Molecular activity underlying working memory

The prefrontal cortex is necessary for directing thought and planning action. Working memory, the active, transient maintenance of information in mind for subsequent monitoring and manipulation, lies at the core of many simple, as well as high-level, cognitive functions. Working memory has been shown to be compromised in a number of neurological and psychiatric conditions and may contribute to the behavioral and cognitive deficits associated with these disorders. It has been theorized that working memory depends upon reverberating circuits within the prefrontal cortex and other cortical areas. However, recent work indicates that intracellular signals and protein dephosphorylation are critical for working memory. The present article will review recent research into the involvement of the modulatory neurotransmitters and their receptors in working memory. The intracellular signaling pathways activated by these receptors and evidence that indicates a role for G(q)-initiated PI-PLC and calcium-dependent protein phosphatase calcineurin activity in working memory will be discussed. Additionally, the negative influence of calcium- and cAMP-dependent protein kinase (i.e., calcium/calmodulin-dependent protein kinase II (CaMKII), calcium/diacylglycerol-activated protein kinase C (PKC), and cAMP-dependent protein kinase A (PKA)) activities on working memory will be reviewed. The implications of these experimental findings on the observed inverted-U relationship between D(1) receptor stimulation and working memory, as well as age-associated working memory dysfunction, will be presented. Finally, we will discuss considerations for the development of clinical treatments for working memory disorders.     

Adrenergic pharmacology: focus on the central nervous system

Norepinephrine and epinephrine are involved in the control of several important functions of the central nervous system (CNS), including sleep, arousal, mood, appetite, and autonomic outflow. Catecholamines control these functions through activation of a family of adrenergic receptors (ARs). The ARs are divided into three subfamilies (alpha1, alpha2, and beta) based on their pharmacologic properties, signaling mechanisms, and structure. ARs in the CNS are targets for several therapeutic agents used in the treatment of depression, obesity, hypertension, and other diseases. Not much is known, however, about the role of specific AR subtypes in the actions of these drugs. In this paper, we provide an overview of adrenergic pharmacology in the CNS, focusing on the pharmacologic properties of subtype-selective AR agonists and antagonists, the accessibility of these drugs to the CNS, and the distribution of ARs in different areas of the brain.     

Molecular mechanisms of stress-induced prefrontal cortical impairment: implications for mental illness

The symptoms of mental illness often involve weakened regulation of thought, emotion, and behavior by the prefrontal cortex. Exposure to stress exacerbates symptoms of mental illness and causes marked prefrontal cortical dysfunction. Studies in animals have revealed the intracellular signaling pathways activated by stress exposure that induce profound prefrontal cortical impairment: Excessive dopamine stimulation of D1 receptors impairs prefrontal function via cAMP intracellular signaling, leading to disconnection of prefrontal networks, while excessive norepinephrine stimulation of alpha1 receptors impairs prefrontal function via phosphatidylinositol-protein kinase C intracellular signaling. Genetic studies indicate that the genes disrupted in serious mental illness (bipolar disorder and schizophrenia) often encode for the intracellular proteins that serve as brakes on the intracellular stress pathways. For example, disrupted in schizophrenia 1 (DISC1) normally regulates cAMP levels, while regulator of G protein signaling 4 (RGS4) and diacylglycerol kinase (DGKH)-the molecule most associated with bipolar disorder- normally serve to inhibit phosphatidylinositol-protein kinase C intracellular signaling. Patients with mutations resulting in loss of adequate function of these genes likely have weaker endogenous regulation of these stress pathways. This may account for the vulnerability to stress and the severe loss of PFC regulation of behavior, thought, and affect in these illnesses. This review highlights the signaling pathways onto which genetic vulnerability and stress converge to impair PFC function and induce debilitating symptoms such as thought disorder, disinhibition, and impaired working memory.     

Regulation and Mechanism of L-Type Calcium Channel Activation via V1a Vasopressin Receptor Activation in Cultured Cortical Neurons

We have sought to elucidate the biochemical mechanisms that underlie the memory enhancing properties of the neural peptide vasopressin. Toward that goal we have investigated vasopressin induction of calcium signaling cascades, long held to be involved in long-term memory function, in neurons derived from the cerebral cortex, a brain region associated with long-term memory. Our previous studies demonstrated that in cultured cortical neurons, V1a vasopressin receptor (V1aR) activation resulted in a sustained rise in intracellular calcium concentration that was dependent on calcium influx (Son & Brinton, 1998). To investigate the mechanism of V1aR-induced calcium influx, we investigated V1aR activation of the calcium channel subtype(s) in cortical neurons cultured from Sprague-Dawley rat embryonic day 18 fetuses. The results of these analyses demonstrated that the L-type calcium channel blocker nifedipine blocked 250 nM V1 vasopressin receptor agonist (V1 agonist)-induced calcium influx. Intracellular calcium imaging analyses using fura-2AM demonstrated that blockade of L-type calcium channels prevented the 250 nM V1 agonist-induced rise in intracellular calcium concentration. These results indicate that the influx of extracellular calcium via L-type calcium channels is an essential step in the initiation of the V1 agonist-induced rise in intracellular calcium concentration. To determine the mechanism of V1aR activation of L-type calcium channels, regulatory components of the phosphatidylinositol signaling pathway were investigated. The results of these analyses demonstrated that V1 agonist-induced calcium influx was blocked by both a phospholipase C inhibitor (U-73122) and a protein kinase C inhibitor (bisindolylmaleimide I). Further analysis of V1aR activation of protein kinase C (PKC) demonstrated that V1 agonist induced PKC activity within 1 min of exposure in cultured cortical neurons. These data indicate that in cultured cortical neurons, V1aR activation regulates the influx of extracellular calcium via L-type calcium channel activation through a protein kinase-C-dependent mechanism. The results of these studies provide biochemical mechanisms by which vasopressin could enhance memory function. Those mechanisms include a complex cascade that is initiated by activation of the phosphatidylinositol pathway, activation of protein kinase C, followed by phosphorylation of L-type calcium channels to initiate the influx of extracellular calcium to activate a cascade of calcium-dependent release of intracellular calcium.     

Beta-adrenergic receptor activation rescues theta frequency stimulation-induced LTP deficits in mice expressing C-terminally truncated NMDA receptor GluN2A subunits

Through protein interactions mediated by their cytoplasmic C termini the GluN2A and GluN2B subunits of NMDA receptors (NMDARs) have a key role in the formation of NMDAR signaling complexes at excitatory synapses. Although these signaling complexes are thought to have a crucial role in NMDAR-dependent forms of synaptic plasticity such as long-term potentiation (LTP), the role of the C terminus of GluN2A in coupling NMDARs to LTP enhancing and/or suppressing signaling pathways is unclear. To address this issue we examined the induction of LTP in the hippocampal CA1 region in mice lacking the C terminus of endogenous GluN2A subunits (GluN2AΔC/ΔC). Our results show that truncation of GluN2A subunits produces robust, but highly frequency-dependent, deficits in LTP and a reduction in basal levels of extracellular signal regulated kinase 2 (ERK2) activation and phosphorylation of AMPA receptor GluA1 subunits at a protein kinase A site (serine 845). Consistent with the notion that these signaling deficits contribute to the deficits in LTP in GluN2AΔC/ΔC mice, activating ERK2 and increasing GluA1 S845 phosphorylation through activation of β-adrenergic receptors rescued the induction of LTP in these mutants. Together, our results indicate that the capacity of excitatory synapses to undergo plasticity in response to different patterns of activity is dependent on the coupling of specific signaling pathways to the intracellular domains of the NMDARs and that abnormal plasticity resulting from mutations in NMDARs can be reduced by activation of key neuromodulatory transmitter receptors that engage converging signaling pathways.     

Possible involvement of the vagus nerve in monitoring plasma catecholamine levels

In their article Miyashita and Williams (Neurobiology of Learning and Memory 2006, 85, 116-124) describe the effect of peripheral administration of epinephrine on neural discharge in vagal afferent fibers. It seems that described data supports the hypothesis of the vagus nerve participation in monitoring plasma catecholamine levels and consequently modifying brain functions. However, do these results indicate indeed that afferent vagus nerve pathways are activated by circulating epinephrine? Catecholamines influence virtually all tissues and many functions. Vagus nerve participates significantly in monitoring of those effects. Therefore epinephrine-induced increases of afferent vagus nerve activity described by Miyashita and Williams may reflect not only exclusive activation of beta-adrenergic receptors but also an activation of other types of receptors on vagal sensory nerve endings, e.g., mechanosensors, chemoreceptors, and osmosensors. Discussion is focused on the possibility that the increase in afferent vagus nerve activity may reflect activation of mechanoreceptors of the vagus nerve endings in the epinephrine-activated heart.     

骨桥蛋白在心肌梗死后心力衰竭中研究进展

骨桥蛋白是一种糖基化的多功能蛋白,其具有激活细胞内信号传导、参与炎症细胞的趋化聚集、促进肿瘤的生长迁移等多种生物学功能。近年来研究表明其在心肌梗死后的炎症反应、心室重塑、细胞外基质沉积及肾素-血管紧张素-醛固酮系统的过度激活中具有重要的作用,同时其与心肌梗死后心力衰竭的严重程度及顸后亦密切相关。本文就骨桥蛋白在心肌梗死后心力衰竭中研究进展做一综述。     

Non-ligand activation of estrous behavior in rodents: cross-talk at the progesterone receptor

Estrous behavior in rodents is triggered by the binding of progesterone (P) to its intracellular receptor (PR). Non-steroidal agents (i.e., gonadotropin-releasing hormone, noradrenaline, dopamine and others), acting at the membrane, can facilitate estrous behavior in estrogen-primed rats. This action is mediated through the generation of second messengers (cyclic AMP, cyclic GMP, calcium) which, in turn, phosphorylate through diverse kinase systems (protein kinases A, G or C) either the PR or associated effector proteins linking the PR to the trans-activation machinery. P or its metabolites also activate cyclic AMP-signaling pathways by acting directly on the membrane or by modulating neurotransmitter release. Molecular processes resulting from second messenger signaling pathways and those from the progesterone-RP interaction synergize to elicit a full behavioral response.     

前额皮层肾上腺素能受体在工作记忆中的作用

前额皮层去甲肾上腺素能神经支配主要来自脑干蓝斑核。前额皮层存在不同类型的肾上腺素能受体。其中突触后α2及β2肾上腺素能受体的激活提高工作记忆;α1及β1肾上腺素能受体的激活损害工作记忆。不同受体是通过激活不同的信号通路发挥对工作记忆的调节作用。来自人类被试的研究结果与对动物的研究结果之间尚存在不一致。了解前额皮层不同肾上腺素受体的作用为开发治疗与前额皮层功能失调相关疾病的药物提供了新的方向。     

A fresh look at an ancient receptor family: emerging roles for low density lipoprotein receptors in synaptic plasticity and memory formation

The well-known family of low-density lipoprotein receptors represents a collection of ancient membrane receptors that have been remarkably conserved throughout evolution. These multifunctional receptors, known to regulate cholesterol transport, are becoming increasingly interesting to the neuroscience community due to their ability to transduce a diversity of extracellular signals across the membrane in the adult CNS. Their roles in modulating synaptic plasticity and necessity in hippocampus-specific learning and memory have recently come to light. In addition, genetic, biochemical and behavioral studies have implicated these signaling systems in a number of human neurodegenerative and neuropsychiatric disorders involving loss of cognitive ability, such as Alzheimer's disease, schizophrenia and autism. This review describes the known functions of these receptors and discusses their potential role in processes of synaptic regulation and memory formation.     

Stress and cardiac beta adrenoceptors

Most modern theories about stress recognize that although stress is not a disease, it may be the trigger for the majority of diseases when allostatic overload has been generated. During stress, the glucocorticoids and catecholamines play a key role in the regulation of physiological parameters and homeostasis during stress. In the heart, positive chronotropic, inotropic, and lusitropic responses to catecholamines are mediated by various subtypes of adrenergic receptors (beta-ARs), mainly beta1- and beta2-adrenergic receptors. beta-ARs also control cardiomyocyte growth and death, thus contributing to cardiac remodelling. The structural basis of each beta-AR subtype, as well as their signalling pathways, and adaptive responses to stress are discussed. The participation of beta3- and putative beta4-ARs in the control of cardiac function is also discussed, with emphasis on low affinity beta-AR isoforms and the role they play in the response to the catecholamines under stress. The changes in beta-AR signalling under pathogenic conditions as well as under stress are reviewed.     

Multimodal encoding in a simplified model of intracellular calcium signaling

Many cells use calcium signaling to carry information from the extracellular side of the plasma membrane to targets in their interior. Since virtually all cells employ a network of biochemical reactions for Ca²⁺ signaling, much effort has been devoted to understand the functional role of Ca²⁺ responses and to decipher how their complex dynamics is regulated by the biochemical network of Ca²⁺-related signal transduction pathways. Experimental observations show that Ca²⁺ signals in response to external stimuli encode information via frequency modulation (FM) or alternatively via amplitude modulation (AM). Although minimal models can capture separately both types of dynamics, they fail to exhibit different and more advanced encoding modes. By arguments of bifurcation theory, we propose instead that under some biophysical conditions more complex modes of information encoding can also be manifested by minimal models. We consider the minimal model of Li and Rinzel and show that information encoding can occur by AM of Ca²⁺ oscillations, by FM or by both modes (AFM). Our work is motivated by calcium signaling in astrocytes, the predominant type of cortical glial cells that is nowadays recognized to play a crucial role in the regulation of neuronal activity and information processing of the brain. We explain that our results can be crucial for a better understanding of synaptic information transfer. Furthermore, our results might also be important for better insight on other examples of physiological processes regulated by Ca²⁺ signaling.     

Multimodal encoding in a simplified model of intracellular calcium signaling

Many cells use calcium signaling to carry information from the extracellular side of the plasma membrane to targets in their interior. Since virtually all cells employ a network of biochemical reactions for Ca²⁺ signaling, much effort has been devoted to understand the functional role of Ca²⁺ responses and to decipher how their complex dynamics is regulated by the biochemical network of Ca²⁺-related signal transduction pathways. Experimental observations show that Ca²⁺ signals in response to external stimuli encode information via frequency modulation (FM) or alternatively via amplitude modulation (AM). Although minimal models can capture separately both types of dynamics, they fail to exhibit different and more advanced encoding modes. By arguments of bifurcation theory, we propose instead that under some biophysical conditions more complex modes of information encoding can also be manifested by minimal models. We consider the minimal model of Li and Rinzel and show that information encoding can occur by AM of Ca²⁺ oscillations, by FM or by both modes (AFM). Our work is motivated by calcium signaling in astrocytes, the predominant type of cortical glial cells that is nowadays recognized to play a crucial role in the regulation of neuronal activity and information processing of the brain. We explain that our results can be crucial for a better understanding of synaptic information transfer. Furthermore, our results might also be important for better insight on other examples of physiological processes regulated by Ca²⁺ signaling.     

A behavioral study of alpha-1b adrenergic receptor knockout mice: increased reaction to novelty and selectively reduced learning capacities

Knockout mice lacking the alpha-1b adrenergic receptor were tested in behavioral experiments. Reaction to novelty was first assessed in a simple test in which the time taken by the knockout mice and their littermate controls to enter a second compartment was compared. Then the mice were tested in an open field to which unknown objects were subsequently added. Special novelty was introduced by moving one of the familiar objects to another location in the open field. Spatial behavior and memory were further studied in a homing board test, and in the water maze. The alpha-1b knockout mice showed an enhanced reactivity to new situations. They were faster to enter the new environment, covered longer paths in the open field, and spent more time exploring the new objects. They reacted like controls to modification inducing spatial novelty. In the homing board test, both the knockout mice and the control mice seemed to use a combination of distant visual and proximal olfactory cues, showing place preference only if the two types of cues were redundant. In the water maze the alpha-1b knockout mice were unable to learn the task, which was confirmed in a probe trial without platform. They were perfectly able, however, to escape in a visible platform procedure. These results confirm previous findings showing that the noradrenergic pathway is important for the modulation of behaviors such as reaction to novelty and exploration, and suggest that this is mediated, at least partly, through the alpha-1b adrenergic receptors. The lack of alpha-1b adrenergic receptors in spatial orientation does not seem important in cue-rich tasks but may interfere with orientation in situations providing distant cues only.     

Hypothalamic-pituitary-adrenal axis dysregulation and behavioral analysis of mouse mutants with altered glucocorticoid or mineralocorticoid receptor function

Corticosteroid receptors are critical for the maintenance of homeostasis after both psychological and physiological stress. To understand the different roles and interactions of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) during stress, it is necessary to dissect the role of corticosteroid signaling at both the system and sub-system level. A variety of GR transgenic mouse lines have recently been used to characterize the role of GR in the CNS as a whole and particularly in the forebrain. We will describe both the behavioral and cellular/molecular implications of disrupting GR function in these animal models and describe the implications of this data for our understanding of normal endocrine function and stress adaptation. MRs in tight epithelia have a long established role in sodium homeostasis. Recently however, evidence has suggested that MRs in the limbic brain also play an important role in psychological stress. Just as with GR, targeted mutations in MR induce a variety of behavioral changes associated with stress adaptation. In this review, we will discuss the implications of this work on MR. Finally, we will discuss the possible interaction between MR and GR and how future work using double mutants (through conventional means or virus based gene alteration) will be needed to more fully understand how signaling through these two steroid receptors provides the adaptive mechanisms to deal with a variety of stressors.     

Physiological changes during physical and psychological stress

Changes in urine catecholamines, blood pressure and heart rate during two physical exercise test sessions (35% VO_2max and 50% VO_2max) and one psychological stress session which involved reading under delayed auditory feedback (DAF) were compared. Increases in both the haemodynamic parameters and in the excretion of catecholamines were found in response to all three tests. The changes in adrenaline (A) did not differentiate between the test situations. Noradrenaline (NA) levels were significantly larger for physical exercise conditions and graded according to the relative workload. The ratio ΔNA/ΔA was similar for both physical tests but statistically different for the DAF session. Significant and positive correlations between haemodynamic parameters and catecholamine excretion were found only for the DAF test. These correlations and the differences in catecholamine excretion suggest different bodily responses to physical and psychological stress. These findings may have practical implications in industrial field studies.     

Stress and memory: opposing effects of glucocorticoids on memory consolidation and memory retrieval

It is well established that glucocorticoid hormones, secreted by the adrenal cortex after a stressful event, influence cognitive performance. Some studies have found glucocorticoid-induced memory enhancement. However, many studies have reported impairing effects of glucocorticoids on memory function. This paper reviews recent findings from this laboratory on the acute effects of glucocorticoids in rats on specific memory phases, i.e., memory consolidation and memory retrieval. The evidence suggests that the consequences of glucocorticoid activation on cognition depend largely on the different memory phases investigated. Posttraining activation of glucocorticoid-sensitive pathways involving glucocorticoid receptors enhances memory consolidation in a pattern highly similar to that previously described for adrenal catecholamines. Also, similar to catecholamine effects on memory consolidation, glucocorticoid influences on memory consolidation depend on noradrenergic activation of the basolateral complex of the amygdala and interactions with other brain regions. By contrast, memory retrieval processes are usually impaired with high circulating levels of glucocorticoids or following infusions of glucocorticoid receptor agonists into the hippocampus. The hypothesis is proposed that these apparently dual effects of glucocorticoids on memory consolidation and memory retrieval might be related and that the basolateral complex of the amygdala is a key structure in a memory-modulatory system that regulates, in concert with other brain regions, stress and glucocorticoid effects on both memory consolidation and memory retrieval.     

Intracellular calcium chelation and pharmacological SERCA inhibition of Ca2+ pump in the insular cortex differentially affect taste aversive memory formation and retrieval

Variation in intracellular calcium concentration regulates the induction of long-term synaptic plasticity and is associated with a variety of memory/retrieval and learning paradigms. Accordingly, impaired calcium mobilization from internal deposits affects synaptic plasticity and cognition in the aged brain. During taste memory formation several proteins are modulated directly or indirectly by calcium, and recent evidence suggests the importance of calcium buffering and the role of intracellular calcium deposits during cognitive processes. Thus, the main goal of this research was to study the consequence of hampering changes in cytoplasmic calcium and inhibiting SERCA activity by BAPTA-AM and thapsigargin treatments, respectively, in the insular cortex during different stages of taste memory formation. Using conditioned taste aversion (CTA), we found differential effects of BAPTA-AM and thapsigargin infusions before and after gustatory stimulation, as well as during taste aversive memory consolidation; BAPTA-AM, but not thapsigargin, attenuates acquisition and/or consolidation of CTA, but neither compound affects taste aversive memory retrieval. These results point to the importance of intracellular calcium dynamics in the insular cortex during different stages of taste aversive memory formation.     

McEwen-Induced Modulation of Endocrine History: A Partial Review

In endless facets of physiology, there are points of homeostatic balance, such that too much or too litttle of something can both be deleterious (i.e., an "inverse U" pattern). This is particularly true when considering glucocorticoids (GCs), the adrenals steroid secreted during stress. In the first part of this paper, I review a number of realms in which a paucity and an excess of GCs are both damaging. Some findings are classical (for example, concerning GC effects upon body weight), while some are quite recent and have considerable implications for both physiology and pathophysiology (for example, inverse U's of GC actions in the realm of immunity and neuronal survival). The second part of the review considers the far thornier issue of how such inverse U's of GC actions are generated on a cellular and molecular level. One solution that has evolved, primarily in the hippocampus within the nervous system, involves the presence of two different types of receptors for GCs within the same cells; so long as the two receptors have very different affinities and mediate opposing effects on some cellular endpoint, an inverse U will emerge. The second solution, found in a number of peripheral tissues, involves GCs having opposing effects on the amount of some signal being generated (e.g., an immune cytokine) and the sensitivity of target tissues to that signal; under conditions that appear to be physiologically relevant, inverse U's emerge from this pattern as well. The final section of this review considers the enormous role played by Bruce McEwen in the emergence of this literature. I suggest that while much of this obviously has to do with the facts that have come from his group, another substantial contribution is from his steadying and supportive personality, the veritable embodiment of homeostatic balance.     

From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning

One of the most rigorously investigated problems in modern neuroscience is to decipher the mechanisms by which experience-induced changes in the central nervous system are translated into behavioral acquisition, consolidation, retention, and subsequent recall of information. Brain-derived neurotrophic factor (BDNF) has recently emerged as one of the most potent molecular mediators of not only central synaptic plasticity, but also behavioral interactions between an organism and its environment. Recent experimental evidence indicates that BDNF modulates synaptic transmission and plasticity by acting across different spatial and temporal domains. BDNF signaling evokes both short- and long-term periods of enhanced synaptic physiology in both pre- and postsynaptic compartments of central synapses. Specifically, BDNF/TrkB signaling converges on the MAP kinase pathway to enhance excitatory synaptic transmission in vivo, as well as hippocampal-dependent learning in behaving animals. Emerging concepts of the intracellular signaling cascades involved in synaptic plasticity induced through environmental interactions resulting in behavioral learning further support the contention that BDNF/TrkB signaling plays a fundamental role in mediating enduring changes in central synaptic structure and function. Here we review recent literature showing the involvement of BDNF/TrkB signaling in hippocampal-dependent learning paradigms, as well as in the types of cellular plasticity proposed to underlie learning and memory.