Acan downregulation in parvalbumin GABAergic cells reduces spontaneous recovery of fear memories.

While persistence of fear memories is essential for survival, a failure to inhibit fear in response to harmless stimuli is a feature of anxiety disorders. Extinction training only temporarily suppresses fear memory recovery in adults, but it is highly effective in juvenile rodents. Maturation of GABAergic circuits, in particular of parvalbumin-positive (PV+) cells, restricts plasticity in the adult brain, thus reducing PV+ cell maturation could promote the suppression of fear memories following extinction training in adults. Epigenetic modifications such as histone acetylation control gene accessibility for transcription and help couple synaptic activity to changes in gene expression. Histone deacetylase 2 (Hdac2), in particular, restrains both structural and functional synaptic plasticity. However, whether and how Hdac2 controls the maturation of postnatal PV+ cells is not well understood. Here, we show that PV+- cell specific Hdac2 deletion limits spontaneous fear memory recovery in adult mice, while enhancing PV+ cell bouton remodeling and reducing perineuronal net aggregation around PV+ cells in prefrontal cortex and basolateral amygdala. Prefrontal cortex PV+ cells lacking Hdac2, show reduced expression of Acan, a critical perineuronal net component, which is rescued by Hdac2 re-expression. Pharmacological inhibition of Hdac2 before extinction training is sufficient to reduce both spontaneous fear memory recovery and Acan expression in wild-type adult mice, while these effects are occluded in PV+-cell specific Hdac2 conditional knockout mice. Finally, a brief knock-down of Acan expression mediated by intravenous siRNA delivery before extinction training but after fear memory acquisition is sufficient to reduce spontaneous fear recovery in wild-type mice. Altogether, these data suggest that controlled manipulation of PV+ cells by targeting Hdac2 activity, or the expression of its downstream effector Acan, promotes the long-term efficacy of extinction training in adults.

The Effects of Exercise on Pain and Reproductive Performance in Female Pregnant Mice With Neuropathic Pain.

Pain can have negative, physiological and psychological impacts on pregnancy. Pregnant women are fearful of using pain medication because of teratogenic effects. In this study, we evaluated whether exercise could lower pain sensitivity in pregnant mice with neuropathic pain and reduce the negative effects of maternal pain on newborns. We randomly assigned 32 female mice to one of four groups (eight mice/group): Sham surgery with standard environment (SE) or enriched environment (EE) or spare nerve injury (SNI) with SE or EE. Mice in EE groups had access to an exercise wheel. Mothers were evaluated for mechanical sensitivity with Von Frey filaments and for exercise performance with computerized running wheels. Mice were impregnated 2 weeks after the initiation of EE. Pups were weighed and measured for length at birth and evaluated for negative geotaxis, righting, forelimb grasping, rooting, and crawling at 3 days postpartum and for crawling at 6 days postpartum. Following euthanasia, mothers' frontal cortexes were analyzed for selected neuropeptides. After exercise exposure, only SNI-SE females remained neuropathic. Exercise levels were similar between EE groups. Some brain neuropeptides (endorphins, enkephalins, and oxytocin) from SNI females showed significant differences with exercise. Number of pups was significantly smaller in the SNI-SE group. Significantly more pups died at birth in the SNI-SE group, but pup behavior tests (except righting) were similar across groups. Exercise can reduce neuropathic pain in pregnant mice. Neuropathic pain does not impact motor neurodevelopment of mice pups but does appear to affect litter size and neonatal mortality.

Pharmacokinetics of ketamine and xylazine in young and old Sprague-Dawley rats.

To compare the pharmacokinetics of coadministered intraperitoneal ketamine and xylazine in young (8 to 10 wk; n = 6) and old rats (2 to 2.4 y; n = 6), blood samples obtained at 15 and 30 min and 1, 2, and 4 h after drug administration were analyzed by HPLC-tandem mass spectrometry. In both groups, the withdrawal reflex was absent during anesthesia and was present at 1.1 (± 0.2) and 2.6 (± 0.7) h after drug administration in young and old rats, respectively, with the first voluntary movement at 1.5 ± 0.2 and 4.9 ± 1.0 h. Drug availability of ketamine and xylazine was 6.0 and 6.7 times greater, respectively, in old than young rats. The rate constant of elimination of both drugs was greatly decreased and the elimination half-life was significantly greater in old compared with young rats. In conclusion, age and associated factors affect the availability of ketamine and xylazine when coadministered to attain clinical anesthesia, changing the pharmacokinetics of these drugs and prolonging anesthesia duration and recovery times with aging. Compared with their young counterparts, aged rats required much higher doses to attain a similar level of anesthesia. Finally, the long half-life of both ketamine and xylazine, when coadministered to old rats, may be a factor in research protocols because residual plasma concentrations could still be present for as long as 3 and 5 d, respectively, after administration.