Locomotor Response Research Articles

Prenatal Amphetamine-Induced Dopaminergic Alteration in a Gender- and Estrogen-Dependent Manner.

Prenatal exposure to amphetamine induces changes in dopamine receptors in mesolimbic areas and alters locomotor response to amphetamine during adulthood. Sex differences have been reported in amphetamine-induced brain activity and stress sensitivity. We evaluated the effects of prenatal amphetamine exposure on locomotor activity, dopamine receptors and tyrosine hydroxylase mRNA expression in nucleus accumbens and caudate-putamen in response to amphetamine challenge in adult female and male rats. The role of estrogen in the response to restraint stress was analyzed in ovariectomized, prenatally amphetamine-exposed rats. Pregnant rats were treated with D-amphetamine during days 15-21 of gestation. Nucleus accumbens and caudate-putamen were processed for mRNA determination by real-time PCR. In nucleus accumbens, higher mRNA dopamine (D3) receptor expression was found in basal and D-amphetamine-challenge conditions in female than male, and prenatal amphetamine increased the difference. No sex differences were observed in caudate-putamen. Basal saline-treated females showed higher locomotor activity than males. Amphetamine challenge in prenatally amphetamine-exposed rats increased locomotor activity in males and reduced it in females. In nucleus accumbens, estrogen diminished mRNA D1, D2 and D3 receptor expression in basal, and D1 and D3 in ovariectomized stressed rats. Estrogen prevented the increase in tyrosine hydroxylase expression induced by stress in ovariectomized prenatally exposed rats. In conclusion, estrogen modulates mRNA levels of D1, D2 and D3 receptors and tyrosine hydroxylase expression in nucleus accumbens; prenatal amphetamine-exposure effects on D3 receptors and behavioral responses were gender dependent.

Ankk1 Loss of Function Disrupts Dopaminergic Pathways in Zebrafish.

Ankyrin repeat and kinase domain containing 1 (ANKK1) is a member of the receptor-interacting protein serine/threonine kinase family, known to be involved in cell proliferation, differentiation and activation of transcription factors. Genetic variation within the ANKK1 locus is suggested to play a role in vulnerability to addictions. However, ANKK1 mechanism of action is still poorly understood. It has been suggested that ANKK1 may affect the development and/or functioning of dopaminergic pathways. To test this hypothesis, we generated a CRISPR-Cas9 loss of function ankk1 zebrafish line causing a 27 bp insertion that disrupts the ankk1 sequence introducing an early stop codon. We found that ankk1 transcript levels were significantly lower in ankk1 mutant (ankk127ins) fish compared to their wild type (ankk1+/+) siblings. In ankk1+/+ adult zebrafish brain, ankk1 protein was detected in isocortex, hippocampus, basolateral amygdala, mesencephalon, and cerebellum, resembling the mammalian distribution pattern. In contrast, ankk1 protein was reduced in the brain of ankk127ins/27ins fish. Quantitative polymerase chain reaction analysis revealed an increase in expression of drd2b mRNA in ankk127ins at both larval and adult stages. In ankk1+/+ adult zebrafish brain, drd2 protein was detected in cerebral cortex, cerebellum, hippocampus, and caudate homolog regions, resembling the pattern in humans. In contrast, drd2 expression was reduced in cortical regions of ankk127ins/27ins being predominantly found in the hindbrain. No differences in the number of cell bodies or axonal projections detected by anti-tyrosine hydroxylase immunostaining on 3 days post fertilization (dpf) larvae were found. Behavioral analysis revealed altered sensitivity to effects of both amisulpride and apomorphine on locomotion and startle habituation, consistent with a broad loss of both pre and post synaptic receptors. Ankk127ins mutants showed reduced sensitivity to the effect of the selective dopamine receptor antagonist amisulpride on locomotor responses to acoustic startle and were differentially sensitive to the effects of the non-selective dopamine agonist apomorphine on both locomotion and habituation. Taken together, our findings strengthen the hypothesis of a functional relationship between ANKK1 and DRD2, supporting a role for ANKK1 in the maintenance and/or functioning of dopaminergic pathways. Further work is needed to disentangle ANKK1’s role at different developmental stages.

Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder.

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD‐93 protein reduction) a novel clinically relevant Dlg2 +/− rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N‐Methyl‐D‐aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD‐93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2 +/− rats show a potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, and partially dissimilar to behavioural deficits previously reported in Dlg2 +/− mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks.

Behavioral and Neuroanatomical Consequences of Cell-Type Specific Loss of Dopamine D2 Receptors in the Mouse Cerebral Cortex

Developmental dysregulation of dopamine D2 receptors (D2Rs) alters neuronal migration, differentiation, and behavior and contributes to the psychopathology of neurological and psychiatric disorders. The current study is aimed at identifying how cell-specific loss of D2Rs in the cerebral cortex may impact neurobehavioral and cellular development, in order to better understand the roles of this receptor in cortical circuit formation and brain disorders. We deleted D2R from developing cortical GABAergic interneurons (Nkx2.1-Cre) or from developing telencephalic glutamatergic neurons (Emx1-Cre). Conditional knockouts (cKO) from both lines, Drd2fl/fl, Nkx2.1-Cre+ (referred to as GABA-D2R-cKO mice) or Drd2fl/fl, Emx1-Cre+ (referred to as Glu-D2R-cKO mice), exhibited no differences in simple tests of anxiety-related or depression-related behaviors, or spatial or nonspatial working memory. Both GABA-D2R-cKO and Glu-D2R-cKO mice also had normal basal locomotor activity, but GABA-D2R-cKO mice expressed blunted locomotor responses to the psychotomimetic drug MK-801. GABA-D2R-cKO mice exhibited improved motor coordination on a rotarod whereas Glu-D2R-cKO mice were normal. GABA-D2R-cKO mice also exhibited spatial learning deficits without changes in reversal learning on a Barnes maze. At the cellular level, we observed an increase in PV+ cells in the frontal cortex of GABA-D2R-cKO mice and no noticeable changes in Glu-D2R-cKO mice. These data point toward unique and distinct roles for D2Rs within excitatory and inhibitory neurons in the regulation of behavior and interneuron development, and suggest that location-biased D2R pharmacology may be clinically advantageous to achieve higher efficacy and help avoid unwanted effects.

Coordinating Clearance and Postural Reorientation When Avoiding Physical and Virtual Pedestrians.

Community ambulation requires efficient locomotor adaptations to avoid collisions with other pedestrians. Virtual reality (VR) offers the possibility to experimentally manipulate the environment, allowing researchers to safely assess locomotor responses during pedestrian interactions. In this paper, locomotor adjustments in response to interferers approaching from different directions were examined in both a physical and a virtual environment. Further analysis compared the extent to which locomotor adjustments were influenced by different circumvention strategies. To achieve these goals, twelve healthy young participants were assessed while walking towards a target and avoiding pedestrians approaching from the left, middle, or right, in both VR and the real world. Results showed that in VR, participants walked with slower velocities, maintained larger minimum distances, and reached larger trajectory deviations. Additionally, trajectory deviations and postural reorientations were executed earlier in VR. There were additional differences according to whether participants had to give way to a head-on approaching interferer or choose to pass in front or behind a diagonally approaching interferer. Compared to the other circumvention strategies, passing in front was associated with faster walking speeds as well as smaller and later trajectory deviations and postural reorientations. Lastly, while a cephalocaudal sequence of segment reorientation was observed in both environments, no difference between the onset of head and thorax reorientation was observed in VR. In conclusion, obstacle clearance and postural reorientation are modulated by the environment and circumvention strategies. These modulations should be considered when designing experiments or clinical interventions.

Dietary novel oils modulate neural function and preserve locomotor response in gilthead sea bream (Sparus aurata) juveniles by regulating synthesis and contents of fatty acids in brain

N-3 long-chain polyunsaturated fatty acids (LC-PUFA), particularly docosahexaenoic acid (22:6n-3, DHA), are the most important fatty acids with physiological significance in brain function of all vertebrates. Recently, novel lipid sources are available for the industry, including products obtained from microorganisms. Dietary fatty acid profiles may affect tissue composition and cell functioning. To determine the effect of novel lipid sources on behaviour and neural function in gilthead sea bream (Sparus aurata), juveniles were fed three isoproteic and isoenergetic diets containing either (FO), a microalgae oil combined with poultry oil (DD) or only poultry oil (PO). Behaviour response, brain fatty acid composition and relative expression of neurogenesis and neural activity related-genes in telencephalon were evaluated during 5 months of feeding with the experimental diets. Brain of sea bream fed diet PO showed the highest DHA content as well as increased desaturation and elongation products, contrary to the dietary pattern. This, together with an increased telencephalic fads2 expression denoted the effective activation of LC-PUFA synthesis and retention as a compensatory mechanism for a dietary deficiency. Furthermore, neurod6, bdnf and nos1 were proportionally upregulated in relation to the neural DHA content. Locomotor performance during cruising and escape responses was not affected by the experimental diets. However, there was a tendency for escape latency to be longest in fish fed PO and DD diets, and a relationship between escape latency and brain n-6 docosapentaenoic acid (DPA) contents was suggested. Indeed, the relation of n-6 DPA with behavioural deficits was shown previously in mammals and might deserve further attention and corroboration in fish as well in the future.

Exercise against cocaine sensitization in mice: a [18F]fallypride micro-PET study.

Wheel-running exercise in laboratory rodents (animal model useful to study the neurobiology of aerobic exercise) decreases behavioural markers of vulnerability to addictive properties of various drugs of abuse including cocaine. However, neurobiological mechanisms underpinning this protective effect are far from fully characterized. Here, 28-day-old female C57BL/6J mice were housed with (n = 48) or without (n = 48) a running wheel for 6 weeks before being tested for acute locomotor responsiveness and initiation of locomotor sensitization to intraperitoneal injections of 8 mg/kg cocaine. The long-term expression of sensitization took place 3 weeks after the last session. On the day after, all mice underwent a micro-PET imaging session with [18F]fallypride radiotracer (dopamine 2/3 receptors antagonist). Exercised mice were less sensitive to acute and sensitized cocaine hyperlocomotor effects, such attenuation being particularly well marked for long-term expression of sensitization (η2P = 0.262). Chronic administration of cocaine was associated with a clear-cut increase of [18F]fallypride binding potential in mouse striatum (η2P = 0.170) while wheel-running exercise was associated with a moderate decrease in dopamine 2/3 receptors density in striatum (η2P = 0.075), a mechanism that might contribute to protective properties of exercise against drugs of abuse vulnerability.

Rewarding Social Interaction in Rats Increases CaMKII in the Nucleus Accumbens.

Calcium/calmodulin-dependent protein kinase II (CaMKII) is known to be involved in the sensitized locomotor responses and drug-seeking behavior to psychostimulants. However, little is known about the contribution of CaMKII signaling in the nucleus accumbens (NAc) in natural rewards such as social interaction. The present experiments explored the implication of CaMKII signaling in drug versus natural reward. In the NAc of rats expressing cocaine or social interaction conditioned place preference (CPP), αCaMKII activation was induced in those expressing social interaction but not cocaine CPP. In order to investigate the role of NAc CaMKII in the expression of reward-related learning of drug versus non-drug stimuli, we inhibited CaMKII through an infusion of KN-93, a CaMKII inhibitor, directly into the NAc shell or core, before the CPP test in a concurrent paradigm in which social interaction was made available in the compartment alternative to the one associated with cocaine during conditioning. Whereas vehicle infusions led to equal preference to both stimuli, inhibition of CaMKII by a KN-93 infusion before the CPP test in the shell but not the core of the NAc shifted the rats’ preference toward the cocaine-associated compartment. Altogether, these results suggest that social interaction reward engages CaMKII in the NAc.

The GhsrQ343X allele favors the storage of fat by acting on nutrient partitioning.

The Growth Hormone Secretagogue Receptor (GHSR) mediates key properties of the gut hormone ghrelin on metabolism and behavior. Nevertheless, most recent observations also support that the GHSR is a constitutively active G protein-coupled receptor endowed of a sophisticated tuning involving a balance of endogenous ligands. Demonstrating the feasibility of shifting GHSR canonical signaling in vivo, we previously reported that a model with enhanced sensitivity to ghrelin (GhsrQ343X mutant rats) developed fat accumulation and glucose intolerance. Herein, we investigated the contribution of energy homeostasis to the onset of this phenotype, as well as behavioral responses to feeding or pharmacological challenges, by comparing GhsrM/M rats to wild-type littermate rats 1) as freely behaving animals and 2) in feeding and locomotor paradigms. Herein, GhsrM/M rats showed enhanced locomotor response to a GHSR agonist while locomotor or anorexigenic responses to amphetamine or cabergoline (dopamine receptor 2 agonist), respectively, were preserved. Ad libitum fed GhsrM/M rats consumed and conditioned for sucrose similarly to littermate control rats. In calorie-restricted conditions, GhsrM/M rats retained food anticipatory activity and maintained better their body weight and glycemia. Importantly, prior to fat accumulation, male GhsrM/M rats preferentially used carbohydrates as fuel substrate without alterations of energy intake, energy expenditure or physical activity and showed alterations of the GHSR system (i.e. enhanced ratio of GHSR hormones LEAP2:acyl-ghrelin and increased Ghsr expression in the hypothalamus). Overall, the present study provides proof of concept that shifted GHSR signaling can specifically alter nutrient partitioning resulting in modified balance of carbohydrate/lipid utilization.

Antarctic teleosts with and without hemoglobin behaviorally mitigate deleterious effects of acute environmental warming.

Recent studies forecast that many ectothermic animals, especially aquatic stenotherms, may not be able to thrive or even survive predicted climate change. These projections, however, generally do not call much attention to the role of behavior, an essential thermoregulatory mechanism of many ectotherms. Here we characterize species-specific locomotor and respiratory responses to acute ambient warming in two highly stenothermic Antarctic Notothenioid fishes, one of which (Chaenocephalus aceratus) lacks hemoglobin and appears to be less tolerant to thermal stress as compared to the other (Notothenia coriiceps), which expresses hemoglobin. At the onset of ambient warming, both species perform distinct locomotor maneuvers that appear to include avoidance reactions. In response to unavoidable progressive hyperthermia, fishes demonstrate a range of species-specific maneuvers, all of which appear to provide some mitigation of the deleterious effects of obligatory thermoconformation and to compensate for increasing metabolic demand by enhancing the efficacy of branchial respiration. As temperature continues to rise, Chaenocephalus aceratus supplements these behaviors with intensive pectoral fin fanning which may facilitate cutaneous respiration through its scaleless integument, and Notothenia coriiceps manifests respiratory-locomotor coupling during repetitive startle-like maneuvers which may further augment gill ventilation. The latter behaviors, found only in Notothenia coriiceps, have highly stereotyped appearance resembling Fixed Action Pattern sequences. Altogether, this behavioral flexibility could contribute to the reduction of the detrimental effects of acute thermal stress within a limited thermal range. In an ecologically relevant setting, this may enable efficient thermoregulation of fishes by habitat selection, thus facilitating their resilience in persistent environmental change.

Vitamin C Mitigates Oxidative Stress and Behavioral Impairments Induced by Deltamethrin and Lead Toxicity in Zebrafish.

Environmental contamination from toxic metals and pesticides is an issue of great concern due to their harmful effects to human health and the ecosystems. In this framework, we assessed the adverse effects when aquatic organisms are exposed to toxicants such as deltamethrin (DM) and lead (Pb), alone or in combination, using zebrafish as a model. Moreover, we likewise evaluated the possible protective effect of vitamin C (VC) supplementation against the combined acute toxic effects of the two toxicants. Juvenile zebrafish were exposed to DM (2 μg L−1) and Pb (60 μg L−1) alone and in combination with VC (100 μg L−1) and responses were assessed by quantifying acetylcholinesterase (AChE) activity, lipid peroxidation (MDA), some antioxidant enzyme activities (SOD and GPx), three-dimension locomotion responses and changes of elements concentrations in the zebrafish body. Our results show that VC has mitigative effects against behavioral and biochemical alterations induced by a mixture of contaminants, demonstrating that it can be used as an effective antioxidant. Moreover, the observations in the study demonstrate zebrafish as a promising in vivo model for assessing the neuroprotective actions of bioactive compounds.

Light-stimulus intensity modulates startle reflex habituation in larval zebrafish

The startle reflex in larval zebrafish describes a C-bend of the body occurring in response to sudden, unexpected, stimuli of different sensory modalities. Alterations in the startle reflex habituation (SRH) have been reported in various human and animal models of neurological and psychiatric conditions and are hence considered an important behavioural marker of neurophysiological function. The amplitude, offset and decay constant of the auditory SRH in larval zebrafish have recently been characterised, revealing that the measures are affected by variation in vibratory frequency, intensity, and interstimulus-interval. Currently, no study provides a model-based analysis of the effect of physical properties of light stimuli on the visual SRH. This study assessed the effect of incremental light-stimulus intensity on the SRH of larval zebrafish through a repeated-measures design. Their total locomotor responses were normalised for the time factor, based on the behaviour of a (non-stimulated) control group. A linear regression indicated that light intensity positively predicts locomotor responses due to larger SRH decay constants and offsets. The conclusions of this study provide important insights as to the effect of light properties on the SRH in larval zebrafish. Our methodology and findings constitute a relevant reference framework for further investigation in translational neurophysiological research.

A conserved neuropeptide system links head and body motor circuits to enable adaptive behavior.

Neuromodulators promote adaptive behaviors that are often complex and involve concerted activity changes across circuits that are often not physically connected. It is not well understood how neuromodulatory systems accomplish these tasks. Here, we show that the Caenorhabditis elegans NLP-12 neuropeptide system shapes responses to food availability by modulating the activity of head and body wall motor neurons through alternate G-protein coupled receptor (GPCR) targets, CKR-1 and CKR-2. We show ckr-2 deletion reduces body bend depth during movement under basal conditions. We demonstrate CKR-1 is a functional NLP-12 receptor and define its expression in the nervous system. In contrast to basal locomotion, biased CKR-1 GPCR stimulation of head motor neurons promotes turning during local searching. Deletion of ckr-1 reduces head neuron activity and diminishes turning while specific ckr-1 overexpression or head neuron activation promote turning. Thus, our studies suggest locomotor responses to changing food availability are regulated through conditional NLP-12 stimulation of head or body wall motor circuits.

Detection of locomotion deficit in a post-traumatic syringomyelia rat model using automated gait analysis technique.

Syringomyelia (SM) is a spinal cord disorder in which a cyst (syrinx) filled with fluid forms in the spinal cord post-injury/disease, in patients syrinx symptoms include loss of pain and temperature sensation or locomotion deficit. Currently, there are no small animal models and connected tools to help study the functional impacts of SM. The objective of this study was to determine the detectability of subtle locomotion deficits due to syrinx formation/expansion in post-traumatic syringomyelia (PTSM) rat model using the recently reported method of Gait Analysis Instrumentation, and Technology Optimized for Rodents (GAITOR) with Automated Gait Analysis Through Hues and Areas (AGATHA) technique. First videos of the rats were collected while walking in an arena (using GAITOR) followed by extracting meaningful locomotion information from collected videos using AGATHA protocol. PTSM injured rats demonstrated detectable locomotion deficits in terms of duty factor imbalance, paw placement accuracy, step contact width, stride length, and phase dispersion parameters compared to uninjured rats due to SM. We concluded that this technique could detect mild and subtle locomotion deficits associated with PTSM injury, which also in future work could be used further to monitor locomotion responses after different treatment strategies for SM.

Developmental exposure to MDMA (ecstasy) in zebrafish embryos reproduces the neurotoxicity adverse outcome ‘lower motor activity’ described in humans

The recreational use of MDMA (ecstasy) by pregnant women is associated with impaired neuromotor function in infants, but the Adverse Outcome Pathway behind this effect is not clear yet. We present for the first time the evaluation of developmental neurotoxic (DNT) effects of MDMA in zebrafish embryos. The aim of the study was to determine whether the zebrafish model reproduces the adverse outcome occurring in humans. We have studied the DNT effects of MDMA in zebrafish within a range of 5–250 μM performing different behavioural tests: spontaneous tail-coiling and light-dark locomotor response; after exposing the embryos to 4 different scenarios combining changes in pH, in starting exposure time and exposure duration. In these scenarios we evaluated the effects of MDMA in general embryonic development and compared the concentrations producing them with those inducing specific DNT effects. As a result, we have established the experimental conditions leading to the adverse outcome “lower motor activity” in zebrafish without producing general developmental delay or general toxicity. The experimental condition chosen opens the door to use this model in future mechanistic investigations to better characterize the Adverse Outcome Pathway associated with the adverse effects caused by MDMA prenatal exposure in humans.

M-CF3-substituted diphenyl diselenide attenuates all phases of morphine-induced behavioral locomotor sensitization in mice

BackgroundBehavioral sensitization, thought to underlie some aspects of drug dependence, is typically measured as increased locomotion in response to repeated administration of a drug. The study aimed to investigate the (m-CF3-PhSe)2 effects on the acquisition, withdrawal, and re-exposure phases of morphine-induced behavioral locomotor sensitization. MethodsSwiss male mice were treated with saline or morphine at 10 mg/kg twice a day for 3 days; those of the morphine group were kept in the morphine withdrawal period (5 days). On day 9, mice were re-exposed to morphine. (m-CF3-PhSe)2 (10 mg/kg) or vehicle was administered at all phases of morphine protocol, and mice performed locomotor activity test. Oxidative stress markers and the levels of opioid, dopamine, and glutamate receptors were determined in samples of the cerebral cortex. (m-CF3-PhSe)2 administered at all phases of protocol attenuated morphine-induced locomotor sensitization. ResultsMice exposed to morphine showed reduced weight gain and increased locomotor activity, but (m-CF3-PhSe)2 treatment attenuates the weight gain and behavioral hyperlocomotion effects. (m-CF3-PhSe)2, independent of the administration phase, modulated the increase of opioidergic (MOR, DOR, KOR) and glutamatergic (NMDA 2A and 2B) protein contents and attenuated redox imbalance in the cerebral cortex of mice exposed to morphine. However, (m-CF3-PhSe)2 did not modulate cortical protein levels of dopaminergic (D1 and D2) receptors in the acquisition phase of morphine-induced locomotor sensitization protocol. Conclusion(m-CF3-PhSe)2 was effective against the behavioral and molecular alterations caused by morphine at all phases of locomotor sensitization.

Developmental titanium dioxide nanoparticle exposure induces oxidative stress and neurobehavioral changes in zebrafish.

The widespread commercial application of titanium dioxide nanoparticles (TiO2 NPs) leads to ubiquitous presence of TiO2 NPs in the aquatic environment, which highlights the necessity to determine their potential adverse effects on aquatic organisms. The developing nerve system is particularly susceptible to environment perturbation. However, few studies have explored the developmental neurobehavioral toxicity of TiO2 NPs, especially at smaller particle size ranges (≤20nm) that have relatively longer retention time in the water column. In this study, zebrafish embryos were exposed to non-teratogenic concentrations of 0.1 and 1mg/L TiO2 NPs (average size of 14-20nm) from 8 to 108h post-fertilization (hpf) followed by various assessments at different time points up to 12 days post-fertilization (dpf). Our findings revealed that 1mg/L TiO2 NPs perturbed the motor and social behaviors in larval zebrafish. These behavioral changes were characterized by decreased swimming speed in a locomotor response test at 5dpf, increased travel distance in a flash stimulus test at 5dpf, increased preference to the light zone in a light/dark preference test at 10dpf, and increased mirror attack and percent time spent in the mirror zone in a mirror stimulus response assay at 12dpf. Mechanistic examinations at 5dpf revealed elevated cell apoptosis and oxidative stress. Cell apoptosis was characterized by increased acridine orange (AO) positive cells in the olfactory region and neuromasts of the lateral line system. Oxidative stress was characterized by increased lipid peroxidation, increased ROS production, and upregulated catalase (cat) gene expression. In addition, TiO2 NP exposure also upregulated genes associated with the developmental nervous system such as the growth associated protein 43 (gap43) and proliferating cell nuclear antigen (pcna). Our results suggest that the neurobehavioral changes in larvae exposed to 1mg/L TiO2 NPs during early development may result from cell apoptosis and oxidative stress induced neuronal damages.

Panx1b Modulates the Luminance Response and Direction of Locomotion in the Zebrafish.

Pannexin1 (Panx1) can form ATP-permeable channels that play roles in the physiology of the visual system. In the zebrafish two ohnologs of Panx1, Panx1a and Panx1b, have unique and shared channel properties and tissue expression patterns. Panx1a channels are located in horizontal cells of the outer retina and modulate light decrement detection through an ATP/pH-dependent mechanisms and adenosine/dopamine signaling. Here, we decipher how the strategic localization of Panx1b channels in the inner retina and ganglion cell layer modulates visually evoked motor behavior. We describe a panx1b knockout model generated by TALEN technology. The RNA-seq analysis of 6 days post-fertilization larvae is confirmed by real-time PCR and paired with testing of locomotion behaviors by visual motor and optomotor response tests. We show that the loss of Panx1b channels disrupts the retinal response to an abrupt loss of illumination and it decreases the larval ability to follow leftward direction of locomotion in low light conditions. We concluded that the loss of Panx1b channels compromises the final output of luminance as well as motion detection. The Panx1b protein also emerges as a modulator of the circadian clock system. The disruption of the circadian clock system in mutants suggests that Panx1b could participate in non-image forming processes in the inner retina.

Npas4 regulates medium spiny neuron physiology and gates cocaine-induced hyperlocomotion

We show here that the transcription factor Npas4 is an important regulator of medium spiny neuron spine density and electrophysiological parameters and that it determines the magnitude of cocaine-induced hyperlocomotion in mice. Npas4 is induced by synaptic stimuli that cause calcium influx, but not dopaminergic or PKA-stimulating input, in mouse medium spiny neurons and human iPSC-derived forebrain organoids. This induction is independent of ubiquitous kinase pathways such as PKA and MAPK cascades, and instead depends on calcineurin and nuclear calcium signalling. Npas4 controls a large regulon containing transcripts for synaptic molecules, such as NMDA receptors and VDCC subunits, and determines in vivo MSN spine density, firing rate, I/O gain function and paired-pulse facilitation. These functions at the molecular and cellular levels control the locomotor response to drugs of abuse, as Npas4 knockdown in the nucleus accumbens decreases hyperlocomotion in response to cocaine in male mice while leaving basal locomotor behaviour unchanged.

MK-801-induced behavioral and dopaminergic responses in the shell part of the nucleus accumbens in adult male rats are disrupted after neonatal blockade of the ventral subiculum

The present study was conducted in the context of animal modeling of schizophrenia. It investigated in adult male rats, after transient neonatal blockade of the ventral subiculum (VSub), the impact of a very specific non-competitive antagonist of NMDA receptors (MK-801) on locomotor activity and dopaminergic (DAergic) responses in the dorsomedial shell part of the nucleus accumbens (Nacc), a striatal subregion described as the common target region for antipsychotics.The functional neonatal inactivation of the VSub was achieved by local microinjection of tetrodotoxin (TTX) at postnatal day 8 (PND8). Control pups were microinjected with the solvent phosphate buffered saline (PBS). Locomotor responses and DAergic variations in the dorsomedial shell part of the Nacc were measured simultaneously using in vivo voltammetry in awake, freely moving male animals after sc administration of MK-801. The following results were obtained: 1) a dose-dependent increase in locomotor activity in PBS and TTX animals, greater in TTX rats/PBS rats; and 2) divergent DAergic responses for PBS and TTX animals. A decrease in DA levels with a return to around basal values was observed in PBS animals. An increase in DA levels was obtained in TTX animals. The present data suggest that neonatal blockade of the VSub results in disruption in NMDA glutamatergic transmission, causing a disturbance in DA release in the dorsomedial shell in adults male rats. In the context of animal modeling of schizophrenia using the same approach it would be interesting to investigate possible changes in postsynaptic NMDA receptors-related proteins in the dorsomedial shell region in the Nacc.