Ina Weiner

The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum.

This Commentary compares the connections of the dopaminergic system with the striatum in rats and primates with respect to two levels of striatal organization: a tripartite functional (motor, associative and limbic) subdivision and a compartmental (patch/striosome-matrix) subdivision. The topography of other basal ganglia projections to the dopaminergic system with respect to their tripartite functional subdivision is also reviewed. This examination indicates that, in rats and primates, the following observations can be made. (1) The limbic striatum reciprocates its dopaminergic input and in addition innervates most of the dopaminergic neurons projecting to the associative and motor striatum, whereas the motor and associative striatum reciprocate only part of their dopaminergic input. Therefore, the connections of the three striatal subregions with the dopaminergic system are asymmetrical, but the direction of asymmetry differs between the limbic versus the motor and associative striatum. (2) The limbic striatum provides the main striatal input to dopamine cell bodies and proximal dendrites, with some contribution from a subset of neurons in the associative and motor striatum (patch neurons in rats; an unspecified group of neurons in primates), while striatal input to the ventrally extending dopamine dendrites arises mainly from a subset of neurons in the associative and motor striatum (matrix neurons in rats; an unspecified group of neurons in primates). (3) Projections from functionally corresponding subdivisions of the striatum, pallidum and subthalamic nucleus to the dopaminergic system overlap, but the specific targets (dopamine cells, dopamine dendrites, GABA cells) of these projections differ. Major differences include the following. (1) In rats, neurons projecting to the motor and associative striatum reside in distinct regions, while in primates they are arranged in interdigitating clusters. (2) In rats, the terminal fields of projections arising from the motor and associative striatum are largely segregated, while in primates they are not. (3) In rats, patch- and matrix-projecting dopamine cells are organized in spatially, morphologically, histochemically and hodologically distinct ventral and dorsal tiers, while in primates there is no (bi)division of the dopaminergic system that results in two areas which have all the characteristics of the two tiers in rats. Based on the anatomical data and known dopamine cell physiology, we forward an hypothesis regarding the influence of the basal ganglia on dopamine cell activity which captures at least part of the complex interplay taking place within the substantia nigra between projections arising from the different basal ganglia nuclei. Finally, we incorporate the striatal connections with the dopaminergic system into an open-interconnected scheme of basal ganglia-thalamocortical circuitry.

Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophrenia.

Prenatal exposure to infection is associated with increased liability to schizophrenia, and it is believed that such an association is mediated by the maternal immune response, in particular, the proinflammatory cytokines released by the maternal immune system, which may disrupt fetal brain development. Impaired capacity to ignore irrelevant stimuli is one of the central deficits in schizophrenia, and is manifested, among others, in loss of latent inhibition (LI), a phenomenon whereby repeated inconsequential pre-exposure to a stimulus impairs its subsequent capacity to signal significant consequences. We tested the effects of prenatal immune activation induced by peripheral administration of the synthetic cytokine releaser polyriboinosinic–polyribocytidilic acid (poly I : C) to pregnant dams, on LI in juvenile and adult offspring. Consistent with the characteristic maturational delay of schizophrenia, prenatal immune activation did not affect LI in the juvenile offspring, but led to LI disruption in adulthood. Both haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) reinstated LI in the adult offspring. In addition, prenatal immune activation led to a postpubertal emergence of increased sensitivity to the locomotor-stimulating effects of amphetamine and increased in vitro striatal dopamine release, as well as to morphological alterations in the hippocampus and the entorhinal cortex in the adult offspring, consistent with the well-documented mesolimbic dopaminergic and temporolimbic pathology in schizophrenia. These results suggest that prenatal poly I : C administration may provide a neurodevelopmental model of schizophrenia that reproduces a putative inducing factor; mimics the temporal course as well as some central abnormalities of the disorder; and predicts responsiveness to antipsychotic drugs.

Neural substrates of latent inhibition: the switching model.

Latent inhibition (LI) refers to decrement in conditioning to a stimulus as a result of its prior nonreinforced preexposure. It is a robust phenomenon that has been demonstrated in a variety of classical and instrumental conditioning procedures and in many mammalian species, including humans. The development of LI is considered to reflect decreased associability of, or attention to, stimuli that predict no significant outcome. The fact that LI is considered to be a reflection of attentional processes has become of increasing importance to neuroscientists who see LI as a convenient tool for measuring the effects of drug treatments and lesions on attention. The present article surveys the data on brain systems, which have been studied in regard to their involvement in LI. These are reviewed and discussed separately in sections on noradrenergic, cholinergic, dopaminergic, serotonergic, and septo-hippocampal manipulations. On the basis of these data, it is concluded that the neural substrates of LI include the mesolimbic dopaminergic system, the mesolimbic serotonergic system, and the hippocampus. It is proposed that the preexposed stimulus loses its capacity to affect behavior in conditioning, even though it predicts reinforcement, because the hippocampus inhibits the switching mechanism of the nucleus accumbens via the subiculum-accumbens pathway. This action of the hippocampus is modulated by the mesolimbic serotonergic system via its interactions with the hippocampal or mesolimbic dopaminergic systems, or both.

The switching model of latent inhibition: an update of neural substrates.

Organisms exposed to a stimulus which has no significant consequences, show subsequently latent inhibition (LI), namely, retarded conditioning to this stimulus. LI is considered to index the capacity to ignore irrelevant stimuli and its disruption has recently received increasing interest as an animal model of cognitive deficits in schizophrenia. Initial studies indicated that LI is disrupted by systemic or intra-accumbens injections of amphetamine and hippocampal lesions, and potentiated by systemic administration of neuroleptics. On the basis of these findings, the switching model of LI proposed that LI depends on the subicular input to the nucleus accumbens (NAC). Subsequent studies supported and refined this proposition. Lesion studies show that LI is indeed disrupted by severing the subicular input to the NAC, and further implicate the entorhinal/ventral subicular portion of this pathway projecting to the shell subterritory of the NAC. There is a functional dissociation between the shell and core subterritories of the NAC, with lesions of the former but not of the latter disrupting LI. This suggests that the shell is necessary for the expression and the core for the disruption of LI. The involvement of the NAC has been also demonstrated by findings that LI is disrupted by intra-accumbens injection of amphetamine and potentiated by DA depletion or blockade in this structure. Disruption and potentiation of LI by systemic administration of amphetamine and neuroleptics, respectively, have been firmly established, and in addition, have been shown to be sensitive to parametric manipulations of the LI procedure. LI is unaffected by lesions and DA manipulations of medial prefrontal cortex and lesions of basolateral amygdala. The implications of these findings for LI as an animal model of schizophrenia are discussed.

The role of mesolimbic dopaminergic and retrohippocampal afferents to the nucleus accumbens in latent inhibition: implications for schizophrenia

Latent inhibition (LI) consists in a retardation of conditioning seen when the to-be-conditioned stimulus is first presented a number of times without other consequence. Disruption of LI has been proposed as a possible model of the cognitive abnormality that underlies the positive psychotic symptoms of acute schizophrenia. We review here evidence in support of the model, including experiments tending to show that: (1) disruption of LI is characteristic of acute, positively-symptomatic schizophrenia; (2) LI depends upon dopaminergic activity; (3) LI depends specifically upon dopamine release in n. accumbens; (4) LI depends upon the integrity of the hippocampal formation and the retrohippocampal region reciprocally connected to the hippocampal formation; (5) the roles of n. accumbens and the hippocampal system in LI are interconnected.

Differential involvement of the shell and core subterritories of the nucleus accumbens in latent inhibition and amphetamine-induced activity

Latent inhibition (LI) consists of retardation in conditioning to a stimulus as a consequence of its prior non-reinforced pre-exposure. In view of findings that LI is disrupted in acute schizophrenic patients and evidence from animal experiments pointing to the involvement of the mesolimbic dopamine (DA) system in this phenomenon, the present study investigated the effects of electrolytic lesions to the shell and core subterritories of the nucleus accumbens on LI in rats (Expt. 1). LI was indexed by the amount of suppression of drinking in the presence of a tone that was either pre-exposed or not prior to its pairing with reinforcement (a foot shock). Expt.2 tested the effects of the DA antagonist, haloperidol, on LI in shell- and core-lesioned animals. Expt. 3 tested the effects of shell and core lesions on spontaneous and amphetamine-induced locomotion. In Expt. 1, LI, i.e., lower suppression of drinking in the pre-exposed as compared to the non-pre-exposed animals, was obtained in the sham-operated condition. Core and shell lesions produced distinct effects on LI. Animals with core lesions developed LI, but exhibited an overall lower suppression of drinking in comparison to the sham-operated animals. In contrast, shell lesions led to a disappearance of LI. Expt. 2 replicated the differential effects of shell and core lesions on LI, although in this experiment, core lesion did not attenuate suppression of drinking. Haloperidol prevented shell-induced abolition of LI. In Expt. 3, shell- but not core-lesioned animals were more active than sham controls following amphetamine administration. These results provide evidence for functional differences between the shell and core subregions, as well as for the involvement of the mesolimbic DA system in LI.

Facilitation of the expression but not the acquisition of latent inhibition by haloperidol in rats.

In the latent inhibition (LI) paradigm, nonreinforced preexposure to a stimulus retards subsequent conditioning to that stimulus. The administration of haloperidol in both the preexposure and the conditioning stages was found to enhance LI in the conditioned emotional response (CER) procedure (Weiner and Feldon, 1986). The present experiments investigated the effects of 0.1 mg/kg haloperidol administration on LI in a two-way avoidance procedure, consisting of two stages: preexposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; and conditioning, in which the animals acquired a two-way avoidance response with the tone serving as the warning signal. Experiments 1 and 2 tested whether the administration of haloperidol confirmed to the preexposure stage, where learning to ignore the nonreinforced stimulus takes place, would suffice to enhance the LI effect. In Experiment 1, preexposure and conditioning were conducted 24 hr apart. LI was obtained in both the placebo and haloperidol conditions, but the effect was not more pronounced under the drug. In addition, haloperidol-treated animals exhibited impaired avoidance performance. In Experiment 2, preexposure and conditioning were given 72 hr apart. With this interval, haloperidol did not affect avoidance performance. However, also under these conditions, the magnitude of the LI effect was not larger in the haloperidol-treated groups, indicating that the administration of the drug in the preexposure stage alone did not suffice to enhance LI.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of excitotoxic lesion of the medial prefrontal cortex on latent inhibition, prepulse inhibition, food hoarding, elevated plus maze, active avoidance and locomotor activity in the rat

Latent inhibition is a measure of retarded conditioning to a previously presented nonreinforced stimulus that is impaired in schizophrenic patients and in rats treated with amphetamine. In terms of neural substrates, latent inhibition depends on the integrity of the nucleus accumbens and the inputs to this structure from the hippocampal formation and adjacent cortical areas. Since another major source of input to the nucleus accumbens is the medial prefrontal cortex, and there are numerous demonstrations that manipulations of this region can modify ventral striatal dopamine, we investigated the effects of N-methyl-D-aspartate lesion to the medial prefrontal cortex on latent inhibition, assessed in an off-baseline conditioned emotional response procedure in rats licking for water. In addition, the effects of the medial prefrontal cortex lesion were assessed on a battery of tasks potentially sensitive to medial prefrontal cortex damage, including spontaneous and amphetamine-induced activity, elevated plus maze exploration, food hoarding, prepulse inhibition, and active avoidance. The lesion decreased hoarding behaviour and increased spontaneous exploratory activity in the open field, while exerting only mild effects on amphetamine-induced activity. Prepulse inhibition, exploration of the elevated plus maze, and the acquisition of two-way active avoidance were unaffected by the lesion. Likewise, latent inhibition was left intact following the lesion, suggesting that neither the destruction of the intrinsic cells of the medial prefrontal cortex nor any potential lesion-induced changes in subcortical dopamine, affect latent inhibition.

Latent inhibition and schizophrenia

The phenomenon of latent inhibition (LI) refers to a decrement in associability of a stimulus previously preexposed without being followed by an event of consequence, and it reflects a process of learning not to attend to, or to ignore, irrelevant stimuli. Recently it was demonstrated that amphetamine-treated animals fail to develop LI. This finding has been used to provide additional support for the analogy between the animal amphetamine model of schizophrenia and the human clinical syndrome. The present experiment tested whether schizophrenics would show a similar failure to develop LI. Groups of paranoid schizophrenics, nonparanoid schizophrenics, and normals were either preexposed or not preexposed to a to-be-associated stimulus. For all three populations, learning a new association to the preexposed stimulus was markedly inferior to learning an association to the same stimulus when it was not preexposed. Thus, contrary to expectations, schizophrenics as well as normal subjects demonstrated a strong LI effect. It was suggested that the failure to find an absence of LI in schizophrenics may be due to the fact that these subjects were on a drug regimen that normalizes attentional processes.

Clozapine Administration in Adolescence Prevents Postpubertal Emergence of Brain Structural Pathology in an Animal Model of Schizophrenia

BACKGROUND Schizophrenia is a neuropsychiatric disorder of a neurodevelopmental origin manifested symptomatically after puberty. Structural neuroimaging studies show that neuroanatomical aberrations occur before onset of symptoms, raising a question of whether schizophrenia can be prevented. Treatment with atypical antipsychotic drugs before the development of the full clinical phenotype might reduce the risk of transition to psychosis, but it remains unknown whether neuroanatomical abnormalities can be prevented. We used a neurodevelopmental animal model of schizophrenia to assess the efficacy of the atypical antipsychotic clozapine to prevent neuroanatomical deterioration. METHODS Pregnant rats received injection on gestational day 15 with the viral mimic polyriboinosinic-polyribocytidylic acid (PolyI:C) or saline. Structural brain changes in the male offspring were assessed at adolescence and adulthood (35 days and 120 days) with structural neuroimaging. In the second part, male offspring of PolyI:C- and saline-treated dams received daily clozapine (7.5 mg/kg) or saline injection in adolescence (days 34-47) and underwent behavioral testing and imaging at adulthood (from 90 days onward). RESULTS In utero exposure to maternal infection led in the offspring to postpubertal emergence of hallmark structural abnormalities associated with schizophrenia, enlarged ventricles, and smaller hippocampus. These abnormalities were not observed in the offspring of mothers who received PolyI:C that were treated with clozapine in adolescence. This was paralleled by prevention of behavioral abnormalities phenotypic of schizophrenia, attentional deficit, and hypersensitivity to amphetamine. CONCLUSIONS This is the first demonstration that pharmacological intervention during adolescence can prevent the emergence of brain structural changes resulting from in-utero insult.