Early and transitory hypoactivity and olfactory alterations after chronic atrazine exposure in female Sprague-Dawley rats.

Several studies have shown that chronic exposure to the herbicide atrazine (ATR) causes alterations in locomotor activity and markers of the dopaminergic systems of male rats. However, few studies have evaluated the sex-dependent effects of atrazine exposure. The aim of the present study was to evaluate whether chronic ATR exposure causes alterations in behavioral performance and dopaminergic systems of female rats. At weaning, two groups of rats were exposed to 1 or 10 mg ATR/kg body weight daily thorough the food, while the control group received food without ATR for 14 months. Spontaneous locomotor activity was evaluated monthly for 12 months, while anxiety, egocentric and spatial memory, motor coordination, and olfactory function tasks were evaluated between 13 and 14 months of ATR exposure. Tyrosine hydroxylase (TH) and monoamine content in brain tissue were assessed at the end of ATR treatment. Female rats treated with 1 or 10 mg ATR showed vertical hypoactivity compared to the control group only in the first month of ATR exposure. Impairments in olfactory functions were found due to ATR exposure. Nevertheless, no alterations in anxiety, spatial and egocentric memory, or motor coordination tasks were observed, while the levels of TH and dopamine and its metabolites in brain tissue were similar among groups. These results suggest that female rats could present greater sensitivity to the neurotoxic effects of ATR on spontaneous locomotor activity in the early stages of development. However, they are unaffected by chronic ATR exposure later in life compared to male rats. More studies are necessary to unravel the sex-related differences observed after chronic ATR exposure.

Hypoactivity and neurochemical alterations in the basal ganglia of female Sprague-Dawley rats after repeated exposure to atrazine.

The herbicide atrazine (ATR) has been one of the most widely used herbicides worldwide. However, due to its indiscriminate use, it has been considered an environmental contaminant. Several studies have classified ATR as an endocrine disruptor, and it has been found to have neurotoxic effects on behavior, along with alterations in the dopaminergic, GABAergic, and glutamatergic systems in the basal ganglia of male rodents. These findings suggest that these neurotransmitter systems are targets of this herbicide. However, there are no studies evaluating the neurotoxicity of ATR in female rodents. Our study aimed to assess the effects of repeated IP injections of 100 mg ATR/kg or a vehicle every other day for 2 weeks (six injections) on the locomotor activity, content of monoamines, GABA, glutamate, and glutamine in the striatum, nucleus accumbens, ventral midbrain, and prefrontal cortex, and tyrosine hydroxylase (TH) protein levels in striatum and nucleus accumbens of female rats. Repeated 100 mg ATR/kg injections immediately decreased all the locomotor activity parameters evaluated, and such hypoactivity persisted for at least 48 h after the last ATR administration. The ATR administration increased dopamine and DOPAC content in the nucleus accumbens and the dopamine and DOPAC and serotonin and 5-HIAA content in the ventral midbrain. In contrast, the TH protein levels in the striatum and nucleus accumbens were similar between groups. Meanwhile, GABA, glutamine, and glutamate levels remained unaltered in all brain regions evaluated. The observed behavioral alterations could be associated with the monoamine changes presented by the rats. These data reveal that the nucleus accumbens and ventral midbrain are susceptible to repeated ATR exposure in female rats.

Contribution and functional connectivity between cerebrum and cerebellum on sub-lexical and lexical-semantic processing of verbs.

Language comprehension involves both sub-lexical (e.g., phonological) and lexical-semantic processing. We conducted a task using functional magnetic resonance imaging (fMRI) to compare the processing of verbs in these two domains. Additionally, we examined the representation of concrete-motor and abstract-non-motor concepts by including two semantic categories of verbs: motor and mental. The findings indicate that sub-lexical processing during the reading of pseudo-verbs primarily involves the left dorsal stream of the perisylvian network, while lexical-semantic representation during the reading of verbs predominantly engages the ventral stream. According to the embodied or grounded cognition approach, modality-specific mechanisms (such as sensory-motor systems) and the well-established multimodal left perisylvian network contribute to the semantic representation of both concrete and abstract verbs. Our study identified the visual system as a preferential modality-specific system for abstract-mental verbs, which exhibited functional connectivity with the right crus I/lobule VI of the cerebellum. Taken together, these results confirm the dissociation between sub-lexical and lexical-semantic processing and provide neurobiological evidence of functional coupling between specific visual modality regions and the right cerebellum, forming a network that supports the semantic representation of abstract concepts. Further, the results shed light on the underlying mechanisms of semantic processing and contribute to our understanding of how the brain processes abstract concepts.

A novel task to evaluate irony comprehension and its essential elements in Spanish speakers.

An ironic statement transmits the opposite meaning to its literal counterpart and is one of the most complex communicative acts. Thus, it has been proposed to be a good indicator of social communication ability. Prosody and facial expression are two crucial paralinguistic cues that can facilitate the understanding of ironic statements. The primary aim of this study was to create and evaluate a task of irony identification that could be used in neuroimaging studies. We independently evaluated three cues, contextual discrepancy, prosody and facial expression, and selected the best cue that would lead participants in fMRI studies to identify a stimulus as ironic in a reliable way. This process included the design, selection, and comparison of the three cues, all of which have been previously associated with irony detection. The secondary aim was to correlate irony comprehension with specific cognitive functions. Results showed that psycholinguistic properties could differentiate irony from other communicative acts. The contextual discrepancy, prosody, and facial expression were relevant cues that helped detect ironic statements; with contextual discrepancy being the cue that produced the highest classification accuracy and classification time. This task can be used successfully to test irony comprehension in Spanish speakers using the cue of interest. The correlation of irony comprehension with cognitive functions did not yield consistent results. A more heterogeneous sample of participants and a broader battery of tests may be needed to find reliable cognitive correlates of irony comprehension.

Delivery of chemotropic proteins and improvement of dopaminergic neuron outgrowth through a thixotropic hybrid nano-gel.

Chemotropic proteins guide neuronal projections to their final target during embryo development and are useful to guide axons of neurons used in transplantation therapies. Site-specific delivery of the proteins however is needed for their application in the brain to avoid degradation and pleiotropic affects. In the present study we report the use of Poly (ethylene glycol)-Silica (PEG-Si) nanocomposite gel with thixotropic properties that make it injectable and suitable for delivery of the chemotropic protein semaphorin 3A. PEG-Si gel forms a functional gradient of semaphorin that enhances axon outgrowth of dopaminergic neurons from rat embryos or differentiated from stem cells in culture. It is not cytotoxic and its properties allowed its injection into the striatum without inflammatory response in the short term. Long term implantation however led to an increase in macrophages and glial cells. The inflammatory response could have resulted from non-degraded silica particles, as observed in biodegradation assays.

What Deception Tasks Used in the Lab Really Do: Systematic Review and Meta-analysis of Ecological Validity of fMRI Deception Tasks.

Interpretation of the neural findings of deception without considering the ecological validity of the experimental tasks could lead to biased conclusions. In this study we classified the experimental tasks according to their inclusion of three essential components required for ecological validity: intention to lie, social interaction and motivation. First, we carried out a systematic review to categorize fMRI deception tasks and to weigh the degree of ecological validity of each one. Second, we performed a meta-analysis to identify if each type of task involves a different neural substrate and to distinguish the neurocognitive contribution of each component of ecological validity essential to deception. We detected six categories of deception tasks. Intention to lie was the component least frequently included, followed by social interaction. Monetary reward was the most frequent motivator. The results of the meta-analysis, including 59 contrasts, revealed that intention to lie is associated with activation in the left lateral occipital cortex (superior division) whereas the left angular gyrus and right inferior frontal gyrus (IFG) are engaged during lying under instructions. Additionally, the right IFG appears to participate in the social aspect of lying including simulated and real interactions. We found no effect of monetary reward in our analysis. Finally, tasks with high ecological validity recruited fewer brain areas (right insular cortex and bilateral anterior cingulate cortex (ACC)) compared to less ecological tasks, perhaps because they are more natural and realistic, and engage a wide network of brain mechanisms, as opposed to specific tasks that demand more centralized processes.

Theory of Mind and Its Elusive Structural Substrate.

Is brain structure related to function? Can one predict the other? These are questions that are still waiting to be answered definitively. In this paper we seek to investigate these questions, in particular, we are interested in the relation between brain structure and theory of mind (ToM). ToM is defined as the ability to attribute mental states to others. Previous studies have observed correlations between performance on ToM tasks, and gray-matter size/volume in dorsomedial prefrontal cortex (dmPFC), temporoparietal junction (TPJ) and precuneus (PCu). Despite these findings, there are concerns about false positive results and replicability issues. In this study we used two different tasks to evaluate ToM, Reading the Mind in the Eyes Test (RMET), and the Short Story Task (SST). Performance in these tasks was correlated to brain anatomy measures including voxel-based morphometry (VBM) and cortical thickness (CT) analysis, from ninety-one neurotypical participants. High-resolution structural brain images were acquired, and whole-brain and region of interest (ROI) analyses were implemented. The analyses did not show statistically significant associations between ToM performance and brain structural measures after correction. Significant associations between performance on ToM tests and a widespread array of regions loosely associated with ToM were observed only for whole brain uncorrected analysis (p < 0.001). These results do not replicate a previous study with neurotypical participants. We tested two different ToM tests, two different softwares for VBM and CT, and we used two samples, one with 91 and a sub-sample with 69 participants. Neither of these conditions made a difference in the results obtained. Consequently, these results suggest that if the population is neurotypical and homogenous, it is unlikely that a reliable association between brain anatomy measures and ToM performance, as measured with these tasks, may be found.

Beta-amyloid protein (25-35) disrupts hippocampal network activity: role of Fyn-kinase.

Early cognitive deficit characteristic of early Alzheimer's disease seems to be produced by the soluble forms of beta-amyloid protein. Such cognitive deficit correlates with neuronal network dysfunction that is reflected as alterations in the electroencephalogram of both Alzheimer patients and transgenic murine models of such disease. Correspondingly, recent studies have demonstrated that chronic exposure to betaAP affects hippocampal oscillatory properties. However, it is still unclear if such neuronal network dysfunction results from a direct action of betaAP on the hippocampal circuit or it is secondary to the chronic presence of the protein in the brain. Therefore, we aimed to explore the effect of acute exposure to betaAP(25-35) on hippocampal network activity both in vitro and in vivo, as well as on intrinsic and synaptic properties of hippocampal neurons. We found that betaAP(25-35), reversibly, affects spontaneous hippocampal population activity in vitro. Such effect is not produced by the inverse sequence betaAP(35-25) and is reproduced by the full-length peptide betaAP(1-42). Correspondingly betaAP(25-35), but not the inverse sequence betaAP(35-25), reduces theta-like activity recorded from the hippocampus in vivo. The betaAP(25-35)-induced disruption in hippocampal network activity correlates with a reduction in spontaneous neuronal activity and synaptic transmission, as well as with an inhibition in the subthreshold oscillations produced by pyramidal neurons in vitro. Finally, we studied the involvement of Fyn-kinase on the betaAP(25-35)-induced disruption in hippocampal network activity in vitro. Interestingly, we found that such phenomenon is not observed in slices obtained from Fyn-knockout mice. In conclusion, our data suggest that betaAP acutely affects proper hippocampal function through a Fyn-dependent mechanism. We propose that such alteration might be related to the cognitive impairment observed, at least, during the early phases of Alzheimer's disease.

Lack of effect of intranigral transplants of a GABAergic cell line on absence seizures.

The substantia nigra pars reticulata (SNpr) is involved in controlling a variety of seizure phenomena. Intranigral transplants of GABAergic cells have been shown to decrease the severity of already established epileptic seizures, but the effects observed have been short-lived. This study evaluated the ability of intranigral transplants of GABA-producing cells to reduce spontaneous absence seizures in a genetic animal model for periods up to 3 months after transplantation. Intranigral transplants did not induce any behavioral deficits in the animals, and they did not form tumors; however, the transplants failed to decrease absence seizures in the genetic model. The assumed increase in intranigral levels of GABA after the transplants may be insufficient to counteract all the factors involved in generating the absence seizures; in this animal model, it may be necessary to further decrease nigral activity by implanting GABAergic cells in another area. These results bear down on the fact that cell transplants need to be tailored for each type of convulsive disorder in terms of the type of cells delivered and the location of the transplants.

Intranigral transplants of a GABAergic cell line produce long-term alleviation of established motor seizures.

We have previously shown that intranigral transplants of immortalized GABAergic cells decrease the number of kainic acid-induced seizures [Castillo CG, Mendoza S, Freed WJ, Giordano M. Intranigral transplants of immortalized GABAergic cells decrease the expression of kainic acid-induced seizures in the rat. Behav Brain Res 2006;171:109-15] in an animal model. In the present study, recurrent spontaneous behavioral seizures were established by repeated systemic injections of this excitotoxin into male Sprague-Dawley rats. After the seizures had been established, cells were transplanted into the substantia nigra. Animals with transplants of control cells (without hGAD67 expression) or with sham transplants showed a death rate of more than 40% over the 12 weeks of observation, whereas in animals with M213-2O CL-4 transplants, the death rate was reduced to less than 20%. The M213-2O CL-4 transplants significantly reduced the percentage of animals showing behavioral seizures; animals with these transplants also showed a lower occurrence of stage V seizures than animals in the other groups. In vivo and in vitro analyses provided evidence that the GABAergic cells show sustained expression of both GAD67 and hGAD67 cDNA, as well as increased gamma-aminobutyric acid (GABA) levels in the ventral mesencephalon of transplanted animals. Therefore, transplantation of GABA-producing cells can produce long-term alleviation of behavioral seizures in an animal model.

A Quantitative Meta-analysis of Neuroimaging Studies of Pragmatic Language Comprehension: In Search of a Universal Neural Substrate.

Pragmatics may be defined as the ability to communicate by expressing and recognizing intentions. The objective of this meta-analysis was to identify neural substrates for comprehension of pragmatic content in general, as well as the differences between pragmatic forms, and to describe if there is differential recruitment of brain areas according to natural language. This meta-analysis included 48 functional magnetic resonance imaging studies that reported pragmatic versus literal language contrasts. The pragmatic forms were speech acts, metaphors, idioms, and irony. Effect Size-Signed Differential Mapping software was used to calculate the mean for all contrasts as well as for each pragmatic form, and make comparisons among all forms. Due to variations in pragmatic content configuration such as natural language, stimulus modality, and writing systems, these variations were also analyzed with subgroups' analyses. The analyses found a highly reproducible bilateral fronto-temporal and medial prefrontal cortex network for pragmatic comprehension. Each pragmatic form showed a specific convergence pattern within this bilateral network. Natural language analyses showed that fronto-temporal regions were recruited by Germanic languages, while only left frontal areas were recruited by Romance languages, and right medial prefrontal cortex by Japanese. In conclusion, pragmatic language comprehension involves classical language areas in bilateral perisylvian regions, along with the medial prefrontal cortex, an area involved in social cognition. Together, these areas could represent the "pragmatic language network". Nonetheless, when proposing a universal neural substrate for all forms of pragmatic language, the diversity among studies in terms of pragmatic form, and configuration, must be taken into consideration.

Risk-taking, locomotor activity and dopamine levels in the nucleus accumbens and medial prefrontal cortex in male rats treated prenatally with alcohol.

BACKGROUND: Prenatal alcohol exposure (PA) restricted to days 8-20 of rat gestation reduces the activity of the dopaminergic neurons (DA) in the ventral tegmental area (VTA). Hyperactivity and impulsivity have been observed under this treatment; however, it is unknown whether DA levels are affected. Decision-making in risk situations, meanwhile, has been associated with impulsive behavior, but because studies of this phenomenon in animal models are limited, we do not yet know whether PA has any effect. The present study investigated the effects of PA on risk-taking behavior and locomotor activity in pre-pubertal male rats. In addition, DA levels in the nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) in response to methylphenidate (MP) were assessed. METHODS: Dams were treated with either two daily 3.0-g/kg doses of alcohol or an isocaloric solution, from days 8-20 of gestation. Locomotor activity and risk-taking in pre-pubertal male rats after PA, and DA levels in the NAcc and mPFC after a single dose of MP (5mg/kg), were analyzed. RESULTS: Hyperactivity and increased risk-taking behavior were observed in the rats treated prenatally with alcohol compared to controls. Methylphenidate increased DA levels in the NAcc regardless of prenatal treatment, but significantly higher DA levels were found in the PA group regardless of postnatal treatment with saline or MP. CONCLUSION: The presence of hyperactivity and increased risk-taking behavior after prenatal alcohol treatment is supported. Results suggest that higher DA levels in the rats with PA could be due to a down-regulation of postsynaptic receptors, the desensitization of presynaptic receptors, or a compensatory over-activity of DA neurons in the VTA.

Intranigral transplants of immortalized GABAergic cells decrease the expression of kainic acid-induced seizures in the rat.

Repeated systemic administration of low doses of kainic acid (KA) induces spontaneous convulsive seizures [Hellier JL, Patrylo PR, Buckmaster PS, Dudek FE. Recurrent spontaneous motor seizures after repeated low-dose systemic treatment with kainate: assessment of a rat model of temporal lobe epilepsy. Epilepsy Res 1998;31:73-84]. In this study, male Sprague-Dawley animals received intranigral transplants of a control cell line M213-2O, or a cell line transfected with human GAD67 cDNA (M213-2O CL4) [Conejero-Goldberg C, Tornatore C, Abi-Saab W, Monaco MC, Dillon-Carter O, Vawter M, et al. Transduction of human GAD67 cDNA into immortalized striatal cell lines using an Epstein-Barr virus-based plasmid vector increases GABA content. Exp Neurol 2000;161:453-61], or no transplant. Eight weeks after transplantation surgery, KA was administered (5 mg/kg/h) until animals reached stage V seizures as described by Racine [Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972;32:281-94]. The group transplanted with CL4 required a larger dose of KA and a longer latency to reach a stage V seizure. In addition, this group exhibited significantly fewer stage III and IV seizures. These results indicate that intranigral transplants of a GABA-producing cell line can decrease the number of kainic acid-induced seizures.

Chronic Exposure to Arsenic in Drinking Water Causes Alterations in Locomotor Activity and Decreases Striatal mRNA for the D2 Dopamine Receptor in CD1 Male Mice.

Arsenic exposure has been associated with sensory, motor, memory, and learning alterations in humans and alterations in locomotor activity, behavioral tasks, and neurotransmitters systems in rodents. In this study, CD1 mice were exposed to 0.5 or 5.0 mg As/L of drinking water for 6 months. Locomotor activity, aggression, interspecific behavior and physical appearance, monoamines levels, and expression of the messenger for dopamine receptors D1 and D2 were assessed. Arsenic exposure produced hypoactivity at six months and other behaviors such as rearing and on-wall rearing and barbering showed both increases and decreases. No alterations on aggressive behavior or monoamines levels in striatum or frontal cortex were observed. A significant decrease in the expression of mRNA for D2 receptors was found in striatum of mice exposed to 5.0 mg As/L. This study provides evidence for the use of dopamine receptor D2 as potential target of arsenic toxicity in the dopaminergic system.

The herbicide glyphosate causes behavioral changes and alterations in dopaminergic markers in male Sprague-Dawley rat.

Glyphosate (Glyph) is the active ingredient of several herbicide formulations. Reports of Glyph exposure in humans and animal models suggest that it may be neurotoxic. To evaluate the effects of Glyph on the nervous system, male Sprague-Dawley rats were given six intraperitoneal injections of 50, 100, or 150 mg Glyph/kg BW over 2 weeks (three injections/week). We assessed dopaminergic markers and their association with locomotor activity. Repeated exposure to Glyph caused hypoactivity immediately after each injection, and it was also apparent 2 days after the last injection in rats exposed to the highest dose. Glyph did not decrease monoamines, tyrosine hydroxylase (TH), or mesencephalic TH+ cells when measured 2 or 16 days after the last Glyph injection. In contrast, Glyph decreased specific binding to D1 dopamine (DA) receptors in the nucleus accumbens (NAcc) when measured 2 days after the last Glyph injection. Microdialysis experiments showed that a systemic injection of 150 mg Glyph/kg BW decreased basal extracellular DA levels and high-potassium-induced DA release in striatum. Glyph did not affect the extracellular concentrations of 3,4-dihydroxyphenylacetic acid or homovanillic acid. These results indicate that repeated Glyph exposure results in hypoactivity accompanied by decreases in specific binding to D1-DA receptors in the NAcc, and that acute exposure to Glyph has evident effects on striatal DA levels. Additional experiments are necessary in order to unveil the specific targets of Glyph on dopaminergic system, and whether Glyph could be affecting other neurotransmitter systems involved in motor control.

Changes in sleep-waking cycle after striatal excitotoxic lesions.

Huntington's disease (HD) patients show severe diurnal choreic movements, while during slow-wave sleep (SWS) abnormal movements subside. Sleep disturbances in HD, including irregular delta activity and decreases in SWS, have also been reported. Striatal excitotoxic lesions have been shown to induce increased nocturnal spontaneous locomotor activity in rodents. In order to characterize the changes in circadian activity and sleep patterns and their correlation with motor activity after striatal excitotoxic lesions, Sprague-Dawley rats were implanted and lesioned; their locomotor and EEG activities were recorded for either 4 or 24 h during baseline or 7 and 30 days post-lesion. Locomotor activity increased significantly at 7 days post-lesion during the dark phase of the light-dark cycle. In contrast, total time spent in wakefulness (W) increased at 30 days post-lesion during the light phase of the cycle. This increase was at the expense of SWS duration. No disruption of the circadian curves was observed. Increases in the number of W-bouts and decreases in the duration of SWS-bouts were also observed. These results suggest the possible participation of the striatum in the regulation of the sleep-waking cycle, independent of locomotor activity. The increase in W could be due to loss of inhibition of target structures involved in regulation of the sleep-waking cycle.

Striatal dopaminergic stimulation produces c-Fos expression in the PPT and an increase in wakefulness.

Striatal activation can modify activity in cortical areas related to specific striatal functions possibly through a process of disinhibition within the basal ganglia. Anatomical studies have shown substantial GABAergic innervation from these nuclei to the pedunculopontine tegmental nucleus (PPT). Thus, dopaminergic stimulation of the striatum could produce PPT disinhibition and result in non-specific cortical activation. To test this hypothesis, d-amphetamine was infused both into the striatum of freely moving rats for motor and electrocorticographic recordings, and into the striatum of animals under deep anesthesia for c-Fos immunohistochemistry. The results show that intrastriatal amphetamine increases wakefulness independent of motor activity, and it increases c-Fos expression in the PPT and adjacent areas. They also suggest that the striatum participates in non-specific cortical activation probably as a result of its relationship with the PPT.

Induction of c-fos in nucleus accumbens in naive male Balb/c mice after wheel running.

Immunocytochemical labeling of the transcription factor c-Fos was used to determine whether wheel running (WR) activates nucleus accumbens (NAcc) neurons in naive male Balb/c mice. The results indicate compared to novel environment exploration and forced locomotor activity, WR increases c-Fos labeling in the middle level of the core but not the shell of the NAcc. These data show that WR activates middle-core NAcc neurons more effectively than other locomotor activities. The middle core of the NAcc may be a critical region for the self-reinforcing properties of WR.

Insulin-like growth factor I partly prevents axon elimination in the neonate rat optic nerve.

Developmental neuronal death ensues after access of innervating neurons to target-derived neurotrophic factors is restricted. Recent evidence suggests, however, that growth factors such as those of the insulin family modulate neuronal death through autocrine/paracrine mechanisms. In rats, retinal ganglion neurons (RGNs) undergo massive death during early postnatal life. During this same period, the expression of various members of the insulin-like growth factor I (IGF-I) protein family is down regulated. To evaluate whether ocular IGF-I might modulate RGN death, we administered IGF-I in the posterior chamber of the eye of newborn rats. Optic nerve fiber number was estimated in control and IGF-I treated animals at postnatal day 5 when RGN death peaks. Intraocular IGF-I treatment at birth partly prevented optic nerve fiber elimination. Because the axon number in the optic nerve correlates to some extent with the RGN number, these results suggest that IGF-I may modulate RGN death in vivo through local interactions.