MPTP toxicity causes vocal, auditory, orientation and movement defects in the echolocation bat.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can damage dopaminergic neurons in the substantia nigra in many mammals with biochemical and cellular changes that are relatively similar to those observed in Parkinson's disease. Our study examined whether MPTP-treated echolocation bats can cause changes in bat echolocation system. By considering ultrasound spectrums, auditory brainstem-evoked potentials and flight trajectories of normal bats, we observed that the vocal, auditory, orientation and movement functions of MPTP-treated bats were significantly impaired, and they exhibited various symptoms resembling those in patients with Parkinson's disease. Our immunohistochemistry and western blot analyses further indicated that expression of vocal-related FOXP2 in the superior colliculus, auditory-related otoferlin in the inferior colliculus, dopamine synthesis-related aromatic l-amino acid decarboxylase in the substantia nigra and dopamine receptor in the striatum was significantly decreased. Furthermore, protein expression related to inflammation, oxidative stress and apoptosis in the substantia nigra was significantly increased in MPTP-treated bats. These results indicate that inflammation, oxidative stress and apoptosis may be instrumental in dopaminergic neurodegeneration in the substantia nigra. The vocal, auditory and orientation and movement dysfunctions of MPTP-treated bats are relatively consistent with symptoms of Parkinson's disease.

Differential navigational strategies during spatial learning in a new modified version of the Oasis maze.

During spatial navigation, some typical parameters of learning have been observed, such as latency or path length. However, these parameters are sensitive to patterns of navigation and orientation that are not easily measurable. In the present study, we used a modified version of the Oasis maze and evaluated different parameters of learning, navigation, and orientation in different animal groups. Through a PCA (Principal component analysis) we found different factors such as learning, navigation, speediness, anxiety, orientation, path variability, and turning behavior. Each factor gathers different groups of behavioral variables. ANOVA analysis of those factors demonstrates that some of them are more strongly modulated by trial progression, while others by animal group differences, indicating that each group of variables is better reflecting one of these dimensions. To understand the nature of these navigation differences, we studied orientation strategies between animal conditions and across trials. We found that the main navigational strategy used by the animals consist of locating the target and directing their behaviors towards this area. When testing how this strategy changed after cognitive impairment or enhancement, we found that AßOs treated animals (Amyloid ß Oligomers, Alzheimer animal model) have strong orientation difficulties at locating the target at longer distances. While animals with learning enhancement (exercised rat) do not show changes in orientation behaviors. These analyses highlight that experimental manipulations affect learning, but also induced changes in the navigational strategies. We concluded that both dimensions can explain the differences observed in typical learning variables, such as latency or path length, motivating the development of new tools that asses this two-dimension as a separate but, interacting phenomenon.

A single exposure to the tremorgenic mycotoxin lolitrem B inhibits voluntary motor activity and spatial orientation but not spatial learning or memory in mice.

The indole diterpenoid toxin lolitrem B is a tremorgenic agent found in the common grass species, perennial ryegrass (Lolium perenne). The toxin is produced by a symbiotic fungus Epichloë festucae (var. lolii) and ingestion of infested grass with sufficient toxin levels causes a movement disorder in grazing herbivores known as 'ryegrass staggers'. Beside ataxia, lolitrem B intoxicated animals frequently show indicators of cognitive dysfunction or exhibition of erratic and unpredictable behaviours during handling. Evidence from field cases in livestock and controlled feeding studies in horses have indicated that intoxication with lolitrem B may affect higher cortical or subcortical functioning. In order to define the role of lolitrem B in voluntary motor control, spatial learning and memory under controlled conditions, mice were exposed to a known dose of purified lolitrem B toxin and tremor, coordination, voluntary motor activity and spatial learning and memory assessed. Motor activity, coordination and spatial memory were compared to tremor intensity using a novel quantitative piezo-electronic tremor analysis. Peak tremor was observed as frequencies between 15 and 25Hz compared to normal movement at approximately 1.4-10Hz. A single exposure to a known tremorgenic dose of lolitrem B (2 mg/kg IP) induced measureable tremor for up to 72 h in some animals. Initially, intoxication with lolitrem B significantly decreased voluntary movement. By 25 h post exposure a return to normal voluntary movement was observed in this group, despite continuing evidence of tremor. This effect was not observed in animals exposed to the short-acting tremorgenic toxin paxilline. Lolitrem B intoxicated mice demonstrated a random search pattern and delayed latency to escape a 3 h post intoxication, however by 27 h post exposure latency to escape matched controls and mice had returned to normal searching behavior indicating normal spatial learning and memory. Together these data indicate that the tremor exhibited by lolitrem B intoxicated mice does not directly impair spatial learning and memory but that exposure does reduce voluntary motor activity in intoxicated animals. Management of acutely affected livestock suffering toxicosis should be considered in the context of their ability to spatially orientate with severe toxicity.

Atomoxetine improves attentional orienting in a predictive context.

The role of norepinephrine (NE) in visuo-spatial attention remains poorly understood. Our goal was to identify the attentional processes influenced by atomoxetine (ATX) injections, a NE-reuptake inhibitor that boosts the level of NE in the brain, and to characterize these influences. We tested the effects of ATX injections, on seven monkeys performing a saccadic cued task in which cues and distractors were used to manipulate spatial attention. We found that when the cue accurately predicted the location of the upcoming cue in 80% of the trials, ATX consistently improved attentional orienting, as measured from reaction times (RTs). These effects were best accounted for by a faster accumulation rate in the valid trials, rather than by a change in the decision threshold. By contrast, the effect of ATX on alerting and distractor interference was more inconsistent. Finally, we also found that, under ATX, RTs to non-cued targets were longer when these were presented separately from cued targets. This suggests that the impact of NE on visuo-spatial attention depends on the context, such that the adaptive changes elicited by the highly informative value of the cues in the most frequent trials were accompanied by a cost in the less frequent trials.

Extinction to amphetamine-associated context in female rats is dependent upon conditioned orienting.

RATIONALE: Females are considered more susceptible to the reinforcing effects of drugs and subsequently at increased risk for drug abuse and relapse after treatment. Estrogen is known to facilitate drug effects in females. However, other factors which contribute to the incidence of drug abuse are important to identify in order to recognize early risk factors and develop effective prevention and treatment schemes. Cue-directed behavior (aka sign tracking) has been implicated as a behavioral phenotype which identifies populations susceptible to drug abuse, partly due to its association with impulsivity and heightened dopamine function. OBJECTIVES AND METHODS: In this study, we investigate the viability of conditioned orienting (a form of cue-directed behavior) as a potential phenotype which predicts drug proclivity in female rats. In addition, we examine any influence endogenous female hormones across the estrous cycle may have on conditioned orienting and drug proclivity. RESULTS AND CONCLUSIONS: Utilizing an amphetamine-conditioned place preference task, results suggest that the orienting phenotype is an effective predictor of drug proclivity in females. Rats exhibiting enhanced orienting behavior show more robust preference for an amphetamine-associated context and are more resistant to extinction of this preference than nonorienting counterparts. Furthermore, both conditioned orienting behavior and conditioned place preference are minimally influenced by the estrous cycle.

Effects of methamphetamine abuse on spatial cognitive function.

Methamphetamine (MA) abuse has been rising rapidly over the past decade, however, its impact in spatial cognitive function remains unknown. To understand its effect on visuospatial ability and spatial orientation ability, 40 MA users and 40 non-MA users conducted the Simple Reaction Task (Task 1), the Spatial Orientation Task (Task 2), and the Mental Rotation Task (Task 3), respectively. There was no significant difference in either accuracy or reaction time (RT) between 2 groups in Task 1. During Task 2, in comparison with non-MA users, MA users performed poorer on RT, but not in accuracy for foot and hand stimuli. In addition, both non-MA and MA users responded much more quickly to upward stimuli than downward stimuli on vertical surface, however, only non-MA users exhibited leftward visual field advantage in horizontal orientation processing. As for Task 3, MA users exhibited poorer performance and more errors than their healthy counterparts. For each group, linear relationship was revealed between RT and orientation angle, whereas MA abuse led to longer intercept for all stimuli involved. Our findings suggested that MA abuse may lead to a general deficit in the visuospatial ability and the spatial orientation ability with more serious impact in the former.

Imidacloprid and chlorpyrifos insecticides impair migratory ability in a seed-eating songbird.

Birds that travel long distances between their wintering and breeding grounds may be particularly susceptible to neurotoxic insecticides, but the influence of insecticides on migration ability is poorly understood. Following acute exposure to two widely used agricultural insecticides, imidacloprid (neonicotinoid) and chlorpyrifos (organophosphate), we compared effects on body mass, migratory activity and orientation in a seed-eating bird, the white-crowned sparrow (Zonotrichia leucophrys). During spring migration, sparrows were captured, held and dosed by gavage daily for 3 days with either the vehicle control, low (10% LD50) or high (25% LD50) doses of imidacloprid or chlorpyrifos and tested in migratory orientation trials pre-exposure, post-exposure and during recovery. Control birds maintained body mass and a seasonally appropriate northward orientation throughout the experiment. Imidacloprid dosed birds exhibited significant declines in fat stores and body mass (mean loss: -17% low, -25% high dose) and failed to orient correctly. Chlorpyrifos had no overt effects on mass but significantly impaired orientation. These results suggest that wild songbirds consuming the equivalent of just four imidacloprid-treated canola seeds or eight chlorpyrifos granules per day over 3 days could suffer impaired condition, migration delays and improper migratory direction, which could lead to increased risk of mortality or lost breeding opportunity.

The effects of intranasal esketamine (84 mg) and oral mirtazapine (30 mg) on on-road driving performance: a double-blind, placebo-controlled study.

RATIONALE: The purpose of this study is to evaluate the single dose effect of intranasal esketamine (84 mg) compared to placebo on on-road driving performance. Mirtazapine (oral, 30 mg) was used as a positive control, as this antidepressant drug is known to negatively affect driving performance. METHODS: Twenty-six healthy volunteers aged 21 to 60 years were enrolled in this study. In the evening, 8 h after treatment administration, participants conducted the standardized 100-km on-road driving test. Primary outcome measure was the standard deviation of lateral position (SDLP), i.e., the weaving of the car. Mean lateral position, mean speed, and standard deviation of speed were secondary outcome measures. For SDLP, non-inferiority analyses were conducted, using +2.4 cm (relative to placebo) as a predefined non-inferiority margin for clinical relevant impairment. RESULTS: Twenty-four participants completed the study. No significant SDLP difference was found between esketamine and placebo (p = 0.7638), whereas the SDLP after mirtazapine was significantly higher when compared to placebo (p = 0.0001). The upper limit of the two-sided 95% confidence interval (CI) of the mean difference between esketamine and placebo was +0.86 cm, i.e., <+2.4 cm, thus demonstrating that esketamine was non-inferior to placebo. Non-inferiority could not be concluded for mirtazapine (+3.15 cm SDLP relative to placebo). No significant differences in mean speed, standard deviation of speed, and mean lateral position were observed between the active treatments and placebo. CONCLUSIONS: No significant difference in driving performance was observed 8 h after administering intranasal esketamine (84 mg) or placebo. In contrast, oral mirtazapine (30 mg) significantly impaired on road driving performance.

Dimethyl Sulfide is a Chemical Attractant for Reef Fish Larvae.

Transport of coral reef fish larvae is driven by advection in ocean currents and larval swimming. However, for swimming to be advantageous, larvae must use external stimuli as guides. One potential stimulus is "odor" emanating from settlement sites (e.g., coral reefs), signaling the upstream location of desirable settlement habitat. However, specific chemicals used by fish larvae have not been identified. Dimethyl sulfide (DMS) is produced in large quantities at coral reefs and may be important in larval orientation. In this study, a choice-chamber (shuttle box) was used to assess preference of 28 pre-settlement stage larvae from reef fish species for seawater with DMS. Swimming behavior was examined by video-tracking of larval swimming patterns in control and DMS seawater. We found common responses to DMS across reef fish taxa - a preference for water with DMS and change in swimming behavior - reflecting a switch to "exploratory behavior". An open water species displayed no response to DMS. Affinity for and swimming response to DMS would allow a fish larva to locate its source and enhance its ability to find settlement habitat. Moreover, it may help them locate prey accumulating in fronts, eddies, and thin layers, where DMS is also produced.

Acyl ghrelin improves cognition, synaptic plasticity deficits and neuroinflammation following amyloid ß (Aß1-40) administration in mice.

Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild-type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid ß peptide 1-40 (Aß1-40 ) was injected into the lateral ventricles i.c.v. Recognition memory, using the novel object recognition task, was significantly impaired in ghrelin KO mice and after i.c.v. Aß1-40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Spatial orientation, as assessed by the Y-maze task, was also significantly impaired in ghrelin KO mice and after i.c.v. Aß1-40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Ghrelin KO mice had deficits in olfactory discrimination; however, neither i.c.v. Aß1-40 treatment, nor acyl ghrelin injections affected olfactory discrimination. We used stereology to show that ghrelin KO and Aß1-40 increased the total number of glial fibrillary acidic protein expressing astrocytes and ionised calcium-binding adapter expressing microglial in the rostral hippocampus. Finally, Aß1-40 blocked long-term potentiation induced by high-frequency stimulation and this effect could be acutely blocked with co-administration of acyl ghrelin. Collectively, our studies demonstrate that ghrelin deletion affects memory performance and also that acyl ghrelin treatment may delay the onset of early events of AD. This supports the idea that acyl ghrelin treatment may be therapeutically beneficial with respect to restricting disease progression in AD.

Spatial memory is impaired by peripubertal GnRH agonist treatment and testosterone replacement in sheep.

Chronic gonadotropin-releasing hormone agonist (GnRHa) is used therapeutically to block activity within the reproductive axis through down-regulation of GnRH receptors within the pituitary gland. GnRH receptors are also expressed in non-reproductive tissues, including areas of the brain such as the hippocampus and amygdala. The impact of long-term GnRHa-treatment on hippocampus-dependent cognitive functions, such as spatial orientation, learning and memory, is not well studied, particularly when treatment encompasses a critical window of development such as puberty. The current study used an ovine model to assess spatial maze performance and memory of rams that were untreated (Controls), had both GnRH and testosterone signaling blocked (GnRHa-treated), or specifically had GnRH signaling blocked (GnRHa-treated with testosterone replacement) during the peripubertal period (8, 27 and 41 weeks of age). The results demonstrate that emotional reactivity during spatial tasks was compromised by the blockade of gonadal steroid signaling, as seen by the restorative effects of testosterone replacement, while traverse times remained unchanged during assessment of spatial orientation and learning. The blockade of GnRH signaling alone was associated with impaired retention of long-term spatial memory and this effect was not restored with the replacement of testosterone signaling. These results indicate that GnRH signaling is involved in the retention and recollection of spatial information, potentially via alterations to spatial reference memory, and that therapeutic medical treatments using chronic GnRHa may have effects on this aspect of cognitive function.

A reduction in long-term spatial memory persists after discontinuation of peripubertal GnRH agonist treatment in sheep.

Chronic gonadotropin-releasing hormone agonist (GnRHa) administration is used where suppression of hypothalamic-pituitary-gonadal axis activity is beneficial, such as steroid-dependent cancers, early onset gender dysphoria, central precocious puberty and as a reversible contraceptive in veterinary medicine. GnRH receptors, however, are expressed outside the reproductive axis, e.g. brain areas such as the hippocampus which is crucial for learning and memory processes. Previous work, using an ovine model, has demonstrated that long-term spatial memory is reduced in adult rams (45 weeks of age), following peripubertal blockade of GnRH signaling (GnRHa: goserelin acetate), and this was independent of the associated loss of gonadal steroid signaling. The current study investigated whether this effect is reversed after discontinuation of GnRHa-treatment. The results demonstrate that peripubertal GnRHa-treatment suppressed reproductive function in rams, which was restored after cessation of GnRHa-treatment at 44 weeks of age, as indicated by similar testes size (relative to body weight) in both GnRHa-Recovery and Control rams at 81 weeks of age. Rams in which GnRHa-treatment was discontinued (GnRHa-Recovery) had comparable spatial maze traverse times to Controls, during spatial orientation and learning assessments at 85 and 99 weeks of age. Former GnRHa-treatment altered how quickly the rams progressed beyond a specific point in the spatial maze at 83 and 99 weeks of age, and the direction of this effect depended on gonadal steroid exposure, i.e. GnRHa-Recovery rams progressed quicker during breeding season and slower during non-breeding season, compared to Controls. The long-term spatial memory performance of GnRHa-Recovery rams remained reduced (P<0.05, 1.5-fold slower) after discontinuation of GnRHa, compared to Controls. This result suggests that the time at which puberty normally occurs may represent a critical period of hippocampal plasticity. Perturbing normal hippocampal formation in this peripubertal period may also have long lasting effects on other brain areas and aspects of cognitive function.

Moderation of nicotine effects on covert orienting of attention tasks by poor placebo performance and cue validity.

INTRODUCTION AND RATIONALE: Given baseline-dependent effects of nicotine on other forms of attention, there is reason to believe that inconsistent findings for the effects of nicotine on attentional orienting may be partly due to individual differences in baseline (abstinence state) functioning. Individuals with low baseline attention may benefit more from nicotine replacement. METHOD: The effects of nicotine as a function of baseline performance (bottom, middle, and top third of mean reaction times during placebo) were assessed in 52 habitual abstinent smokers (26 females/26 males) utilizing an arrow-cued covert orienting of attention task. RESULTS: Compared to a placebo patch, a 14mg nicotine patch produced faster overall reaction times (RTs). In addition, individuals with slower RTs during the placebo condition benefitted more from nicotine on cued trials than did those who had shorter (faster) RTs during placebo. Nicotine also enhanced the validity effect (shorter RTs to validly vs. invalidly cued targets), but this nicotine benefit did not differ as a function of overall placebo-baseline performance. CONCLUSIONS: These findings support the view that nicotine enhances cued spatial attentional orienting in individuals who have slower RTs during placebo (nicotine-free) conditions; however, baseline-dependent effects may not generalize to all aspects of spatial attention. These findings are consistent with findings indicating that nicotine's effects vary as a function of task parameters rather than simple RT speeding or cognitive enhancement.

NEUROPROTECTIVE ACTION OF PHENIBUT AND NEUROGLUTAM IN EXPERIMENTAL CEREBRAL ISCHEMIA ON THE BACKGROUND OF ALTERED IMMUNOREACTIVITY.

Cerebroprotective activity of phenyl derivatives of GABA (phenibut, 25 mg/kg) and L-glutamic acid (neuroglutam, 26 mg/kg) in rats with cerebral ischemia was studied on the background of intact and altered immunoreactivity. Tested compounds were administered intraperitoneally for 7 days after two phase ligation of common carotid arteries (second artery was ligated 3 days after ligation of the first artery). Immunosuppression caused by cyclosporin (daily dose 5 mg/kg, p.o., for 13 days) worsened brain ischemia outcome, as manifested by increased mortality, more severe neurological marker score, increased levels of brain damage markers (NSE and MBP) in the blood serum, decrease in muscle strength and locomotor activity, and impairment of orientation and research activity as compared to animals with brain ischemia and intact immunity. Activation of immune system was caused by lipopolysaccharide (10 mg/kg, i.p., 7 injections every second day). Upon activation of the immune system, brain ischemia produced lower mortality, while the survived rats exhibited more favorable outcome of ischemia than animals with suppression of immune system: lover neurological marker score, lower blood serum NSE and MBP levels (-35% on average,p < 0.05), and much higher level of performance in motor coordination, muscular strength, and locomotor activity (+90% on average, p < 0.05). The state of immune system significantly influenced the neuroprotective activity of drugs tested. Neuroglutam administration produced positive effect both in animals with intact immunity and on the background of altered immunoreactivity. However, most positive outcome after neuroglutam administration in ischemic rats was observed in animals with suppression of immune system, with significant increase in the cerebral blood flow level (+56%), decrease in NSE and MBP blood serum levels (57 and 76%, respectively) after 7-day treatment as compared to the control group. The therapeutic potential of phenibut was somewhat lower than that of neuroglutam, and it was more pronounced in rats with activated immune system, whereas the drug effectiveness in rats with suppressed immune system was less pronounced.