(last updated Sept 2001)
A page from: Eric Hargreaves'Page O'Neuroplasticity
Rhythmical Slow wave Activity (RSA) or "theta" is one of four slow wave activity patterns that are endogenous to the hippocampus. Of the other three patterns Large amplitude Irregular Activity (LIA) commonly alternates with theta as the dominant slow wave activity pattern in awake animals. Slow Wave Sleep (SWS) is the other common pattern occurring in the hippocampus, but as the name indicates, SWS occurs during sleep. The final pattern of Small Irregular Activity (SIA) occurs rarely and only then for a brief second or two (Vanderwolf et al., 1975).
Click on graphics for full view. Theta appears as an approximately sinusoidal wave form of regular amplitude with a frequency range of somewhere between 4-15Hz. This frequency bandwidth encompasses most situations underwhich theta occurs and includes theta that can be demonstrated only under a number of rare and artifical conditions, such as using electrical stimulation of the hypothalamus to drive theta or using anesthetics such as urethane to alter the number of transmitter systems that participate in generating RSA. Thus, most researchers examine a frequency range much smaller than 4-15Hz, and often use a definition of theta that depends upon the specific conditions used for studying theta. (For example, Vanderwolf, 1969 6-12Hz; Bland and Colom, 1993 5-10Hz). However, as a reference, in the awake actively behaving rat most theta occurs between 6-9Hz.
The other common slow wave activity pattern observed in waking animals is Large amplitude Irregular Activity (LIA),
which is more variable in its amplitude and frequency and is sometimes accompanied by sharp waves
that are 50-100ms in duration and 2-5 times the amplitude of the background slow wave activity. Sharp waves are a characteristic of CA1 LIA and are not found to occur in the dentate gyrus.
Also present in the hippocampal electrocorticogram during sleep is Slow Wave Sleep characterized by irregular activity and variable frequencies.
The fourth remaining hippocampal endogenous slow wave activity pattern is Small amplitude Irregular Activity (SIA),
and appears rarely and only then under very specific circumstances,
and only for very brief periods of a few seconds at a time (Vanderwolf et al., 1975).
Type I and Type II behaviors; Relation to hippocampal slow wave patterns
Of these patterns RSA has been the most examined.
Theta's popularity as a phenomenon of study stems from the hope that it may be linked to
higher cognitive functioning such as "attention", "motivational states" or "learning"
(Grastyan et al., 1959;
Yet, after several decades of trying to link RSA to cognitive notions,
the only successful relational scheme associates RSA with specific behaviors for which no underlying common theoretical construct is
immediately apparent (Vanderwolf, 1969).
As such, these behaviors are simply classified as Type I (accompanied by theta) or as Type II (unaccompanied by theta).
A short list of Type I behaviors include walking, running, rearing, jumping, swimming, digging, manipulation of objects with the forelimbs, isolated head movements, posture changes during grooming, and investigatory sniffing accompanied by other Type I behaviors such as head movements, stretching and stepping.
Conversely Type II behaviors include awake immobility, licking, chewing, teeth chattering, sneezing, vocalization, shivering, tremour, defecating, rhythmical grooming movements unaccompanied by posture changes, scratching, pelvic thrusting, ejaculation, piloerection, and sniffing unaccompanied by other Type I movements
(Vanderwolf et al., 1975;Bland, 1986;Vanderwolf, 1988) and in female rats lordosis, ear wiggling, and pup licking
Mead & Vanderwolf (1992).
Although no obvious theoretical construct exists, underwhich the behaviors can be grouped, loosely they have been identified as "voluntary" (Type I) and "instinctual or automatic" (Type II),
but even these classifications are of no obvious utility (Vanderwolf, 1971;
Despite continual arguments of relating RSA/theta to observable events, there has always been a tendency to return to the more inferential "psychological constructs" such as learning, and attention
Vanderwolf & Robinson, 1981;
Currently, theta has once again become popular as a potential learning adjunct, playing some sort of timing or "pacing" role in
A brief history of RSA/Theta recording
The first probable recording of RSA was Saul and Davis (1933), who described a number of spontaneous wave activity patterns that were generated from specific sources within the cat brain. Originally, they had been investigating deep brain potentials in response to sensory stimuli such as odours or flashing lights, which they hoped might enable neurosurgeons to identify specific centres or tracts and thereby act as landmarks during delicate brain operations. Of the brain regions that generated spontaneous activity Saul and Davis (1933) described sites near the hippocampus that generated "regular waves of constant and definite shape" around a frequency of 5Hz. Since only a general written description was given and no electrocorticogram tracings were displayed, it remains unknown whether this truly was the first description of theta or not. However, given that the whole field electroencephalography (EEG recording) was less than a decade old, this oversight, in context, should be understandable. This report was followed 5 years later by Jung and Kornmuller (1938; as cited from Bland, 1986), who elicited theta from the hippocampus of rabbits, by stimulation of peripheral nerves.
Work of this kind was not returned to until well after WWII in the early 1950s, when Maclean et al. (1952), largely recording from the adjacent pyriform cortex, elicited regular fast waves (12-30Hz), in response to odours and tail pinches that were reminiscent of the 5-6Hz regular shaped waves recorded earlier by Kornmuller (personal communication from Kornmuller to Maclean). Within a couple of years the flood gates to hippocampal "theta" research had been opened (Maclean et al., 1955-56; Liberson & Cadilhac, 1954; Liberson & Akert, 1955; Green & Arduini, 1954; Green & Adey, 1956).
Of these papers Green & Arduini (1954) have become the authors generally cited as producing the first classic work on RSA/theta.
The probable reasons for the pre-eminance of the
Green & Arduini (1954)
paper are probably the number of manipulations used, the number of species used (rabbits, cats, and monkeys) and the application of an overall theoretical framework within which theta was conceived (general theory of brainstem activation or arousal).
As such, many of the indepth RSA reviews identify Green & Arduini (1954) as the "benchmark" paper
Bland & Colom, 1993;
Pharmacology of Endogenous Hippocampal EEG patterns
Research on the pharmacological basis of the endogenous hippocampal slow wave activity patterns has largely focussed on RSA. This is primarily due to the fact that the pharmacological removal of RSA leaves a background pattern of "LIA-like" slow wave activity (Vanderwolf, 1988). Fairly early on in the search for the underlying pharmacology of RSA it was found to be based on more than one neurotransmitter system (Vanderwolf et al., 1975 Bland, 1986).
Atropine-sensitive or Cholinergic RSA/theta
An atropine-sensitive form of RSA was found, which could also be abolished by other centrally acting muscarinic antagonists such as scopolamine or quinuclidinyl benzilate (Vanderwolf, 1988). This form of RSA tended to correspond to lower RSA frequencies (4-6Hz) and could appear under specific conditions during Type II behavioral immobility, as in the presence of previously encountered predators, or in a "jump up" avoidance task (Sainsbury and Montoya, 1984; Sainsbury et al., 1987; Vanderwolf, 1980). This form of RSA could also be enhanced or made to occur during Type II behaviors by the application of cholinergic agonists such as eserine or pilocarpine (Vanderwolf, 1988). The cholinergic RSA is presumably mediated through the medial septal and nucleus of the diagonal band inputs to the hippocampus, although evidence exists that suggests that a minor cholinergic pathway enters the hippocampus through the entorhinal cortex originating in the magnocellular pre-optic area (Butcher and Woolf, 1986; Buszaki, 1984; Vanderwolf, 1988).
Atropine-resistant or Serotonergic RSA/theta
A second atropine-resistant form of RSA was found to exist that was not sensitive to cholinergic manipulations and occurred only during Type I movements and typically at higher frequencies (7-12Hz). This form of RSA was sensitive to ether, urethane, chlorpromazine, reserpine, phenyclidine and entorhinal lesions (Vanderwolf, 1975; Vanderwolf & Leung, 1983; Vanderwolf, 1988). Studies using p-chlorophenyalanine (PCPA), a tryptophan hydroxylase inhibitor, preventing the synthesis of serotonin, and 5,7-dihydroxytrypamine a monaminergic specific neurotoxin have led to the conclusion that the atropine-resistant RSA is serotonergic in nature (Vanderwolf & Baker, 1986; Vanderwolf et al., 1989). This was further supported by increases in Type I behavior and atropine-resistant RSA induced either pharmacologically by increases in serotonin through MAO inhibitors, or by stimulating the brainstem raphe nuclei, as one of the main sources of serotonergic fibres (Robertson, Baker & Vanderwolf, 1991; Peck & Vanderwolf, 1991). Lesion experiments in combination with muscarinic antagonists suggest that the atropine-resistant RSA arrives at the hippocampus via the supracallosal striae and fibres running through the cingulate cortex (Vanderwolf, Leung & Cooley, 1985).
GABAergic participation in RSA/theta
Stewart & Fox (1990) have argued for the additional participation of gamma-amino butyric acid (GABA), one of the main inhibitory neurotransmitter systems, in the generation of atropine-resistant RSA.
The basis for their argument lies in the earlier demonstration of an atropine-resistant RSA population of cells in the septal nuclei of urethane anesthetized preparations given atropine
(Stewart & Fox 1989).
Since urethane is a common method for isolating the atropine-sensitive RSA
(Bland & Colom, 1993), atropine and urethane together should block both the cholinergic and serotonergic forms of RSA, and thus, any remaining RSA must be attributed to a third transmitter system.
Smythe, Colom & Bland (1992) also provided evidence for the participation of GABAergic systems in RSA generation.
In urethane anesthetized preparations the medial septum and diagonal band were temporarily suppressed by the application of procaine, a local anesthetic, which disabled spontaneous hippocampal RSA, and RSA electrically driven by stimulation of the dorsomedial-posterior hypothalmus.
Following the suppression, RSA-like oscillations were once again recorded after the application of carbachol (cholinergic agonist) and bicuculline (GABAergic antagonist), but not by either alone
(Smythe, et al., 1992).
Thus, after all theta systems were suppressed, RSA could be re-instated through the local inhibition of GABAergic neurons within the hippocampus, which in turn disinhibited the cholinergic neurons, which when given further facilitation via the carbachol oscillated at RSA frequencies.
Finally, MK801 and aminophosphonovaleric acid (APV), both antagonists of the n-methyl-d-aspartate (nmda), an important excitatory amino acid subreceptor type involved in LTP and related neuroplasticity, abolished alvear surface monopolar RSA
(APV; Leung & Desborough, 1988) and attenuated RSA of the dentate molecular layer
(MK801; Hargreaves, Cote & Shapiro, 1997).
These RSA disruptions may have been mediated through the activation of inhibitory GABA interneurons by EAA transmission
(Davies and Collingridge, 1989;
Davies et al., 1990).
Cellular mechanisms of RSA/theta oscillation
Although it is the principal cells of the CA1-3 (pyramidal cells) and dentate gyrus (granule cells) that are largely responsible for the extracellular currents recorded during EEG, they are driven or paced by the firing of interneurons compacted within the same layers, or distributed within the proximal subcellular layers (Bland & Colom, 1993 Vanderwolf, 1988 Buzsaki, Leung and Vanderwolf, 1983). Hypothesized oscillation mechanisms have included both recurrent inhibition loops and feedforward inhibition (Buzsaki, 1984; Buzsaki and Eidelberg, 1982). Anatomical evidence is available to support both ideas (Freund and Antal, 1988; Frotscher, 1988; Frotscher & Leranth, 1985; 1986; Frotscher et al., 1984; 1986; 1989) and electrophysiological data from single unit recordings of granular layer interneurons have demonstrated the existence of feedforward inhibitory mechanisms (Buzsaki and Eidelberg, 1982). Similar data have been found for CA1 from intracellular recordings of lacunosum-moleculare interneurons (Lacaille & Schwartzkroin, 1988a,b; Lacaille et al., 1989).
Stewart & Fox's (1990) model is also parsimonious with a feedforward mechanism. They suggest that the GABAergic projection from the septal area dually innervates interneurons driving the principal cells and interneurons with cholinergic projections that in turn drive the principal cells, and thus provide an inhibitory/excitatory oscillation of the principal cells via the interneurons. A similar theory has also been put forward by Bland and colleagues (Smythe, et al., 1992; Bland & Colom, 1993). Additionally, pharmacological evidence supports oscillation mechanisms that are both extrinsic and intrinsic to the hippocampus (Vanderwolf, 1988; Bland & Colom, 1993).
RSA Phase Relations
Based on phase relation changes during different Type I behaviors and pharmacological manipulations of the atropine-sensitive and atropine-resistant forms of RSA Leung (1984a; 1984b) hypothesized the differential influence of the two pharmacological RSA generators and their input termination patterns on the dendritic fields of the principal neurons.
RSA/theta phase relations are the degree to which different regions within the hippocampus oscillate in or out of synchrony with each other. During RSA/theta, the tightly packed layers of the granule cells in the dentate and the pyramidal cells in the CA1-3 regions both oscillate as separate generators of slow wave activity, although as previously discussed it is the interneurons driving the theta.
Phase relations also change within each of the CA1-3 and dentate regions of the hippocampus, dependent upon the subcellular components (cell bodies, basal dendrites, apical dendrites, and proximal or distal regions within the dendritic branching) or strata from which one records. Although a cell's firing is near simultaneous, there is still a sequence to the firing, which passes from the dendrites to the cell body to the axon. When recording extracellularly this sequence is enhanced since the recording is picking up the ion exchange summed temporally across the mass cellular action. As such, if two monopolar recordings are taken from CA1, with one of the recordings fixed in the alvear or surface layer, and the other gradually driven down to the hippocampal fissure such that they straddle the cell body layer, then the synchrony of the two signals will diverge until they are opposite to each other or 180 degrees out of phase. Therefore very much like the tidal cycle, the extracellular currents oscillate sequentially on opposite sides of the cell soma (body), and different placements across the soma have set recording phase relations to each other.
The amount of cholinergic and serotonergic release on the different dendritic termination zones can vary dependent upon the Type I behavior engaged in, or the duration since the behavior was initiated. These fluctuations alter the depolarization currents within the local termination zones either hastening or impeding the cells to fire and therefore altering the timing of the firing sequence or oscillation, which ultimately shift the phase relations.
Thus, by systematically examining the phase relations during different behaviors and pharmacological manipulations
Leung (1984a; 1984b) found different influences of the serotonergic and cholinergic RSA generators and their termination patterns.
Leung (1984c) then integrated these data into a predictive mathematical model accounting for the generation of RSA/theta.
Buzsaki and colleagues (Buszaki, 1986; Buszaki et al., 1986) elabourated on a similar system attempting to further encorporate LIA and hippocampal sharpwaves into their model.
Theta "on"/ Theta "off" cells
The single unit recording of cells within the hippocampus of freely behaving animals in the early 1970s yielded two types of cells (O'Keefe and Dostrovsky, 1971). One type fired in short complex bursts and were best characterized as responding to specific locations within an environment. These cells were subsequently named "place cells". The second type of cells also fired phasically, but only simple spikes were recorded, and these units corresponded best to Type I behaviors. The existence of "theta" cells was soon verified by Ranck (1973), who later also provided a classification scheme for complex-spike and theta cells based on firing characteristics. Further, based on the theta cells anatomical localization it was argued that the cells were most likely to be interneurons (Fox & Ranck, 1975; Fox & Ranck, 1981).
Since that time single unit recording within urethane anesthetized preparations has done much to define the firing characteristics of the different putative interneurons that drive the atropine-sensitive RSA (Bland et al., 1980; Bland & Colom, 1993). Throughout the late 1980s this preparation was used by Bland's group to identify the traditional "theta" cells, as well as cells that preferred non-theta states, or "theta-off" cells (Colom and Bland, 1987; Bland and Colom, 1989). Further, they went searching for locations other than the hippocampus that may house theta cells. The most likely candidate structures were naturally those that sent theta-influencing projections to the hippocampus, as well as those structures immediately downstream of the hippocampus, where the theta signal may next project. Thus, upstream of the hippocampus, theta cells were identified in the medial septum and entorhinal cortex (Bland, Ford, and Colom, 1990; Colom and Bland, 1991; Bland & Colom, 1993). Downstream of the hippocampus theta neurons were identified in the cingulate cortex (Colom, Christie, and Bland, 1988). Finally, not only were theta-on and theta-off cells identified, but also were further characterized into firing patterns as either phasic or tonic Bland and Colom, 1988; Bland & Colom, 1993). The tonically firing cells, would simply fire at a constant low theta rate of single spikes, while the phasic theta cells would burst during theta rhythm with an ever increasing intraburst-frequency, and then pause until the next appropriate phase of theta.
Links to Scientists, who do RSA/Theta Research
(last updated July 2007)
RSA/Theta References...Adey, W.R. (1966). Neurophsyiological correlates of information transaction and storage in brain tissue. In E. Stellar and J. Sprague (Eds) Progress In Physiological Psychology, Academic Press, New York, Vol1, pp.1-43.
Bland, B.H. and Colom, L.V. (1988). Responses of phasic and tonic hippocampal theta-on cells to cholinergics, differential effects of muscarinic and nicotinic activation. Brain Research, 440, 167-171.
Bland, B.H., Ford, R.D., and Colom, L.V. (1990). Responses of of septal theta-on and theta-off cells to activation of the dorsomedial-posterior hypothalamic region. Brain Research Bulletin, 24, 71-79.
Buzsaki, G., Czopf, J., Kondakor, I. and Kellenyi, L. (1986). Laminar distribution of hippocampal rhythmic slow activity (RSA) in the behaving rat: current-source density analysis, effects of urethane and atropine. Brain research, 365, 125-137.
Butcher, L.L. and Woolf, N.J. (1986). Central cholinergic systems: synopsis of anatomy and overview of physiology and pathology. In A.B. Scheibel and A.F. Wechsler (Eds) The Biological Substrates of Alzheimer's Disease, New York, Academic Press, pp. 73-86.
Colom, L.V., Christie, B.R., and Bland, B.H. (1988). Cingulate cell discharge patterns related to hippocampal EEG and their modulation by muscarinic and nicotinic agents. Brain Research, 460, 329-338.
Davies, C.H., Davies, S.N., & Collingridge, G.L. (1990). Paired-pulse depression of monosynaptic GABA-mediatyed inhibitory postsynaptic responses in rat hippocampus. Journal of Physiology, 424, 513-531.
Frotscher, M. and Leranth, C. (1985). Cholinergic innervation of the rat hippocampus as revealed by choline acetyltransferase immunocytochemistry: a combined light and electron microscopic study. The Journal of Comparative Neurology, 239, 237-246.
Frotscher, M. and Leranth, C. (1986). The cholinergic innervation of the rat dascia dentata: identification of target structures on granule cells combining choline acetyltransferase immunocytochemistry and golgi impregnation. The Journal of Comparative Neurology, 243, 58-70.
Frotscher, M., Leranth, Cs., Lubbers, K., and Oertel, W.H. (1984). Commissural afferents innervate glutmate decarboxylas immunoreactive non-pyramidal neurons in the guinea pig hippocampus. Neuroscience Letters, 46, 137-143.
Frotscher, M., Nitsch, R., and Leranth, C. (1989). Cholinergic innervation of identified neurons in the hippocampus: electron microscopic double labelling studies. In V. Chan-Palay and C. Kohler (Eds.) Neurology and Neurobiology Vol52: The Hippocampus - New Vistas, New York, Alan R. Liss Inc.,pp 85-96.
Frotscher, M., Schlander M. and Leranth, C. (1986). Cholinergic neurons in the hippocampus: a combined light- and electron-microscopic immunocytochemical study in the rat. Cell Tissue Research, 246, 293-301.
Grastyan, E. (1985). Historical overview of the search for behavioural correlation of brain rhythms. In G. Buszaki and C.H. Vanderwolf (Eds) Electrical Activity of the Archicortex, Akademiai Kiado: Budapest, pp. 1-20.
Grastyan, E., Karmos, G. Vereczkey, R., & Kellinyi, L. (1966). The hippocampal electrical correlates of the homeostatic regulation of motivation. Electroencephalography and Clinical Neurophysiology, 21, 34-46.
Hargreaves, E.L., Côté, D. and Shapiro M.L. (1997). 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. Behavioral Neuroscience, 111, 35-48.
Lacaille, J.-C., Kunkel, D.D., Schwartzkroin, P.A. (1989). Electrophysiological characterization of hippocampal interneurons. In V. Chan-Palay and C. Kohler (Eds.) Neurology and Neurobiology Vol52; The Hippocampus - New Vistas, New York, Alan R. Liss Inc, pp.287-305.
Lacaille, J.-C., and Schwartzkroin, P.A. (1988a). Stratum lacunosum-moleculare interneurons of hippocampal CA1 region: I. intracellular response characteristics, synaptic responses, and morphology. The Journal of Neuroscience, 8, 1400-1410.
Lacaille, J.-C., and Schwartzkroin, P.A. (1988b). Stratum lacunosum-moleculare interneurons of hippocampal CA1 region: II. intrasomatic and intradendritic recordings of local circuit synaptic interactions. The Journal of Neuroscience, 8, 1411-1424.
Leung, L-W.S. (1984b). Theta rhythm during REM sleep and waking: correlations between power, phase and frequency. Electroencephalography and clinical Neurophysiology, 58, 553-564.
Leung, L-W.S. (1984c). Model of gradual phase shift of theta rhythm in the rat. Journal of Neurophysiology, 52, 1051- 1065.
Leung, L-W.S. (1985). Theta rhythm: biophysical model of generationin the hippocampus. In G. Buszaki and C.H. Vanderwolf (Eds) Electrical Activity of the Archicortex, Akademiai Kiado: Budapest, pp. 165-177.
Liberson, W.R., and Cadilhac, J.G. (1954). Hippocampal responses to sensory stimulation in the guinea pig. American EEG Society Proceedings. Electroencephalography and Clinical Neurophysiology, 6, 710-711.
Maclean,P.D., Flannigan, S., Flynn, J.P., Kim, C., and Stevens, J.R. (1955-56). Hippocampal function: tentative correlations of conditioning, EEG, drug, and radioautographic studies. Yale Journal of Biological Medicine, 28, 380-395.
Smythe, J.W., Colom, L.V., and Bland, B.H. (1992). The extrinsicc modulation of hippocampal theta depends on the coactivation of cholinergic and GABA-ergic medial septal inputs. Neuroscience and Biobehavioral Reviews, 16, 289-308.
Vanderwolf, C.H. (1975). Neocortical and hippocampal activation in relation to behavior: effects of atropine eserine phenothiazines and amphetamine. Journal of Comparative Physiological Psychology, 88, 306-323.
Vanderwolf, C.H. (1983). The role of the cerebral cortex and ascending activating systems in the control of behavior. In E. Satinoff and P. Teitlbaum (Eds) Handbook of Behavioral Neurobiology Volume 6, New York, Plenum Press, pp. 67-104.
Vanderwolf, C.H. (1983). The influence of psychological concepts on brain behavior research. In T.E. Robinson (Ed) Behavioral Approaches to Brain Research, Oxford University Press, New York, pp. 3-13.
Vanderwolf, C.H. and Baker, G.B. (1986). Evidence that serotonin mediates non-cholinergic neocortical low voltage fast activity, noncholinergic hippocampal rhythmical slow activity and contributes to intelligent behavior. Brain Research, 374, 342-356.
Vanderwolf, C.H., Leung, L-W,S., Baker, G.B., and Stewart, D.J. (1989). The role of serotonin in the control of cerebral activity: studies with intracerebral 5,7-dihydroxytryptamine. Brain Research, 504, 181-191.
Vanderwolf, C.H., Leung, L.-W.S., and Cooley, R.K. (1985). Pathways through cingulate, neo- and entorhinal cortices mediate atropine-resistant hippocampal rhythmical slow activity. Brain Research, 347, 58-73.
Vanderwolf, C.H. & Leung, L.S. (1983). Hippocampal rhythmical slow activity: a brief history and the effects of entorhinal lesions and phencyclidine. In G.W. Seifert (Ed) Neurobiology of the Hippocampus, Academic Press, New York, 275-302.
Vanderwolf, C.H., Kramis, R., Gillespie, L.A., & Bland, B. (1975). Hippocampal rhythmic slow activity and neo-cortical low-voltage fast activity: relations to behavior. In R.L. Isaacson and K.H. Pribram (Eds.) The Hippocampus, Volume 2 (pp. 101-128) New York, Plenum Press.