Beta-adrenergic receptor activation during distinct patterns of stimulation critically modulates the PKA-dependence of LTP in the mouse hippocampus

Activation of β-adrenergic receptors (β-ARs) enhances hippocampal memory consolidation and long-term potentiation (LTP), a likely mechanism for memory storage. One signaling pathway linked to β-AR activation is the cAMP-PKA pathway. PKA is critical for the consolidation of hippocampal long-term memory and for the expression of some forms of long-lasting hippocampal LTP. How does β-AR activation affect the PKA-dependence, and persistence, of LTP elicited by distinct stimulation frequencies? Here, we use in vitro electrophysiology to show that patterns of stimulation determine the temporal phase of LTP affected by β-AR activation. In addition, only specific patterns of stimulation recruit PKA-dependent LTP following β-AR activation. Impairments of PKA-dependent LTP maintenance generated by pharmacologic or genetic deficiency of PKA activity are also abolished by concurrent activation of β-ARs. Taken together, our data show that, depending on patterns of synaptic stimulation, activation of β-ARs can gate the PKA-dependence and persistence of synaptic plasticity. We suggest that this may allow neuromodulatory receptors to fine-tune neural information processing to meet the demands imposed by numerous synaptic activity profiles. This is a form of “metaplasticity” that could control the efficacy of consolidation of hippocampal long-term memories.The hippocampus importantly contributes to memory function in the mammalian brain (Zola-Morgan et al. 1986; Eichenbaum et al. 1990; Otto and Eichenbaum 1992; Phillips and LeDoux 1992; Remondes and Schuman 2004). It has reciprocal connections with numerous cortical areas, including those responsible for high-level integration of spatial and contextual data from the external environment (Lavenex and Amaral 2000). As such, the hippocampus is well positioned to receive and survey a broad range of information and select behaviorally salient data for long-term storage. Activity-dependent enhancement of hippocampal synaptic strength can store information carried in patterns of afferent neural activity (Bliss and Collingridge 1993; Moser et al. 1998; Nathe and Frank 2003; Whitlock et al. 2006). Substantial evidence suggests that long-term potentiation (LTP) of synaptic strength plays important roles in the formation of long-term memory (LTM) (Doyere and Laroche 1992; Bourtchuladze et al. 1994; Abel and Lattal 2001; Genoux et al. 2002). As such, mechanistic studies of LTP have shed valuable light on how the mammalian brain stores new information.The hippocampus receives dense noradrenergic projections from the locus coeruleus, a brain structure that can influence many vital brain functions, including attention, sleep, arousal, mood regulation, learning, and memory (Berridge and Waterhouse 2003). Both α- and β-adrenergic receptor subtypes are present on hippocampal neurons (Morrison and Foote 1986; Berridge and Waterhouse 2003), and noradrenaline (NA) acts on hippocampal β-adrenergic receptors (β-ARs) to facilitate the retention and recall of memory (Izquierdo et al. 1998; Ji et al. 2003; Murchison et al. 2004). In humans, stimulation of the noradrenergic neuromodulatory system enhances memory for emotional stimuli, and inhibition of β-ARs prevents this memory enhancement (Cahill et al. 1994; van Stegeren et al. 1998; O’Carroll et al. 1999).Consistent with the notion that selective enhancement of LTM may occur following β-AR activation, stimulation of β-ARs can also facilitate the persistence of LTP. In areas CA3 and CA1, β-AR activation facilitates the induction of long-lasting LTP when paired with certain patterns of electrical stimulation (Huang and Kandel 1996; Gelinas and Nguyen 2005). However, the mechanisms by which different patterns of stimulation control synaptic responsiveness to β-AR activation are unclear.β-ARs couple to guanine-nucleotide-binding regulatory Gs proteins to stimulate adenylyl cyclase activity and increase intracellular cAMP (Seeds and Gilman 1971; Maguire et al. 1977). A main target of cAMP signaling is activation of cAMP-dependent protein kinase (PKA), a kinase that is required for some forms of long-lasting LTP and for consolidation of hippocampal LTM (Frey et al. 1993; Abel et al. 1997; Nguyen and Woo 2003). Interestingly, the PKA-dependence of hippocampal LTP displays plasticity: Specific temporal patterns of synaptic stimulation, such as repeated and temporally spaced 100-Hz stimulation, elicit LTP that requires PKA for its expression (Woo et al. 2003). Also, spatial “enrichment” can increase the PKA-dependence of LTP in mice, and this is correlated with improved hippocampal memory function (Duffy et al. 2001). However, it is unclear whether activation of β-ARs can critically gate the PKA-dependence of LTP. In this study, we examine the effects of β-AR activation on LTP generated by various patterns of afferent stimulation in area CA1 of the hippocampus, and we determine the role of PKA in these β-AR-modulated forms of LTP.     

The role of protein synthesis in memory consolidation: progress amid decades of debate

A major component of consolidation theory holds that protein synthesis is required to produce the synaptic modification needed for long-term memory storage. Protein synthesis inhibitors have played a pivotal role in the development of this theory. However, these commonly used drugs have unintended effects that have prompted some to reevaluate the role of protein synthesis in memory consolidation. Here we review the role of protein synthesis in memory formation as proposed by consolidation theory calling special attention to the controversy involving the non-specific effects of a group of protein synthesis inhibitors commonly used to study memory formation in vivo. We argue that molecular and genetic approaches that were subsequently applied to the problem of memory formation confirm the results of less selective pharmacological studies. Thus, to a certain extent, the debate over the role of protein synthesis in memory based on interpretational difficulties inherent to the use of protein synthesis inhibitors may be somewhat moot. We conclude by presenting avenues of research we believe will best provide answers to both long-standing and more recent questions facing field of learning and memory.     

Validity of the Developmental Test of Visual-Motor Integration Supplemental Developmental Test of Visual Perception

Visual perceptual skills of school-age children are often assessed using the Supplemental Developmental Test of Visual Perception of the Developmental Test of Visual-Motor Integration. The study purpose was to consider the construct validity of this test by evaluating its scalability (interval level measurement), unidimensionality, differential item functioning, and hierarchical ordering of its items. Visual perceptual performance scores from a sample of 356 typically developing children (171 boys and 185 girls ages 5 to 11 years) were used to complete a Rasch analysis of the test. Seven items were discarded for poor fit, while none of the items exhibited differential item functioning by sex. The construct validity, scalability, hierarchical ordering, and lack of differential item functioning requirements were met by the final test version. Since 7 test items did not fit the Rasch analysis specifications, the clinical value of the test is questionable and limited.     

Measurement of equity sensitivity: a comparison of the Equity Sensitivity Instrument and Equity Preference Questionnaire

The psychometric properties of the Equity Sensitivity Instrument (Huseman, Hatfield, & Miles, 1985, 1987) and Equity Preference Questionnaire (Sauley & Bedeian, 2000) are compared. 173 undergraduate business majors completed several work attitude and personality measures. Results suggest that the Equity Preference Questionnaire may be a better measure of the equity sensitivity construct than the Equity Sensitivity Instrument which is typically used in research. Reliabilities for the scores on the Equity Sensitivity Instrument and Equity Preference Questionnaire were equivalent (coefficient alphas of .85 and .86, respectively); however, evidence for convergent and content validity was greater for the Equity Preference Questionnaire. Understanding individual differences in perceptions of equity and how best to measure these differences can affect workplace outcomes (e.g., turnover, employee engagement.     

Six Ways of Salvation: How Does Jesus Save?

Abstract : Using the model method for comparative analysis of theological theories, this article compares and contrasts six models of atonement: (1) Jesus as teacher of true knowledge; (2) Jesus as moral example and influence; (3) Jesus as the victorious champion and liberator; (4) Jesus as our satisfaction; (5) Jesus as the happy exchange; and (6) Jesus as the final scapegoat.     

Who wants to live forever? Immortality,authenticity, and living forever in the present

Death is a bad thing by virtue of its ability to frustrate the subjectively valuable projects that shape our identities and render our lives meaningful. While the presumption that immortality would necessarily result in boredom worse than death proves unwarranted, if the constraint of mortality is a necessary element for virtues, relationships, and motivation to pursue our life-projects, then death might nevertheless be a necessary evil. Mortal or immortal, it’s clear that the value of one’s life depends on its subjectively determined quality, rather than its quantity. Thus, it is imperative to live forever in the present, with flourishing always in mind.     

Eye-blink conditioning is associated with changes in synaptic ultrastructure in the rabbit interpositus nuclei

Eye-blink conditioning involves the pairing of a conditioned stimulus (usually a tone) to an unconditioned stimulus (air puff), and it is well established that an intact cerebellum and interpositus nucleus, in particular, are required for this form of classical conditioning. Changes in synaptic number or structure have long been proposed as a mechanism that may underlie learning and memory, but localizing these changes has been difficult. Thus, the current experiment took advantage of the large amount of research conducted on the neural circuitry that supports eye-blink conditioning by examining synaptic changes in the rabbit interpositus nucleus. Synaptic quantifications included total number of synapses per neuron, numbers of excitatory versus inhibitory synapses, synaptic curvature, synaptic perforations, and the maximum length of the synapses. No overall changes in synaptic number, shape, or perforations were observed. There was, however, a significant increase in the length of excitatory synapses in the conditioned animals. This increase in synaptic length was particularly evident in the concave-shaped synapses. These results, together with previous findings, begin to describe a sequence of synaptic change in the interpositus nuclei following eye-blink conditioning that would appear to begin with structural change and end with an increase in synaptic number.     

Investigating naturalistic decision making in a simulated microworld: What questions should we ask?

Computer-simulated microworlds can provide a controlled method for investigating concepts related to naturalistic decision making (NDM). However, the extent to which these tools can be used to generate meaningful outcomes is unknown. The current study used a microworld called Networked Fire Chief (NFC) to explore the range of skills and knowledge acquired as participants gained practice on the program. The complexity of the NFC NDM environment was also explored. Twenty participants each completed 20 equivalent 5-min scenarios on NFC. Interview data, behavioral data and performance scores were collected across the trials. Results confirmed that NFC provides an environment that promotes appropriate perceptual-cognitive processing for NDM. However, performance improved to only a small extent across the 20 trials in four performance areas: speed, accuracy, efficiency and planning. In addition, the number of personal and situational factors to be considered when decision making on NFC was not comparable with real-world NDM environments. Overall, results indicated that the use of microworlds for research should be regulated by an understanding of the limitations of their applicability.     

Community-Based Interventions to Reduce Low Income, African American Women's Risk of Sexually Transmitted Diseases: A Randomized Controlled Trial of Three Theoretical Models

A community-based sample of disadvantaged African American women (n = 445) was recruited to participate in 1 of 3 theoretically driven experimental interventions based on either the theory of gender and power, social learning theory, or cognitive behavioral theory. Intervention outcomes were compared with a waiting list control condition. From baseline to postintervention, women in the experimental interventions showed differential change on cognitive indices (knowledge and attitudes) and skill acquisition (partner negotiation skills, correct condom application, lubricant selection, and information-provision to social networks) whereas control participants were unchanged. Women in the 3 experimental interventions also completed follow-up assessments for 1 year following the interventions. In all 3 experimental conditions, condom use increased relative to the control group and there were no differences between the experimental interventions. Women who participated in one of the theoretically grounded interventions continued to increase condom use over the following year. Women entering new relationships reported significantly more condom use than did women who remained in ongoing relationships. The findings suggest that intervention models that have proven effective for women who engage in high-risk behavior may be less effective for women in established relationships for whom risk is primarily derived from the extrarelationship behavior of their partners.