Cracking addiction the second time around: reconsolidation of drug-related memories

One of the greatest challenges in the understanding and treatment of addiction is cue-elicited relapse to drug use. The present findings of Miller and Marshall and Lee et al. reported in this issue of Neuron demonstrate that retrieved drug-related memories undergo reconsolidation and thus suggest that these maladaptive associations may be more labile than previously thought.     

Updating fearful memories with extinction training during reconsolidation: a human study using auditory aversive stimuli

Learning to fear danger in the environment is essential to survival, but dysregulation of the fear system is at the core of many anxiety disorders. As a consequence, a great interest has emerged in developing strategies for suppressing fear memories in maladaptive cases. Recent research has focused in the process of reconsolidation where memories become labile after being retrieved. In a behavioral manipulation, Schiller et al., (2010) reported that extinction training, administrated during memory reconsolidation, could erase fear responses. The implications of this study are crucial for the possible treatment of anxiety disorders without the administration of drugs. However, attempts to replicate this effect by other groups have been so far unsuccessful. We sought out to reproduce Schiller et al., (2010) findings in a different fear conditioning paradigm based on auditory aversive stimuli instead of electric shock. Following a within-subject design, participants were conditioned to two different sounds and skin conductance response (SCR) was recorded as a measure of fear. Our results demonstrated that only the conditioned stimulus that was reminded 10 minutes before extinction training did not reinstate a fear response after a reminder trial consisting of the presentation of the unconditioned stimuli. For the first time, we replicated Schiller et al., (2010) behavioral manipulation and extended it to an auditory fear conditioning paradigm.     

Molecular mechanisms of memory reconsolidation

Memory reconsolidation has been argued to be a distinct process that serves to maintain, strengthen or modify memories. Specifically, the retrieval of a previously consolidated memory has been hypothesized to induce an additional activity-dependent labile period during which the memory can be modified. Understanding the molecular mechanisms of reconsolidation could provide crucial insights into the dynamic aspects of normal mnemonic function and psychiatric disorders that are characterized by exceptionally strong and salient emotional memories.     

Disrupting the timing of Wolbachia-induced male-killing

Several lineages of maternally inherited symbionts have evolved the ability to kill infected females' sons, a phenomenon known as male-killing. Male-killing varies in its timing, from early (death during embryogenesis) to late (mortality of late larval instars). Following the observation that treatment of male-killer infected adult females Hypolimnas bolina with tetracycline, a bacteriostatic antibiotic, produces a delay in the timing of male death, we hypothesized that early male-killers possess the ability to kill males through bacterial activity outside of embryogenesis. We verified this hypothesis by showing that treatment of surviving larvae with the bacteriocidal antibiotic rifampicin rescues males. This discounted the hypothesis that delayed death occurred due to postponed effects of toxins produced at earlier stages, and thus supported the importance of bacterial activity in the larval phase in delayed male-killing. These results argue against the view that early male-killing is achieved by specifically targeting an early developmental process within the sex determination pathway.     

细菌的群体性行为与耐药

随着抗生素的广泛使用,细菌耐药已经成为一个严重的问题。细菌耐药是一个复杂的过程,涉及宿主、细菌与环境等几个既相互独立又相互作用的因素。很久以来,人们认为细菌以个体为单位进行各种活动,直到发现细菌相互之间也存在联系,才意识到细菌群体对其个体生存的重要性。目前将细菌作为一个群体来研究其耐药行为与机制的研究越来越多,特别是细菌生物膜与细菌程序性死亡两方面受到极大重视。本文综述了细菌生物膜、细菌程序性死亡与耐药相关机制的研究进展。     

Activation of PKCzeta and PKMzeta in the nucleus accumbens core is necessary for the retrieval, consolidation and reconsolidation of drug memory

One of the greatest challenges in the treatment of substance dependence is to reverse the control that drug-associated stimuli have gained over the addict's behavior, as these drug-associated memories increase the risk of relapse even after long periods of abstinence. We report here that inhibition of the atypical protein kinase C isoform PKCzeta and its constitutively active isoform PKMzeta with the pseudosubstrate inhibitor ZIP administered locally into the nucleus accumbens core reversibly inhibited the retrieval of drug-associated memory and drug (remifentanil) seeking, whereas a scrambled ZIP peptide or staurosporine, an effective inhibitor of c/nPKC-, CaMKII-, and PKA kinases that does not affect PKCzeta/PKMzeta activity, was without effect on these memory processes. Acquisition or extinction of drug-associated memory remained unaffected by PKCzeta- and PKMzeta inhibition.     

Disrupting the transmission of a vector-borne plant pathogen

Approaches to control vector-borne diseases rarely focus on the interface between vector and microbial pathogen, but strategies aimed at disrupting the interactions required for transmission may lead to reductions in disease spread. We tested if the vector transmission of the plant-pathogenic bacterium Xylella fastidiosa was affected by three groups of molecules: lectins, carbohydrates, and antibodies. Although not comprehensively characterized, it is known that X. fastidiosa adhesins bind to carbohydrates, and that these interactions are important for initial cell attachment to vectors, which is required for bacterial transmission from host to host. Lectins with affinity to substrates expected to occur on the cuticular surface of vectors colonized by X. fastidiosa, such as wheat germ agglutinin, resulted in statistically significant reductions in transmission rate, as did carbohydrates with N-acetylglucosamine residues. Presumably, lectins bound to receptors on the vector required for cell adhesion/colonization, while carbohydrate-saturated adhesins on X. fastidiosa's cell surface. Furthermore, antibodies against X. fastidiosa whole cells, gum, and afimbrial adhesins also resulted in transmission blockage. However, no treatment resulted in the complete abolishment of transmission, suggesting that this is a complex biological process. This work illustrates the potential to block the transmission of vector-borne pathogens without directly affecting either organism.     

Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory

Relapse into drug taking among addicts often depends on learned associations between drug-paired cues and the rewarding effects of these drugs, such as cocaine (COC). Memory for drug-paired cues resists extinction and contributes to the high rate of relapse; however, the molecular mechanisms underlying these associations are not understood. We show that COC-conditioned place preference (CPP) activates ERK, CREB, Elk-1, and Fos in the nucleus accumbens core (AcbC) but not shell. Intra-AcbC infusions of U0126, an inhibitor of the ERK kinase MEK, prevent both the activation of ERK, CREB, Elk-1, and Fos and retrieval of COC-CPP. When tested again 24 hr or 14 days after intra-AcbC infusions of U0126 or another MEK inhibitor, PD98059, CPP retrieval and concomitant protein activation were significantly attenuated. Together, these findings indicate the necessity of the AcbC ERK signaling pathway for drug-paired contextual cue memories and suggest that these strong memories can become susceptible to disruption by therapeutic agents.     

Recall of associated memories

A mechanism of serial association in the brain is discussed. The passage from one state to another is assumed to be effected by a control operated by the thalamus on the cortex. Memory failure mechanisms are discussed, such as insufficient imprint, as well as Freudian failure phenomena.     

Systems-level reconsolidation: reengagement of the hippocampus with memory reactivation

Certain types of memories are dependent on the hippocampus for a short period of time following training, after which they are no longer susceptible to hippocampal manipulations. Having completed this initial consolidation process, a memory may once again engage the hippocampus (undergo reconsolidation) when recalled. Two studies in the current issue of Neuron make important advances in our understanding of reconsolidation but reach different conclusions about the modifiability of old memories.     

Disrupting Escherichia coli: a comparison of methods

The often-encountered problem of disrupting bacteria for the purpose of extracting soluble protein has generated various methods. Many require specialized equipment. Very often, especially during preliminary studies, investigators need a simple, fast, and inexpensive method for cell disruption that preserves biological activity. This paper compares some simple and inexpensive methods for cell disruption, such as bead-vortexing, freezing-thawing, French pressing, and sonication. It also provides some tips to increase protein yield and preserve biological activity. If performed under optimal conditions, bead-vortexing gives protein yields that are comparable to French pressing and sonication. It also preserves the activities of labile enzymes and releases periplasmic enzymes. Vortexing with glass beads appears to be the simplest method for cell disruption.     

Drought-deciduous behavior reduces nutrient losses from temperate deciduous trees under severe drought

Nutrient resorption from senescing leaves is an important mechanism of nutrient conservation in temperate deciduous forests. Resorption, however, may be curtailed by climatic events that cause rapid leaf death, such as severe drought, which has been projected to double by the year 2100 in the eastern United States. During a record drought in the southeastern US, we studied 18 common temperate winter-deciduous trees and shrubs to understand how extreme drought affects nutrient resorption of the macronutrients N, P, K, and Ca. Four species exhibited drought-induced leaf senescence and maintained higher leaf water potentials than the remaining 14 species (here called drought-evergreen species). This strategy prevented extensive leaf desiccation during the drought and successfully averted large nutrient losses caused by leaf desiccation. These four drought-deciduous species were also able to resorb N, P, and K from drought-senesced leaves, whereas drought-evergreen species did not resorb any nutrients from leaves lost to desiccation during the drought. For Oxydendrum arboreum, the species most severely affected by the drought, our results indicate that trees lost 50% more N and P due to desiccation than would have been lost from fall senescence alone. For all drought-deciduous species, resorption of N and P in fall-senesced leaves was highly proficient, whereas resorption was incomplete for drought-evergreen species. The lower seasonal nutrient losses of drought-deciduous species may give them a competitive advantage over drought-evergreen species in the years following the drought, thereby impacting species composition in temperate deciduous forests in the future.     

Interhemispheric transfer of working memories

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Hippocampal regulation of aversive memories

For many years, the hippocampal formation has been implicated in the regulation of negative emotion, yet the nature of this link has remained elusive. Recent studies have made important links between the hippocampus and regulation of stress hormones that affect aversive memory. Additional studies have shown that the hippocampus regulates the gating of fear by contextual information. An emerging literature also links the hippocampus to prediction errors during fear learning and extinction. The mechanisms by which the hippocampus regulates negative emotion are clearly complicated, but suggest that interventions aimed at restoring normal hippocampal function may help with disorders of negative affect, such as depression or post-traumatic stress disorder and depression.     

The secret life of memories

Recent evidence has challenged the view that memories are made permanent by a consolidation process that happens just once and instead have suggested that memories are "re-consolidated" after reminders. The current findings of Morris et al. in this issue of Neuron suggest that reconsolidation may involve a complex interaction between synaptic and system processing of recent as well as remote experiences.