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Highlights • Generalization of contextual fear memory is used as a mouse model of PTSD. • An incubation time of 4 weeks leads to fear memory generalization. • This process was not affected by gender or neuropeptide S receptor deficiency. • However, corticosterone plasma levels were increased after incubation time. • This increase was significantly higher in neuropeptide S receptor-deficient mice. Abstract One-trial contextual fear conditioning in laboratory mice results in a fear memory which is relatively specific to the original conditioning context shortly after conditioning but becomes more unspecific after an incubation time of one month. This process is called generalization of fear memory and is used to investigate processes which might be involved in the pathogenesis of post-traumatic stress disorder. In the present study, we investigated the effects of sex and neuropeptide S receptor (NPSR) deficiency in one-trial contextual fear conditioning. In addition to contextual fear, we also measured startle reactivity, anxiety and corticosterone plasma levels of the mice. Our data show main effects of sex and NPSR-deficiency on freezing behavior, startle magnitude, and anxiety levels. However, generalization of contextual fear memory after incubation time was not affected by sex. Notably, NPSR-deficient mice had a more specific fear memory shortly after conditioning than their wildtype littermates but after incubation time, all genotypes had a generalized fear memory. The present data further show that plasma corticosterone levels are increased after incubation time. This increase was significantly more pronounced in NPSR-deficient mice. Taken together, our study confirms the suitability of one-trial contextual fear conditioning to study the effects of incubation time on fear memory generalization but also indicates the need for control groups without incubation. We further demonstrate that the increase of plasma corticosterone levels after incubation time is exaggerated in NPSR-deficient mice. The latter finding suggests an important role of the NPS system in the regulation of corticosterone release. [ABSTRACT FROM AUTHOR]

Cognitive flexibility refers to the ability to modify learned behavior in response to changes in the environment. In laboratory rodents, cognitive flexibility can be assessed in reversal learning, i.e., the change of contingencies, for example in T-maze discrimination learning. The present study investigated the role of the neuropeptide S (NPS) system in cognitive flexibility. In the first experiment, mice deficient of NPS receptors (NPSR) were tested in T-maze discrimination and reversal learning. In the second experiment, C57BL/6J mice were tested in the T-maze after nasal administration of NPS. Finally, the effect of nasal NPS on locomotor activity was evaluated. NPSR deficiency positively affected the acquisition of T-maze discrimination but had no effects on reversal learning. Nasal NPS administration facilitated reversal learning and supported an allocentric learning strategy without affecting acquisition of the task or locomotor activity. Taken together, the present data show that the NPS system is able to modulate both acquisition of T-maze discrimination and its reversal learning. However, NPSR deficiency only improved discrimination learning, while nasal NPS administration only improved reversal learning, i.e., cognitive flexibility. These effects, which at first glance appear to be contradictory, could be due to the different roles of the NPS system in the brain regions that are important for learning and cognitive flexibility. [ABSTRACT FROM AUTHOR]

Sex difference has been reported in several behavioral endophenotypes of neuropsychiatric disorder in both rodents and humans. However, sex difference in cognitive symptoms associated with neuropsychiatric disorders has not been studied in detail. In this study, we induced cognitive impairment using the NMDA receptor antagonist, dizocilpine (MK-801), in male and female C57BL/6 J mice and performed a visual discrimination task in an automated touchscreen system. We found that discrimination performance decreased with increased doses of MK-801 in both sexes. However, female mice showed stronger deficit in discrimination performance than the male mice especially after administration of low (0.01 mg/kg) and high (0.15 mg/kg) doses of MK-801. Furthermore, we tested if administration of orexin A, orexin-1 receptor antagonist SB-334867 or orexin-2 receptor antagonist EMPA rescued MK-801 (0.15 mg/kg) induced cognitive impairment in visual discrimination. We found that nasal administration of orexin A partially rescued the cognitive impairment induced by MK-801 in females but not in males. Taken together, our data show that female C57BL/6 J mice are more sensitive compared to males to some doses of MK-801 in discrimination learning task and that orexin A partially rescues this cognitive impairment in females. [ABSTRACT FROM AUTHOR]