Possible novel features of synaptic regulation during long-term facilitation in Aplysia

Most studies of molecular mechanisms of synaptic plasticity have focused on the sequence of changes either at individual synapses or in the cell nucleus. However, studies of long-term facilitation at Aplysia sensory neuron–motor neuron synapses in isolated cell culture suggest two additional features of facilitation. First, that there is also regulation of the number of synaptic contacts between two neurons, which may occur at the level of cell pair-specific branch points in the neuronal arbor. Branch points contain many molecules that are involved in protein synthesis-dependent long-term facilitation including neurotrophins and the RNA binding protein CPEB. Second, the regulation involves homeostatic feedback and tends to keep the total number of contacts between two neurons at a fairly constant level both at rest and following facilitation. That raises the question of how facilitation and homeostasis can coexist. A possible answer is suggested by the findings that they both involve spontaneous transmission and postsynaptic Ca²⁺, which can have bidirectional effects similar to LTP and LTD in hippocampus. In addition, long-term facilitation can involve a change in the set point of homeostasis, which could be encoded by plasticity molecules such as CPEB and/or PKM. A computational model based on these ideas can qualitatively simulate the basic features of both facilitation and homeostasis of the number of contacts.

Synaptic plasticity is a change in strength of the synaptic connection (postsynaptic potential or PSP) between neurons and includes increases during facilitation and decreases during depression. Plasticity is thought to underlie circuit formation during development and learning and memory in adults, and correspondingly to be defective in neurodevelopmental disorders including autism, ADHD, and schizophrenia as well as learning and memory disorders including Alzheimer''s, age-related memory loss, and drug addiction (Hawkins 2013; Hawkins et al. 2017). Most studies of molecular mechanisms of synaptic plasticity have focused on either changes at individual synapses or gene regulation in the cell nucleus. However, studies of long-term facilitation at Aplysia sensory neuron–motor neuron (SN–MN) synapses in isolated cell culture (Glanzman et al. 1990), sensitization in the intact animal (Wainwright et al. 2004), and long-term potentiation in hippocampal neurons (Antonova et al. 2001, 2009) have shown that there are also changes in the number of contacts between presynaptic varicosities and the postsynaptic neuron. We refer to these as synaptic contacts although not all of them are functional synapses (Kim et al. 2003). The number of contacts is thought to be an important determinant of the strength of the PSP (Zhang et al. 2003) and to be different for different neuron pairs. It also increases during long-term facilitation of the PSP and is thought to be a major determinant of the time course of the facilitation (Bailey and Chen 1989).As in other systems (Antonova et al. 2001, 2009; Holtmaat and Svoboda 2009), the contacts are dynamic and are continually being formed and eliminated, but the total number and the PSP remain fairly constant both at rest and during long-term facilitation (Miniaci et al. 2008; Chen et al. 2014). Furthermore, the number of contacts and the PSP return to baseline when maintenance of the facilitation is blocked, but the individual contacts are not all the same as they were before facilitation. These results have led some to suggest that memories are not stored at individual synaptic contacts, as is often supposed, but rather are stored in the nucleus (Chen et al. 2014). However, most of the previous experiments have involved a single SN and a single MN, so it has not been possible to examine the synapse specificity of the effects. Experiments with one SN and two MNs (Martin et al. 1997) or two SNs and 1 MN (Schacher et al. 1997) have shown that facilitation of the number of synaptic contacts and the PSP is specific to the stimulated synaptic pair (e.g., SN–MN1) and does not occur for the other pair (e.g., SN–MN2). These results should generalize to multiple pre- and postsynaptic partners and suggest two novel features of synaptic regulation during plasticity: (1) that the number of synaptic contacts between two neurons is regulated, and (2) that the regulation is homeostatic. We first describe those features and some of the evidence supporting them, then propose a model that could account for them and present computational modeling to illustrate the plausibility of the model.     

脑岛在成瘾中的结构和功能异常

脑岛位于大脑外侧裂的深处, 与情绪和内感受等多种心理功能有关。脑岛在成瘾中的结构变化和功能连接异常, 表明了脑岛在成瘾中的作用, 刺激脑岛区域干预成瘾也逐渐成为研究者们关注的领域。未来的研究应该通过对脑岛进行精细分割和多种方法相结合来进一步考察脑岛在成瘾中的具体作用, 并挖掘不同成瘾类型的共性和特性, 以便更好开展基于脑的成瘾干预。     

Coincident induction of long-term facilitation at sensory-motor synapses in Aplysia: presynaptic and postsynaptic factors

Induction of long-term synaptic changes at one synapse can facilitate the induction of long-term plasticity at another synapse. Here we show that if Aplysia sensory neuron (SN) somata and their remote motor neuron (MN) synapses are simultaneously exposed to serotonin (5HT) pulses, which at either site alone are insufficient to induce long-term facilitation (LTF), processes activated at these sites interact to induce LTF. Coincident induction of LTF requires: (1) that the synaptic pulse occurs within a brief temporal window of the somatic pulse and (2) that local protein synthesis occurs immediately at the synapse, followed by delayed protein synthesis at the soma. LTF at the SN-MN synapses can also be induced with cell-wide application of repeated pulses of 5HT. However, these two forms of LTF differ mechanistically: (1) coincident LTF requires protein synthesis in the postsynaptic motor neuron, whereas repeated 5HT LTF does not, and (2) repeated 5HT LTF is accompanied by intermediate-term (3 h) facilitation, whereas coincident LTF is not. Thus LTF expressed in the same temporal domain can result from different underlying mechanisms.     

Overexpression of and RNA interference with the CCAAT enhancer-binding protein on long-term facilitation of Aplysia sensory to motor synapses

In the marine mollusk Aplysia, the CCAAT/enhancer-binding protein, ApC/EBP, serves as an immediate early gene in the consolidation of long-term facilitation in the synaptic connection between the sensory and motor neurons of the gill-withdrawal reflex. To further examine the role of ApC/EBP as a molecular switch of a stable form of long-term memory, we cloned the full-length coding regions of two alternatively spliced forms, the short and long form of ApC/EBP. Overexpression of each isoform by DNA microinjection resulted in a l6-fold increase in the expression of the coinjected luciferase reporter gene driven by an ERE promoter. In addition, when we overexpressed ApC/EBP in Aplysia sensory neurons, we found that the application of a single pulse of 5-HT that normally induced only short-term facilitation now induced long-term facilitation. Conversely, when we attempted to block the synthesis of native ApC/EBP by microinjecting double-strand RNA or antisense RNA, we blocked long-term facilitation in a sequence-specific manner. These data support the idea that ApC/EBP is both necessary and sufficient to consolidate short-term memory into long-term memory. Furthermore, our results suggest that this double-strand RNA interference provides a powerful tool in the study of the genes functioning in learning and memory in Aplysia by specifically inhibiting both the constitutive and induced expression of the genes.     

Post-training intrahippocampal injection of synthetic poly-alpha-2,8-sialic acid-neural cell adhesion molecule mimetic peptide improves spatial long-term performance in mice

Several data have shown that the neural cell adhesion molecule (NCAM) is necessary for long-term memory formation and might play a role in the structural reorganization of synapses. The NCAM, encoded by a single gene, is represented by several isoforms that differ with regard to their content of alpha-2,8-linked sialic acid residues (PSA) on their extracellular domain. The carbohydrate PSA is known to promote plasticity, and PSA-NCAM isoforms remain expressed in the CA3 region of the adult hippocampus. In the present study, we investigated the effect on spatial memory consolidation of a PSA gain of function by injecting a PSA mimetic peptide (termed pr2) into the dorsal hippocampus. Mice were subjected to massed training in the spatial version of the water maze. Five hours after the last training session, experimental mice received an injection of pr2, whereas control mice received PBS or reverse peptide injections in the hippocampal CA3 region. Memory retention was tested at different time intervals: 24 h, 1 wk, and 4 wk. The results showed that the post-training infusion of pr2 peptide significantly increases spatial performance whenever it was assessed after the training phase. By contrast, administration of the control reverse peptide did not affect retention performance. These findings provide evidence that (1) PSA-NCAM is involved in memory consolidation processes in the CA3 hippocampal region, and (2) PSA mimetic peptides can facilitate the formation of long-term spatial memory when injected during the memory consolidation phase.     

Retrospective analysis of changes in response topographies of escape‐maintained aggressive behavior during functional analyses

We observed changes in the rates of response topographies during the demand condition of functional analyses for participants who demonstrated problem behavior maintained by escape. Over the course of the functional analysis for each participant, the number of topographies decreased from the first to the last session. Additionally, after the first session of the demand condition the rate of responding for one topography increased or remained at high levels while the rates of all other topographies decreased. The implications of these results when conducting functional analysis are discussed.     

Age-related changes in trunk neuromuscular activation patterns during a controlled functional transfer task include amplitude and temporal synergies

While healthy aging is associated with physiological changes that can impair control of trunk motion, few studies examine how spinal muscle responses change with increasing age. This study examined whether older (over 65 years) compared to younger (20–45 years) adults had higher overall amplitude and altered temporal recruitment patterns of trunk musculature when performing a functional transfer task. Surface electromyograms from twelve bilateral trunk muscle (24) sites were analyzed using principal component analysis, extracting amplitude and temporal features (PCs) from electromyographic waveforms. Two PCs explained 96% of the waveform variance. Three factor ANOVA models tested main effects (group, muscle and reach) and interactions for PC scores. Significant (p < .0125) group interactions were found for all PC scores. Post hoc analysis revealed that relative to younger adults, older adults recruited higher agonist and antagonistic activity, demonstrated continuous activation levels in specific muscle sites despite changing external moments, and had altered temporal synergies within abdominal and back musculature. In summary both older and younger adults recruit highly organized activation patterns in response to changing external moments. Differences in temporal trunk musculature recruitment patterns suggest that older adults experience different dynamic spinal stiffness and loading compared to younger adults during a functional lifting task.     

Role reversal changes during the ontogeny of play fighting in male rats: Attack vs. defense

From weaning until sexual maturity, the rates at which young male rats hold each other supine during play fighting appear to become progressively asymmetrical. These changes have been previously thought to reflect an initial lack of dominance and a later development of dominance-subordinance relationships. In this paper it is shown that pairs of male rats exhibit asymmetries in playful attack and playful defense throughout development. The changes, resulting in greater asymmetry of pinning rates, are shown to result from age-dependent changes in defensive tactics; the relationship, therefore, remains constant while the form of the behavior changes. Furthermore, it is not the animals showing the highest rates of playful attack who become dominant in older ages.     

长期戒断海洛因成瘾者冲动性相关脑区的结构及功能特征

冲动性是药物成瘾者的典型特征, 它既包含了抑制控制成瘾者药物使用的力量, 也包含驱动成瘾者使用药物的成分, 两者不平衡导致冲动性用药行为。海洛因成瘾者本身具有冲动性人格特质, 长时间的海洛因使用又会造成成瘾者冲动性相关的大脑结构与功能的异常。目前难以确定戒断后, 冲动性及相关的大脑结构与功能是否还呈异常状态。本研究采用基于体素的形态学分析、低频振幅、局部一致性和功能连接方法, 以35例海洛因成瘾戒断者和无任何成瘾史的健康个体26人为研究对象, 探索在长期戒断后, 海洛因成瘾者与其冲动性相关的驱动、控制系统脑网络的结构和功能情况。结果显示, 相比对照组, 戒断组灰质总体积及右内侧额上回的灰质体积显著减小, 右侧颞中回和左内侧旁扣带回的灰质体积随用药总量的增加而降低; 右侧眶部额下回与尾状核功能连接显著增强, 右侧颞中回和左侧中央前回功能连接显著降低; 右眶额中回的ReHo值、右眶额下回和左海马体的ALFF值比对照组显著更低, 而右中央后回的ReHo值显著更高。这些脑区的状况与冲动性的神经基础相吻合, 说明海洛因成瘾戒断者在戒断44个月, 奖赏、凸显、习惯性行为等网络系统仍然呈现异常状态, 且与成瘾药物使用总量有关。这些异常可能是成瘾冲动性的驱动力的神经基础, 可以作为解释成瘾者戒断后容易复吸的因素之一。     

In vivo neuroanatomy of Alzheimer's disease: evidence from structural and functional brain imaging

In vivo structural (CT, MRI) and functional (SPECT, PET) brain imaging techniques have been widely used to study the neuroanatomy and neurophysiology of Alzheimer's disease (AD) and to identify definite biological markers of the disease. We used meta-analytic methods to synthesize this literature to determine what neuroanatomical structures best differentiate patients with AD from healthy normal controls. A total of 125 studies published between 1984 and 2000 that included 3543 patients with AD and 1698 normal healthy controls met inclusion criteria. We found that measures of the temporal cortices, including the amygdala, hippocampus, and inferior temporal lobes, along with the anterior cingulate cortex, associated with the largest magnitudes of effects and, hence, could serve as the most useful structures to help clinicians differentiate AD from healthy normal aging.     

Correlates across the structural, functional, and molecular phenotypes of fragile X syndrome

Fragile X syndrome (FXS) is characterized by a pattern of morphological, functional, and molecular characteristics with, in at least some cases, apparent relationships among phenotypic features at different levels. Gross morphology differences in the sizes of some human brain regions are accompanied by fine structural alterations in the shapes and in the numbers of dendritic spines in both humans and the knockout mouse model. The excess number of spines, their immature appearance, and the impaired withdrawal of inappropriately oriented dendrites in FXS or the mouse model suggest impairment of neuronal maturation, including dendritic and spine pruning. It is not clear how these differences arise, although regionally or globally impaired translation of the mRNAs that interact with the Fmr1 protein product, FMRP, in the vicinity of the synapse, including genes involved in synapse development and plasticity and dendritic retraction, is certainly plausible. FMRP binds mRNA and may be involved in both transport and translation of the mRNAs it binds. The mRNAs it binds belong to multiple functional classes, apparently indicating that FMRP may impact multiple cellular processes. In one example, the glucocorticoid receptor, whose mRNA binds FMRP, regulates the stress-sensitive glucocorticosteroids. Both human FXS and the mouse model exhibit a protracted elevation in glucocorticosteroids after stress. Possible relationships of other genes to morphological and functional characteristics of FXS are also discussed.     

Comparisons of synthesized and individual reinforcement contingencies during functional analysis

Researchers typically modify individual functional analysis (FA) conditions after results are inconclusive (Hanley, Iwata, & McCord, 2003). Hanley, Jin, Vanselow, and Hanratty (2014) introduced a marked departure from this practice, using an interview‐informed synthesized contingency analysis (IISCA). In the test condition, they delivered multiple contingencies simultaneously (e.g., attention and escape) after each occurrence of problem behavior; in the control condition, they delivered those same reinforcers noncontingently and continuously. In the current investigation, we compared the results of the IISCA with a more traditional FA in which we evaluated each putative reinforcer individually. Four of 5 participants displayed destructive behavior that was sensitive to the individual contingencies evaluated in the traditional FA. By contrast, none of the participants showed a response pattern consistent with the assumption of the IISCA. We discuss the implications of these findings on the development of accurate and efficient functional analyses.     

Hormonal and monoamine signaling during reinforcement of hippocampal long-term potentiation and memory retrieval

Recently it was shown that holeboard training can reinforce, i.e., transform early-LTP into late-LTP in the dentate gyrus during the initial formation of a long-term spatial reference memory in rats. The consolidation of LTP as well as of the reference memory was dependent on protein synthesis. We have now investigated the transmitter systems involved in this reinforcement and found that LTP-consolidation and memory retrieval were dependent on β-adrenergic, dopaminergic, and mineralocorticoid receptor (MR) activation, whereas glucocorticoid receptors (GRs) were not involved. Blockade of the β-adrenergic signaling pathway significantly increased the number of reference memory errors compared with MR and dopamine receptor inhibition. In addition, β-adrenergic blockade impaired the working memory. Therefore, we suggest that β-adrenergic receptor activation is the main signaling system required for the retrieval of spatial memory. In addition, other modulatory interactions such as dopaminergic as well as MR systems are involved. This result points to specific roles of different modulatory systems during the retrieval of specific components of spatial memory. The data provide evidence for similar integrative interactions between different signaling systems during cellular memory processes.     

Pain coping and social support as predictors of long-term functional disability and pain in early rheumatoid arthritis

Pain-related avoidance factors and social resources, as assessed by pain coping and social support, are supposed to have lasting effects on functional disability and pain in chronic pain disorders. As a follow-up to a prospective study demonstrating short-term effects after one year (Behaviour Research and Therapy, 36, 179-193, 1998), the role of pain coping and social support at the time of diagnosis was investigated in relationship to the long-term course of functional disability and pain after three and five years in 78 patients with rheumatoid arthritis (RA), taking into account personality characteristics of neuroticism and extraversion, clinical status and use of medication. In line with findings at the one-year follow-up, results showed that more passive pain coping predicted functional disability at the three-year, but not the five-year follow-up. In addition, low levels of social support at the time of diagnosis consistently predicted both functional disability and pain at the three and five-year follow-ups. Results indicate that pain coping and social support, assessed very early in the disease process, can affect long-term functional disability and pain in RA, and suggest that early interventions focusing on pain-related avoidance factors and social resources for patients at risk may beneficially influence long-term outcomes in RA.     

Availability of related long-term memory during and after attention focus in working memory

In a series of four experiments, we investigated the magnitude and pattern of indirect, semantically mediated priming that emanates from various working memory (WM) processes. When such priming effects are taken to reflect temporary increases in the availability of long-term memory (ALTM), results suggest a close link between the amount and type of attention-driven processing in WM and the resulting accessibility of semantically related memory structures. Patterns of priming were equivalent when attention demands were prior to, versus concurrent with, the priming measures, suggesting that ALTM processes either require no additional cognitive resources or require resources that are independent of those underlying effortful WM processes. The results are discussed with respect to emerging evidence for long-term semantic priming and models of WM that incorporate active but unattended information as part of a limited capacity cognitive workspace.