Annotated Scientific Paper
There follows a copy of an original scientific article published in 1987 by Nestor Schmajuk. This
article is very closely relevant to the account of schizophrenia given in Chapter 23 of the present
book. It is well worth reading to gain an impression of how an author presents a case for an animal
model: the hippocampal lesioned rat as being an animal model of schizophrenia.
Q What is an animal model?
It is an example of a non-human animal that exhibits features in common with the human system.
It is not supposed to suggest identity. Rather, it merely highlights some similar features that could
prove insightful when considering the human situation. Note that Schmajuk documents a number of
different animal models of schizophrenia. These need not be seen as competitive. Rather, each
might capture a different feature of the condition.
As you read Schmajuk’s article, look out for the logic that he develops and the style of argument.
A paper is an act of advocacy and you need to read it with a critical eye. How convincing is the case
that Schmajuk makes? 3
Consider the point made frequently in the text of the book that one cannot draw a neat dichotomy
between genetic and environmental determinants of a condition. Consider how Schmajuk’s
argument illustrates this point.
Schmajuk’s paper is not a recent one. Things move on. By means of a computer citation search,
it might be useful for you to check the subsequent articles that have cited this one and see what are
their conclusions.
The author and publishers are grateful to the journal Schizophrenia Bulletin for permission to
reproduce the article here.
Animal Models for Schizophrenia: The Hippocampally Lesioned Animal
by Nestor A. Schmajuk (Schizophrenia Bulletin, 13, No. 2, 1987, pp.317-327)
Abstract
Animals with hippocampal lesions are evaluated as models for schizophrenia according
to the criteria of McKinney and Bunney (1969). They seem to comply adequately with the
following requirements: (1) similarity of inducing conditions; (2) similarity of behavioral
states; (3) similarity of underlying neurobiological mechanisms; and (4) reversibility by usual
pharmacological treatment. The model seems adequate to reproduce several symptoms of
the disorder, offering a good experimental tool for the analysis of its inducing conditions,
affected neurobiological mechanisms, and clinical treatment.
Animal models can provide a useful tool for the study of some aspects of psychiatric disorders
and their treatment. Evaluation of drugs in the early stages of research, brain manipulations to
reproduce the disease, and rigorous controlled experiments in which some subjects do not receive
treatment pose ethical and practical issues that encourage the development of animal models.
Several animal models have been proposed for schizophrenia (see McKinney and Moran 1981):
the amphetamine model (Kokkinidis and Anisman 1980), the L-dopa model (Feldkircher et al. 1984),
the phenylethylamine (PEA) model (Borison, Havdala, and Diamond 1977), the hallucinogen model,
the noradrenergic reward system lesion model (Stein and Wise 1971), the reticular stimulation
model (Kornetzky and Markowitz 1978), and the social isolation model (Harlow and Harlow 1962).
All these models reproduce some of the major deficits of schizophrenic patients. The amphetamine
and L-dopa models correspond to the dopamine theory of schizophrenia, the hallucinogen model to
the transmethylation theory (Osmond and Smythies 1952), the noradrenergic reward system lesion
model to the Stein and Wise (1971) theory, and the reticular stimulation model to the hyperarousal
theory (Venables 1966).
Torrey and Peterson (1974) suggested that the limbic-mesolimbic system might be involved in
schizophrenia for the following reasons: (1) schizophrenic patients with implanted electrodes in
limbic areas produce electrical abnormalities coinciding with their delusions, agitation, or
hallucinations; (2) humans with known limbic system neuropathologies have schizophrenic
symptoms; (3) many patients with limbic seizures have schizophrenic symptoms; (4) lesions of the
limbic system render animals unable to screen out multiple visual stimuli; (5) lesions or stimulation
of the limbic structures in humans causes schizophrenic symptoms (paranoia, depersonalization,
distortion of perception, violence, and catatonia); (6) chronic schizophrenic patients have different
electroencephalographic profiles; and (7) psychedelic drugs produce maximal electrical
abnormalities in the limbic system of monkeys. Recently, Weinberger, Wagner, and Wyatt (1983)
concluded that pathology of the limbic system is associated with schizophrenia.
More specifically, the hippocampus and the nucleus accumbens have been discussed as
possible regions that might be affected in schizophrenic disorders. Mednick (1974a) suggested that
hippocampal damage was associated with schizophrenic symptoms. He pointed out that after
hippocampal lesions rats are hyperactive (Kimble 1968) and related this behavioral change to the
state of hyperarousal characteristic of schizophrenics (Venables 1966). Poor habituation in rats with
hippocampal lesions (Kimble 1968) would be related to the poor habituation of the galvanic skin
response shown by schizophrenic patients (Zahn 1964). The resistance to extinction shown by
lesioned rats (Isaacson, Douglas, and Moore 1961) corresponds to the unusually large number of
trials shown by schizophrenics to extinguish a conditioned plethysmographic response
(Vinogradova 1962). These results, according to Mednick (1974a), would be related to two
physiological changes observed after hippocampal lesions. First, the lack of inhibition of
adrenocorticotropic hormone (ACTH) release (Knigge 1966), which plays a role during states of
stress, can contribute to prolonging the extinction of a conditioned response (DeWied and Bohus
1966). The second change is the lack of inhibition on the reticular formation after hippocampal
lesion (Redding 1967), which would produce hyperarousal. In the same direction, Venables (1973)
suggested that schizophrenia might be the result of hippocampal dysfunction. He pointed out
hippocampal vulnerability to disturbances, the action of several tranquilizing agents on hippocampal
function, the high methionine uptake by the hippocampus as related to the worsening of
schizophrenic symptoms after methionine administration, and the association of temporal lobe
epilepsy with psychosis. Heath (1977) reported that a number of patients displaying interictal
psychotic behaviors showed electroencephalograms with aberrant activity in deep temporal nuclei
(hippocampus and amygdala).
Matthysse (1974, 1981) suggested that the nucleus accumbens septi (NAS) played a
conspicuous role in schizophrenia. He pointed out similarities between animal behavior after NAS
manipulations and the symptomatology of schizophrenia. Hyperreactivity to stimuli has been found
after electrolytic lesions of NAS, which causes, for instance, more rapid acquisition of avoidance
responses (Lorens, Sorenson, and Harvey 1970).
The cited references suggest that animals with lesions of the limbic system might provide a
model of schizophrenic disorders. In this article I attempt to investigate how animals with bilateral
lesions of the hippocampus meet the requirements proposed by McKinney and Bunney (1969) to
model schizophrenia. These authors proposed the following four criteria for the evaluation of animal
models of psychiatric disorders: (1) similarity of inducing conditions; (2) similarity of behavioral state;
(3) common underlying neurobiological mechanisms; and (4) reversal by clinically effective
treatment techniques. As it will be shown, this animal model can become a useful tool for studying
schizophrenia.
Evaluation of the Model
Similarity of Inducing Conditions. Several factors have been proposed to be the inducing
mechanism for schizophrenia. Among them are hippocampal anoxia, lesions of the noradrenergic
reward system by 6-hydroxydopamine, and steroid changes associated with puberty.
Mednick (1974a) related the presence of schizophrenic symptoms to pregnancy or birth
complications (PBCs) such as anoxia, prematurity, prolonged labor, placental difficulty, or mother’s
illness during pregnancy. The PBCs would trigger a genetically predisposed sensitivity of the
hippocampus to anoxia in children of schizophrenics. Handford (1975) and Luchins, Pollin, and
Wyatt (1980) found that intrauterine or perinatal factors such as anoxia might cause brain damage
that contributes to schizophrenia. Damage of the hippocampus can result in the constellation of
behavioral deficits shown by schizophrenic patients. If Mednick’s view (1974a) were accepted,
lesions of the hippocampus would provide a model complying with the first criterion.
Hippocampally lesioned animals also can provide an adequate model for Stein and Wise’s (1971)
theory. According to Mason and Iversen (1979) and Aston-Jones and Bloom (1981), the function of
the noradrenergic (NA) system is to enhance the activity of the hippocampal cells processing the
most salient external stimuli and ignoring the irrelevant ones. Several behavioral effects of the lesion
of the NA system and those of the destruction of the hippocampus are similar: (1) resistance to
extinction (Mason and Iversen [1978a] and Jarrard, Isaacson, and Wickelgren [1964], respectively);
(2) retardation of discrimination reversal (Mason and Iversen [1978b] and Kimble and Kimble [1965],
respectively); (3) absence of latent inhibition (Mason and Iversen [1978b] and Solomon and Moore
[1975], respectively); (4) attenuation of blocking (Lorden et al. [1980] and Solomon [1977],
respectively). Moreover, McCormick and Thompson (1982) found that the increase in resistance to
extinction produced by the lesion of the locus ceruleus, where the NA system has its origin, was
related to the NA depletion in the hippocampus. Finally, the results of the lesion of the NA system
and the lesion of the hippocampus both have been related to the impairment of attentional
mechanisms as described by Mackintosh’s (1975) attentional theory (Mason [1980] and Moore and
Stickney [1980], respectively).
Stevens (1973) suggested that the temporal relationships of psychotic episodes to steroid
changes associated, for example, with puberty could be related to the specific uptake of steroids by
cells in the hippocampus, hypothalamus, septum, and amygdala.
In summary, if schizophrenia were induced either by hippocampal lesions due to PBC, lesion to
the NA reward system by an endogenous neurotoxin, or hippocampal alterations produced by
steroid increase, the hippocampal lesion model could be considered to share similar inducting
conditions.
Similarity of Behavioral States. Many deficits described in schizophrenic patients have been
found after hippocampal lesions in animals.
Attentional effects. Broadbent’s (1958) model of human information processing interested
psychopathologists in the concept of selective attention. Payne, Matussek, and George (1959)
hypothesized that schizophrenic overinclusive thinking might be one aspect of a defective
attentional filter. Weckowicz and Belwett (1959) suggested that the loss of abstract reasoning was a
consequence of a failure to attend selectively to relevant information.
Several types of evidence support the attentional view. Subjective reports by schizophrenic
patients mention an inability to organize and control incoming information (McGhie and Chapman
1961). Reaction time has been found to be longer in schizophrenic than normal subjects (Rodnick
and Shakow 1940), and it has been considered a reflection of attentional dysfunction. Schizophrenic
subjects were more distractible than normals in a digitspan test in the presence of distracting stimuli
(Lawson, McGhie, and Chapman 1967). Hemsley and Zawada (1976) found that schizophrenic (and
depressive patients) had difficulties in distinguishing between relevant and irrelevant stimuli in a
dichotic memory task when a differentiated voice was reading the relevant digits.
Animals with hippocampal lesions show several behavioral changes that have been interpreted
as attentional deficits. Solomon and Moore (1975) found that lesioned animals failed to show latent
inhibition. Latent inhibition refers to the fact that presenting the conditioned stimulus alone
repeatedly before pairing it with the unconditioned stimulus produces retardation in acquisition.
Rickert, Bennett, and French (1978) and Solomon (1977) found that hippocampal ablation produced
attenuation of blocking. Blocking refers to the weaker conditioning of stimulus B presented together
with stimulus A when stimulus A has been previously paired with the unconditioned stimulus than
conditioning obtained without previous A conditioning, Rickert et al. (1979) and Schmajuk, Spear,
and Isaacson (1983) found absence of overshadowing after hippocampal lesions. Overshadowing
refers to the weaker conditioning of stimulus B when paired together with a second stimulus A to the
unconditioned stimulus than that obtained in the absence of A. This evidence has been interpreted
as the result of the failure to “tune out” irrelevant stimuli (Solomon 1980) after hippocampal lesions.
Schmajuk (1984) and Schmajuk and Moore (1985) suggested that the deficit shown by
hippocampectomized animals could be related to Pearce and Hall’s (1980) attentional theory.
According to this view, animals with hippocampal lesions cannot decrease the value of an
attentional parameter which establishes the rate of association between conditioned and
unconditioned stimuli. In the case of schizophrenic and manic patients, Oltmanns (1978) suggested
that active processing of information, as defined in Schneider and Shiffrin’s (1977) attentional
theory, is disrupted by the presence of irrelevant stimuli. The attentional parameter disrupted
according to Schmajuk’s (1984) model closely corresponds to the concept of active processing as
proposed by Schneider and Shiffrin: after hippocampal lesions, more irrelevant stimuli will be
processed.
Oades (1982) stressed the relationship between the attentional deficits after hippocampal lesions
and schizophrenia, considering that thought disorder is the feature of psychiatric assessment that
correlates best with an attentional disorder as suggested by Neale and Cromwell (1968).
Spatial effects. In a size-constancy procedure, chronic schizophrenic subjects showed size
underestimation, suggesting that they pay too much attention to the retinal image with exclusion of
relevant spatial cues (Weckowicz 1957). Correspondingly, animals with hippocampal lesions show
important spatial deficits (O’Keefe and Nadel 1978), leading these authors to suggest that the
hippocampus would be a “spatial map.”
Contextual effects. Normal individuals can take advantage of contextual information to retrieve
adequate information from memory. If schizophrenic patients are deficient in this ability, their recall
performance should not improve as a function of increasing contextual information. Lawson,
McGhie, and Chapman (1964) found that with noncontextual cues schizophrenic and normal
subjects did not differ, but with more contextual information, the difference was significant.
Chapman (1958) found that schizophrenic patients selected responses mediated by strong verbal
associations, instead of conceptual relationships; he speculated that they might fail to attend to
contextual constraints that inhibit normal individuals from making the same errors. However, Naficy
and Willerman (1980) found that this problem was present in both schizophrenic and manic patients.
Hirsh (1974) proposed that lesions of the hippocampus produce deficits in contextual retrieval of
information from memory. This implies abnormal behavior when there is a conflict between
previously acquired behavior and that to be acquired, since the old information should be canceled
instead of labeled as “old,” and more interference will be present. This would explain, for example,
deficits shown in extinction or discrimination reversal. Hirsh, Holt, and Mosseri (1978) found that
after hippocampal lesions rats were unable to retrieve adequate information according to their
motivational state (internal contextual cues).
Memory organization. The hypothesis that schizophrenic patients are impaired in the ability to
use organizational processes in memory was studied by Koh, Kayton, and Berry (1973). They found
that schizophrenic patients, unlike normals, were unable to improve the number of words recalled
when given a categorized list of words.
Wickelgren (1979) suggested that the hippocampus controls the organization of information
according to categories. An element representing an entire set of elements is called a chunk (e.g.,
furniture for chair or table). This view also incorporates contextual learning since there are
“contextual dependent chunk nodes” (p. 54). O’Keefe and Nadel (1978) also implicate the
hippocampus in memory organization. The extension of their theory to humans proposes that
information is stored in deep structures in the hippocampus which constitute “semantic maps.” It is
predicted that after hippocampal lesions, language functions dependent on the deep structure will
be impaired.
Recognition memory. Bauman and Murray (1968) and Nachmani and Cohen (1969) reported
that although schizophrenics recognized items as well as controls, they were significantly impaired
in their ability to recall stimulus items. In contrast, Gaffan (1972) suggested that recognition
memory, but not associative memory, is affected after hippocampal lesions. However, Winocur
(1982) found that recognition memory was only affected in spatial tasks, suggesting a possible
explanation for the divergent results.
Classical conditioning. Pffafman and Schlosberg (1930) found a knee-jerk response was
conditioned faster in schizophrenic patients than in normals. Mays (1934) and Shipley (1934) found
that galvanic skin response was conditioned faster in schizophrenics. Correspondingly, Schmaltz
and Theios (1972) and Schmajuk and Isaacson (1984) found that animals with hippocampal lesions
showed facilitated classical conditioning.
Generalization. Bender and Schilder (1930) noted over-generalization in conditioned withdrawal
from shock in schizophrenic subjects. Cameron (1951) considered overinclusion and broadening of
generalization as part of the schizophrenic syndrome. However, more recent evidence (Harvey and
Neale 1983) suggests that overinclusion is more common in manic than in schizophrenic patients.
Mastroiani (1979) and Solomon and Moore (1975) found that animals with hippocampal lesions
showed more generalization to auditory stimuli.
Complex learning. Hunt (1936) and Hunt and Cofer (1944) showed that schizophrenic patients
performed poorly on complex tasks, mainly because they were retarded by irrelevant, incorrect
responses. Similarly, animals with hippocampal lesions performed poorly in complex mazes but not
in simple ones (Kimble 1963).
Stereotyped behavior. Bleuler (1911/1950) pointed out the stereotyped behavior of
schizophrenic patients. Devenport, Devenport, and Holloway (1980) found that rats with
hippocampal lesions showed behavioral stereotypy after receiving signaled administration of
reward, similar to that obtained after amphetamine administration.
Superstitious behavior. According to Matthysse (1981), superstitious behavior (operational
responses maintained even if they are not contingent with reward) is a behavioral model for the
failure in reality testing characteristic of schizophrenics. Devenport (1979, 1980) found that animals
with hippocampal lesions behaved as if a relationship existed between their behavior and
reinforcement, when reward was noncontingent on their responses.
Hyperarousal. Venables (1964, 1966) suggested that the schizophrenic syndrome is related to a
state of hyperarousal. Mednick (1974a) related this state to the absence of corticosterone receptors
subsequent to the destruction of the hippocampus, which would increase ACTH release and, as a
consequence, increase the response to stress. Although hippocampal electrical stimulation in
animals confirmed the idea of a hippocampal inhibition on the hypothalamohypophyseal system, it
was not clear until recently that hippocampal lesions led to an increase in ACTH release, and
therefore to higher levels of corticosterone (see Van Hartesveld 1975; Dunn and Orr 1984).
Osborne and Seggie (1980) found increased corticosterone response to stress in rats with fornix
lesions, and this increase was correlated with increased activity in the open field. Interestingly, it has
been found (Rastogi and Singhal 1978) that corticosterone treatment, after adrenalectomy, reduces
monoamine oxidase activity, which can be responsible for increases in cerebral NA and dopamine
concentrations.
Recently, Ryan et al. (1983) found that the hyperactivity shown by rats with hippocampal lesion
could be reduced by a corticosterone synthesis suppressor (metyrapone) treatment. This result
would predict that metyrapone treatment could be of value in treating schizophrenia.
Extinction and habituation. As mentioned above, both schizophrenic patients and animals with
hippocampal lesions show retardation in extinction and poor habituation.
Skin conductance experiments. Mednick (1974b) and Venables (1974) have suggested that
the faster skin conductance recovery (SCR) shown by schizophrenic patients might be linked to
limbic factors. Bagshaw, Kimble, and Pribram (1965) had studied the galvanic skin response in
monkeys with hippocampal ablation. When they reanalyzed the data for SCR, they found that SCR
was faster in hippocampectomized monkeys than in amygdalectomized or control monkeys
(Bagshaw and Kimble 1972). Venables (1977) suggested that since lesions of the hippocampus
increase ACTH levels and adrenocortical steroids, faster sodium reabsorption and shorter SCR
could be expected.
Similar Underlying Neurobiological Mechanisms. We have cited several types of evidence
suggesting that hippocampal dysfunction underlies schizophrenia. Recent reviews of the literature
relating neuropathology and schizophrenia provide some support for the hypothesis.
Weinberger, Wagner, and Wyatt (1983) concluded that most of the data supported the idea of a
limbic system involvement in schizophrenia. For instance, post-mortem histopathological research
suggests that limbic areas are critical for the development of psychosis, though hippocampal cell
disarray has been found only in patients by Scheibel and Kovelman (1980) and Kovelman and
Scheibel (1984), but in patients and controls by Weinberger, Luchins, and Wyatt (1982). The most
typical findings in computed tomography studies have been increased ventricular size and cortical
atrophy. Ventricular enlargement would result from degenerative processes of the structures
surrounding lateral ventricles: limbic areas such as fornix and stria terminalis and nonlimbic areas
such as medial thalamus and caudate.
Seidman’s (1983) review on schizophrenia and brain dysfunction concluded that (1) brain
impairment exists in a substantial number of schizophrenic patients; (2) the type of brain dysfunction
varies from patient to patient, arguing against a unitary disease concept of schizophrenia; (3)
positive symptoms (delusions, hallucinations) originate from pathophysiological dysfunction in
limbic, midbrain, and upper brainstem regions; (4) negative symptoms (apathy, blunted effect, social
withdrawal, and avolition) originate from a frontal lobe dysfunction.
The dopamine hypothesis proposes that the neurobiological mechanism underlying psychotic
symptoms is a dopamine excess in the limbic regions. It is mainly based on the facts that
amphetamine psychosis resembles acute paranoid schizophrenia and that this effect can be
reversed by neuroleptics. However, the available evidence cannot be considered sufficient to
establish that dopaminergic systems are the locus of schizophrenic disturbance (Snyder 1980). In a
recent article, Carlton and Manowitz (1984) point out that dopamine hyperactivity might be either an
etiological or a symptom factor in schizophrenia. Supporting this view, Crow et al. (1978) concluded
that post-mortem studies of schizophrenic patients suggest that the increase in dopaminergic
receptors in nucleus accumbens and putamen is not entirely related to neuroleptic medication. This
increase in dopaminergic receptors might be a consequence of a hippocampal or amygdalar
dysfunction. For instance, Reinstein (1980) found an increase in dopamine receptors in the caudate
and nucleus accumbens, after hippocampal lesions, and Csernansky et al. (1983) found
dopaminergic supersensitivity and increase in dopamine receptors in amygdala, striatum, and
nucleus accumbens after seizures induced in rats by injecting ferric chloride in the amygdaloid
nucleus.
Reversal by Chemically Effective Treatments. For animals with hippocampal lesions to be
considered animal models of schizophrenia, their deficits should be relieved by the same treatments
used to treat schizophrenic patients.
Oades and Isaacson (1978) found that animals with hippocampal lesions made more errors
(visits to nonrewarded holes) when required to locate pellets of food located in 4 of 16 holes in an
open field. Administration of haloperidol reduced the number of visits to nonfood holes in the
lesioned animals but not in normals. The authors suggested that the effect of hippocampal lesions
was similar to that produced by an enhanced dopaminergic activity (Lyon and Robins 1975).
Devenport, Devenport, and Holloway (1980) found that animals with hippocampal lesions had an
exaggerated reaction to reward, consisting of behavioral stereotypies and locomotor activity similar
to those that follow D-amphetamine administration. Behavior returned to normal after haloperidol
administration. A possible site for haloperidol action is the nucleus accumbens septi (NAS).
Matthysse (1981) suggested that the dopaminergic input to the NAS would have a facilitatory effect
in the switching of attention from one stimulus to another. High levels of dopamine would impair
selective attention and, hence, schizophrenics would be inundated by irrelevant ideas and
sensations. Grastyan et al. (1954) proposed that the function of the hippocampus is an inhibitory
effect on the orienting response to nonsignificant stimuli. When the theta rhythm appears, inhibition
disappears and the animal displays an orienting response. De-France, Sikes, and Chronister (1981)
found that dopamine has a suppressive effect on the hippocampal input to the NAS when the input
frequencies are below theta—that is, when the animal is ignoring irrelevant stimuli. When the input
coming from the hippocampus is within the theta range—that is, when the animal is orienting to a
new stimulus—dopamine facilitates the switch of attention. If the schizophrenic syndrome is related
to a decreased or defective hippocampal input to the NAS, blocking the activity of dopamine at that
place would tend to decrease attentional shifts and, hence, selective attention would be improved. It
should be pointed out that the effect of neuroleptic drugs appears to be limited to the positive
symptoms of schizophrenia (Crow et al. 1978), which are correlated with limbic neuropathology
(Seidman 1983).
Discussion
In general, animals with hippocampal lesions seem to comply adequately with the criteria to be
regarded as models for schizophrenia. The similarity of inducing conditions, behavioral states, and
underlying neurobiological mechanisms, as well as the reversibility by chemical treatments,
suggests that animals with bilateral lesions of the hippocampus show many of the behavioral and
biological characteristics of schizophrenic patients.
Questions about the inducing conditions and the underlying neurobehavioral mechanisms of
schizophrenia have not been satisfactorily answered. This is a problem for the validation of the
model, but at the same time the study of animals with hippocampal lesions might be useful in this
respect.
A neurobiological mechanism cited in relation to schizophrenic disorders is an increase in
dopaminergic receptors (Cross et al. 1983). As pointed out, however, this phenomenon could be a
consequence of a hippocampal dysfunction. Another effect of a hippocampal lesion is an increase in
dopamine concentrations due to higher corticosterone levels. As mentioned, metyrapone alleviates
some of the effects of hippocampectomy, indicating a potential clinical application in schizophrenia.
The data shown also support a hippocampal theory of schizophrenia (Mednick 1974a). Caution
should be taken, however, since some of the behavioral results of the hippocampal lesion might be
due to changes in membrane protein phosphorylation in the NAS and the caudate (Bar, Gispen, and
Isaacson 1980), and, as mentioned before, some of the behavioral deficits that appear after
hippocampectomy are also present after lesions of the neostriatum, the frontal cortex, or the
olfactory bulbs. This suggests that the hippocampal lesion offers a good model either because the
hippocampus is a block of a system controlling some behaviors or because the lesion produces
secondary changes in other brain regions.
Kessler and Neale (1974) criticized the hippocampal theory of schizophrenia on the following
basis: (1) hippocampal control of ACTH would not be inhibitory, but inhibitory or excitatory according
to the type of stress induced; (2) there would be species differences in the type of behavioral deficits
observed after hippocampectomy; (3) a common effect observed after hippocampal lesions would
be a learning deficit considerably broader than the schizophrenic deficits; and (4) the site of anoxic
lesions would depend on species and gestational level.
New evidence is relevant to Kessler and Neale’s points. The inhibitory control of ACTH by the
hippocampus, even if not clear at that time (Van Hartesveldt 1975), is supported by more recent
data (Osborne and Seggie 1980; Dunn and Orr 1984). The interspecies differences do not seem
more important than the differences sometimes found in the same species when different
researchers approach the same problems (O’Keefe and Nadel 1978). This problem seems to be
more critical for a hippocampal theory than for an animal model, because in the latter case those
species sharing common behavioral deficits can be selected. Deficits shown by hippocampally
lesioned animals are not learning deficits; instead, animals with these lesions seem to learn more
than control animals, as mentioned before. After hippocampectomy, animals show a variety of
psychological deficits, many in common with schizophrenic patients. Finally, as suggested
previously, even though anoxia is only one factor that might trigger the onset of schizophrenia, more
recent evidence supports it (Luchins, Pollin, and Wyatt 1980).
When compared with the amphetamine model, the hippocampal model has been shown to share
many common behavioral states: extinction is retarded, spontaneous alternation is abolished,
shuttle-box avoidance is improved, active avoidance is improved, passive avoidance is impaired,
tasks requiring lower rates of responding prove difficult, and superstitious behavior appears
(Devenport, Devenport, and Holloway 1980).
In conclusion, animals with bilateral lesion of the hippocampus may provide an adequate animal
model for several symptoms of schizophrenia. The model deserves further study, and consideration
of the hippocampal lesion literature may be fruitful for the analysis of psychiatric disorders.
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Acknowledgment
The research reported was supported in part by the National Science Foundation (NSF IST8417756).
The Author
Nestor A. Schmajuk, Ph.D., is Research Associate, Department of Mathematics, Center for
Adaptive Systems, Boston University, Boston, MA.
*Reprint requests should be sent to Dr N.A. Schmajuk, Center for Adaptive Systems, Boston
University, III Cummington St., Boston, MA 02215.