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Autism spectrum disorders (ASD) are a group of behaviorally defined neurodevelopmental disorders characterized with three core symptom clusters: social behavior impairments, deficient communication and in creased repetitive behaviors. The etiology of the disease remains poorly understood as many factors seem to contribute to ASD phenotype. Several mutations in genes encoding synaptic proteins have been linked with aberrant social behaviors in mouse models of autism. The condition of the synapse relies not only on the expression of these proteins but also on the state of the extracellular millieu surrounding it. The extracellular matrix (ECM) regulates formation and maturation of dendritic spines, scaffolding and presentation of growth factors to newly born neurons as well as migration of neurons and axons to their designated brain regions both during development and adulthood. The aberrant expression of its components may lead to neuropathologies observed in patients diagnosed with ASD. Here we have looked at the expression of ECM components (laminin and heparan sulfate) in the brains of BTBR T+tf/J mice, the best-studied mouse model of ASD, displaying not only behavioral deficits but also neuroanatomical features resembling those of ASD patients. We found the expression markedly decreased as compared with highly-social c57BL/6J mice, which opens an entirely new field of search for molecular basis and biomarkers of their autistic-like behaviors.
INTRODUCTION: Lately, we can observe a steady increase in the number of autism spectrum disorder (ASD) diagnoses every year. ASD is often connected with empathy impairments, a phenomenon thought to be limited only to humans, yet the simplest form of empathy, emotional contagion, can be examined also in rodents. AIM(S): In our previous study we have shown that C57BL/6 mice are capable of transferring the emotional information, but Keum and colleagues (2015) reported that strain is a major factor influencing empathic fear responses. They showed that FVB mice are not capable of Observational Fear Learning. In the current study, we tested if exposure to a stressed Demonstrator in the safe environment of the home cage (providing remote information about the stressor) elicits emotional contagion in the FVB mice. METHOD(S): Between subject transfer of emotional information paradigm was used, in which mice are housed in pairs for three weeks, one of them labelled as a Demonstrator, and the other as an Observer. In the test session, the Demonstrator is subjected to a series of aversive stimuli outside of the home cage, while the Observer remains there undisturbed. Then, the Demonstrator is returned to the home cage, where it can freely interact with the Observer. The following interactions are recorded and then analysed using BehaView software. RESULTS: Here we report that FVB mice display emotional contagion in the between-subject transfer of emotional information paradigm. Observers exposed to stressed Demonstrators show increased social behaviours towards the Demonstrators. Results are similar to these obtained on C57BL/6 mice, albeit the behavioural response was slightly different. CONCLUSIONS: Confirmation of empathic abilities in the FVB strain allows for further studies of genetic influence on empathic responsivity. FVB mice lacking Fmr1 gene, encoding the fragile X mental retardation protein, are considered a strong animal model for autism spectrum disorder (ASD). FINANCIAL SUPPORT: This study was supported by NCN Sonata BIS grant no. 2015/18/E/NZ4/00600 to Ksenia Meyza.
In humans subanesthetic doses of noncompetitive NMDA receptor (NMDAR) antagonists can produce symptoms similar to those observed in schizophrenia. In rodents, systemic application of NMDAR antagonists produce hyperactivity, stereotypies and abnormal social interactions used to model certain features of schizophrenia. It was also shown that NMDAR antagonists induce the high frequency oscillations (HFO, 140–180 Hz) in the nucleus accumbens (NAc). Several neurophysiological models of schizophrenia emphasize the role of interactions between frontal cortical areas especially medial prefrontal cortex (mPFC) and NAc. The aim of this study was to examine the effects of local infusion of MK-801 (a selective NMDAR antagonist) in the mPFC on oscillatory activity recorded in the NAc. Experiments were performed on freely moving rats, bilaterally implanted with guides in the mPFC and an electrode in the right NAc. Bilateral administration of MK-801 to the mPFC produced a substantial increase in the power of HFO, which was associated with NMDAR antagonist-induced changes in locomotor activity and behavior. In another group of animals we examined the effects of local infusion of MK-801 into mPFC on c-Fos expression in NAc. Prominent c-Fos response was observed in the NAc in relation to saline and control groups. These results suggest that local administration of MK-801 to the mPFC modifi es oscillatory activity and c-Fos expression in the NAc.
The experiment was designed to examine whether the relationship between anxiety level and social behavior depends on sex in animal model of individual differences (Roman RHA/RLA rats). Hyperemotional RLA and hypoemotional RHA males and females were subjected to a set of nonsocial (OF, EPM) and social tests. Females were tested during selected phase of ovary cycle – estrus or diestrus. Social settings ranged from low aversive – Social Affiliation/Recognition Test (SART / three chamber test) through mildly stressful social interactions (SI) to highly stressful Resident-Intruder paradigm (RI – males only). Between-line differences in emotional reactivity in nonsocial situations were observed both in males and females. The character of social interactions differs between RLA and RHA and between males and females. In SART RHA males explored more than RLA, without any preference toward the social stimulus. RLA males preferred to stay in the compartment containing unknown rat, although during SI and RI they avoided contacts. Females in SART exhibited no between lines differences and displayed significant preference toward social stimulus while during SI test differences between lines were observed. In all tests the influence of ovary cycle was insignificant. Our results suggest that the relation between anxiety level and social behavior is not linear and is gender specific.
The psychogenetically selected Roman High (RHA/Verh) and Roman Low (RLA/Verh) Avoidance rats constitute a widely accepted model of diverse emotional reactivity. They show divergent stressrelated behavioral and neuronal responses when confronted with a novel and/or stressogenic environment (Meyza et al. 2009). Here, we have explored the possibility that the difference might be also refl ected in the electrical activity of prefrontal cortex (mPFC), amygdala (Amy) and hippocampus (CA1) – structures involved in generation of emotions. Spectral analysis of telemetrically recorded local fi eld potentials (LFPs) from mPFC, Amy and CA1 in freely moving rats performing behavioral tests differing with aversiveness (Open Field, Elevated Plus Maze, Hole Board test and Acute Restraint) showed that power of 4 distinct frequency bands (delta: 0–3 Hz, theta: 4–12 Hz, beta: 13–30 Hz and gamma: 31–90 Hz) is higher in the LFPs of RLA/Verh than of RHA/Verh rats, especially in the CA1 and mPFC. This difference seems to be stress-dependent (among tests measuring spontaneous behavior). Acute restraint elicited differences only in the delta and gamma bands in the mPFC. Strikingly, the difference is most clear while the animal is performing a decisive/risk assesment behavior (e.g. leaning towards aversive part of the arena). Moreover, individual differences in the power of bands can be observed at that time, thus they may be considered a neuronal correlate of individual differences in emotional reactivity.
INTRODUCTION: Social support during exposure-based psychotherapy has been suggested to have an important influence on the course of exposure treatment, however some clinical trials show that individual therapy may be more effective than group therapy. The mechanisms of social influence on fear extinction remain unknown. METHOD(S): To study neuronal correlates of social buffering in fear extinction, we have developed a rat model. In our model, rats showed a significant lowering of fear response during fear extinction when exposed to fear‑associated stimuli with a companion. The buffering magnitude depended on familiarity and physical similarity of the tested animals but not on their emotional status; the fear‑conditioned partners were as effective as naïve ones. However, the effect was transient and disappeared when rats were tested individually the next day. To test whether social buffering shares neuronal mechanisms with fear extinction, we measured activation of fear regulating neuronal circuits. Lower fear response during exposure with a partner was associated with lower activation of the infralimbic (IL), prelimbic (PL), and anterior cingulate (ACC) cortices. However, although optogenetic blocking of the IL increased fear response in rats tested separately, it left the social buffering effect intact. RESULTS: Analyzing inputs to the cortex from the ventral hippocampus (vHIPP) and basolateral amygdala (BL), we found significantly more vHIPP innervated neurons activated in the PL but not IL or ACC of the socially buffered rats. CONCLUSIONS: The results show that fear memory suppression by the presence of a companion is transient and relies, at least partially, on different neuronal circuits than fear extinction.
Ketamine, phencyclidine and MK801 are uncompetitive NMDA receptor (NMDAR) antagonists which are used widely to model certain features of schizophrenia in rats. Systemic administration of NMDAR antagonists, in addition to provoking an increase in c-Fos expression, leads to important neurochemical and electrophysiological changes within the medial prefrontal cortex (mPFC). Since the mPFC is considered to exert a top-down regulatory control of subcortical brain regions, we examined the effects of local infusion of the NMDAR antagonist, MK801, into the mPFC on the expression of c-Fos protein (widely used marker of neuronal activation) in several subcortical structures. The experiment was performed on freely moving rats, bilaterally implanted with guide cannulae in the prelimbic mPFC, infused with MK801 or saline. Bilateral administration of MK801 to the mPFC produced changes in the behavior (increased stereotypy and decreased sleep-like behavior) and complex changes in c-Fos protein expression with significant increases observed in the nucleus accumbens (core and shell), amygdala (basolateral and central nuclei), the CA1 field of the hippocampus, and mediodorsal and paraventricular thalamic nuclei, as compared to the saline group. Together, we demonstrate that blockade of NMDA receptors in the mPFC is sufficient to lead to behavioral abnormalities and increased c-Fos expression in many, but not all, of the subcortical structures examined. Our findings suggest that some of the behavioral abnormalities produced by uncompetitive NMDAR antagonists may result from aberrant activity in cortico-subcortical pathways. These data support an increasing body of literature, suggesting that the mPFC is an important site mediating the effects of NMDAR antagonists.
Matrix metalloproteinases are a major group of enzymes regulating cell-matrix composition, which are essential for many biological processes. Matrix Metalloproteinase-9 (MMP-9) has recently emerged as an important molecule in control of extracellular proteolysis in the synaptic plasticity. Using conventional transgenesis, we have created rats with overexpression of MMP-9 limited to the neurons of the hippocampus, cerebral cortex and cerebellum (MMP-9-gene is under control of neuronal, synapsin-1 promoter). A battery of behavioral tests, including Open Field and Elevated Plus Maze tests, revealed no signifi cant difference between young transgenic and control rats. However, age-related changes in expression level of MMP-9 in wild type rats led to some dysfunctions in behavior, as we noticed differences in general activity between the transgenic and wild type rats increasing with age. The old transgenic rats demonstrated higher activity and better motor functions and coordination than controls. Moreover, the level of anxiety was decreased in the old transgenic rats in comparison with their wild type siblings. Also, the old transgenic rats showed better taste memory than wild type. These results strongly suggest that MMP-9 may have an important role in control of the behavior of animals.
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