Ontogeny of isolation rearing-induced deficits in sensorimotor gating in rats.

Presentation of a weak stimulus immediately before a startling stimulus decreases the magnitude of the resultant startle response. This phenomenon, termed prepulse inhibition (PPI), provides an operational measure of sensorimotor gating, and is deficient in schizophrenia patients. Clinically observed PPI deficits can be modeled in rodents by housing rats individually from weaning until adulthood. The developmental time course of isolation rearing-induced PPI deficits, however, is unknown. The present studies characterized the ontogeny of isolation-induced PPI deficits and hyperactivity. Separate groups of Sprague-Dawley and Lister hooded rats were either singly housed (ISO) or socially housed (SOC, groups of two to three per cage) upon weaning and then maintained in these housing conditions for different periods of time until assessment of PPI and locomotor activity; animals were tested at time points that roughly corresponded to before puberty (2 weeks postweaning), during puberty (4 weeks postweaning), or after puberty (6-7 weeks post weaning). PPI deficits were seen in Sprague-Dawley ISO rats at either the 4- or 6-, but not the 2-week time points. In contrast, hyperactivity was noted in these animals starting at the 2-week time point. Lister rats showed the same general pattern of ISO-induced effects, with ISO-induced hyperactivity (observed 4 weeks postweaning) preceding ISO-induced PPI deficits (observed 7 weeks postweaning). Therefore, ISO produces dissociable effects on PPI and locomotor activity, with PPI deficits emerging only during or after puberty. ISO might thus provide a useful noninvasive tool with which to study the neural substrates of delayed-onset sensorimotor gating abnormalities.     

Selective breeding for deficient sensorimotor gating is accompanied by increased perseveration in rats

Prepulse inhibition (PPI) of the acoustic startle response is a measure of sensorimotor gating that is deficient in some neuropsychiatric disorders, such as schizophrenia and Tourette's syndrome. Experimentally induced PPI deficits in rats are regarded as endophenotype to study the biological mechanisms and therapeutic strategies of these disorders. We have recently shown that selectively breeding rats for high and low PPI levels, respectively, leads to groups with different PPI performance that remains stable from the second generation on. We here tested whether the low PPI is accompanied by other behavioral deficits. Different spatial and operant learning paradigms were used to assess rats' learning and memory abilities as well as their behavioral flexibility. In the delayed alternation T-maze task the two groups did not differ in task acquisition and working memory. Rats with low PPI showed enhanced perseveration during switching between an egocentric and allocentric radial maze task. Enhanced perseveration was also found in an operant behavioral task, where different demands, i.e. a different number of lever presses for a pellet-reward, were assigned to and switched between two levers of a Skinner box. Rats with low PPI stayed longer at the ineffective lever before switching, thus being less able to adjust their behavior to changing reward values. Additionally, PPI low rats had a higher breakpoint value during a progressive ratio-schedule of reinforcement. Rats selectively bred for low PPI showed some cognitive deficits that are apparent in a number of psychiatric disorders with deficient information processing. Specifically in both, spatial and operant behavioral paradigms, PPI low rats are deteriorated in their ability to modulate behavior based upon new changing information. They may thus provide a non-pharmacological model that can be used to evaluate new therapeutic strategies ranging from pharmacological treatment to functional neurosurgery.     

Neuroanatomical, sensorimotor and cognitive deficits in adult rats with white matter injury following prenatal ischemia

Perinatal brain injury including white matter damage (WMD) is highly related to sensory, motor or cognitive impairments in humans born prematurely. Our aim was to examine the neuroanatomical, functional and behavioral changes in adult rats that experienced prenatal ischemia (PI), thereby inducing WMD. PI was induced by unilateral uterine artery ligation at E17 in pregnant rats. We assessed performances in gait, cognitive abilities and topographical organization of maps, and neuronal and glial density in primary motor and somatosensory cortices, the hippocampus and prefrontal cortex, as well as axonal degeneration and astrogliosis in white matter tracts. We found WMD in corpus callosum and brainstem, and associated with the hippocampus and somatosensory cortex, but not the motor cortex after PI. PI rats exhibited mild locomotor impairments associated with minor signs of spasticity. Motor map organization and neuronal density were normal in PI rats, contrasting with major somatosensory map disorganization, reduced neuronal density, and a marked reduction of inhibitory interneurons. PI rats exhibited spontaneous hyperactivity in open-field test and short-term memory deficits associated with abnormal neuronal density in related brain areas. Thus, this model reproduces in adult PI rats the main deficits observed in infants with a perinatal history of hypoxia-ischemia and WMD.     

Articulatory rehearsal in verbal working memory: a possible neurocognitive endophenotype that differentiates between schizophrenia and schizoaffective disorder

Recent fMRI studies have identified brain systems underlying different components of working memory in healthy individuals. The aim of this study was to compare the functional integrity of these neural networks in terms of behavioural performance in patients with schizophrenia, schizoaffective disorder and healthy controls. In order to detect specific working memory deficits based on dysfunctions of underlying brain circuits we used the same verbal and visuospatial Sternberg item-recognition tasks as in previous neuroimaging studies. Clinical and performance data from matched groups consisting of 14 subjects each were statistically analyzed. Schizophrenic patients exhibited pronounced impairments of both verbal and visuospatial working memory, whereas verbal working memory performance was preserved in schizoaffective patients. The findings provide first evidence that dysfunction of a brain system subserving articulatory rehearsal could represent a biological marker which differentiates between schizophrenia and schizoaffective disorder.     

The involvement of Type II Neuregulin-1 in rat visuospatial learning and memory

The cognitive deficits observed in schizophrenia are considered a core feature of the disease. Neuregulin-1 is a risk gene for schizophrenia that is involved in many neurodevelopmental and synaptic plasticity-related processes relevant to schizophrenia. Here, we have utilized a rat model (Nrg1^Tn), which is hypomorphic for the neuregulin-1 (Nrg1) gene, to test whether reduced Type II NRG1 in the rat brain leads to cognitive deficits relevant to schizophrenia. Wild-type and homozygous Nrg1^Tn male rats were tested in memory tasks that evaluated spatial memory (Morris water maze) and visuospatial working and reference memory (Can Test). Nrg1^Tn rats were not impaired on the Morris water maze, but did show a deficit in the appetitive visuospatial discrimination test. Nrg1^Tn rats committed more reference and working memory errors in this test. These results indicate that decreased Type II NRG1 in the brain may lead to deficits in visuospatial learning and memory.     

What can research on schizophrenia tell us about the cognitive neuroscience of working memory?

Work with individuals with lesions to specific brain regions has long been used to test or even generate theories regarding the neural systems that support specific cognitive processes. Work with individuals who have neuropsychiatric disorders that also involve neurobiological disturbances may be able to play a similar role in theory testing and building. For example, schizophrenia is a psychiatric disorder thought to involve a range of neurobiological disturbances. Further, individuals with schizophrenia are known to suffer from deficits in working memory, meaning that examining the work on the neurobiology of working memory deficits in schizophrenia may help to further our understanding of the cognitive neuroscience of working memory. This article discusses the pros and cons of extrapolating from work in schizophrenia to models of healthy working memory function, and reviews the literature on working memory function in schizophrenia in relationship to existing human and non-human primate models of the cognitive neuroscience of working memory.     

Impact of postnatal blockade of N-methyl-D-aspartate receptors on rat behavior: a search for a new developmental model of schizophrenia

The malfunction of glutamatergic neurotransmission in the neonatal or postnatal periods may be a risk factor for the appearance of neuroanatomical, neurochemical or functional changes that are characteristic of schizophrenia. Thus, the present study was undertaken to investigate whether blockade of N-methyl-d-aspartate (NMDA) receptors in the postnatal period influences rat behavior in tests characterizing schizophrenia-like deficits such as psychomotor agitation, impairments of sensorimotor gating, working memory, and intensity of social interactions. (E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), a competitive antagonist of NMDA receptors, was given postnatally (1.25 mg/kg on days 1, 3, 6, 9; 2.5 mg/kg on days 12, 15, 18; and finally 5 mg/kg on day 21, all injections s.c.), and rats were tested at 60 days old. We found that blockade of NMDA receptors in the postnatal period led to an enhancement of exploration, mimicking psychomotor agitation, impairments in sensorimotor gating as measured by a prepulse-evoked inhibition of acoustic startle response, and an impaired working memory, as measured by an increase in the latency to achieve accurate rate of response in the delayed alternation task. Decreases in non-aggressive social interactions and increases in aggressive interactions were also observed. In addition to cognitive deficits typical of schizophrenia, rats treated postnatally with NMDA receptor antagonists also showed higher level of fear exhibited in the elevated plus maze. Thus, the blockade of NMDA receptors in the postnatal period may model deficits that are characteristic of schizophrenia.     

Prepulse inhibition in patients with non-psychotic major depressive disorder

BACKGROUND: Prepulse inhibition (PPI) of the startle response is a measure of sensorimotor gating. PPI deficits have been reported in schizophrenia and in patients characterized by a known dysfunction in the cortico-striato-pallido-thalamic (CSPT) brain substrates that regulate PPI. Patients with Major Depressive Disorder (MDD) are also thought to have impairment in the CSPT circuitry as they are characterized by clinical gating deficits. Therefore, we assessed PPI in non-psychotic MDD patients and compared their results to schizophrenia patients and non-patients. METHOD: PPI was assessed in 19 non-psychotic hospitalized MDD patients and compared to 14 hospitalized patients with schizophrenia and 13 archival normal comparison subjects. RESULTS: MDD patients had PPI levels that were significantly higher than schizophrenia patients. The MDD subjects had PPI levels that were lower than non-patients but these differences were not statistically significant. CONCLUSIONS: MDD patients without psychosis do not exhibit PPI deficits comparable to schizophrenia patients. However, the MDD patients demonstrated a non-significant tendency towards lower PPI than the non-patients. Our results replicate previous findings that PPI deficits are found in acutely hospitalized schizophrenia patients, even when treated with atypical antipsychotic medication. Future studies with psychotic MDD patients are necessary to fully understand the relationship between MDD, psychosis, symptom severity and PPI.     

Two phases of behavioral plasticity in rats following unilateral excitotoxic lesion of the hippocampus.

We investigated the effects of dizocilpine, a non-competitive N-methyl-D-aspartate receptor antagonist, on spatial reference and working memory in a radial arm maze task in rats with a unilateral hippocampal lesion. At a dose of 0.2 mg/kg to intact rats, dizocilpine significantly impaired both reference and working memory, and produced ataxia and impairment of food intake; at 0.1 mg/kg, dizocilpine had no effect on performance. Unilateral hippocampal lesion induced by quinolinic acid produced a marked working memory deficit concomitant with a slight but significant impairment of reference memory when mnemonic ability was examined one week after the lesion. The spatial memory deficits in the rats with a unilateral hippocampal lesion were ameliorated by repeated daily trainings over a 21-day period. Following recovery of the spatial memory deficits produced by the brain lesion (four weeks after the brain lesion), dizocilpine (0.1 mg/kg) significantly impaired both reference and working memory, without affecting general behavior or food intake in the brain-lesioned rats. An impairment of working memory, but not reference memory, by dizocilpine was observed six weeks after the brain lesion. However, the disrupting effect of dizocilpine at 0.1 mg/kg on spatial working memory had disappeared at eight weeks after the lesion. Ten weeks after the brain lesion, dizocilpine at 0.2 mg/kg was necessary to induce spatial memory impairment, which was accompanied by motor and food intake deficits, as in intact rats. In sham-operated rats, the dose-response effects of dizocilpine did not differ from those in intact rats at any time after the operation. These results suggest that two phases of behavioral plasticity take place, depending on demand, to compensate for brain dysfunction after the unilateral lesion of the hippocampus in rats.     

Forebrain D1 function and sensorimotor gating in rats: effects of D1 blockade, frontal lesions and dopamine denervation

Prefrontal D1 hypoactivity is implicated in the pathophysiology of schizophrenia, and might contribute to sensorimotor gating deficits in schizophrenia patients, based on evidence that D1 blockade in the medial prefrontal cortex (MPFC) reduces prepulse inhibition of startle (PPI) in animal models. PPI is disrupted by systemic and intra-MPFC infusion of the D1 antagonist, SCH23390. We investigated the role of the MPFC in the PPI-disruptive effects of systemic SCH23390 administration, and more generally, in the dopaminergic regulation of PPI. PPI was measured in rats after forebrain manipulations, including systemic administration of SCH23390, ibotenic acid lesions of the MPFC, and 6OHDA-induced dopamine (DA) depletion from MPFC or nucleus accumbens. Systemic SCH23390 disrupted PPI; these effects were not opposed by ibotenic acid lesions of the MPFC. PPI remained intact after MPFC DA depletion, but--as predicted by Bubser and Koch [M. Bubser, M. Koch, Prepulse inhibition of the acoustic startle response of rats is reduced by 6 hydroxydopamine lesions of the medial prefrontal cortex, Psychopharmacology 113 (1994) 487-492]--a reduction in PPI from pre- to post-surgery correlated significantly with MPFC DA loss. The effects of systemic SCH23390 were not opposed by NAC DA depletion. D1 receptors regulate PPI in rats, but this effect does not appear to be mediated either by the MPFC or by increased mesolimbic DA activity.     

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.     

Spatial working memory deficits in schizophrenia patients and their first degree relatives from Palau,Micronesia

Spatial working memory deficits associated with dorsolateral prefrontal dysfunction have been found in Caucasian samples of schizophrenia patients and their first‐degree relatives. This study evaluated spatial working memory function in affected and unaffected members of multiplex schizophrenia families from the Republic of Palau to determine whether the spatial working memory deficits associated with schizophrenia extend to this non‐Caucasian population. Palau is an isolated island nation in Micronesia with an elevated prevalence of schizophrenia and an aggregation of cases in large multigenerational families. Our objective was to evaluate the potential for spatial working memory function to serve as one of multiple endophenotypes in a genetic linkage study of these Palauan schizophrenia families. A spatial delayed response task requiring resistance to distraction and a sensorimotor control task were used to assess spatial working memory in 32 schizophrenia patients, 28 of their healthy first‐degree relatives, and 19 normal control subjects. Schizophrenia patients and their relatives were significantly less accurate than normal control subjects on the spatial delayed response task but not on the sensorimotor control task. On both tasks, patients and relatives were slower to respond than the normal controls. There were no age or gender effects on accuracy, and working memory performance in schizophrenia patients was not significantly correlated with medication dosage. In summary, spatial working memory deficits that have been found in Caucasian schizophrenia patients and relatives were confirmed in this isolated Pacific Island family sample. These results suggest that spatial working memory deficits may be a potentially useful addition to the endophenotypic characterization of family members to be used in a comprehensive genome wide linkage analysis of these Palauan families. © 2002 Wiley‐Liss, Inc.     

Isolation rearing-induced deficits in prepulse inhibition and locomotor habituation are not potentiated by water deprivation

Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating and is reduced in neuropsychiatric disorders such as schizophrenia. Isolation rearing of rats is a developmentally specific, nonpharmacological manipulation that leads to deficits in sensorimotor gating that mimic those observed in schizophrenia patients. This study examined the effects of an added stressor (water deprivation) on the magnitude of the isolation rearing effect on PPI and locomotor activity. At the time of weaning, male (n = 80) and female (n = 80) rats were assigned to either social housing or isolation housing and were subsequently assigned to the water-deprived or non-water-deprived groups. Rats were tested for acoustic startle and PPI at 3, 5 and 7 weeks postweaning. Isolated rats showed a significant decrease in PPI that was apparent at all 3 weeks. Water deprivation did not significantly affect PPI, nor was there a significant interaction between housing and water treatment or between sex and housing. When tested in the Behavior Pattern Monitor to assess locomotor activity, isolated rats displayed decreased habituation across the 1-h test session. Water deprivation did not affect locomotor activity in any significant, independent manner, nor did it potentiate the effects of isolation rearing on locomotor habituation. In these studies, both male and female Long-Evans rats were sensitive to the PPI-disruptive and locomotor-activating effects of social isolation. Isolation rearing significantly disrupts PPI and locomotor habituation independent of any effects of water deprivation.     

Spatial working memory deficits in schizophrenia patients and their first degree relatives from Palau,Micronesia

Spatial working memory deficits associated with dorsolateral prefrontal dysfunction have been found in Caucasian samples of schizophrenia patients and their first-degree relatives. This study evaluated spatial working memory function in affected and unaffected members of multiplex schizophrenia families from the Republic of Palau to determine whether the spatial working memory deficits associated with schizophrenia extend to this non-Caucasian population. Palau is an isolated island nation in Micronesia with an elevated prevalence of schizophrenia and an aggregation of cases in large multigenerational families. Our objective was to evaluate the potential for spatial working memory function to serve as one of multiple endophenotypes in a genetic linkage study of these Palauan schizophrenia families. A spatial delayed response task requiring resistance to distraction and a sensorimotor control task were used to assess spatial working memory in 32 schizophrenia patients, 28 of their healthy first-degree relatives, and 19 normal control subjects. Schizophrenia patients and their relatives were significantly less accurate than normal control subjects on the spatial delayed response task but not on the sensorimotor control task. On both tasks, patients and relatives were slower to respond than the normal controls. There were no age or gender effects on accuracy, and working memory performance in schizophrenia patients was not significantly correlated with medication dosage. In summary, spatial working memory deficits that have been found in Caucasian schizophrenia patients and relatives were confirmed in this isolated Pacific Island family sample. These results suggest that spatial working memory deficits may be a potentially useful addition to the endophenotypic characterization of family members to be used in a comprehensive genome wide linkage analysis of these Palauan families.     

Schizophrenic-like neurocognitive deficits in children and adolescents with 22q11 deletion syndrome.

22q11.2 Deletion Syndrome (22q11DS) is the most common genetic microdeletion syndrome affecting humans. The syndrome is associated with general cognitive impairments and specific deficits in visual-spatial ability, non-verbal reasoning, and planning skills. 22q11DS is also associated with behavioral and psychiatric abnormalities, including a markedly elevated risk for schizophrenia. Research findings indicate that people with schizophrenia, as well as those identified as schizoptypic, show specific cognitive deficits in the areas of sustained attention, executive functioning, and verbal working memory. The present study examined such schizophrenic-like cognitive deficits in children and adolescents with 22q11DS (n = 26) and controls (n = 25) using a cross-sectional design. As hypothesized, 22q11DS participants exhibited deficits in intelligence, achievement, sustained attention, executive functioning, and verbal working memory compared to controls. Furthermore, deficits in attention and executive functioning were more pronounced in the 22q11DS sample relative to general cognitive impairment. These findings suggest that the same pattern of neuropsychological impairment seen in patients with schizophrenia is present in non-psychotic children identified as at-risk for the development of schizophrenia based on a known genetic risk marker.     

Quetiapine produces a prolonged reversal of the sensorimotor gating-disruptive effects of basolateral amygdala lesions in rats

Prepulse inhibition (PPI) of startle is impaired in schizophrenia and in rats after manipulations of limbic cortical and subcortical regions. The atypical antipsychotic quetiapine was used to reverse PPI deficits after basolateral amygdala (BLA) lesions in rats. BLA quinolinic acid lesions significantly disrupted PPI 1 week postsurgery. Tests with quetiapine (0 vs. 7.5 mg/kg) in a within-subject design 2-3 weeks postsurgery revealed a normalization of PPI. Carry-over effects lasted up to 3 weeks, with a return of lesion-induced deficits by Week 5 postsurgery. This dose of quetiapine also blocked the PPI-disruptive effects of phencyclidine. PPI deficits after BLA lesions are reversed by quetiapine, in a manner that is sustained beyond its acute pharmacological effects and which may be mediated downstream from the BLA.     

Antisense knockdown of drebrin A, a dendritic spine protein, causes stronger preference, impaired pre-pulse inhibition, and an increased sensitivity to psychostimulant

Drebrin located in dendritic spines regulates their morphological changes and plays a role in the synaptic plasticity via spine function. Reduced drebrin has been found in the brain of patients with Alzheimer's disease or Down's syndrome. To examine whether the down-regulation of drebrin protein levels causes deficits in higher brain function, such as memory or cognition, we performed antisense-induced knockdown of drebrin A expression in rat brain using an hemagglutinating virus of Japan (HVJ)-liposome gene transfer technique. We investigated the effects of drebrin in vivo knockdown on spatial memory in a water-maze task, sensorimotor gating in a pre-pulse-inhibition test, adaptive behaviors in an open-field test, and sensitivity to psychostimulant in an amphetamine-induced locomotor response. Rats with drebrin A in vivo knockdown displayed a stronger preference for a previous event due to perseverative behavior, impaired pre-pulse inhibition (PPI), increased locomotor activity, anxiety-like behavior, and an increased sensitivity to psychostimulant, suggesting behaviors related to schizophrenia. These findings indicated that decreased drebrin produces deficits in cognitive function but not in spatial memory, probably via hypofunction of dendritic spines.     

Age-related changes in the cholinergic components within the central nervous system. II. Working memory impairment and its relation to hippocampal muscarinic receptors

Cognitive performance in aging Wistar rats was monitored using the radial arm maze and the latter was correlated with the density of muscarinic receptors in the CNS, using quantitative in vitro receptor autoradiography. Significant working memory deficits were observed in 12, 17 and 24-month-old rats as compared to 3-month-old animals. In addition, the number of the muscarinic receptors declined significantly with age (from 27 to 42% depending on the brain region sampled) utilising [3H]QNB and [3H]PZ receptor binding assays. The above trend became evident already at the age of 12 months. The present findings support the association of central cholinergic activity with memory processes.     

Impaired SynGAP expression and long-term spatial learning and memory in hippocampal CA1 area from rats previously exposed to perinatal hypoxia-induced insults: beneficial effects of A68930

Hypoxic encephalopathy is a common cause of neonatal seizures and long-term neurological cognitive deficits. In rats at postnatal days 10-12 (P10-P12), global hypoxia induced spontaneous seizures and chronic brain injury, mimicking clinical aspects of neonatal hypoxia. Synaptic Ras-GTPase activating protein (SynGAP) has important roles in RAS/MAPK-dependent synaptic plasticity and mammalian learning. We investigated possible alterations of SynGAP expression occurring in memory-impaired animals previously exposed to perinatal hypoxia insults. We also evaluated the therapeutic efficacy of A68930, a selective agonist of dopamine D1/D5 receptors, on perinatal hypoxia insults. In the hippocampal CA1 region, perinatal hypoxia insults (P10) led to a reduction in SynGAP expression associated with impairment in long-term spatial learning and memory performance at P45. The use of A68930 (at a dose of 1, 2, 3mg/kg, P17-P23) effectively attenuated the deleterious effects as described above. Our results may indicate the involvement of SynGAP in certain forms of brain injury, leading to long-term learning and memory deficits. A68930 may have clinical potential as a therapeutic agent for alleviation of long-term cognitive deficits in rats and other animal models.     

Effects of fetal treatment with methylazoxymethanol acetate on radial maze performance in rats.

Pregnant rats (Wistar-Imamichi strain) were treated with 15 mg/kg/d of methylazoxymethanol acetate (MAM) on days 13-15 of gestation. Nine male rats, which were randomly selected from the MAM-treated offspring (MAM rats), were examined for their spatial recognition ability by the radial maze technique and compared with control offspring. Although the performances of MAM rats were inferior to the control, they could reach the predetermined criterion within 15 trials. Subsequent retention tests revealed the drastic impairment of performance in MAM rats when the retention interval was over 15 min. The total activity of choline acetyltransferase showed a significant decrease in the hippocampus and cerebral cortex of MAM rats. These results suggest that working memory disorders of MAM rats on radial maze tasks may be due to the lowering of cholinergic functions in their hippocampus and cerebral cortex.