Intrahippocampal infusions of anisomycin produce amnesia: Contribution of increased release of norepinephrine,dopamine, and acetylcholine

Intra-amygdala injections of anisomycin produce large increases in the release of norepinephrine (NE), dopamine (DA), and serotonin in the amygdala. Pretreatment with intra-amygdala injections of the β-adrenergic receptor antagonist propranolol attenuates anisomycin-induced amnesia without reversing the inhibition of protein synthesis, and injections of NE alone produce amnesia. These findings suggest that abnormal neurotransmitter responses may be the basis for amnesia produced by inhibition of protein synthesis. The present experiment extends these findings to the hippocampus and adds acetylcholine (ACh) to the list of neurotransmitters affected by anisomycin. Using in vivo microdialysis at the site of injection, release of NE, DA, and ACh was measured before and after injections of anisomycin into the hippocampus. Anisomycin impaired inhibitory avoidance memory when rats were tested 48 h after training and also produced substantial increases in local release of NE, DA, and ACh. In an additional experiment, pretreatment with intrahippocampal injections of propranolol prior to anisomycin and training significantly attenuated anisomycin-induced amnesia. The disruption of neurotransmitter release patterns at the site of injection appears to contribute significantly to the mechanisms underlying amnesia produced by protein synthesis inhibitors, calling into question the dominant interpretation that the amnesia reflects loss of training-initiated protein synthesis necessary for memory formation. Instead, the findings suggest that proteins needed for memory formation are available prior to an experience, and that post-translational modifications of these proteins may be sufficient to enable the formation of new memories.A dominant view of the molecular basis for memory is that the formation of long-term memory for an experience depends on de novo protein synthesis initiated by that experience (Davis and Squire 1984; Frey and Morris 1998; Kandel 2001; Dudai 2002; Nader 2003; Alberini 2008). This view is supported by numerous studies showing that drugs that interfere with protein synthesis by inhibiting translational processes near the time of training produce later amnesia.Despite the centrality of experience-induced protein synthesis in contemporary models of memory formation, the necessity of protein synthesis for memory consolidation and long-term potentiation (LTP) stabilization has been questioned since the beginning of experiments of this type (e.g., Flexner and Goodman 1975; Barraco and Stettner 1976; Flood et al. 1978; Martinez et al. 1981), and continues to be questioned in several recent reviews (Routtenberg and Rekart 2005; Gold 2006, 2008; Radulovic and Tronson 2008; Routtenberg 2008; Rudy 2008). There are many instances of intact memories formed in the presence of extensive inhibition of protein synthesis, and a wide range of behavioral and pharmacological manipulations can rescue memory impaired by protein synthesis inhibitors. For example, amnesia is attenuated in a graded manner by increasing the training trials and foot shock intensity in avoidance tasks (Flood et al. 1975, 1978). Moreover, a wide range of stimulants, such as amphetamine, strychnine, corticosteroids, and caffeine, block amnesia induced by anisomycin (Flood et al. 1978). Like memory, LTP is sometimes insensitive to protein synthesis inhibitors. Simultaneous inhibition of both protein synthesis and degradation does not interfere with induction and maintenance of LTP (Fonseca et al. 2006a). Also, the specific schedule and frequency of test pulses after induction of LTP determine the vulnerability of LTP to anisomycin-induced impairment; anisomycin treatment does not impair LTP unless test pulses at a rate of 1/10 sec were administered during the anisomycin exposure (Fonseca et al. 2006b).Findings that memory and LTP can survive the inhibition of protein synthesis challenge the necessity of specific training- or stimulation-initiated protein synthesis for memory formation and synaptic plasticity. Several actions of protein synthesis inhibitors offer alternative accounts for amnesia produced by these drugs. These include cell sickness (Rudy et al. 2006; Rudy 2008), activation of protein kinases and superinduction of immediate early genes (Radulovic and Tronson 2008), abnormal neural electrical activity (Agnihotri et al. 2004; Xu et al. 2005), and intrusion of neural “noise” that masks the primary changes representing memory formation (Gold 2006). Neural responses to inhibition of protein synthesis such as these may impair memory either secondary to or independent of interference with protein synthesis.Another example of the mechanisms by which inhibition of protein synthesis might impair memory is by altering neurotransmitter functions. This possibility was suggested in early studies (e.g., Flexner and Goodman 1975; Quartermain et al. 1977) and has recently been supported by studies of neurotransmitter release at the site of intra-amygdala injections of anisomycin (Canal et al. 2007). In addition to impairing later memory after inhibitory avoidance training, pretraining injections of anisomycin into the amygdala produced rapid and dramatic increases in release of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) at the sites of injection. The release of NE and DA then plummeted below baselines from 2 to 6 h after anisomycin injections, recovering within 48 h after anisomycin injection. The possibility that these neurochemical changes contribute to anisomycin-induced amnesia was supported by studies showing attenuation of amnesia in rats pretreated with intra-amygdala injections of the β-adrenergic receptor antagonist propranolol, apparently acting to blunt the effects of the large increases in release of NE after anisomycin injection. In addition, amnesia was produced by injections of high doses of norepinephrine into the amygdala.In addition to amnesias produced by anisomycin injections into the amygdala, as above, anisomycin also impairs memory when administered to other memory systems, including the hippocampus, where anisomycin impairs inhibitory avoidance memory (Quevedo et al. 1999; Debiec et al. 2002; Milekic et al. 2006). The present study extends the prior findings (Canal et al. 2007) in several respects. Experiments presented here determine whether anisomycin injections into the hippocampus result in changes in release of the catecholamines, NE and DA, at the site of injection, as seen previously in the amygdala. Additionally, the present experiments determine whether intrahippocampal injections of anisomycin result in increased release of acetylcholine, a neurotransmitter not examined in the previous study. To examine parallels with earlier amygdala findings, a further experiment determines whether intrahippocampal pretreatment with propranolol is effective in attenuating anisomycin-induced amnesia.     

Does natural law have non-normative foundations?

This paper addresses one aspect of the natural law theory of Germain Grisez. According to Grisez, practical reason identifies the goods of human life prior to the invocation of any moral or normative notions. It can thus provide a non-normative foundation for moral theory. I present Grisez’s position and argue that the apparently non-normative aspect of natural law cannot support the moral position built upon it. I argue, in particular, that practical principles, as Grisez understands them, are best understood as speech acts. If this is correct, it is possible to develop a sceptical challenge to Grisez’s position. I am grateful to Michael Frede, Robert George, Richard Holton, Philip Pettit, and two anonymous reviewers for many helpful comments on this paper. This paper was presented at a seminar in the Department of Philosophy at Princeton University in November 1987, and I am grateful for the comments I received from the audience—in particular, Germain Grisez—on that occasion.     

Self-image of punk rock and nonpunk rock juvenile delinquents

The purpose of this study was to provide some understanding of punk rockers. Although they have received media attention in the depiction of their unusual hair and clothing styles, there is limited information about their personalities. In this study a delinquent group of punk rockers was compared with a delinquent group of nonpunk rockers on self-image, a personality factor related to teenagers' mental health and adjustment. Each group consisted of 20 subjects, 15 males and 5 females, aged 14 to 17. Subjects were administered a Screening Questionnaire, the Offer Self-Image Questionnaire (OSIQ), and the California Psychological Inventory (CPI) while detained at a Southern California juvenile hall. Interest in the CPI was focused on the Socialization (So) scale. A one-way analysis of variance was conducted on each of the five OSIQ dimensions. No significant differences were found between the groups. The importance of these findings is that even though punk rockers may look and act unusual, they may actually be similar to other groups. Due to possibly invalid CPI test protocols a t test and content analysis of the CPI So scale was conducted. The t test was significant and the chi-square analyses were significant on two questions of the CPI So scale. This suggests that there may be differences between the groups in terms of family dynamics. Professionals can utilize these findings in their work with this misunderstood segment of society.     

Bayesian Risk Assessment in Genetic Testing for Autosomal Dominant Disorders with Age-Dependent Penetrance

Risk assessment is an essential component of genetic counseling and testing, and the accuracy of risk assessment is critical for decision making by consultands. However, it has been shown that genetic risk calculations may have high error rates in practice. Risk calculations for autosomal dominant disorders are frequently complicated by age-dependent penetrance and sensitivities of less than 100% in genetic testing. We provide methods of risk calculation for prototypical pedigrees of a family at risk for an autosomal dominant disorder with age-dependent penetrance. Our risk calculations include scenarios in which the sensitivity of genetic testing is less than 100%, and in which the sensitivity of genetic testing varies for different family members at risk. Our Bayesian methods permit autosomal dominant disease probabilities to be calculated accurately, taking into account all relevant information. Our methods are particularly useful for hereditary cancer syndromes, in which genetic testing can seldom achieve 100% sensitivity. Our methods can be applied to many different scenarios, including those where the sensitivity of genetic testing varies for different family members at risk. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.     

Learning and forgetting in schizophrenia

Recent studies of patients with schizophrenia have consistently demonstrated marked deficits on measures of initial learning. However, contradictory results have been reported concerning retention and forgetting. The present study examined the level of initial and delayed recall of stories and visual figures in a group of 76 patients with schizophrenia and 51 normal controls. Schizophrenia patients demonstrated marked impairments in initial and delayed recall as well as significantly worse percentage retention scores. However, schizophrenia patients and healthy controls individually matched on level of initial recall had nearly identical delayed recall performance. The results suggest a primary deficit in the initial acquisition of information rather than an accelerated rate of forgetting in schizophrenia.     

An open-label trial of bromocriptine in nonfluent aphasia: a qualitative analysis of word storage and retrieval

Anomia is a commonly found in aphasia and has been attributed to a loss of representations (storage deficit) or to a loss of access to these representations (retrieval deficit). Bromocriptine, a dopamine agonist, was tested on four patients, two men and two women, with nonfluent aphasia. The patients were tested in an open-label ABBA design using a stochastic model that measured the degree of storage and retrieval deficits. All patients showed significant improvements in word retrieval. Bromocriptine may be a useful adjunct in the treatment of selected patients with a nonfluent aphasia in which retrieval deficits play a major role.     

Reducing sedentary behavior: the relationship between park area and the physical activity of youth

This study was designed to determine whether the characteristics of the neighborhood environment are related to the substitution of physical activity for sedentary behavior among youth. Fifty-eight 8- to 15-year-old youth were studied in a within-subjects crossover design with three phases: baseline, increased sedentary behavior, and decreased sedentary behavior. The relations between changes in physical activity and design, diversity, and density attributes of the neighborhood environment were determined using random coefficient models. Compared with girls, boys showed greater increases in physical activity when sedentary behaviors were reduced and greater decreases in physical activity when sedentary behaviors were increased. Greater access to parks was associated with greater physical activity when sedentary behaviors were reduced.     

Visual noise reveals category representations

How are categories represented in human memory? Exemplar models assume that a category is represented by individual instances from that category that have been experienced. More generally, a category might be represented by multiple templates stored in memory. A new item is classified according to its similarity to these templates.Prototype models represent a category with a single summary abstraction (i.e., a single template), often the central tendency of the experienced items. A new item is classified according to its similarity to these category prototypes. Here, we show how a technique for correlating observers’ responses with external noise can be used not only to distinguish single- from multiple-template representations, but also to induce the form of these templates. The technique is applied to two tasks requiring categorization of simple visual patterns; the results demonstrate that observers used multiple traces to represent their categories, and thus highlight the procedure’s potential for use in more complex settings.     

Visual memory decay is deterministic

After observers see an object or pattern, their visual memory of what they have seen decays slowly over time. Nearly all current theories of vision assume that decay of short-term memory occurs because visual representations are progressively and randomly corrupted as time passes. We tested this assumption using psychophysical noise-masking methods, and we found that visual memory decays in a completely deterministic fashion. This surprising finding challenges current ideas about visual memory and sets a goal for future memory research: to characterize the deterministic "forgetting function" that describes how memories decay over time.     

Adrenocortical reactivity and social competence in seven year-olds

We examined temporal changes in salivary cortisol in response to a peer self-presentation task in a group of seven year-olds, some of whom scored high, average, and low on the Harter, 1983 Perceived Social Competence Scale. Salivary cortisol was measured pre-task, and 20 and 35 min post-task. We found a significant relation between individual differences in perceived social competence and salivary cortisol reactivity in response to the task. Children who perceived themselves as socially competent exhibited a significantly greater decrease in salivary cortisol from 20 to 35 min following the task compared with children who self-reported a relatively lower degree of social competence. We speculate on the meaning of salivary cortisol changes in childrens socio-emotional development.