Brian H. Bland

Two types of hippocampal rhythmical slow activity in both the rabbit and the rat: Relations to behavior and effects of atropine, diethyl ether, urethane, and pentobarbital

Abstract A series of experiments in rats and rabbits indicates that the hip;ocampus receives two nonspecific inputs from the brain stem, each capable of producing rhythmical slow activity (theta rhythm). One type of theta rhythm can be abolished by injections of atropine sulfate (5 mg/kg, iv, or 25–50 mg/kg, ip) but not by atropine methyl nitrate. Such theta activity typically has a frequency of 4 7 Hz and occurs during ether or urethane anesthesia as well as during behavioral immobility in the undrugged state. A second type of theta activity is relatively unaffected by large doses of atropine sulfate but is abolished selectively during ether or urethane induced anesthesia. Such theta activity typically has a frequency of 7–12 Hz and occurs in waking animals if, and only if, such motor patterns as head movements, walking, or rearing are being performed concurrently. Both types of theta activity can be elicited by electrical stimulation at sites in the hypothalamus or midbrain reticular formation. Atropine-sensitive theta activity may result from excitation of ascending cholinergic fibers, but the nature of the ascending atropine-resistant system remains unknown. Atropine-resistant activation of the cerebrum may play a role in the emission and control of normal behavior and may mediate many of the behavioral effects of centrally acting drugs such as anesthetics, tranquilizers, or stimulants.

Theta band oscillation and synchrony in the hippocampal formation and associated structures: the case for its role in sensorimotor integration.

The current review advances the argument that it is naïve to ascribe a unitary function to the hippocampal formation (HPC). Rather, it is more productive to consider the hippocampal formation as consisting of a number of subsystems, each subsystem defined by its own particular neural circuitry. Among examples of neural circuitry appearing in current hippocampal literature are theta, beta and gamma oscillations, sharp waves, place cells and head orientation cells. Data are reviewed supporting the case that theta band oscillation and synchrony is involved in mechanisms underlying sensorimotor integration. Specifically, the neural circuitry underlying the production of oscillation and synchrony (theta) in limbic cortex and associated structures function in the capacity of providing voluntary motor systems with continually updated feedback on their performance relative to changing environmental (sensory) conditions. A crucial aspect of this performance is the intensity with which the motor programs are initiated and maintained. The ascending brainstem HPC synchronizing pathways make the primary contribution in this regard. These pathways originate in the rostral pontine region, ascend and synapse with caudal diencephalic nuclei, which in turn send projections to the medial septal region. The medial septum functions as the node in the ascending pathways, sending both cholinergic and GABA-ergic projections to the HPC. An updated version of the sensorimotor integration model including anatomical details is presented and discussed.

Generators and topography of hippocampal theta (RSA) in the anaesthetized and freely moving rat.

Spontaneous and hypothalamically induced hippocampal rhythmical slow activity (RSA or theta) was studied acutely in rats anaesthetized with urethane or immobilized with D-tubocurarine. Systematic tracking of microelectrodes showed two foci of hippocampal RSA, one located in the basal part (stratum oriens) of CAl (mean amplitude 1 mV) and the other located in stratum moleculare of the dorsal blade of the fascia dentata (mean amplitude 2 mV). The hippocampal RSA recorded from the lower blade of the fascia dentata was always smaller than that found in the upper blade (mean amplitude 1 mV). The whole dorsal hippocampal extent within each generator zone was shown to be in synchrony, and the respective generator zones of both hippocampi were synchronous with one another. A null zone in stratum radiation was found interposed between the two generators and a zone of large amplitude fast activity (30-50 Hz) was localized to the hilus of the fascia dentata. Wave form analysis showed that the RSA recorded from the two generators was approximately 180 degrees out of phase. Amplitude and analysis of phase changes of RSA recorded in brain areas outside of the two generator zones suggested that such activity was due to physical spread from the two generators, with the possible exception of a restricted portion of CA3. The existence of the two generators, 180 degrees out of phase, was demonstrated in freely moving rats. Behavioural observations showed that the two generators were related systematically to concurrent motor behaviour. Preliminary observations suggest that, of the two generators, the one located in CAl may be the more variable.

Two generators of hippocampal theta activity in rabbits

Spontaneous and hypothalamically induced theta activity was studied in rabbits lightly anaesthetized with urethane or urethane-chloralose. Well-developed theta activity was found over a large area of the dorsal part of the hippocampal formation, roughly corresponding to the CA1 field. Cross-correlation analysis between a stationary and a moving electrode showed that a large sheet of tissue oscillated in remarkable synchrony. This region was at least 8 mm along the longitudinal axis of the hippocampus and 6 mm in a plane transverse to this axis, thus comprising the whole of the rostro-caudal extension of the CA1 region. For technical reasons the temporal half was not explored. Depth recordings showed two foci of theta activity, one in the basal part of CA1 (stratum oriens) and a second, separate region with considerably larger amplitudes in the dentate region, having its maximum in the molecular layer. Due to the folded nature of the dentate fascia, an electrode often recorded two maxima corresponding to its upper and lower blades. Wave form analysis showed that the dentrate and CA1 rhythmic activity was roughly 180 degrees out of phase. The dentate theta activity remained in conditions where the CA1 theta activity was absent, either spontaneously or due to experimental interference. Systematic micro-electrode tracking showed absence of theta activity in the CA3 region. Nor was convincing theta activity found in the subiculum, parasubiculum, presubiculum or entohinal areas.

Hippocampal Rhythmic Slow Activity and Neocortical Low-Voltage Fast Activity: Relations to Behavior

Experimental studies attempting to relate brain electrical activity to behavior have become commonplace in the last 25 years. During this period, there have been many advances in the development of techniques of analysis of slow waves or spike events generated in the brain, but comparable sophistication has not yet been applied to the behavioral side of the brain-behavior problem. Many investigators have been content to refer to the activities of their experimental animals or human subjects in terms that are not descriptive of behavior at all but appear to refer to unseen “inferred processes” instead. Thus various types of brain electrical activity have been said to be related to perception, information processing, attention, motivation, arousal, emotion, learning, memory, and the like. These terms are notoriously difficult to define and therefore impair communication from one researcher to another. Thus one researcher may say that an animal is “attentive” when it stands motionless with head up and eyes open, suggesting that it is “staring at something.” A second researcher may interpret the word attentive” to mean that the animal is actively interacting with the environment by sniffing, biting, or manipulating objects. As the data summarized here will show, details of actual behavior are important in the study of brain and behavior, and merit careful observation and precise description.

Organization of the hippocampal output

Summary1.The spatial organization of the efferent projections of CA1 and CA3 hippocampal pyramids has been studied using recordings of fibre volleys, orthodromic and antidromic population spikes and synaptic field potentials, following microelectrode stimulation of the fimbria, CA1 alveus, or subiculum.2.Only CA3 pyramidal cells were found to send their axons into the fimbria. In the septal two thirds of the hippocampus the CA1 pyramidal cells project in a caudal direction to the pyramidal part of the subiculum. The temporal third was not explored for technical reasons.3.Fimbrial fibres are arranged in a strictly parallel fashion, the rostro-medial CA3 cells distributing their axons near to the hippocampus, while those located at the temporal extreme distribute their axons to the outer edge of the fimbria. The organization of the Schaffer collaterals and the projections of the CA1 cells consisted of parallel lamellae, oriented nearly transversely to the longitudinal axis of the hippocampus in rabbits (more obliquely in cats). The findings indicate that CA3 cell discharge via the Schaffer collaterals represents a major input driving the CA1 cells.4.The dichotomy with regard to hippocampal output suggests that the CA3 and CA1 regions of the hippocampus may subserve different functions, thus probably participating differentially in various behavioural situations.5.This organization makes it possible to study the behaviour of animals with selective and regional de-efferentation of the CA3 or of the CA1 regions by making discrete lesions in the fimbria and alveus, respectively. Alternatively, recording the fibre volley from the fimbria may provide a useful monitor of the output of the CA3 region during different behaviours.

Carbachol-induced EEG ‘theta’ activity in hippocampal brain slices

Application of the cholinergic agonist carbachol (50 microM) produced theta-like rhythmical waveforms, recorded in the stratum moleculare of the dentate gyrus. Atropine sulfate (50 microM) antagonized the carbachol-induced theta-like activity, consistent with this action of atropine in vivo. These results provide the first direct evidence that hippocampal neurons are capable of producing synchronized slow-wave activity when isolated from pulsed rhythmic inputs of the medial septum and other brain regions.

Diencephalic and hippocampal mechanisms of motor activity in the rat: Effects of posterior hypothalamic stimulation on behavior and hippocampal slow wave activity

Summary Slow wave activity was recorded from the hippocampus in chronically prepared rats. During spontaneous or learned behavior, rhythmical slow activity (RSA) accompanied walking, rearing, climbing, manipulation of objects with the forelimbs, isolated movements of the head or one limb and changes in posture (voluntary movement) but did not accompany alert immobility, licking, chewing, face-washing, or scratching (more automatic behavior). During stimulation of the hypothalamus similar behavior-EEG relations were observed. Walking, running, jumping, and isolated head movements were always accompanied by RSA, but this waveform was absent during alert immobility, chewing, face washing, piloerection or chattering of the teeth. Stimulation of the dorsomedial posterior hypothalamus was especially effective in the elicitation of RSA in the hippocampus and also consistently produced head movement, running, or jumping when administered in conscious animals. Sites in the dorsomedial-posterior hypothalamus would also support self-stimulation behavior. Increases in the voltage of posterior hypothalamic stimulation produced increases in the frequency of the RSA during the first few seconds of stimulation, and a corresponding increase in running speed or in the force with which jumping was initiated. Relations between behavior and hippocampal activity were the same during tests of learning (active and passive avoidance) and during spontaneous behavior ( e.g. , exploration). It is suggested that an ascending hypothalamo-hippocampal mechanism plays a role in the control of voluntary movement.

Electrical stimulation of the hippocampal formation: Behavioral and bioelectrical effects

Summary Hippocampal slow wave activity was recorded in freely moving rats. Rhythmical slow activity (RSA) was present during walking, jumping, struggling, head movement, and bar-pressing (voluntary behavior), but was usually absent during behavioral immobility in the alert state or during face-washing, licking, scratching, or shivering (more automatic behavior). Electrical stimulation of points in the dentate gyrus—CA 4 are produced short latency evoked potentials bilaterally in the hippocampus. These potentials supplanted the normal RSA pattern, and concomitantly, behaviors normally accompanied by RSA were abruptly halted (behavioral arrest). Shivering and licking, on the other hand, were not reliably affected by dentate stimulation. It is suggested that the hippocampal formation plays a role in the control of voluntary movements such as walking or manipulation but does not control more automatic movements such as shivering or licking.

Anatomical, electrophysiological and pharmacological studies of ascending brainstem hippocampal synchronizing pathways.

The present review has provided evidence that very potent ascending brainstem hippocampal synchronizing pathways originate in the rostral pons region (RPO and PPT), and ascend to and synapse with several midline caudal diencephalic nuclei (posterior hypothalamic and supramammillary) which send projections to the medial septal region (MS/vDBB). The medial septal region in turn is a critical nodal point, sending projections to limbic structures such as the hippocampal formation, cingulate cortex, and entorhinal cortex. The pontine and diencephalic nuclei appear to play a critical role in determining the translation of increasing levels of activation into moment to moment changes in the frequency of hippocampal theta field and theta-related cellular discharges, relayed to the MS/vDBB nuclei. The MS/vDBB nuclei appear to play a critical role in translating increasing levels of ascending synchronizing activation into moment to moment changes in the amplitude of hippocampal theta field activity and the accompanying rate and pattern of phasic theta-ON cells. The MS/vDBB carries out this role through a balance of activity in the septohippocampal cholinergic and GABA-ergic projections. Cholinergic projections provide the afferent excitatory drive for hippocampal theta-ON cells and the GABA-ergic projections act to reduce the overall level of inhibition by inhibiting hippocampal GABA-ergic interneurons (theta-OFF cells). Both activities must be present for the generation of hippocampal theta and theta-related cellular activities. The balance between the cholinergic and GABA-ergic projections may determine whether hippocampal synchrony (theta) or asynchrony (LIA, large amplitude irregular activity) occurs. These same ascending pathways influence the electrophysiological and pharmacological properties of the neocortex as well. The functional significance of the ascending brainstem synchronizing pathways is the generalized regulation of activities in these cortical structures as they relate to sensorimotor behavior.