VTg, the medial MB, AV, and the subiculum/EC; the lat-
eral system (HD) consists of the dorsal tegmental
nucleus, lateral MB, AD and the pre-, para-, and
postsubiculum.
Vann and Aggleton (2004) suggested that the recent
demonstration that the MB contains two (theta and HD)
functionally segregated systems (or in their terms, two
memory systems in one) may be a key to understanding
the role of MB in memory, which has remained elusive
despite the fact that “the mammillary bodies have been
implicated in amnesia perhaps for longer than any other
single brain region” (p. 35). Regarding these two systems
and their possible interaction in memory processing,
they stated,
At the same time it is assumed that the medial and lateral
mammillary systems function in a synergistic way, as
reflected by their common connections with the hippo
-
campus, tegmentum and anterior thalamus. This coop
-
erative activity raises the question of where the functions
of these two systems might interact. Anatomically, the
most plausible candidate regions are the retrosplenial
cortex and the hippocampal formation, although this
has not been formally examined. There is, in addition,
the functional question of why head direction and theta
might have a special relationship. The answer to this pre
-
sumably lies in the hippocampus, as so many of the
effects of mammillary body damage mimic those of
hippocampal damage, but to a lesser degree. (p. 42)
The question of “why head direction and theta might
have a special relationship” is an intriguing one and may
involve the special properties of bursting neurons
(Lisman, 1997). For instance, in a review comparing the
characteristics of single spikes to bursts, Lisman (1997)
concluded that, relative to single spikes, bursts represent
a much more effective (or reliable) mode of communi-
cation between neurons. Specifically, Lisman pointed
out that there is a very low probability that single
presynaptic spikes can generate action potentials in
postsynaptic cells (unreliable synapses), compared to a
high probability that presynaptic bursts would drive
postsynaptic neurons (reliable synapses). Hence, bursts
convert unreliable to reliable synapses (Lisman, 1997).
Although various factors undoubtedly contribute to the
efficacy of bursts, presumably one of the most important
is the steady accumulation of intracellular calcium in
presynaptic terminals with successive spikes of bursts,
eventually leading to the release of sufficient amounts of
transmitter 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 behaving
cats that a large percentage (71%) of cells of the lateral
geniculate nucleus of thalamus discharged in bursts to a
gradient passed through the visual field and concluded
that bursting “provides a form of visual amplification”
serving to detect salient visual stimuli. In like manner,
182 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
Septum
Supramammillary nuclei
Tuberomammilary nuclei
Anterior medial
and anterior
ventral nuclei
Subiculum
Medial
entorhinal
cortex
Ventral
tegmental
nucleus
Medial mammillary nucleus
Lateral mammillary nucleus
Anterior dorsal
nucleus
Thalamus
Dorsal
tegmental
nucleus
Gudden's tegmental nuclei
Presubiculum
Postsubiculum
Parasubiculum
Hippocampal formation
Hippocampal formation
Figure 5: Schematic Representation of the Main Nuclei and Their In
-
terconnections Associated With the Medial Mammillary
Theta System and the Lateral Mammillary Head Direction
System.
SOURCE: Reprinted from Vann and Aggleton (2004), p. 38, with per
-
mission of the authors.
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

Fanselow, Sameshima, Baccala, and Nicolelis (2001)
reported that cells of the ventrobasal thalamus, when fir
-
ing in bursts during whisker movements/twitches, are
maximally sensitive to somatosensory stimulation in the
periods immediately (120 ms) following the burst. They
indicated that bursts “generate a period during which
neurons are highly sensitive to incoming stimuli.”
Finally, Swadlow and Gusev (2001) demonstrated in
awake rabbits that ventrobasal thalamic neurons pro
-
duce significantly stronger postsynaptic actions on cells
of the somatosensory cortex when firing in bursts than
tonically.
In a manner similar, then, to relay cells of the
thalamus, the burst firing of neurons of Papez’s circuit at
theta frequency could selectively modify the activity of
postsynaptic targets, rendering them more responsive to
other inputs. For example, the theta burst discharge of
neurons of the AV nucleus of the thalamus could modify
the activity of target cells of the hippocampus and/or the
retrosplenial cortex, increasing their responsiveness to
other inputs, such as from HD cells of the AD thalamus,
thereby magnifying the influence of anterodorsal HD
cells on hippocampal/retrosplenial neurons.
It would appear that directional information is very
critical for a rat (and other species) when engaged in
locomotor/exploratory behaviors (theta states) and less
so during nonlocomotor activities such as grooming or
consumatory acts (nontheta states). Accordingly, theta
may 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 HD
activity is coupled with theta-rhythmic discharge is HD
activity 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, possibly
involved in memory processing functions of this circuit.
Two parallel, and anatomically segregated, systems
within Papez’s circuit have been identified: theta and
HD circuits. The two systems may functionally interact at
multiple levels of the circuit to process HD information
used for spatial learning/navigation.
THE NUCLEUS REUNIENS (RE) OF THE
THALAMUS: A MAJOR SOURCE OF
MULITMODAL LIMBIC INFORMATION
TO THE HIPPOCAMPUS
Although the hippocampus receives a diverse array of
information, there are few direct inputs to the hippo
-
campus. Excluding monoaminergic afferents, few struc
-
tures project directly to the hippocampus, essentially
only 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 the
third ventricle and ventral to the rhomboid nucleus of
the thalamus, and extends longitudinally, virtually
throughout the thalamus (see Swanson, 1998). The RE is
the largest of the midline nuclei of the thalamus. The RE
is 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’s
horn, the ventral subiculum, and the medial EC, as well
as moderately to the dorsal subiculum, the
parasubiculum, and the lateral EC (Bokor et al., 2002; Su
& Bentivoglio, 1990; Wouterlood, 1991; Wouterlood
et al., 1990). There are essentially no RE projections to
the dentate gyrus. RE fibers form asymmetric (excit
-
atory) contacts predominantly on distal dendrites of
pyramidal cells in stratum lacunosum-moleculare of
CA1 (Wouterlood et al., 1990).
Based on the relationship of RE to the hippocampus,
we were interested in sources of afferent projections to
the RE. In an initial report (Vertes, 2002), we examined
projections from the medial prefrontal cortex (mPFC)
to the thalamus, with a concentration on RE. Injections
of the anterograde tracer, PHA-L, were made in the four
divisions of the mPFC (medial agranular, anterior
cingulate, prelimbic cortex, and infralimbic cortex) and
patterns of labeling determined. In brief, we showed that
(a) the infralimbic (IL), prelimbic (PL), and anterior
cingulate cortices distribute heavily and selectively to
midline/medial structures of the thalamus, including
the paratenial, paraventricular, interanteromedial,
anteromedial, intermediodorsal, mediodorsal,
reuniens, and central medial nuclei; (b) the medial
agranular cortex distributes strongly to the rostral
intralaminar nuclei (central lateral, paracentral, central
medial nuclei) and to the ventromedial and
ventrolateral nuclei of thalamus; and (c) importantly, all
four divisions of the mPFC project densely (or massively)
to the RE.
The pattern of distribution of infralimbic fibers to the
thalamus is schematically illustrated in Figure 6. As
depicted, labeling is restricted to the midline nuclei of
the thalamus, and within the midline thalamus is very
dense in the mediodorsal nucleus and RE. At the
rostral thalamus (Figure 6A-6C), labeling spreads
dorsoventrally throughout the midline, whereas at the
caudal thalamus (Figure 6D-6G), labeling is essentially
confined to the paraventricular and mediodorsal nuclei,
Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 183
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

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 abundant
in the lateral wings of RE, ipsilaterally (left side).
Several reports in various species have described
prominent projections from the hippocampus to the
prefrontal 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; van
Groen & Wyss, 1990). In rats, hippocampal projections
to the mPFC arise from temporal aspects of CA1 and the
subiculum and terminate in a fairly restricted region of
the ventral mPFC, including the medial orbital area, IL,
and PL (Jay et al., 1989; Jay & Witter, 1991). Despite well-
documented hippocampal to mPFC projections, there
are essentially no direct projections from the mPFC
to 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 to
the 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 the
transfer 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 prefrontal
cortex 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 examined
other afferents to the RE, or the totality of inputs to the
RE (McKenna & Vertes, 2004). Injections of the retro-
grade tracer Fluorogold were made into various regions
of RE and patterns of retrogradely labeled cells deter
-
mined. We showed that RE receives a very diverse and
widely distributed set of afferent projections. Figure 8
schematically depicts patterns of projections to the
rostromedial RE. As illustrated, the RE receives pro
-
nounced projections from several cortical and
subcortical sites. They include (a) the orbitomedial (see
also above), insular, ectorhinal, perirhinal, and
retrosplenial cortices; (b) the CA1/subiculum of hippo
-
campus; (c) the claustrum, lateral septum, substantia
innominata, and lateral preoptic nucleus of the basal
forebrain; (d) the medial nucleus of amygdala (MEA);
(e) the paraventricular and lateral geniculate nuclei of
thalamus; (f) the zona incerta; (g) the anterior,
ventromedial, lateral, posterior, supramammillary, and
dorsal premammillary nuclei of the hypothalamus; and
(h) the ventral tegmental area, periaqueductal gray,
medial and posterior pretectal nuclei, superior
colliculus, precommissural nucleus, parabrachial
nucleus, laterodorsal and pedunculopontine tegmental
nuclei, nucleus incertus, and the dorsal and median
raphe nuclei of the brainstem.
184 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
IC
PVa
AV
ST
VAL
AMv
RE
B
LV
FI
PT
AD
AM
RT
RE
F
AV
SM
A
LD
VAL
CL
CEM
PV
VB
PC
VM
AV
LD
MD
VAL
VM
AM
RH
ZI
RE
C
LD
CA3
MH
MDl
PO
ZI
CEM
IMD
VB
F
LD
IC
VB
CL
MD
PO
VM
RT
ZI
RE
E
3V
LGNv
PF
FR
PH
PO
LP
H
LH
LGNd
CL
VB
SME
CEM
ZI
PO
LP
PVp
G
D
AD
MD
IAM
IMD
MD
IAM
Figure 6: Schematic Representation of Selected Sections Through
the Diencephalon Depicting Labeling Present in the
Thalamus Produced by a PHA-L Injection in the
Infralimbic Cortex.
SOURCE: Reprinted from Vertes (2002), p. 168, with permission of
Wiley-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 = fimbria
of hippocampal formation; FR = fasciculus retroflexus; IAM =
interanteromedial nucleus; IC = internal capsule; IMD =
intermediodorsal nucleus; LGNd,v = lateral geniculate nucleus, dorsal
and 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 = nucleus
reuniens; RH = rhomboid nucleus; RT = reticular nucleus; SM = stria
medullaris, SME = submedial nucleus; ST = stria terminalis; VAL = ven
-
tral anterior-lateral complex; VB = ventrobasal complex; VM =
ventromedial nucleus; ZI = zona incerta; 3V = third ventricle.
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 185
Figure 7: Darkfield Photomicrograph of a Transverse Section Through the Rostral Diencephalon Showing Patterns of Labeling at the Rostral
Thalamus 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.
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

186 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
Figure 8: Series of Representative Rostrocaudally Aligned Schematic Transverse Sections (A-P) Depicting the Location of Retrogradely Labeled
Cells 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 = medial
agranular (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 stria
terminalis; 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 nucleus
of 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 of
thalamus; MgRe = magnocellular reticular nucleus; MO5 = motor nucleus of trigeminal nerve; MPN = medial preoptic nucleus; MPO = medial
preoptic 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 of
hippocampus; 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 nucleus
of thalamus; PVR = parvocellular reticular nucleus; RE = nucleus reuniens of thalamus; RM = raphe magnus; RPC = nucleus reticularis pontis
(continued)
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

Figure 9 depicts patterns of retrograde labeling in the
subiculum (of hippocampus) following the RE injection
of Figure 8. As shown, the entire dorsoventral extent of
the ventral subiculum (postsubiculum, dorsal/ventral
subiculum) was densely labeled. These pronounced
subicular-RE projections complement equally dense
return RE projections to the hippocampus (Bokor et al.,
2002; Dolleman-Van der Weel & Witter, 1996;
Wouterlood, 1991; Wouterlood et al., 1990), indicating
strong reciprocal connections between these structures.
Figure 10 shows prominent cell labeling in the amygdala
following a rostrolateral RE injection, mainly within the
MEA and to a lesser extent in the anterior cortical and
basomedial nuclei. An early report by Canteras, Simerly,
and Swanson (1995) also described strong projections
from the MEA to the RE, leading them to conclude that
“another potentially significant way for the MEA to
access the hippocampal formation is by way of inputs
from the nucleus reuniens” (p. 238).
In summary, the RE receives pronounced projections
from diverse regions of the brain involved in a host of
functions. To our knowledge, no other nucleus of the
thalamus, and certainly none outside of the midline
thalamus, receives a comparable degree and diversity of
inputs. Although RE receives projections from several
structures 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 a
critical site for the convergence of information from var
-
ious sources (mainly from limbic/limbic-related struc
-
tures) and its transfer to the hippocampus and
prefrontal cortex.
RE Actions on the Hippocampus and mPFC
Although it has been know for some time that the RE
is a major input to the hippocampus (Herkenham,
1978), few studies have examined the physiological
effects 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) demonstrated
that RE stimulation produced large negative-going field
potentials at the stratum lacunosum-moleculare of CA1
of the hippocampus, indicative of prominent depolariz
-
ing actions on distal apical dendrites of CA1 pyramidal
cells, as well as a marked facilitation of evoked responses
at CA1 using a paired-pulse paradigm. They proposed
that the RE may “exert a persistent influence on the state
of pyramidal cell excitability,” depolarizing cells to close
to threshold for activation by other excitatory inputs (p.
5684).
Consistent with this, Bertram and Zhang (1999)
recently compared the effects of stimulation of the RE
with stimulation of the CA3 region of the hippocampus
on population responses (field excitatory postsynaptic
potentials and spikes) at CA1 and reported that RE
actions 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 “allows
for the direct and powerful excitation of the CA1 region.
This thalamohippocampal connection bypasses the
trisynaptic/commissural pathway that has been thought
to 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 the
orbitomedial prefrontal cortex (see Vertes et al., 2003).
In a manner shown for the hippocampus (Bertram &
Zhang, 1999; Dollemann-Van der Weel et al., 1997), we
recently demonstrated that RE stimulation produced
marked excitatory actions on the mPFC. As depicted in
Figure 11, RE stimulation gave rise to short-latency (~20
ms), large-amplitude (1-2 mV) evoked responses in the
mPFC. The typical response consisted of a small positive
deflection (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 observed
throughout the dorsoventral extent of the mPFC with
RE stimulation, they were most pronounced (i.e., largest
amplitude) in the prelimbic and infralimbic cortices of
the ventral mPFC (Figure 11).
The hippocampus and prefrontal cortex serve well-
recognized roles in memory processing. In an interest
-
Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 187
(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 = secondary
somatosensory cortex; SN,c,r = substantia nigra, pars compacta, pars reticulata; SN5 = spinal nucleus of trigeminal nerve; SV = superior vestibular
nucleus; 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 = fourth
ventricle.
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

188 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
Figure 9: Low- (A) and High-Magnification (B, C) Light-Field Photomicrographs Depicting Retrograde Cell Labeling in the Ventral Subicular
Complex 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 dorsal
and 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.
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

ing variant on the role of the mPFC in memory (via inter
-
actions with the hippocampus), Buckner, Kelley, and
Peterson (1999) suggested that the prefrontal cortex
may promote memory formation without being directly
involved in “intentional memorization.” According to
the authors, the prefrontal cortex uses information in
short-term (working) memory to deal with impending
task demands, and its long-term storage may simply be a
by-product of its use in meeting immediate demands. As
such, the conversion from working memory to long-term
stores involves the transfer of information from the
mPFC to the hippocampus and adjacent structures of
the temporal lobe. They stated,
One speculation would be that the critical cascade driv
-
ing human memory formation occurs only when frontal
activity provides information to medial temporal lobe
structures. The medial temporal lobe may then function
to bind together from frontal and other cortical regions
to form lasting, recollectable memory traces. Thus, both
regions would be critical to the conception of a memory,
and lack of participation of either brain region would
disrupt memory formation. (p. 313)
The demonstration that the RE is strongly reciprocally
linked to the hippocampus and to the mPFC, and exerts
pronounced excitatory actions on both structures, sug
-
gests that the RE may represent a critical interface be
-
tween the hippocampus and orbitomedial prefrontal
cortex in memory processing.
THE ROLE OF THE THETA RHYTHM OF
THE HIPPOCAMPUS IN MEMORY
Although theta has been implicated in several func-
tions including arousal (Green & Arduini, 1954) and
recently sensorimotor integration (Bland & Colom,
1993; Bland & Oddie, 2001), the prevailing view is that
theta serves a critical role in mnemonic functions of the
hippocampus (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 medial
septal lesions that eliminated theta in the hippocampus
produced severe spatial memory deficits in rats. Subse
-
quent studies similarly reported that the loss of theta
with 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 that
theta may promote memory in a manner comparable to
the long-term changes produced by tetanic stimulation
in long-term potentiation (LTP) experiments. Specifi
-
cally, we stated that “theta rhythm, which involves the
synchronous activation of large numbers of
septohippocampal neurons, may act as a ‘natural
tetanizer’ producing synaptic modifications at specific
hippocampal sites supportive of long term changes at
these sites” (p. 65). In effect, Vertes suggested that theta
may potentiate the actions of other inputs to the hippo
-
Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 189
Figure 10: Low- (A) and High-Magnification (B) Light-Field Photomi
-
crographs Depicting Labeled Neurons in the Amygdala
Produced by Fluorogold Injection in the Rostrolateral Part
of the Nucleus Reuniens.
SOURCE: Reprinted from McKenna and Vertes (2004), p. 130, with
permission of Wiley-Liss, Inc.
NOTE: Note pronounced numbers of labeled cells in the medial
(MEA), anterior cortical (COA), and basomedial nuclei of the
amygdala (BMA). (B) High-magnification photomicrograph of a small
cluster of labeled cells in the cortical nucleus of amygdala (arrow in A).
Scale bar for (A) = 350 µm; for (B) = 70 µm.
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

campus, possibly to encode information arriving via
these afferents. This was supported by the early demon
-
stration that septal stimulation, mimicking theta,
significantly enhanced population responses in the
hippocampus.
For instance, Krnjevic and Robert (1982) showed that
single-pulse or tetanic stimulation of the medial septum
significantly potentiated commissurally-elicited popula
-
tion spikes at CA1 and likened the process to what occurs
naturally with theta. They stated,
The fact that the septal facilitatory action is evoked most
effectively by brief tetanic volleys at 50-100 Hz seems sig
-
nificant in view of previous observations that many septal
units fire in 50-100 Hz bursts and that theta waves are
especially 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 commissural
stimulation) during theta-associated behaviors (e.g.,
running) than during nontheta associated behaviors
(e.g., grooming and drinking) in freely moving rats and
concluded that the medial septum, through its role in
generating theta, “exerts a potent biasing effect on the
efficacy of other afferents to the hippocampus” (p. 235).
Perhaps the strongest support, however, for the view
that theta may act as “natural tetanizer” in the long-term
modification of hippocampal activity is the demonstra
-
tion that LTP is optimally elicited in the hippocampus
with stimulation at theta frequency (for review, see
Vertes & Kocsis, 1997). In an initial report, using the
hippocampal slice preparation, Larson, Wong, and
Lynch (1986) showed that LTP was most effectively
induced in the CA1 area of rats by trains of stimulation
that were separated by 200 ms (i.e., 5 Hz). Intervals
shorter or longer than 200 ms produced significantly
less, or no, potentiation. In a follow-up study, Staubli and
Lynch (1987) showed that stimulation at theta fre
-
190 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
Figure 11: Evoked Field Potentials in the Infralimbic/Prelimbic Cortex of the Medial Prefrontal Cortex (Left Side) to Stimulation (300 A) at 250
m 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 paraventricular
nucleus and nucleus reuniens, respectively. There was a null zone between them. The highest amplitude evoked potentials were produced with
stimulation 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.
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

quency also very effectively produced LTP at CA1 in the
behaving rat, and it remained stable for 1 to 5 weeks or
until the preparation deteriorated. The authors com
-
mented that it seemed remarkable that a brief period of
stimulation (at theta frequency), which in total lasted
about 300 ms, produced effects that persisted for several
weeks 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 occurring
theta rhythm and the development of synaptic changes
of the type needed for memory storage” (p. 233).
Diamond, Dunwiddie, and Rose (1988) subsequently
examined various parameters of this effect in the
hippocampal slice and behaving rat. Stimulation con
-
sisted of a single priming pulse followed 140 to 170 ms
later by a high-frequency (100 Hz) burst ranging from 2
to 10 pulses. This was termed, and is now commonly
referred to as, primed burst (PB) stimulation and the LTP
elicited by it as primed burst potentiation. The authors
showed that (a) priming intervals of 140 to 170 ms (i.e.,
between the priming pulse and bursts) produced LTP
and shorter or longer intervals were ineffective; (b) 5 or
10 pulses that were not preceded by a priming pulse
failed to elicit LTP; (c) significant PB potentiation was
obtained with as few as 3 pulses (a single priming pulse
followed 170 ms later by a 2-pulse burst); (d) PB
potentiation could be elicited both homo- and
heterosynaptically, that is, with the priming pulse and
bursts delivered to the same or separate sets of afferents
to CA1, respectively; (e) LTP elicited with PB and con-
ventional stimulation parameters were not additive, sug-
gesting common underlying mechanisms for the two
forms of LTP; and (f) the magnitude and duration of PB
potentiation at CA1 was virtually the same for the slice
and awake preparation.
Rose and Dunwiddie (1986) pointed out that prior to
the demonstration of PB potentiation, a major problem
in viewing LTP as an endogenous substrate for memory
was that the stimulation parameters commonly used to
induce it (e.g., 100 Hz for 1 second) were very
nonphysiological. This problem has seemingly been cir
-
cumvented with the demonstration that LTP can be
induced in the hippocampus with as few three to five
pulses, when pulses are delivered at theta frequencies.
The findings that LTP can be optimally induced in the
hippocampus with stimuli mimicking theta suggest a
role for the naturally occurring theta rhythm in LTP/
LTP-like effects. In this regard, it has been shown in the
hippocampal slice (Huerta & Lisman, 1993, 1995, 1996)
and intact preparation (Bramham & Srebro, 1989;
Holscher, Anwyl, & Rowan, 1997; Pavlides, Greenstein,
Grudman, & Winson, 1988) that stimulation delivered in
the 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) showed
in urethane anesthetized rats that PB stimulation of the
perforant path delivered on the positive phase of the
theta rhythm induced LTP, whereas that given on the
negative phase of theta resulted in a decrease in popula
-
tion spike amplitudes or was without effect. Huerta and
Lisman (1995, 1996) similarly reported that a single
burst of four pulses at the peaks of carbachol-elicited
theta in the hippocampal slice produced long-lasting
LTP at CA1, whereas stimulation of the trough of theta
produced a suppression (depotentiation) of previously
potentiated 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-related
functions in transgenic mice in which calcium-
calmodulin-dependent kinase II (CaMKII) was ren-
dered persistently active by replacing threonine
286
with
an aspartate group (CaMKII-Asp
286
). The genetically
altered mice (CaMKII-Asp
286
) showed (a) a loss of LTP
elicited with stimulation at theta frequency but not that
elicited with high-frequency stimulation, (b) a disrup-
tion of place cell activity, and (c) severe deficits in spatial
learning. Based on these findings, Kandel and associates
(Bach et al., 1995)proposed that the endogenous theta
rhythm may exert LTP-like effects, synaptically strength-
ening place cells leading to the formation of spatial maps
necessary for spatial learning/memory. They stated,
There are, however, several reasons to believe that fre
-
quencies of about 5 Hz may be particularly important for
spatial memory, because these frequencies stimulate
endogenous 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 the
medial septum. Cholinergic activation in turn leads to a
depolarizing oscillation at the theta frequency in the
membrane potential of the CA3 pyramidal neurons. At
the peak of these depolarizations, the CA3 cells fire one
or more action potentials that, in turn, might induce
theta frequency LTP in the CA1 neurons. Thus, the
learning impairment seen in CaMKII-Asp-286 trans
-
genic mice may be due to the lost capacity to form LTP in
response to the synaptic activation patterns that occur
during learning. (p. 913)
Finally, in line with the demonstration that LTP can
be effectively elicited in the presence but not in the
absence of theta, Berry and colleagues (Griffin, Asaka,
Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 191
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

Darling, & Berry, 2004; Seager, Johnson, Chabot, Asaka,
& Berry, 2002) recently reported that the rate of acquisi
-
tion of a classically conditioned eye-blink response in
rabbits was significantly accelerated when conditioning
trials were given in the presence than in the absence of
theta. Essentially, rabbits reached criteria responding in
approximately half the time (or with 50% few trials)
when trials were timed to occur with theta than without
it. The researchers concluded that “naturally occurring
theta activity plays a facilitatory role in the establishment
of 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 to
memory-processing functions in humans (for review, see
Basar, Schurmann, & Sakowitz, 2001; Bastiaansen &
Hagoort, 2003; Klimesch, 1999). In an initial report,
Klimesch, Doppelmayr, Russegger, and Pachinger
(1996) described significant increases in the power of
theta (4-7 Hz) during the encoding of words that were
subsequently successfully recalled compared to those
not recalled. In a follow-up study, they demonstrated
equivalent increases in theta during the successful
retrieval of lists of words, more pronounced in good
than poor performers (Doppelmayr, Klimesch,
Schwaiger, Auinger, & Winkler, 1998).
Similar changes in the percentage and/or power of
theta have been described for the encoding/retrieval of
visual (e.g., pictures; Klimesch et al., 2001), auditory
(Krause, Sillanmaki, Haggqvist, & Heino, 2001), and tac-
tile (Grunwald et al., 1999, 2001) information, as well as
for tasks involving declarative memory, recognition
memory, working memory, and spatial memory in
humans (see below).
With respect to recognition memory, A. P. Burgess
and Gruzelier (1997) described a greater than 2-fold
increase in the power of theta during the presentation of
a 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 anterior
cingulate 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 a
probe letter with a letter n-back on the list (e.g., three
back)—the letter or its location. Theta increased as a
function of increased (working) memory load on the
task, with additional changes occurring with improved
performance on the task. These basic findings have been
confirmed 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 conventional
scalp recordings), Kahana, Sekuler, Caplan, Kirschen,
and Madsen (1999) demonstrated task-dependent
changes in theta in various regions of the cortex during
the navigation of virtual mazes. They showed that theta
activity (a) was not continuously present but occurred
during distinct well-defined episodes associated with the
learning/recall of virtual mazes, (b) was visible in the
raw 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 “it
is likely that theta oscillations are important in human
spatial navigation” (p. 783).
These investigators (Raghavachari et al., 2001) subse
-
quently described similar findings using a nonspatial,
verbal working memory task: the Sternberg task. Similar
to the n-back task (see above), participants were pre
-
sented with a list of one to four letters (consonants) and
were required to determine whether a “probe” matched
letters on the list. They showed that theta activity dramat-
ically increased at the start of the trial, continued
through the trial, and abruptly ended at the termination
of the trial, a phenomena termed gating. They further
reported that increases in theta were dependent on
working memory components of the task and not on
sensory or motor aspects of the task.
In contrast to (or in addition to) overall changes in
levels of theta during memory-associated tasks, recent
reports have described changes in degrees of coherence
(spectral covariance) of theta between regions of the
cortex (or between cortex and hippocampus) during
working memory tasks. Sarnthein et al. (1998) reported
strong theta coherence between the prefrontal and pos
-
terior association cortices during the acquisition of ver
-
bal and visuospatial working memory tasks. Participants
were shown either a short sequence of (keyboard) char
-
acters or abstract line drawings and, following a 4-second
delay, were required to reproduce them. Coherence was
high during the 4-second working memory interval,
leading the authors to conclude that “low frequency
interactions between the prefrontal cortex and posterior
association areas mediate working memory processes”
(p. 7096).
In like manner, Fell et al. (2003) demonstrated that
theta activity was highly coherent between the hippo
-
campus and rhinal cortex during the encoding of suc
-
cessfully versus nonsuccessfully recalled words. The
authors stated that this coupling of theta between the
hippocampus and rhinal cortex “supports the hypothe
-
sis of a specific function of theta oscillations in declara
-
tive memory formation” (p. 1086).
192 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

Summary
Several lines of evidence indicate that the theta
rhythm is critically involved in memory processing func
-
tions, as follows: (a) LTP in the hippocampus is optimally
elicited with stimulation at theta frequency, (b) stimula
-
tion delivered in the presence but not in the absence of
theta potentiates population responses in the hippocam
-
pus, (c) discrete medial septal lesions that abolish theta
produce severe learning/memory deficits, (d) the loss
of LTP with PB (or theta) stimulation in mutant mice is
associated with a pronounced disruption of place cell
activity and spatial memory, and (e) task-dependent
increases in the percentage and/or power of theta have
been described in the cortex and hippocampus of
humans during performance of various episodic/
declarative, recognition, spatial, and working memory
tasks.
CONCLUSIONS
As reviewed above, theta promotes memory, and the
question 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). In
a 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 drives
postsynaptic neurons to threshold for the opening of
NMDA receptor channels, which become activated by
the simultaneous release of glutamate from synaptic
inputs to these neurons. This was referred to as the “pair
-
ing protocol.” As further pointed out, the opening of
NMDA receptor channels results in a massive influx of
calcium, which initiates a series of events that leads to a
restructuring of the postsynaptic membrane and an
eventual strengthening of connections between pre- and
postsynaptic 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
Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 193
Figure 12: Schematic Diagram Showing the Two Major Types of Input to the Hippocampal Formation: A Theta System Involving Ascending Brain
Stem–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 = medial
prefrontal cortex; RE = nucleus reuniens; RPO = nucleus pontis oralis; SUM = supramammillary nucleus.
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

information-carrying synaptic input to the hippocampus
and, when coupled, produce lasting changes. Specifi
-
cally, during theta-associated states, theta would drive
large populations of hippocampal neurons to threshold
for the activation of NMDA receptor channels, which,
when coupled with the release of glutamate from other
inputs to these cells, would result in the opening of
NMDA channels and consequent cellular changes.
Accordingly, events occurring coincident with theta
would 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 arriving
with theta would be stored (at least temporarily) in the
hippocampus, whereas information arriving in the
absence of theta would not be encoded—or not to the
same degree as that reaching the hippocampus
concurrently with theta.
To conclude, the hippocampus receives two main
types of input: theta from ascending brain stem–
diencephalo-septohippocampal systems (Figure 12) and
information bearing mainly from thalamocortical/
cortical systems (Figure 12). The temporal convergence
of activity from these two systems would result in the
encoding of information in the hippocampus mainly
reaching it from the EC and RE (Figure 12).
REFERENCES
Aggleton, J. P., & Brown, M. W. (1999). Episodic memory, amnesia
and the hippocampal-anterior thalamic axis. Behavioral and Brain
Sciences, 22, 425-489.
Aghajanian, G. K., Foote, W. E., & Sheard, M. H. (1968). Lysergic acid
diethylamide sensitive neuronal units in midbrain raphe. Science,
161, 706-708.
Aghajanian, G. K., Foote, W. E., & Sheard, M. H. (1970). Action of
psychotogenic drugs on single midbrain raphe neurons. Journal of
Pharmacology and Experimental Therapeutics, 171, 178-187.
Albo,Z.,VianaDiPrisco,G.,Truccolo,W.,Vertes,R.P.,&Ding,M.
(2001). A study of neural interactions within the limbic system
using partial coherence and direct transfer functions analysis.
Society for Neuroscience Abstracts, 27, 315.14.
Albo, Z., Viana Di Prisco, G., & Vertes, R. P. (2003). Anterior thalamic
unit discharge profiles and coherence with hippocampal theta
rhythm. Thalamus and Related Systems, 2, 133-144.
Allen, G. V., & Hopkins, D. A. (1989). Mammillary body in the rat:
Topography and synaptology of projections from the subicular
complex, prefrontal cortex, and midbrain tegmentum. Journal of
Comparative Neurology, 286, 311-336.
Allen, G. V., & Hopkins, D. A. (1990). Topography and synaptology of
mammillary body projections to the mesencephalon and pons in
the rat. Journal of Comparative Neurology, 301, 214-231.
Alonso, A., & Garcia-Austt, E. (1987). Neuronal sources of theta
rhythm in the entorhinal cortex of the rat: II. Phase-relations
between unit discharges and theta field potentials. Experimental
Brain Research, 67, 502-509.
Alreja, M. (1996). Excitatory actions of serotonin on GABAergic neu
-
rons of the medial septum and diagonal band of Broca. Synapse,
22, 15-27.
Amaral, D. G., & Witter, M. P. (1995). Hippocampal formation. In G.
Paxinos (Ed.), Theratnervoussystem(2nd ed., pp. 443-493). New
York: Academic Press.
Asaka, Y., Griffin, A. L., & Berry, S. D. (2002). Reversible septal inacti
-
vation disrupts hippocampal slow-wave and unit activity and
impairs trace conditioning in rabbits (Oryctolagus cuniculus).
Behavioral Neuroscience, 116, 434-442.
Assaf, S. Y., & Miller, J. J. (1978). Role of a raphe serotonin system in
control of septal unit activity and hippocampal desynchroni-
zation. Neuroscience, 3, 539-550.
Aznar, S., Qian, Z. X., & Knudsen, G. M. (2004). Non-serotonergic
dorsal and median raphe projection onto parvalbumin- and
calbindin-containing neurons in hippocampus and septum. Neu
-
roscience, 124, 573-581.
Bach,M.E.,Hawkins,R.D.,Osman,M.,Kandel,E.R.,&Mayford,M.
(1995). Impairment of spatial but not contextual memory in
CaMKII mutant mice with a selective loss of hippocampal LTP in
the range of the theta frequency. Cell, 81, 905-915.
Basar, E., Schurmann, M., & Sakowitz, O. (2001). The selectively dis
-
tributed theta system: Functions. International Journal of
Psychophysiology, 39, 197-212.
Bassant, M. H., & Poindessous-Jazat, F. (2001). Ventral tegmental
nucleus of Gudden: A pontine hippocampal theta generator? Hip
-
pocampus, 11, 809-813.
Bassett, J. P., & Taube, J. S. (2001). Neural correlates for angular head
velocity in the rat dorsal tegmental nucleus. Journal of Neuroscience,
21, 5740-5751.
Bastiaansen, M., & Hagoort, P. (2003). Event-induced theta responses
as a window on the dynamics of memory. Cortex, 39, 967-992.
Beckstead, R. M. (1979). Autoradiographic examination of
corticocortical and subcortical projections of the mediodorsal-
projection (prefrontal) cortex in the rat. Journal of Comparative
Neurology, 184, 43-62.
Bertram, E. H., & Zhang, D. X. (1999). Thalamic excitation of
hippocampal CA1 neurons: A comparison with the effects of CA3
stimulation. Neuroscience, 92, 15-26.
Blair, H. T., Cho, J. W., & Sharp, P. E. (1998). Role of the lateral
mammillary nucleus in the rat head direction circuit: A combined
single unit recording and lesion study. Neuron, 21, 1387-1397.
Blair, H. T., Cho, J. W., & Sharp, P. E. (1999). The anterior thalamic
head-direction signal is abolished by bilateral but not unilateral
lesions of the lateral mammillary nucleus. Journal of Neuroscience,
19, 6673-6683.
Blair, H. T., Lipscomb, B. W., & Sharp, P. E. (1997). Anticipatory time
intervals of head-direction cells in the anterior thalamus of the
rat: Implications for path integration in the head-direction cir-
cuit. Journal of Neurophysiology, 78, 145-159.
Blair, H. T., & Sharp, P. E. (1995). Anticipatory head direction signals
in anterior thalamus: Evidence for a thalamocortical circuit that
integrates angular head motion to compute head direction. Jour
-
nal of Neuroscience, 15, 6260-6270.
Bland, B. H. (1986). The physiology and pharmacology of
hippocampal formation theta rhythms. Progress in Neurobiology, 26,
1-54.
Bland, B. H., & Colom, L. V. (1993). Extrinsic and intrinsic properties
underlying oscillation and synchrony in limbic cortex. Progress in
Neurobiology, 41, 157-208.
Bland, B. H., Colom, L. V., & Ford, R. D. (1990). Responses of septal θ-
on and θ-off cells to activation of the dorsomedial-posterior hypo
-
thalamic region. Brain Research Bulletin, 24, 71-79.
Bland, B. H., Colom, L. V., Konopacki, J., & Roth, S. H. (1988).
Intracellular records of carbachol-induced theta rhythm in
hippocampal slices. Brain Research, 447, 364-368.
Bland,B.H.,Konopacki,J.,Kirk,I.J.,Oddie,S.D.,&Dickson,C.T.
(1995). Discharge patterns of hippocampal theta-related cells in
the caudal diencephalon of the urethane-anesthetized rat. Journal
of Neurophysiology, 74, 322-333.
Bland, B. H., & Oddie, S. D. (1998). Anatomical, electrophysiological
and pharmacological studies of ascending brainstem
hippocampal synchronizing pathways. Neuroscience and
Biobehavioral Reviews, 22, 259-273.
Bland, B. H., & Oddie, S. D. (2001). Theta band oscillation and syn
-
chrony in the hippocampal formation and associated structures:
Thecaseforitsroleinsensorimotorintegration.Behavioural Brain
Research, 127, 119-136.
Bland, B. H., Oddie, S. D., Colom, L. V., & Vertes, R. P. (1994). Extrin
-
sic modulation of medial septal cell discharges by the ascending
194 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

brainstem hippocampal synchronizing pathway. Hippocampus, 4,
649-660.
Bocian, R., & Konopacki, J. (2004). The effect of posterior hypotha
-
lamic injection of cholinergic agents on hippocampal formation
theta in freely moving cat. Brain Research Bulletin, 63, 283-294.
Bokor, H., Csaki, A., Kocsis, K., & Kiss, J. (2002). Cellular architecture
of the nucleus reuniens thalami and its putative aspartatergic/
glutamatergic projection to the hippocampus and medial septum
in the rat. European Journal of Neuroscience, 16, 1227-1239.
Borhegyi, Z., Magloczky, Z., Acsady, L., & Freund, T. F. (1998). The
supramammillary nucleus innervates cholinergic and GABAergic
neurons in the medial septum-diagonal band of Broca complex.
Neuroscience, 82, 1053-1065.
Bramham, C. R., & Srebro, B. (1989). Synaptic plasticity in the hippo
-
campus is modulated by behavioral state. Brain Research, 493, 74-
86.
Brazhnik, E. S., & Fox, S. E. (1997). Intracellular recordings from
medial septal neurons during hippocampal theta rhythm. Experi
-
mental Brain Research, 114, 442-453.
Brazhnik, E. S., & Vinogradova, O. S. (1986). Control of the neuronal
rhythmic bursts in the septal pacemaker of theta-rhythm: Effects
of anesthetic and anticholinergic drugs. Brain Research, 380, 94-
106.
Brazhnik, E. S., Vinogradova, O. S., & Karanov, A. M. (1985). Fre
-
quency modulation of neuronal theta-bursts in rabbit’s septum by
low-frequency repetitive stimulation of the afferent pathways.
Neuroscience, 14, 501-508.
Brazhnik,E.S.,Vinogradova,O.S.,Stafekhina,V.S.,&Kitchigina,V.
F. (1993). Acetylcholine, theta-rhythm and activity of
hippocampal neurons in the rabbit: I. Spontaneous activity. Neuro-
science, 53, 961-970.
Buchanan,S.L.,Thompson,R.H.,Maxwell,B.L.,&Powell,D.A.
(1994). Efferent connections of the medial prefrontal cortex in
the rabbit. Experimental Brain Research, 100, 469-483.
Buckner, R. L., Kelley, W. H., & Petersen, S. E. (1999). Frontal cortex
contributes to human memory formation. Nature Neuroscience, 2,
311-314.
Burgess, A. P., & Gruzelier, J. H. (1997). Short duration synchroniza-
tion of human theta rhythm during recognition memory.
Neuroreport, 8, 1039-1042.
Burgess, N., Maguire, E. A., & O’Keefe, J. (2002). The human hippo
-
campus and spatial and episodic memory. Neuron, 35, 625-641.
Buzsaki,G.,Grastyan,E.,Czopf,J.,Kellenyi,L.,&Prohaska,O.
(1981). Changes in neuronal transmission in the rat hippocam
-
pus during behavior. Brain Research, 225, 235-247.
Byatt, G., & Dalrymple-Alford, J. C. (1996). Both anteromedial and
anteroventral thalamic lesions impair radial-maze learning in
rats. Behavioral Neuroscience, 110, 1335-1348.
Canteras, N. S., Simerly, R. B., & Swanson, L. W. (1995). Organization
of projections from the medial nucleus of the amygdala: A PHAL
study in the rat. Journal of Comparative Neurology, 360, 213-245.
Carr, D. B., & Sesack, S. R. (1996). Hippocampal afferents to the rat
prefrontal cortex: Synaptic targets and relation to dopamine ter
-
minals. Journal of Comparative Neurology, 369, 1-15.
Cavada, C., Llamas, A., & Reinoso-Suarez, F. (1983). Allocortical
afferent connections of the prefrontal cortex in the cat. Brain
Research, 260, 117-120.
Chen, L. L., Lin, L. H., Green, E. J., Barnes, C. A., & McNaughton, B. L.
(1994). Head-direction cells in the rat posterior cortex: I. Ana
-
tomical distribution and behavioral modulation. Experimental
Brain Research, 101, 8-23.
Cho, J. W., & Sharp, P. E. (2001). Head direction, place, and move
-
ment correlates for cells in the rat retrosplenial cortex. Behavioral
Neuroscience, 115, 3-25.
Colom, L. V., & Bland, B. H. (1987). State-dependent spike train
dynamics of hippocampal formation neurons: Evidence for theta-
on and theta-off cells. Brain Research, 422, 277-286.
Conde, F., Maire-Lepoivre, E., Audinat, E., & Crepel, F. (1995). Affer
-
ent connections of the medial frontal cortex of the rat: II. Cortical
and subcortical afferents. Journal of Comparative Neurology, 352,
567-593.
Contreras, D., & Steriade, M. (1996). Spindle oscillation in cats: The
role of corticothalamic feedback in a thalamically generated
rhythm. Journal of Physiology (London), 490, 159-179.
Diamond, D. M., Dunwiddie, T. V., & Rose, G. M. (1988). Characteris
-
tics of hippocampal primed burst potentiation in vitro and in the
awake rat. Journal of Neuroscience, 8, 4079-4088.
Dickson, C. T., Kirk, I. J., Oddie, S. D., & Bland, B. H. (1995). Classifi
-
cation of theta-related cells in the entorhinal cortex: Cell dis
-
charges are controlled by the ascending brainstem synchronizing
pathway in parallel with hippocampal theta-related cells. Hippo
-
campus, 5, 306-319.
Dolleman-Van der Weel, M. J., Lopes da Silva, F. H., & Witter, M. P.
(1997). Nucleus reuniens thalami modulates activity in
hippocampal field CA1 through excitatory and inhibitory mecha
-
nisms. Journal of Neuroscience, 17, 5640-5650.
Dolleman-Van der Weel, M. J., & Witter, M. P. (1996). Projections
from the nucleus reuniens thalami to the entorhinal cortex,
hippocampal field CA1, and the subiculum in the rat arise from
different populations of neurons. Journal of Comparative Neurology,
364, 637-650.
Donovick, P. J. (1968). Effects of localized septal lesions on
hippocampal EEG activity and behavior in rats. Journal of Compara
-
tive and Physiological Psychology, 66, 569-578.
Doppelmayr,M.,Klimesch,W.,Schwaiger,J.,Auinger,P.,&Winkler,
T. (1998). Theta synchronization in the human EEG and episodic
retrieval. Neuroscience Letters, 257, 41-44.
Dutar, P., Bassant, M.-H., Senut, M. C., & Lamour, Y. (1995) The
septohippocampal pathway: Structure and function of a central
cholinergic system. Physiological Reviews, 75, 393-427.
Fanselow,E.E.,Sameshima,K.,Baccala,L.A.,&Nicolelis,M.A.
(2001). Thalamic bursting in rats during different awake behav-
ioral states. Proceedings of the National Academy of Sciences of the United
States of America, 98, 15330-15335.
Fell, J., Klaver, P., Elfadil, H., Schaller, C., Elger, C. E., & Fernandez, G.
(2003). Rhinal-hippocampal theta coherence during declarative
memory formation: Interaction with gamma synchronization?
European Journal of Neuroscience, 17, 1082-1088.
Ferino, F., Thierry, A. M., & Glowinski, J. (1987). Anatomical and
electrophysiological evidence for a direct projection from
Ammon’s horn to the medial prefrontal cortex in the rat. Experi-
mental Brain Research, 65, 421-426.
Forchetti, C. M., & Meek, J. L. (1981). Evidence for a tonic GABAergic
control of serotonin neurons in the median raphe nucleus. Brain
Research, 206, 208-212.
Ford, R. D., Colom, L. V., & Bland, B. H. (1989). The classification of
medial septum-diagonal band cells as theta-on or theta-off in rela
-
tion to hippocampal EEG states. Brain Research, 493, 269-282.
Fox, S. E., & Ranck, J. B. (1981). Electrophysiological characteristics
of hippocampal complex-spike cells and theta-cells. Experimental
Brain Research, 41, 399-410.
Freund, T. F., & Antal, M. (1988). GABA-containing neurons in the
septum control inhibitory interneurons in the hippocampus.
Nature, 336, 170-173.
Frotscher, M., & Leranth, C. (1985). Cholinergic innervation of the
rat hippocampus as revealed by choline acetyltransferase
immunocytochemistry: A combined light and electron micro
-
scopic study. Journal of Comparative Neurology, 239, 237-246.
Gabriel, M., Cuppernell, C., Shenker, J. I., Kubota, Y., Henzi, V., &
Swanson, D. (1995). Mammillothalamic tract transection blocks
anterior thalamic training-induced neuronal plasticity and
impairs discriminative avoidance-behavior in rabbits. Journal of
Neuroscience, 15, 1437-1445.
Gevins, A., Smith, M. E., McEvoy, L., & Yu, D. (1997). High-resolution
EEG mapping of cortical activation related to working memory:
Effects of task difficulty, type of processing, and practice. Cerebral
Cortex, 7, 374-385.
Gogolak, G., Stumpf, C., Petsche, H., & Sterc, J. (1968). The firing
pattern of septal neurons and the form of the hippocampal theta
wave. Brain Research, 7, 201-207.
Golob, E. J., Wolk, D. A., & Taube, J. S. (1998). Recordings of
postsubiculum head direction cells following lesions of the
laterodorsal thalamic nucleus. Brain Research, 780, 9-19.
Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 195
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

Goodridge, J. P., & Taube, J. S. (1997). Interaction between the
postsubiculum and anterior thalamus in the generation of head
direction cell activity. Journal of Neuroscience, 17, 9315-9330.
Gray, J. A. (1971). Medial septal lesions, hippocampal theta rhythm
and control of vibrissal movement in freely moving rat. Electroen
-
cephalography and Clinical Neurophysiology, 30, 189-197.
Gray, J. A., & McNaughton, N. (2000). The neuropsychology of anxiety
(2nd ed.). New York: Oxford University Press.
Green, J. D., & Arduini, A. A. (1954). Hippocampal electrical activity
in arousal. Journal of Neurophysiology, 17, 533-557.
Griffin, A. L., Asaka, Y., Darling, R. D., & Berry, S. D. (2004). Theta-
contingent trial presentation accelerates learning rate and
enhances hippocampal plasticity during trace eyeblink condition
-
ing. Behavioral Neuroscience, 118, 403-411.
Grunwald,M.,Weiss,T.,Krause,W.,Beyer,L.,Rost,R.,Gutberlet,I.,
et al. (1999). Power of theta waves in the EEG of human subjects
increases during recall of haptic information. Neuroscience Letters,
260, 189-192.
Grunwald,M.,Weiss,T.,Krause,W.,Beyer,L.,Rost,R.,Gutberlet,I.,
et al. (2001). Theta power in the EEG of humans during ongoing
processing in a haptic object recognition task. Cognitive Brain
Research, 11, 33-37.
Guido, W., Lu, S. M., & Sherman, S. M. (1992). Relative contributions
of burst and tonic responses to the receptive field properties of lat
-
eral geniculate neurons in the cat. Journal of Neurophysiology, 68,
2199-2211.
Guido, W., & Weyand, T. (1995). Burst responses in thalamic relay
cells of the awake behaving cat. Journal of Neurophysiology, 74, 1782-
1786.
Gulyas,A.I.,Seress,L.,Toth,K.,Acsady,L.,Antal,M.,&Freund,T.F.
(1991). Septal GABAergic neurons innervate inhibitory
interneurons in the hippocampus of the macaque monkey. Neuro-
science, 41, 381-390.
Haglund, L., Swanson, L. W., & Kohler, C. (1984). The projection of
the supramammillary nucleus to the hippocampal formation: An
immunohistochemical and anterograde transport study with the
lectin PHA-L in the rat. Journal of Comparative Neurology, 229, 171-
185.
Hajszan, T., Alreja, M., & Leranth, C. (2004). Intrinsic vesicular gluta-
mate transporter 2-immunoreactive input to septohippocampal
parvalbumin-containing neurons: Novel glutamatergic local cir-
cuit cells. Hippocampus, 14, 499-509.
Hasselmo, M. E. (2000). Septal modulation of hippocampal dynam
-
ics: What is the function of the theta rhythm? In R. Numan (Ed.),
The behavioral neuroscience of the septal region (pp. 92-114). New York:
Springer-Verlag.
Hasselmo, M. E., Bodelon, C., & Wyble, B. P. (2002). A proposed func
-
tion for hippocampal theta rhythm: Separate phases of encoding
and retrieval enhance reversal of prior learning. Neural Computa
-
tion, 14, 793-817.
Hayakawa, T., & Zyo, K. (1990). Ultrastructure of the
mammillotegmental projections to the ventral tegmental nucleus
of gudden in the rat. Journal of Comparative Neurology, 293, 466-475.
Hayakawa, T., & Zyo, K. (1991). Quantitative and ultrastructural-
study of ascending projections to the medial mammillary nucleus
in the rat. Anatomy and Embryology, 184, 611-622.
Herkenham, M. (1978). Connections of nucleus reuniens thalami:
Evidence for a direct thalamo-hippocampal pathway in the rat.
Journal of Comparative Neurology, 177, 589-610.
Holscher, C., Anwyl, R., & Rowan, M. J. (1997). Stimulation on the
positive phase of hippocampal theta rhythm induces long-term
potentiation that can be depotentiated by stimulation on the neg
-
ative phase in area CA1 in vivo. Journal of Neuroscience, 17, 6470-
6477.
Huerta, P. T., & Lisman, J. E. (1993). Heightened synaptic plasticity of
hippocampal CA1 neurons during a cholinergically induced
rhythmic state. Nature, 364, 723-725.
Huerta, P. T., & Lisman, J. E. (1995). Bidirectional synaptic plasticity
induced by a single burst during cholinergic theta oscillation in
CA1 in vitro. Neuron, 15, 1053-1063.
Huerta, P. T., & Lisman, J. E. (1996). Low-frequency stimulation at the
troughs of θ-oscillation induces long-term depression of previ
-
ously potentiated CA1 synapses. Journal of Neurophysiology, 75, 877-
884.
Hurley, K. M., Herbert, H., Moga, M. M., & Saper, C. B. (1991). Effer
-
ent projections of the infralimbic cortex of the rat. Journal of Com
-
parative Neurology, 308, 249-276.
Irle, E., & Markowitsch, H. J. (1982). Widespread cortical projections
of the hippocampal formation in the cat. Neuroscience, 7, 2637-
2647.
Jacobs, B. L., & Azmitia, E. C. (1992). Structure and function of the
brain serotonin system. Physiological Reviews, 72, 165-229.
Jacobs, B. L., Heym, J., & Steinfels, G. F. (1984). Physiological and
behavioral analysis of raphe unit activity. In L. L. Iverson, S. D.
Iversen, & S. H. Snyder (Eds.), Handbook of psychopharmacology (pp.
343-395). New York: Plenum.
James,D.T.D.,McNaughton,N.,Rawlins,J.N.P.,Feldon,J.,&Gray,
J. A. (1977). Septal driving of hippocampal theta rhythm as a func
-
tion of frequency in free moving male rat. Neuroscience, 2, 1007-
1017.
Jay, T. M., Glowinski, J., & Thierry, A. M. (1989). Selectivity of the
hippocampal projection to the prelimbic area of the prefrontal
cortex in the rat. Brain Research, 505, 337-340.
Jay, T. M., & Witter, M. P. (1991). Distribution of hippocampal CA1
and subicular efferents in the prefrontal cortex of the rat studied
by means of anterograde transport of Phaseolus vulgaris-
leucoagglutinin. Journal of Comparative Neurology, 313, 574-586.
Jensen, O., & Tesche, C. D. (2002). Frontal theta activity in humans
increases with memory load in a working memory task. European
Journal of Neuroscience, 15, 1395-1399.
Kahana, M. J., Seelig, D., & Madsen, J. R. (2001). Theta returns. Cur
-
rent Opinion in Neurobiology, 11, 739-744.
Kahana,M.J.,Sekuler,R.,Caplan,J.B.,Kirschen,M.,&Madsen,J.R.
(1999). Human theta oscillations exhibit task dependence during
virtual maze navigation. Nature, 399, 781-784.
Kinney, G. G., Kocsis, B., & Vertes, R. P. (1994). Injections of excit-
atory amino acid antagonists into the median raphe nucleus pro-
duce hippocampal theta rhythm in the urethane anesthetized rat.
Brain Research, 654, 96-104.
Kinney, G. G., Kocsis, B., & Vertes, R. P. (1995). Injections of
muscimol into the median raphe nucleus produce hippocampal
theta rhythm in the urethane anesthetized rat. Psychopharmacology,
120, 244-248.
Kinney, G. G., Kocsis, B., & Vertes, R. P. (1996). Medial septal unit fir
-
ing characteristics following injections of 8-OH-DPAT into the
median raphe nucleus. Brain Research, 708, 116-122.
Kirk, I. J. (1998). Frequency modulation of hippocampal theta by the
supramammillary nucleus, and other hypothalamo-hippocampal
interactions: Mechanisms and functional implications. Neurosci
-
ence and Biobehavioral Reviews, 22, 291-302.
Kirk, I. J., & Mackay, J. C. (2003). The role of theta-range oscillations
in synchronising and integrating activity in distributed mnemonic
networks. Cortex, 39, 993-1008.
Kirk, I. J., & McNaughton, N. (1991). Supramammillary cell firing
and hippocampal rhythmical slow activity. Neuroreport, 2, 723-725.
Kirk, I. J., & McNaughton, N. (1993). Mapping the differential effects
of procaine on frequency and amplitude of reticularly elicited
hippocampal rhythmical slow activity. Hippocampus, 3, 517-526.
Kirk, I. J., Oddie, S. D., Konopacki, J., & Bland, B. H. (1996). Evidence
for differential control of posterior hypothalamic,
supramammillary, and medial mammillary theta-related cellular
discharge by ascending and descending pathways. Journal of Neuro
-
science, 16, 5547-5554.
Kiss, J., Csaki, A., Bokor, H., Shanabrough, M., & Leranth, C. (2000).
The supramammillo-hippocampal and supramammillo-septal
glutamatergic/aspartatergic projections in the rat: A combined
[3H]D-aspartate autoradiographic and immunohistochemical
study. Neuroscience, 97, 657-669.
Kitchigina,V.F.,Kudina,T.A.,Kutyreva,E.V.,&Vinogradova,O.S.
(1999). Neuronal activity of the septal pacemaker of theta rhythm
under the influence of stimulation and blockade of the median
raphe nucleus in the awake rabbit. Neuroscience, 94, 453-463.
196 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

Klimesch, W. (1999). EEG alpha and theta oscillations reflect cogni
-
tive and memory performance: A review and analysis. Brain
Research Reviews, 29, 169-195.
Klimesch, W., Doppelmayr, M., Russegger, H., & Pachinger, T. (1996).
Theta band power in the human scalp EEG and the encoding of
new information. Neuroreport, 7, 1235-1240.
Klimesch, W., Doppelmayr, M., Stadler, W., Pollhuber, D., Sauseng, P.,
& Rohm, D. (2001). Episodic retrieval is reflected by a process spe
-
cific increase in human electroencephalographic theta activity.
Neuroscience Letters, 302, 49-52.
Kocsis, B., & Vertes, R. P. (1994). Characterization of neurons of the
supramammillary nucleus and mammillary body that discharge
rhythmically with the hippocampal theta rhythm in the rat. Journal
of Neuroscience, 14, 7040-7052.
Kocsis, B., & Vertes, R. P. (1996). Midbrain raphe cell firing and
hippocampal theta rhythm in urethane anaesthetized rats.
Neuroreport, 7, 2867-2872.
Kocsis, B., & Vertes, R. P. (1997). Phase relations of rhythmic
neuronal firing in the supramammillary nucleus and mammillary
body to the hippocampal theta activity in urethane anesthetized
rats. Hippocampus, 7, 204-214.
Kocsis, B., Viana Di Prisco, G., & Vertes, R. P. (2001). Theta synchroni
-
zation in the limbic system: The role of Gudden’s tegmental
nuclei. European Journal of Neuroscience, 13, 381-388.
Konopacki, J. (1998). Theta-like activity in the limbic cortex in vitro.
Neuroscience and Biobehavioral Reviews, 22, 311-323.
Konopacki, J., MacIver, M. B., Bland, B. H., & Roth, S. H. (1987).
Carbachol-induced EEG “theta” activity in hippocampal brain
slices. Brain Research, 405, 196-198.
Kramis, R., & Vanderwolf, C. H. (1980). Frequency specific RSA-like
hippocampal patterns elicited by septal, hypothalamic, and
brainstem electrical stimulation. Brain Research, 192, 383-398.
Krause, C. M., Sillanmaki, L., Haggqvist, A., & Heino, R. (2001). Test-
retest consistency of the event-related desynchronization/event-
related synchronization of the 4-6, 6-8, 8-10 and 10-12 Hz fre-
quency bands during a memory task. Clinical Neurophysiology, 112,
750-757.
Krnjevic, K., & Ropert, N. (1982). Electrophysiological and pharma-
cological characteristics of facilitation of hippocampal popula-
tion spikes by stimulation of the medial septum. Neuroscience, 7,
2165-2183.
Lamour, Y., Dutar, P., & Jobert, A. (1984). Septo-hippocampal and
other medial septum-diagonal band neurons: Electrophysiolo-
gical and pharmacological properties. Brain Research, 309, 227-
239.
Larson, J., Wong, D., & Lynch, G. (1986). Patterned stimulation at the
theta frequency is optimal for the induction of hippocampal long-
term potentiation. Brain Research, 368, 347-350.
LeDoux, J. E. (1993). Emotional memory systems in the brain. Behav
-
ioural Brain Research, 58, 69-79.
Leranth, C., & Frotscher, M. (1989). Organization of the septal
region in the rat brain: Cholinergic-GABAergic interconnections
and the termination of hippocampo-septal fibers. Journal of Com
-
parative Neurology, 289, 304-314.
Leranth, C., & Kiss, J. (1996). A population of supramammillary area
calretinin neurons terminating on medial septal area cholinergic
and lateral septal area calbindin-containing cells are aspartate/
glutamatergic. Journal of Neuroscience, 16, 7699-7710.
Leranth, C., & Vertes, R. P. (1999). Median raphe serotonergic
innervation of medial septum diagonal band of Broca (MSDB)
parvalbumin-containing neurons: Possible involvement of the
MSDB in the desynchronization of the hippocampal EEG. Journal
of Comparative Neurology, 410, 586-598.
Leranth, C., & Vertes, R. P. (2000). Neuronal networks that control
the septal pacemaker system: Synaptic interconnections between
the septal complex, hippocampus, supramammillary area, and
median raphe. In R. Numan (Ed.), The behavioral neuroscience of the
septal region (pp. 15-47). New York: Springer-Verlag.
Leung, L. W. S., & Borst, J. G. G. (1987). Electrical activity of the
cingulate cortex: I. Generating mechanisms and relations to
behavior. Brain Research, 407, 68-80.
Leung, L. S., & Shen, B. (2004). Glutamatergic synaptic transmission
participates in generating the hippocampal EEG. Hippocampus,
14, 510-525.
Leutgeb, S., & Mizumori, S. J. Y. (1999). Excitotoxic septal lesions
result in spatial memory deficits and altered flexibility of
hippocampal single-unit representations. Journal of Neuroscience,
19, 6661-6672.
Lisman, J. E. (1997). Bursts as a unit of neural information: Making
unreliable synapses reliable. Trends in Neurosciences, 20, 38-43.
Liu, W., & Alreja, M. (1997). Atypical antipsychotics block the excit
-
atory effects of serotonin in septohippocampal neurons in the rat.
Neuroscience, 79, 369-382.
Macadar, A. W., Chalupa, L. M., & Lindsley, D. B. (1974). Differentia
-
tion of brain stem loci which affect hippocampal and neocortical
electrical activity. Experimental Neurology, 43, 499-514.
Magloczky, Z., Acsady, L., & Freund, T. F. (1994). Principal cells are
the postsynaptic targets of supramammillary afferents in the hip
-
pocampus of the rat. Hippocampus, 4, 322-334.
Malenka, R. C., & Nicoll, R. A. (1999). Long-term potentiation: A
decade of progress? Science, 285, 1870-1874.
Maloney, K. J., Mainville, L., & Jones, B. E. (1999). Differential c-Fos
expression in cholinergic, monoaminergic, and GABAergic cell
groups of the pontomesencephalic tegmentum after paradoxical
sleep deprivation and recovery. Journal of Neuroscience, 19, 3057-
3072.
Marrosu, F., Fornal, C. A., Metzler, C. W., & Jacobs, B. L. (1996). 5-
HT1A agonists induce hippocampal theta activity in freely moving
cats: Role of presynaptic 5-NT1A receptors. Brain Research, 739,
192-200.
Maru, E., Takahashi, L. K., & Iwahara, S. (1979). Effects of median
raphe nucleus lesions on hippocampal EEG in the freely moving
rat. Brain Research, 163, 223-234.
Mayford,M.,Bach,M.E.,Huang,Y.Y.,Wang,L.,Hawkins,R.D.,&
Kandel, E. R. (1996). Control of memory formation through regu-
lated expression of a CaMKII transgene. Science, 274, 1678-1683.
Mayford, M., Wang, J., Kandel, E. R., & Odell, T. J. (1995). CaMKII
regulates the frequency-response function of hippocampal synap-
ses for the production of both LTD and LTP. Cell, 81, 891-904.
McKenna, J. T., & Vertes, R. P. (2001). Collateral projections from the
median raphe nucleus to the medial septum and hippocampus.
Brain Research Bulletin, 54, 619-630.
McKenna, J. T., & Vertes, R. P. (2004). Afferent projections to nucleus
reuniens of the thalamus. Journal of Comparative Neurology, 480,
115-142.
McNaughton, N., Azmitia, E. C., Williams, J. H., Buchan, A., & Gray,
J. A. (1980). Septal elicitation of hippocampal theta rhythm after
localized de-afferentation of serotoninergic fibers. Brain Research,
200, 259-269.
McNaughton,N.,James,D.T.D.,Stewart,J.,Gray,J.A.,Valero,I.,&
Drewnowski, A. (1977). Septal driving of hippocampal theta
rhythm as a function of frequency in male rat: Effects of drugs.
Neuroscience, 2, 1019-1027.
McNaughton, N., Richardson, J., & Gore, C. (1986). Reticular elicita
-
tion of hippocampal slow waves: Common effects of some anxio
-
lytic drugs. Neuroscience, 19, 899-903.
M’Harzi, M., & Jarrard, L. E. (1992). Effects of medial and lateral
septal lesions on acquisition of a place and cue radial maze task.
Behavioural Brain Research, 49, 159-165.
Mitchell, S. J., Rawlins, J. N. P., Steward, O., & Olton, D. S. (1982).
Medial septal area lesions disrupt θ rhythm and cholinergic stain
-
ing in medial entorhinal cortex and produce impaired radial arm
maze behavior in rats. Journal of Neuroscience, 2, 292-302.
Mizumori,S.J.Y.,Perez,G.M.,Alvarado,M.C.,Barnes,C.A.,&
McNaughton, B. L. (1990). Reversible inactivation of the medial
septum differentially affects two forms of learning in rats. Brain
Research, 528, 12-20.
Morin, L. P., & Meyer-Bernstein, E. L. (1999). The ascending
serotonergic system in the hamster: Comparison with projections
of the dorsal and median raphe nuclei. Neuroscience, 91, 81-105.
Mugnaini, E., & Oertel, W. H. (1985). An atlas of the distribution of
GABAergic neurons and terminals in the rat CNS as revealed by
GAD immunohistochemistry. In A. Bjorklund & T. Hokfelt (Eds.),
Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 197
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

Handbook of chemical neuroanatomy: GABA and neuropeptides in the
CNS (pp. 436-608). New York: Elsevier.
Nishikawa, T., & Scatton, B. (1985a). Inhibitory influence of GABA
on central serotonergic transmission: Involvement of the
habenulo-raphe pathways in the GABAergic inhibition of ascend
-
ing cerebral serotonergic neurons. Brain Research, 331, 81-90.
Nishikawa, T., & Scatton, B. (1985b). Inhibitory influence of GABA
on central serotonergic transmission: Raphe nuclei as the neuro
-
anatomical site of the GABAergic inhibition of cerebral
serotonergic neurons. Brain Research, 331, 91-103.
Numan, R. (2000). The behavioral neuroscience of the septal region.New
York: Springer.
Oddie, S. D., Bland, B. H., Colom, L. V., & Vertes, R. P. (1994). The
midline posterior hypothalamic region comprises a critical part of
the ascending brainstem hippocampal synchronizing pathway.
Hippocampus, 4, 454-473.
Ohtake, T., & Yamada, H. (1989). Efferent connections of the nucleus
reuniens and the rhomboid nucleus in the rat: An anterograde
PHA-L tracing study. Neuroscience Research, 6, 556-568.
Pan, W. X., & McNaughton, N. (1997). The medial supramammillary
nucleus, spatial learning and the frequency of hippocampal theta
activity. Brain Research, 764, 101-108.
Pan, W. X., & McNaughton, N. (2002). The role of the medial
supramammillary nucleus in the control of hippocampal theta
activity and behaviour in rats. European Journal of Neuroscience, 16,
1797-1809.
Papez, J. W. (1937). A proposed mechanism of emotion. Archives of
Neurology and Psychiatry, 7, 103-112.
Pavlides, C., Greenstein, Y. J., Grudman, M., & Winson, J. (1988).
Long-term potentiation in the dentate gyrus is induced preferen
-
tially on the positive phase of theta-rhythm. Brain Research, 439,
383-387.
Petsche, H., Gogolak, G., & Van Zwieten, P.A. (1965). Rhythmicity of
septal cell discharges at various levels of reticular excitation. Elec-
troencephalography and Clinical Neurophysiology, 19, 25-33.
Petsche, H., Stumpf, C., & Gogolak, G. (1962). Significance of rab-
bit’s septum as a relay station between midbrain and hippocam-
pus: I. Control of hippocampus arousal activity by septum cells.
Electroencephalography and Clinical Neurophysiology, 14, 202-211.
Plenz, D., & Kital, S. T. (1999). A basal ganglia pacemaker formed by
the subthalamic nucleus and external globus pallidus. Nature, 400,
677-682.
Raghavachari,S.,Kahana,M.J.,Rizzuto,D.S.,Caplan,J.B.,Kirschen,
M. P., Bourgeois, B., et al. (2001). Gating of human theta oscilla
-
tions by a working memory task. Journal of Neuroscience, 21, 3175-
3183.
Ramcharan, E. J., Gnadt, J. W., & Sherman, S. M. (2000). Burst and
tonic firing in thalamic cells of unanesthetized, behaving mon
-
keys. Visual Neuroscience, 17, 55-62.
Rasmussen, K., Heym, J., & Jacobs, B. L. (1984). Activity of serotonin-
containing neurons in nucleus centralis superior of freely moving
cats. Experimental Neurology, 83, 302-317.
Reep, R. L., & Corwin, J. V. (1999). Topographic organization of the
striatal and thalamic connections of rat medial agranular cortex.
Brain Research, 841, 43-52.
Reep, R. L., Corwin, J. V., Hashimoto, A., & Watson, R. T. (1987).
Efferent connections of the rostral portion of medial agranular
cortex in rats. Brain Research Bulletin, 19, 203-221.
Reep, R. L., Corwin, J. V., & King, V. (1996). Neuronal connections of
orbital cortex in rats: Topography of cortical and thalamic
afferents. Experimental Brain Research, 111, 215-232.
Riley, J. N., & Moore, R. Y. (1981). Diencephalic and brainstem
afferents to the hippocampal formation of the rat. Brain Research
Bulletin, 6, 437-444.
Risold, P. Y., Thompson, R. H., & Swanson, L. W. (1997). The struc
-
tural organization of connections between hypothalamus and
cerebral cortex. Brain Research Reviews, 24, 197-254.
Ritz, R., & Sejnowski, T. J. (1997). Synchronous oscillatory activity in
sensory systems: New vistas on mechanisms. Current Opinion in
Neurobiology, 7, 536-546.
Room, P., & Groenewegen, H. J. (1986). Connections of the
parahippocampal cortex in the cat: II. Subcortical afferents. Jour
-
nal of Comparative Neurology, 251, 451-473.
Room, P., Russchen, F. T., Groenewegen, H. J., & Lohman, A. H. M.
(1985). Efferent connections of the prelimbic (area 32) and the
infralimbic (area 25) cortices: An anterograde tracing study in the
cat. Journal of Comparative Neurology, 242, 40-55.
Rose, G. M., & Dunwiddie, T. V. (1986). Induction of hippocampal
long-term potentiation using physiologically patterned stimula
-
tion. Neuroscience Letters, 69, 244-248.
Rotenberg, A., Mayford, M., Hawkins, R. D., Kandel, E. R., & Muller,
R. U. (1996). Mice expressing activated CaMKII lack low fre
-
quency LTP and do not form stable place cells in the CA1 region of
the hippocampus. Cell, 87, 1351-1361.
Sainsbury, R. S., & Bland, B. H. (1981). The effects of selective septal
lesions on theta production in CA1 and the dentate gyrus of the
hippocampus. Physiology & Behavior, 26, 1097-1101.
Sarnthein,J.,Petsche,H.,Rappelsberger,P.,Shaw,G.L.,&vonStein,
A. (1998). Synchronization between prefrontal and posterior
association cortex during human working memory. Proceedings of
the National Academy of Sciences of the United States of America, 95,
7092-7096.
Seager,M.A.,Johnson,L.D.,Chabot,E.S.,Asaka,Y.,&Berry,S.D.
(2002). Oscillatory brain states and learning: Impact of
hippocampal theta-contingent training. Proceedings of the National
Academy of Sciences of the United States of America, 99, 1616-1620.
Seki, M., & Zyo, K. (1984). Anterior thalamic afferents from the
mammillary body and the limbic cortex in the rat. Journal of Com
-
parative Neurology, 229, 242-256.
Sesack, S. R., Deutch, A. Y., Roth, R. H., & Bunney, B. S. (1989). Topo
-
graphical organization of the efferent projections of the medial
prefrontal cortex in the rat: An anterograde tract-tracing study
with Phaseolus vulgaris leucoagglutinin. Journal of Comparative Neu-
rology, 290, 213-242.
Sharp, P. E., Tinkelman, A., & Cho, J. W. (2001). Angular velocity and
head direction signals recorded from the dorsal tegmental
nucleus of Gudden in the rat: Implications for path integration in
the head direction cell circuit. Behavioral Neuroscience, 115, 571-
588.
Sherman, S. M. (1996). Dual response modes in lateral geniculate
neurons: Mechanisms and functions. Visual Neuroscience, 13, 205-
213.
Shibata, H. (1992). Topographic organization of subcortical projec
-
tions to the anterior thalamic nuclei in the rat. Journal of Compara
-
tive Neurology, 323, 117-127.
Smythe,J.W.,Christie,B.R.,Colom,L.V.,Lawson,V.H.,&Bland,
B. H. (1991). Hippocampal θ field activity and θ-on/θ-off cell dis
-
charges are controlled by an ascending hypothalamo-septal path
-
way. Journal of Neuroscience, 11, 2241-2248.
Sprouse, J. S., & Aghajanian, G. K. (1987). Electrophysiological
responses of serotoninergic dorsal raphe neurons to 5-HT
1A
and
5-HT
1B
agonists. Synapse, 1,3-9.
Stackman, R. W., & Taube, J. S. (1998). Firing properties of rat lateral
mammillary single units: Head direction, head pitch, and angular
head velocity. Journal of Neuroscience, 18, 9020-9037.
Staubli, U., & Lynch, G. (1987). Stable hippocampal long-term
potentiation elicited by “theta” pattern stimulation. Brain
Research, 435, 227-234.
Stewart, M., & Fox, S. E. (1989). Firing relations of medial septal neu
-
rons to the hippocampal theta rhythm in urethane anesthetized
rats. Experimental Brain Research, 77, 507-516.
Stewart, M., Quirk, G. J., Barry, M., & Fox, S. E. (1992). Firing rela
-
tions of medial entorhinal neurons to the hippocampal theta
rhythm in urethane anesthetized and walking rats. Experimental
Brain Research, 90, 21-28.
Su, H. S., & Bentivoglio, M. (1990). Thalamic midline cell popula
-
tions projecting to the nucleus accumbens, amygdala, and hippo
-
campus in the rat. Journal of Comparative Neurology, 297, 582-593.
Sutherland, R. J., Whishaw, I. Q., & Kolb, B. (1988). Contributions of
cingulate cortex to two forms of spatial learning and memory. Jour
-
nal of Neuroscience, 8, 1863-1872.
198 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

Swadlow, H. A., & Gusev, A. G. (2001). The impact of “bursting”
thalamic impulses at a neocortical synapse. Nature Neuroscience, 4,
402-408.
Swanson, L. W. (1981). A direct projection from Ammon’s horn to
prefrontal cortex in the rat. Brain Research, 217, 150-154.
Swanson, L. W. (1998). Brain maps: Structure of the rat brain.NewYork:
Elsevier.
Swanson, L. W., & Cowan, W. M. (1977). Autoradiographic study of
organization of efferent connections of hippocampal formation
in rat. Journal of Comparative Neurology, 172, 49-84.
Sziklas, V., & Petrides, M. (1993). Memory impairments following
lesions to the mammillary region of the rat. European Journal of
Neuroscience, 5, 525-540.
Sziklas, V., & Petrides, M. (1999). The effects of lesions to the anterior
thalamic nuclei on object-place associations in rats. European Jour
-
nal of Neuroscience, 11, 559-566.
Takagishi, M., & Chiba, T. (1991). Efferent projections of the
infralimbic (area 25) region of the medial prefrontal cortex in the
rat: An anterograde tracer PHA-L study. Brain Research, 566, 26-39.
Talk, A. C., Kang, E., & Gabriel, M. (2004). Independent generation
of theta rhythm in the hippocampus and posterior cingulate cor
-
tex. Brain Research, 1015, 15-24.
Tank, D. W., Regehr, W. G., & Delaney, K. R. (1995). A quantitative
analysis of presynaptic calcium dynamics that contribute to short-
term enhancement. Journal of Neuroscience, 15, 7940-7952.
Taube, J. S. (1998). Head direction cells and the neurophysiological
basis for a sense of direction. Progress in Neurobiology, 55, 225-256.
Taube, J. S., & Muller, R. U. (1998). Comparisons of head direction
cell activity in the postsubiculum and anterior thalamus of freely
moving rats. Hippocampus, 8, 87-108.
Taube, J. S., Muller, R. U., & Ranck, J. B. (1990). Head-direction cells
recorded from the postsubiculum in freely moving rats: II. Effects
of environmental manipulations. Journal of Neuroscience, 10, 436-
447.
Tesche, C. D., & Karhu, J. (2000). Theta oscillations index human
hippocampal activation during a working memory task. Proceed-
ings of the National Academy of Sciences of the United States of America,
97, 919-924.
Tulving, E., & Markowitsch, H. J. (1997). Memory beyond the hippo-
campus. Current Opinion in Neurobiology, 7, 209-216.
Van der Werf, Y. D., Witter, M. P., & Groenewegen, H. J. (2002). The
intralaminar and midline nuclei of the thalamus: Anatomical and
functional evidence for participation in processes of arousal and
awareness. Brain Research Reviews, 39, 107-140.
Vanderwolf, C. H. (1969). Hippocampal electrical activity and volun
-
tary movement in rat. Electroencephalography and Clinical
Neurophysiology, 26, 407-418.
van Groen, T., Kadish, I., & Wyss, J. M. (2002). Role of the
anterodorsal and anteroventral nuclei of the thalamus in spatial
memory in the rat. Behavioural Brain Research, 132, 19-28.
van Groen, T., & Wyss, J. M. (1990). Extrinsic projections from area
CA
1
of the rat hippocampus: Olfactory, cortical, subcortical, and
bilateral hippocampal formation projections. Journal of Compara
-
tive Neurology, 302, 515-528.
van Groen, T., & Wyss, J. M. (1995). Projections from the anterodorsal
and anteroventral nucleus of the thalamus to the limbic cortex in
the rat. Journal of Comparative Neurology, 358, 584-604.
Vann, S. D., & Aggleton, J. P. (2004). The mammillary bodies: Two
memory systems in one? Nature Reviews Neuroscience, 5, 35-44.
Varga, V., Sik, A., Freund, T. F., & Kocsis, B. (2002). GABA(B) recep
-
tors in the median raphe nucleus: Distribution and role in the
serotonergic control of hippocampal activity. Neuroscience, 109,
119-132.
Veazey, R. B., Amaral, D. G., & Cowan, W. M. (1982). The morphology
and connections of the posterior hypothalamus in the
cynomolgus monkey (Macaca fascicularis): II. Efferent connec
-
tions. Journal of Comparative Neurology, 207, 135-156.
Vertes, R. P. (1977). Selective firing of rat pontine gigantocellular
neurons during movement and REM sleep. Brain Research, 128,
146-152.
Vertes, R. P. (1979). Brain stem gigantocellular neurons: Patterns of
activity during behavior and sleep in the freely moving rat. Journal
of Neurophysiology, 42, 214-228.
Vertes, R. P. (1980). Brain stem activation of the hippocampus: A role
for the magnocellular reticular formation and the MLF. Electroen
-
cephalography and Clinical Neurophysiology, 50, 48-58.
Vertes, R. P. (1981). An analysis of ascending brain stem systems
involved in hippocampal synchronization and
desynchronization. Journal of Neurophysiology, 46, 1140-1159.
Vertes, R. P. (1982). Brain stem generation of the hippocampal EEG.
Progress in Neurobiology, 19, 159-186.
Vertes, R. P. (1986). Brainstem modulation of the hippocampus:
Anatomy, physiology and significance. In R. L. Isaacson & K. H.
Pribram (Eds.), The hippocampus (Vol. 4, pp. 41-75). New York:
Plenum.
Vertes, R. P. (1988). Brainstem afferents to the basal forebrain in the
rat. Neuroscience, 24, 907-935.
Vertes, R. P. (1990). Fundamentals of brainstem anatomy: A behav
-
ioralperspective.InW.R.Klemm&R.P.Vertes(Eds.),Brainstem
mechanisms of behavior (pp. 33-103). New York: John Wiley.
Vertes, R. P. (1992). PHA-L analysis of projections from the
supramammillary nucleus in the rat. Journal of Comparative Neurol
-
ogy, 326, 595-622.
Vertes, R. P. (2002). Analysis of projections from the medial
prefrontal cortex to the thalamus in the rat, with emphasis on
nucleus reuniens. Journal of Comparative Neurology, 442, 163-187.
Vertes, R. P. (2004). Differential projections of the infralimbic and
prelimbic cortex in the rat. Synapse, 51, 32-58.
Vertes, R. P., Albo, Z., & Viana Di Prisco, G. (2001). Theta-rhythmi
-
cally firing neurons in the anterior thalamus: Implications for
mnemonicfunctions of Papez’s circuit. Neuroscience, 104, 619-625.
Vertes, R. P., Crane, A. M., Colom, L. V., & Bland, B. H. (1995).
Ascending projections of the posterior nucleus of the hypothala-
mus: PHA-L analysis in the rat. Journal of Comparative Neurology,
359, 90-116.
Vertes, R. P., Fortin, W. J., & Crane, A. M. (1999). Projections of the
median raphe nucleus in the rat. Journal of Comparative Neurology,
407, 555-582.
Vertes, R. P., Hoover, W. B., & Sherman, A. (2002). Afferent projec-
tions to the medial prefrontal cortex in rats. Society for Neuroscience
Abstract, Program No 282.2.
Vertes, R. P., Kinney, G. G., Kocsis, B., & Fortin, W. J. (1994). Pharma
-
cological suppression of the median raphe nucleus with seroto
-
nin
1A
agonists, 8-OH-DPAT and buspirone, produces
hippocampal theta-rhythm in the rat. Neuroscience, 60, 441-451.
Vertes, R. P., & Kocsis, B. (1997). Brainstem-diencephalo-
septohippocampal systems controlling the theta rhythm of the
hippocampus. Neuroscience, 81, 893-926.
Vertes, R. P., & Martin, G. F. (1988). Autoradiographic analysis of
ascending projections from the pontine and mesencephalic
reticular formation and the median raphe nucleus in the rat. Jour
-
nal of Comparative Neurology, 275, 511-541.
Vertes, R. P., & McKenna, J. T. (2000). Collateral projections from the
supramammillary nucleus to the medial septum and hippocam
-
pus. Synapse, 38, 281-293.
Vertes, R. P., McKenna, J. T., do Valle, A., Sherman, A., & Hoover, W. B.
(2003). Efferent projections of ventral midline nuclei of the
thalamus. Society for Neuroscience Abstract, Program No 921.5.
Viana Di Prisco, G., Albo, Z., Vertes, R. P., & Kocsis, B. (2002). Dis
-
charge properties of neurons of the median raphe nucleus during
hippocampal theta rhythm in the rat. Experimental Brain Research,
145, 383-394.
Vinogradova, O. S. (1995). Expression, control, and probable func
-
tional significance of the neuronal theta rhythm. Progress in
Neurobiology, 45, 523-583.
Vinogradova,O.S.,Kitchigina,V.F.,Kudina,T.A.,&Zenchenko,K.I.
(1999). Spontaneous activity and sensory responses of
hippocampal neurons during persistent theta-rhythm evoked by
median raphe nucleus blockade in rabbit. Neuroscience, 94, 745-
753.
Vertes et al. / THETA RHYTHM OF THE HIPPOCAMPUS 199
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from

Warburton, E. C., Baird, A. L., & Aggleton, J. P. (1997). Assessing the
magnitude of the allocentric spatial deficit associated with com
-
plete loss of the anterior thalamic nuclei in rats. Behavioural Brain
Research, 87, 223-232.
Weiss, S., Muller, H. M., & Rappelsberger, P. (2000). Theta synchroni
-
zation predicts efficient memory encoding of concrete and
abstract nouns. Neuroreport, 11, 2357-2361.
Weyand, T. G., Boudreaux, M., & Guido, W. (2001). Burst and tonic
response modes in thalamic neurons during sleep and wakeful
-
ness. Journal of Neurophysiology, 85, 1107-1118.
Winson, J. (1972). Interspecies differences in occurrence of theta.
Behavioral Biology, 7, 479-487.
Winson, J. (1978). Loss of hippocampal theta rhythm results in spa
-
tial memory deficit in rat. Science, 201, 160-163.
Witter, M. P., & Amaral, D. G. (2004). Hippocampal formation. In
G. Paxinos (Ed.), Theratnervoussystem(3rd ed., pp. 635-704). San
Diego, CA: Elsevier Academic Press.
Witter, M. P., Ostendorf, R. H., & Groenewegen, H. J. (1990). Hetero
-
geneity in the dorsal subiculum of the rat: Distinct neuronal zones
project to different cortical and subcortical targets. European Jour
-
nal of Neuroscience, 2, 718-725.
Woodnorth,M.A.,Kyd,R.J.,Logan,B.J.,Long,M.A.,&
McNaughton, N. (2003). Multiple hypothalamic sites control the
frequency of hippocampal theta rhythm. Hippocampus, 13, 361-
374.
Wouterlood, F. G. (1991). Innervation of entorhinal principal cells by
neurons of the nucleus reuniens thalami: Anterograde PHA-L
tracing combined with retrograde fluorescent tracing and
intracellular injection with lucifer yellow in the rat. European Jour
-
nal of Neuroscience, 3, 641-647.
Wouterlood, F. G., Saldana, E., & Witter, M. P. (1990). Projection from
the nucleus reuniens thalami to the hippocampal region: Light
and electron microscopic tracing study in the rat with the
anterograde tracer Phaseolus vulgaris-leucoagglutinin. Journal of
Comparative Neurology, 296, 179-203.
Wu, L. G., & Saggau, P. (1994). Presynaptic calcium is increased dur
-
ing normal synaptic transmission and paired-pulse facilitation,
but not in long-term potentiation in area CA1 of hippocampus.
Journal of Neuroscience, 14, 645-654.
Wyss, J. M., Swanson, L. W., & Cowan, W. M. (1979a). Evidence for an
input to the molecular layer and the stratum granulosum of the
dentate gyrus from the supramammillary region of the hypothala
-
mus. Anatomy and Embryology, 156, 165-176.
Wyss, J. M., Swanson, L. W., & Cowan, W. M. (1979b). A study of
subcortical afferents to the hippocampal formation in the rat.
Neuroscience, 4, 463-476.
Yamamoto, T., Watanabe, S., Oishi, R., & Ueki, S. (1979). Effects of
midbrain raphe stimulation and lesion on EEG activity in rats.
Brain Research Bulletin, 4, 491-495.
Yanagihara, M., Niimi, K., & Ono, K. (1987). Thalamic projections to
the hippocampal and entorhinal areas in the cat. Journal of Com
-
parative Neurology, 266, 122-141.
Zhang, D. X., & Bertram, E. H. (2002). Midline thalamic region:
Widespread excitatory input to the entorhinal cortex and
amygdala. Journal of Neuroscience, 22, 3277-3284.
Zugaro,M.B.,Tabuchi,E.,Fouquier,C.,Berthoz,A.,&Wiener,S.I.
(2001). Active locomotion increases peak firing rates of antero
-
dorsal thalamic head direction cells. Journal of Neurophysiology, 86,
692-702.
200 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
at FLORIDA ATLANTIC UNIV on January 6, 2011bcn.sagepub.comDownloaded from