Hippocampal Slow Wave Research Articles

Decline in hippocampal theta activity during cessation of locomotor approach sequences: Amplitude leads frequency and relates to instrumental behavior

Hippocampal theta frequency and amplitude decrease as locomotor approach slows and the goal is reached. This study compared the declines of these theta parameters and related them to behavioral events. Theta activity was recorded with bipolar electrodes spanning cornu Ammon, sector 1 or cornu Ammon, sectors 2/3 cell layers of the dorsal hippocampus in 12 rats trained to approach and depress a treadle which exposed a milk dipper. Behavioral events were identified using a video capture system (20-ms sampling) synchronized to the hippocampal recording system (10-ms sampling). Peri-event averages of theta activity were made around the initial paw contact with the treadle, the presentation of the dipper, and the first lick at the dipper. Phase relationships between averaged hippocampal slow wave activity and behavioral events occasionally were found but they were inconsistent. In averages of both amplitude and frequency, times of minimum were less variable around paw contact indicating that compared with reward presentation and consummatory behavior, it more closely related to the processes determining the declines. Theta amplitude declined more rapidly than frequency and reached an earlier minimum in averages around initial paw contact and dipper presentation. Mean amplitude minimum occurred after the paw contact at 159 ms but the decline of frequency continued into the licking bout with its minimum occurring at 343 ms. The findings indicate that during the termination of approach locomotion, the amplitude of hippocampal theta activity is closely related to specific expected sensorimotor events.

Hippocampal theta activity and behavioral sequences in a reward‐directed approach locomotor task

Hippocampal rhythmic slow wave activity (theta) has been implicated in the processing of stimuli associated with movement. This study determined whether the theta rhythm showed phase relationships or changes in amplitude and frequency with the onset of stimuli and behavioral sequences in a skilled locomotor approach task. Rats with bipolar electrodes spanning CA1 approached a stall, turned to enter it, approached and depressed a treadle, waited 1.35 s, and approached a milk reward located forward either to the right or to the left. Auditory cues indicated the location of the reward during the waiting period and at the reward onset. A video capture system (20-ms sampling) was synchronized to the hippocampal recording system (10-ms sampling). Behavioral events identified by motion analysis were used to generate averages of hippocampal slow wave activity, theta peak amplitudes, and intervals between peaks. Theta activity at 8-10 Hz was almost continuous during the behavioral sequences. Phase relations with stimuli or movement onsets occurred infrequently and were not consistent across the four subjects. Theta peak amplitude and frequency decreased as the rat slowed locomotion in the stall and reached the treadle. Onset of locomotion directed to a reward location occurred on a positive peak of averaged theta activity. When locomotion had short latencies, increases in theta frequency appeared after the onset but, when it had longer latencies, frequency increases appeared 200 ms before onset. The results indicate that the execution of instrumental movement modulates both theta amplitude and frequency, and that the preparation for locomotion modulates theta frequency.

Cellular Signaling Mechanisms for Muscarinic Acetylcholine Receptors

Signaling pathways for muscarinic acetylcholine receptors (mAChRs) include several enzymes and ion channels. Recent studies have revealed the importance of various isoforms of both alpha and betagamma subunits of G proteins in initiation of signaling as well as the role of the small monomeric G protein, Rho, in the activation of phospholipase D. Modulation of adenylyl cyclase activity by mAChRs appears more diverse as the interaction of various receptor subtypes with the many isoforms of the enzyme are studied. Both alpha and beta subunits of G(i/o) may be involved. Some mAChR responses arise through release of nitric oxide from nitrergic nerves, including salivary gland secretion and hippocampal slow wave activity. mAChRs utilize a variety of intracellular pathways to activate various mitogen-activated protein kinases. The kinases are involved in cholinergic regulation of kidney epithelial function, catabolism of amyloid precursor protein, hippocampal long-term potentiation, activation of phospholipase A(2), and gene induction. mAChR activation can also stimulate or inhibit cellular growth and apoptosis, dependent on prior levels of cellular activity. Modulation of ion channels by mAChR agonists appears increasingly complex, based on recent studies. K(+) channels may be activated by M(2) and M(4) mAChR stimulation, although in the rat superior cervical ganglion topographical constraints appear to limit the effect to the M(2) mAChR. Another ganglionic K(+) current, the M current, is inhibited by M(1) mAChR activation, but in murine hippocampus inhibition involves another receptor subtype. R-type Ca(2+) channels are both facilitated and inhibited by M(1) and M(2) mAChRs; facilitation being more pronounced with activation of M(1) mAChRs and inhibition with M(2) mAChRs.

Cellular Signaling Mechanisms for Muscarinic Acetylcholine Receptors

Signaling pathways for muscarinic acetylcholine receptors (mAChRs) include several enzymes and ion channels. Recent studies have revealed the importance of various isoforms of both alpha and betagamma subunits of G proteins in initiation of signaling as well as the role of the small monomeric G protein, Rho, in the activation of phospholipase D. Modulation of adenylyl cyclase activity by mAChRs appears more diverse as the interaction of various receptor subtypes with the many isoforms of the enzyme are studied. Both alpha and beta subunits of G(i/o) may be involved. Some mAChR responses arise through release of nitric oxide from nitrergic nerves, including salivary gland secretion and hippocampal slow wave activity. mAChRs utilize a variety of intracellular pathways to activate various mitogen-activated protein kinases. The kinases are involved in cholinergic regulation of kidney epithelial function, catabolism of amyloid precursor protein, hippocampal long-term potentiation, activation of phospholipase A(2), and gene induction. mAChR activation can also stimulate or inhibit cellular growth and apoptosis, dependent on prior levels of cellular activity. Modulation of ion channels by mAChR agonists appears increasingly complex, based on recent studies. K(+) channels may be activated by M(2) and M(4) mAChR stimulation, although in the rat superior cervical ganglion topographical constraints appear to limit the effect to the M(2) mAChR. Another ganglionic K(+) current, the M current, is inhibited by M(1) mAChR activation, but in murine hippocampus inhibition involves another receptor subtype. R-type Ca(2+) channels are both facilitated and inhibited by M(1) and M(2) mAChRs; facilitation being more pronounced with activation of M(1) mAChRs and inhibition with M(2) mAChRs.

Hippocampal Theta Oscillations and Classical Conditioning

Studies are reviewed that support a hypothesized role for hippocampal theta oscillations in the neural plasticity underlying behavioral learning. Begun in Richard F. Thompson's laboratory in the 1970s, these experiments have documented a relationship between free-running 3- to 7-Hz hippocampal slow waves (theta) and rates of acquisition in rabbit classical nictitating membrane (NM) conditioning. Lesion and drug manipulations of septohippocampal projections have affected NM and jaw movement conditioning in ways consistent with a theta-related brain state being an important modulator of behavioral acquisition. These findings provide essential empirical support for the recently developed neurobiological and computational models that posit an important role for rhythmic oscillations (such as theta) in cellular plasticity and behavioral learning.

Medial septal microinfusion of scopolamine disrupts hippocampal activity and trace jaw movement conditioning.

This study investigated the effects of microinfusion of scopolamine into the medial septum (MS Scp) on hippocampal neurophysiology and learning of the rabbit's classically conditioned jaw movement response. The percentage of hippocampal theta slow waves (2-8 Hz) decreased after drug infusion in the MS Scp group but did not change in control groups that received infusion of saline into the MS or scopolamine into the cortex. Unit recordings from the MS Scp group showed significantly smaller conditioning-related hippocampal neural responses than seen in controls, and during conditioning, rabbits in the MS Scp group took significantly longer to reach learning criterion than either control group. Thus, the neural and behavioral impairments previously reported for systemic muscarinic blockade were reproduced by microinfusions restricted to the medial septal nucleus.

Hippocampal theta activity and facilitated locomotor stepping produced by GABA injections in the midbrain raphe region

Inactivation of neurons in the midbrain raphe region produces increases in locomotor activity, and it appears that they function to suppress locomotion. Inactivation of neurons there also produces hippocampal slow wave (theta) activity and it appears that they also function to inhibit rhythmic activity in the hippocampus. We determined whether the degree of association between the two effects was consistent with the operation of a single mechanism. Stimulation electrodes were implanted into locomotor sites of the hypothalamus of 34 urethane-anesthetized rats. Hindlimb stepping was elicited by 5.12-s trains of perifornical electrical stimulation presented once per minute. Hippocampal theta activity was recorded across the CA1 layer of the dorsal hippocampus. GABA injections were used to locate raphe sites at which neuronal inactivation influenced stepping and hippocampal activity. A glass pipette (80-μm tip) was inserted into the midbrain, and injections of GABA (50–100 mg/0.1–0.2 μl) were made in 70 sites in the midbrain. Injections at 34 sites facilitated stimulation-elicited stepping, and at 17 sites, they also produced intertrial stepping. Facilitating injections, but not ineffective or suppressive injections, increased the mean peak frequency of hippocampal activity, and increased power in the 4–5 Hz band during the period that preceded the stimulation trains, but did not change the 5–6 Hz activity produced during the stimulation trains. Priming locomotor stimulation which also facilitated stepping produced generally similar increases in pre-stimulation peak frequency and 4-Hz power. The magnitudes of the increases in stepping and 4-Hz power were uncorrelated. The increase in 4-Hz power appeared earlier than the increase in stepping in 18 of 34 cases, and later in 11 cases; no increases in 4-Hz power were apparent in five cases. The results indicate that pre-locomotor 4-Hz hippocampal activity in the urethane-anesthetized rat is loosely coupled with facilitated locomotor initiation. Neurons in the midbrain raphe region appear to suppress both processes, but the low degree of association between the magnitudes and onset times of increases in stepping and hippocampal 4-Hz power indicate the operation of multiple mechanisms.

A dose of MK801 previously shown to impair spatial learning in the radial maze attenuates primed burst potentiation in the dentate gyrus of freely moving rats.

Spatial learning but not memory performance in the radial maze is disrupted by low doses of MK801 (0.0625 mg/kg ip), a noncompetitive N-methyl-D-aspartate receptor channel blocker (M. L. Shapiro & C. O'Connor, 1992). The effect of this low dose of MK801 on hippocampal physiology and synaptic plasticity was assessed in 16 behaving female Sprague-Dawley rats. The drug increased the frequency (0.5 Hz), marginally reduced the amplitude of hippocampal rhythmical slow wave activity (RSA), did not alter non-RSA slow wave activity, and reduced normal synaptic transmission from the entorhinal cortex to the dentate gyrus by approximately 8%. Independent of these effects on normal physiology. MK-801 also reduced primed burst potentiation, a form of synaptic plasticity produced by physiologically patterned stimulation, by approximately 20% in the same pathway. Thus, low doses of MK801 may impair spatial learning by reducing, directly or indirectly, the likelihood of synaptic plasticity in the hippocampus.

Enhanced hippocampal theta EEG during whole body rotations in awake restrained rats

Hippocampal slow wave activity in the theta band was studied in awake restrained rats as they were rotated in the horizontal plane both in light and in darkness. Monopolar recordings were made with an insulated silver wire (200 μm diameter) implanted in the dentate gyrus with reference to the occipital bone. Fast Fourier transforms were made of data recorded when the rat was either rotated passively or remained immobile. The power in the 6–9 Hz frequency band (‘type I’ theta) was significantly increased during rotations. The same results were obtained in experiments performed in the light or in complete darkness. These results provide evidence for a role of inertial (possibly, vestibular) information in hippocampal spatial representations.

Pressure on the snout immobilizes the spontaneously active, scopolaminized, and amphetaminized hyperactive rat

Rats that are brought into a novel environment or that are given stimulants or anti-muscarinic drugs exhibit high levels of motor activity. Application of moderate pressure on the sides of the snout of such rats results in immediate cessation of all movements for extended time periods. Hippocampal electrocorticograms show that hippocampal slow wave activity during such induced immobility is equivalent to the hippocampal slow wave pattern typically associated with spontaneous immobility. However, neocortical activity following scopolamine administration contains more 2-6 Hz irregular activity during spontaneous than induced immobility.

Reticular elicitation of hippocampal slow waves: Common effects of some anxiolytic drugs

Anxiolytic drugs share many of the common behavioural effects of septal and hippocampal lesions in animals. Gray 3,5 attributes this to changes which the anxiolytics produce in septal generation of hippocampal rhythmical slow activity. However, lesions of the dorsal ascending noradrenergic bundle reproduce this electrophysiological effect of the anxiolytics while only reproducing part of the behavioural profile of the anxiolytics. The present paper reports what appears to be a second common effect of anxiolytic drugs on the generation of hippocampal slow waves which could underlie their behavioural effects. Freely moving rats, previously implanted with electrodes, received high frequency electrical stimulation of the midbrain reticular formation to elicit hippocampal rhythmic slow activity. The frequency of the slow waves produced increased linearly with increasing stimulation intensity as has been reported previously. A barbiturate (amylobarbitone, 15mg/kg, i.p.) and three benzodiazepines (chlordiazepoxide, 5 mg/kg; diazepam, 5 mg/kg; alprazolam, 1 mg/kg) all decreased the slope of the voltage-frequency function and decreased overall frequency of slow waves produced. Two antipsychotic drugs (haloperidol, 0.2 mg/kg; chlorpromazine, 2 mg/kg) produced similar behavioural sedation to the anxiolytics but did not decrease either the slope of the voltage-frequency function nor the overall frequency of slow waves. The results show that these barbiturates and benzodiazepines produce a common reduction in the frequency of hippocampal rhythmical slow activity. Given the importance attached to slow waves in current theories of hippocampal function, it is possible that this electrophysiological effect could have some relation to the behavioural effects of these anxiolytic drugs. If the effect can be shown to generalise to other classes of anxiolytic drug it could reflect changes in the substrate for the common effects of anxiolytic drugs on behaviour.

Hippocampal theta rhythm and the firing of neurons in walking and urethane anesthetized rats.

Recordings were taken from single neurons in the hippocampus and dentate gyrus of rats during walking and urethane anesthesia. Firing histograms for these cells were constructed as a function of the phase of the concurrent extracellularly recorded hippocampal slow wave theta rhythm. Care was taken to be sure of the site of recording of the theta rhythm and its phase with respect to a reliable reference, so that comparisons of the phases of firing could be made across animals. The firing of most of these neurons is deeply modulated as a function of the phase of the theta rhythm. This is true whether the theta rhythm occurs during walking or during urethane anesthesia, but for some types of cells the mean phases of firing are different in the two types of theta rhythm. During walking, pyramidal cells and interneurons in all hippocampal subregions and dentate granule cells have a maximum probability of firing near the positive peak of the theta rhythm recorded in the outer molecular layer of the dentate (dentate theta). During urethane anesthesia, the maximum firing probability for interneurons in CA1 and for dentate granule cells occurs near the negative peak of the dentate theta, while the phases of maximum firing for pyramidal cells and interneurons in CA3 and CA4 become widely distributed. The phases of maximum firing of pyramidal cells in CA1 are, if anything, more narrowly distributed around the positive peak of the dentate theta during urethane anesthesia than during walking. These differences in the firing of hippocampal cells during walking and urethane anesthesia represent some of the differences in cellular mechanisms distinguishing two kinds of hippocampal theta rhythm.

Depth profiles of hippocampal rhythmic slow activity (‘theta rhythm’) depend on behaviour

Wave shape patterns and spectral properties of hippocampal slow wave activity (RSA) were studied in behaving rats equipped with stationary recording/stimulating electrodes and a movable microelectrode. RSA waves had maximum power at about the hippocampal fissure, and two minima just below the pyramidal cells of CA1 and the inner molecular layer of the dentate gyrus, respectively. The phase profile of RSA was gradual during both running and lever pressing, but the two profiles showed phase differences in the stratum radiatum of CA1 and the hilus. Averaged RSA waves consisted of fast rising and slow decaying components, giving a saw-tooth like pattern. RSA waves were more asymmetric during running than during lever pressing. The slow component showed a sudden polarity reversal below the pyramidal layer of CA1. The fast component of RSA showed a gradual shift and change of the slope with depth. An additional small amplitude wave riding on the slow component (‘notch’) was present during running. The amplitude increase of the ‘notch’ occasionally caused frequency doublin of RSA and consequent high power of the second harmonic. The gradual shift and change of the fast component are explained by the hypothesis that somatic inhibitory and dendritic excitatory RSA dipoles in CA1 and dentate gyrus are active at different times of the RSA cycle.

Lateral septal lesions enhance conditioned bradycardia in the rabbit.

New Zealand albino rabbits received sham lesions or complete, medial, lateral, or posterior septal lesions and were subjected to differential conditioning in which tones of different frequencies served as conditioned stimuli and paraorbital electric shock was the unconditioned stimulus. Electromyographic (EMG), heart rate (HR), and blood pressure (BP) conditioned responses (CRs) as well as hippocampal rhythmic slow wave activity (RSA) were recorded. Lateral or complete septal lesions enhanced the bradycardiac HR CR but had no effect on the BP depressor response. Both unconditioned and conditioned EMG responses occurred infrequently and were unaffected by any lesion. Unconditioned HR responses and somatomotor threshold determinations to unsignaled electric shock were also unaffected by the lesions. Complete septal lesions increased locomotor activity relative to sham or other septal lesions. Little hippocampal RSA was detected in animals with medial lesions, but the HR CR was unimpaired in these animals. These data implicate the septo-hippocampal circuit in classical conditioning of cardiovascular changes and further suggest that diencephalic forebrain structures may modulate forebrain processing of sensory stimulation, perhaps in terms of assessing its biological significance.

Hippocampal slow wave activity during appetitive and aversive conditioning in the cat

The electrical activity of the dorsal and ventral divisions of the hippocampus was investigated quantitatively during the development of discriminative operant training and defensive conditioning. Signal-related (respondent, sign-tracking) and goal-directed (operant, ‘voluntary’) activities and their hippocampal electrical correlates were compared. Signal-related behaviour was accompanied by significantly higher frequency spectral peaks than lever press behaviour. Spectral peaks were higher during lever pressing in early stages of training as compared to criterion performance. In defensive conditioning overt sing-tracking behaviour disappeared but spectral peak shifts toward higher values upon signal presentation persisted. Comparison of dorsal and ventral hippocampal activity revealed high coherence values and similar frequency shifts during behaviour transitions. These findings argue against suggestions that a close relationship exists between elementary motor acts and hippocampal EEG.

Brain stem activation of the hippocampus: A role for the magnocellular reticular formation and the MLF

In previous reports (Vertes 1977, 1979) we have shown that cells of the medial magnocellular reticular formation (MMRF) discharge at high rates of activity during both waking-movement and REM sleep and at low rates during quiet waking and slow wave sleep. We suggested that some of these reticular cells may be involved in the generation of the hippocampal theta rhythm since they fire maximally during the identical states (general movement and REm sleep) in which theta is present in the hippocampus of the rat. In the present study the influence of the brain stem on the hippocampus was analyzed by systematically mapping the entire brain stem with stimulation to determine its effect on hippocampal slow wave activity. The results showed that the most effective stimulation sites for eliciting hippocampal synchronization were those within the medial magnocellular reticular formation and in or near the medial longitudinal fasciculus (MLF) at the level of the pons. These results suggest that cells of the MMRF are critically involved in hippocampal theta generation and that the fibers of these theta-eliciting cells primarily ascend in the MLF in their route rostrally from the brain stem.

Postnatal hippocampal granule cell agenesis in the rat: effects on two types of rhythmical slow activity (RSA) in two hippocampal generators

Hippocampal slow wave activity was studied in rats which were normal or had been subjected to dentate gyrus granule cell agenesis by focal X-irradiation starting at birth (0-day group) or two days (2-day group) of age. X-irradiation reduced adult brain weight, abolished most (2-day) or all (0-day) granule cells in the lower (endal) blade of the dentate gyrus, and reduced granule cell density by up to 70% in the upper (ectal) blade of the dentate gyrus. X-irradiation did not affect pyramidal cells of the hippocampus proper. Tracking with microelectrodes in urethane anesthetized rats given eserine, sensory, or brain stimulation showed two foci of hippocampal rhythmical slow activity (theta or RSA), one in stratum oriens of CA1 and one in stratum moleculare of the dentate gyrus. These were opposite in phase by approximately 180° and separated by a null zone and phase reversal point occurring at stratum radiatum. There were no significant differences in the amplitude, frequency, null, or phase reversal points in the normal or X-irradiated groups. However, the width of the RSA amplitude peak in the ectal blade was reduced, correlated with the reduction in the length of the ectal blade, and the RSA amplitude peak in the lower blade was absent, correlated with the absence of the lower blade. The fast activity recorded in the hilus of normal rats was absent in the X-irradiated groups. RSA recorded during spontaneous movement (walking) had identical amplitude, frequency, anatomical foci, and phase in both the hippocampus proper and dentate gyrus in normal and X-irradiated rats. Antimuscarinic, but not antinicotinic, agents abolished anesthesia-related RSA, but not movement-related RSA, in all groups of rats. The results are discussed in terms of their relevance to the two-generator hypothesis of RSA.

Place units in the hippocampus of the freely moving rat

Single units were recorded from the CA1 field of the hippocampus in the freely-moving rat. They were classified as place units, displace units or others. Place units were defined as those for which the rat's position on the maze was a necessary condition for maximal unit firing. Some of these place units ( misplace units) fired maximally when the animal sniffed in a place, either because it found something new there or failed to find something which was usually there. Displace units increased their rates during behaviors associated with theta activity in the hippocampal slow waves. In general these were behaviors which changed the rat's position relative to the environment. The influence of various environmental manipulations (e.g., turning off the room lights) on the firing pattern of the place units was tested and the results suggest that they were not responding to a simple sensory stimulus nor to a specific motor behavior. Nor could the unit firing be due purely to motivational or incentive factors. The results are interpreted as strong support for the cognitive map theory of hippocampal function.

Temporal relationships between hippocampal slow waves and exploratory sniffing in hamsters

Temporal relationships between inhalation, vibrissal protraction, and hippocampal slow wave activity during exploratory sniffing were studied in freely moving hamsters. Subjects exhibited stereotyped sniffing bouts during which respiration rates routinely were faster than 5 Hz, and inhalations were accompanied by protractions of the mystacial vibrissae. Sniffing invariably was accompanied by rhythmical slow wave activity (RSA) in the dorsal hippocampus. During presentations of various odorants, RSA generally appeared prior to the commencement of sniffing and continued for several minutes beyond the cessation of sniffing bouts. Sniffing and RSA rates were similar, but rarely identical for the full duration of a bout. Bouts typically contained more than 15 sniffs and occasionally consisted of more than 200 successive sniff cycles. During the course of bouts, sniffing and RSA often assumed identical repetition rates for periods of four to ten successive sniff cycles. These recurring periods of entrainment generally were preceded by brief accelerations or decelerations in sniffing rate, or a skipped inhalation cycle or vibrissae twitch. Except for such single skips, inhalation and vibrissal protraction were coordinated regardless of whether the sniffing and limbic rhythms were entrained. For individual subjects, there appeared to be preferred temporal relationships between inhalation cycles and hippocampal waves during entrainments. Analyses of 3000–11,000 sniff cycles and 6000–12,000 slow waves per subject indicated that the repetition rates for hippocampal waves were not altered during sniffing, and that each subject consistently exhibited a preferred temporal relationship between sniffing and RSA in the presence of different odorants. It is suggested that the limbic rhythm does exert a modulating or facilitating influence on the sniffing rhythm but does not directly drive it, and that recurring entrainments with a similar temporal relationship may provide a basis for correlating odorinduced changes in the timing of olfactory unit activity relative to rhythmic unit activity in the limbic system.

Hippocampal electrical activity during long-continued avoidance performance: Effects of fatigue

Rats were trained to avoid electric shock by jumping out of a box to a height of 35.5 or 48 cm. Hippocampal slow wave activity was then recorded continuously during a single session in which avoidance testing was continued to the point of extreme fatigue. Rhythmical slow activity (RSA) always appeared prior to a successful avoidance response and rose in frequency as the instant of jump initiation approached. As the rats became fatigued and failed to avoid, this anticipatory upward shift in frequency failed to occur.