A mutant mouse with a highly specific contextual fear-conditioning deficit found in an N-ethyl-N-nitrosourea (ENU) mutagenesis screen

Targeted mutagenesis in mice has shown that genes from a wide variety of gene families are involved in memory formation. The efficient identification of genes involved in learning and memory could be achieved by random mutagenesis combined with high-throughput phenotyping. Here, we provide the first report of a mutagenesis screen that has generated memory mutants in the mouse. We tested a group of N-ethyl-N-nitrosourea (ENU) mutagenized mice in the conditioned fear paradigm. We screened for both dominant and recessive mutations that caused impairments in contextual or tone fear conditioning. Heritability testing confirmed three fear conditioning mutants, i.e., Forgetful, Slowlearner, and Scatterbrain. All three have a learning or short-term memory deficit in contextual fear conditioning. Forgetful was further characterized and showed a highly specific phenotype. The contextual fear-conditioning deficit was apparent when Forgetful was trained with tone-shock pairings, but not when trained with shock alone. The deficit was not due to changes in shock sensitivity or anxiety. Forgetful was not impaired in two other memory tests (hidden platform version of Morris water maze and object recognition). Our data show that a mutagenesis screen can generate mutant mice with highly specific memory phenotypes that can supplement existing mice with targeted mutations. Mapping of Slowlearner found linkage to a region of chromosome 12 (LOD score of 6.5 close to D12Mit171), which suggests that ENU mutants should enable the positional cloning of genes involved in memory formation.     

Status,testosterone, and human intellectual performance: stereotype threat as status concern

Results from two experiments suggest that stereotype-threat effects are special cases of a more general process involving the need to maintain or enhance status. We hypothesized thatsituations capable of confirming a performance stereotype might representeither a threat to status or an opportunity for enhancement of status,depending on the nature of the stereotype. The positive relationship betweenbaseline testosterone and status sensitivity led us to hypothesize that hightestosterone levels in males and females would amplify existing performanceexpectations when gender-based math-performance stereotypes were activated.In Study 1, high-testosterone females performed poorly on a math test when anegative performance stereotype was primed. In Study 2, high-testosteronemales excelled on a math test when a positive performance stereotype wasprimed. The moderating effect of testosterone on performance suggests that astereotype-relevant situation is capable of conferring either a loss or again of status on targets of the stereotype.     

A prospective study of stressful life events and schizophrenic relapse

In this prospective, longitudinal study, 11 recent-onset schizophrenic outpatients who met criteria for psychotic relapse or significant psychotic exacerbation during a 1-year period of standardized maintenance medication, and 19 patients who did not relapse during this follow-up period, were interviewed monthly regarding life events. As hypothesized, for relapsing patients, a significantly higher number of independent life events (those not the result of symptomatology or personal influence) occurred in the month preceding relapse. This increase was apparent relative to either the analogous month of a "nonrelapse" period in the same patient or the average number of independent events per month during a 1-year standardized medication period for nonrelapsing patients. The methodological advances of this design as well as the consistency of these findings with those of previous retrospective studies supports the hypothesis that life events may sometimes "trigger" schizophrenic episodes.     

Adjunctive brainstem behaviors in the rat

Adjunctive behaviors refers to behaviors that are “out of context” and/or excessive in amount. The terminology was first used for unexplained behaviors associated with food pellet ratio contingencies in food deprived rats (Falk, 1971). Clinically, unrelated and complex excessive behaviors were also noted with brainstem and diencephalic discharges (Andy, 1986, 1989 and 1995; Andy and Jurko, 1986). The objective of this study was to develop a model of brainstem generated adjunctive behaviors in the rat. Method: Sixty-one adult rats were used. Kindling was induced by mechanical and DC electrical perturbations in the midbrain. Nine different treatment groups were established in which lesions and drugs were used separately and in different combinations. Cocaine was used to accentuate, and dextrorphan to attenuate the kindling process. Behaviors were visually analyzed and recorded by video camera; they were not quantified. DC stimulation and EEGs were done with Grass instruments. Recording and stimulation sights were verified histologically. Results: A total of 45 different behaviors were elicited. DC stimulation kindled subjects had significantly more behaviors than did electrode insertion alone and cocaine alone. However, cocaine combined with DC stimulation increased the number and intensity of the kindled behaviors. Dextrorphan tended to facilitate catatonic and sleep states. Behaviors occurred randomly and were unrelated, even when they occurred in clusters. The behaviors were associated with four abnormal EEG discharge patterns. Conclusion: We speculate that brainstem behaviors are innate adjunctive drives that are generated in the brainstem reticular formation. They are monitored by the cortex and partially modified by environmental and cortical inputs.     

Which behaviours? Identifying the most common and burdensome behaviour changes in amyotrophic lateral sclerosis

Behaviour change is increasingly recognised as a common feature of amyotrophic lateral sclerosis (ALS), and may be similar to that seen in frontotemporal dementia (FTD). The behaviours most disturbed in ALS, and those that relate most significantly to caregiver burden, however, have not been well established. Forty ALS participants and their caregivers, and 27 age- and gender-matched healthy controls and their relatives, participated in this study. ALS participants were assessed on a disease rating scale, and caregivers and control informants completed the revised version of the Cambridge Behaviour Inventory and a measure of burden. ALS caregivers reported significantly more disturbance than healthy control informants on the functional domains of everyday skills, self-care, and sleep, and in the behavioural domains of mood and motivation. There were no differences between groups in frequency of memory and orientation difficulties, or behaviours characteristic of FTD, such as changes to eating habits or stereotypic and motor behaviour, indicating that the behavioural profile in ALS may differ from FTD. In the ALS group, the domains with the strongest relationship to caregiver burden were everyday skills, motivation and memory, likely because poor motivation, memory dysfunction and difficulties completing activities of daily living require more carer support via direct supervision, prompting or hands on care. Services to support ALS patients and caregivers need to provide targeted interventions for those functional and behavioural changes which are most burdensome in the disease.     

The Effect of Non-Stroke Cardiovascular Disease States on Risk for Cognitive Decline and Dementia: A Systematic and Meta-Analytic Review

Cardiovascular disease is associated with increased risk for cognitive decline and dementia, but it is unclear whether this risk varies across disease states or occurs in the absence of symptomatic stroke. To examine the evidence of increased risk for cognitive decline and dementia following non-stroke cardiovascular disease we conducted two independent meta-analyses in accordance with PRISMA guidelines. The first review examined cardiovascular diagnoses (atrial fibrillation, congestive heart failure, periphery artery disease and myocardial infarction) while the second review assessed the impact of atherosclerotic burden (as indicated by degree of stenosis, calcification score, plaque morphology or number of plaques). Studies eligible for review longitudinally assessed risk for clinically significant cognitive decline and/or dementia and excluded stroke and cognitive impairment at baseline. Summary statistics were computed via the inverse variance weighted method, utilising Cox Proportional Hazards data (Hazard Ratios, HR). Both atrial fibrillation (n = 5, HR = 1.26, 95% CI [1.12, 1.43]) and severe atherosclerosis (n = 4, HR = 1.59, 95% CI [1.12, 2.26]) emerged as significant risk factors for cognitive decline and/or dementia. A small set of studies reviewed, insufficient for meta-analysis, examining congestive heart failure, peripheral artery disease and myocardial infarction suggested that these conditions may also be associated with an increased risk of cognitive decline/dementia. In the absence of stroke, patients with atrial fibrillation or generalised atherosclerosis are at heightened risk for cognitive deterioration. Nonetheless, this paper highlights the need for methodologically rigorous and prospective investigation of the relationship between CVD and dementia.     

A Global Happiness Scale for Measuring Wellbeing: A Test of Immunity Against Hedonism

Wellbeing is gaining acceptance as an indicator of social and economic progress by many governments and agencies. As such the scientific community is actively engaging in developing scales to gauge wellbeing at a community and national level. A common approach used comprises of asking subjects a single question on happiness. A major issue with single questions is the difficulty to establish reliability. Recognising this issue, researchers have developed an itemised Global Happiness Scale (GHS) comprising of four items. GHS is reported to have satisfactory reliability and convergent validity and the scale has been translated into a number of different languages. However to ensure GHS is measuring happiness at a global level, that is measuring eudaimonic happiness, it is necessary to ensure it is immune to hedonic happiness. GHS had not been previously subjected to a hedonic immunity test, which the current study addressed. This paper reports and discusses the reliability and hedonic immunity of GHS.     

The Intensive Other: Deleuze and Levinas on the Ethical Status of the Other

This paper develops a response to the ethical conception of the human Other formulated by Gilles Deleuze in his review of Michel Tournier’s 1967 novel Friday. The central contention here is that although Deleuze develops a compelling notion of intensive ethics in response to Tournier’s novel, that ethics also remains deeply problematic in refusing to ascribe a positive role to the human Other. My wager is that some of these problems can be brought to light by placing Deleuze’s philosophy in dialogue with that of Emmanuel Levinas. As I seek to show, Levinas’s philosophy of alterity not only reveals that Deleuze is mistaken in failing to ascribe a positive ethical role to the human Other, but also begins to point the way toward a more positive conception of ethics that does not oppose the Other to the intensive realm that Deleuze so much values.