Formation and consolidation of memories for highly stressful (traumatic) events is a complex process that involves interplay between multiple memory systems and has implications for etiology and treatment of stress- and trauma-related disorders. Here we study effects of sleep/wake states and high intra-hippocampal corticosterone on consolidation of aversive contextual memories, as well as consolidation of association between auditory unpaired phasic background cues and fear response in rats. Animals were implanted with EEG and EMG electrodes for sleep assessment and cannulas for intra-hippocampal corticosterone application. They were familiarized to a "safe box" and then trained in a fear conditioning paradigm in a distinct "shock box" with a prominent unpaired phasic background auditory cue. Immediately after conditioning, animals received bilateral intra-hippocampal saline (1 μl) or corticosterone (10 ng in 1 μl) injection and were either allowed to sleep or were kept awake for a following two-hour consolidation period. Memory tests 24 h later revealed that the saline-injected animals that slept during consolidation had significantly stronger fear responses in the shock box compared to the safe box as well as increased fear response in response to the auditory cue. Lack of sleep during the consolidation period in saline injected animals led to generalization of the fear response to the safe context, while association between auditory cue and fear response was preserved. High intra-hippocampal corticosterone levels during memory consolidation led to generalization of fear response to the safe context, regardless of sleep/wake state, while enhancement of response to auditory cue was not observed. Our results show how manipulation of conditions during consolidation can lead to greatly variable memories for an aversive episode with distinct behavioral outcomes. Observed overgeneralization of fear to safe context and altered fear response to background phasic cue has implications for understanding etiology of pathological memory alternations in stress-related conditions e.g., in posttraumatic stress disorder in humans.

• MeSH
• hipokampus fyziologie   MeSH
• kortikosteron * farmakologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• paměť * fyziologie   MeSH
• spánek fyziologie   MeSH
• strach fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Schizophrenia is severe neuropsychiatric disease, which is commonly accompanied not only by positive or negative symptoms, but also by cognitive impairment. To study neuronal mechanisms underlying cognitive distortions and mechanisms underlying schizophrenia, animal pharmacological models of cognitive symptoms are commonly used. Between various cognitive impairments in schizophrenia patients, disturbed time perception has often been reported. Here, we examined temporal and spatial cognition in a modified Carousel maze task in the animal model of schizophrenia induced by non-competitive NMDA-receptor antagonists MK-801. Male Long-Evans rats (n = 18) first learned to avoid the aversive sector on a rotating arena in both dark and light intervals. We verified that during dark, rats used temporal cues, while during light they relied predominantly on spatial cues. We demonstrated that the timing strategy depends on the stable rotation speed of the arena and on the repositioning clues such as aversive stimuli. During testing (both in light and dark intervals), half of the rats received MK-801 and the control half received saline solution. We observed dose-dependent disruptions of both temporal and spatial cognition. Namely, both doses of MK-801 (0.1 and 0.12 mg/kg) significantly impaired timing strategy in the dark and increased locomotor activity. MK-801 dose 0.1 mg/kg, but not 0.12, also impaired spatial avoidance strategy in light. We found that the timing strategy is more sensitive to NMDA antagonist MK-801 than the spatial strategy. To conclude, a modified version of the Carousel maze is a useful and sensitive tool for detecting timing impairments in the MK-801 induced rodent model of schizophrenia.

• MeSH
• antagonisté excitačních aminokyselin aplikace a dávkování   farmakologie   MeSH
• bludiště - učení účinky léků   MeSH
• chování zvířat účinky léků   MeSH
• dizocilpinmaleát aplikace a dávkování   farmakologie   MeSH
• kognitivní dysfunkce chemicky indukované   patofyziologie   MeSH
• krysa rodu rattus MeSH
• modely nemocí na zvířatech MeSH
• potkani Long-Evans MeSH
• schizofrenie chemicky indukované   MeSH
• učení vyhýbat se účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Evidence from clinical and preclinical studies implicates dysfunction of N-methyl-D-aspartate receptors (NMDARs) in schizophrenia progression and symptoms. We investigated the antipsychotic effect of two neuroactive steroids in an animal model of schizophrenia induced by systemic application of MK-801. The neuroactive steroids differ in their mechanism of action at NMDARs. MS-249 is positive, while PA-Glu is a negative allosteric NMDAR modulator. We hypothesized that the positive NMDA receptor modulator would attenuate deficits caused by MK-801 co-application more effectively than PA-Glu. The rats were tested in a battery of tests assessing spontaneous locomotion, anxiety and cognition. Contrary to our expectations, PA-Glu exhibited a superior antipsychotic effect to MS-249. The performance of MS-249-treated rats in cognitive tests differed depending on the level of stress the rats were exposed to during test sessions. In particular, with the increasing severity of stress exposure, the performance of animals worsened. Our results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses. Positive NMDAR modulation can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.

• MeSH
• antipsychotika farmakologie   MeSH
• bicyklické sloučeniny heterocyklické metabolismus   MeSH
• chování zvířat účinky léků   MeSH
• dizocilpinmaleát farmakologie   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• potkani Long-Evans MeSH
• potkani Wistar MeSH
• pregnenolon metabolismus   farmakologie   MeSH
• receptory N-methyl-D-aspartátu antagonisté a inhibitory   metabolismus   MeSH
• schizofrenie farmakoterapie   metabolismus   MeSH
• steroidy farmakologie   MeSH
• test vyvýšeného křížového bludiště MeSH
• úleková reakce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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

• MeSH
• chování zvířat * MeSH
• imunohistochemie MeSH
• imunomodulace * MeSH
• interneurony metabolismus   MeSH
• krysa rodu rattus MeSH
• lipopolysacharidy imunologie   MeSH
• matka - expozice noxám MeSH
• mikroglie imunologie   metabolismus   MeSH
• mozek imunologie   metabolismus   MeSH
• parvalbuminy metabolismus   MeSH
• sexuální faktory MeSH
• sociální chování MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

We have demonstrated previously that activation of either the ETA or ETB receptor can induce acute electrographic seizures following the intrahippocampal infusion of endothelin-1 (ET-1) in immature (P12) rats. We also demonstrated that activation of the ETA receptor is associated with marked focal ischemia, while activation of the ETB receptor is not. Exploring the mechanisms underlying seizures induced by these two ET-1 receptor interactions can potentially provide insight into how focal ischemia in immature animals produces seizures and whether ischemiarelated seizures differ from seizures not associated with ischemia. To explore these seizure mechanisms we used microdialysis to determine biomarkers associated with seizures in P12 rats following the intrahippocampal infusion of two different agents: (1) ET-1, which activates both the ETA and ETB receptors and causes focal ischemia and (2) Ala-ET-1, which selectively activates only the ETB receptor and does not cause ischemia. Our results show that seizures associated with combined ETA and ETB receptor activation (and ischemia) have a different temporal distribution and microdialysis profile from seizures associated with ETB activation alone (and without ischemia). Seizures with combined activation peak within the first hour after infusion and the microdialysis profile is characterized by a significant increase in the ratio of glutamic acid to GABA. By contrast, seizures with activation of only the ETB receptor peak in the second hour after infusion and microdialysis shows a significant increase in the ratio of leukotriene B4 to prostaglandin E2. These findings suggest that ischemia-related seizures in immature animals involve an imbalance of excitation and inhibition, while non-ischemiarelated seizures involve an inflammatory process resulting from an excess of leukotrienes.

• MeSH
• endotelin-1 toxicita   MeSH
• hipokampus účinky léků   metabolismus   MeSH
• ischemie mozku chemicky indukované   metabolismus   MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• receptor endotelinu A metabolismus   MeSH
• receptor endotelinu B metabolismus   MeSH
• záchvaty chemicky indukované   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Infection during the prenatal or neonatal stages of life is considered one of the major risk factors for the development of mental diseases such as schizophrenia or autism. However, the impacts of such an immune challenge on adult behavior are still not clear. In our study, we used a model of early postnatal immune activation by the application of bacterial endotoxin lipopolysaccharide (LPS) to rat pups at a dose of 2 mg/kg from postnatal day (PD) 5 to PD 9. In adulthood, the rats were tested in a battery of tasks probing various aspects of behavior: spontaneous activity (open field test), social behavior (social interactions and female bedding exploration), anxiety (elevated plus maze), cognition (active place avoidance in Carousel) and emotional response (ultrasonic vocalization recording). Moreover, we tested sensitivity to acute challenge with MK-801, a psychotomimetic drug. Our results show that the application of LPS led to increased self-grooming in the female bedding exploration test and inadequate emotional reactions in Carousel maze displayed by ultrasonic vocalizations. However, it did not have serious consequences on exploration, locomotion, social behavior or cognition. Furthermore, exposition to MK-801 did not trigger social or cognitive deficits in the LPS-treated rats. We conclude that the emotional domain is the most sensitive to the changes induced by neonatal immune activation in rats, including a disrupted response to novel and stressful situations in early adulthood (similar to that observed in human patients suffering from schizophrenia or autism), while other aspects of tested behavior remain unaffected.

• MeSH
• antagonisté excitačních aminokyselin farmakologie   MeSH
• chování zvířat * MeSH
• dizocilpinmaleát farmakologie   MeSH
• emoce * MeSH
• infekce komplikace   psychologie   MeSH
• kognice účinky léků   MeSH
• lipopolysacharidy MeSH
• modely nemocí na zvířatech MeSH
• novorozená zvířata MeSH
• pátrací chování MeSH
• pohybová aktivita účinky léků   MeSH
• potkani Wistar MeSH
• úzkost * MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The prevention of engram interference, pattern separation, flexibility, cognitive coordination and spatial navigation are usually studied separately at the behavioral level. Impairment in executive functions is often observed in patients suffering from schizophrenia. We have designed a protocol for assessing these functions all together as behavioral separation. This protocol is based on alternated or sequential training in two tasks testing different hippocampal functions (the Morris water maze and active place avoidance), and alternated or sequential training in two similar environments of the active place avoidance task. In Experiment 1, we tested, in adult rats, whether the performance in two different spatial tasks was affected by their order in sequential learning, or by their day-to-day alternation. In Experiment 2, rats learned to solve the active place avoidance task in two environments either alternately or sequentially. We found that rats are able to acquire both tasks and to discriminate both similar contexts without obvious problems regardless of the order or the alternation. We used two groups of rats, controls and a rat model of psychosis induced by a subchronic intraperitoneal application of 0.08mg/kg of dizocilpine (MK-801), a non-competitive antagonist of NMDA receptors. Dizocilpine had no selective effect on parallel/sequential learning of tasks/contexts. However, it caused hyperlocomotion and a significant deficit in learning in the active place avoidance task regardless of the task alternation. Cognitive coordination tested by this task is probably more sensitive to dizocilpine than spatial orientation because no hyperactivity or learning impairment was observed in the Morris water maze.

• MeSH
• analýza rozptylu MeSH
• antagonisté excitačních aminokyselin toxicita   MeSH
• bludiště - učení účinky léků   MeSH
• dizocilpinmaleát toxicita   MeSH
• krysa rodu rattus MeSH
• lokomoce účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• poruchy učení chemicky indukované   patofyziologie   MeSH
• potkani Long-Evans MeSH
• reakční čas účinky léků   MeSH
• učení vyhýbat se účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH