28 Smith, M. L. and Milner, B. (1989) Neuropsychologia 27, 71-81 29 Ettlinger, G. (1990) Cortex 26, 319-341 30 Milner, A. D. etal. (1991) Brain 114, 405-428 31 Goodale, M. A., Milner, A. D., Jakobson, L. S. and Carey, D. P. (1991) Nature 349, 154-156 32 Andersen, R. A. (1987) in Higher Functions of the Brain, Part 2 (The Nervous System, VoL V, Handbook of Physiology, Section 1) (Mountcastle, V. B., Plum, F. and Geiger, S. R., eds), pp. 483-518, American Physiological Association 33 Andersen, R. A., Asanuma, C., Essick, G. and Siegel, R. M. (1990) J. Comp. Neurol. 296, 65-113 34 Taira, M., Mine, S., Georgopoulos, A. P., Murata, A. and Sakata, H. (1990) Exp. Brain Res. 83, 29-36 35 Felleman, D. J. and Van Essen, D. C. (1987) J. Neurophysiol. 57, 889-920 36 Mountcastle, V. B., Motter, B. C., Steinmetz, M. A. and Duffy, C. J. (1984) in Dynamic Aspects of Neocortical Function (Edelman, G. M., Gall, W. E. and Cowan, W. M., eds), pp. 159-193, Wiley 37 Perrett, D. I., Mistlin, A. J., Harries, M. H. and Chitty, A. J. (1990) in Vision and Action: The Control of Grasping (Goodale, M. A., ed.), pp. 163-180, Ablex 38 Cavada, C. and Goldman-Rakic, P. S. (1989) J. Comp. Neurol. 287,422-445 39 Gentilucci, M. and Rizzolatti, G. (1990) in Vision andAction: The Control of Grasping (Goodale, M. A., ed.), pp. 147-162, Ablex 40 Milner, A. D. and Goodale, M. A. Prog. Brain Res. (in press) 41 Bates, J. A. V. and Ettlinger, G. (1960) Arch. Neurol. 3, 177-192 42 Faugier-Grimaud, S., Frenois, C. and Stein, D. G. (1978) Neuropsychologia 16, 151-168 43 Haaxma, R. and Kuypers, H. G. J. M. (1975) Brain 98, 239-260

44 Perrett, D. I., Mistlin, A. J. and Chitty, A. J. (1987) Trends Neurosci. 10, 358-364 45 Pribram, K. H. (1967) in Brain Function and Learning (Lindsley, D. B. and Lumsdaine, A. A., eds), pp. 79-122, University of California Press 46 Perrett, D. I. et al. (1991) Exp. Brain Res. 86, 159-173 47 Humphrey, N. K. and Weiskrantz, L. (1969) Quart. J. Exp. Psychol. 21,225-238 48 Weiskrantz, L. and Saunders, R. C. (1984) Brain 107, 1033-1 O72 49 Marr, D. (1982) Vision, Freeman 50 Goldberg, M. E. and Colby, C. L. (1989) in Handbook of Neuropsychology (Vol. 2) (Boller, F. and Grafman, J., eds), pp. 301-315, Elsevier 51 Bushnell, M. C., Goldberg, M. E. and Robinson, D. L. (1981) J. Neurophysiol. 46, 755-772 52 Lawler, K. A. and Cowey, A. (1987) Exp. Brain Res. 65, 695-698 53 Fischer, B. and Boch, R. (1981) Exp. Brain Res. 44, 129-137 54 Moran, J. and Desimone, R. (1985) Science 229, 782-784 55 Rizzolatti, G., Gentilucci, M. and Matelli, M. (1985) in Attention and Performance XI (Posner, M. I. and Marin, O. S. M., eds), pp. 251-265, Erlbaum 56 Tipper, S., Lortie, C. and Baylis, G. J. Exp. Psychol. Human Percept. Perform. (in press) 57 Warrington, E. K. and Taylor, A. M. (1973) Cortex 9, 152-164 58 Goodale, M. A., Pelisson, D. and Prablanc, C. (1986) Nature 320, 748-750 59 Sejnowski, T. J. (1991) Nature 352, 669-670 60 Cavada, C. and Goldman-Rakic, P. S. (1989) J. Comp. Neurol. 287, 393-421 61 Posner, M. I. and Rothbart, M. K. (1991) in The Neuropsychology of Consciousness (Milner, A. D. and Rugg, M. D., eds), pp. 91-111, Academic Press

Acknowledgements Theauthors are grateful to D. Carey, L. Jakobsonand D. Perrett for their comments on a draft of thls paper.

Controlofneuronalexcitabilityby corticosteroidhormones Marian JoEls and E. Ronald de Kloet The rat adrenal hormone corticosterone can cross the blood-brain barrier and bind to two intracellular receptor populations in the brain - the mineralocorticoid and glucocorticoid receptors. Recent studies have revealed that the corticosteroid hormones are able to restore changes in neuronal membrane properties induced by current or neurotransmitters, probably through a genomic action. In general, mineralocorticoid receptors mediate steroid actions that enhance cellular excitability, whereas activated glucocorticoid receptors can suppress temporarily raised neuronal activity. The steroid-mediated control of excitability and the implications for information processing in the brain are reviewed in this article. It has been acknowledged for many years that adrenal corticosteroid hormones that are released into the blood circulation can cross the blood-brain barrier and bind to intraceilular receptors in the brain (see Refs 1-3). During the 1960s, McEwen and co-workers showed with the help of radioligand binding and autoradiography that [3H]corticosterone, administered to adrenalectomized (ADX) rats, is retained by intracellular receptors in some brain structures, particularly in the hippocampus 4. The steroid-receptor complex displays increased affinity for the cell nuclear compartment; it can bind to the genome and act as a transcription factor for specific genes 1-3. The localization of intracellular corticosteroid hormone receptors in brain structures naturally raised TINS, Vol. 15, No. I, 1992

the question as to whether cellular activity, and particularly the electrical properties of neurons, could be affected by the hormones. An early study by Pfaff et al. showed that in hypophysectomized rats that received a peripheral injection of cortisol (the adrenocortical steroid found in humans and primates), spontaneous single-unit activity in the hippocampus was reduced with a delay of approximately 30 min (Ref. 5). However, subsequent extracellular recording of hippocampal, forebrain and hypothalamic neurons revealed a disparity in the effects of corticosteroid hormones, which were excitatory or inhibitory or which exerted no changes at all6-9. In retrospect, two important factors may have contributed to the variability in results. One factor relates to the background electrical activity of the tissue exposed to the corticosteroid hormones. The effects of corticosteroid may well be voltage dependent and derive their excitatory or inhibitory nature from the prevailing level of excitability. The extracellular recording methods used in vivo in the studies mentioned above do not allow control of the background electrical activity, in contrast to methods developed for use in vitro over the past decades. The second factor stems from the realization over the past six years that corticosterone in the rat brain binds to two intracellular receptor populations: the mineralocorticoid receptor (MR), which binds corticosterone with high affinity and is discretely localized, particularly in neurons of limbic structures; and the

© 1992,ElsevierSciencePublishersLtd,(UK) 0166- 22361921505.00

Marian Jo#lsis at the Dept of Experimental Zoology, University of Amsterdam, 1098 ENIAmsterdam, The Netherlands, and E. Ronaldde Kloet is at the Center for Biopharmaceutical Sciences, Leiden University, 2300 RA Leiden, The Netherlands.

25

Box 1. Corticosteroid receptors in the brain The binding of steroid hormones to a cytosolic fraction from rat hippocampal tissue in vitro revealed that corticosterone binds to a heterogeneous pool of receptors "3. With the development of selective glucocorticoids such as RU 28362, which displays negligible affinity to the classical mineralocorticoid receptor (MR) in the kidney and has no effect on the mineral balance, a further distinction between the receptor populations in the hippocampus became feasible 1°. Inclusion of RU 28362 revealed a homogeneous receptor population with high affinity to aldosterone and corticosterone, which is indistinguishable from the kidney MR in its primary structure 19. Therefore, the high-affinity corticosterone or type-1 receptor in the brain is referred to here as an MR. Although MRs in the brain are structurally homogeneous, tissue factors can determine their ligand selectivity. Thus, MRs in some neurons display aldosterone-selective properties, while an apparent corticosterone selectivity is observed in other cells particularly in neurons in limbic structures. Aldosterone selectivity is induced by the local presence of the enzyme 1113-hydroxysteroid dehydrogenase, which converts corticosterone (or cortisol) into metabolites with lower biological activity 44,45. Aldosterone-selective MRs in the brain prevail in periventricular brain regions, where these sites are involved in central control of Na + homeostasis and cardiovascular functions. The characteristics of the aldosterone-selective MRs are not addressed in this review. Corticosterone-selective MRs are found in neurons where the metabolic conversion of corticosterone by 111~-hydroxysteroid dehydrogenase is probably limited. Although MRs display high affinity to both atdosterone and corticosterone, these sites will be predominantly occupied by corticosterone since this steroid circulates in a lO0-1000-fold excess over aldosterone. The corticosterone-preferring MRs in the limbic structures mediate a tonic influence of corticosterone, which is relevant for the threshold or sensitivity of the stress response and the organization of behavioral responses to stress3. Radioautography of rat brain sections labelled with [3H]RU 28362 showed that the distribution of glucocorticoid receptors (GRs) is much more widespread than that of MRs (see Figure). GRs are found in a variety of brain structures such as the paraventricular nucleus, supraoptic nucleus, arcuate nucleus, thalamic nuclei, all nuclei of the ascending aminergic pathways, hippocampus, septum, amygdala, and the neocortex. This anatomical distribution was confirmed using immunohistochemistry lt12 and in situ hybridization ~3-15. GRs are involved in the glucocorticoid-mediated regulation of the stress response and facilitate the storage of information 3. During uptake into the cell, corticosteroids may be metabolized and interact with membrane-associated

glucocorticoid receptor (GR), which binds corticosterone with a tenfold lower affinity and is widely distributed in the brain (see Box 1) 1°. Experimental approach The CA1 hippocampal area of the rat is particularly enriched with both MRs and GRs 1°-15. In fact, colocalization of MRs and GRs seems to occur in almost every CA1 pyramidal neuron 16. The fact that both types of receptor bind corticosterone, albeit with different affinity, has important implications for the 26

low corticosterone

high corticosterone Distribution of mineralocorticoid receptors (MRs) (black circles) and glucocorticoid receptors (GRs) (blue circles) in the rat brain. MRs are mainly found in the septum and the hippocampus; GRs are widespread but enriched in the paraventricular nucleus. When the circulating corticosterone levels are low (A), Le. in the morning under non-stressed conditions, MRs are already largely occupied, while GRs are only partly occupied. When corticosterone levels are high (B), e.g. at the peak of the circadian cycle for corticosterone secretion or after stress, most of the GRs will also become fully occupied. receptor proteins, which would rapidly lead to modulation of membrane characteristics "6 or transmitter responses such as the GABAA-receptor-mediated enhancement of CI- conductance 47. This raises the interesting possibility that after metabolic conversion, adrenal steroids - in addition to affecting neuronal excitability through slow, gene-mediated processes - can also regulate neuronal activity at a comparatively fast rate. However, it should be noted that, so far, these rapid membrane effects are displayed by steroids with reduced A rings, while the endogenous corticosteroid hormones are not very potent in this respect. The rapid effects of steroids have been reviewed in detail elsewhere and are not discussed here48,49.

study of the effects of corticosterone on neuronal properties. First, it has been shown that, due to the differential affinity of MRs and GRs to corticosterone, MRs in the brain are already occupied to a considerable degree at basal levels of circulating corticosterone (in the morning), while GRs are mostly unoccupied. When the level of circulating corticosterone is high (during the peak of the circadian cycle or post-stress), GRs gradually become occupied; MR saturation having previously occurred at lower corticosterone levels 1°'17'18. Since steroid receptors, in contrast to TINS, VoL 15, No. 1, 1992

receptors for classical transmitters and peptides, are intraceUularly localized and mediate long-lasting genomic actions, activation of MRs and GRs by endogenous corticosterone in vivo may well persist for a considerable time - it may even persist in brain slices in vitro. This means that exogenous application of corticosterone to intact rats or to slices from rats that had an intact pituitary-adrenal axis will at best reveal GR-mediated actions, since most of the MRs in the brain will already be occupied. Studying the effects of corticosterone in animals from which the adrenal has been removed, so that both types of receptor are unoccupied, enables the examination not only of GRbut also of MR-mediated activity. A second implication of corticosterone binding to both MRs and GRs is that the activated MR-steroid complex might predominantly bind to MR-responsive elements of the genome, while the GR-steroid complex will preferably bind to GR-responsive elements. Activation of one or other type of receptor may thus induce the expression of different sets of genes, which would potentially lead to entirely different MR- and GR-mediated effects on neuronal activity. If MRs in CA1 neurons can to some degree bind to GR-responsive elements (or vice versa), synergism or antagonism of MR- and GR-mediated actions may arise 19'2°. Evidently, interpretation of the effects of a 'mixed agonist' like corticosterone is difficult, since the relative contributions of MRmediated and GR-mediated events to the net effect of corticosterone varies with the concentration of the steroid. The availability of selective MR- and GRanalogues now means that MR- and GR-mediated effects on electrical properties can be studied separately. For the reasons outlined above, a series of electrophysiological studies was recently undertaken, using (1) hippocampal preparations in vitro that allowed a better control of transmitter input to and membrane potential of the recorded neurons, (2) tissue from ADX animals in addition to sham-operated controls, and (3) combinations of selective agonists and antagonists for MRs and GRs.

A

1 nM ALD

1 nM CORT

30 nM CORT

-180

-140_ ~

B

~ 20 mV 100 ms

ADX

ADX + 1 nM CORT

C

___J20 mV 1s

ADX

ADX + RU 28362

Fig. 1. (A) Relative increase in the number of spikes elicited by a depolarizing current pulse ((9.5 hA, 500 ms) in CA 1 pyramidal neurons of hippocampal slices from adrenalectomized (ADX) rats before steroid perfusion (open bars), 20 min after the start of a steroid perfusion (stippled bars), and 30-90 min after steroid perfusion (20 min in total) was terminated (hatched bars). The MR agonist aldosterone enhances the number of spikes, i.e. accommodation and the slow afterhyperpolarization (AHP) are decreased. (B) Similar results are initially seen after a 20 min perfusion with a 1 nM solution of the mixed MR/ GR agonist corticosterone (,4). However, the MR-mediated effect is gradually reversed and overridden; this is even more apparent when a higher corticosterone concentration is applied. (C) The reverse effect is probably induced by the activation of GRs, since selective occupation of GRs by RU 28362 enhances accommodation and the amplitude of the AHP. (Taken, with permission, from

invitro

Ref. 50.)

Low concentrations of corticosterone and the mineralocorticoid aldosterone, applied for 20 min to brain slices taken from ADX rats, diminish the accommodation and the amplitude of the AHP in CA1 pyramidal neurons, an effect that is blocked by the MR antagonist spironolactone 23. Thus, activation of the MR seems to decrease the accommodation and the AHP, and thereby enhance excitability in the CA1 area (see Fig. 1). By contrast, high corticosterone MR- and G R - m e d i a t e d e f f e c t s o n i n t r i n s i c concentrations and the selective glucocorticoid cell properties In most studies carried out so far, application of RU 28362 increase the amplitude of the AHP, resultcorticosterone in vitro does not induce apparent: ing in an effect opposite to MR activation; i.e. potenchanges in the resting membrane potential and tial suppression of hippocampal excitability 21'22. The resistance of CA1 hippocampal neurons in slices from fact that both the MR- and GR-mediated effects on ADX rats 21-2s. However, if the membrane potential accommodation and the AHP develop with a considerof the cell is temporarily shifted from the resting level able delay (maximal effects occur after more than to a depolarized level, actions of corticosteroid 40 min for MR effects and more than 1 hr for GRhormones become apparent. CA1 pyramidal neurons mediated effects, i.e. long after application of the that are temporarily depolarized do not continuously steroid has terminated), and that GR-mediated effects fire action potentials, as might be expected, but fire do not occur in the presence of a protein synthesis only a few action potentials and then remain silent for inhibitor 2~ support the idea that effects mediated by the rest of the depolarization period. This phenom- the steroid involve the genome. At present, it is not enon - accommodation - is due to activation of a slow clear whether the steroid-mediated modulation of Ca2+-dependent K + conductance (IA~p) (see Ref. IAHP reflects a direct change in the K + conductance or 26). At the end of the depolarization period, the K + whether it is caused by changes in the intracellular conductance is slowly inactivated, resulting in a linger- Ca 2+ level. A role for Ca2+, at least in the GRing hyperpolarization known as the slow afterhyper- mediated effects, is indicated by the fact that high polarization (AHP). Both the accommodation and the levels of corticosterone also affect Ca2+-related AHP attenuate the transmission of excitatory signals membrane events other than the slow AHP~1. Interestingly, when relatively high concentrations and therefore potentially decrease the excitability of of the mixed agonist corticosterone were used, MRthe structure. TINS, Vol. 15, No. 1, 1992

27

5-HT(1A) GABA (B) adenosine (A1) somatostatin noradrenaline (o¢2)

¢ corticoste;o:e/~)

~RI~

A~

IK

noradrenaline (1~) histamine (H2) ACh (M) CRF 5-HT Imp

¢

Ca 2+

out membrane

( second , .,¢ messenger

- ~../second

~'". I messenger/ \' proteins

•

in

-"

Fig. 2. Corticosterone passes through the cell membrane and binds to intracellular mineralocorticoid receptors (MRs)

(hatched) and glucocorticoid receptors (GRs) (grey). In the nucleus, the activated steroid-receptor complexes can alter gene expression. The steroid-induced changes in protein synthesis eventually affect ionic conductances through the membrane. On the right is a diagram showing how two ionic conductances (IK and IAHP)are altered by many classical transmitters and peptides 26. The transmitters and peptides bind to membrane receptors (R), which, via a G protein (G), are coupled either directly or through activation of a second messenger system to the K + conductances. At present, there is evidence that steroid-induced actions interfere with the cascade from transmitter receptor to IK or IAHP,and that they may enhance Ca2+ conductances, Abbreviation: CRF, corticotropin-releasing factor.

mediated effects were only temporarily expressed and were gradually overridden by the GR-mediated effects - even when not all of the GRs were presumably occupied23. Accordingly, CA1 pyramidal neurons of sham-operated rats under mild stress, in which almost all MRs but not all of the GRs are occupied, displayed larger AHP amplitudes than the neurons in ADX rats 21'~2. MR- and GR-mediated effects on synaptic transmission Physiologically, changes in the resting membrane potential in CA1 cells are brought about by the action of neurotransmitters. A major excitatory input to the CA1 area is formed by the Schaffer collaterals that use an excitatory amino acid as transmitter (see Ref. 27). Population spikes elicited by electrical stimulation of the Schaffer collaterals are enhanced by low to moderate concentrations of corticosterone 28'29, but depressed by high corticosterone levels in brain slices taken from ADX rats 28. The enhancement may be due to an MR-mediated effect on amino acid transmission, while the decrease of the synaptic potential is due to a GR-mediated effect3°. In sham-operated or intact rats, high concentrations of corticosterone or cortisol induce GR-like effects28'31. Long-term potentiation of the Schaffer collateral input, a process that involves transmission mediated by excitatory amino acids, is reduced by stress or by adrenalectomy, but this is probably related to adrenomedullary factors rather than to corticosterone 32'33. Another source of excitatory input to the CA1 area is a noradrenergic projection that exerts its effects through [~-adrenoceptors. Noradrenaline acting via [3adrenoceptors blocks the accommodation and the AHP of CA1 neurons (see Ref. 26). The application of high amounts of corticosterone and other GR agonists into slices taken from ADX rats, attenuates this effect 28

with a delay of at least 1 hr 22. In sham-operated rats, the effect of noradrenaline is diminished compared with that in ADX rats 22. Facilitating effects of noradrenaline on the population spike elicited by stimulation of the Schaffer collaterals are also much smaller in tissue taken from sham-operated than from ADX Fats34. In contrast to amino acids and noradrenaline, 5-HT mainly hyperpolarizes CA1 pyramidal neurons, via activation of 5-HT1A receptors. The hyperpolarization is caused by an increase in Ca2+-independent K ÷ conductances (IK)26. A brief application (20 mill) of MR agonists to brain slices taken from ADX rats largely blocks responses to 5-HT recorded 1-4 hr after steroid administration is terminated 24. It was argued that the steroid may act on the coupling of the 5-HT1A receptor to its target G protein 24 and, indeed, it has been shown that adrenal steroids can have an effect on G proteins35; primary effects of sex steroids on kinase activity have also been reported 36. The MRmediated effect on responses to 5-HT is blocked in the presence of a protein synthesis inhibitor 25, suggesting that interaction with the genome is involved. Surprisingly, responses to 5-HT in slices from shamoperated rats are almost similar to the responses in ADX rats. This may be explained by the observation in this case that GR agonists functionally antagonize the MR-mediated attenuation of responses to 5-HT, possibly by interaction of the activated GR and MR complexes with the same hormone-responsive elements 37. In summary, excitatory effects mediated by amino acids are enhanced by MR-mediated effects and diminished by GR ligands. Excitatory responses mediated by [5-adrenoceptors are decreased by GR agonists, while inhibitory responses to 5-HT are decreased by MR ligands. Therefore, like the effects of steroids on current-induced phenomena, changes in TINS, Vol. 15, No. 1, 1992

excitability caused by the effects of transmitters are subject to steroid modulation such that MR ligands enhance whereas GR ligands decrease excitability in the CA1 area. Concluding remarks Although the recent electrophysiological studies have established that corticosteroid hormones, via brain MRs and GRs, alter specific neuronal membrane properties, the role of steroids in information processing in the brain is still far from being resolved. Are the steroids just another class of compounds altering ionic conductances? After all, the data so far indicate that the steroids eventually (directly or indirectly) modulate at least two K + conductances, IK and IAHP, that are also affected by a large variety of amines and peptides (see Fig. 2). At present, we can at least say that the message conveyed by the steroids adds new elements to the spatial and temporal aspects of information processing. First, corticosterone, in contrast to the classical transmitters and peptides, is synthesized outside the brain and therefore represents a humoral rather than a neuronal reaction to environmental challenges. Once in the brain, its sites of action do not depend on distributional networks but exclusively on the localization of intracellular steroid receptors. Second, activated MRs and GRs can alter genomic expression, resulting in a wide array of cellular events that all develop with a considerable rime-lag and are longlasting. Because of the marked convergence of amines, peptides and steroids on a limited number of membrane conductances, this delay is important in differentiating between the fast-acting transmitters and the slowly acting steroids. The long duration of the steroid-mediated effects enables the hormones to change the state of excitability of neuronal networks for long periods of time. Two features of the effects of steroids in the hippocampus stand out. (1) They may be considered as being conditional in that they mainly appear when the membrane potential is shifted from its resting level by injection of current or the effects of transmitters. (2) MR-mediated effects, which act predominantly under conditions of low adrenocortical activity, appear to enhance cellular excitability; GR-mediated events, which determine the excitability at the peak of the circadian corticosterone cycle and after stress, induce a delayed suppression of neuronal activity. The effects of GR-mediated events are in line with Munck's concept that glucocorticoids in general dampen the effect of tissue reactions to excitatory stimuli 38. MR- and GR-mediated events in the brain may thus, each in their own way, restore changes in neuronal activity induced by transmitters, thus contfibuting to a homeostatic control of cellular excitability. Evidently, the effects of steroids on other neurotransmitter systems need to be investigated to find out if the principle of reciprocal MR- and GRmediated effects on cellular excitability holds in general. More importantly, it is necessary to prove that the MR- and GR-mediated control of excitability observed in vitro will indeed occur in vivo, where cells are continuously exposed to synaptic input carried by numerous transmitters and peptides. Many questions about the effects of steroids on neuronal activity are presently unaddressed: inforTINS, Vol. 15, No. 1, 1992

marion about how the expression of proteins is controlled by steroids is still limited39-41; the processes taking place between protein synthesis and changes in ionic conductances are entirely unknown. Do the steroid-induced factors act directly on ionic conductances, on transmitter- and peptide-receptors, G proteins, second messengers, or do they alter processes that are important for cellular homeostasis, such as control of intracellular Ca2+ levels? As most of the brain structures contain mainly GRs and only low amounts of MRs, it would be interesting to find out about the role of corticosterone in information processing in the predominantly GR-containing regions. Finally, most of the recently discovered effects of steroids described in this review were obtained after a brief exposure of tissue to relatively low concentrations of the hormone in vitro. Chronic exposure of brain tissue to high steroid levels may alter energy metabolism of the cells and result in different effects, which perhaps contribute to the degenerative actions of glucocorticoids42. All of these questions form an exciting challenge for future research and may eventually lead to a better understanding of the effects of steroids on the brain during physiological and pathological conditions. Selected references 1 McEwen, B. S., de Kloet, E. R. and Rostene, W. (1986) Physio/. Rev. 66, 1121-1188 2 Funder, J. W. (1986) in Frontiers in Neuroendocrino/ogy (Vo[. 10) (Ganong, W. F. and Martini, L., eds), pp. 169-189, Raven Press 3 de Kloet, E. R. (1991) in Frontiers in Neuroendocrinology (Vol. 12) (Ganong, W. F. and Martini, L., eds), pp. 95-165, Raven Press 4 McEwen, B. S., Weiss, B. M. and Schwartz, L. S. (1968) Nature 220, 911-912 5 Pfaff, D. W., Silva, M. T. A. and Weiss, J. M. (1971) Science 171,394-395 6 Dafny, N., Philips, M. I., Taylor, A. N. and Gilman, S. (1973) Brain Res. 59, 257-272 7 Ben Barak, Y., Gutnick, M. J. and Feldman, S. (1977) Neuroendocrinology 23,248-256 8 Saphier, D. (1987) Brain Res. Bull. 19, 519-524 9 Saphier, D. and Feldman, S. (1988) Brain Res. 453, 183-190 10 Reul, J. M. H. M. and de Kloet, E. R. (1985) Endocrinology 117, 2505-2512 11 Fuxe, K. et al. (1985) Endocrinology 117, 1803-1812 12 Van Eekelen, J., Kiss, J. Z., Westphal, H. M. and de Kloet, E. R. (1987) Brain Res. 436, 120-128 13 Aronsson, M., Fuxe, K. and Dong, Y. (1988) Proc. NatlAcad. 5ci. USA 85, 9331-9335 14 Van Eekelen, J. A. M., Jiang, W. and de Kloet, E. R. (1988) J. Neurosci. Res. 21, 88-94 15 Herman, J. P., Patel, P. D., Akil, H. and Watson, S. J. (1989) /vloL Endocrinol. 3, 1886-1894 16 Bohn, M. C., Howard, E. and Krozowski, Z. (1990) Soc. Neurosci. Abstr. 16, 977 17 Reul, J., van de Bosch, F. and de KIoet, E. R. (1987) Neuroendocrinology 45, 407-412 18 Dallman, M. F. etal. (1987) Prog. Horm. Res. 43, 113-173 19 Arriza, J. L., Weinberger, C. and Cerelli, G. (1987) Science 237, 268-275 20 Evans, R. M. and Arriza, J. L. (1989) Neuron 2, 1105-1112 21 Kerr, D. S., Campbell, L. W., Hao, S-Y. and Landfield, P. W. (1989) Science 245, 1505-1507 22 JoEIs, M. and de Kloet, E. R. (1989) Science 245, 1502-1505 23 JoWls,M. and de Kloet, E. R. (1990) Proc. NatlAcad. Sci. USA 87, 4495-4498 24 JoWls, M., Hesen, W. and de Kloet, E. R. (1991) J. Neurosci. 11, 2288-2294 25 Karst, H. and Joi~ls, M. (1991) Neurosci. Lett. 130, 27-31 26 Nicoll, R. A., Malenka, R. C. and Kauer, J. A. (1990) Physiol. Rev. 70, 518-565 27 Lopes da Silva, F. H., Witter, M. P., Boeijinga, P. H. and Lohman, A. H. M. (1990) Physiol. Rev. 70, 453-511 29

28 Rey, M., Carlier, E. and Soumireu-Mourat, B. (1987) Neuroendocrinology 46, 424-429 29 Reiheld, C. T. and Teyler, T. J. (1984) Brain Res. Bull. 12, 349-353 30 Rey, M., Carlier, E. and Soumireu-Mourat, B. (1989) Neuroendocrinology 49, 120-125 31 Vidal, C., Jordan, W. and Zieglgansberger,W. (1986) Brain Res. 383, 54-59 32 Shors,T. J., Seib,T. B., Levine,S. and Thompson, R. F. (1989) Science244, 224-226 33 Shors,T. J., Levine, S. and Thompson, R. F. (1990) Neuroendocrinology 51, 70-75 34 JoEIs,M., Bouma, G., Hesen,W. and Zegers,Y. (1991) Brain Res. 550, 347-352 35 Saito, N. et a1. (1989) Proc. Natl Acad. Sci. USA 86, 3906-3910 36 Auricchio, F., Migliaccio, A., Di Domenico, M. and Nola, E. (1987) E/vlBO J. 6, 2923-2929 37 JoWls,M. and de Kloet, E. R. Neuroendocrinology (in press) 38 Munck, A., Guyre, P. M. and Holbrook, N J. (1984) Endocr. Rev. 5, 25-44

books

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I

Cortico-Hippocam pal Interplay and the Representation of Contexts in the Brain Steven E. Fox Dept Physiology, Box 31, State University of New York, Health Science Center, Brooklyn, NY 11203, USA.

30

by Robert Miller, Springer-Verlag, 1991. $70. O0 (267 pages) ISBN 0 387 531092

Miller attempts to do for research on the hippocampal theta rhythm what O'Keefe and Nadel did for research on hippocampal 'place cell' activity; that is, present a comprehensive, testable theory of how it works. He considers the behavioral, physiological and anatomical data suggesting that the hippocampus is providing the brain with its 'sense' of context, and outlines an explicit hypothetical mechanism. The arguments supporting the theory come from an excellent review of the diverse literature on the hippocampal theta rhythm, from its biophysical mechanisms to its relationship to learning. The author assumes that Hebbian isocortical 'cell assemblies' can represent and link stimuli and responses. The cell assemblies are neuronal groups that are presumed to be self organized by a process of synaptic strengthening, which is induced by temporally contiguous activity within a population of neurons having overlapping connectivity. Once an assembly is formed, Miller expects that it can be activated by a subset of the original afferents. He proposes that although cell assemblies can represent simple types of behavior or objects, the connectivity of real isocortical

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39 Etgen,A. M., Lee, K. S. and Lynch,G. (1979) Brain Res. 165, 37-45 40 Nichols, N. R. etal. (1988) 44ol. Endocrino1. 2,284-290 41 Schlatter, L. K., Ting, S., Meserve, L. A, and Dokas, L. A. (1990) Brain Res. 522, 215-223 42 Sapolsky, R. M., Krey, L. C. and McEwen, B. S. (1986) Endocr. Rev. 7, 284-304 43 Moguilevski, M. and Raynaud, J. P. (1980) J. Steroid Biochem. 12, 309-314 44 Funder,J. W., Pearce,P. T., Smith, R. and Smith,A. I. (1988) Science 242, 583-586 45 Edwards,C. R. W. et a1. (1988) Lancet ii, 986-989 46 Hua, S-Y. and Chen, Y-Z. (1989) Endocrinology 124, 687-691 47 Majewska, M. D., Harrison, N. L., Schwartz, R. D., Barker, J. L. and Paul, S. M. (1986) Science 232, 1004-1007 48 Schumacher,M. (1990) Trends NeuroscL 13, 359-362 49 McEwen,B. S. (1991) Trends Pharmacol. Sci. 12, 141-147 50 JoEIs,M. and de Kloet, E. R. (1991) in Aldosterone: Fundamental Aspects (Vol. 215) (Bonvalet, J. P., Farman, N., LombEs, M. and Rafestin-Oblin, M. E., eds), pp. 239-248, John Libbey

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neurons is not sufficiently com- simple, yet it unifies a wide varplex to generate the represen- iety of complex data and uses parts tation of a context. Miller defines of existing hypotheses. A coma context as 'a framework (or prehensive, mechanistic theory background) of information with has been conspicuously lacking. respect to which more specific However, the theory does have "items" of information can be some weak points. The author's identified or manipulated.' He electrophysiological arguments are goes on to define it operationally incomplete. For example, a crucial by suggesting a mechanism for its component of the theory is the representation in the brain. time delays in hippocampo-isoAccording to Miller, a context is cortical loops that approximate represented as a pattern of theta the period of the theta rhythm frequency resonance between the ( - 1 4 0 ms). Miller suggests that hippocampus and a unique, these could be accounted for by widely dispersed group of iso- conduction delays in unmyelinated cortical neurons. Loop delays cortico-cortical axons, but the approximating the theta period average conduction delays alone maximize the positive feedback are probably not sufficiently long. necessary for the self organization The delay in the sequence of of such groups. He argues that relays through the hippocampus, once organized, such groups starting in the entorhinal cortex would have properties similar to and continuing through the subthose of cell assemblies. The iculum, is proposed to be multiple collaterals of a hippo- 40-50 ms. In response to intense campal neuron, which make electrical stimulation, that delay is available hippocampo-isocortical actually more like 20ms. The loops that have different delays author does not discuss the between sequences of relays, effects of natural stimuli that would allow each neuron to par- produce temporal dispersion and ticipate in many different reson- integration delays at each synant circuits. The hippocampus, apse. Only with the inclusion of then, is seen as 'pointing' to the such integration delays is it likely isocortical neurons that actually that the delay could be as long as represent the context. The sep- 40-50 ms. turn is thought to initiate the The intrahippocampal delays rhythm, whereas the resonance leave a remainder of about 50 ms strengthens it. According to this for conduction and integration scheme, pure septally driven times on each side of the hippotheta rhythm occurs during im- campo-isocortical connections. mobility. The isocortical reson- The author contends that corticoance converts it to the type of cortical conduction velocities are theta rhythm associated with 0.15 ms -1. Such values are unmovement. likely to be typical, but values of This is an appealing theory. It is 0.5 m s-1 may be fairly common. TINS, Vol. 15, No. 1, 1992