Correlation Between Cataleptic Freezing and Prepulse Inhibition of the Startle Reflex in Rats

GC rats, bred for a predisposition to cataleptic freezing, were found to show a significant negative correlation between the duration of freezing and the level of prepulse inhibition of the startle reflex. In addition, a group of GC rats characterized by increased "nervousness" also showed a negative correlation between the duration of freezing and the extent of habituation of the startle reflex. These correlations were not seen in Wistar rats. Since decreases in the level of prepulse inhibition and habituation of the startle reflex are regarded as characteristic of schizophrenia, it is suggested that cataleptic freezing in GC rats might be used as a model of schizophrenic pyschopathology.     

On the Relationships of High-Frequency Hearing Loss and Cochlear Pathology to the Acoustic Startle Response (ASR) and Prepulse Inhibition of the ASR in the BXD Recombinant Inbred Series

The measurement of the acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR in many inbred strains of mice, including C57BL/6 and DBA/2, may be complicated by age-related high-frequency hearing loss (HFHL) and the associated cochlear pathology. Willott and Erway (1998) have recently reported on the age-related changes of the acoustic brain response in the BXD recombinant inbred (RI) series. Based on these data, the RI series was divided into three groups: juvenile-, intermediate-, and adult-onset HFHL. Each of these groups was tested using paradigms which varied the frequency or intensity of the auditory startle and prepulse stimuli. The results obtained in adolescent mice (6–8 weeks) demonstrate that ASR performance is independent of HFHL; there was no group-dependent decline in the ASR amplitudes for high-frequency stimuli. The expected effect of HFHL on PPI is to increase the salience of the still-audible tones. In response to a white-noise prepulse stimulus, the PPI in the juvenile-onset group (which shows marked HFHL at 6 weeks) was similar to that in the adult-onset group. However, when the prepulse stimulus was a pure tone, the juvenile group showed a decrease in salience across all frequencies tested (5–20 kHz). The data point out the need for carefully constructing auditory tasks in the BXD RI series, to avoid the confounding effects of HFHL.     

Effect of Substance P on Intravenous Self-Administration of Morphine in Different Rat Strains

We studied the effects of substance P on intravenous self-administration of morphine in WAG/G and Fischer-344 rats. By the end of week 2 the daily amount of self-administered morphine in WAG/G rats was higher than in Fischer-344 rats. Treatment with substance P markedly suppressed self-injection of morphine, particularly in low doses. The most pronounced effects were observed in Fischer-344 rats. Substance P did not change food-procuring behavior of animals in the same experimental chambers. Since the content of substance P in the hippocampus, hypothalamus, and midbrain of Fischer-344 rats is much lower than in WAG/G rats, and morphine addiction in Fischer-344 rats is less pronounced than in WAG/G rats, the degree of opiate addiction is not determined by the content of substance P in rat brain. However, in our experiments treatment with substance P abolished morphine addiction, particularly in animals with low content of this compound in the brain.     

Latent inhibition of conditioned odor potentiation of startle: a developmental analysis

We conducted a two-part study of age and latent inhibition in the rat. In the first part of the study, rats given odor-shock pairings at 23 or 75 days of age exhibited a potentiated startle response in the presence of the odor the following day. This effect did not occur in rats trained at 16 or 20 days of age. Odor pre-exposure on the day prior to conditioning markedly reduced the odor potentiation of startle effect in 23- and 75-day-old rats but had no effect in 16 and 20-day-olds. In the second part of the study, rats were pre-exposed to the odor at 16 or 20 days of age and then conditioned at 23 days of age. When tested the day after conditioning, these pre-exposed rats exhibited a disruption in the odor potentiation of startle effect. We compare our results with other studies of latent inhibition, and with recent studies on whether conditioned responses are appropriate to the animal's age at training or their age at test.     

CHRNA4 was associated with prepulse inhibition of schizophrenia in Chinese: a pilot study

Introduction: Prepulse inhibition (PPI) of the auditory startle reflex, as an operational measurement used to evaluate the function of brain sensorimotor gating, appears to be a sensitive potential endophenotype for schizophrenia. CHRNA4 is highly expressed in the central nervous system and has been demonstrated to be significantly associated with schizophrenia by previous studies. The purpose of the current study was to evaluate the effect of CHRNA4 on PPI and acoustic startle parameters in schizophrenia.

Methods: 77 patients with schizophrenia and 62 controls were administered the test PPI, and 3 single nucleotide polymorphisms (SNPs) (rs3746372, rs1044396, and rs3787140) of CHRNA4 were genotyped in these subjects.

Results: Patients with schizophrenia showed significantly lower levels of PPI at the 120?ms prepulse intervals and longer peak latency than controls, and the GG genotype of rs3746372 and the TT genotype of rs1044396 were associated with decreased PPI levels in schizophrenia but not in controls.

Conclusion: PPI may be influenced by the polymorphisms of the CHRNA4 in schizophrenia and it may be a potential endophenotype of schizophrenia. An independent replication would greatly increase the value of this study.     

Projections from ventral hippocampus to medial prefrontal cortex but not nucleus accumbens remain functional after fornix lesions in rats

Sensorimotor gating, as measured by prepulse inhibition (PPI) of startle, is deficient in human beings with schizophrenia and is greatly reduced in rats after bilateral infusion of N-methyl-D-aspartate (NMDA) into the ventral hippocampus (VH). The disruption of PPI by bilateral VH NMDA infusion is blocked by bilateral medial prefrontal cortex (mPFC) lesions, but not by bilateral lesions of the fornix, which is the principal output pathway of the hippocampal formation of the VH. Tract-tracing studies have shown the presence of additional nonfornical pathways by which the VH and neighboring structures of the amygdala may reach forebrain regions that regulate PPI, including the mPFC. To determine whether these nonfornical pathways might mediate forebrain activation after VH NMDA infusion, we examined the effects of bilateral VH NMDA infusion on c-Fos protein expression in the mPFC and nucleus accumbens (NAC) after sham vs. bilateral fornix lesions. Significant increases of c-Fos expression were observed in both the mPFC and NAC after bilateral VH NMDA infusions. Fornix lesions blocked enhanced c-Fos expression in the NAC but not the mPFC after VH NMDA infusion. The results suggest that an intact fornix may be necessary for VH activation of the NAC, but that the VH uses additional nonfornical projections to activate PPI-regulatory circuits within the mPFC.     

Strain-Specificity in Nicotine Attenuation of Phencyclidine-Induced Disruption of Prepulse Inhibition in Mice: Relevance to Smoking in Schizophrenia Patients

Schizophrenia patients may exhibit high tobacco smoking rates in part to self-medicate sensory gating deficits with nicotine contained in tobacco. To test this hypothesis, we induced sensori-motor gating deficits in four mouse strains with phencyclidine, a noncompetitive antagonist of glutamatergic N -methyl-d-aspartate receptors. Nicotine attenuated the disruption in prepulse inhibition induced by phencyclidine in DBA/2J and C3H/HeJ but not in C57BL/6J or 129T2/SvEmsJ mice. These results highlight genetic variations in the regulation by nicotinic cholinergic systems of the dysfunction in glutamatergic transmission contributing to gating deficits in schizophrenia. Further, these findings support the hypothesis of self-medication of gating deficits in schizophrenia through tobacco smoking, and suggest that treatments targeting genetic dysfunctions in nicotinic-glutamatergic interactions that would treat cognitive deficits will assist schizophrenia patients in minimizing tobacco smoking.     

The cellular and behavioral consequences of interleukin-1 alpha penetration through the blood-brain barrier of neonatal rats: a critical period for efficacy

Proinflammatory cytokines circulating in the periphery of early postnatal animals exert marked influences on their subsequent cognitive and behavioral traits and are therefore implicated in developmental psychiatric diseases such as schizophrenia. Here we examined the relationship between the permeability of the blood-brain barrier to interleukin-1 alpha (IL-1 alpha) in neonatal and juvenile rats and their later behavioral performance. Following s.c. injection of IL-1 alpha into rat neonates, IL-1 alpha immunoreactivity was first detected in the choroid plexus, brain microvessels, and olfactory cortex, and later diffused to many brain regions such as neocortex and hippocampus. In agreement, IL-1 alpha administration to the periphery resulted in a marked increase in brain IL-1 alpha content of neonates. Repeatedly injecting IL-1 alpha to neonates triggered astrocyte proliferation and microglial activation, followed by behavioral abnormalities in startle response and putative prepulse inhibition at the adult stage. Analysis of covariance with a covariate of startle amplitude suggested that IL-1 alpha administration may influence prepulse inhibition. However, adult rats treated with IL-1 alpha as neonates exhibited normal learning ability as measured by contextual fear conditioning, two-way passive shock avoidance, and a radial maze task and had no apparent sign of structural abnormality in the brain. In comparison, when IL-1 alpha was administered to juveniles, the blood-brain barrier permeation was limited. The increases in brain IL-1 alpha content and immunoreactivity were less pronounced following IL-1 alpha administration and behavioral abnormalities were not manifested at the adult stage. During early development, therefore, circulating IL-1 alpha efficiently crosses the blood-brain barrier to induce inflammatory reactions in the brain and influences later behavioral traits.     

Quantitative Trait Loci Associated with Reversal Learning and Latent Inhibition in Honeybees (Apis mellifera)

A study was conducted to identify quantitative trait loci (QTLs) that affect learning in honeybees. Two F₁ supersister queens were produced from a cross between two established lines that had been selected for differences in the speed at which they reverse a learned discrimination between odors. Different families of haploid drones from two of these F₁ queens were evaluated for two kinds of learning performance—reversal learning and latent inhibition—which previously showed correlated selection responses. Random amplified polymorphic DNA markers were scored from recombinant, haploid drone progeny that showed extreme manifestations of learning performance. Composite interval mapping procedures identified two QTLs for reversal learning (lrn2 and lrn3: LOD, 2.45 and 2.75, respectively) and one major QTL for latent inhibition (lrn1: LOD, 6.15). The QTL for latent inhibition did not map to either of the linkage groups that were associated with reversal learning. Identification of specific genes responsible for these kinds of QTL associations will open up new windows for better understanding of genes involved in learning and memory.     

Preferential relocation of the N-methyl-D-aspartate receptor NR1 subunit in nucleus accumbens neurons that contain dopamine D1 receptors in rats showing an apomorphine-induced sensorimotor gating deficit

Sensorimotor gating as measured by prepulse inhibition (PPI) to startle-evoking auditory stimulation (AS) is disrupted in schizophrenia and in rodents receiving systemic administration of apomorphine, a dopamine D1/D2 receptor agonist, or MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. The functional analogies and our prior results showing apomorphine- and AS-induced relocation of the dopamine D1 receptor (D1R) in the nucleus accumbens (Acb) shell suggest that apomorphine and AS may affect the subcellular distribution of the NMDA receptor NR1 subunit, a protein that forms protein-protein interactions with the D1R. We quantitatively compared the electron microscopic immunogold labeling for NR1 in dendritic profiles distinguished with respect to presence of D1R immunoreactivity and location in the Acb shell or core of rats receiving a single s.c. injection of vehicle (VEH) or apomorphine (APO) alone, or combined with AS (VEH+AS, APO+AS). The rats in the APO+AS group were previously shown to have PPI deficits, whereas the rats in the VEH+AS group had normal PPI. A significantly higher percentage of plasmalemmal and a lower percentage of cytoplasmic NR1 immunogold particles were seen in D1R-labeled dendritic spines in the Acb shell of the APO+AS group compared with all other groups. D1R-containing small dendrites in the Acb shell of the APO+AS group also showed a significantly higher density of plasmalemmal and a lower density of cytoplasmic NR1 immunogold particles compared with VEH or APO groups. In the Acb core, the APO+AS group had significantly fewer dendritic spines co-expressing NR1 and D1R compared with VEH or VEH+AS groups. These results, together with our earlier findings, suggest that NMDA receptors are preferentially mobilized in D1R-containing Acb neurons of rats showing apomorphine-induced disruption of PPI in a paradigm using acoustic stimulation.     

Effects of social isolation rearing on the limbic brain: A combined behavioral and magnetic resonance imaging volumetry study in rats

Rearing rats in social isolation from weaning induces robust behavioral and neurobiological alterations resembling some of the core symptoms of schizophrenia, such as reduction in prepulse inhibition of acoustic startle (PPI) and locomotor hyperactivity in a novel arena. The aim of this study was to investigate whether social isolation rearing induces volumetric remodeling of the limbic system, and to probe for anatomical structure–behavioral interrelations.     

Differences in Serotonin and Dopamine Metabolism in the Rat Brain in Latent Inhibition

Monoamine oxidase activity during deamination of serotonin and dopamine in the amygdaloid complex, hippocampus, striatum and prefrontal cortex of the brain was studied at different stages in the formation of latent inhibition, acquired by rats on the basis of a conditioned passive avoidance reaction. Latent inhibition is a behavioral phenomenon consisting of a worsening in learning using a stimulus when attention to this stimulus is quenched before acquisition of the conditioned response. At the stage of preliminary repeated presentation of the conditioned stimulus, serotonin metabolism was seen to change in the amygdaloid complex and striatum, while dopamine metabolism changed in the amygdaloid complex and hippocampus. Metabolic shifts in transmitter handling during quenching of attention to the stimulus occurred in the opposite directions: the serotonin-deaminating activity of monoamine oxidase increased, while the dopamine-deaminating activity of the enzyme decreased. Unlike the reaction to the quenched stimulus, the latent inhibition effect, seen on testing the conditioned response after conditioning of the pre-exposed stimulus with unconditioned reinforcement, was accompanied by changes in serotoninergic activity only. High levels of serotonin deamination by monoamine oxidase were seen in the amygdaloid complex and striatum. In addition, there was a reduction in serotonin deamination in the prefrontal cortex specific for the stage of testing latent inhibition. At the same time, dopamine metabolism did not change in any of the brain structures studied in latent inhibition. These data lead to the conclusion that the latent inhibition effect may be based on increases in serotoninergic activity in subcortical brain structures – the amygdaloid complex and the striatum – induced by reactions to presentation of the quenched stimulus.     

Latent inhibition in the developing rat: an examination of context-specific effects

Latent inhibition (LI) refers to the reduction in conditioned responding when the conditioned stimulus (CS) is preexposed prior to CS-unconditioned stimulus pairings. Experiment 1a demonstrated that preexposure to an odor CS prior to odor-shock pairings markedly reduced conditioned freezing in 25-day-old rats; however, this LI effect was observed only if odor preexposure and odor-shock pairings occurred in the same context (i.e., LI was context-specific at this age). The results of Experiment 1b showed that 18-day-olds also exhibited LI, but this effect was not context-specific at this age. In Experiment 2, rats were preexposed to the odor at 18 days of age and given odor-shock pairings at 25 days of age. These rats exhibited context-specific latent inhibition, suggesting that 18-day-old rats encoded the preexposure context. In Experiment 3, all parameters were identical to Experiment 2, with the exception that odor-shock pairings were given at approximately PN18 and testing occurred at approximately PN25. These rats exhibited latent inhibition at test, but this effect was not context-specific. The results of this study suggest that (a) PN18 rats can exhibit latent inhibition, and (b) the expression of context-specific latent inhibition depends on the age at which conditioning occurs.     

Identification of Quantitative Trait Loci for Anxiety and Locomotion Phenotypes in Rat Recombinant Inbred Strains

Anxiety disorders are phenotypically complex and may involve multiple genetic influences on many neurotransmitter systems. Rodent tests used to investigate genetic influences on anxiety-like phenotypes have face and predictive validity as models for anxiety in humans. If multiple genes contribute additively to a trait, the trait will be continuously distributed and be amenable to detection of associations between allelic variation at specific chromosomal loci and the phenotypes being studied via quantitative trait loci (QTL) mapping. The elevated plus-maze test provides quantitative measures of both anxiety-like and locomotion phenotypes. Using this test, we assessed four phenotypes in a set of 22 rat recombinant inbred (RI) strains derived from Brown Norway (BN.Lx /Cub) and Spontaneously Hypertensive rat (SHR/Ola) progenitors. QTL analyses were used to determine whether allelic variation at specific chromosomal loci contribute significantly to RI strain-dependent variance in each phenotype. Significant QTL for an anxiety phenotype were found on chromosomes 2, 5, 6, and 7. For a phenotype reflecting both anxiety and locomotion, QTL were found on chromosomes 2, 7, and 8, while for a locomotion phenotype, significant QTL were found on chromosomes 3 and 18.     

Thermoalgesic stimuli induce prepulse inhibition of the blink reflex and affect conscious perception in healthy humans

All sensory stimuli produce transient excitability changes in various central nervous system circuits. One example is prepulse inhibition (PPI), which is the inhibition generated by a preceding weak stimulus (prepulse) over the reflex response to a subsequent suprathreshold stimulus. The PPI is a ubiquitous phenomenon, common to many different sensory modalities. However, it has not yet been studied with thermoalgesic stimuli. These stimuli take a relatively long time to reach their peak, which implies some uncertainty in the exact timing of prepulse effects with respect to stimulus onset. In 20 healthy volunteers, we determined when thermoalgesic stimuli cause PPI of the blink reflex and measured conscious awareness (AW) of thermoalgesic stimulus perception using the Libet's clock. In this way, we determined the temporal relationship between AW and PPI. In a second experiment, we investigated whether prepulse effects on blink reflex also involved a change in conscious perception of the supraorbital nerve stimulus. Our results show that thermoalgesic stimuli generate PPI of the blink reflex long before subjects were consciously aware of the stimulus, confirming the already‐known principle that conscious perception is not required for PPI to take place, and that prepulse stimuli induce a change in the time of conscious perception of prepulse and pulse stimuli, in such a way that AW of both stimuli tended to become closer to each other.     

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.     

Altered mnemonic functions and resistance to N-METHYL-d-Aspartate receptor antagonism by forebrain conditional knockout of glycine transporter 1

Converging evidence from pharmacological and molecular studies has led to the suggestion that inhibition of glycine transporter 1 (GlyT1) constitutes an effective means to boost N-methyl-d-aspartate receptor (NMDAR) activity by increasing the extra-cellular concentration of glycine in the vicinity of glutamatergic synapses. However, the precise extent and limitation of this approach to alter cognitive function, and therefore its potential as a treatment strategy against psychiatric conditions marked by cognitive impairments, remain to be fully examined. Here, we generated mutant mice lacking GlyT1 in the entire forebrain including neurons and glia. This conditional knockout system allows a more precise examination of GlyT1 downregulation in the brain on behavior and cognition. The mutation was highly effective in attenuating the motor-stimulating effect of acute NMDAR blockade by phencyclidine, although no appreciable elevation in NMDAR-mediated excitatory postsynaptic currents (EPSC) was observed in the hippocampus. Enhanced cognitive performance was observed in spatial working memory and object recognition memory while spatial reference memory and associative learning remained unaltered. These findings provide further credence for the potential cognitive enhancing effects of brain GlyT1 inhibition. At the same time, they indicated potential phenotypic differences when compared with other constitutive and conditional GlyT1 knockout lines, and highlighted the possibility of a functional divergence between the neuronal and glia subpopulations of GlyT1 in the regulation of learning and memory processes. The relevance of this distinction to the design of future GlyT1 blockers as therapeutic tools in the treatment of cognitive disorders remains to be further investigated.     

Investigating Cognitive Inhibition in Dissociative Identity Disorder Compared to Depression,Posttraumatic Stress Disorder and Psychosis

ABSTRACT

Cognitive inhibition refers to the mental capacity to suppress distracting stimuli that compete with target stimuli for processing resources. Using neutral word stimuli in a flanker task, a recent study suggested that dissociative identity disorder (DID) is characterized by weakened cognitive inhibitory functioning (Dorahy, Irwin, & Middleton, 2002). The current study used single digit stimuli in the flanker task and tested cognitive inhibitory ability in samples with DID, depression, posttraumatic stress disorder and psychosis. The DID, depressed and PTSD groups displayed no evidence of weakened cognitive inhibitory functioning. Consistent with previous research, however, the psychosis sample displayed a reduced capacity to engage in cognitive inhibition. Cognitive inhibitory ability was not related to measures of dissociation, childhood traumatic experience or schizotypy. Results are discussed in terms of the positive symptoms of schizophrenia and the nature of stimuli used in the flanker task.     

Inhibition of bacterial translocation by chronic ethanol consumption in the rat

Chronic ethanol ingestion has been associated with small intestine morphological changes, disrupted host mucosal defenses and bacterial overgrowth. Since bacterial translocation (BT) may result from such alterations, we have investigated the potential effect of chronic ethanol consumption on BT. For this purpose, male Wistar rats were fed a liquid diet containing 5% v/v ethanol for 4 weeks (EG, n=16), and a pair-fed group received equal daily amounts of calories in a similar diet without ethanol (PFG, n=16). On experimental day 29, distal ileum ligature and small intestine inoculation of a tetracycline-resistant E. coli strain (Tc E. coli R6) followed by duodenal ligature was performed. After 1 or 5 h post inoculation, mesenteric lymph nodes, liver, spleen and kidney were excised. Unexpectedly, rats of the EG presented markedly less BT to the mesenteric lymph nodes (p<0.001) and to the other organs examined compared to rats of the PFG. This BT inhibition was observed at 1 and 5 h after bacterial inoculation, and may be attributed exclusively to chronic ethanol ingestion. Since alcoholism is well known to decrease host immunity, these results suggest that other factors, independent of the immune function, may be involved in the BT inhibition observed in this study.