The locus coeruleus cortical plasticity

T I N S - September 1978

5'3

The locus coeruleus cortical plasticity John D. Pettigrew i

i

lu

i

The blue spot in the brainstem, the locus coeruleus, may play an important role in the memory of events which have survival value. Not least, this may occur at early sta~es of development of d~fferent cortical regions. The noradrenergic output of this nucleus appear~ to convey plasticity to the cortex, until, as John Pettigrew proposes, such time as the serotonergic output frgm the raphe nuclei develops sufficiently to override these plastic effects. The nucleus locus coeruleus has always sors to have gone on endlessly memorizing received attention because of the bluish the details of contours on the ceiling of his concentration of copper-containing lair if he were lying there safe. sound, and enzymes which makes it visible in fresh satiated; but that it wouldhave made evolupontine sections of some species and which tionary sense to record even apparently provoked its name 'blue spot'. The nucleus 'trivial" sen+ory details associated with a has attracted an increasingly large circle of life-threatening encounter, for example. The students since the discovery that each of neuronal substrat¢ of the strong emotion its neurones has extraordinarily wide felt in the latter situation would also turn ramifications within the central nervous on the storage mechanism, presumably by system. This discovery was made by tr:e enabling synaptic modification to take Swedish group s wi th their histofl uorescence place at the diverse cortical sites of sensory method, a technique making it possible to inflow: Kety proposed that this neuronal trace the profusely-branching characteris- substrate was in fact the monoaminergic tic, green-fluorescent, noradrefiergic axons fibre system, of which the locus coeruleus of locus coeruleus neurones to, the far is the noradrenergic representative. The difficulty in testing such notions lies orners of the nervous system. The ratker small number of neurones involved and not so much with techmcal problems of the fact that each neurone appears to send manipulating the locus coeruleus and its branches to such widely separated destina- pathway, for which a profusion of fairly tions as tbc- spinal cord, cerebelFam, sharp pharmacological tools is available. diencephalon, and cerebral corW.x, suggest but more wi'th the choice of the approthat the fimcfionai role played by ~uch a priate parad;gm of information storage system mu':;t be of a rather global, regula- within the nervous system on which to test a tory kind. Such an executive role is com- possible role for the locus coeruleus. For patible with its links to the sleep-wakit,g example, learning-paradigms encompass a rhythm and with the high-level information range of diverse phenomena with little being supplied to the locus coeruleus, informatien available about the underlying whose inputs have yet to be worked out in neural basis. Some suffer uncertainties detail, but may, among others, include about whether they indeed involve informinformation sampled from most of the ation storage at all and the negative effects of locus coeruleus manipulations in these cerebral mantle via the hippocampus ~.8. cases are complicated to interpret. Survival role? One functional role for the locus coeruleus which is teleologically appealing has been proposed by Kety 8. According to his formulation, there arose during evolution of the brain a subsystem which identified situations of great survival value and sent out an ins~ruc:aon that incoming sensory information at such times was to be stored for later retrieval - a 'now print' decision to use the late James Olds' term for it, or a "to whom it may concern' message, to use T. J. Crow's. By analogy it is easy to see that it would have made little sense for one of the brains of our predeces-

Paradigm for study However, a promising new line of investigation on the locus coeruleus uses the paradigm of visual cortical plasticitx in neonatal kittens. This involves a study of the properties and afferent connections of single neurones in the visual cor'.ex of cats whose earb visual experience has been limited by some form of visual deprivation procedure, such as a unilateral eye closure or rearing in a striped drum. Such studies reveal a remarkable degree of plasticity in the developing visual system of kittens, monkeys, and even some birds.

Neuronal response properties reflect the nature of the rearing, e.g. monocularlydeprived cat~ do not have the :~stal complement of binocularl:]-acti-'ated neurones, instead most neurones are origen exclusively by the eye which had been open. This approach wa,: intr,3duc~.'d by Wiesei and HubeP and is aow supported by a host of associated physiological. anatomic~'l, and behavioural obser~:~tion.~ on the virtually permanent chan~.,.es in neural connectivity which fol!o~s comparatively brief periods of selected ~isual exposure during a narrowly-dehned postnatal ('critical') period. (Indeed. in ~: number of striking cases, the experimenters, on the basis of cortical recording, accurately guessed the visual environment to which kittens had been exposed in the early months, in spite of the fact that there had been up to 3 )'ears subsequ,:nt experience in a normal em, ironment.) -[he plastic cha.ages in x.isual cortical c,.mt~cctivity produced b~ early selected ~i.qual exposure represent an une~uivocul t\wm of information storage, albeit of a somewhat unusual kind. Opinion i~ divided about the fu:ctiunal significa'ace of xisual cortical plasticit? for normal d..~velopmen'.. :,ome authors regarOing the anatomical and physiological changes produced by deprb, ation a, pathological or degeneraw, e. Ho,.~e~e'-. it is likely that the critical period el ,,isual cortical plasticity represents a time v, ben an animal might be benefitted by normal visual experience, as well as handicapped ~f,, isual experience is limited, ant' con~tructi,,e roles fc,r the critical period during normal development have been put forward". Whether visual cortical plasticity is involved in information storage during normal development or not. there is no doubt that it provides a means for longterm storage of detailed information about particular visual deprivation procedures, as attested by the large number of consisteu and detailed observations on monocular dr.privation (to take the best known example 1.

Role of the catecholaminergic system Monocular deprivation was the paradigm of visual cortical plasticity chosen by Kasamatsu and Pettigrew 7.t° to investigate a possible role for the locus c,,eruleus. In initial experiments they lesioned the whole neocortical arborization of the catecholaminergic system with intraventricular injections of 6-hydroxydopamine (6-OHDA) u in young kittens to assess the effects of such treatment on the response of cortical neurones to moi~ocular deprivation, lntraventricular injections El.~vicrlNorth-Holland Biomedical Press 1978

74 without affecting neighbouring regions. With this technique it was possible to restore plasticity of localized regions of the cortex by perfusing with noradrenaline. For example, noradrenaline applied locally reversed the effects of prior 6-OHDAtreatment in monocularly-deprived kittens. The region of the visual cortex reached by the noradrenaline had neurones dominated by the open eye, whereas surrounding neurones were binocular. Surprisingly, local noradrenaline perfusion also restored some degree of plasticity to the cortex of adult cats outside of the accepted limits of the critical period. Such cats showed a change in binocularity after a week of eye occlusion in those regions perfused with noradrenaline, like that seen following a few days' occlusion in kittens at the peak of critical period. Unperfused regions of the cortex were unaffected by the eye occlusion, with a normal distribution of binocular neurones as expected on the basis of the age of the cats. The loss of binocular connectiuns seen in the cortex of monocularly-deprived adults perfused with noradrenaline was not seen in the cc.rtex of noradrenalineperfused adult cal:s given normal binocular experience. The role of noradrenaline thus appears to be modulatory, or permissive, and does not it,.elf cause the change in connectivity. The reorganization ofconnections only occurs in the presence of both the amine and the abnormal pattern of activity in the visual pathway to the cortex. If the locus coeruleus an.d its noradrenergic projections make an important contribution to the high level of plasticity which characterizes the critical period, then a high-priority task for the future will be the determination of factors governing the excitability of the nucleus on a much more extended time-scale than those in present use to monitor neuronal activity. In this connection it is intriguing that the locus coeruleus is one of the very few brainstem nuclei whose neuronal number shows a decline with age. Plasticity restored Even with more knowledge about While the results with intraventricuiar patterns of activity in the locus coeruleus it 6-OHDA are consistent with a hypothesis is unlikely that the termination of the linking cortical plasticity with the nora- critical period in the: visuat cortex will be drenergic innervation from the locus readily accounted f o r in terms of the coer deus, they are not conclusive of such a noradrenergic projection. This may derole. The widespread nature of the changes velop early enough to explain the onser of following intraventricular administration the critical period but it appears to make interpretation difficult, particularly continue functioning long after the crkical with rel;ard to possible s~tes of action of the period ends. In addition, since critical effect. In attempts to narrow down the periods are almost certainly not synchropos~.ibiities, Pettigrew and Kasamatsu nous in different cortical areas it is difficult used the recently-developed osmotic mini- to see how the rather uniform cortical pumps to perfuse small areas of cortex projection of the locus coeruleus is corn-

were chosen in prefere,~ce to a direct attack with 6-OHDA upon the cell bodies of locus coeruleus neurones since the latter have a widespread distribution throughout the pons of the cat, in contrast with their more localized grouping in primates and rodents. Attempts to lesion the whole Iocuz coeruleus in kittens would have been fraught with even more problems than were experienced with assault of the axonal arbors during this period of rapid growth. The large doses of 6-OHDA needed for ~uccess with the intraventricular approach (10mg cumulative) were a source of concern to the investigators and a source of horror to referees accustomed to the much lower doses use.d in work with 6OHDA on rodents. However, in kittens, even at these huge doses of 6-OHDA, catecholamine levels tended to increase in ~he pons, where the locus coeruleus neurones, deep enough to be protected from the direct effects of the toxin, were presumably reacting to the damage inflicted upontheir axonal endings in the cortex. Kittens monocularly-deprived subsequent to this kited of 6-OHDA treatment are unaffected by the deprivation procedure as judged by the normal binocular responses recorded from visual cortical net:rones, in cor, trast with recordings from vehicle-injected littermates. In these control kittens the vast majority of visual cortical neurones could be driven only by the eye which had been open, as were those of other control kittens subjected to catecholamine-depletion a]'er a period of monocular deprivation. These, and other control recordings from catecholaminedepleted normal ar~imals, suggested that the catecholaminergic fibres make only a minor contribution to the established patterns of connections responsible for visual response properties, but that they might play a major role in facilitating the obscure process by which changes are brought about in patterns of connectivity following visual deprivation.

T I N S - September 1978

patible with the probable heterogeneity of cortical areas with respect to the time taken for each one to show a marked reduction in plasticity. Interaction with the raphe system? Both of these problems may be illuminated by a study of one of the monoaminergic partners of the locus coeruleus in global, regulatory affairs within the brain, viz. the serotonergic ~aphe system. A contrapuntal relationship between the raphe a n d the locus coeruleus has been suggested many times, both on the grounds of functional interrelationships of their neuronal activity, particularly in sleep and wakefulness, but also on pharmacological grounds. In relation to the present discussion, my suggestion is that one role of the serotonergic projections may be to turn off cortical plasticity and thus oppose the hypothesized action of the noradrenergic system in turning on plasticity. The gradual decline in plasticity which marks the end of the criticul period could then be accounted for by the lag in the development of the conical serotonergic .;ystem behind the conical noradrenergic system which has been observed in some cases; variability in the end of the critical period from one cortical region to another could be related to the more heterogeneous nature of the various raphe nuclei and their projections. Such speculations are not idle in that they can readily be tested in the paradigm of visual cortical plasticity, where the behavioural, physiological, and anatomical change~ are almost as striking as a picture of fluorescent monoaminergic neuro'nes. Reading list 1. Amaral, D. G. and Sinnamon, H. M. (1977) Prog. Neurobioi. 9, 147-196. 2. Crow, T. J. (1968) Nature 219, 709-710. 3. Descarries, L., Watkins, K. C. and LaPierre, Y. (1977) Brain ges. 133, 197-22~. 4. Dismukes, K. (1977) Nature 269, 557-558. 5. Fuxe, K., H6kfelt, T. and Ungerstedt, U. (1970) Int. Rev. NeurobioL 13, 93-126. • 6. Hubel, D. H. and Wiesel,T. N. (1977) Proe. Roy. Soe. London Set. B 198, 1-59. 7. Kasamatsu, T. and Pettigrew, J. D. (1976) Science 194, 206-209. 8. Kety, S. S. (1970) In: F. O. Schmitt (ed.), The Neurosciences, Second Study Program,

Rofkefeller Univ. Press, New York. 9. Pettigrew, J. D. (1978) In: C. Cotman (ed.), Neuronal Plasticity, Raven Press, New York. 10. Pettigrew, J. D. and Kasamatsu. T. (1978) Nature 271,761-763. II. Ungerstedt, U. (1971) in: T. Malmfots and H. Thooncn (eds), 6-Hydroxydopamine and Catecholamine Neurons', North-Holland, Amsterdam. J. D. Pettingrew is Associate Professor of Biology at the California Institute of Technology, Pasadena, CA 91125. U.S.A.