Search

Deficient prepulse inhibition (PPI) of the acoustic startle reaction after injection of the dopamine receptor agonist apomorphine has been experimentally used to model certain aspects of Tourette syndrome (TS) in rats. Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) complex alleviates tics in patients with TS. The CM-Pf projects to striatal regions, which might mediate the effect of DBS via the cortico basal-ganglia circuitry implicated in the pathophysiology of TS. We tested the effect of CM-Pf DBS on apomorphine-induced deficient PPI and on striatal neuronal activity in rats. Electrodes were stereotaxically implanted bilaterally in the CM-Pf of adult male Sprague Dawley rats. Thereafter, rats were stimulated (150 μA and 130 Hz) or sham-stimulated (no application of current) to test the effect on apomorphine-induced deficient PPI (vehicle and 1.0 mg/kg). Additionally, the neuronal activity of the dorsomedial striatum (DMS) and the nucleus accumbens (NAC), as well as its coherence with the sensorimotor cortex (SM-Ctx) was recorded after apomorphine injection and CM-Pf DBS. CM-Pf DBS prevented the apomorphine-induced PPI-deficit. In striatal neurons apomorphine enhanced burst activity, as well as oscillatory theta band coherence with SM-Ctx electrocorticogram (SM-Ctx ECoG), which was reduced by CM-Pf DBS. Overall, the effect was stronger in the NAC than in the DMS. Modulation of neuronal activity in striatal regions may mediate the effects of CM-Pf DBS on PPI. This model may be used to test and improve novel neuro-modulation strategies.

Maternal immune activation (MIA) during pregnancy represents an important environmental factor in the etiology of schizophrenia and autism spectrum disorders (ASD). Our goal was to investigate the impacts of MIA on the brain and behavior of adolescent and adult offspring, as a rat model of these neurodevelopmental disorders. We injected bacterial lipopolysaccharide (LPS, 1 mg/kg) to pregnant Wistar dams from gestational day 7, every other day, up to delivery. Behavior of the offspring was examined in a comprehensive battery of tasks at postnatal days P45 and P90. Several brain parameters were analyzed at P28. The results showed that prenatal immune activation caused social and communication impairments in the adult offspring of both sexes, males were affected already in adolescence. MIA also caused prepulse inhibition deficit in females and increased the startle reaction in males. Anxiety and hypolocomotion were apparent in LPS-affected males and females. In the 28-day-old LPS offspring, we found enlargement of the brain and decreased numbers of parvalbumin-positive interneurons in the frontal cortex in both sexes. To conclude, our data indicate that sex of the offspring plays a crucial role in the development of the MIA-induced behavioral alterations, whereas changes in the brain apparent in young animals are sex-independent.

Psilocybin has recently attracted a great deal of attention as a clinical research and therapeutic tool. The aim of this paper is to bridge two major knowledge gaps regarding its behavioural pharmacology - sex differences and the underlying receptor mechanisms. We used psilocin (0.25, 1 and 4 mg/kg), an active metabolite of psilocybin, in two behavioural paradigms - the open-field test and prepulse inhibition (PPI) of the acoustic startle reaction. Sex differences were evaluated with respect to the phase of the female cycle. The contribution of serotonin receptors in the behavioural action was tested in male rats with selective serotonin receptor antagonists: 5-HT1A receptor antagonist (WAY100635 1 mg/kg), 5-HT2A receptor antagonist (MDL100907 0.5 mg/kg), 5-HT2B receptor antagonist (SB215505 1 mg/kg) and 5-HT2C receptor antagonist (SB242084 1 mg/kg). Psilocin induced dose-dependent inhibition of locomotion and suppression of normal behaviour in rats (behavioural serotonin syndrome, impaired PPI). The effects were more pronounced in male rats than in females. The inhibition of locomotion was normalized by 5-HT1A and 5-HT2B/C antagonists; however, PPI was not affected significantly by these antagonists. Our findings highlight an important issue of sex-specific reactions to psilocin and that apart from 5-HT2A-mediated effects 5-HT1A and 5-HT2C/B receptors also play an important role. These findings have implications for recent clinical trials.

Whereas schizophrenia affects both human sexes, there are known sex-dependent disparities. We developed a chronic animal model that shows some schizophrenia-related deficits in rats by applying selective breeding after subchronic ketamine administration connected with postweaning social isolation (complex treatment). Our aim was to determine the sex-specific effects of these interventions on several processes. Sensory gating to acoustic stimulation, pain sensitivity, motor behavior, spatial learning and memory deficits on the hole-board test were assessed in the 17th generation of selectively bred Wistar rats compared to their naive counterparts with or without complex treatment. We found differences between the sexes: selectively bred males with complex treatment showed the lowest pain sensitivity; however, the results of the prepulse inhibition test indicated that female rats showed enhanced impairment of sensory gating and increased acoustic startle reaction. The cognitive performance, working and reference memory ratios were significantly decreased by selective breeding and showed sex-specific alterations, with the smallest value in male rats of the new substrain. Based on these results, the animals of the new substrain could be classified into the high-risk for schizophreniform phenotype with the highest sensitivity of males with complex treatment. Decreased cognitive performance highlighted spatial learning deficits in the selectively bred and treated rats that escalate the validity of our new and complex rat model of schizophrenia. The results indicate the same sex selectivity as observed in humans, with increased incidence of risk ratios for men to develop schizophrenia relative to women.

Mirror movements are involuntary movements on one side of the body that occur simultaneously with intentional movements on the contralateral side. Humans with heterozygous mutations in the axon guidance receptorDCCdisplay such mirror movements, where unilateral stimulation results in inappropriate bilateral motor output. Currently, it is unclear whether mirror movements are caused by incomplete midline crossing and reduced commissural connectivity ofDCC-dependent descending pathways or by aberrant ectopic ipsilateral axonal projections of normally commissural neurons. Here, we show that in response to unilateral tactile stimuli, zebrafishdccmutant larvae perform involuntary turns on the inappropriate body side. We show that these mirror movement-like deficits are associated with axonal guidance defects of two identified groups of commissural reticulospinal hindbrain neurons. Moreover, we demonstrate that indccmutants, axons of these identified neurons frequently fail to cross the midline and instead project ipsilaterally. Whereas laser ablation of these neurons in wild-type animals does not affect turning movements, their ablation indccmutants restores turning movements. Thus, our results demonstrate that indccmutants, turns on the inappropriate side of the body are caused by aberrant ipsilateral axonal projections, and suggest that aberrant ipsilateral connectivity of a very small number of descending axons is sufficient to induce incorrect movement patterns.

Haloperidol is an efficacious antipsychotic drug that has serious, unpredictable motor side effects that limit its utility and cause noncompliance in many patients. Using a drug–placebo diallel of the eight founder strains of the Collaborative Cross and their F1 hybrids, we characterized aggregate effects of genetics, sex, parent of origin, and their combinations on haloperidol response. Treating matched pairs of both sexes with drug or placebo, we measured changes in the following: open field activity, inclined screen rigidity, orofacial movements, prepulse inhibition of the acoustic startle response, plasma and brain drug level measurements, and body weight. To understand the genetic architecture of haloperidol response we introduce new statistical methodology linking heritable variation with causal effect of drug treatment. Our new estimators, “difference of models” and “multiple-impute matched pairs”, are motivated by the Neyman–Rubin potential outcomes framework and extend our existing Bayesian hierarchical model for the diallel (Lenarcic et al. 2012). Drug-induced rigidity after chronic treatment was affected by mainly additive genetics and parent-of-origin effects (accounting for 28% and 14.8% of the variance), with NZO/HILtJ and 129S1/SvlmJ contributions tending to increase this side effect. Locomotor activity after acute treatment, by contrast, was more affected by strain-specific inbreeding (12.8%). In addition to drug response phenotypes, we examined diallel effects on behavior before treatment and found not only effects of additive genetics (10.2–53.2%) but also strong effects of epistasis (10.64–25.2%). In particular: prepulse inhibition showed additivity and epistasis in about equal proportions (26.1% and 23.7%); there was evidence of nonreciprocal epistasis in pretreatment activity and rigidity; and we estimated a range of effects on body weight that replicate those found in our previous work. Our results provide the first quantitative description of the genetic architecture of haloperidol response in mice and indicate that additive, dominance-like inbreeding and parent-of-origin effects contribute strongly to treatment effect heterogeneity for this drug.

A number of studies have implicated disruptions in prepulse inhibition (PPI) of the startle response in both schizophrenia patients and animal models of this disorder. These disruptions are believed to reflect deficits in sensorimotor gating and are ascribed to aberrant filtering of sensory inputs leading to sensory overload and enhanced “noise” in neural structures. Here we examined auditory evoked potentials in a rodent model of schizophrenia (MAM-GD17) during an auditory PPI paradigm to better understand this phenomenon. MAM rats exhibited reductions in specific components of auditory evoked potentials in the orbtiofrontal cortex and an abolition of the graded response to stimuli of differing intensities indicating deficient intensity processing in the orbitofrontal cortex. These data indicate that aberrant sensory information processing, rather than being attributable to enhanced noise in neural structures, may be better attributed to diminished evoked amplitudes resulting in a reduction in the “signal-to-noise” ratio. Therefore, the ability for sensory input to modulate the ongoing background activity may be severely disrupted in schizophrenia yielding an internal state which is insufficiently responsive to external input.

SUMMARYZebrafish (Danio rerio) have become a valuable model for investigating the molecular genetics and development of the inner ear in vertebrates. In this study, we employed a prepulse inhibition (PPI) paradigm to assess hearing in larval wild-type (AB) zebrafish during early development at 5–6 days post-fertilization (d.p.f.). We measured the PPI of the acoustic startle response in zebrafish using a 1-dimensional shaker that simulated the particle motion component of sound along the fish's dorsoventral axis. The thresholds to startle-inducing stimuli were determined in 5–6 d.p.f. zebrafish, and their hearing sensitivity was then characterized using the thresholds of prepulse tone stimuli (90–1200 Hz) that inhibited the acoustic startle response to a reliable startle stimulus (820 Hz at 20 dB re. 1 m s−2). Hearing thresholds were defined as the minimum prepulse tone level required to significantly reduce the startle response probability compared with the baseline (no-prepulse) condition. Larval zebrafish showed greatest auditory sensitivity from 90 to 310 Hz with corresponding mean thresholds of −19 to −10 dB re. 1 m s−2, respectively. Hearing thresholds of prepulse tones were considerably lower than previously predicted by startle response assays. The PPI assay was also used to investigate the relative contribution of the lateral line to the detection of acoustic stimuli. After aminoglycoside-induced neuromast hair-cell ablation, we found no difference in PPI thresholds between treated and control fish. We propose that this PPI assay can be used to screen for novel zebrafish hearing mutants and to investigate the ontogeny of hearing in zebrafish and other fishes.

Bipolar disorder (BD) is a pervasive neuropsychiatric disorder characterized by episodes of mania and depression. The switch between mania and depression may reflect seasonal changes and certainly can be affected by alterations in sleep and circadian control. The circadian locomotor output cycles kaput (CLOCK) protein is a key component of the cellular circadian clock. Mutation of the Clock gene encoding this protein in Clock△19 mutant mice leads to behavioral abnormalities reminiscent of BD mania. To date, however, these mice have not been assessed in behavioral paradigms that have cross-species translational validity. In the present studies of Clock△19 and wildtype (WT) littermate mice, we quantified exploratory behavior and sensorimotor gating, which are abnormal in BD manic patients. We also examined the saccharin preference of these mice and their circadian control in different photoperiods. Clock△19 mice exhibited behavioral alterations that are consistent with BD manic patients tested in comparable tasks, including hyperactivity, increased specific exploration, and reduced sensorimotor gating. Moreover, compared to WT mice, Clock△19 mice exhibited a greater preference for sweetened solutions and greater sensitivity to altered photoperiod. In contrast with BD manic patients however, Clock△19 mice exhibited more circumscribed movements during exploration. Future studies will extend the characterization of these mice in measures with cross-species translational relevance to human testing.

Maternal infection is a risk factor for autism spectrum disorder (ASD) and schizophrenia (SZ). Indeed, modeling this risk factor in mice through maternal immune activation (MIA) causes ASD- and SZ-like neuropathologies and behaviors in the offspring. Although MIA upregulates pro-inflammatory cytokines in the fetal brain, whether MIA leads to long-lasting changes in brain cytokines during postnatal development remains unknown. Here, we tested this possibility by measuring protein levels of 23 cytokines in the blood and three brain regions from offspring of poly(I:C)- and saline-injected mice at five postnatal ages using multiplex arrays. Most cytokines examined are present in sera and brains throughout development. MIA induces changes in the levels of many cytokines in the brains and sera of offspring in a region- and age-specific manner. These MIA-induced changes follow a few, unexpected and distinct patterns. In frontal and cingulate cortices, several, mostly pro-inflammatory, cytokines are elevated at birth, followed by decreases during periods of synaptogenesis and plasticity, and increases again in the adult. Cytokines are also altered in postnatal hippocampus, but in a pattern distinct from the other regions. The MIA-induced changes in brain cytokines do not correlate with changes in serum cytokines from the same animals. Finally, these MIA-induced cytokine changes are not accompanied by breaches in the blood–brain barrier, immune cell infiltration or increases in microglial density. Together, these data indicate that MIA leads to long-lasting, region-specific changes in brain cytokines in offspring—similar to those reported for ASD and SZ—that may alter CNS development and behavior.

Rationale: Inhibition of glycine transporter 1 (GlyT1) elevates extracellular glycine and can thus increase N-methyl-d-aspartate receptor (NMDAR) excitability in the brain. The potent GlyT1 inhibitor, SSR504734, has also been shown to potentiate the behavioral effects of direct and indirect dopamine agonists. Thus, an acute systemic dose of SSR504734 was sufficient to exacerbate the motor-stimulant effect of the dopamine releaser amphetamine in C57BL/6 mice, even though SSR504734 alone exerted no significant effect on motor activity. Objectives: Here, we explore if SSR504734 might modulate dopamine-dependent sensory gating in the paradigm of prepulse inhibition (PPI) of the acoustic startle reflex. Methods: Experiment 1 characterized the effect of SSR504734 (10 and 30mg/kg i.p.) on PPI expression when administered alone. Experiments 2 and 3 investigated the impact of SSR504734 when administered in conjunction with the dopamine receptor agonist, apomorphine (1 and 2mg/kg s.c.), which is known to reliably disrupt PPI. Results: When administered alone, acute SSR504734 enhanced PPI only at 30mg/kg—a dose that has been shown to improve cognitive functions including working memory, which has been linked to enhanced NMDAR function resulting from the elevation of extracellular glycine. However, this effect did not allow SSR504734 to antagonize the PPI-disruptive effect of apomorphine. At the lower dose of 10mg/kg—that was insufficient to enhance PPI when administered alone—SSR504734 even exacerbated the deleterious effect of apomorphine on PPI. Conclusions: The therapeutic potential of GlyT1 inhibition against distinct behavioral/cognitive deficiency might require different magnitudes of GlyT1 inhibition

Neuropsychiatric disease frequently presents with an underlying hyporeactivity or hyperreactivity of the HPA stress axis, suggesting an exceptional vulnerability of this circuitry to external perturbations. Parental lifetime exposures to environmental challenges are associated with increased offspring neuropsychiatric disease risk, and likely contribute to stress dysregulation. While maternal influences have been extensively examined, much less is known regarding the specific role of paternal factors. To investigate the potential mechanisms by which paternal stress may contribute to offspring hypothalamic–pituitary–adrenal (HPA) axis dysregulation, we exposed mice to 6 weeks of chronic stress before breeding. As epidemiological studies support variation in paternal germ cell susceptibility to reprogramming across the lifespan, male stress exposure occurred either throughout puberty or in adulthood. Remarkably, offspring of sires from both paternal stress groups displayed significantly reduced HPA stress axis responsivity. Gene set enrichment analyses in offspring stress regulating brain regions, the paraventricular nucleus (PVN) and the bed nucleus of stria terminalis, revealed global pattern changes in transcription suggestive of epigenetic reprogramming and consistent with altered offspring stress responsivity, including increased expression of glucocorticoid-responsive genes in the PVN. In examining potential epigenetic mechanisms of germ cell transmission, we found robust changes in sperm microRNA (miR) content, where nine specific miRs were significantly increased in both paternal stress groups. Overall, these results demonstrate that paternal experience across the lifespan can induce germ cell epigenetic reprogramming and impact offspring HPA stress axis regulation, and may therefore offer novel insight into factors influencing neuropsychiatric disease risk.

Homer postsynaptic scaffolding proteins regulate forebrain glutamate transmission and thus, are likely molecular candidates mediating hypofrontality in addiction. Protracted withdrawal from cocaine experience increases the relative expression of Homer2 versus Homer1 isoforms within medial prefrontal cortex (mPFC). Thus, this study used virus-mediated gene transfer strategies to investigate the functional relevance of an imbalance in mPFC Homer1/2 expression as it relates to various measures of sensorimotor, cognitive, emotional and motivational processing, as well as accompanying alterations in extracellular glutamate in C57BL/6J mice. mPFC Homer2b overexpression elevated basal glutamate content and blunted cocaine-induced glutamate release within the mPFC, whereas Homer2b knockdown produced the opposite effects. Despite altering mPFC glutamate, Homer2b knockdown failed to influence cocaine-elicited conditioned place preferences, nor did it produce consistent effects on any other behavioral measures. In contrast, elevating the relative expression of Homer2b versus Homer1 within mPFC, by overexpressing Homer2b or knocking down Homer1c, shifted the dose-response function for cocaine-conditioned reward to the left, without affecting cocaine locomotion or sensitization. Intriguingly, both these transgenic manipulations produced glutamate anomalies within the nucleus accumbens (NAC) of cocaine-naive animals that are reminiscent of those observed in cocaine experienced animals, including reduced basal extracellular glutamate content, reduced Homer1/2 and glutamate receptor expression, and augmented cocaine-elicited glutamate release. Together, these data provide novel evidence in support of opposing roles for constitutively expressed Homer1 and Homer2 isoforms in regulating mPFC glutamate transmissionin vivoand support the hypothesis that cocaine-elicited increases in the relative amount of mPFC Homer2 versus Homer1 signaling produces abnormalities in NAC glutamate transmission that enhance vulnerability to cocaine reward.

The periaqueductal gray (PAG) columns have been implicated in controlling stress responses through corticotropin-releasing factor (CRF), which is a neuropeptide with a prominent role in the etiology of fear- and anxiety-related psychopathologies. Several studies have investigated the involvement of dorsal PAG (dPAG) CRF mechanisms in models of unconditioned fear. However, less is known about the role of this neurotransmission in the expression of conditioned fear memories in the dPAG and ventrolateral PAG (vlPAG) columns. We assessed the effects of ovine CRF (oCRF 0.25 and 1.0μg/0.2μL) locally administered into the dPAG and vlPAG on behavioral (fear-potentiated startle and freezing) and autonomic (arterial pressure and heart rate) responses in rats subjected to contextual fear conditioning. The lower dose injected into the columns promoted proaversive effects, enhanced contextual freezing, increased the blood pressure and heart rate and decreased tail temperature. The lower dose of oCRF into the vlPAG, but not into the dPAG, produced a pronounced enhancement of the fear-potentiated startle response. The results imply that the PAG is a heterogeneous structure that is involved in the coordination of distinct behaviors and autonomic control, suggest PAG involvement in the expression of contextual fear memory as well as implicate the CRF as an important modulator of the neural substrates of fear in the PAG.

Despite evidence for a strong genetic contribution to several major psychiatric disorders, individual candidate genes account for only a small fraction of these disorders, leading to the suggestion that multigenetic pathways may be involved. Several known genetic risk factors for psychiatric disease are related to the regulation of actin polymerization, which plays a key role in synaptic plasticity. To gain insight into and test the possible pathogenetic role of this pathway, we designed a conditional knock-out of the Arp2/3 complex, a conserved final output for actin signaling pathways that orchestratesde novoactin polymerization. Here we report that postnatal loss of the Arp2/3 subunit ArpC3 in forebrain excitatory neurons leads to an asymmetric structural plasticity of dendritic spines, followed by a progressive loss of spine synapses. This progression of synaptic deficits corresponds with an evolution of distinct cognitive, psychomotor, and social disturbances as the mice age. Together, these results point to the dysfunction of actin signaling, specifically that which converges to regulate Arp2/3, as an important cellular pathway that may contribute to the etiology of complex psychiatric disorders.

Many human subjects suffering from chronic tinnitus also suffer from hyperacusis, a heightened perception of loudness at moderate to intense sound levels. While numerous studies suggest that animals develop chronic tinnitus following intense noise exposure, it is not yet clear whether sound exposure also induces chronic hyperacusis-like responses in animals. We addressed this question by examining the chronic effects of intense sound exposure on the acoustic startle response (ASR) and its suppression by background noise containing brief gaps. We compared startle amplitudes in intense tone-exposed (10 kHz, 115 dB SPL, 4 h) and age-matched controls at 2–28 weeks post-exposure. While both groups showed similar startle thresholds, exposed animals showed a hyperacusis-like augmentation of ASR at high stimulus levels. Addition of background noise had little effect on ASR in controls but had a strong suppressive effect on startle in exposed animals, indicating a sensitization to background noise. When the background noise contained a gap preceding the startle stimulus, ASR was suppressed in control animals, but exposed animals showed a marked weakening of gap-induced suppression of ASR. This weakening of gap-induced startle suppression is consistent with the interpretation that the gap may have been masked by tinnitus. The associated hyper-responsiveness to startle stimuli presented alone and the sensitization to background noise suggest that hyperacusis may have also been induced. The results indicate that noise exposure leads to increases in the gain of auditory responsiveness and may offer a model of the association of hyperacusis with tinnitus.

Many laboratories obtain their experimental animals from commercial suppliers and are therefore dependent on their conditions and breeding schedules. A breeding stop or the substitution of a particular rat line by the supplier forces the customers to abandon their conventional test animals and to re-establish all behavioral paradigms with a new rat line. Therefore, it is vital to know whether behavioral differences emerge in various breeding lines of the same rat strain. In a recent case, the commercial supplier Harlan Laboratories GmbH is substituting the previous HsdHan:WIST line of Wistar rats with the RccHan:WIST line descending from a different breeding stock. We therefore tested animals of both lines (RccHan:WIST and HsdHan:WIST from Harlan Laboratories GmbH) as well as Wistar rats of the same line but obtained from a different supplier (Janvier) in a broad range of behavioral paradigms. We observed differences in locomotor activity, in classical anxiety-related paradigms (elevated plus maze and light/dark emergence test), as well as in object recognition memory and prepulse inhibition (PPI) of the acoustic startle reflex (ASR). We also found differences in ethanol intake and preference, but not regarding the intake of a palatable food reward and a bitter solution (quinine). These results demonstrate considerable variations in the behavioral phenotype between different breeding lines of the same Wistar rat strain and aim to increase the awareness of behavioral scientists for line and supplier differences affecting animal behavior.

Animal models of tinnitus require a behavioral correlate thereof. Various conditioned response methods and gap-startle reflex methods are in use and the outcomes generally correspond with putative electrophysiological substrates of tinnitus. However, for salicylate-induced tinnitus there is discordance between the behavioral and electrophysiological test results. As a result, it is not clear what the various tests are reflecting. A review of the, mostly sub-cortical, neural circuits that underlie the behavioral responses suggests that cortical electrophysiological correlates do not necessarily have to correspond with behavioral ones. Human objective correlates of tinnitus point heavily into cortical network, but not just auditory cortex, correlates of tinnitus. Furthermore, the synaptic mechanisms underlying spontaneous firing rate changes may be different from those involved in driven neural activity.

In 2006, Turner and colleagues (Behav. Neurosci., 120:188–195) introduced the gap-startle paradigm as a high-throughput method for tinnitus screening in rats. Under this paradigm, gap detection ability was assessed by determining the level of inhibition of the acoustic startle reflex produced by a short silent gap inserted in an otherwise continuous background sound prior to a loud startling stimulus. Animals with tinnitus were expected to show impaired gap detection ability (i.e., lack of inhibition of the acoustic startle reflex) if the background sound containing the gap was qualitatively similar to the tinnitus pitch. Thus, for the gap-startle paradigm to be a valid tool to screen for tinnitus, a robust startle response from which to inhibit must be present. Because recent studies have demonstrated that the acoustic startle reflex could be dramatically reduced following noise exposure, we endeavored to 1) modify the gap-startle paradigm to be more resilient in the presence of hearing loss, and 2) evaluate whether a reduction in startle reactivity could confound the interpretation of gap prepulse inhibition and lead to errors in screening for tinnitus. In the first experiment, the traditional broadband noise (BBN) startle stimulus was replaced by a bandpass noise in which the sound energy was concentrated in the lower frequencies (5–10 kHz) in order to maintain audibility of the startle stimulus after unilateral high-frequency noise exposure (16 kHz). However, rats still showed a 57% reduction in startle amplitude to the bandpass noise post-noise exposure. A follow-up experiment on a separate group of rats with transiently-induced conductive hearing loss revealed that startle reactivity was better preserved when the BBN startle stimulus was replaced by a rapid airpuff to the back of the rat’s neck. Furthermore, it was found that transient unilateral conductive hearing loss, which was not likely to induce tinnitus, caused an impairment in gap prepulse inhibition as assessed with the traditional BBN gap-startle paradigm, resulting in a false-positive screening for tinnitus. Thus, the present study identifies significant caveats of the traditional gap-startle paradigm, and describes experimental parameters using an airpuff startle stimulus which may help to limit the negative consequences of reduced startle reactivity following noise exposure, thereby allowing researchers to better screen for tinnitus in animals with hearing loss.

Prepulse inhibition (PPI) is a model of sensorimotor gating, a sensory filtering mechanism which is disrupted in schizophrenia. Here, investigation of the role of the serotonin-1A (5-HT(1A)) receptor in the regulation of PPI in two mouse strains, C57Bl/6 and Balb/c, was used to address findings in the PPI literature on species and mouse strain differences that question the usefulness of PPI as a cross-species preclinical test. Although the full 5-HT(1A) receptor agonist, 8-OH-DPAT, induced markedly different strain-specific responses in PPI, other selective 5-HT(1A) receptor ligands with partial agonist or antagonist activity elicited similar effects across strains. Pretreatment with the serotonin precursor, 5-HTP, to increase serotonergic activity in the brain, unmasked a decrease in PPI caused by 8-OH-DPAT in C57Bl/6 mice. Pretreatment with the serotonin synthesis inhibitor, PCPA, to decrease serotonergic activity in the brain, unmasked an 8-OH-DPAT-induced increase in PPI in this strain. These studies show that the strain-dependent involvement of 5-HT(1A) receptors in PPI can be modulated by the type of 5-HT(1A) ligand used, or increasing or decreasing serotonin levels in the brain. These results help to clarify some of the mouse strain and species differences in PPI regulation and strengthen its usefulness as a cross-species measure of sensorimotor gating.

Early life stress is thought to enhance adult susceptibility to stress and stress-related mood disorders. In this study, fear-potentiated startle was used to model the acquisition of a traumatic event-related memory in female rats experiencing early life stress. Daily 1-hr maternal and sibling separation throughout day 2-9 postpartum (D2-9 PP) caused a decrease in the fear-potentiated startle, but not acoustic startle baseline, in adult female rats. The separation procedure did not affect corticosterone secretion but produced an increase in serum estradiol concentration. Moreover, the separation procedure did not affect histone 3 lysine 9 (H3K9) acetylation but decreased H3K9 mono- and tri-methylation in frontal cortices. Treatment with 5-aza-2'-deoxycytidine (AZA) (5mg/kg at alternative days from D2PP to D9PP or 10mg/kg at D5PP and D9PP), a DNA methylation inhibitor, did not affect the separation-decreased fear-potentiated startle. Treatment with valproic acid (VPA), a histone deacetylase inhibitor, at 3 dosing regimens (300mg/kg at D2-9PP; 100mg/kg at D2-4PP, 200mg/kg at D5-7PP, 300mg/kg at D8-9PP; 100mg/kg at D2-5PP, 200mg/kg at D6-9PP) prior to daily separation reversed such a decrease in fear-potentiated startle. The lowest effective VPA dosing regimen used (100mg/kg at D2-5PP, 200mg/kg at D6-9PP) reversed the separation-decreased H3K9 mono- and tri-methylation in frontal cortices. Eight-day VPA (300mg/kg/day) and AZA (5mg/kg/day) administrations starting at D28PP were ineffective in altering the separation-decreased fear-potentiated startle. We, hereby, suggest that decreased frontal cortical H3K9 mono- and tri-methylation may be involved in early life separation-decreased fear memory of adult rats.

Huntington's disease (HD) is a progressive neurodegenerative disorder with a spectrum of cognitive, behavioral, and motor abnormalities. The mitochondrial toxin 3-nitropropionic acid (3-NP) effectively induces specific behavioral changes, primarily manifested as prepulse inhibition (PPI) deficit of acoustic startle stimuli, and selective striatal lesions in rats and primates mimicking those in HD. The implications of nitric oxide in a variety of neurodegenerative diseases attract attention to study the possible role of flavonoids in interaction with nitric oxide pathways involved in HD. The present study investigates the potential effect of hesperidin, a flavanone group member, on 3-NP-induced behavioral, neurochemical, histopathological and cellular changes. Systemic administration of 3-NP to rats for 5 days (20 mg/kg) caused reduction of locomotor activity by days 2 and 5, 55% deficit of PPI response, elevation of cortical, striatal and hippocampal malondialdehyde (MDA) levels by 63%, 41% and 56%, reduction of respective catalase activity by 50%. Immunohistochemical staining of cortices, striata and hippocampi showed patches of iNOS positive cells. Electron microscopic ultrastructural examination showed marked mitochondrial swelling, perivascular edema and shrunken nerve cells. Pretreatment with hesperidin (100 mg/kg) ahead of 3-NP prevented any changes of locomotor activity or PPI response, slightly increased cortical, striatal and hippocampal MDA levels by 10% and reduced respective catalase activity by 22%, 20% and 5%. Only few iNOS positive cells were detected in sections from rats pretreated with hesperidin which also reduced cellular abnormalities induced by 3-NP. This study suggests a potential neuroprotective role of hesperidin against 3-NP-induced Huntington's disease-like manifestations. Such neuroprotection can be referred to its antioxidant and anti-inflammatory activities.

A combination of early neurodevelopmental disruptions and young-adult cannabis use may lead to the development of neuropsychiatric disorders. The aim of this study was to investigate in adult Wistar rats (12–14 weeks of age) the long-term ‘two hit’ behavioural effects of chronic young-adult treatment with the cannabinoid receptor agonist, CP55,940 (0.2 mg/kg, 8–10 weeks of age) in combination with maternal separation (MS) (3 h every day from postnatal days 2–14). Two weeks after chronic CP55,940 treatment had ceased, baseline locomotor activity was reduced in male, but not female rats and irrespective of MS. In male rats only, the combination of MS and cannabinoid exposure, but not either ‘hit’ alone, induced a significant decrease in sucrose preference. In contrast, in male rats both MS and CP55,940 treatment reduced time spent on the open arms of the plus maze or centre time in the open field and this was most pronounced after a combination of these ‘hits’. Prepulse inhibition was reduced by MS in both sexes but there was no additional effect of CP55,940 treatment. Memory performance in the Y-maze and novel object recognition test was not affected by either of the two ‘hits’. These results indicate that early developmental disruptions and young-adult cannabis use on their own or in combination can differentially and sex-specifically affect behaviours related to neuropsychiatric disorders.

Neonatal lipopolysaccharide (LPS) exposure increases anxiety-like behaviour and alters neuroendocrine responses to stress in adult rats. The current study assessed whether this anxiety-related phenotype observed in rats neonatally exposed to LPS is transferable to subsequent generations. Wistar rats were exposed to LPS (0.05 mg/kg, Salmonella enteritidis) or non-pyrogenic saline (equivolume) on postnatal days 3 and 5. In adulthood, animals were subjected to restraint and isolation stress or no stress, and subsequently evaluated for anxiety-like behaviours on the elevated plus maze, acoustic startle response, and holeboard apparatus. Blood was collected to examine corticosterone responses to stress and behavioural testing in adulthood. Animals from both treatment groups which exhibited the anxiety-like phenotype were bred with untreated partners. Maternal care of the second generation (F2) was monitored over the first week of life. In adulthood, the F2 generation underwent identical testing procedures as the parental (F1) generation. The F2 offspring of females exposed to LPS as neonates exhibited an anxiety-like phenotype in adulthood and a potentiated corticosterone response to stress (p

GABA(A) receptor modulating drugs such as benzodiazepines (BZs) have been used to treat anxiety disorders for over five decades. In order to determine whether the same or different GABA(A) receptor subtypes are necessary for the anxiolytic-like action of BZs in unconditioned anxiety and conditioned fear models, we investigated the role of different GABA(A) receptor subtypes by challenging wild type, α1(H101R), α2(H101R) and α3(H126R) mice bred on the C57BL/6J background with diazepam or chlordiazepoxide in the elevated plus maze and the fear-potentiated startle paradigms. Both drugs significantly increased open arm exploration in the elevated plus maze in wild type, α1(H101R) and α3(H126R), but this effect was abolished in α2(H101R) mice; these were expected results based on previous published results. In contrast, while administration of diazepam and chlordiazepoxide significantly attenuated fear-potentiated startle (FPS) in wild type mice and α3(H126R) mice, the fear-reducing effects of these drugs were absent in both α1(H101R) and α2(H101R) point mutants, indicating that both α1- and α2-containing GABA(A) receptors are necessary for BZs to exert their effects on conditioned fear responses. Our findings illustrate both an overlap and a divergence between the GABA(A) receptor subtype requirements for the impact of BZs, specifically that both α1- and α2-containing GABA(A) receptors are necessary for BZs to reduce conditioned fear whereas only α2-containing GABA(A) receptors are needed for BZ-induced anxiolysis in unconditioned tests of anxiety. This raises the possibility that GABAergic pharmacological interventions for specific anxiety disorders can be differentially tailored.

Perturbation of Disrupted-In-Schizophrenia-1 (DISC1) and D-serine/NMDA receptor hypofunction have both been implicated in the pathophysiology of schizophrenia and other psychiatric disorders. In the present study, we demonstrate that these two pathways intersect with behavioral consequences. DISC1 binds to and stabilizes serine racemase (SR), the enzyme that generates D-serine, an endogenous co-agonist of the NMDA receptor. Mutant DISC1 fails to bind to SR, facilitating ubiquitination and degradation of SR and a decrease in D-serine production. To elucidate DISC1-SR interactions in vivo, we generated a mouse model of selective and inducible expression of mutant DISC1 in astrocytes, the main source of D-serine in the brain. Expression of mutant DISC1 downregulates endogenous DISC1 and decreases protein but not mRNA levels of SR, resulting in diminished production of D-serine. In contrast, mutant DISC1 does not alter levels of ALDH1L1, connexins, GLT-1 or binding partners of DISC1 and SR, LIS1 or PICK1. Adult male and female mice with lifelong expression of mutant DISC1 exhibit behavioral abnormalities consistent with hypofunction of NMDA neurotransmission. Specifically, mutant mice display greater responses to an NMDA antagonist, MK-801, in open field and pre-pulse inhibition of the acoustic startle tests and are significantly more sensitive to the ameliorative effects of D-serine. These findings support a model wherein mutant DISC1 leads to SR degradation via dominant negative effects, resulting in D-serine deficiency that diminishes NMDA neurotransmission thus linking DISC1 and NMDA pathophysiological mechanisms in mental illness.

Since the introduction of combination antiretroviral therapy (cART) in the mid-90s, the most severe forms of HIV-1-associated neurocognitive disorders (HAND) have diminished. However, milder forms of HAND remain prevalent. Basic and clinical studies implicate alterations in the dopaminergic (DAergic) system in HIV-1 infection. We used the Fischer 344 HIV-1 transgenic (HIV-1 Tg) rat, which expresses 7 of the 9 HIV-1 genes, to examine potential DAergic alterations. Animals were studied beginning at 35 days of age to assess early-onset DAergic alterations, well before any documented neurological symptoms or clinical signs of "wasting". At 48 hr intervals, animals were administered a single dose of methamphetamine (METH) (0, 0.5, 1, 2.5 and 5 mg/kg/ml s.c.) and tested for the auditory startle response (ASR) and prepulse inhibition (PPI), using an auditory prepulse [85 dB(A) broad-band noise stimulus] and an auditory startle stimulus [100 dB(A) broad-band noise stimulus] in a sound-attenuating chamber with a continuous 70 dB(A) white noise background. The protocol used a 5-min acclimation period, 6 startle trials, and 36 PPI trials [ISIs of 0, 8, 40, 80, 120, and 4000 ms, 6-trial blocks, Latin square design]. As the dose of METH increased, PPI of the startle response decreased. The HIV-1 Tg rats displayed a greater dose-dependency to the METH-induced disruption of PPI compared to non-transgenic controls. Western blot analysis of midbrain extracts revealed lower tyrosine hydroxylase (TH) protein levels and higher monoamine oxidase A (MAO-A) protein levels in HIV-1 Tg rats treated with METH compared to non-transgenic controls. Early-detected cognitive alterations in the preattentive process of sensorimotor gating may have significant predictive utility regarding the progression of DAergic alterations in HIV-1 infection.

Psychiatric illnesses, such as schizophrenia, are most likely caused by an interaction between genetic predisposition and environmental factors, including stress during development. The neurotrophin, brain-derived neurotrophic factor (BDNF) has been implicated in this illness as BDNF levels are decreased in the brain of patients with schizophrenia. The aim of the present study was to assess the combined effect of reduced BDNF levels and postnatal stress, simulated by chronic young-adult treatment with the stress hormone, corticosterone. From 6 weeks of age, female and male BDNF heterozygous mice and their wild-type controls were chronically treated with corticosterone in their drinking water for 3 weeks. At 11 weeks of age, male, but not female BDNF heterozygous mice treated with corticosterone exhibited a profound memory deficit in the Y-maze. There were no differences between the groups in baseline prepulse inhibition (PPI), a measure of sensorimotor gating, or its disruption by treatment with MK-801. However, an increase in startle caused by MK-801 treatment was absent in male, but not female BDNF heterozygous mice, irrespective of corticosterone treatment. Analysis of protein levels of the NMDA receptor subunits NR1, NR2A, NR2B and NR2C, showed a marked increase of NR2B levels in the dorsal hippocampus of male BDNF heterozygous mice treated with corticosterone. In the ventral hippocampus, significantly reduced levels of NR2A, NR2B and NR2C were observed in male BDNF heterozygous mice. The NMDA receptor effects in hippocampal sub-regions could be related to the spatial memory deficits and the loss of the effect of MK-801 on startle in these mice, respectively. No significant changes in NMDA receptor subunit levels were observed in any of the female groups. Similarly, no significant changes in levels of BDNF or its receptor, TrkB, were found other than the expected reduced levels of BDNF in heterozygous mice. In conclusion, the data show differential interactive effects of reduced levels of BDNF expression and corticosterone treatment on spatial memory and startle in male and female mice, accompanied by significant, but region-specific changes in NMDA receptor subunit levels in the dorsal and ventral hippocampus. These results could be important for our understanding of the interaction of neurodevelopmental stress and BDNF deficiency in cognitive and anxiety-related symptoms of psychiatric illnesses, such as schizophrenia.

Aims : An assessment of the acoustic startle response (ASR) and prepulse inhibition (PPI) of ASR in laboratory animals is used to model human anxiety and psychotic states, respectively. The aim of the study was to evaluate ASR and PPI in alcohol-naive male and female Warsaw alcohol high-preferring (WHP) and Warsaw alcohol low-preferring (WLP) rats. Methods : ASR and PPI were assessed in two separate experiments by using the SR-LAB apparatus (San Diego Instruments, San Diego, CA, USA). In the ASR session, animals ( n = 13–16 rats per group) were exposed to startling stimuli of different intensities (72, 84, 98, 112 and 124 dB) in a random order. In the PPI session, prepulse stimuli (78, 81, 84 and 90 dB) preceded a pulse startling stimulus (120 dB) in a random order. The background white noise was set at 70 dB. PPI was calculated according to the formula: [(startle amplitude in pulse alone trials—startle amplitude in prepulse-and-pulse trials)/startle amplitude in pulse alone trials] × 100%. Results : The WHP males exhibited higher startle amplitudes in response to 112 dB stimuli when compared with their WLP counterparts. The WHP females showed higher startle reactivity to 112 and 124 dB stimuli when compared with the WLP females. There were no differences between the WHPs and WLPs in PPI of ASR. Conclusion : The results of the present study suggest that exaggerated startle responses can be a physiological/behavioral marker of a propensity to abuse alcohol.

Prepulse inhibition (PPI) of the acoustic startle reflex refers to the reduction of the startle response to an intense acoustic pulse stimulus when it is shortly preceded by a weak non-startling prepulse stimulus and provides a cross-species measure of sensory-motor gating. PPI is typically impaired in schizophrenia patients, and a similar impairment can be induced in rats by systemic scopolamine, a muscarinic cholinergic receptor antagonist that can evoke a range of cognitive and psychotic symptoms in healthy humans that are commonly referred to as the “anti-muscarinic syndrome” resembling some clinical features of schizophrenia. Scopolamine-induced PPI disruption has therefore been proposed as an anti-muscarinic animal model of schizophrenia, but parallel investigations in the mouse remain scant and the outcomes are mixed and often confounded by an elevation of startle reactivity. Here, we distinguished the PPI-disruptive and the confounding startle-enhancing effects of scopolamine (1 and 10 mg/kg, i.p.) in C57BL/6 wild-type mice by showing that the latter partly stemmed from a shift in spontaneous baseline reactivity. With appropriate correction for between-group differences in startle reactivity, we went on to confirm that the PPI-disruptive effect of scopolamine could be nullified by clozapine pre-treatment (1.5 mg/kg, i.p.) in a dose-dependent manner. This is the first demonstration that scopolamine-induced PPI disruption is sensitive to atypical antipsychotic drugs. In concert with previous data showing its sensitivity to haloperidol the present finding supports the predictive validity of the anti-muscarinic PPI disruption model for both typical and atypical antipsychotic drug action.

Spatially distributed sensory information is topographically mapped in the brain by point-to-point correspondence of connections between peripheral receptors and central target neurons. In fishes, for example, the axonal projections from the mechanosensory lateral line organize a somatotopic neural map. The lateral line provides hydrodynamic information for intricate behaviors such as navigation and prey detection. It also mediates fast startle reactions triggered by the Mauthner cell. However, it is not known how the lateralis neural map is built to subserve these contrasting behaviors. Here we reveal that birth order diversifies lateralis afferent neurons in the zebrafish. We demonstrate that early- and late-born lateralis afferents diverge along the main axes of the hindbrain to synapse with hundreds of second-order targets. However, early-born afferents projecting from primary neuromasts also assemble a separate map by converging on the lateral dendrite of the Mauthner cell, whereas projections from secondary neuromasts never make physical contact with the Mauthner cell. We also show that neuronal diversity and map topology occur normally in animals permanently deprived of mechanosensory activity. We conclude that neuronal birth order correlates with the assembly of neural submaps, whose combination is likely to govern appropriate behavioral reactions to the sensory context.

The stress response is a multifaceted physiological reaction that engages a wide range of systems. Animal studies examining stress and the stress response employ diverse methods as stressors. While many of these stressors are capable of inducing a stress response in animals, a need exists for an ethologically relevant stressor for female rats. The purpose of the current study was to use an ethologically relevant social stressor to induce behavioral alterations in adult female rats. Adult (postnatal day 90) female Wistar rats were repeatedly exposed to lactating Long Evans female rats to simulate chronic stress. After six days of sessions, intruder females exposed to defeat were tested in the sucrose consumption test, the forced swim test, acoustic startle test, elevated plus maze, and open field test. At the conclusion of behavioral testing, animals were restrained for 30 minutes and trunk blood was collected for assessment of serum hormones. Female rats exposed to maternal aggression exhibited decreased sucrose consumption, and impaired coping behavior in the forced swim test. Additionally, female rats exposed to repeated maternal aggression exhibited an increased acoustic startle response. No changes were observed in female rats in the elevated plus maze or open field test. Serum hormones were unaltered due to repeated exposure to maternal aggression. These data indicate the importance of the social experience in the development of stress-related behaviors: an acerbic social experience in female rats precipitates the manifestation of depressive-like behaviors and an enhanced startle response.

Excitability is probably the concept that fits better with the definition of the role of neurophysiology in the study of brainstem functions and circuits. Neurophysiological techniques are likely the best suited of all paraclinical tests for documenting the eventual excitability changes that may occur in certain physiological states and in many neurological disorders. The best known test of brainstem excitability is the blink reflex. While a single stimulus can already indicate the readiness of the interneuronal path and the facial motoneurons to fire, pairs of stimuli (conditioning and test) are suited to analyze the degree of excitability recovery after a single discharge. Another brainstem reflex circuit, which excitability testing can be of interest for physiological and clinical exams is the one involved in the startle reaction. The size of the responses and their habituation are the typical measures of excitability of the startle reflex circuit. Prepulse inhibition is a method to modulate both, the blink reflex and the startle reaction. It is defined as the inhibitory effect caused by a stimulus of an intensity low enough not to induce a response by itself on the response elicited by a subsequent stimulus. The circuits of the blink reflex, startle reaction and prepulse inhibition share some commonalities but they are different enough for the three techniques to provide unique, clinically relevant, information in certain conditions. The role of neurophysiology is not limited to testing those functions. It is important also for the assessment of many other circuits, such as those implicated in eye movements, vestibular reflexes, arousal, sleep, breathing, or autonomic reactions, which are not considered in this review.

The origin of the startle reflex lies in the caudal brainstem; it can be elicited by an unexpected stimulus resulting in a bilateral activation of many muscles. Two subsequent responses can be measured during EMG recordings; after the initial motor reflex, lasting until about 150 ms, a second response can occur. The second response contains more emotional and voluntary behavioral responses. Clinically, syndromes with hyperstartling as common feature can be divided into three groups: hyperekplexia, stimulus-induced disorders, and neuropsychiatric disorders. Classification of startle syndromes within these three groups remains challenging. Generalized stiffness at birth, excessive startling and temporary generalized stiffness after being startled point towards hyperekplexia. Stimulus-induced disorders are distinguished by careful clinical and neurophysiological evaluation, including video recordings. Neuropsychiatric disorders usually have additional behavioural and psychiatric symptoms. Polymyographic EMG startle recordings exhibit an exaggeration of the initial motor startle reflex in hyperekplexia, while neuropsychiatric startle syndromes demonstrate a variable response pattern and abnormal behavioural features. Neurophysiological investigation of the startle reflex can help to further delineate between the startle syndromes and unravel the aetiology of neuropsychiatric startle disorders. (C) 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved

Contest theory predicts the evolution of a stable mixture of different strategies for fighting. Here, we investigate the possibility that stable between-individual differences in startle-response durations influence fighting ability or ‘resource-holding potential’ (RHP) in the beadlet sea anemone, Actinia equina . Both winners and losers showed significant repeatability of pre-fight startle-response durations but mean pre-fight startle-response durations were greater for eventual losers than for eventual winners, indicating that RHP varies with boldness. In particular, individuals with short startle responses inflicted more attacks on their opponent. Both repeatability and mean-level responses were changed by the experience of fighting, and these changes varied with outcome. In losers, repeatability was disrupted to a greater extent and the mean startle-response durations were subject to a greater increase than in winners. Thus, following a fight, this behavioural correlate of RHP behaves in a way similar to post-fight changes in physiological status, which can also vary between winners and losers. Understanding the links between aggression and boldness therefore has the potential to enhance our understanding of both the evolution of animal personality and the ‘winner and loser effects’ of post-fight changes in RHP.

Recent clinical reports found a high incidence of recurrent otitis media in children suffering hyperacusis, a marked intolerance to an otherwise ordinary environmental sound. However, it is unclear whether the conductive hearing loss caused by otitis media in early age will affect sound tolerance later in life. Thus, we have tested the effects of tympanic membrane (TM) damage at an early age on sound perception development in rats. Two weeks after the TM perforation, more than 80% of the rats showed audiogenic seizure (AGS) when exposed to loud sound (120 dB SPL white noise, < 1 minute). The susceptibility of AGS lasted at least sixteen weeks after the TM damage, even the hearing loss recovered. The TM damaged rats also showed significantly enhanced acoustic startle responses compared to the rats without TM damage. These results suggest that early age conductive hearing loss may cause an impaired sound tolerance during development. In addition, the AGS can be suppressed by the treatment of vigabatrin, acute injections (250 mg/kg) or oral intakes (60 mg/kg/day for 7 days), an antiepileptic drug that inhibits the catabolism of GABA. c-Fos staining showed a strong staining in the inferior colliculus (IC) in the TM damaged rats, not in the control rats, after exposed to loud sound, indicating a hyper-excitability in the IC during AGS. These results indicate that early age conductive hearing loss can impair sound tolerance by reducing GABA inhibition in the IC, which may be related to hyperacusis seen in children with otitis media.

We have identified a point mutation in Npc1 that creates a novel mouse model (Npc1(nmf164)) of Niemann-Pick type C1 (NPC) disease: a single nucleotide change (A to G at cDNA bp 3163) that results in an aspartate to glycine change at position 1005 (D1005G). This change is in the cysteine-rich luminal loop of the NPC1 protein and is highly similar to commonly occurring human mutations. Genetic and molecular biological analyses, including sequencing the Npc1(spm) allele and identifying a truncating mutation, confirm that the mutation in Npc1(nmf164) mice is distinct from those in other existing mouse models of NPC disease (Npc1(nih), Npc1(spm)). Analyses of lifespan, body and spleen weight, gait and other motor activities, as well as acoustic startle responses all reveal a more slowly developing phenotype in Npc1(nmf164) mutant mice than in mice with the null mutations (Npc1(nih), Npc1(spm)). Although Npc1 mRNA levels appear relatively normal, Npc1(nmf164) brain and liver display dramatic reductions in Npc1 protein, as well as abnormal cholesterol metabolism and altered glycolipid expression. Furthermore, histological analyses of liver, spleen, hippocampus, cortex and cerebellum reveal abnormal cholesterol accumulation, glial activation and Purkinje cell loss at a slower rate than in the Npc1(nih) mouse model. Magnetic resonance imaging studies also reveal significantly less demyelination/dysmyelination than in the null alleles. Thus, although prior mouse models may correspond to the severe infantile onset forms of NPC disease, Npc1(nmf164) mice offer many advantages as a model for the late-onset, more slowly progressing forms of NPC disease that comprise the large majority of human cases.

The startle reaction (also known as the startle response, the startle reflex, or the alarm reaction) is the psychological and physiological response to a sudden unexpected stimulus, such as a flash of light, a loud noise (acoustic startle reflex), or a quick movement near the face. Abnormalities of startle response have been observed in many stress-related mental disorders, such as schizophrenia and post-traumatic stress disorder (PTSD). However, the molecular mechanisms of startle in stress-associated conditions – for example, whether the startle reaction is associated with any gene variance – is still unknown. In this paper, we will carry out a systematic review by retrieving, assessing, and combining, when applicable, individual studies investigating association of the molecular variation of candidate gene with the startle response. The systematic review is based on the search for numerous publications using the keywords ‘‘startle gene’’ on September 15, 2010 using PubMed, which comprises more than 20 million citations for biomedical literature from MEDLINE and life science journals. A total of 486 publications regarding genes associated with startle have been obtained and reviewed here. There are fewer than 20 publications associating genes with the startle response between 1979, when the first valuable paper was published, and 1999. However, publications have dramatically increase from 2001 and reaches over 70 in 2009. We have characterized them into three categories: startle-associated gene studies in humans, in animals, as well as in both human and animals. This review of research strategy may provide the information for identifying a biomarker for startle response, with the objective of translating research into clinical utility: diagnosis and treatment of stress-induced mental disorders.

Lead (Pb(2+)) exposure continues to be an important concern for fish populations. Research is required to assess the long-term behavioral effects of low-level concentrations of Pb(2+) and the physiological mechanisms that control those behaviors. Newly fertilized zebrafish embryos (

Background: Both coplanar and noncoplanar polychlorinated biphenyls (PCBs) exhibit neurotoxic effects in animal studies, but individual congeners do not always produce the same effects as PCB mixtures. Humans genetically have > 60-fold differences in hepatic cytochrome P450 1A2 (CYP1A2)-uninduced basal levels and > 12-fold variability in aryl hydrocarbon receptor (AHR)affinity; because CYP1A2 is known to sequester coplanar PCBs and because AHR ligands include coplanar PCBs, both genotypes can affect PCB response. Objectives: We aimed to develop a mouse paradigm with extremes in Cyp1a2 and Ahr genotypes to explore genetic susceptibility to PCB-induced developmental neurotoxicity using an environmentally relevant mixture of PCBs. Methods: We developed a mixture of eight PCBs to simulate human exposures based on their reported concentrations in human tissue, breast milk, and food supply. We previously characterized specific differences in PCB congener pharmacokinetics and toxicity, comparing high-affinity–AHR Cyp1a2 wild-type [Ahrb1_Cyp1a2(+/+)], poor-affinity–AHR Cyp1a2 wild-type [Ahrd_Cyp1a2(+/+)], and high-affinity–AHR Cyp1a2 knockout [Ahrb1_Cyp1a2(–/–)] mouse lines [Curran CP, Vorhees CV, Williams MT, Genter MB, Miller ML, Nebert DW. 2011. In utero and lactational exposure to a complex mixture of polychlorinated biphenyls: toxicity in pups dependent on the Cyp1a2 and Ahr genotypes. Toxicol Sci 119:189–208]. Dams received a mixture of three coplanar and five noncoplanar PCBs on gestational day 10.5 and postnatal day (PND) 5. In the present study we conducted behavioral phenotyping of exposed offspring at PND60, examining multiple measures of learning, memory, and other behaviors. Results: We observed the most significant deficits in response to PCB treatment in Ahrb1_Cyp1a2(–/–) mice, including impaired novel object recognition and increased failure rate in the Morris water maze. However, all PCB-treated genotypes showed significant differences on at least one measure of learning or behavior. Conclusions: High levels of maternal hepatic CYP1A2 offer the most important protection against deficits in learning and memory in offspring exposed to a mixture of coplanar and noncoplanar PCBs. High-affinity AHR is the next most important factor in protection of offspring.

Whole organism–based small-molecule screens have proven powerful in identifying novel therapeutic chemicals, yet this approach has not been exploited to identify new cognitive enhancers. Here we present an automated high-throughput system for measuring nonassociative learning behaviors in larval zebrafish. Using this system, we report that spaced training blocks of repetitive visual stimuli elicit protein synthesis–dependent long-term habituation in larval zebrafish, lasting up to 24 h. Moreover, repetitive acoustic stimulation induces robust short-term habituation that can be modulated by stimulation frequency and instantaneously dishabituated through cross-modal stimulation. To characterize the neurochemical pathways underlying short-term habituation, we screened 1,760 bioactive compounds with known targets. Although we found extensive functional conservation of short-term learning between larval zebrafish and mammalian models, we also discovered several compounds with previously unknown roles in learning. These compounds included a myristic acid analog known to interact with Src family kinases and an inhibitor of cyclin dependent kinase 2, demonstrating that high-throughput chemical screens combined with high-resolution behavioral assays provide a powerful approach for the discovery of novel cognitive modulators.