Effects of D-cycloserine on extinction of learned fear to an olfactory cue

D-cycloserine (DCS), a partial NMDA receptor agonist, facilitates extinction of learned fear in rats and has been used to treat anxiety disorders in clinical populations. However, research into the effects of DCS on extinction is still in its infancy, with visual cues being the primary fear-eliciting stimuli under investigation. In both human and animal subjects odors have been found to associate strongly with aversive events. Therefore, this study examined the generality of the effects of DCS on extinction by testing odor cues. Sprague-Dawley rats were conditioned and extinguished to an odor using varying parameters, injected with either saline or DCS (15 mg/kg) following extinction, and then tested for a freezing response 24 h later. Experiment 1 demonstrated that after 3 odor-shock pairings, rats did not display short-term extinction and DCS had no effect on long-term extinction. Experiment 2 demonstrated that after 3 odor-noise pairings, rats displayed significant short-term extinction and DCS significantly facilitated long-term extinction. Following 2 odor-shock pairings in Experiment 3, half the rats displayed short-term extinction ("extinguishers") and half did not ("non-extinguishers"). DCS facilitated long-term extinction in the "extinguishers" condition but not in the "non-extinguishers" condition. In Experiment 4, following 2 odor-shock pairings and an extra extinction session, DCS had a significant facilitatory effect on long-term extinction. Thus, extinction of freezing to an odor cue was facilitated by systemic injections of DCS, but only when some amount of within-session extinction occurred prior to injection.     

Effects of multiple exposures to D-cycloserine on extinction of conditioned fear in rats

Previous research has shown that an acute, post-training injection of D-cycloserine (DCS) facilitates extinction of conditioned fear in rats; however, the effects of multiple exposures to DCS in this situation are not known. In Experiment 1, rats were conditioned (light-shock pairings) and 24 h later given six extinction (light-alone) trials followed by an injection of DCS (15 mg/kg) or saline. The next day, all rats were tested for light-elicited freezing. In Experiment 2, the effect of DCS on extinction was tested in the same manner, except that rats were pre-exposed to DCS (0, 1, or 5 injections) just prior to conditioning. In Experiment 3, rats received five pre-exposures of DCS but conditioning occurred either 2 or 28 days after the last pre-exposure. The results showed that DCS facilitated extinction of conditioned freezing to the light CS when no drug pre-exposure had occurred, but pre-exposure to DCS just prior to conditioning disrupted the facilitation of extinction effect. When 28 days were interposed between pre-exposure and conditioning, the facilitatory effects of DCS on extinction were restored. These findings suggest that DCS has significant clinical value but that behavioral desensitization may occur with multiple exposures; however, desensitization is not permanent and is reduced by the passage of time.     

Need for speed: Evaluating slopes of OCD recovery in behavior therapy enhanced with d-cycloserine

Evidence suggests that the antibiotic d-cycloserine (DCS) enhances the treatment effects of exposure and response prevention (ERP) for Obsessive-Compulsive Disorder (OCD). Further, evidence suggests that the effects of DCS diminish partway through treatment, but it is unclear to what extent. In an effort to evaluate these issues, the current study re-analyzes data from a 10-session randomized controlled trial of ERP + DCS versus ERP + placebo in a sample of 22 adults with OCD. We analyzed repeated-measures mixed models with random slopes and intercepts across different intervals: sessions 1-10, 1-5, and 6-10. The results indicate that the course of ERP was 2.3 times faster over the full 10 sessions for the DCS compared to the placebo group, and nearly six times quicker in the first half of ERP. Further interpretation of the results suggests that DCS does not amplify the effects of ERP, but instead initiates treatment effects sooner in treatment. In addition, DCS does not necessarily lose its effect over repeated use, but instead may exhaust its maximum utility after effectively jump-starting ERP. Ultimately, DCS may provide a means for curtailing treatment costs, decreasing treatment dropout and refusal rates, and enhancing access to care.     

An example of formalizing recent mathematical results in Mizar

This paper describes an example of the successful formalization of quite advanced and new mathematics using the Mizar system. It shows that although much effort is required to formalize nontrivial facts in a formal computer deduction system, still it is possible to obtain the level of full logical correctness of all inference steps. We also discuss some problems encountered during the formalization, and try to point out some of the features of the Mizar system responsible for that. The formalization described in this paper allows also for contrasting the linguistic capability of the Mizar language and some of the phrases commonly used in “informal” mathematical papers that the Mizar system lacks, and consequently presents the methods of how to cope with it during the formalization. Yet, apart from the problems, this paper shows some definite benefits from using a formal computer system in the work of a mathematician.     

The expression of c-Fos and colocalisation of c-Fos and glucocorticoid receptors in brain structures of low and high anxiety rats subjected to extinction trials and re-learning of a conditioned fear response

We designed an animal model to examine the mechanisms of differences in individual responses to aversive stimuli. We used the rat freezing response in the context fear test as a discriminating variable: low responders (LR) were defined as rats with a duration of freezing response one standard error or more below the mean value, and high responders (HR) were defined as rats with a duration of freezing response one standard error or more above the mean value. We sought to determine the colocalisation of c-Fos and glucocorticoid receptors-immunoreactivity (GR-ir) in HR and LR rats subjected to conditioned fear training, two extinction sessions and re-learning of a conditioned fear. We found that HR animals showed a marked decrease in conditioned fear in the course of two extinction sessions (16 days) in comparison with the control and LR groups. The LR group exhibited higher activity in the cortical M2 and prelimbic areas (c-Fos) and had an increased number of cells co-expressing c-Fos and GR-ir in the M2 and medial orbital cortex after re-learning a contextual fear. HR rats showed increased expression of c-Fos, GR-ir and c-Fos/GR-ir colocalised neurons in the basolateral amygdala and enhanced c-Fos and GR-ir in the dentate gyrus (DG) in comparison with LR animals. Our data indicate that recovery of a context-related behaviour upon re-learning of contextual fear is accompanied in HR animals by a selective increase in c-Fos expression and GRs-ir in the DG area of the hippocampus.