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1.
Fear is maladaptive when it persists long after circumstances have become safe. It is therefore crucial to develop an approach that persistently prevents the return of fear. Pavlovian fear-conditioning paradigms are commonly employed to create a controlled, novel fear association in the laboratory. After pairing an innocuous stimulus (conditioned stimulus, CS) with an aversive outcome (unconditioned stimulus, US) we can elicit a fear response (conditioned response, or CR) by presenting just the stimulus alone1,2 . Once fear is acquired, it can be diminished using extinction training, whereby the conditioned stimulus is repeatedly presented without the aversive outcome until fear is no longer expressed3. This inhibitory learning creates a new, safe representation for the CS, which competes for expression with the original fear memory4. Although extinction is effective at inhibiting fear, it is not permanent. Fear can spontaneously recover with the passage of time. Exposure to stress or returning to the context of initial learning can also cause fear to resurface3,4.Our protocol addresses the transient nature of extinction by targeting the reconsolidation window to modify emotional memory in a more permanent manner. Ample evidence suggests that reactivating a consolidated memory returns it to a labile state, during which the memory is again susceptible to interference5-9. This window of opportunity appears to open shortly after reactivation and close approximately 6hrs later5,11,16, although this may vary depending on the strength and age of the memory15. By allowing new information to incorporate into the original memory trace, this memory may be updated as it reconsolidates10,11. Studies involving non-human animals have successfully blocked the expression of fear memory by introducing pharmacological manipulations within the reconsolidation window, however, most agents used are either toxic to humans or show equivocal effects when used in human studies12-14. Our protocol addresses these challenges by offering an effective, yet non-invasive, behavioral manipulation that is safe for humans.By prompting fear memory retrieval prior to extinction, we essentially trigger the reconsolidation process, allowing new safety information (i.e., extinction) to be incorporated while the fear memory is still susceptible to interference. A recent study employing this behavioral manipulation in rats has successfully blocked fear memory using these temporal parameters11. Additional studies in humans have demonstrated that introducing new information after the retrieval of previously consolidated motor16, episodic17, or declarative18 memories leads to interference with the original memory trace14. We outline below a novel protocol used to block fear recovery in humans.  相似文献   

2.
Green MD  Jiang X  King CD 《Life sciences》2004,75(8):947-953
Characterization of new chemical entities for their potential to produce drug-drug interactions is an important aspect of early drug discovery screening. In the present study, the potential for three metabotropic glutamate receptor antagonists to interact with recombinant human CYPs was investigated. 2-Methyl-6-(phenylethenyl) pyridine (SIB-1893), 2-methyl-6-(phenylethynyl) pyridine (MPEP) and 3-[2-methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP) were moderate competitive inhibitors of recombinant human CYP1A2 (Ki, 0.5-1 microM). SIB-1893, but not MPEP or MTEP, was also a moderate competitive inhibitor of CYP1B1. MPEP and MTEP were weak inhibitors of CYP2C19. None of the three compounds tested were significant inhibitors (IC(50) values >50 microM) of CYP3A4, 2C9, 2D6, 2A6, 2B6 or 2E1. The results suggest that MTEP is a selective inhibitor of CYP1A2 and may prove to be a useful tool in studying drug-drug interactions involving this enzyme.  相似文献   

3.
One of the hypotheses about the pathogenesis of posttraumatic stress disorder (PTSD) is the dysfunction of serotonin (5-HT) neurotransmission. While certain 5-HT receptor subtypes are likely critical for the symptoms of PTSD, few studies have examined the role of 5-HT3 receptor in the development of PTSD, even though 5-HT3 receptor is critical for contextual fear extinction and anxiety-like behavior. Therefore, we hypothesized that stimulation of 5-HT3 receptor in the dorsal hippocampus (DH) could prevent hippocampal autophagy and the development of PTSD-like behavior in animals. To this end, we infused SR57227, selective 5-HT3 agonist, into the DH after a single prolonged stress (SPS) treatment in rats. Three weeks later, we evaluated the effects of this pharmacological treatment on anxiety-related behaviors and extinction of contextual fear memory. We also accessed hippocampal autophagy and the expression of 5-HT3A subunit, Beclin-1, LC3-I, and LC3-II in the DH. We found that SPS treatment did not alter anxiety-related behaviors but prolonged the extinction of contextual fear memory, and such a behavioral phenomenon was correlated with increased hippocampal autophagy, decreased 5-HT3A expression, and increased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. Furthermore, intraDH infusions of SR57227 dose-dependently promoted the extinction of contextual fear memory, prevented hippocampal autophagy, and decreased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. These results indicated that 5-HT3 receptor in the hippocampus may play a critical role in the pathogenesis of hippocampal autophagy, and is likely involved in the pathophysiology of PTSD.  相似文献   

4.
Laboratory and in situ experiments were performed in order to evaluate the role of UV radiation on bacterial activity. Particular attention was given to the determination of the role of UV-A and photosynthetic active radiation (PAR) and different nutrient conditions on the recovery of bacterial activity. Laboratory experiments with nearly natural radiation intensities indicated a 20 to 40% reduction from the initial level of bacterial activity after UV-B exposure for 2 to 4 h. Bacterial activity in freshly collected seawater showed a more pronounced inhibition and faster recovery than bacterial activity in aged, nutrient-depleted seawater. The results of in situ experiments with filtered water (0.8-(mu)m-pore-size filter) and natural surface solar radiation levels agreed with those of the laboratory experiments and revealed that UV-A and PAR are important for the recovery of bacterial activity and result in levels of bacterial activity that are higher than those prior to exposure to full solar radiation. Bacterioplankton exposed to full solar radiation for 3 h and subsequently incubated at different depths within the upper mixed water column showed an increase in bacterial activity with increased depth; the highest bacterial activity was detected at depths of 5.5 to 10.5 m, where the short-wavelength UV-B was already largely attenuated, but enough long wavelength UV-A and short PAR were available to allow recovery. This elevated bacterial activity following exposure to UV-B was attributed to the photolysis of dissolved organic matter (DOM) exposed to near-surface radiation and to the rapid recovery of bacteria from UV stress once they were mixed into deeper layers of the upper mixed water column, where they efficiently utilize the photolytically cleaved DOM. It is concluded that studies on the role of UV on the carbon and energy flux through the upper layer of the ocean should take into account the highly dynamic radiation conditions.  相似文献   

5.
Extinction of conditioned fear has been extensively studied in male rodents. Recently, there have been an increasing number of studies indicating that neural mechanisms for certain behavioral tasks and response behaviors are different in females and males. Using females in research studies can represent a challenge because of the variation of gonadal hormones during their estrous cycle. This protocol describes well-established procedures that are useful in investigating the role of estrogen in fear extinction memory consolidation in female rats. Phase of the estrous cycle and exogenous estrogen administration prior to extinction training can influence extinction recall 24 hr later. The vaginal swabbing technique for estrous phase identification described here aids the examination and manipulation of naturally cycling gonadal hormones. The use of this basic rodent model may further delineate the mechanisms by which estrogen can modulate fear extinction memory in females.  相似文献   

6.
Adaptive anxiety relies on a balance between the generalization of fear acquisition and fear extinction. Research on fear (extinction) generalization has focused mostly on perceptual similarity, thereby ignoring the importance of conceptual stimulus relations in humans. The present study used a laboratory procedure to create de novo conceptual categories of arbitrary stimuli and investigated fear and extinction generalization among these stimuli. A matching-to-sample task produced two four-member categories of abstract figures. Next, a member from one category was coupled with an aversive electrical stimulation, while a member from the other category was presented alone. As expected, conditioned fear responses generalized to the other members of the first category (skin conductance and online shock-expectancy). Subsequent extinction of the conditioned member also generalized to the other members. However, extinguishing a non-conditioned member failed to reduce fear of the conditioned member itself. We conclude that fears generalize readily across conceptually related stimuli, but that the degree of extinction generalization depends on the stimulus subjected to extinction.  相似文献   

7.
Recovery of somatomedin activity from plasma fractions was increased approximately 5-fold by prolonged extraction of isolates with formic acid. Extraction for 72 hours enhanced the yields of active peptides in the 6,000, 8,000 and >20,000 dalton range. Yields of smaller peptides were similar following short (2 hrs) and long (72 hrs) extraction periods. Active fractions obtained after prolonged extraction possessed sulfation activity and insulin-receptor affinity comparable to somatomedin isolated during short extraction with formic acid.  相似文献   

8.
Structure-activity relationship investigations of the thiopyrimidine (1), an HTS hit with micromolar activity as a metabotropic glutamate receptor 5 (mGluR5) antagonist, led to compounds with sub-micromolar activity.  相似文献   

9.
Inductive expression of early growth response 1 (Egr-1) in neurons is associated with many forms of neuronal activity. However, only a few Egr-1 target genes are known in the brain. The results of this study demonstrate that Egr-1 knockout (KO) mice display impaired contextual extinction learning and normal fear acquisition relative to wild-type (WT) control animals. Genome-wide microarray experiments revealed 368 differentially expressed genes in the hippocampus of Egr-1 WT exposed to different phases of a fear conditioning paradigm compared to gene expression profiles in the hippocampus of KO mice. Some of genes, such as serotonin receptor 2C (Htr2c), neuropeptide B (Npb), neuronal PAS domain protein 4 (Npas4), NPY receptor Y1 (Npy1r), fatty acid binding protein 7 (Fabp7), and neuropeptide Y (Npy) are known to regulate processing of fearful memories, and promoter analyses demonstrated that several of these genes contained Egr-1 binding sites. This study provides a useful list of potential Egr-1 target genes which may be regulated during fear memory processing.  相似文献   

10.
Metabotropic glutamate receptors 5 (mGluR5) are members of the growing group C G protein-coupled receptor family. Widely expressed in mammalian brain, they are involved in modulation of the glutamate transmission. By means of transfection of mGluR5 receptors in COS-7 cells and primary hippocampal neurons in culture followed by immunocytochemistry and quantitative image analysis and by a biochemical assay, we have studied the internalization of mGluR5 splice variants. mGluR5a and -5b were endocytosed in COS-7 cells as well as in axons and dendrites of cultured neurons. Endocytosis occurred even in the absence of receptor activity, because receptors mutated in the glutamate binding site were still internalized as well as receptors in which endogenous activity had been inhibited by an inverse agonist. We have measured a constitutive rate of endocytosis of 11.7%/min for mGluR5a. We report for the first time the endocytosis pathway of mGluR5. Internalization of mGluR5 is not mediated by clathrin-coated pits. Indeed, inhibition of this pathway by Eps15 dominant negative mutants did not disturb their endocytosis. However, the large GTPase dynamin 2 is implicated in the endocytosis of mGluR5 in COS-7. mGluR5 is the first shown member of the group C G-protein coupled receptor family internalized by a nonconventional pathway.  相似文献   

11.
5-Fluoroindole (5FI) was more inhibitory than 5-fluorotryptophan (5FT) to Coprinus cinereus. A mutant blocked in the conversion of indole to tryptophan, but not one blocked earlier in the tryptophan pathway, was resistant to 5FI. This is consistent with the hypothesis that 5FI was converted in vivo to 5FT which inhibited growth.  相似文献   

12.
Three cases of xylene poisoning occurred after prolonged inhalation of paint fumes. Analysis showed that xylene comprised more than 90% of the solvent in the paint, the total solvent comprising 34% of the paint by weight. One patient was dead on admission, while the other two recovered after at least 15 hours'' loss of consciousness. Both patients had transient liver cell damage, and one temporary impairment of renal function.  相似文献   

13.
14.
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16.
Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Aβ) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding protein whose expression is lost in fragile X syndrome. Here we show that FMRP binds to the coding region of APP mRNA at a guanine-rich, G-quartet–like sequence. Stimulation of cortical synaptoneurosomes or primary neuronal cells with the metabotropic glutamate receptor agonist DHPG increased APP translation in wild-type but not fmr-1 knockout samples. APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment. Soluble Aβ40 or Aβ42 levels were significantly higher in multiple strains of fmr-1 knockout mice compared to wild-type controls. Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome.  相似文献   

17.
18.
Interrupting each long night with a prolonged period of far red radiant energy resulted in the inhibition of floral initiation in cocklebur. Irradiations inducing different relative levels of PFR from 1 to 2% to 80% had about the same effect under 4-hour photoperiods. The lower levels of PFR induced by continuous far red irradiation were not as effective as the higher levels induced by red under 8 and 12-hours photoperiods. The critical PFR level required to induce inhibition of flowering seems to increase with increasing photoperiods.  相似文献   

19.
20.
This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype identified by a functional HTS approach. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and further examples of a mode of pharmacology ‘switch’ to provide PAMs with a non-MPEP scaffold.  相似文献   

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