Immediate-early genes, neuronal plasticity, and memory1

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H. A. ROBERTSON Department of Pharmacology, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, N.S., Canada B3H 4H7 Received December 20, 1991 ROBERTSON, H. A. 1992. Immediate-early genes, neuronal plasticity, and memory. Biochem. Cell Biol. 70: 729-737. The demonstration that the immediate-early gene c-fos is rapidly and transiently expressed in brain following a variety of manipulations has led to intense study of these genes to determine what physiological role they play. The very wide range of stimuli which lead to induction of immediate-early genes (IEGs) in the brain has raised concerns for the specificity of their actions and the suggestion that they might merely be involved in housekeeping functions. On the other hand, there is evidence that these genes may play a role in the transmission of information from cell surface receptors to the genetic material in many instances of neuronal plasticity, including development of seizure susceptibility (kindling), long-term potentiation, drug-induced changes, the phase shift in circadian rhythms, and spreading neuronal depression. In addition to being a putative third (or fourth) messenger involved in transduction of signals to the genetic material, activation of IEGs has proven to be a useful tool for the study of transsynaptic activation of certain neuronal pathways in the brain. Thus, studies on the induction of IEGs are proving to be especially useful in understanding some important functions and properties of the mammalian brain. Key words: immediate-early genes, brain, memory. neuronal plasticity, gene expression. H. A. 1992. Immediate-early genes, neuronal plasticity, and memory. Biochem. Cell Biol. 70 : 729-737. ROBERTSON, La dtmonstration que le gtne prkcoce immtdiat c-fos est exprimt rapidement et transitoirement dans le cerveau suite h diverses manipulations a conduit h l'etude intense de ces gtnes pour dtterminer quel r61e physiologique ils jouent. Le trts large hentail de stimuli qui permettent l'induction des gtnes prtcoces immtdiats (IEG) dans le cerveau a provoqut IYinttrCtpour la sptcificitt de leurs actions et la suggestion qu'ils seraient simplement impliquts dans des fonctions domestiques. D'autre part, il est hident que ces gtnes jouent un r61e dans la transmission de l'information depuis les rkcepteurs de la surface des cellules au mattriel gknttique dans plusieurs cas de plasticitt neuronale dont le dheloppement de la susceptibilitt A l'apoplexie, la potentiation A long terme, les changements induits par les drogues, le changement de phase dans les rythmes circadiens et I'ttalement de la dtpression neuronale. En plus d'are un probable troisikme (ou quatritme) messager engagk dans la transduction de signaux au mattriel gtnttique, l'activation des IEG s'est avtrke un outil utile pour I'ttude de l'activation transsynaptique de certaines voies neuronales dans le cerveau. Ainsi, les ttudes sur l'induction des IEG se sont montrkes particulitrement utiles a la comprehension de plusieurs fonctions importantes et des propriCtCs du cerveau mammalien. Mots clPs : gtnes prkcoces immtdiats, cerveau, mtmoire, plasticitk neuronale, expression des gtnes. [Traduit par la rtdaction]

Introduction Neurons can be viewed as cells which have evolved unique morphological and biochemical properties that permit them to receive, transmit, and store information. While we now know a great deal about how neurons receive and transmit information, we as yet know little about how the information is stored. Theories of the biological basis for long-term changes in the brain have, historically, involved ideas including changes in neuronal connections and even the idea that information storage might somehow be encoded in a macromolecule such as protein or a nucleic acid (for reviews, see Squire 1987; Alkon 1990). The idea that information might be stored in macromolecules gained its credibility from the development of molecular biology and the discovery that species memory (genetic information passed from generation to generation) is encoded in the base sequence of DNA. ABBREVIATIONS: IEG, immediate-early gene; LTP, long-term potentiation; NMDA, N-methyl-D-aspartic acid; . SCN, suprachiasmatic nucleus. as his review is based on a talk and abstract presented at the 34th Annual Meeting of the Canadian Federation of Biological Societies. Printed in Canada / Imprim4 au Canada

However, a series of experiments which claimed, among other things, that base ratios in rat brain were altered following training experiences (Hyden and Lange 1965) and the transfer of conditioned reflexes following injections of RNA from trained Planaria into naive worms (Jacobson et al. 1966) largely discredited this idea. In any event, there was little theoretical underpinning for the idea that memories could be laid down in macromolecules which were then transferable from one organism to another. Thus, the situation remained until about 1985, largely because of this lack of any theoretically coherent basis on this old problem. In 1984, F.H.C. Crick wrote a brief commentary drawing attention to this fundamental problem of neurobiology. Crick asked where is the trace of memory stored? Crick began the answer by adopting the assumption that memory involves alterations in the synapses, an idea popularized by the Canadian psychologist Donald 0.Hebb in 1949 in his book "The organization of behavior." A central point in Crick's analysis was the point that we have a difficulty in finding the trace of memory, because memory is by definition a persistent property (i.e., it lasts years or decades) in a brain composed of proteins which have half-lives measured

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in days or weeks at most. If the building blocks are changed every few weeks, where can the plan be retained? Crick (1984) did suggest ways in which changes in proteins might be permanently retained and such ideas have been pursued by Lisman and others (Lisman 1989). However, Crick left dangling the question, if the trace of memory is not found in protein, where might it be found? At least part of the answer, as we suggested previously (Robertson and Dragunow 1990), might lie in the genetic material. The genetic material is the only permanent part of a cell, and after all, from one point of view, DNA can be viewed as the biological mechanism by which information is stored over time. The problem, in brief, was this. On one hand, we believe that memory and other long-term changes in the brain are based on alterations in synaptic activity. On the other hand, some of these changes persist for years and may involve the genetic material DNA. What then is the link between activity in the synapse and DNA? The answer came from experiments which demonstrated that known neurotransmitters would rapidly and transiently increase expression of a number of genes known as proto-oncogenes. These are now generally described as IEGs because of this rapid but transient induction. Most importantly, the idea that I will present of a molecular basis for memory and long-term change in the brain is one in which the same basic molecular events that regulate growth and development are involved in regulating such long-term changes as memory. The basic idea is derived from a suggestion made by Berridge (1986) that control of both development and memory may be based on changes in gene expression regulated by IEGs. My purpose here is to present some of the evidence which suggests that memory, an important part of the consciousness that Monod (1976) described as one of the final frontiers for mankind, will be soluble in the same molecular biological terms as growth and development. An important part of these mechanisms is the IEGs, which serve as a messenger system between electrical activity in the brain and the genetic material. While exact mechanisms have not yet been worked out, there now exists a framework for studying these problems. Because the focus for the interest in IEGs in the brain has been towards understanding long-term changes, it is the IEGs that encode nuclear proteins that are of the greatest interest. Five of the recognized IEGs encode previously identified transcriptional factors and at least six others encode transcriptional factors encountered only through the study of proto-oncogenes (Bishop 1991). Since mammalian brain neurons are generally thought to be postmitotic, the suggestion is that IEGs may play a role in regulation of gene expression associated with long-term change rather than cell proliferation or development. There is some evidence that these long-term changes can involve regulation of expression of so-called late response genes by IEGs. Within the context of the central nervous system, such late response genes may include nerve growth factor and preproenkephalin (see below). To reiterate, definitive experiments have not yet traced a precise path from IEG activation to memory, but at least we now have a plausible route for such a path. Definitive proof for a role of particular IEGs in learning and memory must await techniques which will allow us to manipulate specific IEG products. At present, evidence is very circumstantial. For example, there is evidence that long-term potentiation, a possible neurophysiological correlate of learning

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TABLE1. Some IEGs encoding nuclear transcription factors Family

fos

jun Zinc finger

Steroid hormone receptor

IEG

c-fos ~OS-B fra-1 fra-2 c-jun jun-B jun-D NGFZ-A (zif/268, egr-I, krox-24) NGFI-C Krox-20 NGFZ-A (nur/77)

(Davis et al. 1992), involves increased expression of c-fos (Dragunow et al. 1989; Jeffery et al. 1990) and NGFI-A (Cole et al. 1989). Likewise, it is known that Dl dopamine receptors are involved in working memory in primate prefrontal cortex (Sawaguchi and Goldman-Rakic 1991) and in rodent caudate (Packard and White 1991; Izquierdo 1992). Activation of Dl dopamine receptors in rat striatum leads to increased synthesis of Fos protein (Robertson et al. 1989), thus suggesting a possible role for c-fos in this aspect of memory formation. Manipulation of particular genes is actually a goal that may be realized in the near future. One highly selective means of accomplishing this is to use antisense oligodeoxyribonucleic acid probes to prevent either gene transcription or translation (the exact mechanism is currently uncertain) for particular genes. Very recently, we have shown that it is possible to interfere with the actions of dopaminergic agonists using an antisense oligodeoxyribonucleic acid probe directed against c-fos (Chiasson et al. 1992; Robertson et al. 1992). This approach, once selectivity and efficacy are established, will provide a powerful technique for manipulating the central nervous system in general and the role of IEGs in particular. IEG induction and the brain: what are IEGs? The first reports on activation of IEGs in the brain referred to these genes at proto-oncogenes. This reflected the history of the discovery of viral oncogenes and the realization that viral oncogenes are merely an attempt by the virus to control cell growth and division by mimicking the cellular genes involved in the control of growth and cell division (see Bishop 1991 for review). Thus viral oncogenes have the prefix v (as in v-fos, for example) to contrast them with the cellular or proto-oncogenes (c-fos, for example) (the c is for cellular). The actual nomenclature of proto- or cellular oncogenes is not yet well organized, in that protooncogenes have been named as found. Thus we have some IEGs that have been described under as many as four names. An example of this is the IEG of the zinc-finger family, which has been variously described as NGFI-A (Milbrandt 1987), zif268 (Cristy et al. 1988), egr-l (Sukhatme et al. 1988), and krox-24 (Lemaire et al. 1988). Oncogenes are often given a three-letter abbreviation reflecting their origin and the type of cancer they induce; the first such gene identified was the Rous sarcoma virus now called src; the fos

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TABLE2. Some neurotransmitters involved in activation of IEGs

Neurotransmitter

Cell or tissue

Ref.

Glutamate Cholinergic (nicotinic) Cholinergic (muscarinic) Dopamine (Dl, DS?) Adenosine Nerve growth factor Calcitonin gene-related peptide

Cerebellar neurons PC-12 PC-12 Striatal neurons Neuron-glia hybrids PC-12 Rat astrocytes

Szekely et al. 1989 Greenberg et al. 1985 Morgan and Curran et al. 1986 Robertson et al. 1989a, 1989b Gubits et al. 1990 Greenberg et al. 1985 Haas et al. 1991

gene is the oncogene associated with viruses that cause osteogenic sarcoma in two closely related mouse strains (FBJ and FBR); the name fos derives from the first letter of the mouse strain coupled with the nature of the tumour induced, osteogenic sarcoma. Table 1 lists a number of the important IEGs which may play roles in the central nervous system. Here I will use the convention of italicizing the names of the genes and using regular letters and numerals (with the first letter capitalized) for the protein products of these genes. In the absence of stimulation, the expression of IEGs is generally low. Following stimulation, transcriptional activation is rapid and transient and the mRNAs transcribed from these genes often have very short half-lives. The subsequent shutoff of transcription requires new protein synthesis; IEGs are, therefore, superinduced in the presence of protein synthesis inhibitors (Sheng and Greenberg 1990). Activation of IEGs is not a unique property of neurons and indeed IEGs were first characterized in nonneuronal cells during attempts to identify genes that might respond to growth factors (Cochran et al. 1983). This resulted in the description of a class of genes whose transcription was rapidly (in minutes), but transiently (usually for a few hours at most), activated following growth factor application. Using differential screening of cDNA libraries from growth factor stimulated cells, a large number of IEGs have been characterized and the number of these, now at about 100, continues to grow. The crucial step linking these growthactivated IEGs to neuronal events was accomplished when several groups at about the same time demonstrated that not only growth factors, but also neurotransmitters and neurotransmitter-related events such as depolarization and calcium influx, will induce transcription of IEGs both in cells in culture (Greenberg et al. 1985, 1986; Morgan and Curran 1986) and in the brain in vivo (Morgan et al. 1987; Hunt et al. 1987; Dragunow and Robertson 1987). Since c-fos was originally thought to be involved in cell division, studies demonstrating c-fos induction in differentiated PC-12 cells and the discovery of fos activation in brain was important in suggesting that IEGs could have a function in postmitotic cells (Greenberg et al. 1986; Morgan et al. 1987; Hunt et al. 1987; Dragunow and Robertson 1987a, 1987b). It is now clear from many studies that neurotransmitters and neuronal growth factors in a number of systems will induce expression of IEGs (summarized in Table 2). Rapid c-fos induction occurs in PC-12 cells following application of elevated K', the calcium channel agonist BAY K8644, or external ~ a (Curran ~ + and Morgan 1985; Morgan and Curran 1986; Sheng et al. 1988), suggesting that c a 2 + , entering through voltage-dependent c a 2 + channels and (or)

L-type c a 2 + channels, is the major second messenger regulating IEG expression. There is also evidence that ca2+-calmodulin dependent protein kinases I and I1 play a role in the transduction of electrical signals to the nucleus, and the CAMPresponse element-binding protein may function to integrate c a 2 + and CAMP signals (Morgan and Curran 1986; Greenberg et al. 1985, 1986; Sheng et al. 1991). Differential regulation of IEGs It is now becoming clear that a variety of IEGs are simultaneously activated by physiological stimulation, neurotransmitters, and growth factors. It has been suggested that various combinations of IEGs could confer specificity of cell response to different stimuli (Sonnenberg et al. 1989a; Sheng and Greenberg 1990; Wisden et al. 1990; Moratalla et al. 1992; Rusak et al. 1992), though there is little or no evidence for thus idea. The best-known example of regulatory interaction between IEGs is the interactions between the fos and jun families. Protein products of members of these two IEG families can interact with each,other to form heterodimeric transcriptional factor complexes via a conserved dimerization domain called the leucine zipper. Briefly, the protein c-Fos dimerizes with c J u n to form a c-Fos-c-Jun transcriptional factor which binds with high affinity and specificity to DNA elements of the consensus sequence -TGACTCA(the AP-1 site) and this thus leads to the activation of nearby promoters by an unknown mechanism (Curran and Franza 1988). However, it is clear that the situation is even more complicated than a large number of IEGs activating transcription, because some heterodimeric combinations are transcriptional inhibitors. The heterodimer formed by c-Fos and Jun-B (the protein product of the jun family member jun-B) represses transcription of genes with AP-1 sites in the promoter region (Chiu et al. 1989; Schutte et al. 1989). Moreover, the situation is made more complicated by the fact that c J u n is an efficient activator of the c-jun promoter, while Jun-B inhibits activation of the c-jun promoter. Thus Jun-B is a negative regulator of c-jun (Chiu et al. 1989). Since there are three mammalian Jun proteins (c-Jun, Jun-B, Jun-D) and at least four Fos family members (c-Fos, Fos-B, Fra-1, Fra-2) to which the Jun proteins can bind, there exists a large number of possible combinations of Fos-Jun proteins. In addition, there is also the possibility of Jun-Jun and Fos-Fos homodimers with unknown potentials. Other members of the two families also probably have unrealized potentials. For example, it has recently been shown that a truncated form of Fos-B inhibits the transcriptional activation of Fos-Jun heterodimers (Nakabeppu and Nathans

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1991). Similarly, Fra-1 can combine with Jun and bind to the AP-1 recognition element, raising the possibility that this Fos family member might play a role in regulation at the AP-1 site (Cohen et al. 1989). Finally, it is now becoming apparent that Fos-Jun can regulate other receptors; for example, Fos and Fos-Jun can inhibit the glucocorticoid receptor (Touray et al. 1991) and, in turn, other factors such as retinoic acid (Schule et al. 1991) can regulate AP-1 responsive genes. The issue is further confused because in many studies, as detailed below, especially for neural tissue, stimulation leads to activation of a variety of Fos and Jun family members (in addition to other IEGs). For example, stimulation with Dl dopamine agonists can cause rapid expression of c-fos, c-jun, and jun-B in striaturn. Are these IEGs all in the same cell or, more attractively, are c-fos and c-jun expressed in one type of cell leading to transcriptional activation, while in another cell c-fos and jun-B expression is producing transcriptional inhibition? It is clear that the answers to such questions are of great importance. However, in some tissues, such as the dentate granule cells after seizure activity, it seems clear that c-fos, c-jun, and jun-B activation all occur in the same cells (H.A. Robertson, unpublished observations). In addition to this complexity, it is now suspected that the so-called flanking sequences to the AP-1 site play an important role in the binding of Jun proteins to the AP-1 site (Ryseck and Bravo 1991). It is important to note that AP-1-like sites are sometimes common and it is not immediately obvious which sites might be active (see Hengerer et al. 1990, for example). It is also clear that differential regulation of IEGs does occur and there are several instances where c-fos is expressed in the absence of c-jun or together with jun-B rather than c-jun (Bartel et al. 1989; Naranjo et al. 1991). Indeed, there are now known to be instances where the c-jun message is expressed following stimulation, but no c-Jun protein appears to be expressed, suggesting among other possibilities that IEG protein levels might be regulated at the transcription level (Rusak et al. 1992). In summary, it is now clear that the simple picture of activation of IEGs that encode nuclear proteins which regulate gene expression is misleading. The more accurate picture has been described as regulation by committee, a series of IEGs, and members of various families, all interacting with one another and with other second and third messengers to affect several transcriptional regulating sites and thus altering gene expression. What has become clear is that these genes probably play a role in postmitotic tissue, the best example being neurons in the brain. However, it should be kept in mind that some IEGs may perform not as messengers in tightly linked signalling systems but as "housekeeping" genes, regulating the response of cellular metabolism to particular alterations in conditions. It is remarkable to note, for example, the similarity between the activation of c-fos in cerebral cortex ipsilateral to a lesion (Dragunow and Robertson 1988; Herrera and Robertson 1989, 1990~)and the activation of the heat shock protein HSP-71 (Gonzalez et al. 1989). However, having raised this caution, it is clear from a number of examples in the brain that there is good circumstantial evidence that c-fos and other IEGs play an important role in the transduction of neuronal stimulation into specific neuronal changes (plasticity); this neuronal stimulation can be elicited by physiological (e.g., light, pain) or pharmacological means.

IEG activation as a mapping tool for the brain From the early studies done by Hunt et al. (1987) on the effects of pain on the induction of c-fos in spinal cord, it has been apparent that, apart from the importance that the IEGs might play in cellular function in brain systems, the robust response of the IEGs might be generally useful as an indication of transsynaptic activation and in the mapping of polysynaptic pathways in the brain. This usefulness has generally been confirmed in subsequent studies (Sagar et al. 1988; Rusak et al. 1990, 1991;MacDonald et al. 1990). This, of course, does not detract from the significance of IEGs as possibly extremely important third or fourth messengers in signal transduction. However, it does make monitoring IEG activation into something that has the potential of a second messenger labelled with horse-radish peroxidase. Expression of IEGs in the mammalian brain seizures, kindling, and LTP Induction of IEGs has now been demonstrated in a number of systems in the brain and in association with a number of neurotransmitter systems. The initial studies that suggested an important role for IEGs in the brain described activation of c-fos and other IEGs in the brain following drug-induced seizure activity (Morgan et al. 1987; Dragunow and Robertson 1987a; Saffen et al. 1988; Le Gal La Salle 1988; Sonnenberg et al. 1989~).A single electrical stimulus to amygdala or hippocampus (at an intensity known to lead to the long-lasting effect known as kindling) will also produce an increase in c-fos protein in the hippocampal formation, with an especially high concentration in the dentate granule cells (Dragunow and Robertson 1987a; White and Gall 1987; Dragunow et al. 1988). There is a continuing discussion over the possible role of c-fos and other IEGs in the phenomenon of LTP. LTP refers to the persistent (up to several weeks) increase in the excitatory postsynaptic potential elicited at synapses following a high frequency stimulation of afferent neurons. Our early studies suggested that LTP could develop in the absence of c-fos induction (Douglas et al. 1988) and this was confirmed by Cole et al. (1989) and Wisden et al. (1990) who did, however, demonstrate a correlation between LTP and induction of NGFI-A. Surprisingly, LTP induced using burst stimulation involves c-fos induction, but LTP induced by the same number of stimulations evenly spaced over the same train duration (i.e., LTP induced by the same number of stimulations, but with different spacing) is not associated with increases in Fos protein (Dragunow et al. 1989). However, all earlier studies were done on anesthetized animals, and more recent studies on the development of LTP in unanesthetized animals revealed that in this situation c-fos induction accompanies LTP induction (Jeffery et al. 1990). From all this work, several points are clear. First, we already know that LTP develops in milliseconds, while c-fos mRNA only appears after between 10 and 15 min, with c-Fos protein appearing shortly later. The same is true for other IEGs. Thus, while it remains possible that the IEGs play a role in maintenance of LTP (see Jeffery et al. 1990), it seems unlikely that the IEGs play any role in induction of LTP. Second, some stimulation parameters produce LTP with c-fos activation and others produce LTP without c-fos activation. This suggests (as was already suspected) that there

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TABLE 3. Some possible associations between drug-induced activation of the IEGs and pathophysiological effects of dopaminergic drugs

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~

-

Effect

IEG activator

Drug class

Ref.

Dystonias Tardive dyskinesias Drug addiction

L-Dopa Haloperidol Amphetamine, cocaine

Dl dopamine agonists D2 dopamine antagonists Psychostimulants

Robertson et al. 1989a, 19896 Dragunow et al. 1990 Graybiel et al. 1990

are different types of LTP, differing perhaps in persistence or other properties. The kindling model is interesting in that, unlike LTP, induction of kindling appears to be a permanent change in the brain (see Cain 1989, for a review of the differences between kindling and LTP). A kindling stimulus will activate c-fos in the dentate granule cells and in the hippocampal pyramidal neurons (Dragunow and Robertson 1987a; White and Gall 1987). Other IEGs (c-jun, jun-B, NGFZ-A) are also activated by the kindling stimulus (H.A. Robertson, unpublished). It is known that kindling stimuli lead to synaptic reorganization in the molecular layer of the dentate gyrus of the hippocampus (Sutula et al. 1988). Kindling has also been shown to produce increased synthesis of neurotrophic factors in the dentate gyrus (Ernfors et al. 1991; H.A. Robertson, unpublished observations), and Funabashi et al. (1988) demonstrated that injections of antibody against nerve growth factor into the cerebral ventricals during stimulation would prevent kindling. At least in one other system, IEGs appear to play a role in the regulation of nerve growth factor synthesis (Hengerer et al. 1990, see below). Thus, it is reasonable to suggest that IEG induction may be the first step in a sequence of changes involving secretion of neurotrophic factors and synaptic reorganization, culminating in a permanent alteration in the susceptibility of this part of the brain to seizures. Generalized seizures are accompanied by a marked activation of IEGs, especially in the hippocampus and the dentate gyrus (Morgan et al. 1987; Dragunow and Robertson 1987b; Le Gal La Salle 1988; Crosby et al. 1991, and others). However, a generalized seizure in a small mammal can also include changes in cerebral blood flow and (or) cerebral ischemia. It is difficult accordingly to know what part ischemia plays in the effect. Dopamine and IEG activation Dopamine plays a pivotal role in the regulation of the control of movement by the striatum (caudate-putamen). When dopamine neurons are lost (as in Parkinson's disease), there is a profound loss of control of motor function. Dopamine is also thought to play a similar part in higher functions, and disorders of dopaminergic neurotransmission are generally assumed to lie behind the schizophrenias and may also contribute in large part to the disturbances of both thought and movement seen in Huntington's chorea. Activation of c-fos in an animal model for Parkinson's disease was first demonstrated using the antiparkinsonian drug L-Dopa (the immediate precursor of dopamine) and drugs selective for the Dl dopamine receptor (Robertson et al. 1989a, 19896; Paul et al. 1992). After exposure to L-Dopa or a Dl dopamine agonist, c-Fos protein was found only in the regions of the brain (striatum) that were experimentally depleted of dopamine and where dopamine receptors were

known to be supersensitive. Significantly, activation of IEGs appears to be a Dl dopamine receptor linked function (Robertson et al. 1989b). Compounds that act indirectly to release dopamine (such as cocaine and amphetamine) also increase expression of c-fos and other IEGs in striatum via D l dopamine receptors (Robertson et al. 19896; Graybiel et al. 1990; Young et al. 1991; Moratalla et al. 1992). It is most important to note that while amphetamine and cocaine activate IEGs in naive, untreated animals, directly acting Dl dopamine receptor agonists only induce IEG transcription in supersensitive tissue. Thus, even high doses of a Dl agonist or apomorphine will not produce IEG expression in animals which have not been depleted of their dopamine content. While D2 dopamine agonists apparently have little effect on IEG activation, it is significant that the combination of a Dl and a D2 dopamine agonist has synergistic effects on induction of c-fos, c-jun, jun-B, and NGFI-A (Paul et al. 1990, 1992), reminiscent of the synergism seen in studies on locomotion in animal models for Parkinson's disease (Robertson and Robertson 1986, 1989). Moreover, while c-fos activation in the striatum following Dl agonist stimulation is spread over the entire striatum, the combination of Dl and D2 agonists produces a pattern which reveals the compartmentalization of this brain region (Paul et al. 1992). This once again illustrates the fact that IEG activation is a potent tool for studying the anatomical organization of neuronal structures. Another potentially very important, and at the same time surprising, finding was c-fos induction following administration of D2 dopamine receptor antagonists such as haloperidol (Dragunow et al. 1990; Miller 1990). These drugs are widely used in the treatment of mental disorders such as schizophrenia. The finding then of IEG activation by these drugs in clinically relevant doses suggests the possibility that either the beneficial effects or some of the side effects of these drugs might be mediated by changes ingene expression. Both the symptoms of schizophrenia and the development of some side effects of these drugs have time courses consistent with alterations in gene expression. Dopaminergic drugs play a central role in drug addiction and the use of such drugs is associated with significant side effects (see Table 3). Some of these effects (drug addiction, tardive dyskinesia) are very long-lasting effects, and it is tempting to suggest that IEG activation and consequent changes in gene expression might play a role. There is yet, however, no firm evidence for these suppositions.

IEGs and neuroendocrine control Early studies noted activation of c-fos in neurons in paraventricular hypothalamus following osmotic stress, suggesting that monitoring IEGs may be a useful method for following manipulations of the neuroendocrine system

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(Sagar et a/. 1988; Herrera and Robertson 1990a). This has indeed proven to be the case and Fos immunohistochemistry has been useful in demonstrating activation of the arcuate nucleus by NMDA receptor agonists (MacDonald et al. 1990) and the activation of luteinizing hormone-releasing hormone neurons during the oestrous cycle in rats (Lee et a i 1987). IEGs and control of circadian rhythms In mammals. the SCN is the site of the central control mechanism forihe regulation of circadian rhythms (Rusak and Zucker 1979). The clock in the SCN is set (entrained to the environmental lighting) by neurons in the retina which project to the SCN. Exposing an animal to light during its dark phase will alter or shift the circadian rhythm. Exposing rats or hamsters to light during the night will result in the induction of c-fos and NGFZ-A (Rusak et a/. 1990) and other IEGs (Rusak et a/. 1992). Most importantly, light will only induce c-fos during the expected dark phase in animals kept in total darkness. Such animals continue to maintain the circadian rhythm established before they were placed in total darkness. During the expected light phase, exposure to light will not lead to the induction of c-fos and other IEGs (Rusak et a/. 1990, 1992). There is also a good correlation between the intensity of the light required to produce the physiological effect (a shift in the circadian rhythm) and the induction of mRNA production (Kornhauser et a/. 1990). There is some evidence that the photic induction of IEGs in the SCN is regulated by glutamate receptors of the NMDA type, at least in part (Abe et a/. 1991). The mechanism which prevents light stimulation from inducing the IEGs during the subjective day is pretranscriptional, but otherwise unknown. Feasible mechanisms include the possibilities that the retinal ganglion cells do not transmit the information or that the receptors in the SCN themselves exhibit rhythmic sensitivity. As it appears that the NMDA type of glutamate receptor is at least involved, another possibility is that the sensitivity of the NMDA receptor is being regulated via alterations in the depolarization state of the SCN neurons by another endogenous or exogenous factor. Damage-induced activation of IEGs Since damage to tissues often produces homeostatic responses which include the release of growth factor and induction of cell proliferation, the discovery that brain damage will produce widespread activation of c-fos (Dragunow and Robertson 1988) was not surprising. Indeed, early experiments attempting to look at the activation of IEG synthesis in slices had been compromised by the fact that the process of preparing the slice produced a maximum activation of IEG expression (S.P. Hunt, personal communication). Similarly, when first reported, damage-induced activation of IEGs in brain in vivo was (and is) a serious complication for in vivo experimentation. It meant that introduction of a cannula or an electrode into brain, by itself, produced significant IEG expression. Furthermore, induction of IEGs was seen not only adjacent to the site of damage, but often in parts of the cortex remote to the damage (Dragunow and Robertson 1988; Herrera and Robertson 1989, 1990a, 1990b). Surprisingly, for c-fos, this activation was confined to the damaged hemisphere and was sensitive to NMDA receptor antagonists (Herrera and Robertson 1989, 1990a, 1990b; Dragunow et a/. 1990;

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Traboulsee et al. 1991). There is at least some circumstantial evidence that damage-induced IEG activation in cerebral cortex is partially the result of spreading neuronal depression (Herrera and Robertson 19906). It must be kept in mind that the IEGs may also play a role in repair after an insult of some sort (ischemia, a physical wound, etc). It remains absolutely essential that this be kept in mind when designing experimental paradigms to test the role of IEGs in a particular physiological system. IEGs and changes in gene expression The excitement associated with the discovery of IEG activation in the instances cited above (and many others as well) is that we now have a key for the problem of how neuronal activity might alter gene expression. There is, however, very little direct evidence for such changes and what evidence we have is circumstantial. For example, a kindling stimulus activates c-fos expression, but there is no direct evidence that c-fos expression is absolutely required for kindling to occur. Similarly, light exposure during the dark phase leads to IEG expression in the suprachiasmatic nucleus, and in every instance studied so far, there is a relationship between IEG activation and the phase shift in the circadian rhythms. But this cannot be construed as other than circumstantial. On the positive side, there are several situations where we can say that IEG expression can lead to changes in gene expression. For example, the availability of mice with a transgenic c-fos linked to a metallothionine reporter has been used by Thoenen and his colleagues (Hengerer et a/. 1990) to demonstrate that activation of c-fos in fibroblasts in sciatic nerve precedes nerve growth factor synthesis. Furthermore, they were able to show that an AP-1 site in the first intron of the nerve growth factor promoter is necessary for nerve growth factor synthesis. It is interesting to note that there are eight AP-1 sites in the promoter region of nerve growth factor in the mouse, but only one, apparently, is essential for nerve growt factor synthesis. There is also a suggestion that the proenkephalin gene may be up-regulated via a AP-1 site present in its promoter (Sonnenberg et a/. 1989b). However, such regulation of proenkephalin is probably complex, involving several other control elements (Comb et a/. 1988). It is clearly most important to define the nature of the late response genes. Are there any long-term changes that result from activation of IEGs? What are these changes and how are they carried out? The other task is to show conclusively that the IEGs are involved (or not involved) in longor short-term changes in function. Acknowledgements I am grateful to the Medical Research Council of Canada (MT 10402 and MT 10644) and the Human Frontier Science Organization for their support, and to Drs. Ben Rusak, Stephen Hunt, and Ann Graybiel for their discussions. Abe, H., Rusak, B., and Robertson, H.A. 1991. Photic induction of Fos protein in the suprachiasmatic nucleus is inhibited by the NMDA receptor antagonist MK-801. Neurosci. Lett. 127: 9-12. Alkon, D.L., and Nelson, T.J.1990. Specificity of molecular changes in neurons involved in memory storage. FASEB J. 4: 1567-1576. Bartel, D.P., Sheng, M., Lau, L.E., and Greenberg, M.E. 1989. Growth factors and membrane depolarization activate distinct

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