Neonatal Ventral Hippocampal Lesion Research Articles

Neonatal ventral hippocampus lesions disrupt extra-dimensional shift and alter dendritic spine density in the medial prefrontal cortex of juvenile rats

Recent data showed that neonatal ventral hippocampus (VH) lesions, an approach used to model schizophrenia symptoms in rodents, produce premature deficits of working memory believed to be associated with early medial prefrontal cortex (mPFC) maldevelopment. This experiment expands the investigation of mPFC integrity in juvenile rats with neonatal VH lesions by assessing behavioral flexibility and dendritic spine density. Sixteen Sprague–Dawley male pups received bilateral microinjections of ibotenic acid in the VH or SHAM surgery on postnatal day (PND) 6. On PND 29 and 30, rats were subjected to a spatial shift task in a cross-maze; an attentional set-shifting task was then administered on two consecutive days, between PND 33 and PND 35. Rats were sacrificed at PND 36 and dendritic spine density in the mPFC was assessed using Golgi-Cox staining procedure. Results revealed impaired extra-dimensional shift in VH-lesioned rats and inconsistent reversal discrimination outcomes. Although lesioned animals displayed intact performance in the spatial shift, rates of perseverative responses were higher than normal in this task. Neonatal VH damage resulted in lower dendritic spine density in the mPFC than measured in control brains; however, no significant correlation was found between this outcome and behavioral data. Juvenile morphological and cognitive perturbations are consistent with the early emergence of mPFC anomalies following neonatal VH lesions. Results are discussed in relation with potential common mechanisms linking pre- and post-pubertal onsets of behavioral dysfunction.

Enhanced α1 adrenergic sensitivity in sensorimotor gating deficits in neonatal ventral hippocampus-lesioned rats

Neonatal ventral hippocampus (nVH) lesion in rats is a widely used animal model of schizophrenia due to the predominantly post-pubertal emergence of many schizophrenia-like behaviours. Our previous studies have shown increased ligand binding of alpha1 adrenergic receptors (AR) in the frontal cortex of post-pubertal, but not pre-pubertal, nVH-lesioned rats, compared to sham-lesioned control rats. Moreover, pretreatment with the alpha1 adrenergic receptor antagonist prazosin reversed amphetamine-induced hyperlocomotion in controls, but failed to do so in lesioned animals. This led to our hypothesis that nVH lesions may lead to post-pubertal hyperactivity of alpha1 adrenergic receptors. In order to test the functional relevance of alpha1 adrenergic hyperactivity to schizophrenia-like behaviours of nVH-lesioned animals, we conducted prepulse inhibition (PPI) studies in post-pubertal (postnatal days 56-120) sham and lesioned animals in response to systemic injections of alpha1 adrenergic receptor antagonist and agonist, prazosin and cirazoline, respectively. Our results show that PPI deficits in nVH-lesioned animals were reversed with prazosin treatment, without a significant effect on PPI in sham animals. Further, at various doses, cirazoline had a significantly greater PPI disruptive effect in nVH-lesioned animals than in sham animals. Together, these results suggest that nVH-lesioned animals show a hyperactive alpha1 adrenergic receptor system that may mediate sensorimotor gating abnormalities reported in these animals.

Rewarded associative and instrumental conditioning after neonatal ventral hippocampus lesions in rats

Sprague Dawley rats were submitted to bilateral ventral hippocampus lesions 7 days after birth. This corresponds to the Lipska and Weinberger's procedure for modeling schizophrenia. The aim of the present work was to test the learning capacity of such rats with an associative Pavlovian and an instrumental learning paradigm, both methods using reward outcome (food, sucrose or polycose). The associative paradigm comprised also a second learning test with reversed learning contingencies. The instrumental conditioning comprised an extinction test under outcome devaluation conditions. Neonatally lesioned rats, once adults (over 60 days of age), showed a conditioning deficit in the associative paradigm but not in the instrumental one. Lesioned rats remained able to adapt as readily as controls to the reversed learning contingency and were as sensitive as controls to the devaluation of outcome. Such observations indicate that the active access (instrumental learning) to a reward could have compensated for the deficit observed under the “passive” stimulus–reward associative learning condition. This feature is compared to the memory management impairments observed in clinical patients.

Accentuated behavioral sensitization to nicotine in the neonatal ventral hippocampal lesion model of schizophrenia

The prevalence of smoking in schizophrenia patients far exceeds that in the general population. Increased vulnerability to nicotine and other drug addictions in schizophrenia may reflect the impact of developmental limbic abnormalities on cortical–striatal mediation of behavioral changes associated with drug use. Rats with neonatal ventral hippocampal lesions (NVHLs), a neurodevelopmental model of schizophrenia, have previously been shown to exhibit altered patterns of behavioral sensitization to both cocaine and ethanol. This study explored nicotine sensitization in NVHLs by testing locomotor activity of NVHL vs. SHAM-operated controls over 3 weeks in response to nicotine (0.5 mg/kg) or saline injections (s.c.) followed by a nicotine challenge delivered to all rats 2 weeks later. At the beginning of the initial injection series, post-injection locomotor activation was indistinguishable among all treatment groups. However, nicotine but not saline injections produced a progressive sensitization effect that was greater in NVHLs compared to SHAMs. In the challenge session, rats with previous nicotine history showed enhanced locomotor activation to nicotine when compared to drug naïve rats, with NVHL-nicotine rats showing the greatest degree of activity overall. These results demonstrate that NVHLs exhibit altered short- and long-term sensitization profiles to nicotine, similar to altered long-term sensitization profiles produced by cocaine and ethanol. Collectively, these findings suggest the neurodevelopmental underpinnings of schizophrenia produce enhanced behavioral sensitization to addictive drugs as an involuntary and progressive neurobehavioral process, independent of the acute psychoactive properties uniquely attributed to nicotine, cocaine, or alcohol.

Dissociable onset of cognitive and motivational dysfunctions following neonatal lesions of the ventral hippocampus in rats.

This research examined cognitive and motivational processes at different developmental stages in rats with neonatal ventral hippocampus (VH) lesions, an approach used to model schizophrenia. In Experiment 1, performance in a T-maze alternation task was assessed on postnatal days (PNDs) 22 and 23. VH-lesioned rats displayed a severe deficit relative to controls. In Experiment 2, behaviorally naive rats were tested for spontaneous alternation at PND 29. Alternation was intact in VH-lesioned rats only when successive alternations were separated by >5 s. In Experiment 3, motivation was tested in a cost-benefit T-maze task and in a saccharine-water preference test. Between PNDs 22-37, behaviorally naive rats with neonatal VH lesions displayed weaker saccharine preference than controls, but the 2 groups did not differ on the cost-benefit task. At adulthood, between PNDs 56-72, the difference on saccharine preference persisted and an impairment on the cost-benefit task emerged. Overall, these results suggest that working memory deficits observed at the weaning stage were not secondary to spontaneous alternation or motivation dysfunctions.

Postweaning social isolation enhances morphological changes in the neonatal ventral hippocampal lesion rat model of psychosis

Neonatal ventral hippocampal (nVH) lesions in rats have been widely used as a neurodevelopmental model that mimics schizophrenia-like behaviors. Recently, we reported that nVH-lesions result in significant decreases in both length of dendrites and dendritic density of spines of pyramidal neurons of the prefrontal cortex (PFC) and in the density of dendritic spines of medium spiny neurons of the nucleus accumbens (NAcc). Moreover, postweaning social isolation induces major decreases in dendritic spiny density of PFC neurons. We investigated here the comparative dendritic morphology of PFC pyramidal neurons and NAcc medium spiny neurons in nVH rats, following social isolation after weaning (8 weeks). Morphological characteristics of dendrites were measured using the Golgi-Cox procedure followed by a Sholl analysis. Social isolation (SI) by itself induced decreases in dendritic length and dendritic spine density of the NAcc. In socially isolated nVH-lesion rats decrease in dendritic length in PFC and NAcc neurons were exacerbated whereas an increase in spine density of medium spiny neurons was observed in the NAcc. These results indicate that nVH-lesions alter dendritic morphology of NAcc and PFC neurons. These anatomical modifications in both structures may be relevant to behaviors observed in schizophrenia.

Sleep and EEG profile in neonatal hippocampal lesion model of schizophrenia

Sleep architecture, EEG power pattern and locomotor activity were investigated in a putative animal model of schizophrenia. The model was prepared by excitotoxic damage of the ventral hippocampus on postnatal day 7 (PD 7), after which locomotor activity and electroencephalographic (EEG) sleep profile were compared between lesioned and sham operated animals respectively, at prepuberty (postnatal day PD 35) and postpuberty (PD 56). An enhancement of locomotor activity was observed in lesioned adult PD 56, but not in juvenile PD 35 rats. Spontaneous EEG/EMG recordings during 24 h showed no major differences between both groups at PD 35 and at PD 56. However, quantitative analysis of the EEG revealed an enhancement of power in delta (δ), theta (θ) and alpha (α) activities in lesioned animals at PD 35 during wakefulness in both light and dark phases. At PD 56, the power in the δ and θ bands was increased during the light and dark periods in both wakefulness and non-REM sleep. These findings suggest that ventral hippocampus lesion is not associated with disturbance of sleep architecture in rats, while consistent changes were observed in the dynamic of EEG slow wave frequency domain. Thus, the data indicate that neonatal lesion of ventral hippocampus did not mimic sleep abnormalities observed in schizophrenia, however this rodent model may model some EEG features seen in schizophrenia such as a frontally pronounced slowing of the slow EEG activity in δ and θ frequency bands.

Alterations in GABAA receptor expression in neonatal ventral hippocampal lesioned rats: Comparison of prepubertal and postpubertal periods

Rats with neonatal ventral hippocampal lesions (NVHL) have been studied as a neurodevelopmental animal model of schizophrenia. NVHL rats exhibit postpubertal emergence of hyperresponsiveness to stress, suggesting increased mesolimbic dopamine (DA) activity. However, previous studies have not yielded clear evidence of this. Disturbances in the gamma-amino-butyric acid (GABA)-ergic system as well as the dopaminergic system are thought to be present in schizophrenia. To determine whether GABA(A) receptors play a role in the abnormal postpubertal behavior in NVHL rats, we compared changes in expression of mRNA of GABA(A) receptor subunits and in [(35)S] t-butylbicyclophosphorothionate ([(35)S] TBPS) binding in the prepubertal and postpubertal periods. Male pups were lesioned with ibotenic acid at postnatal day 7 (PD 7), and in situ hybridization and quantitative autoradiography were then performed. In NVHL rats, alpha1 subunit mRNA expression in prefrontal cortex was decreased at PD 35 (prepubertal period; by 21.7%), but increased at PD 56 (postpubertal period; by 21.4%) when compared with sham controls. beta2 subunit mRNA expression was increased in PFC in the postpubertal period (by 24.3%). beta3 subunit mRNA expression was increased in the caudate-putamen in the postpubertal period (by 37.2%). [(35)S] TBPS binding was increased in PFC only in the postpubertal period (by 17.7%). These findings suggest that dysfunction of the GABAergic system exists in NVHL rats. Furthermore, developmental and regional changes in GABA(A) receptor expression appear to occur in compensation for the attenuation of GABAergic system activity in NVHL rats.

Alteration of conditioned emotional response and conditioned taste aversion after neonatal ventral hippocampus lesions in rats

Sprague–Dawley rats were submitted to bilateral ventral hippocampus lesions 7 days after birth according to the Lipska and Weinberger’s procedure for modeling schizophrenia. The aim of the present work was to better characterize their learning capacity. A double latent inhibition study was conducted using respectively conditioned taste aversion and conditioned emotional response. In the background of this evaluation, locomotion under apomorphine and startle reactions, inhibited or not by prepulses, was also evaluated. Our experimental methods were the same as those used in previous studies from the laboratory which were found to be sensitive to pharmacological manipulations and shown by others to be unaffected by lesions of the ventral hippocampus carried out in adult rats. In contrast, neonatally lesioned rats, once adults (over 60 days old), were hyper-responsive to noise – i.e., the startle response to a 105 db(A) noise pulse was enhanced – and hyperactive under apomorphine (0.7 mg/kg). The prepulse inhibition properties of the startle remained unchanged. Lesioned rats showed a deficit but not a suppression of conditioning, similar in both tests, but latent inhibition was preserved. Such observations complement the already known memory deficit produced in this neurodevelopmental model of schizophrenia.

Post-Pubertal Disruption of Medial Prefrontal Cortical Dopamine–Glutamate Interactions in a Developmental Animal Model of Schizophrenia

A neonatal ventral hippocampal lesion (NVHL) induces behavioral and physiological anomalies mimicking pathophysiological changes of schizophrenia. Because prefrontal cortical (PFC) pyramidal neurons recorded from adult NVHL rats exhibit abnormal responses to activation of the mesocortical dopaminergic (DA) system, we explored whether these changes are due to an altered DA modulation of pyramidal neurons. Whole-cell recordings were used to examine the effects of DA and glutamate agonists on cell excitability in brain slices obtained from pre- (postnatal day [PD] 28-35) and post-pubertal (PD > 61) sham and NVHL animals. N-methyl d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA), and the D(1) agonist SKF38393 increased excitability of deep layer pyramidal neurons in a concentration-dependent manner. The opposite effect was observed with the D(2) agonist quinpirole. The effects of NMDA (but not AMPA) and SKF38393 on cell excitability were significantly higher in slices from NVHL animals, whereas quinpirole decrease of cell excitability was reduced. These differences were not observed in slices from pre-pubertal rats, suggesting that PFC DA and glutamatergic systems become altered after puberty in NVHL rats. A disruption of PFC dopamine-glutamate interactions might emerge after puberty in brains with an early postnatal deficit in hippocampal inputs, and this disruption could contribute to the manifestation of schizophrenia-like symptoms.

Decreased dopamine D2 mRNA expression in rats with neonatal ventral hippocampus lesion after puberty

Decreased dopamine D2 mRNA expression in rats with neonatal ventral hippocampus lesion after puberty

Ethanol sensitization in a neurodevelopmental lesion model of Schizophrenia in rats

Substance use disorder comorbidity in schizophrenia may reflect dysfunctional cortical-striatal-limbic circuitry commonly involved in the addiction process and the pathogenesis of schizophrenia. Rats with neonatal ventral hippocampal lesions (NVHL) demonstrate post-adolescent onset of schizophrenia-like symptoms and increased addiction vulnerability in paradigms using cocaine in adulthood. Here, we investigated response profiles of young adult NVHL vs. SHAM rats to ethanol, an addictive drug with many psychopharmacological effects divergent from those of cocaine, in a locomotor sensitization paradigm. Over 15 days of daily injections of saline, low (0.15 g/kg) or high (1.0 g/kg) doses of ethanol, NVHL rats showed stimulatory effects at the low dose compared to saline and high-dose conditions, while SHAM rats showed expected patterns of dose-dependent suppression of locomotor activity. In a challenge session 2 weeks later in which a moderate dose (0.25 g/kg) of ethanol was given to all subjects, NVHL rats with history of prior ethanol exposure showed greater locomotor activity consistent with installment of alcohol-induced sensitization not present in SHAMs. These findings provide further evidence of enhanced short- and long-term responsivity to abused drugs in a neurodevelopmental model of schizophrenia, and may reflect potentiation of common mechanisms of addiction shared between pharmacologically diverse addictive drugs.

Neonatal Ventral Hippocampal Lesions Potentiate Amphetamine-Induced Increments in Dopamine Efflux in the Core, but Not the Shell, of the Nucleus Accumbens

In rats, neonatal ventral hippocampal lesions (NVHLs) result in the postpubertal emergence of alterations reminiscent of several features of schizophrenia, including increased responsivity to the behavioral effects of amphetamine (AMPH). The precise nature of presynaptic aspects of accumbal dopamine (DA) function in these alterations is however uncertain: previous studies have found that the exacerbated responses to AMPH of NVHL rats are associated with either decreased or unchanged DA efflux in the nucleus accumbens (NAc) as compared with shams. Because these studies investigated DA output in the whole NAc, it was considered of interest to examine the impact of NVHLs on DA transmission in NAc subregions involved in distinct aspects of goal-directed behavior. The effects of AMPH (.25 mg/kg, subcutaneous) on the accumbal DA efflux of adult rats were evaluated using brain microdialysis, and motor activity was recorded alongside dialysate sample collection. The enhanced behavioral responsivity to AMPH of NVHL rats is associated with potentiation of AMPH-induced DA output in the NAc core and a concomitant attenuation of DA overflow in the NAc shell. The functional alterations in the NAc core induced by NVHLs provide a link between the hippocampal damage and striatal DA hyperactivity in schizophrenia.

Altered Prefrontal Cortical Metabolic Response to Mesocortical Activation in Adult Animals with a Neonatal Ventral Hippocampal Lesion

Adult animals with a neonatal ventral hippocampal lesion (NVHL) exhibit deficits in working memory and sensorimotor gating similar to those observed in schizophrenia. As cognitive deficits in this disorder are typically associated with changes in cortical metabolic levels, we investigated here whether an NVHL affects metabolic responses to ventral tegmental area (VTA) activation, a procedure that elicits abnormal cell firing in the prefrontal cortex (PFC) of NVHL animals. Prefrontal cortex metabolic activity was determined by measuring cytochrome oxidase I (CO-I) staining. Cytochrome oxidase I levels were quantified by densitometry in pre- and postpubertal sham-operated and lesioned rats that received one or three series of fifteen 20-Hz trains of VTA stimuli every 20 seconds. Ventral tegmental area stimulation yielded higher levels of PFC CO-I in NVHL animals when compared with the sham-operated group, an effect that appeared only after puberty. Increasing the series of burst stimulations further elevated CO-I in sham-operated, but not in NVHL animals. Increased PFC CO-I activity after VTA burst stimulation in NVHL rats highlights the enhanced energy demand that could be linked to the exaggerated response to stress observed in these animals. The inability to further increase the response with higher mesocortical activity, as observed in sham-operated animals, could be expression of a reduced PFC functional capacity in lesioned animals. Thus, a hyperexcitable PFC with a reduced ability to further increase activity could be a plausible pathophysiological scenario for schizophrenia. Human functional studies could be interpreted in the light of this conceptual framework.

S.19.02 Mechanisms of dopaminergic dysfunction in rats with neonatal ventral hippocampus lesions

Neonatal ventral hippocampal (NVH) lesions in rats have been shown to induce behavioral abnormalities at adulthood thought to simulate some aspects of positive, negative and cognitive deficits classically observed in schizophrenic patients. Such lesions induced a post-pubertal emergence of prepulse inhibition deficits reminiscent of the sensorimotor gating deficits observed in a large majority of schizophrenic patients. Here we have investigated the capacity of typical and atypical antipsychotics to reverse PPI deficits seen in NVH-lesioned rats.We show that three atypical antipsychotics (clozapine, olanzapine and risperidone) were able to reverse lesion-induced PPI deficits, in contrast to haloperidol, a classical neuroleptic.These results show that the NVH lesion model seems to be endowed with a fair predictive validity as, like in schizophrenic patients, PPI deficits in lesioned animals were reversed by atypical antipsychotics but not by the typical neuroleptic haloperidol.

Neonatal lesions of the ventral hippocampus in rats lead to prefrontal cognitive deficits at two maturational stages

This experiment assessed the effect of neonatal ventral hippocampus lesions in rats, a heuristic approach to model schizophrenia, on continuous delayed alternation and conditional discrimination learning performance before and after complete cerebral maturation. Delays (0, 5, 15, and 30 s) were introduced in the tasks to help dissociate between a hippocampal and a prefrontal cortex dysfunction. At postnatal day (PND) 6 or 7, rats received bilateral microinjections of ibotenic acid or phosphate-buffered saline in the ventral hippocampus. From PND 26 to PND 35, rats were tested on the alternation task in a T-maze; from PND 47 to PND 85, the same rats were tested in the discrimination task where a stimulus and a response location had to be paired. Deficits in ventral hippocampus-lesioned rats were observed in both tasks whether a delay was introduced before a response or not. Impaired performance regardless of delay length, combined with high rates of perseverative errors, suggested a post-lesional prefrontal cortex dysfunction which persisted from the juvenile stage into adulthood. Premature cognitive impairments could not be predicted on the basis of the neurodevelopmental animal model of schizophrenia. Nevertheless, they appear consistent with accounts of premorbidly compromised memory, both immediate and delayed, in subgroups of schizophrenia patients.

Effect of Dopamine D3 Antagonists on PPI in DBA/2J Mice or PPI Deficit Induced by Neonatal Ventral Hippocampal Lesions in Rats

Schizophrenic patients typically exhibit impairment of sensorimotor gating, which can be modeled in animal models such as the test of prepulse inhibition of startle response (PPI) in rodents. It has been found that antipsychotics enhanced PPI in DBA mice and reversed the PPI deficit induced by neonatal ventral hippocampal (NVH) lesions in rats. However, the relative involvement of D(3) and D(2) receptors in these effects is unknown since all antipsychotics are D(2)/D(3) antagonists with limited binding preference at D(2) receptors. Therefore, in the current study, we investigated the influence of several dopamine antagonists with higher selectivity at D(3) vs D(2) receptors on PPI in DBA/2J mice and in NVH-lesioned rats. The PPI in DBA/2J mice was enhanced by the nonselective D(2)/D(3) antagonists, haloperidol at 0.3-3 mg/kg, or risperidone at 0.3-1 mg/kg, while PPI-enhancing effects were observed after the administration of higher doses of the preferential D(3)/D(2) antagonist, BP 897 at 8 mg/kg, and the selective D(3) antagonists, SB 277011 at 30 mg/kg and A-437203 at 30 mg/kg. No effect was observed following the treatment with the selective D(3) antagonist, AVE 5997 up to 30 mg/kg. The PPI deficits induced by NVH lesions were reversed by haloperidol but not by the more selective D(3) antagonists, A-437203 and AVE 5997. BP 897 enhanced PPI nonselectivity, that is, in both lesioned and nonlesioned rats. In summary, the present study indicates that PPI-enhancing effects induced by antipsychotics in DBA/2J mice and in NVH-lesioned rats are unlikely to be mediated by D(3) receptors.

Cerebral metabolic consequences in the adult brain after neonatal excitotoxic lesions of the amygdala in rats

In the present study the effects of neonatal excitotoxic lesions of the amygdala or ventral hippocampus on local cerebral glucose utilisation in the adult rat were studied by means of the [ 14C]2-deoxyglucose autoradiographic method. Our hypothesis was that damage to the brain during early development leads to long-term functional activity changes in brain regions outside the primary lesioned area which might underlie the behavioural deficits observed in animals with neonatal brain damage. Cerebral glucose utilisation in animals with a neonatal amygdala lesion was significantly decreased in the amygdala itself and in several other brain regions. The neonatal ventral hippocampal lesion did not cause significant changes in cerebral glucose utilisation, except for a decrease in the primary damaged region (i.e. caudal ventral hippocampus). Behaviourally, animals lesioned in the amygdala displayed increased ambulatory activity both before and after puberty when exposed to a novel open field, while neonatal ventral hippocampal lesions did not affect adult exploratory behaviour as compared to sham controls. These results support our hypothesis that neonatal brain damage leads to long-term functional activity changes in brain regions outside the primary lesioned area. Moreover, they suggest that this long-term effect depends on the primary area lesioned since only damage to the amygdala, and not to the ventral hippocampus, affects the functional organisation of the brain of the animals later in life. Additionally, the findings may suggest that the functional changes in the brain may underlie the behavioural deficits observed after neonatal amygdala lesion in the rat.

Cortical gene expression in the neonatal ventral-hippocampal lesion rat model

Schizophrenia is a chronic, debilitating psychotic illness of unknown etiology that has been the subject of many genetic studies. We studied the neonatal ventral-hippocampal lesioned rat as an animal model of schizophrenia in order to identify novel candidate genes for schizophrenia. Temporal and frontal cortices were assessed using cDNA microarrays for differences in mRNA expression associated with the lesion, haloperidol treatment and in two rat strains with differential sensitivity to the behavioural effects of the lesion. Genes that had altered expression levels as a result of the lesion, that were normalized by haloperidol treatment, and that differed between rat strains were selected. The pattern of differential transcription was confirmed with quantitative PCR for all six candidate genes: large conductance calcium-activated potassium channel, subfamily M, beta member 1 (Kcnmb1); doublecortex (dcx); adenylyl cyclase-associated protein 1 (CAP1); adenosine monophosphate deaminase 2-isoform L (AMPD2); malic enzyme 3, NADP(+)-dependent, mitochondrial (Me3); and aspartylglucosaminidase (AGA). None of these genes has been extensively studied in schizophrenia, and further work with post-mortem tissue and genetic studies are ongoing.

Functional magnetic resonance imaging reveals similar brain activity changes in two different animal models of schizophrenia

In schizophrenia research, most of the functional imaging studies have been performed in psychotic patients, but little is known about brain areas involved in the expression of psychotic-like symptoms in animal models. The objective of this study was to visualize and compare brain activity abnormalities in a neurodevelopmental and a pharmacological animal model of schizophrenia. Blood perfusion of specific brain areas, taken as indirect measure of brain activity, was investigated in adult rats following either neonatal ventral hippocampal lesion or acute administration of phencyclidine. Quantitative perfusion magnetic resonance imaging was performed on five frontal brain slices using the continuous arterial spin labeling technique. The mean perfusion was calculated in several brain structures, which were identified on anatomical images. Lesioned animals exhibiting deficits in prepulse inhibition of the startle reflex showed a significant blood perfusion increase in the nucleus accumbens, basolateral amygdala, ventral pallidum, entorhinal-piriform cortex, orbital prefrontal cortex, and in the bed nucleus of the stria terminalis, and a decrease of perfusion in the temporal cortex. Similar effects were seen following acute phencyclidine administration in naïve animals. Our data point out specific cortical and subcortical brain areas involved in the development of psychotic-like symptoms in two different animal models of schizophrenia. The observed brain activity abnormalities are reminiscent of classical neuroimaging findings described in schizophrenic patients.