Neurobehavioral alterations in autoimmune mice

~

Neumscience and Biobehavioral Reviews, Vol. 21, No. 3, pp. 327-340, 1997 Copyright © 1997 Elsevier Science Ltd Printed in Great Britain. All fights reserved 0149-7634/97 $32.00 + .00

Pergamon

PII: S0149-7634(96)00018-8

Neurobehavioral Alterations in Autoimmune Mice B O R I S SAKI(~, 1 H E N R Y S Z E C H T M A N A N D J U D A H A. D E N B U R G Departments of Biomedical Sciences and Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

SAKIC, B., H. SZECHTMANAND J.A. DENBURG. Neurobehavioral alterations in autoimmune mice. NEUROSCIBIOBEHAV REV, 21(3) 327-340. 1997.-- Inbred MRL, NZB and BXSB strains of mice spontaneouslydevelop a systemic,lupus-like autoimmune disease. The progress of autoimmunity is accompanied with a cascade of behavioral changes, most consistently observed in tasks reflective of emotionalIeactivityand the two-wayavoidancelearning task. Given the possibilitythat behavioral alterations may reflect a detrimental consequence of autoimmune-inflammatoryprocesses and/or an adaptive response to chronic malaise, they are tentatively labeled as autoimmunity-associated behavioral syndrome (AABS). It is hypothesized that neuroactive immune factors (proinflammatory cytokines, brain-reactive antibodies) together with endocrine mediators (corticotropin-releasingfactor, glucocorticoids) participate in the etiology of AABS. Since AABS develops natively, and has a considerable face and predictive validity, and since the principal pathway to autoimmunityis known, AABS may be a useful model for the study of CNS involvementin human autoimmune diseases and by extension, for testing autoimmune hypotheses of several mental disorders (major depression, schizophrenia, Alzheimer's disease, atttism and AIDS-related dementia). © 1997 Elsevier Science Ltd.

1. INTRODUCTION

autoimmune mice in having a congenic MRL/MpJ + / + (MRL + / + ) substrain that develops a later form of disease (207). Recently, an accumulating body of evidence suggests that autoimmune mice, like many patients suffering from autoimmune diseases and SLE in particular, show changes in behavior in parallel with abnormalities in the immune system. This has raised the possibility that study of behavioral alterations in autoimmune mice may help to elucidate the potential biological links between autoimmunity and behavior, documented in SLE of the central nervous system [neuropsychiatric, or NP-SLE; (41)], and proposed in mental disorders, such as schizophrenia (59,114), depression (109,111), autism (230), or Alzheimer's disease (55,57,101). The focus of this paper is to review the current literature on neurobehavioral manifestations in autoimmune NZB, BXSB and MRL strains. The term "neurobehavioral" is used to refer to both neuroanatomical abnormalities and measurable behavioral changes. Although underlying mechanisms are far from proven, immunological factors that are hypothesized to affect behavior in autoimmune disease are discussed. To this end, we highlight the biological impfications of the MRL model.

A U T O I M M U N E disease-prone mice have been made available by selective inbreeding and include MRL, BXSB, NZB and hybrid NZB/W strains. These animals spontaneously exhibit, over varying lengths of time, clinical and serological features which mimic truman systemic autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis and Sj6gren's syndrome (88,132,207). In these conditions the inunune system ceases to tolerate self, allowing for the production of excessive amounts of auto-reactive antibodies (autoantibodies) which bind to various tissue proteins (7),. The binding results in a series of pathophysiological events characterized by immune complex formation and deposition, inflammation, and ultimately, multisystem organ compromise (e.g. renal failure). As part of systemic autoimmune disease, there is also aberrant regulation of various pro-inflammatory cytokines (e.g. interleukin-1, interleeakin-6, tumor-necrosis factor) [for a detailed description of immunological changes in autoimmune mice see (64,207)]. There are differences in autoimmune disease manifestations among MRL, BXSB and NZB strains: e.g. age o f onset, rate of development, severity of symptoms, and sex differences. The mean life span is the shortest in the MRL-lpr substrain and BXSB males ( 5 6 months), while BXSB females can live up to 2 years. The average survival times for NZB mice is 15 months and for NZB/W females and males 8 and 13 months, respectively. The MRL/MpJ-lpr/lpr (MRL-lpr) substrain is unique among

2. BEHAVIORALS~-DmS IN Atrronv~VNE MICE During the last decade, several groups of investigators have examined the behavior of autoimmune mice, aiming

Tel: 905-525-9140 ext. 24012. Fax: 905-522-8804. Abbreviations: ACTH, adrenocorticotropichormone; BRA, brain-reactive antibodies; CRF, corticotropin-releasingfactor; HSP, heat-shock proteins; anti-

HSP Ab, anti-HSP antibodies. 327

328 to understand behavioral adaptations in autoimmunity as well as cognitive dysfunction accompanying age-associated changes in the immune system. Recent results from our and other laboratories indicate that behavior of autoimmune mice changes early, when serologic indices of autoimmunity are manifest (e.g. autoantibody hyperproduction) or before signs of aging and/or systemic involvement become evident. In this paper we use the term autoimmunity-associated behavioral "syndrome" (AABS) rather than the label behavioral "deficit" [e.g. in (14,77,129,193)] because it is possible that not all changes in behavior reflect detrimental consequence of autoimmune/inflammatory processes, but may include adaptive behavioral responses to sickness (71,72). Findings from studies on behavioral adaptation and age-associated cognitive decline in autoimmunity are reviewed elsewhere (3,57,101), we briefly discuss these below.

2.1. Studies on behavioral adaptation in autoimmune disease In 1982 Ader and Cohen reported a study in which they tested the hypothesis that conditioned immunosuppression has an impact on the development of autoimmune disease (1). NZB/W mice were given a saccharin solution by pipette and then were injected with either an immunosuppressive drug (cyclophosphamide, CY) or saline according to a Pavlovian conditioning paradigm. Animals that had received paired exposures to saccharin and CY showed a delay in the onset of autoimmune disease in response to mere presentation of saccharin, indicating that saccharin became an effective conditioned immunosuppresant. Although the physiological mechanism by which the conditioned stimulus (CS) exerted this immunosuppressive effect was unknown, the results suggested that pharmacologic treatments with toxic drugs (such as CY) need not be continuous but could involve a therapeutic regimen in which a placebo acquired immunomodulatory properties. The same research group reported that NZB/W mice did not develop conditioned taste aversion when CY was used as the unconditioned stimulus (US), but they did when lithium-chloride was the US (2). Similar results were obtained when MRL mice were tested (61). That is, when CY was used as the US, diseased autoimmune MRL-Ipr mice showed poorer taste aversion learning than control MRL + / + mice, but did not differ from controls when lithium-chloride was used. Moreover, before indices of autoimmunity appeared, the substrains showed no differences in conditioning to CY. These findings implied that diseased mice somehow recognize the positive effects of an immunosuppressive drug. This hypothesis was supported in subsequent experiments: water-deprived and nondeprived MRL-lpr and MRL + / + mice were given a CY solution to drink; diseased MRL-lpr voluntarily drank more than asymptomatic MRL + / + mice but only at an age when clinical lupus-like disease was manifest (62,63). Taken together, the above studies with classical conditioning and learning paradigms suggested that the immune system is subject both to conditioned and unconditioned behavioral regulation.

SAKIC, SZECHTMAN AND DENBURG

2.2. Studies on learning~memory deficits produced by altered immunity during aging The fact that autoimmune phenomena and cognitive deficits occur at a higher rate in aging led to an hypothesis that autoimmunity plays a role in age-associated cognitive decline. In particular, a higher incidence of brain-reactive autoantibodies (BRA) in serum and cerebrospinal fluid in elderly people and Alzheimer's patients suggested that the development of autoimmune process with age may be a key factor in the etiology of dementia [reviewed in (55)]. Given that MRL, NZB and BXSB mice have a relatively short life span and produce antibodies reactive to nervous tissue, the links among aging, cognitive dysfunction and autoantibodies (especially BRA) have been examined in these strains. In 1983 Nandy and colleagues reported an age-associated correlation between learning deficits and serum BRA (129). The one-way step-up avoidance paradigm was used to assess learning capacities of 2-20-week-old NZB mice. These animals, showing a high concentration of BRA in serum, were virtually unable to learn the active avoidance response, as evidenced by poor avoidance of the aversive stimulus (foot shock) at all ages. A similar problem was observed in control C57BL mice, but only in aged animals. From the results obtained, the authors proposed that autoimmune mice may serve as a useful model to study presenile dementia, highlighting the importance of BRA in cognitive decline. Learning of active avoidance was also impaired in two other autoimmune strains, MRL-Ipr and BXSB, which, like NZB, show an early onset of autoimmunity (56). Impaired performance in the active avoidance paradigm was accounted for by two major factors: aging, which was related to long-term memory deficits, and autoimmunity, which was associated with acquisition (learning) of the active avoidance response. In summary, these studies suggested that aged autoimmune mice are deficient in learning an active avoidance. However, it appeared that these animals had a task-specific reduced capacity for learning since their performance in taste and passive avoidance paradigms was not deficient (2,61).

2.3. Studies on the autoimmunity-associated behavioral syndrome (AABS ) The behavioral consequences of autoirnmune disease in animals have been discussed previously (165). The following section updates this topic by providing new evidence on behavioral manifestations in autoimmune strains and suggesting immunopathogenic mechanisms not previously taken into consideration.

2.3.1. NZB and NZB/W mice. The first report that explicitly proposed a causal link between autoimmunity and behavioral profile was published in 1986 by Spencer and colleagues (193). NZB autoimmune-prone mice were tested in a battery of behavioral tests including a neurological examination of simple reflexes and three learning/memory paradigms (taste aversion, passive avoidance and active avoidance tests). It was observed that in comparison to non-autoimmune CFW controls, 7 10-month-old NZB mice showed a "slight sensorimotor

NEUROBEHAVIORAL ALTERATIONS IN AUTOIMMUNE MICE disadvantage" which manifested itself as impaired motor coordination on a rotating rod, reduced locomotion in an open-field, and slower tail flick response to a noxious stimulus. In addition, the NZB group performed more poorly in the passive/active avoidance paradigms but not in the taste aversion test. Based on their poorer avoidance learning, the authors concluded that NZB mice show cognitive dysfunction unrelated to sensorimotor impairment. When tested in other learning paradigms NZB mice showed deficits in a complex spatial learning task (the Lashley maze) (4"7,171), but superior performance in the water-maze test (202) and in a linear brightnessdiscrimination test (214). 1-)espite apparent discrepancies in performance in two spatial tasks (Lashley maze versus water-maze), the interpretations from two different studies (171,202) were placed in the context of an aberrant hippocampal cytoarchitecVare in the NZB strain (10). Poor active avoidance is the most consistent deficit associated with the development of autoimmunity in NZB mice. This was first shown in a one-way (step-up) test (56,193) and later in the two-way active avoidance paradigm (44). In the latter study, a causal relationship between autoimmunity and avoidance deficit was suggested in a study of fertilized ova transfer from NZB into the uteri of non-autoimmune females, and vice versa. The NZB offspring reared in a non-autoimmune environment showed less severe symptoms of autoimmunity and better learning performance. Conversely, mice reared in a maternal NZB uterine environment developed autoimmunity and performed more poorly in a two-way (shuttlebox) avoidance and a water escape task. This significant negative correlation between the severity of autoimmunity and performance in an active avoidance task was not due to altered sensitivity to foot-shock (168), could not be modified by environmental enrichment (172) and was confirmed using recombinant inbred strains (173). More recently, Schrott and Crnic showed that NZB/W mice can achieve avoidance response when a conflict situation is absent (the one-way avoidance task) or when the two-way avoidance task was made easier by increasing inter-trial period and CS cue salience (170); poor performance in avoidance paradigms (44,56,193) may be related to increased an):iety in this strain, as evidenced by their low preference for open-arms in the plus-maze test and avoidance of central areas in the open-field (33,169). 2.3.2. BXSB mice. In BXSB mice, males develop autoimmunity much earlier than females (in contrast to NZB and NZB/W strains). This accelerated autoimmunity is accounted for by a nmtant Yaa gene on the male Y chromosome (87). Forster and colleagues initially reported a decline in the acquisition of a one-way (step-up) avoidance response in BXSB mice (56). This was later confirmed by others in a two-way avoidance paradigm, although in comparison to consomic BXSB-Yaa + controls, autoimmune BXSB-Yaa mice showed superior discrimination and spatial learning (174). As in the NZB strain, the severity of the avoidance learning deficit correlated with the severity of autoimmunity (44,45). 2.3.3. MRL mice. Given the availability of a congenic MRL/MpJ-+/+ (MRL + / + ) substrain as a genetically appropriate control, as well as the lack of cortical abnormalities reported in other autoimmune strains (179-

329 181), we proposed that MRL/MpJ-lpr/lpr (MRL-lpr) mice can be used to better examine AABS (160). When compared to young, congenic MRL + / + controls (which develop autoimmune symptoms substantially later in life) MRL-lpr mice show a variety of differences in their behavioral profile: lower nocturnal and open-field activity, impaired performance in a psychomotor (beam-walking) task, perseverative responses on a "reversal" water-maze task (160), and longer escape latencies in a spatial learning task (158). The altered behavior in the MRL-lpr group was partially accounted for by the presence of serum brainreactive antibodies (BRA). In particular, the presence of BRA within MRL-lpr mice was associated with slower locomotion, impaired exploration, and thigmotactic swimming (i.e. along the wall of a large water pool) (157). When tested on a battery of tests measuring emotionality (e.g. plus-maze, novel-object test, forced swim tets, step-down test) autoimmune MRL-lpr mice showed significantly different performance from agematched MRL + / + controls (163). This altered behavioral performance could not be related to musculoskeletal pathology (161) and was not evident before the development of severe manifestations of autoimmunity (162). In particular, asymptomatic 4-5-week old MRL-lpr mice explored the open field as much as age-matched MRL + / + controls. However, 8-week old MRL-Ipr mice (already showing serologic abnormalities of autoimmunity) explored the open-field less than MRL + / + controls (160). Some alterations indicative of anxiety and depressive-like behavior (reduced exploration of novel objects, blunted preference for a sweet palatable solution) were prevented by treatment with CY (155,159), thus suggesting a major role for autoimmunity in the pathogenesis of AABS. An impaired performance of MRL-lpr mice in the spatial learning/memory task (Morris water-maze) had been previously reported by Hess and colleagues, and interpreted as a cognitive deficit (77). However, Vogelweid and colleagues did not observe a deficit in the Morris water-maze, but found neurologic problems and impaired performance on a water-escape, distal cue discrimination task and on a food rewarded, proximal cue discrimination task (214). In summary, studies on MRL-lpr mice indicated that altered emotionality and neurological abnormalities should be considered as important factors in accounting for task-specific deficits. 3.

T i m NATURE OF AABS

From the diversity of data obtained in several different learning/memory paradigms, it has become evident that an autoimmunity-associated learning deficit in lupus-prone mice is not global, but rather a strain-, and/or task-specific phenomenon (214). It appears that poor active avoidance learning is common to NZB, BXSB and MRL-lpr strains and moreover, consistently associated with the development of autoimmunity. Although the theoretical basis of active avoidance is not a part of the present discussion [for a review see (24,134)], it is of importance to note that "fear" represents a major factor in active avoidance conditioning (125). Reduction (or elimination) of " f e a r " in this highly conflict situation is necessary (99) because fear may produce immobility (freezing, crouching), thus interfering

330 with the acquisition of an active avoidance response (24). Because of this, the notion that autoimmune mice develop a "cognitive" deficit [e.g. in (56,193)], as evidenced by poor active avoidance performance, should be reconsidered: an alternative hypothesis would propose an autoimmunityinduced alteration in emotional reactivity. The hypothesis that cognitive ability is impaired in autoimmune mice was questioned in our study where 10week old MRL-lpr mice were able to acquire an escape response in the Morris water-maze but showed perseveration bias during extinction and reversal learning (160). It was not clear whether this reflected cognitive dysfunction or represented a trait of "timid" behavior; the latter was suggested by reduced open-field activity and impaired performance on a psychomotor (beam-walking) task. A follow-up study examined whether performance in cognitive tasks deteriorates in parallel with age or progression of autoimmune disease (158). Although latencies to locate the platform in the Morris water-maze were longer in autoimmune MRL-Ipr than in MRL + / + mice, the learning rate (assessed from regression slopes) and memory performance did not differ between MRL-lpr and MRL + / + mice and did not deteriorate with advancing age or increasing autoimmunity. The baseline performance was shifted in diseased MRL-lpr mice, as evidenced by constantly longer latencies to escape to a hidden platform. Thigmotactic swimming in the MRL-lpr group accounted for much of the observed difference in latency at all ages; the results indicated that the acquisition rate of spatial responses was not impaired in autoimmune MRL-lpr mice. Conversely, increased thigmotaxis [considered an index of anxiety (24,208)] supported the hypothesis that emotional reactivity in MRL-lpr mice was increased. Given that the latter hypothesis was derived mainly from measures reflective of general locomotor activity, we turned to paradigms that are less demanding of activity or employ more activity-independent measures (76,153,154). The results obtained in the step-down test, novel-object test, the plus-maze and other paradigms suggested that autoimmune MRL-lpr mice show pattens of behavior which reflect depressive-like behavior and anxiety (163). The most pronounced difference in performance was observed in the forced swim test, in which MRL-lpr mice showed extensive floating. In comparison to age-matched MRL + / + controls, MRL-lpr mice visited the open-arms in the plus-maze less often, defecated less in the open field, and hesitated in stepping down from an elevated platform or in making contact with a novel object. These results directly supported the hypothesis that emotional reactivity is altered during the development of autoimmunity. The same study (163) revealed that MRL-lpr mice with high autoantibody titres hesitated the most to explore a novel object. This led us to hypothesize that the novel object test may be useful to examine the relationship between autoimmunity and behavior. As expected, pretreatment with CY prevented the development of the deficit in the novel object, thus suggesting a causal relationship between autoimmunity and emotional reactivity (159). Intrigued by the possibility that MRL-lpr mice showed depressive-like behavior (163) in a screening test for novel antidepressant drugs (144,145), we tested 16-week-old MRL-lpr and MRL + / + mice in a procedure proposed to measure impaired sensitivity to reward or "anhedonia", a behavioral deficit considered in

SAKIC, SZECHTMAN AND DENBURG humans as the second cardinal symptom of major depression, and one which can be successfully modeled in animals (223). Decreased sucrose intake and a rightward shift of the concentration-intake function suggested that autoimmune MRL-lpr mice are less responsive to a pleasurable stimulus (155). A reduced sucrose intake was found as early as 5 weeks of age and was presumed to be closely related to autoimmunity because CY pretreatment normalized sucrose preference in the MRL-Ipr substrain (156). The hypothesis that the development of autoimmunity affects emotional reactivity is consistent with the evidence previously obtained from NZB mice. For example, these mice locomote less in an open field and leave a brigtly lit compartment sooner in the acquisition trial of step-through passive avoidance (193). Moreover, the hypothesis that autoimmunity alters emotionality helps to account for discrepancies in the literature regarding cognitive performance of autoimmune mice in various learning paradigms. While Forster and colleagues observed that learning performance declined with development of autoimmunity in MRL-lpr mice (56), Grota and colleagues reported normal learning (61). In both studies, the unconditioned stimulus was electric shock, although in one the learning paradigm it was step-up avoidance (56), while in the other it was taste aversion leaming (61). We hypothesized that in what could be regarded as a "timid" MRL-Ipr substrain, electric shock would induce relatively greater immobility ("freezing") thus interfering with the requirements of an active response in step-up avoidance but not of a passive one in taste aversion learning; this would account for the differential learning in the two paradigms (158). Recent results from studies where NZB mice were tested in paradigms reflective of emotional reactivity (plus-maze and novel object test) support the above hypothesis. In particular, Cmic and Schrott have shown that NZB mice can learn a one-way avoidance task (where conflict situation is absent) or a twoway avoidance task if the CS cue salience and trial spacing are increased (170), but none the less show symptoms of increased anxiety, such as less time spent in the open arms of the plus maze, increased freezing behavior, avoidance of central zones of the open-field, and reduced exploration of a novel object (33). Although the hypothesis that autoimmunity primarily affects emotional reactivity early during the course of autoimmune disease appears more viable at this point, the possibility that immune factors impair sensorimotor and specific learning/memory performance during advanced disease cannot be discounted. Studies aimed at determining the behavioral domain primarily affected in autoimmunity have implications in identifying brain structures targeted by the immune system in autoimmune disease. If the hypothesis of autoimmunityinduced alterations in emotional reactivity is correct, then limbic structures would represent a primary focus of interest in examining neuro-immune interactions in autoimmune disease. 4. AASSAND SICKNESSBEHAVIOR It is possibile that AABS (or some aspect of it) reflects "sickness behavior", that has been described to accompany infection, inflammation and fever (72). Sickness behavior refers to a cluster of symptoms which include loss of interest, depressed motor activity, reduced social

NEUROBEHAVIORAL ALTERATIONS IN AUTOIMMUNE MICE interaction, anorexia, adipsia and hypersonmia (94). It has been suggested that sickness behavior may reflect an adaptive, homeostatic response to overcome febrile infections (70,73). A burgeoning body of evidence suggests that cytokine responses to infection not only activate neuroendocrine pathways as seen in acute stress (51), but may also produce sickness behavior (36). Like responses to infection, autoimmune reactions involve an inflammatory cascade in various organs, with release of acute-phase proteins as a result of the actions of pro-inflammatory cytokines (interleukin-1, interleukin-6 and tumor necrosis factor). In autoimmune disease however, there is production of autoantibodies. The appearance of self-reactive autoantibodies (in particular brain-reactive autoantibodies) and the chronic inflammatory response which accompanies it, may represent etiological factors in AABS. It would not be unreasonable to hypothe,;ize that the initial behavioral changes observed during the development of AABS may serve a similar adaptive functions as sickness behavior, while at a later time point AABS may reflect the detrimental consequences of systemic disease. Further research is required to delineate the similarities and differences between sickness behavior and AABS. 5. POSSIBLE FACTORS AND MECHANISMS UNDERLYING AABS

Given the complexity of autoimmune diseases, it is unlikely that behavioral manifestations (both in humans and animals) can be accounted for by a single causal factor. Clinical and experimental studies have largely failed to identify a principal pathogen that produces behavioral alterations during autoinunune disease, thus suggesting that AABS represents a phenomenon mediated by several factors, such as imbalances in cytokines, production of autoantibodies, and chronic inflammation (123). Individual differences in the severity of autoimmune disease, the frequent absence of putatively important autoimmune factors (e.g. brain-reactive antibodies), and different coping mechanisms can accoum for the fact that not all SLE patients (25) and lupus-prone mice show changes in behavior (163). Even within the subpopulation that shows altered behavior there is a considerable variability in severity and specificity of behavioral symptoms (42). Factors which may contribute to the altered behavioral profile seen in autoimmune mice are shown in Fig. 1. These

Genetic difference

\

Endocrine factors (homlones frompituitary, adrenal gonads) glandand

331 are not mutually exclusive, and may in fact interact; they are separated only for classification purposes.

5.1. Genetic factors In earlier studies non-autoimmune strains were often used as control animals to assess the performance of autoimmune mice [e.g. (56,193,202)]. Although substantial and valuable information on AABS has been collected in this way, the inevitable criticism is that such a comparison involves the confounding effect of dissimilar genetic backgrounds on behavioral performance. In other words, it is unclear whether some of observed behavioral differences in autoimmune strains reflect inherited programs, rather than the acquired consequences of autoimmune disease. This problem of a different genetic background of controls has been minimized with the availability of congenic MRL + / + for the MRL-lpr, and consomic BXSB-Yaa+ mice for BXSBYaa animals. The genetic dissimilarity between these strains and their relevant autoimmune test groups has been reduced to a set of genes and single chromosome, respectively. However, despite the fact that MRL-Ipr and MRL + / + substralns differ less than 0.1% in their genome (207), the possibility that this subtle genetic dissimilarity is what contributes to the observed differences in behavior between two MRL substrains cannot be fully dismissed. This is particularly important, in light of the findings that the lpr gene represents a mutation which causes a defect in the cell surface Fas antigen, which has structural similarity to the low-affinity nerve growth factor (NGF) receptor (217) and regulates apoptosis (programed cell death) (195). Developmental brain abnormalities (produced by a putative absence of apoptosis, dysfunction in NGF binding, or both) could occur in parallel to lymphoproliferation. According to this view, autoimmunity and AABS may represent two independent consequences of the Ipr gene. The notion that some of the behavioral dissimilarities between the MRL substrains are due to inherited factors was tested by comparing the behavioral profiles of young mice, before hyperproduction of autoantibodies is evident. As observed in diseased MRL-Ipr mice, young MRL-Ipr mice showed reduced locomotion in activity monitors and slower locomotion in an open field, but other behavioral differences were absent (162). The positive finding is consistent with either an inherited effect or alternatively,

Inherited neuropathology (cortical ectopias, hydrocephalus)

/

> I (anxiety, depressive-like behavior,) ~ ~ l e a m i n ~

' (kidneys,joints, skin, eyes)

Autoimmunity

(cytokines, autoantibodies, ~mmanecomplexes) FIG. 1. Possible etiologic factors of AABS in NZB, BXSB and MRL mice. The involvement and relative contribution of each factor may vary among strains and during different stages in the development of autoimmune disease.

332 with the consequence of early immune changes which precede autoantibody production. So far there are no studies which have examined behavioral profiles in transgenic or knock-out mice using lymphoproliferative genes (e.g. lpr, gld, Yaa). Such an approach may better elucidate the contribution of individual genes in the etiology of AABS.

5.2. Inherited neuropathology Various neuro-anatomical abnormalities in autoimmune strains are another confounding factor in assessing the direct relationship between autoimmunity and behavior. In a series of studies, Sherman and colleagues have shown an increased incidence of ectopic neuronal collections in the brains of NZB and BXSB mice (179-183). This inherited abnormality (45) in the NZB strain is observed in neocortical layer I (179), in the molecular layer of the dentate gyrus (138), as well as in the granular layer of the cerebellum (177). Ectopic changes, and likely reduced neuronal density in several hippocampal regions (10), were associated with poor performance of NZB mice in a black-white discrimination task and in the Morris spatial maze (172). Although such neuroanatomical abnormalities are not frequent in the MRL-lpr substrain, up to 46% of adult MRL-lpr mice have severely enlarged ventricles (hydrocephalus), which can be associated with impaired performance in a discrimination task, less paw asymmetry and lower activity in a swimming task (46). Although occurring at a low rate, hydrocephalus has also been reported in congenic MRL + / + mice (180), and so far there is no evidence that the difference in incidence of hydrocephalus may account for differences in behavioral profiles between the MRL substrains.

5.3. Autoimmunity Emerging evidence suggests that some behavioral alterations in young autoimmune strains are produced by the progression of disease itself. The ova transfer experiments referred to earlier (44), the production of reciprocal strain crosses (45), and the response to immunosuppressive treatment in MRL-lpr mice all argue in favour of an autoimmunity-related etiology (155,159). However, given that autoimmune disease is multisystemic there are two major pathways by which autoimmune processes may affect behavior. First, autoimmunity can cause peripheral pathology (in specific organs such as the joints and kidneys) and/or contribute to abnormal function of the endocrine glands. Second, autoimmune processes can alter behavior via several factors which access the brain (neuroactive cytokines, brain reactive autoantibodies, immune complexes) and/or via infiltration of lymphoid cells into the brain, with subsequent inflammation.

5.3.1. Multisystem disease-related mechanisms 5.3.1.1. Specific organ dysfunction. Systemic malaise and specific organ involvement are factors that should be taken into consideration when assessing behavioral performance in autoimmune mouse strains. Kidney failure (7,50), arthritic-like changes in limb joints (132,204), vasculitis (126,199), and lacrimal gland inflammation (88) are some of the factors that can significantly impair sensorimotor

SAKIC, SZECHTMAN AND DENBURG capacity in autoimmune animals. Indeed, abnormal neurologic features (slower tail-flick response, abnormal placing responses, tremors) are reported in aged NZB and MRL-Ipr mice (193,214). Despite the development of neurological deficits in severely affected animals, a reliable correlation beween sensorimotor disadvantage and behavioral performance has not been established (77,193,214). For example, in young NZB/W mice there was no change in sensitivity to foot shock, which could potentially account for their poor acquisition of active avoidance response (168). In our studies we attempted to minimize the confounding effect of specific organ dysfunction by using young mice or employing measures that do not demand excessive activity (latency to step-down from elevated platform, latency to make a contact with a novel-object) or are not activity-dependant (choice between visits into open and closed arms, slope of a concentrationintake response in the sucrose test). Since a mild form of joint disease is evident in 11-week old MRL-lpr mice (160), we asked whether even in the absence of synovial thickening (which occurs much later), the pain caused by mild inflammation (115) could have contributed to changes detected in sensorimotor tasks. This question was examined by looking at the relationship between performance in brief sensorimotor tasks (beam walking and swimming test) and joint pathology scores (161). It was expected that mice showing excessive joint pathology would be significantly worse on those tasks: however, the lack of a significant correlation suggested that altered performance observed in young mice cannot be readily accounted for by joint pathology. The relative independence of AABS from sensorimotor capacity has been supported by recent studies where less activitydemanding [the novel object test, the step down test, and the plus-maze test (163)] or activity-independent measures were used [the open/total arm entry ratio in the plus-maze (163); preference for a sucrose solution (155)]. Similarly, no significant correlations between neurological and cognitive deficits in aged MRL-lpr (77,214) and NZB mice were observed (168,193).

5.3.1.2. Endocrine-mediated changes in behavior. The endocrine system is a principal communication link between the nervous and the immune systems (17,218). Hormones from the pituitary, adrenal gland and gonads are known as potent modulators of the immune response both in health and disease (35,37,83), including autoimmunity (221). A protective effect of male hormones and an accelerating effect of female hormones on the development of autoimmunity in mice have been shown in several studies (23,27,28,118,176,178,203). Similarly, pro-inflammatory cytokines have documented effects on gonadal (11), pituitary (139,149,190,225) and adrenal function (164), possibly accounting for an altered pituitary-adrenal axis (89) and catabolism of adrenal hormones in autoimmune disease (95,222). Receptors for certain neuroactive cytokines are probably located, among other sites, in the pituitary (136) and adrenal glands; in addition, these glands can synthesize and release cytokines in both paracrine and autocrine ways (106,107, 167,189,192). Disturbances in cytokine production in autoimmune mice are well-known (74,102,104,200,205,209), and could play an important role in the abnormal release

NEUROBEHAVIORAL ALTERATIONS IN AUTOIMMUNE MICE of gonadal and adrenal honaaones, which in turn may affect behavior and lead to AABS. The potential interactions among hormones, cytokines and behavior are extremely complex and need careful examination. This is further complicated by evidence that lymphoid cells (e.g. T cells, B cells) themselves (abundant in autoimmunity) can synthesize several biologically active, neuroendocrine peptide hormones (17,218). 5.3.2. Central nervous system (CNS) mechanisms 5.3.2.1. CNS inflammation. Infiltration of lymphoid cells and perivascular leakage of IgG into brain tissue begins at 8 weeks of age (213) and results in CNS inflammation, restricted to the choroid plexus and meninges of adult, 6month old MRL-lpr mice (5). The cell infiltrates are composed mainly of CD4 + cells and are accompanied by perivascular leakage of IgG (213). Prolonged treatment with anti-CD4 monoclonal antibody (133) and the immunosuppressive drug cyclophosphamide (52a) effectively prevent the lymphoid infiltration into the brain, suggesting a role for these cells in the pathogenesis of CNS inflammation in MRL-lpr mice. These studies sugest that CNS inflammation plays a role in the etiology of AABS in autoimmune MRL-lpr mice. So far there is no evidence that a similar inflammatory process occurs in young NZB (21:3) or BXSB mice. 5.3.2.2. Functional inte~,rence. In the last two decades the hypothesis that brain-reactive autoantibodies (BRA) play an important role in the etiology of AABS has attracted considerable attention (19,20,40,49,66,68, 84,93,105,146). It was proposed that BRA may bind to neurotransmitter receptors and block signal transduction (analogous to antibodies to the acetylcholine receptor in myasthenia gravis), or induce antibody-mediated receptor endocytosis. Either activity could interfere with normal function. Support for a causal relationship between BRA and behavior has been obtained from animal studies in which passive transfer of BRA to immunologically naive animals has been observed to produce neuropathologic changes, accompanied by cerebral edema, motor discoordination, epileptic seizures (90,186), impaired memory retrieval (98), and slower active avoidance acquisition (100). Similar to SLE patients, autoimmune mice produce BRA against neuronal cells that have a wide range of target speciflcities (31,32,69,81,82,121,122,130,131). When sera from individual mice are applied to brain sections and cortical neuronal plasma membrane preparations, intense immunofluorescent staining is observed in the cerebellum and hippocampus (79); proteins with several different molecular weights are targetted by these sera on immunoblots (120). Since these studies did not involve behavioral testing, the relationship between BRA specificity and behavior is not clear. When autoimmune MRL-Ipr mice were divided according to the presence or absence of serum BRA, those with BRA showed slower locomotion, impaired exploration of a novel environment, and thigmotaxic swimming (157). To the exr~ent that those measures can be interpreted as an index of anxiety, this suggests a pathogenic relationship between BRA and anxiety. So far there is not much information regarding the effect of BRA on neuro-

333 transmitter systems, but two earlier pharmacological studies on NZB mice indicate disturbed neurotransmission in the cholinergic system (147,148). As mentioned before, the abnormal production of various cytokines represents another variable feature of autoimmune disease (34). In addition to their regulatory effect on immune responses, several pro-inflammatory cytokines such as IL-1, IL-6, and TNF-ct have effects on behavior, neural plasticity, temperature and sleep control (36,142). They also participate in the regulation of three major neuroendocrine pathways: the hypothalamic-pituitaryadrenal (HPA) (201), hypothalamic-pituitary-gonadal and hypothalamic-pituitary-thyroid axes (166). It has been recently suggested that during autoimmune and inflammatory diseases, cytokines play a role not only in inflammatory response, but also in the pathogenesis of behavioral syndromes, such as depression (196). According to this hypothesis, these cytokines are also neuroactive, chronically stimulating HPA axis/sympathetic system and promoting the release of corticotropin-releasing-factor (CRF). This is followed by the secretion of catecholamines in tissues, as well as adrenocorficotropic hormone (ACTH) and subsequently, corticosteroids, in an attempt to physiologically attenuate infammation (15). Similarly, proinflammatory cytokines can stimulate the pituitary-adrenal system via the pituitary gland (150,151). Such neuroendocrine responses during autoimmune/inflammatoryprocesses are accompanied by a series of behavioral responses, similar to those observed in chronic stress situations where the HPA axis is stimulated. Sustained CRF release may result in the appearance of an affective disorder and anxiety (8,9,52,135), and prolonged cytokine-induced activation of hippocampal neurons and shifts in the balance of activation of mineralocorticoid/glucocorticoid receptors may participate in the development of a stress-like behavioral profile (38). Although still somewhat speculative, there is some support for the idea that neuro-immuno-endocrine mechanisms are operative in AABS, in particular in the MRL-lpr (Fig. 2) and NZB mice. First, there is similarity between AABS and stress-induced behavior because both are characterized by anxiety (33) and depressive-like profiles (155,163). Second, autoimmunity-associated decrease in plasma corticosterone (30), impaired responsiveness of the HPA axis (85) and cyclophosphamide-preventable decreases in norepinephrine levels in the spleen (22) may reflect the chronic involvement of HPA/sympathetic system in murine autoimmune disease. It is well-documented that the binding of glucocorticoids to their cytoplasmic receptors is accompanied by the membrane expression of heat-shock proteins. Therefore, overexpression of heat-shock protein HSP90 and subsequent production of anti-HSP90 in MRL-lpr mice (54) and in CNS-SLE patients (48,103) may be a marker of sustained glucocorticoid binding to somatic cells. Finally, the high prevalence of depression in SLE (219) and in rheumatoid arthritis (RA) (91,108,112,152), the enhanced metabolism of glucocorticoids in SLE (95), the abnormal responsiveness of HPA axis in RA patients (65,89), and the elevated levels of IL-6 in CSF of patients suffering from SLE, RA and Sj6gren's syndrome (78,197,210,228) are clinical findings that are compatible with a role for neuroimmunoendocrine factors in AABS. The possibility that interleukin-6 (IL-6) plays an

334

SAK/(~, SZECHTMAN AND DENBURG

ca

c y t o k BRA I lymphoid ceils ~ -

i

n

~

Autoimmunity

+ ACTH

~=~

+

__

gluc~cortic~d~

glucocorticoids

somatic cells

• HSP

~

anti-HSPAb

FIG. 2. A schematic representation of neuroendocrine pathways proposed to mediate AABS in the autoimmune MRL-Ipr substrain. The onset of autoimmunity in MRL-lpr mice is characterized by a cascade of immunological events: (a) upregulation of proinflammatory cytokines, in particular interleukin-6 (205); (b) production of BRA (82,157); and (c) infiltration of lymphoid cells into the brain tissue (213). These events may result in the chronic activation of the pituitary-adrenal system, either at the level of hypothalamus and/or pituitary (dashed lines). The sustained release of CRF, prolactin, ACTH, glucocorticoids and noradrenaline tends to suppress immune activity. The markers of such a chronic neuroendocrine regulation could be: (a) depleted levels of splenic norepinephrine (22); (b) impaired responsivenes of the HPA axis (85); and (c) overexpression of HSP in MRL-lpr mice (54), the latter resulting from glucocorticoid binding to its cellular receptor. Consequently, the appearance HSP on cell surface may lead to increased production of anti-HSP antibodies (53). Chronic stresslike activation of HPA axis-regulatory neurons by glucocorticoids, cytokines (38) or BRA may produce morphological changes in hippocampus (116), relevant to intense BRA binding to the hippocampus (79) and altered performance of MRL-lpr mice in the spatial task (77,160). Note: ( + ) represents stimulatory and ( - ) inhibitory pathways.

important role in the etiology of AABS in the MRL-lpr substrain has been a focus of our recent attention. Blunted responsiveness to a palatable stimulus was detected as early as 5 weeks of age [i.e. before autoantibody hyperproduction is evident (162)] and was preventable by immunosuppressive treatment (156), thus suggesting involvement of an immune factor different from autoantibodies. 1L-6 appears to be a good candidate for this since, even though the production of IL-1 [the IL-6 inducer/HPA axis stimulator (15,96,191)] is impaired (104), serum levels of IL-6 are elevated in MRL-Ipr mice as early as 3 weeks of age (205) and soluble IL-6 receptors are overexpressed in all three autoimmune strains (200). The production of IL-6 is a necessary prerequisite for B cell differentiation into hyperactive, autoantibody-producing plasma cells (97) and may be directly responsible for the blunted 'hedonic' responsiveness in 5-week old MRL-lpr males (156) as well as naive mice transiently infected with an IL-6 adenovirus

vector (ms in preparation). Similarly, from clinical studies it is evident that psychiatric symptoms may occur before SLE is diagnosed (212) and that IL-6 levels correlate with disease activity and CNS involvement in SLE patients (4,16,86,197,210,228). Although these results appear to support the IL-6 hypothesis, the importance of other cytokines (102,124,137), MHC gene expression in the brain (117), reduced IL-1 receptor density in the dentate gyrus (206), and reduced cerebral glucose utilization (226) in the etiology and pathogenesis of AABS, needs to be determined. The hypothesis that autoimmunity interferes with normal brain functioning rests on the notion that the CNS can be targetted by blood-borne immune factors. One of the major obstacles to proving this is the lack of a clear explanation for the passage of autoantibodies or cytokines through the tight junctions formed by the endothelial cells of the blood-brain barrier (BBB). However, there are several mechanisms that may account for the presence of immune factors in the brain (142). For example, it is known that the choroid plexus, area postrema, and organum vasculosum of lamina terminalis are sites where the normal permeability of BBB is reduced. There is evidence that immune complexes may accumulate in the choroid plexus during autoimmune disease, increase the BBB permeability, and allow the access of immune factors to the brain parenchyma (80,142). Active diapedesis of immune cells (autoantibody and cytokine-producing lymphocytes) through a "leaky" BBB represents another mechanism that can account for the presence of immune factors in the brain during inflammatory disease (224). Banks and colleagues have recently reported that [as is found with other cytokines (12)] small amounts of circulating IL-6 can penetrate mouse BBB via a saturable transport system, inducing CNS effects (13). Alternatively, local production of cytokines and antibodies could be another source of immune factors found in the brain (15,21,166). 6. IMPLICATIONS FOR AABS AS A MODEL OF BEHAVIORAL DYSFUNCTION IN HUMAN AUTOIMMUNE DISORDERS

Patients suffering from systemic autoimmune disorders develop various neurologic and psychiatric problems of unknown etiology during the course of their illness (6,18,39,67,75,91,113,127,219). The mean prevalence of neurologic/psychiatric symptoms and signs in SLE patients is high (219), which includes depression, psychosis, seizures, schizophrenic episodes, organic brain syndrome, and cognitive dysfunction (18,26,43,112,211,219,220). Although in a lesser frequency than in SLE, neurologic/ psychiatric manifestations such as depression and cognitive dysfunction have been reported in patients suffering from primary Sjrgren's syndrome (92,113,194). As in SLE, depression, sleep disturbance, and loss of appetite are frequently seen in many patients suffering from rheumatoid arthritis (9 I, 108,112). Conversely, autoimmune phenomena have been recently reported in patients suffering from major depression (110,175), schizophrenia (29,58-60,128,184, 185,188,198,227), autism (187,215,216,229), Alzheimer's disease (55,57,101), AIDS-related dementia (119,140,141) and epilepsy (143), thus raising the possibility that some immune factors may have a role in pathogenesis of these mental disorders. In the study of certain neuroimmunological diseases,

NEUROBEHAVIORAL ALTERATIONS IN AUTOIMMUNE MICE

CNS-SLE

,,,

AABS

t

i,,

Autoimmnnity

t

Schizophrenia Depression Alzheimer's disease Autism AIDS-related dementia

335

human autoimmune disorders and, by extension, in the understanding of classic mental disorders where immune factors may play important roles. AABS may, in addition, help to further understand adaptive behavioral mechanisms elicited in response to inflammatory/antoimmune processes.

Genetics

7. SOMMARV

FIG. 3. Autoimmune mice as a model system for the study of the link between autoimmunity and behavior. AABS may be a model of the behavioral changes found not only in CNS-SLE but also in mental disorders where an autoimmune process is suspected. The identified genetic abnormality in autoimmune mice provi&~sa known pathway to autoimmnnity and permits the study of the interaction of this pathway with other factors in affecting AABS.

such as multiple sclerosis, chronic inflammatory polyneuritis and myasthenia gravis, various animal models have been used to further understanding of pathogenesis. Experimental allergic encephalomyelitis, experimental allergic neuritis, experimental auto-immune myasthenia gravis, and experimental allergic myositis can all be induced in various animal species by immunization with appropriate antigens. The results presented here with respect to mice which spontaneously develop autoimmune disease and AABS suggest that autoimmune strains represent novel preparations for the study of neural, endocrine and immune interactions (Fig. 3). The knowledge obtained regarding neurobehavioral alterations in autoimmune mice may have direct implications in the study of CNS involvement in

Three autoimmune murine strains (NZB, BXSB and MRL-lpr) develop changes in behavior (AABS) in the course of spontaneous, systemic autoimmune disease. These changes are most consistently noted in active avoidance conditioning and paradigms reflective of emotional reactivity. Neuroactive cytokines and brain-reactive antibodies are immune factors which may contribute to AABS, in a cascade of age-determined events. The chronic HPA axis activation by immune factors may represent one of the principal neuroendocrine mechanisms which underlies AABS. ACKNOWLEDGEMENTS

We thank Mrs Lynne Larocque for technical assistance in preparing the manuscript. This work was supported by a grant from the Natural Sciences and Engineering Research Council of Canada (OGP000544), and funds from Lupus Society of Hamilton and Lupus Foundation of Ontario. B. Sakic was supported by a Postdoctoral Fellowship from the Ontario Mental Health Foundation. H. Szechtman is a Research Associate of the Ontario Mental Health Foundation.

REFERENCES 1. Ader, R.; Cohen, N., Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 215:1534-1536; 1982. 2. Ader, R.; Grota, L. J.; Cohen, N., Conditioning phenomena and immune function. Ann. N. Y. Acad. Sci. 496:532-544; 1987. 3. Ader, R.; Grota, L. J.; Moynihan, J. A.; Cohen, N. Behavioral adaptations in autoimmune disease-susceptible mice. In: Ader, R., Felten, D. L., Cohen, N. (eds) Psychoneuroimmunology. San Diego: Academic Press, Inc.; 1991; 685-708.; 4. Alcocer-Varela, J.; Aleman-Hoey, D.; Alarcon-Segovia, D., Interleukin-1 and intedenkin-6 activities are increased in the cerebrospinal fluid of patients with CNS lupus erythematosus and correlate with local late T cell activation markers. Lupus 1:111-117; 1992. 5. Alexander, E. L.; Murphy, E. D.; Roths, J. B.; Alexander, G. E., Congenic autoimmune omrine models of central nervous system disease in connective tissue disorders. Ann. Neurol. 14:242-248; 1983. 6. Alexander, G. E.; Provost, T. T.; Stevens, M. B.; Alexander, E. L., Sjogren syndrome: central nervous system manifestations. Neurology 3h1391-1396; 1981. 7. Andrews, B. S.; Eisenberg, R. A.; Theofilopoulos, A. N.; Izui, S.; Wilson, C. B.; McConahcy, P. J.; Murphy, E. D.; Roths, J. B.; Dixon, F. J., Spontaneous routine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J. Exp. Med. 148:1198-1215; 1978. 8. Anisman, H.; Zacharko, R. M., Multiple neurochemical and behavioral consequences of s~ressors:implications for depression. Pharm. Ther. 46:119-136; 1990. 9. Anisman, H.; Zacharko, R. M., Depression as a consequence of inadequate neurochemic~d adaptation in response to stressors. Br. J. Psychiatry Suppl:36-43; 1992. 10. Anstatt, T., Quantitative and cytoarchitectural studies of the entorhinal region and the hippocampus of New Zealand black mice. J. Neural. Transm. 73:249-257; 1988.

11. Banks, W. A.; Kastin, A. J., Human interleukin-1 alpha crosses the blood-testis barriers of the mouse. J. Androl. 13:254-259; 1992. 12. Banks, W. A.; Kastin, A. J., Physiological consequences of the passage of peptides across the blood-brain barrier. Rev. Neurosci. 4:365-372; 1993. 13. Banks, W. A.; Kastin, A. J.; Gutierrez, E. G., Penetration of interleukin-6 across the murine blood-brain barrier. Neurosci. Lett. 179:53-56; 1994. 14. Barrera, C. M.; Banks, W. A.; Fasold, M. B.; Kastin, A. J., Effects of various reproductive hormones on the penetration of LHRH across the blood-brain barrier. Pharm. Biochem. Behav. 41:255257; 1992. 15. Berkenbosch, F.; Derijk, R.; Schotanus, K.; Wolvers, D. and van Dam, A. The immune-hypothalamo-pituitary adrenal axis: Its role in immunoregulation and tolerance to self-antigens. In: Rothwell, N. J., Dantzer, R. D. (eds) Interleukin-1 in the Brain. Oxford: Pergamon Press; 1992: 75-91.; 16. Bertero, M. T.; Converso, M.; Aimo, G.; Merico, F., Serum levels of cytokines and soluble (s) CD23 in systemic lupus erythematosus. Fundamental. Clinical. Immunol. 2:37-43; 1994. 17. Blalock, J. E., A molecular basis for bidirectional communication between the immune and neuroendocrine systems. Physiol. Rev. 69:1-32; 1989. 18. Bluestein, H. G. The central nervous system in systemic lupus erythematosus. In: Lahita, R. G. (ed) Systemic lupus erythematosus. New York: Churchill Livingstone; 1992:639-655.; 19. Bluestein, H. G.; Williams, G. W.; Steinberg, A. D., Cerebrospinal fluid antibodies to neuronal cells: association with neuropsychiatric manifestations of systemic lupus erythematosus. Am. J. Med. 70:240-246; 1981. 20. Bluestein, H. G.; Woods, V. L., Antineuronai antibodies in systemic lupus erythematosus. Arthritis Rheum. 25:773-778; 1982. 21. Blumenthal, H. T., Does the brain possess an independent immune compartment?. Drug Dev. Res. 15:207-226; 1988.

336 22. Breneman, S. M.; Moynihan, J. A.; Grota, L. J.; Felten, D. L.; Felten, S. Y., Splenic norepinephrine is decreased in MRL-lpr/lpr mice. Brain Behav. Immun. 7:135-143; 1993. 23. Brick, J. E.; Walker, S. E.; Wise, K. S., Hormone control of autoantibodies to calf thymus nuclear extract (CTE) and DNA in MRL-lpr and MRL-+/+ mice. Clin. Immunol. Immunopathol. 46:68-81; 1988. 24. Bures, J.; Buresova, O.; Huston, J. Techniques and basic experiments for the study of brain and behavior. Amsterdam/New York Elsevier; 1983.; 25. Carbotte, R. M.; Denburg, S. D.; Denburg, J. A., Prevalence of cognitive impairment in systemic lupus erythematosus. J. Nerv. Ment. Dis. 174:357-364; 1986. 26. Carbotte, R. M.; Denburg, S. D.; Denburg, J. A. Cognitive dysfunction and systemic lupus erythematosus. In: Lahita, R. G. (ed) Systemic Lupus Erythematosus. New York: Churchill Livingstone; 1992: 865-881.; 27. Carlsten, H.; Holmdahl, R.; Tarkowski, A.; Nilsson, L. A., Oestradiol- and testosterone-mediated effects on the immune system in normal and autoimmune mice are genetically linked and inherited as dominant traits. Immunology 68:209-214; 1989. 28. Carlsten, H.; Nilsson, N.; Jonsson, R.; Tarkowski, A., Differential effects of oestrogen in murine lupus: acceleration of glomerulonephritis and amelioration of T cell-mediated lesions. J. Autoimmun. 4:845-856; 1991. 29. Chengappa, K. N.; Carpenter, A. B.; Keshavan, M. S.; Yang, Z. W.; Kelly, R. H.; Rabin, B. S.; Ganguli, R., Elevated IGG and IGM anticardiolipin antibodies in a subgroup of medicated and unmedicated schizophrenic patients. Biol. Psychiatry 30:731-735; 1991. 30. Chesnokova, V. M.; Chukhlib, V. L.; Ignat'eva, E. V.; Ivanova, L. N., The possible involvement of glucocorticoids in the development of genetically determined autoimmune pathology in NZB mice. Biomed. Sci. 2:557-561; 1991. 3 I. Crimando, J.; Hoffman, S. A., Detection of brain-reactive autoantibodies in the sera of autoimmune mice using ELISA. J. Imnmnol. Methods 149:87-95; 1992. 32. Crimando, J.; Hoffman, S. A., Characterization of murine hrainreactive monoclonal IgG autoantibodies. Brain Behav. Immun. 9:165-181; 1995. 33. Cmic, L. S., Schrott, L. M. Increased anxiety behaviors in autoimmune mice. Behav. Neurosci. 110:492-502; 1996.; 34. Crow, M. K.; Christian, C. L. Etiologic hypotheses for systemic lupus erythematosus. In: Lahita, R. G. (ed) Systemic Lupus Erythematosus. 1992:51-64.; 35. Cutolo, M.; Sulli, A.; Barone, A.; Seriolo, B.; Accardo, S., The role of androgens in the pathophysiology of rheumatoid arthritis. Fundamental. Clin. Immunol. 3:9-18; 1995. 36. Dantzer, R.; Bluthe, R. M.; Kent, S.; Kelley, K. W. Cytokines and sickness behavior. In: Husband, A. J. (ed) Psychoimmunology: CNSImmune Interactions. Boca Raton: CRC Press, Inc.; 1994: 1-16.; 37. Dasilva, J. A. P., Sex hormones, glucocorticoids and autoimmunity: facts and hypotheses. Ann. Rheum. Dis. 54:6-16; 1995. 38. De Kloet, E. R.; Oitzl, M. S.; Schobitz, B., Cytokines and the brain corticosteroid receptor balance: relevance to pathophysiology of neuroendocrine-immune communication. PsychoneuroendocrinoL 19:121-134; 1994. 39. Denburg, J. A., Clinical and Subclinical Involvement of the Central Nervous System in Systemic Lupus Erythematosus. In: Waksman, B. H. (ed) Immunologic Mechanisms in Neurologic and Psychiatric Disease. New York: Raven Press, Ltd.; 1990: 171-178.; 40. Denburg, J. A.; Carbotte, R. M.; Denburg, S. D., Neuronal antibodies and cognitive function in systemic lupus erythematosus. Neurology 37:464-467; 1987. 41. Denburg, J. A.; Carbotte, R. M.; Denburg, S. D., Central nervous system lupus. Rheum. Rev. 2:123-132; 1993. 42. Denburg, S. D.; Carbotte, R. M.; Denburg, J. A., Cognitive impairment in systemic lupus erythematosus: a neuropsychological study of individualandgroupdeficits. J. Clin. Exp. Neuropsychol. 9:323-339; 1987. 43. Denburg, S. D.; Denburg, J. A.; Carbotte, R. M.; Fisk, J. D.; Hanly, J. G., Cognitive deficits in systemic lupus erythematosus. Rheum. Dis. Clin. North Am. 19:815-831; 1993. 44. Denenberg, V. H.; Mobraaten, L. E.; Sherman, G. F.; Morrison, L.; Schrott, L. M.; Waters, N. S.; Rosen, G. D.; Behan, P. O.; Galaburda, A. M., Effects of the autoimmune uterine/maternal environment upon cortical ectopias, behavior and autoimmunity. Brain Res. 563:114122; 1991.

SAKI(~, SZECHTMAN AND DENBURG 45. Denenberg, V. H.; Sherman, G. F.; Morrison, L.; Schrott, L. M.; Waters, N. S.; Rosen, G. D.; Behan, P. O.; Galaburda, A. M., Behavior, ectopias and immunity in BD/DB reciprocal crosses. Brain Res. 571:323-329; 1992. 46. Denenberg, V. H,; Sherman, G. F.; Rosen, G. D.; Morrison, L.; Behan, P. O.; Galaburda, A. M., A behavior profile of the MRL/Mp lpr/lpr mouse and its association with hydrocephalus. Brain Behav. Immun. 6:40-49; 1992. 47. Denenberg, V. H.; Sherman, G. F.; Schrott, L. M.; Rosen, G. D.; Galaburda, A. M., Spatial learning, discrimination learning, paw preference and neocortical ectopias in two autoimmune strains of mice. Brain Res. 562:98-104; 1991. 48. Dhillon, V. B.; Mccallum, S.; Latchman, D. S.; Isenberg, D. A., Elevation of the 90 kda heat-shock protein in specific subsets of systemic lupus erythematosus. Q. J. Med. 87:215-222; 1994. 49. Diededchsen, H.; Pyndt, I. C., Antibodies against neurons in a patient with systemic lupus erythematosus, cerebral palsy, and epilepsy. Brain 93:407-412; 1970. 50. Dixon, F. J.; Andrews, B, S.; Eisenberg, R. A.; McConahey, P. J.; Theofilopoulos, A. N.; Wilson, C. B., Etiology and pathogenesis of a spontaneous lupus-like syndrome in mice. Arthritis Rheum. 21 :$64$67; 1978. 51. Dunn, A. J., Infection as a stressor: a cytokine-mediated activation of the hypothalamo-pituitary-adrenal axis? Ciba Found. Symp. 172, 226-39; 1993.; 52. Dunn, A. J.; Berridge, C. W., Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain Res. Rev. 15:71-100; 1990. 52a. Farrell, M.; Sakir, B.; Szechtman, H.; Denburg, J. A., Effect of cyclophosphamide on leucocytic infiltration in the brain of MRL/ lpr micr. Lupus (in press). 53. Faulds, G.; Conroy, S.; Madaio, M.; Isenberg, D.; Latchman, D., Increased levels of antibodies to heat shock proteins with increasing age in MRL/Mp-lpr/lpr mice. Br. J. Rheum. 34:610615; 1995. 54. Fanlds, G. B.; Isenberg, D. A.; Latchman, D. S., The tissue specific elevation in synthesis of the 90 kDa heat shock protein precedes the onset of disease in lupus prone MRL/Lpr Mice. J. Rheumatol. 21:234-238; 1994. 55. Forster, M. J.; Lal, H. Autoimmunity and cognitive decline in aging and Alzheimer's disease. In: Ader, R., Felten, D. L., Cohen, N. (eds) Psychoneuroimmunology. San Diego: Academic Press, Inc.; 1991: 709-748.; 56. Forster, M. J.; Popper, M. D.; Retz, K. C.; Lal, H., Age differences in acquisition and retention of one-way avoidance learning in C57BL/ 6NNia and autoimmune mice. Behav. Neural Biol. 49:139-151; 1988. 57. Forster, M. J.; Retz, K. C.; Lal, H., Learning and memory deficits associated with autoimmunity: significance in aging and Alzheimer's disease. Drug Dev. Res. 15:253-273; 1988. 58. Galinowski, A.; Barbouche, R.; Truffinet, P.; Louzir, H.; Poirier, M. F.; Bouvet, O.; Loo, H.; Avrameas, S., Natural autoantibodies in schizophrenia. Acta Psychiat. Scand. 85:240-242; 1992. 59, Ganguli, R.; Brar, J. S.; Chengappa, K. N.; Yang, Z. W.; Nimgaonkar, V. L.; Rabin, B. S., Autoimmunity in schizophrenia: a review of recent findings. Ann. Med. 25:489-496; 1993. 60. Ganguli, R.; Brar, J. S.; Solomon, W.; Chengappa, K. N.; Rabin, B. S., Altered interleukin-2 production in schizophrenia: association between clinical state and autoantibody production. Psychiat. Res. 44:113-123; 1992. 61. Grota, L. J.; Ader, R.; Cohen, N., Taste aversion learning in autoimmune Mrl-lpr/lpr and Mrl + / + mice. Brain Behav. Immun. 1:238-250; 1987. 62. Grota, L. J.; Ader, R.; Moynihan, J. A.; Cohen, N., Voluntary consumption of cyclophosphamide by nondeprived Mrl-lpr/lpr and Mrl + / + mice. Pharm. Biochem. Behav. 37:527-530; 1990. 63. Grota, L. J.; Schachtman, T. R.; Moynihan, J. A.; Cohen, N.; Ader, R., Voluntary consumption of cyclophosphamide by Mrl mice. Brain Behav. Immun. 3:263-273; 1989. 64. Hahn, B. H. Animal models of systemic lupus erythematosus. In: Wallace, D. J. and Hahn, B. H. (eds) Dubois' Lupus Erythematosus. Philadelphia: Lea and Febiger; 1993:157-177.; 65. Hall, J.; Morand, E. F.; Medbak, S.; Zaman, M.; Perry, L.; Goulding, N. J.; Maddison, P. J.; O'Hare, J. P., Abnormal hypothalamicpituitary-adrenal axis function in rheumatoid arthritis. Arthritis Rheum. 37:1132-1137; 1994.

N E U R O B E H A V I O R A L ALTERATIONS IN A U T O I M M U N E MICE 66. Hanly, J. G.; Behmann, S.; Denburg, S. D.; Carbotte, R. M.; Denburg, J. A., The association between sequential changes in serum antineuronal antibodies and neuropsychiatric systemic lupus erythematosus. Postgrad. Med. J. 65:622-627; 1989. 67. Hanly, J. G.; Fisk, J. D.; Sherwood, G.; Jones, E.; Jones, J. V.; Eastwood, B., Cognitive impairment in patients with systemic lupus erythematosus. J. Rheumatnl. 19:562-567; 1992. 68. Hanly, J. G.; Rajaraman, S.; Behmann, S.; Denburg, J. A., A novel neuronal antigen identified lay sera from patients with systemic lupus erythematosus. Arthritis Rheum. 31:1492-1499; 1988. 69. Harbeck, R. J.; Hoffman, A. A.; Hoffman, S. A.; Shucard, D. W.; Cart, R. I., A naturally occurring antibody in New Zealand mice cytotoxic to dissociated cerebellar cells. Clin. Exp. Immunol. 31:313-320; 1978. 70. Hart, B. L., Behavior of sick animals. Food Animal Practice 3:383391; 1987. 71. Hart, B. L., Biological basis of the behavior of sick animals. Neurosci. Biobehav. Rev. 1L2:123-137; 1988. 72. Hart, B. L., Behavioral adaptations to pathogens and parasites: five strategies. Neurosci. Biobehav. Rev. 14:273-294; 1990. 73. Hart, B. L., Behavioral adaptations to parasites: an ethological approach. J. Parasitol. 78:256-265; 1992. 74. Hartwell, D.; Levine, J.; Fenton, M.; Francis, C.; Leslie, C.; Beller, D., Cytokine dysregulation and the initiation of systemic autoimmuuity. Immunol. Lett. 43:15-21; 1994. 75. Hay, E. M.; Black, D.; Huddy, A.; Creed, F.; Tomenson, B.; Bernstein, R. M.; Holt, P. J., Psychiatric disorder and cognitive impairment in systemic lupus erythematosus. Arthritis Rheum. 35:411-416; 1992. 76. Henn, F. A.; McKinney, W. T. Animal Models in Psychiatry. In: Meltzer, H. Y. (ed) Psychopharmacology: The Third Generation of Progress. New York: Raven Press; 1987: 687-695. 77. Hess, D. C.; Taormina, M.; Thompson, J.; Sethi, K. D.; Diamond, B.; Rao, R.; Feldman, D. S., Cognitive and neurologic deficits in the MR1./lpr mouse: a clinicopathologic study. J. Rheumatol. 20:610617; 1993. 78. Hirohata, S.; Miyamoto, T., Elevated levels of interleukin-6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement. Arthritis Rheum. 33:644649; 1990. 79. Hoffman, S. A.; Arbogast, D. N.; Ford, P. M.; Shucard, D. W.; Harbeck, R. J., Brain-reactive autoantibody levels in the sera of ageing autoimmune mice. Clin. Exp. Immunol. 70:74-83; 1987. 80. Hoffman, S. A.; Harbeck R. J. CNS Lupus and the Blood-Brain Barrier, Vol. 2 (Clinical Aspects) In: Neuwelt, E. A. (ed) Implications of the Blood-Brain Barrier and its Manipulation. New YorkLondon: Plenum Medical Book Co.; 1989: 469-494.; 81. Hoffman, S. A.; Hoffman, A. A.; Shucard, D. W.; Harbeck, R. J., Antibodies to dissociated cerebellar cells in New Zealand mice as demonstratedby immunofluorescence. Brain Res. 142:477-486; 1978. 82. Hoffman, S. A.; Madsen, C. S., Brain specific autoantibodies in murine models of systemic lupus erythematosus. J. Neuroimmunol. 30:229-237; 1990. 83. Homo-Delarche, F.; Fitzpatrick, F.; Christeff, N.; Nunez, E. A.; Bach, J. F., Sex steroids, glucocorticoids, stress and autoimmunity. J. Ster. Biocbem. Mol. Bial. 40:619-637; 1991. 84. How, A.; Dent, P. B.; Liao, S. K.; Denburg, J. A., Antineuronal antibodies in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 28:789-795; ] 985. 85. Hu, Y.; Dietrich, H.; Hero~!d,M.; Heinrich, P. C.; Wick, G., Disturbed immnno-endocrine comrnnnication via the hypothalamo-pituitaryadrenal axis in autoimmune disease. Int. Arch. Allergy Immunol. 102:232-241; 1993. 86. Isshi, K.; Hirohata, S.; Hashimoto, T.; Miyashita, H., Systemic lupus erythematosus presenting with diffuse low density lesions in the cerebral white matter on computed axial tomography scans: its implication in the pathogenesis of diffuse central nervous system lupus. J. Rheuinatol. 21:1758-1762; 1994. 87. Izui, S.; Iwamoto, M.; Fo~sati, L.; Merino, R.; Takahashi, S.; IbnouZekri, N., The Yaa gene model of systemic lupus erythematosus. Immunol. Rev. 144:137-193; 1995. 88. Jabs, D. A.; Prendergat;t, R. A., Murine models of Sjogren's syndrome. Adv. Exp. Med. Biol. 350:623-630; 1994. 89. Jorgensen, C.; Sany, J., Modulation of the immune response by the neuro-endocrine axis in rheumatoid arthritis. Clin. Exp. Rheumatol. 12:435-441; 1994.

337 90. Karpiak, S. E.; Graf, L.; Rapport, M. M., Antiserum to brain gangliosides produces recurrent epileptiforrn activity. Science 194:735737; 1976. 91. Katz, P. P.; Yelin, E. H., Prevalence and correlates of depressive symptoms among persons with rheumatoid arthritis. J. Rheumatol. 20:790-796; 1993. 92. Kawashima, N.; Shindo, R.; Kohno, M, Primary Sjogren's syndrome with subcortical dementia. Inter. Med. 32:561-564; 1993. 93. Kelly, M. C.; Denburg, J. A., Cerebruspinal fluid immunoglobulins and neuronal antibodies in neuropsychiatric systemic lupus erythematosus and related conditions. J. Rheumatol. 14:740-744; 1987. 94. Kent, S.; Bluthe, R. M.; Kelley, K. W.; Dantzer, R., Sickness behavior as a new target for drug development. Trends Pharmacol. Sci. 13:24-28; 1992. 95. Klein, A.; Buskila, D.; Gladman, D.; Bruser, B.; Malkin, A., Cortisol catabolism by lymphocytes of patients with systemic lupus erythematosus and rheumatoid arthritis. J. Rheumatol. 17:30-33; 1990. 96. Klir, J. J., McClellan, J. L., Kluger, M. J. Interleukin-1 beta causes the increase in anterior hypothalamic intedeukin-6 during LPS-induced fever in rats. Am. J. Physiol. 266:Pt 2:R18458, 1994. 97. Kobayashi, I.; Matsuda, T.; Saito, T.; Yasukawa, K.; Klkutani, H.; Hirano, T.; Kishirnoto, T., Abnormal distribution of IL-6 receptor in aged MRL/lpr mice: elevated expression on B cells and absence on CD4 + cells. Int. Immunol. 4:1407-1412; 1992. 98. Kobiler, D.; Fuchs, S.; Samuel, D., The effect of antisynaptosomal plasma membrane antibodies on memory. Brain Res. 115:129-138; 1976. 99. Konorski, J. Structure of the type II conditioned reflex arc. In: Konorski, J. (ed) Integrative activity of the brain. Chicago and London: The University of Chicago Press; 1995: 424.; 100. Lal, H.; Bennett, M.; Bennett, D.; Forster, M. J.; Nandy, K., Learning deficits occur in young mice following transfer of immunity from senescent mice. Life Sci. 39:507-512; 1986. 101. Lal, H.; Forster, M. J., Autoimmunity and age-associated cognitive decline. Neurobiol. Aging 9:733-742; 1988. 102. Lampe, M. A.; Patarca, R.; Iregui, M. V.; Cantor, H., Polyclonal B cell activation by the Eta- 1 cytokine and the development of systemic autoimmune disease. J. Immunol. 147:2902-2906; 1991. 103. Latchman, D. S.; Isenberg, D. A., The role of hsp90 in SLE. Autoimmunity 19:211-218; 1994. 104. Levine, J. S.; Pugh, B. J.; Hartwell, D.; Fitzpatrick, J. M.; MarshakRothstein, A., Interleukin-1 dysregulation is an intrinsic defect in macrophages from MRL autoimmune-prone mice. Eur. J. Immunol. 23:2951-2958; 1993. 105. Long, A. A.; Denburg, S. D.; Carbotte, R. M.; Singal, D. P.; Denburg, J. A., Serum lymphocytotoxic antibodies and neurocognitive function in systemic lupus erythematosus. Ann. Rheum. Dis. 49:249253; 1990, 106. Lyson, K.; McCann, S. M., The effect of interleukin-6 on pituitary hormone release in vivo and in vitro. Neuroendocrinology 54:262266; 1991. 107. Lyson, K.; McCann, S. M., Induction of adrenocorticotropic hormone release by interleukin-6 in vivo and in vitro. Ann. N. Y. Acad. Sci, 650:182-185; 1992. 108. Maag, T. J.; Hoffman, S. A., Anti-brain antibodies in the sera of rheumatoid arthritis patients: relation to disease activity and psychological status. J. Neuroimmunol. 45:37-45; 1993. 109. Maes, M., A review on the acute phase response in major depression. Rev. Neurosci. 4:407-416; 1993. 110. Maes, M., Evidence for an immune response in major depression: a review and hypothesis. Prog. Neuro-Psychopharmacol. Biol. Psychiat. 19:11-38; 1995. 111. Maes, M.; Meltzer, H.; Jacobs, J.; Suy, E.; Calabrese, J.; Minner, B.; Raus, J., Autoimmunity in depression: increased antiphospholipid autoantibodies. Acta Psychiat. Scand. 87:160-166; 1993. 112. Magner, M. B., Psychiatric morbidity in outpatients with systemic lupus erytbematosus. S. Afr. Med. J. 80:291-293; 1991. 113. Malinow, K. L.; Molina, R.; Gordon, B.; Seines, O. A.; Provost, T. T.; Alexander, E. L., Neuropsychiatric dysfunction in primary Sjogren's syndrome. Ann. Int. Med. 103:344-350; 1985. 114. McAllister, C. G.; Rapaport, M. H.; Pickax, D.; Paul, S. M. Autoimmunity and schizophrenia. In: Tamminga, C. A., Schultz, S. C. (eds) Advances in Neuropsychiatry and Psychopharmacology. New York: Raven Press, Ltd.; 1991: 111-118.

338 115. McCombe, P. A.; McLeod, J. G.; Pollard, J. D.; Gut, Y. P.; Ingall, T. J., Peripheral sensorimotor and autonomic neuropathy associated with systemic lupus erythematosus. Clinical, pathological and immunological features. Brain 110:533-549; 1987. 116. McEwen, B. S.; Gould, E. A.; Sakal, R. R., The vulnerability of the hippocampus to protective and destructive effects of glucocorticoids in relation to stress. Br. J. Psychiatry Suppl:18-23; 1992. 117. Mclntyre, K. R.; Ayer-LeLievre, C.; Persson, H., Class II major histocompatibility complex (MHC) gene expression in the mouse brain is elevated in the autoimmune MRL/Mp-lpr/lpr strain. J. Neuroimmunol. 28:39-52; 1990. 118. McKenzie, W. N. Jr.; Sunderrajan, E. V.; Kavanaugh, J. L.; Braun, S.; Ansbacher, L.; Walker, S. E., Sex hormones modulate the response of pulmonary perivascular inflammation to cyclophosphamide therapy in MRL/MpJ-lpr/lpr mice. Am. J. Pathol. 131:530-538; 1988. 119. Merrill, J. E.; Chen, I. S., HIV-1, macrophages, glial cells, and cytokines in AIDS nervous system disease. FASEB J. 5:2391-2397; 1991. 120. Moore, P. M., Immunoglobulin binding to neuronal cell surface epitopes in murine systemic lupus erythematosus. J. Neuroimmunol. 30:101-109; 1990. 121. Moore, P. M., Evidence for bound antineuronal antibodies in brains of NZB/W mice. J. Neuroimmunol. 38:147-154; 1992. 122. Moore, P. M.; Joshi, I.; Ghanekar, S. A., Affinity isolation of neuronreactive antibodies in MRL/Ipr mice. J. Neurosci. Res. 39:140-147; 1994. 123. Moore, P. M.; Lisak, R. P., Systemic lupus erythematosus: Immunopathogenesis of neurologic dysfunction. Springer Semin. Immunopathol. 17:43-60; 1995. 124. Mori, K.; Kobayashi, S.; Inobe, M.; Jia, W. Y.; Tamakoshi, M.; Miyazaki, T.; Uede, T., In vivo cytokine gene expression in various T cell subsets of the autoimmune MRL/MP-Lpr/Lpr mouse. Autoimmunity 17:49-57; 1994. 125. Mowrer, O. H., On the dual nature of learning: a reinterpretation of "conditioning" and "problem solving". Harvard Educat. Rev. 17:102-148; 1947. 126. Moyer, C. F.; Strandberg, J. D.; Reinisch, C. L., Systemic mononuclear-cell vasculitis in MRL/Mp-lpr/lpr mice. A histologic and immunocytochemical analysis, Am. J. Pathol. 127:229-242; 1987. 127. Mukai, M.; Sagawa, A.; Baba, Y.; Amasaki, Y.; Katsumata, K.; Yoshikawa, M.; Nakabayashi, T.; Watanabe, I.; Yasuda, I.; Fujisaku, A., Neuro-psychiatric symptom associated with primary Sjogren's syndrome. Ryumachi 30:109-118; 1990. 128. Muller, N., Psychoneuroimmunology: implications for the drug treatment of psychiatric disorders. CNS. Drugs 4:125-140; 1995. 129. Nandy, K.; Lal, H.; Bennett, M.; Bennett, D., Correlation between a learning disorder and elevated brain-reactive antibodies in aged C57BL/6 and young NZB mice. Life Sci. 33:1499-1503; 1983. 130. Narendran, A.; Hoffman, S. A., Identification of autoantibody reactive integral brain membrane antigens--a two dimensional analysis. J. Immunol. Methods 114:227-234; 1988. 131. Narendran, A.; Hoffman, S. A., Characterization of brain-reactive autoantibodies in murine models of systemic lupus erythematosus. J. Neuroimmunol. 24:113-123; 1989. 132. O'Sullivan, F. X.; Fassbender, H. G.; Gay, S.; Koopman, W. J., Etiopathogenesis of the rheumatoid arthritis-like disease in MRL/1 mice. I., The histomorphologic basis of joint destruction. Arthritis Rheum. 28:529-536; 1985. 133. O'Sullivan, F. X.; Vogelweid, C. M.; Beschwilliford, C. L.; Walker, S. E., Differential effects of CD4( + ) T cell depletion on inflammatory central nervous system disease, arthritis and sialadenitis in MRL/lpr mice. J. Autoimmun. 8:163-175; 1995. 134. Overmier, J. B. Avoidance learning. In: Bitterman, M. E., LoLordo, V. M., Overmier, J. B., Rashotte, M. E. (eds) Animal learning. New York: Plenum Press; 1979: 313-348.; 135. Owens, M. J.; Nemeroff, C. B., The role of corticotropin-releasing factor in the pathophysiology of affective and anxiety disorders: laboratory and clinical studies. Ciba Found. Syrup. 172:296-316; 1993. 136. Parnet, P.; Brunke, D. L.; Goujon, E.; Mainard, J. D.; Biragyn, A.; Arkins, S.; Kelley, K. W., Molecular identification of two types of interleukin-1 receptors in the murine pituitary gland. J. Neuroendocrinol. 5:213-219; 1993. 137. Patarca, R.; Wei, F. Y.; Singh, P.; Morasso, M. I.; Cantor, H., Dysregulated expression of the T cell cytokine Eta-1 in CD4-8-

SAKIC, SZECHTMAN AND DENBURG

138. 139. 140. 141.

142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162.

lymphocytes during the development of murine autoimmune disease. J. Exp. Med. 172:1177-1183; 1990. Patrylo, P. R.; Nowakowski, R. S., Morphology and distribution of astrocytes in the molecular layer of the dentate gyrus in NZB/BINJ, Dreher, and C57BL/6J mice. Glia 10:1-9; 1994. Payne, L. C.; Weigent, D. A.; Blalock, J. E., Induction of pituitary sensitivity to interleukin-1: a new function for corticotropin-releasing hormone. Biochem. Biophys. Res. Comm. 198:480-484; 1994. Perrella, O.; Carrieri, P. B.; Guarnaccia, D.; Soscia, M., Cerebrospinal fluid cytokines in AIDS dementia complex. J. Neurol. 239:387388; 1992. Perrella, O.; Guerriero, M.; Izzo, E.; Soscia, M.; Carrieri, P. B., Interleukin-6 and granulocyte macrophage-CSF in the cerebrospinal fluid from HIV infected subjects with involvement of the central nervous system. Arquivos de Neuro-Psiquiatria 50:180-182; 1992. Plata-Salaman, C. R., Immunoregulators in the nervous system. Neurosci. Biobehav. Rev. 15:185-215; 1991. Plioplys, A. V.; Greaves, A.; Yoshida, W., Anti-CNS antibodies in childhood neurologic diseases. Neuropediatrics 20:93-102; 1989. Porsolt, R. D.; Benin, A.; Jalfre, M., "Behavioural despair" in rats and mice: strain differences and the effects of imipramine. Eur. J. Pharmacol. 51:291-294; 1978. Porsolt, R. D.; Le Pichon, M.; Jalfre, M., Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730-732; 1977. Quismorio, F. P.; Friou, G. J., Antibodies reactive with neurons in SLE patients with neuropsychiatric manifestations. Int. Arch. Allergy Appl. Immunol. 43:740-748; 1972. Retz, K. C.; Forster, M. J.; Frantzz, N.; Lal, H., Differences in behavioral responses to oxotremorine and physostigmine in NZB/ BINJ and C57BL/6 mice. Neuropharmacol. 26:445-452; 1987. Retz, K. C.; Trimmer, C. K.; Forster, M. J.; Lal, H., Motor responses of autoimmune NZB/BINJ and C57BL/6Nnia mice to arecoline and nicotine. Phann. Biochem. Behav. 28:275-282; 1987. Rivier0 C., Role of endotoxin and interleukin-1 in modulating ACTH, LH and sex steroid secretion. Adv. Exp. Med. Biol. 274:295-301; 1990. Rivier, C., Effect of peripheral and central cytokines on the hypothalamic-pituitary-adrenal axis of the rat. Ann. N. Y. Acad. Sci. 697:97105; 1993. Rivier, C.; Rivest, S.; Mechanisms mediating the effects of cytokines on neuroendocrine functions in the rat. Ciba Found. Symp. 1993; 172:204-20.; Rogers, M. P.; Reich, P.; Kelly, M. J.; Liang, M. H., Psychiatric consultation among hospitalized arthritis patients. Gen. Hosp. Psychiatry 2:89-94; 1980. Royce, J. R.; Holmes, T. M.; Poley, W., Behavior genetic analysis of mouse emotionality Ill. The diallel analysis. Behav. Genet. 5:351-372; 1975. Royce, J. R.; Poley, W.; Yeudall, L. T., Behavior-genetic analysis of mouse emotionality I. Factor analysis. J. Comp. Physiol. Psychol. 83:36-47; 1973. Saki6, B.; Denburg, J. A.; Denburg, S. D.; Szechtman, H., Blunted sensitivity to sucrose reward in autoimmune MRL-lpr mice: a curveshift study. Brain Res. Bull. 41:305 -311; 1996. Saki6, B.; Szechtman, H.; Denburg, J. A., Depressive-like behavior and interleukin-6 during autoimmune disease. Soc. Neurosci. Abst. 21:1396; 1995. Saki6, B.; Szechtman, H.; Denburg, S. D.; Carbotte, R. M.; Denburg, J. A., Brain-reactive antibodies and behavior of autoimmune MRLlpr mice. Physiol. Behav. 54:1025-1029; 1993. Saki6, B.; Szechtman, H.; Denburg, S. D.; Carbotte, R. M.; Denburg, J. A., Spatial learning during the course of autoimmune disease in MRL mice. Behav. Brain Res. 54:57-66; 1993. Saki6, B.; Szechtman, H.; Denburg, S. D.; Denburg, J. A., Immunosuppressive treatment prevents behavioral deficit in autoimmune MRL-lpr mice. Physiol. Behav. 58:797-802; 1995. Saki6, B.; Szechtman, H.; Keffer, M.; Talangbayan, H.; Stead, R.; Denburg, J. A., A behavioral profile of antoimmune lupus-prone MRL mice. Brain Behav. Immun. 6:265-285; 1992. Saki6, B. Szechtman, H., Stead, R., Denburg, J. A., Joint pathology and behavioral performance in autoimmune MRL-lpr mice. Physiol. Behav. 60:901-905; 1996. Saki6, B.; Szechtman, H.; Talangbayan, H.; Denburg, S. D.; Carbotte, R. M.; Denburg, J. A., Behaviour and immune status of MRL mice in the postweaning period. Brain Behav. Immun. 8:1-13; 1994.

N E U R O B E H A V I O R A L ALTERATIONS IN A U T O I M M U N E MICE 163. Sakit, B.; Szechtman, H ; Talangbayan, H.; Denburg, S, D.; Carbotte, R. M.; Denburg, J. A., Disturbed emotionality in autoimmune MRL-lpr mice. Physiol. Behav. 56:609-617; 1994. 164. Salas, M. A.; Evans, S. W.; Levell, M. J.; Whicher, J. T., Interleukin6 and ACTH act synergistically to stimulate the release of corticosterone from adrenal gland ceils. Clin. Exp. Immunol. 79:470-473; 1990. 165. Schiffer, R. B.; Hoffman, S. A. Behavioral sequelae of autoimmune disease. In: Ader, R., Felten, D. L., Cohen, N. eds. Psychoneuroimmunology. San Diego: Academic Press Inc; 1991:1037-1066.; 166. Schobitz, B.; De Kloet, E. R.; Holsboer, F., Gene expression and function of interleukin 1, interleukin 6 and tumor necrosis factor in the brain. Prog. Neurobiol. 44:397-432; 1994. 167. Schobitz, B.; Holsboer, F.; Kikkert, R.; Sutanto, W.; De Kloet, E. R., Peripheral and central regulation of IL-6 gene expression in endotoxin-treated rats. Endocr. Regul. 26:103-109; 1992. 168. Schrott, L. M.; Cmic, L. S., Sensitivity to foot shock in autoimmune NZB × NZW FI hybrid mice. Physiol. Behav. 56:849853; 1994. 169. Schrott, L. M.; Cruic, L. S. Emotionality and learning in autoimmune mice. Soc. Neurosci. Abst.;1994: 20:948.; 170. Schrott, L. M., Crnic, L. S., The role of performance factors in the active avoidance condition~ing deficit in autoimmune mice. Behav. Neurosci. 110:481-496; 1996. 171. Schrott, L. M.; Denenber[;, V. H.; Sherman, G. F.; Rosen, G. D.; Galaburda, A. M., Lashley maze learning deficits in NZB mice. Physiol. Behav. 52:1085-] 089; 1992. 172. Schrott, L. M.; Denenberg, V. H.; Sherman, G. F.; Waters, N. S.; Rosen, G. D.; Galaburda, A. M., Environmental enrichment, neocortical ectopias, and behavior in the autoimmune NZB mouse, Dev. Brain Res. 67:85-93; 199:'.. 173. Schrott, L. M.; Morrison, L.; Wimer, R.; Wimer, C.; Behan, P. O.; Denenberg, V. H., Autoimmunity and avoidance learning in NXRF recombinant inbred strains. Brain Behav. Immun. 8:100110; 1994. 174. Schrott, L. M.; Waters, N. S.; Boehm, G. W.; Sherman, G. F.; Morrison, L.; Rosen, G. D.; Galaburda, A. M.; Denenberg, V. H., Behavior, cortical ectopias, and autoimmunity in BXSB-Yaa and BXSB-Yaa + mice. Brain Behav. Immun. 7:205-223; 1993. 175. Scott, E.; Hickie, I., Lovdc, K.; Autoimmune disease in patients hospitalized with depres,;ive disorders. In: Husband, A. J. ed. Psychoimmunology: CNS-immune interactions. Boca Raton: CRC Press, Inc.; 1995: 79-85.; 176. Seggev, J. S.; Sunderrajan, E. V.; Palomo, T.; McKenzie, W. N.; Braun, S. R.; O'Sullivan, F. X.; Walker, S. E., Pulmonary perivascular and interstitial inflammation in MRL/MpJ-lpr/lpr mice. III. Modulation by cyclophosphamide and sex hormones in 4- and 6-month-old animals. Cfin. Immunol. Immunopathol. 60:289-298; 1991. 177. Sekiguchi, M.; Shimai, K.; Moriya, M.; Nowakowski, R. S., Abnormalities of foliation and neuronal position in the cerebellum of NZB/BINJ mouse. Dev. Brain Res. 64:189-195; 1991. 178. Shear, H. L.; Wofsy, D.; Talal, N., Effects of castration and sex hormones on immune clearance and autoimmune disease in MRL/ Mp-lpr/lpr and MRL/Mp-+/+ mice. Clin. Immunol. Immunopathol. 26:361-369; 1983. 179. Sherman, G. F.; Galaburda, A. M.; Behan, P. O.; Rosen, G. D., Neuroanatomical anomalies in autoimmune mice. Acta Neuropathol. (Bed.) 74:239-242; 1987. 180. Sherman, G. F.; Morrison, L.; Rosen, G. D.; Behan, P. O.; Galaburda, A. M., Brain abnormalities in immune defective mice. Brain Res. 532:25-33; 1990. 181. Sherman, G. F.; Rosen, G. D.; Galaburda, A. M., Neocorical anomalies in autoimmune mice: a model for the developmental neuropathology seen in the dyslexic brain. Drug Dev. Res. 15:307314; 1988. 182. Sherman, G. F.; Stone, J. S.; Press, D. M.; Rosen, G. D.; Galaburda, A. M., Abnormal architexzture and connections disclosed by neurofilament staining in the cerebral cortex of autoimmune mice. Brain Res. 529:202-207; 1990. 183. Sherman, G. F.; Stone, J. S.; Rosen, G. D.; Galaburda, A. M., Neocortical VIP neurons are increased in the hemisphere containing focal cerebrocortical microdysgenesis in New Zealand black mice. Brain Res. 532:232-236; 1990. 184. Shima, S.; Yano, K.; Sugiura, M.; Tokunaga, Y., Anticerebral antibodies in functional psychoses. Biol. Psychiatry 29:322-328; 1991.

339 185. Shinitzky, M.; Deckmann, M.; Kessler, A.; Sirota, P.; Rabbs, A.; Elizur, A., Platelet autoantibodies in dementia and schizophrenia. Possible implication for mental disorders. Ann. N. Y. Acad. Sci. 621:205-217; 1991. 186. Simon, J.; Simon, O., Effect of passive transfer of anti-brain antibodies to a normal recipient. Exp. Neurol. 47:523-534; 1975. 187. Singh, V. K.; Warren, R. P.; Odell, J. D.; Warren, W. L.; Cole, P., Antibodies to myelin basic protein in children with autistic behavior. Brain Behav. Immun. 7:97-103; 1993. 188. Sirota, P.; Firer, M. A.; Schild, K.; Tanay, A.; Elizur, A.; Meytes, D.; Slor, H., Autoantibodies to DNA in multicase families with schizophrenia. Biol. Psychiatry 33:450-455; 1993. 189. Spangelo, B. L.; deHoll, P. D.; Kalabay, L.; Bond, B. R.; Arnaud, P., Neurointermediate pituitary lobe cells synthesize and release interleukin-6 in vitro: effects of lipopolysaccharide and intedeukin- 1 beta. Endocrinology 135:556-563; 1994. 190. Spangelo, B. L.; Judd, A. M.; Isakson, P. C.; MacLeod, R. M., Intedeukin-6 stimulates anterior pituitary hormone release in vitro. Endocrinology 125:575-577; 1989. 191. Spangelo, B. L.; Judd, A. M.; Isakson, P. C.; MacLeod, R. M., Interleukin-1 stimulates interleukin-6 release from rat anterior pituitary cells in vitro. Endocrinology 128:2685-2692; 1991. 192. Spangelo, B. L.; MacLeod, R. M.; Isakson, P. C., Production of intedeukin-6 by anterior pituitary cells in vitro. Endocrinology 126:582-586; 1990. 193, Spencer, D. G. Jr.; Humphries, K.; Mathis, D.; Lal, H., Behavioral impairments related to cognitive dysfunction in the autoimmnne New Zealand black mouse. Behav. Neurosci. 100:353-358; 1986. 194. Spezialetti, R.; Bluestein, H. G.; Peter, J. B.; Alexander, E. L., Neuropsychiatric disease in Sjogren's syndrome: anti-ribosomal P and anti-neuronal antibodies, Am. J. Med. 95:153-160; 1993. 195. Steinberg, A. D., MRL-lpr/lpr disease: theories meet Fas. Semin. Immunol. 6:55-69; 1994. 196. Steinberg, E. M.; Chrousos, G. P.; Wilder, R. L.; Gold, P. W., The stress response and the regulation of inflammatory disease. Ann. Int. Med. 117:854-866; 1992. 197. Stuart, R. A.; Littlewood, A. J.; Maddison, P. J.; Hall, N. D., Elevated serum intedeukin-6 levels associated with active disease in systemic connective tissue disorders. Clin. Exp. Rheumatol. 13:17-22; 1995. 198. Sundin, U.; Thelander, S., Antibody reactivity to brain membrane proteins in serum from schizophrenic patients. Brain Behav. Immun. 3:345-358; 1989. 199. Suzuka, H.; Yoshifusa, H.; Nakamura, Y.; Miyawaki, S.; Shibata, Y., Morphological analysis of autoimmune disease in MRL-lpr,Yaa male mice with rapidly progressive systemic lupus erythematosus. Autoimmunity 14:275-282; 1993. 200. Suzuki, H.; Yasukawa, K.; Saito, T.; Narazaki, M4 Hasegawa, A.; Taga, T., Serum soluble interleukin-6 receptor in MRL/lpr mice is elevated with age and mediates the interleukin-6 signal. Eur. J. Immunol. 23:1078-1082; 1993. 201. Sweep, F.; Rijnkels, C.; Hermus, A., Activation of the hypothalamuspituitary-adrenal axis by cytokines. Acta Endocrinol. 125 Suppl 1:84-91; 1991. 202. Symons, J. P.; Davis, R. E.; Marriott, J. G., Water-maze learning and effects of cholinergic drugs in mouse strains with high and low hippocampal pyramidal cell counts. Life Sci. 42:375-383; 1988. 203. Talal, N.; Dang, H.; Ahmed, S. A.; Kralg, E.; Fischbach, M., Interleukin 2, T cell receptor and sex hormone studies in autoimmune mice. J. Rheumatol. 14 Suppl 13:21-25; 1987. 204. Tanaka, A.; O'Sullivan, F. X.; Koopman, W. J.; Gay, S., Etiopathogenesis of rheumatoid arthritis-like disease in MRL/1 mice: II. Ultrastructural basis of joint destruction. J. Rheumatol. 15:10-16; 1988. 205. Tang, B.; Matsuda, T.; Akira, S.; Nagata, N.; Ikehara, S.; Hirano, T.; Kishimoto, T., Age-associated increase in interleukin 6 in MRL/lpr mice. Int. Immunol. 3:273-278; 1991. 206. Tehrani, M. J.; Hu, Y.; Marquette, C.; Dietrich, H.; Haour, F.; Wick, G., Interleukin-1 receptor deficiency in brains from NZB and (NZB/ NZW)F1 autoimmune mice. J. Neuroimmunol. 53:91-99; 1994. 207. Theofilopoulos, A. N. Murine models of lupus. In: Lahita, R. G. ed. Systemic lupus erythematosus. New York: Churchill Livingstone; 1992: 121-194.; 208. Treit, D.; Fundytus, M., Thigmotaxis as a test for anxiolytic activity in rats. Pharm. Biochem. Behav. 31:959-962; 1988.

340 209. Tsai, C. Y.; Wu, T. H.; Huang, S. F.; Sun, K. H,; Hsieh, S. C.; Han, S. H.; Yu, H. S.; Yu, C. L., Abnormal splenic and thymic IL-4 and TNFalpha expression in MRL-lpr/lpr mice. Scan. J. Rheumatol. 41:157163; 1995. 210. Tsal, C. Y.; Wu, T. H.; Tsai, S. T.; Chen, K. H.; Thajeb, P.; Lin, W. M.; Yu, H. S.; Yu, C. L., Cerebrospinal fluid interleukin-6, prostaglandin E2 and autoantibodies in patients with neuropsychiatric systemic lupus erythematosus and central nervous system infections. Scan. J. Rheumatol. 23:57-63; 1994. 211. Utset, T. O.; Golden, M.; Siberry, G.; Kiri, N.; Crum, R. M.; Petri, M., Depressive symptoms in patients with systemic lupus erythematosus: association with central nervous system lupus and Sjogren's syndrome. J. Rheumatol. 21:2039-2045; 1994. 212. Vandam, A. P.; Wekking, E. M.; Callewaert, J. A. C.; Schipperijn, A. J. M.; Oomen, H. A.P.C.; Dejong, J.; Swaak, A. J. G.; Smeenk, R. J. T.; Feltkamp, T. E. W., Psychiatric symptoms before systemic lupus erythematosus is diagnosed. Rheumatol. Int. 14:57-62; 1994. 213. Vogelweid, C. M.; Johnson, G. C.; Besch-Williford, C. L.; Basler, J.; Walker, S. E., Inflammatory central nervous system disease in lupusprone MRL/lpr mice: comparative histologic and immunohistochemical findings. J. Neuroimmunol. 35:89-99; 1991. 214. Vogelweid, C. M.; Wright, D. C.; Johnson, J. C.; Hewett, J. E.; Walker, S. E., Evaluation of memory, learning ability, and clinical neurologic function in pathogen-free mice with systemic lupus erythematosus. Arthritis Rheum. 37:889-897; 1994. 215. Warren, R. P.; Cole, P.; Odell, J. D.; Pingree, C. B.; Warren, W. L.; White, E.; Yonk, J., Detection of maternal antibodies in infantile autism. J. Am. Acad. Child Adol. Psychiat. 29:873-877; 1990. 216. Warren, R. P.; Yonk, L. J.; Burger, R. A.; Cole, P.; Odell, J. D.; Warren, W. L.; White, E., Deficiency of suppressor-inducer (CD4 + CD45RA + ) T cells in autism. Immunol. Invest. 19:245-251; 1990. 217. Watanabe-Fukunaga, R.; Brannan, C. 1.; Itoh, N.; Yonehara, S.; Copeland, N. G.; Jenkins, N. A.; Nagata, S., The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J. Immunol. 148:1274-1279; 1992. 218. Weigent, D. A.; Can', D. J.; Blalock, J. E., Bidirectional communication between the neuroendocrine and immune systems. Common hormones and hormone receptors. Ann. N. Y. Acad. Sci. 579:17-27; 1990.

SAKI(~, SZECHTMAN AND DENBURG 219. Wekking, E. M., Psychiatric symptoms in systemic lupus erythematosus--an update. Psychosom. Med. 55:219-228; 1993. 220. Wekking, E. M.; Nossent, J. C.; van Dam, A. P.; Swaak, A. J, Cognitive and emotional disturbances in systemic lupus erythematosus. Psychother. Psychosom. 55:126-131; 1991. 221. Wilder, R. L., Neuroendocrine-immune system interactions and autoimmunity. Ann. Rev. lmmunol. 13:307-338; 1995. 222. Wilder, R. L.; Stemberg, E. M., Neuroendocrine hormonal factors in rheumatoid arthritis and related conditions. Curr. Opin. Rheumatol. 2:436-440; 1990. 223. Willner, P.; Muscat, R.; Papp, M., Chronic mild stress-induced anhedonia: a realistic animal model of depression. Neurosci. Biobehav. Rev. 16:525-534; 1992. 224. Wisniewski, H. M.; Lossinsky, A. S., Structural and functional aspects of the interaction of inflammatory cells with the bloodbrain barrier in experimental brain inflammation. Brain Pathol. 1:8996; 1991. 225. Woloski, B. M.; Smith, E. M.; Meyer, W. J.; Fuller, G. M.; Blalock, J. E., Corticotropin-releasing activity of monokines. Science 230:1035-1037; 1985. 226. Wree, A.; Beck, T.; Bielenberg, G. W.; Schleicher, A.; Zilles, K., Local cerebral glucose utilization in the autoimmune New Zealand black (NZB) mouse. Histochemistry 92:343-348; 1989. 227. Yannitsi, S. G.; Manoussakis, M. N.; Mavridis, A. K.; Tzioufas, A. G.; Loukas, S. B.; Plataris, G. K.; Liakos, A. D.; Moutsopoulos, H. M., Factors related to the presence of autoantibodies in patients with chronic mental disorders. Biol. Psychiatry 27:747756; 1990. 228. Yeh, T. S.; Wang, C. R.; Jeng, G. W.; Lee, G. L.; Chen, M. Y.; Wang, G. R.; Lin, K. T.; Chuang, C. Y.; Chen, C. Y., The study of anticardiolipin antibodies and interleukin-6 in cerebrospinal fluid and blood of Chinese patients with systemic lupus erythematosus and central nervous system involvement. Autoimmunity 18:169-175; 1994. 229. Yonk, L. J.; Warren, R. P.; Burger, R. A.; Cole, P.; Odell, J. D.; Warren, W. L.; White, E., CD4 + helper T cell depression in autism. Immunol. Lett. 25:341-345; 1990. 230. Zimmerman, A. W.; Frye, V. H.; Potter, N. T., Immunological aspects of autism. Int. Pediat. 8:161-166; 1993.