Endogenous opioid peptides contribute to associative LTP in the hippocampal CA3 region

The medial and lateral perforant path projections to the hippocampal CA3 region display distinct mechanisms of long-term potentiation (LTP) induction, N-methyl-d-aspartate (NMDA) and opioid receptor dependent, respectively. However, medial and lateral perforant path projections to the CA3 region display associative LTP with coactivation, suggesting that while they differ in receptors involved in LTP induction they may share common downstream mechanisms of LTP induction. Here we address this interaction of LTP induction mechanisms by evaluating the contribution of opioid receptors to the induction of associative LTP among the medial and lateral perforant path projections to the CA3 region in vivo. Local application of the opioid receptor antagonists naloxone or Cys2-Tyr3-Orn5-Pen7-amide (CTOP) normally block induction of lateral perforant path-CA3 LTP. However, these opioid receptor antagonists failed to block associative LTP in lateral perforant path-CA3 synapses when it was induced by strong coactivation of the medial perforant pathway which displays NMDAR-dependent LTP. Thus strong activation of non-opioidergic afferents can substitute for the opioid receptor activation required for lateral perforant path LTP induction. Conversely, medial perforant path-CA3 associative LTP was blocked by opioid receptor antagonists when induced by strong coactivation of the opioidergic lateral perforant path. These data indicate endogenous opioid peptides contribute to associative LTP at coactive synapses when induced by strong coactivation of an opioidergic afferent system. These data further suggest that associative LTP induction is regulated by the receptor mechanisms of the strongly stimulated pathway. Thus, while medial and lateral perforant path synapses differ in their mechanisms of LTP induction, associative LTP at these synapses share common downstream mechanisms of induction.     

Cholinergic dependence of taste memory formation: evidence of two distinct processes

Learning the aversive or positive consequences associated with novel taste solutions has a strong significance for an animal's survival. A lack of recognition of a taste's consequences could prevent ingestion of potential edibles or encounter death. We used conditioned taste aversion (CTA) and attenuation of neophobia (AN) to study aversive and safe taste memory formation. To determine if muscarinic receptors in the insular cortex participate differentially in both tasks, we infused the muscarinic antagonists scopolamine at distinct times before or after the presentation of a strong concentration of saccharin, followed by either an i.p. injection of a malaise-inducing agent or no injection. Our results showed that blockade of muscarinic receptors before taste presentation disrupts both learning tasks. However, the same treatment after the taste prevents AN but not CTA. These results clearly demonstrate that cortical cholinergic activity participates in the acquisition of both safe and aversive memory formation, and that cortical muscarinic receptors seem to be necessary for safe but not for aversive taste memory consolidation. These results suggest that the taste memory trace is processed in the insular cortex simultaneously by at least two independent mechanisms, and that their interaction would determine the degree of aversion or preference learned to a novel taste.     

Depression in early adolescence: Contributions from relational aggression and variation in the oxytocin receptor gene

Interpersonal stress arising from relational aggression (RA)—the intentional effort to harm others via rejection and exclusion—may increase risk for depression in youth. Biological vulnerabilities related to the hormone oxytocin, which affects social behavior and stress responses, may exacerbate this risk. In a community sample of 307 youth (52% female; age range = 10–14 years), we tested whether (1) the association between RA and subsequent depressive symptoms was mediated through social problems and (2) a single nucleotide polymorphism (rs53576) in the oxytocin receptor gene (OXTR) moderated this indirect association between RA and depression, where GG homozygotes are predicted to be more sensitive to the effects of social problems than A‐allele carriers. Youth‐reported RA and depressive symptoms were measured using a structured interview and a questionnaire, respectively. DNA was extracted from saliva collected with Oragene kits. Consistent with the interpersonal theory of depression, the association between relational aggression and subsequent depressive symptoms was mediated by social problems. This indirect effect was further moderated by rs53576 genotype, such that GG homozygotes showed a stronger mediation effect than A‐carriers. These results suggest that rs53576 variants confer vulnerability for depression within the context of interpersonal risk factors, such that youth with the GG genotype may be particularly sensitive to the social consequences resulting from RA.

     

Inhibition of aggression by progesterone and its metabolites in female Syrian hamsters

The sequence of estradiol and progesterone is known to inhibit the expression of aggression in female hamsters. Despite the key importance of progesterone in the inhibition of aggression, little is known of the mechanisms through which progesterone may exert this effect. Three experiments were performed to assess the degree to which metabolites of progesterone can affect aggression in female Syrian hamsters. Systemic estradiol treatment followed by injections of either progesterone (300 μg IP) or 4‐pregnen‐21‐ol‐3,20‐dione (DOC, 300 μg IP) reliably inhibited aggression. Systemic injection (75, 150, or 300 μg IP) of either 5α‐pregnan‐3α,21‐diol‐20‐one (THDOC) or 5α‐pregnan‐3α‐ol‐20‐one (3α,5α‐THP) did not affect aggression. Intracerebroventricular infusion of 3α,5α‐THP following systemic estradiol treatment also did not affect aggression. In a third experiment, female hamsters were given systemic treatments with estradiol and progesterone that were subthreshold with respect to inhibition of aggression. In these females, intracerebroventricular infusion of THDOC inhibited aggression. These results indicate that metabolites of progesterone can inhibit aggression, most notably in synergy with progesterone itself. Aggr. Behav. 27:372–381, 2001. © 2001 Wiley‐Liss, Inc.     

中枢白细胞介素-1在应激升压反应中的作用

分别在乌拉坦麻醉及清醒的雄性SD大鼠观察到：(1)脑室注射IL-113出现升压效应,(2)条件恐惧应激刺激、足电击及脑室注射IL-1β诱发的升压反应均被脑室注射0．5pg的白细胞介素-1拮抗剂IL-1ra明显衰减;(3)静脉注射0．5μgIL-1ra对足电击引起的升压反应无明显影响。以上结果提示中枢IL-1介导条件恐惧应激刺激、及足电击诱发的升压反应。     

Tuning the engine of cognition: a focus on NMDA/D1 receptor interactions in prefrontal cortex

The prefrontal cortex of the primate frontal lobes provides the capacity for judgment which can constantly adapt behavior in order to optimize its outcome. Adjudicating between long-term memory programs and prepotent responses, this capacity reviews all incoming information and provides an interpretation dependent on the events that have just occurred, the events that are predicted to happen, and the alternative response strategies that are available in the given situation. It has been theorized that this function requires two essential integrated components, a central executive which guides selective attention based on mechanisms of associative memory, as well as the second component, working memory buffers, in which information is held online, abstracted, and translated on a mental sketchpad of work in progress. In this review, we critically outline the evidence that the integration of these processes and, in particular, the induction and maintenance of persistent activity in prefrontal cortex and related networks, is dependent upon the interaction of dopamine D1 and glutamate NMDA receptor signaling at critical nodes within local circuits and distributed networks. We argue that this interaction is not only essential for representational memory, but also core to mechanisms of neuroadaptation and learning. Understanding its functional significance promises to reveal major new insights into prefrontal dysfunction in schizophrenia and, hence, to target a new generation of drugs designed to ameliorate the debilitating working memory deficits in this disorder.     

THE EFFECTS OF RESPONSE INTERRUPTION AND REDIRECTION AND SERTRALINE ON VOCAL STEREOTYPY

Although response interruption and redirection (RIRD) has been shown to be successful in reducing vocal stereotypy, recent reports have suggested that selective serotonin reuptake inhibitors (SSRIs) may also reduce these behaviors. The purpose of the current investigation was to examine the effects of RIRD with and without sertraline on automatically maintained vocal stereotypy of a 4‐year‐old boy with autism. Results suggested that vocal stereotypy decreased when RIRD was implemented and that sertraline did not affect the participant's vocal stereotypy.     

Dopamine and serotonin systems modify environmental effects on human behavior: A review

The relative influences of genetic and environmental factors in the development of human behavior have been a long‐term topic for an intense debate. Recent behavioral genetic studies suggest focusing on the joint effect of genes and environment, and especially on the life‐course developmental interplay between nature and nurture. Vulnerability to environmental adversities and sensitivity to its benefits may be conditional on genetic background, and regarding psychological outcomes, these kinds of gene × environment interactions may be of higher importance than direct gene–trait associations. In our recent series of studies, we have shown that different variants of serotonergic and dopaminergic genes may moderate the influence of environmental conditions on a range of psychological outcomes, i.e. temperament, depression, hostility, and educational attainment. These studies suggest that depending on their genotype, people may be differentially sensitive to the environmental conditions they encounter. In the light of these results it seems highly plausible that the effects of genes may become evident only when studied in the context of environmental factors.     

Activation of nociceptin opioid peptide (NOP) receptor impairs contextual fear learning in mice through glutamatergic mechanisms

The present study investigated whether the selective nociceptin opioid peptide (NOP) receptor agonist, Ro64-6198, impairs acquisition of fear conditioning through glutamatergic mechanisms. Systemic administration of Ro64-6198 (0.3 and 1 mg/kg) or the non-competitive NMDA receptor antagonist, MK-801 (0.03 and 0.1 mg/kg) prior to conditioning severely impaired contextual but not cued fear learning in C57BL/6N mice. When administered together at sub-effective doses, Ro64-6198 (0.5 mg/kg) and MK-801 (0.05 mg/kg), synergistically impaired contextual fear learning, but left cued fear learning intact. We next used the immediate shock deficit paradigm (ISD) to examine the effects of Ro64-6198 and MK-801 on contextual memory formation in the absence of the foot-shock. As expected, naive mice that were shocked briefly after being placed in the training chamber displayed no contextual fear conditioning. This learning deficit was elevated by prior exposure of mice to the training context. Furthermore, administration of Ro64-6198 and MK-801, either separately at amnesic doses (1 mg/kg and 0.1 mg/kg, respectively) or concomitantly at sub-effective doses (0.5 mg/kg and 0.05 mg/kg, respectively) significantly reduced the facilitating effects of context preexposure. These findings demonstrate the existence of functional antagonism between NOP and NMDA receptors that predominantly contributes to modulation of conditioned fear learning which involves spatial-processing demands.     

Interspecific aggression and reactivity in rats: Effects of selective raphe lesions and additional olfactory bulb ablation

Large depletion of brain 5 HT has been shown to induce mouse-killing behavior in the rat. Selective lesions of the raphe nuclei have been investigated in order to determine whether the various components of the 5 HT system exert some specific control over this aggressive behavior. Electrolytic lesions of the dorsal or the median raphe nucleus do not induce mouse killing, whereas combined lesions of these nuclei elicit this behavior in about 40% of naive rats. Consequently, it appears that serotonergic neurons originating in the dorsal and median raphe nuclei work synergistically in mediating inhibitory control over mouse-killing behavior. Loco-motor activity is increased in novel environments by each of the selective lesions and to a larger extent by combined raphe lesions; 24 hours activity in resting conditions is unchanged during the light period, and increased during the dark period of the daily cycle by the various lesions. As it has been shown previously that hyper-activity in response to novelty following raphe lesions is not directly related to the 5 HT decrease in the brain, it appears that interspecific aggression and motor responsiveness must not be dependent on the same neural substrate within the raphe nuclei. The raphe lesions do not facilitate the elicitation of mouse killing by further olfactory bulb ablations, in contrast to earlier results where bulbectomy facilitated the induction of this behavior by raphe lesions.