Stress effects in the hippocampus: synaptic plasticity and memory

It is now well-documented that exposures to uncontrollable (inescapable and unpredictable) stress in adulthood can have profound effects on brain and behavior. Converging lines of evidence from human and animal studies indicate that stress interferes with subsequent performances on a variety of hippocampal-dependent memory tasks. Animal studies further revealed that stress impedes ensuing induction of long-term potentiation (LTP) in the hippocampus. Because the hippocampus is important for key aspects of memory formation and because LTP has qualities congruent to an information storage mechanism, it is hypothesized that stress-induced modifications in hippocampal plasticity contribute to memory impairments associated with stress. Recent studies provide evidence that the amygdala, a structure important in stress- and emotion-related behaviors, plays a necessary role in the emergence of stress-associated changes in hippocampal LTP and memory. Early life stress also alters hippocampal plasticity and memory in a manner largely consistent with effects of adult stress exposure. This review focuses on endocrine-system-level mechanisms of stress effects in the hippocampus, and how stress, by altering the property of hippocampal plasticity, can subsequently influence hippocampal memory.     

Neural functions of calcineurin in synaptic plasticity and memory

Major brain functions depend on neuronal processes that favor the plasticity of neuronal circuits while at the same time maintaining their stability. The mechanisms that regulate brain plasticity are complex and engage multiple cascades of molecular components that modulate synaptic efficacy. Protein kinases (PKs) and phosphatases (PPs) are among the most important of these components that act as positive and negative regulators of neuronal signaling and plasticity, respectively. In these cascades, the PP protein phosphatase 2B or calcineurin (CaN) is of particular interest because it is the only Ca(2+)-activated PP in the brain and a major regulator of key proteins essential for synaptic transmission and neuronal excitability. This review describes the primary properties of CaN and illustrates its functions and modes of action by focusing on several representative targets, in particular glutamate receptors, striatal enriched protein phosphatase (STEP), and neuromodulin (GAP43), and their functional significance for synaptic plasticity and memory.     

Genetic approaches to the study of synaptic plasticity and memory storage

Long-term memory is believed to depend on long-lasting changes in the strength of synaptic transmission known as synaptic plasticity. Understanding the molecular mechanisms of long-term synaptic plasticity is one of the principle goals of neuroscience. Among the most powerful tools being brought to bear on this question are genetically modified mice with changes in the expression or biological activity of genes thought to contribute to these processes. This article reviews how strains of mice with alterations in the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate-response element-binding protein signaling pathway have advanced our understanding of the biological basis of learning and memory.     

Role of the somatostatin system in contextual fear memory and hippocampal synaptic plasticity

Somatostatin has been implicated in various cognitive and emotional functions, but its precise role is still poorly understood. Here, we have made use of mice with somatostatin deficiency, based upon genetic invalidation or pharmacologically induced depletion, and Pavlovian fear conditioning in order to address the contribution of the somatostatin system to associative fear memory. The results demonstrate an impairment of foreground and background contextual but not tone fear conditioning in mice with targeted ablation of the somatostatin gene. These deficits were associated with a decrease in long-term potentiation in the CA1 area of the hippocampus. Both the behavioral and the electrophysiological phenotypes were mimicked in wild-type mice through application of the somatostatin-depleting substance cysteamine prior to fear training, whereas no further deficits were observed upon application in the somatostatin null mutants. These results suggest that the somatostatin system plays a critical role in the acquisition of contextual fear memory, but not tone fear learning, and further highlights the role of hippocampal synaptic plasticity for information processing concerning contextual information.     

Lost in the great divide: Motivation in religious studies classrooms

One of the most illuminating finds in Barbara E. Walvoord's Teaching and Learning in College Introductory Religion Courses (2008) is what she calls “the great divide,” a mismatch between instructors’ goals for their courses, which are academic, and the students’ reasons for taking them, which relate to their personal interests and development. Motivation – or, rather, the lack thereof – is not explicitly considered as a potential victim of this mismatch. This article will turn its attention squarely to this issue. First, I will review data about the “great divide” and link them to the common practice of asking our students to bracket the personal when they take our courses. The article will juxtapose this practice with what research tell us about motivation, which will allow us to further explore why the divide Walvoord and others have identified is so problematic. The article will conclude with pedagogical strategies that can help instructors intentionally influence motivation in religion courses. Ultimately, I suggest that we may be doing students – as well as ourselves, as the purveyors of our discipline – a disservice, if we do not attend to (or, worse, if we actively avoid) what we know motivates students to learn.     

Across the great divide: pluralism and the hunt for missing heritability

Synthese - Genetic explanation of complex human behavior presents an excellent test case for pluralism. Although philosophers agree that successful scientific investigation of behavior is...     

The roles of MAPK cascades in synaptic plasticity and memory in Aplysia: facilitatory effects and inhibitory constraints

Synaptic plasticity is thought to contribute to memory formation. Serotonin-induced facilitation of sensory-motor (SN-MN) synapses in Aplysia is an extensively studied cellular analog of memory for sensitization. Serotonin, a modulatory neurotransmitter, is released in the CNS during sensitization training, and induces three temporally and mechanistically distinct phases of SN-MN synaptic facilitation. The role of protein kinase A and protein kinase C in SN-MN synaptic facilitation is well documented. Recently, it has become clear that mitogen-activated protein kinase (MAPK) cascades also play a critical role in SN-MN plasticity. Here, we summarize the roles of MAPK cascades in synaptic plasticity and memory for sensitization in Aplysia.     

Reorganization of learning-associated prefrontal synaptic plasticity between the recall of recent and remote fear extinction memory

We have previously shown that fear extinction is accompanied by an increase of synaptic efficacy in inputs from the ventral hippocampus (vHPC) and mediodorsal thalamus (MD) to the medial prefrontal cortex (mPFC) and that disrupting these changes to mPFC synaptic transmission compromises extinction processes. The aim of this study was to examine whether these extinction-related changes undergo further plasticity as the memory of extinction becomes more remote. Changes in synaptic efficacy in both vHPC-mPFC and MD-mPFC inputs were consequently analyzed when the memory was either 1 d or 7 d old. Increases of synaptic efficacy in the vHPC-mPFC pathway were observed when the memory was 1 d old, but not 7 d after initial extinction. In contrast, potentiation of synaptic efficacy in the MD-mPFC pathway increased over time. In rats that received low-frequency vHPC stimulation immediately after extinction, both vHPC-mPFC and MD-mPFC inputs failed to develop potentiation, and the recall of extinction (both recent and remote memories) was impaired. These findings suggest that post-extinction potentiation in vHPC-mPFC inputs may be necessary for both the recall of recent memory and post-extinction potentiation in the MD-mPFC inputs. This late potentiation process may be required for the recall of remote extinction memory.     

Preservation of long-term memory and synaptic plasticity despite short-term impairments in the Tc1 mouse model of Down syndrome

Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21). Recently, O’Doherty and colleagues in an earlier study generated a new genetic mouse model of DS (Tc1) that carries an almost complete Hsa21. Since DS is the most common genetic cause of mental retardation, we have undertaken a detailed analysis of cognitive function and synaptic plasticity in Tc1 mice. Here we show that Tc1 mice have impaired spatial working memory (WM) but spared long-term spatial reference memory (RM) in the Morris watermaze. Similarly, Tc1 mice are selectively impaired in short-term memory (STM) but have intact long-term memory (LTM) in the novel object recognition task. The pattern of impaired STM and normal LTM is paralleled by a corresponding phenotype in long-term potentiation (LTP). Freely-moving Tc1 mice exhibit reduced LTP 1 h after induction but normal maintenance over days in the dentate gyrus of the hippocampal formation. Biochemical analysis revealed a reduction in membrane surface expression of the AMPAR (α-amino-3-hydroxy-5-methyl-4-propionic acid receptor) subunit GluR1 in the hippocampus of Tc1 mice, suggesting a potential mechanism for the impairment in early LTP. Our observations also provide further evidence that STM and LTM for hippocampus-dependent tasks are subserved by parallel processing streams.     

Long-term exposure to environmental enrichment since youth prevents recognition memory decline and increases synaptic plasticity markers in aging

Aging-associated brain changes include functional alterations that are usually related with memory decline. Epidemiological reports show that a physically and intellectually active life provides a protective effect on this decline and delays the onset of several neurodegenerative diseases. The cellular mechanisms behind the behavioral-based therapies, such as environmental enrichment (EE) exposure, as a method for alleviating age-related memory impairments, are still unknown. Although some reports have shown the benefits of EE exposure in cognitive outcomes in old mice and in animals with experimental neurodegenerative conditions, the effects of lifelong animal exposure to EE have not been explored in detail. In the present work we tested in a rat model the effects of intermittent lifelong exposure since youth to EE on behavioral performance, object recognition memory and anxiety level, as well as on some morphological and biochemical markers of brain plasticity such as hippocampal neurogenesis, synaptophysin content and synaptic morphology. We found that environmental factors have a positive impact on short-memory preservation, as well as on the maintenance of synapses and in the increase in number of new generated neurons within the hippocampus during aging.     

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.     

The NO-cGMP-PKG signaling pathway regulates synaptic plasticity and fear memory consolidation in the lateral amygdala via activation of ERK/MAP kinase

Recent studies have shown that nitric oxide (NO) signaling plays a crucial role in memory consolidation of Pavlovian fear conditioning and in synaptic plasticity in the lateral amygdala (LA). In the present experiments, we examined the role of the cGMP-dependent protein kinase (PKG), a downstream effector of NO, in fear memory consolidation and long-term potentiation (LTP) at thalamic and cortical input pathways to the LA. In behavioral experiments, rats given intra-LA infusions of either the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibited dose-dependent impairments or enhancements of fear memory consolidation, respectively. In slice electrophysiology experiments, bath application of Rp-8-Br-PET-cGMPS or the guanylyl cyclase inhibitor LY83583 impaired LTP at thalamic, but not cortical inputs to the LA, while bath application of 8-Br-cGMP or the guanylyl cyclase activator YC-1 resulted in enhanced LTP at thalamic inputs to the LA. Interestingly, YC-1-induced enhancement of LTP in the LA was reversed by concurrent application of the MEK inhibitor U0126, suggesting that the NO-cGMP-PKG signaling pathway may promote synaptic plasticity and fear memory formation in the LA, in part by activating the ERK/MAPK signaling cascade. As a test of this hypothesis, we next showed that rats given intra-LA infusion of the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibit impaired or enhanced activation, respectively, of ERK/MAPK in the LA after fear conditioning. Collectively, our findings suggest that an NO-cGMP-PKG-dependent form of synaptic plasticity at thalamic input synapses to the LA may underlie memory consolidation of Pavlovian fear conditioning, in part, via activation of the ERK/MAPK signaling cascade.     

Progesterone regulation of synaptic transmission and plasticity in rodent hippocampus

Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the highest concentration of P4 tested (10(-6) M) decreased the baseline synaptic transmission and magnitude of LTP, but did not affect LTD. Intracellular studies suggest the P4 effect to be mediated, at least in part, by GABA(A) activity. These results establish a general effect of P4 on synaptic transmission, multiple forms of synaptic plasticity, and a possible mechanism of P4 action in hippocampus.     

Receptivity to dating and marriage across the religious divide in Northern Ireland: The role of intergroup contact

Intergroup contact has long been recognized as an important factor in promoting positive intergroup attitudes. However, in operationalizing intergroup attitudes, previous studies have rarely investigated attitudes toward one of the most intimate forms of contact, romantic relationships. In this study (N = 176), we expand the intergroup contact literature to examine the association between intergroup contact and, arguably, a litmus test of intergroup attitudes: receptivity to intergroup romance. We do so in Northern Ireland, a context that is historically and presently characterized by sectarian division and tension between Catholics and Protestants. Our findings reveal that intergroup contact is positively associated with receptivity to both dating and marrying an outgroup member. These associations are mediated by ingroup norms toward outgroup romances. General outgroup attitudes were also found to be positively associated with contact but, in contrast to romantic attitudes, this association was shown, for the first time, to be simultaneously mediated by ingroup norms, anxiety, empathy, and trust. In addition, strength of ingroup identification played a moderating role, with a stronger positive relationship between contact and both romantic and general outgroup attitudes among higher identifiers. The findings highlight the importance of examining attitudes toward intergroup romantic relationships, as well as understanding the different mediating and moderating mechanisms which may account for how contact influences general attitudes and romantic attitudes. In the wake of the UK vote to leave the European Union, they also serve as an important reminder of how intergroup contact can be effective in promoting peace in Northern Ireland.     

Isoform specificity of protein kinase Cs in synaptic plasticity

Protein kinase Cs (PKCs) are implicated in many forms of synaptic plasticity. However, the specific isoform(s) of PKC that underlie(s) these events are often not known. We have used Aplysia as a model system in order to investigate the isoform specificity of PKC actions due to the presence of fewer isoforms and a large number of documented physiological roles for PKC in synaptic plasticity in this system. In particular, we have shown that distinct isoforms mediate distinct types of synaptic plasticity induced by the same neurotransmitter: The novel calcium-independent PKC Apl II is required for actions mediated by serotonin (5-HT) alone, while the classical calcium-dependent PKC Apl I is required for actions mediated when 5-HT is coupled to activity. We will discuss the reasons for PKC isoform specificity, assess the tools used to uncover isoform specificity, and discuss the implications of isoform specificity for understanding the roles of PKC in regulating synaptic plasticity.     

Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage

Deletions, translocations, or point mutations in the CREB-binding protein (CBP) gene have been associated with Rubinstein-Taybi Syndrome; a human developmental disorder characterized by retarded growth and reduced mental function. To examine the role of CBP in memory, transgenic mice were generated in which the CaMKII alpha promoter drives expression of an inhibitory truncated CBP protein in forebrain neurons. Examination of hippocampal long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory storage, revealed significantly reduced late-phase LTP induced by dopamine-regulated potentiation in hippocampal slices from CBP transgenic mice. However, four-train induced late-phase LTP is normal. Behaviorally, CBP transgenic mice exhibited memory deficits in spatial learning in the Morris water maze and deficits in long-term memory for contextual fear conditioning, two hippocampus-dependent tasks. Together, these results demonstrate that CBP is involved in specific forms of hippocampal synaptic plasticity and hippocampus-dependent long-term memory formation.