Interleukin-18 levels in the hippocampus and behavior of adult rat offspring exposed to prenatal restraint stress during early and late pregnancy

Exposure to maternal stress during prenatal life is associated with an increased risk of neuropsychiatric disorders, such as depression and anxiety, in offspring. It has also been increasingly observed that prenatal stress alters the phenotype of offspring via immunological mechanisms and that immunological dysfunction, such as elevated interleukin-18 levels, has been reported in cultures of microglia. Prenatal restraint stress(PRS) in rats permits direct experimental investigation of the link between prenatal stress and adverse outcomes. However, the majority of studies have focused on the consequences of PRS delivered in the second half of pregnancy, while the effects of early prenatal stress have rarely been examined. Therefore, pregnant rats were subjected to PRS during early/middle and late gestation(days 8–14 and 15–21, respectively). PRS comprised restraint in a round plastic transparent cylinder under bright light(6500 lx) three times per day for 45 minutes. Differences in interleukin-18 expression in the hippocampus and in behavior were compared between offspring rats and control rats on postnatal day 75. We found that adult male offspring exposed to PRS during their late prenatal periods had higher levels of anxiety-related behavior and depression than control rats, and both male and female offspring exhibited higher levels of depression-related behavior, impaired recognition memory and diminished exploration of novel objects. Moreover, an elevated level of interleukin-18 was observed in the dorsal and ventral hippocampus of male and female early-and late-PRS offspring rats. The results indicate that PRS can cause anxiety and depression-related behaviors in adult offspring and affect the expression of interleukin-18 in the hippocampus. Thus, behavior and the molecular biology of the brain are affected by the timing of PRS exposure and the sex of the offspring. All experiments were approved by the Animal Experimentation Ethics Committee at Kunming Medical University, China(approval No. KMMU2019074) in January 2019.

Brain regional changes of guanine nucleotide binding protein-inhabitant 2 in acute and chronic morphine-tolerant and-dependent rats

BACKGROUND： Drug addiction involves two main central nervous systems, namely the dopamine and noradrenaline systems. These systems are primarily distributed in five brain regions： the ventral tegmental area, the nucleus accumbens, the prefrontal cortex, the hippocampus, and the locus coeruleus. OBJECTIVE： To investigate regional changes of guanine nucleotide binding protein-inhabitant 2 （Gi2） in dopaminergic and noradrenergic neurons in brains of morphine-tolerant and -dependent rats. DESIGN, TIME, AND SETTING： A randomized control study was performed at the Department of Neurobiology in the Second Military Medical University of Chinese PLA （Shanghai, China） between September 2002 and March 2004. MATERIALS： Thirty-six, healthy, male, Sprague-Dawley （SD） rats were used to establish morphine-dependent models. Morphine hydrochloride was a product of Shenyang First Pharmaceutical Factory （China）; naloxone hydrochloride was a product of Beijing Four-Ring Pharmaceutical Factory （China）; and α subunit of Gi2 antibody was offered by Santa Cruz Biotechnology, lnc （USA）. METHODS： Thirty-six SD rats were randomly divided into six groups （n = 6）： （1） acute morphine-dependent group, （2） acute abstinent group, （3） acute control group, （4） chronic morphine-dependent group, （5） chronic abstinent group, and （6） chronic control group. Rats in the acute morphine-dependent and the acute groups were injected with morphine （5 mg/kg）, one injection every two hours, for a total of eight injections. In the acute and chronic morphine-dependent rat models, morphine withdrawal syndrome was precipitated by an injection of naloxone （5 mg/kg）. Rats in the acute control group were given a peritoneal injection of physiological saline at the same administration time as the above two groups. Rats in the chronic morphine-dependent and chronic abstinent groups were injected with morphine three times per day. The administration dose on day 1 was initially 5 mg/kg at 20：00, which increased by 5 mg/kg at 8：00, 12：00, and 20：00 until day 7. On day 13, the dose continuously increased by 10 mg/kg until a chronic morphine-dependent rat model was successfully induced. Afterwards, the rats presented with withdrawal syndromes on naloxone （5 mg/kg） at 8：00 on the same day. Rats in the chronic control group were injected with physiological saline at the same time of the two chronic groups. MAIN OUTCOME MEASURES： The concentration of Gi2 protein in the five brain regions （ventral tegmental area, nucleus accumbens, prefrontal cortex, locus coeruleus, and hippocampus） was detected by immunohistochemistry. RESULTS： In the acute morphine-dependent and acute abstinent groups, Gi2 protein concentration was significantly decreased in the nucleus accumbens, compared to the acute control group （P 〈 0.01）, while no obvious changes were detected in other brain regions. In the chronic morphine-dependent and chronic abstinent groups, Gi2 protein concentration was significantly decreased in the nucleus accumbens, but significantly increased in the locus coeruleus （P 〈 0.01 ） compared to the chronic control group. CONCLUSION： Morphine dependence and tolerance may induce obvious reductions of Gi2 protein levels in the nucleus accumbens of rats. Chronic morphine dependence desensitizes the homologous neurons.

Memory Trace for Fear Extinction:Fragile yet Reinforceable

Fear extinction is a biological process in which learned fear behavior diminishes without anticipated reinforcement,allowing the organism to re-adapt to ever-changing situations.Based on the behavioral hypothesis that extinction is new learning and forms an extinction memory,this new memory is more readily forgettable than the original fear memory.The brain’s cellular and synaptic traces underpinning this inherently fragile yet reinforceable extinction memory remain unclear.Intriguing questions are about the whereabouts of the engram neurons that emerged during extinction learning and how they constitute a dynamically evolving functional construct that works in concert to store and express the extinction memory.In this review,we discuss recent advances in the engram circuits and their neural connectivity plasticity for fear extinction,aiming to establish a conceptual framework for understanding the dynamic competition between fear and extinction memories in adaptive control of conditioned fear responses.