Trace fear conditioning is enhanced in mice lacking the delta subunit of the GABAA receptor

The delta subunit of the GABA(A) receptor (GABA(A)R) is highly expressed in the dentate gyrus of the hippocampus. Genetic deletion of this subunit reduces synaptic and extrasynaptic inhibition and decreases sensitivity to neurosteroids. This paper examines the effect of these changes on hippocampus-dependent trace fear conditioning. Compared to controls, delta knockout mice exhibited enhanced acquisition of tone and context fear. Hippocampus-independent delay conditioning was normal in these animals. These results suggest that reduced inhibition in the dentate gyrus facilitates the acquisition of trace fear conditioning. However, the enhancement in trace conditioning was only observed in female knockout mice. The sex-specificity of this effect may be a result of neuroactive steroids. These compounds vary during the estrus cycle, can increase GABAergic inhibition, and have been shown to impair hippocampus-dependent learning. We propose that activation of GABA(A)Rs by neuroactive steroids inhibits learning processes in the hippocampus. Knockouts are immune to this effect because of the reduced neurosteroid sensitivity that accompanies deletion of the delta subunit. Relationships between neurosteroids, hippocampal excitability, and memory are discussed.     

Neurosteroids in the Hippocampus: Neuronal Plasticity and Memory

The hippocampus, which is critically involved in learning and memory processes, is known to be a target for the neuromodulatory actions of steroid hormones produced by the adrenal glands and gonads. Much of the work of B.S. McEwen and collaborators has focused on the role of glucocorticosteroids and estrogen in modulating hippocampal plasticity and functions. In addition to hormones derived from the endocrine glands, cells in the hippocampus may be exposed to locally synthesized neurosteroids, including pregnenolone, dehydroepiandrosterone and their sulfated esters as well as progesterone and its reduced metabolites. In contrast to hormones derived from the circulation, neurosteroids have paracrine and/or autocrine activities. In the hippocampus, they have been shown to have trophic effects on neurons and glial cells and to modulate the activity of a variety of neurotransmitter receptors and ion channels, including type A gamma-aminobutyric acid, N-methyl-D-aspartate and sigma receptors and N- and L-type Ca2+ channels. There is accumulating evidence that some neurosteroids, in particular pregnenolone sulfate, have strong influences on learning and memory processes, most likely by regulating neurotransmission in the hippocampus. However, the hippocampus is not the only target for the mnesic effects of neurosteroids. Associated brain regions, the basal nuclei of the forebrain and the amygdaloid complex, are also involved. Some neurosteroids may thus be beneficial for treating age- or disease-related cognitive impairments.     

GABA(A) receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders

Protracted social isolation in laboratory animals causes stress, which induces a variety of behavioral abnormalities including increased aggressiveness, anxiety-related behaviors, cognitive deficits and hyper locomotion. Many of these disorders are similar to the symptoms found in psychiatric disorders, such as depression, anxiety, premenstrual dysphoria and posttraumatic stress disorders (PTSD). Recent studies have demonstrated that male mice that have been socially isolated for more than 4 weeks show: (a) reduced responsiveness of GABA(A) receptors (GABA(A)-R) to the administrations of GABA mimetic drugs at GABA(A)-R; (b) downregulated biosynthesis of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP) (allopregnanolone: ALLO), a neurosteroid with a potent positive allosteric modulatory effect on the action of GABA on GABA(A)-R; and (c) alterations in the expression of GABA(A)-R subunits (i.e. a decrease of alpha1/alpha2 and gamma2 subunits and an increase of alpha4 and alpha5 subunits). The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) and its congener norfluoxetine (Nor-FLX), when administered systemically at nmol/kg doses, normalize the reduced content of brain ALLO and the reduced responsiveness of GABA(A)-R to GABA mimetic drugs (i.e. pentobarbital) and also attenuate aggressive behavior in socially isolated mice in a stereospecific manner. Although these compounds inhibit ex vivo serotonin reuptake into brain tissue, their SSRI activities require high micromol/kg dose ranges and are not stereospecific. These studies suggest that in socially isolated mice, abnormalities of GABA(A)-R signal transduction are attributable to the downregulation of ALLO production and to a switch in heteropentameric GABA(A)-R subunit assembly composition. Hence, the normalization of ALLO biosynthesis may be a new target for the development of drugs effective for psychiatric disorders related to neurosteroid biosynthesis downregulation.     

Endocrinology of menopausal transition and its brain implications

The central nervous system is one of the main target tissues for sex steroid hormones, which act on both through genomic mechanisms, modulating synthesis, release, and metabolism of many neuropeptides and neurotransmitters, and through non-genomic mechanisms, influencing electrical excitability, synaptic function, morphological features, and neuron-glia interactions. During the climacteric period, sex steroid deficiency causes many neuroendocrine changes. At the hypothalamic level, estrogen withdrawal gives rise to vasomotor symptoms, to eating behavior disorders, and altered blood pressure control. On the other hand, at the limbic level, the changes in serotoninergic, noradrenergic, and opioidergic tones contribute to the modifications in mood, behavior, and nociception. Hormone replacement therapy (HRT) positively affects climateric depression throughout a direct effect on neural activity and on the modulation of adrenergic and serotoninergic tones and may modulate the decrease in cognitive efficiency observed in climaterium. The identification of the brain as a de novo source of neurosteroids, suggests that the modifications in mood and cognitive performances occurring in postmenopausal women may also be related to a change in the levels of neurosteroids. These findings open new perspectives in the study of the effects of sex steroids on the central nervous system and on the possible use of alternative and/or auxiliary HRT.     

Social isolation stress-induced aggression in mice: a model to study the pharmacology of neurosteroidogenesis

Long-term social isolation of laboratory animals is a model to study the behavioral and neurochemical consequences of the absence of social interaction in rodents. Many of the symptoms induced by isolation resemble depression and anxiety disorder symptomatology. Our studies have revealed that male mice socially isolated for more than 4 weeks, exhibit increased aggressiveness, a reduced responsiveness to GABA(A) receptor acting drugs, and a downregulation of brain levels of 3alpha,5alpha-tetrahydroprogesterone (allopregnanolone: 3alpha,5alpha-THP), a neurosteroid endowed with potent positive allosteric modulatory activity of the action of GABA at various GABA(A) receptor subtypes. This downregulation of 3alpha,5alpha-THP appeared to be associated with the reduction of brain type I 5alpha-reductase mRNA and protein expression. Systemic administration of the selective serotonin reuptake inhibitor fluoxetine and its metabolite norfluoxetine normalized brain 3alpha,5alpha-THP content and reduced responsiveness to GABA(A) mimetic drugs in a stereospecific manner. These drugs in nanomolar doses also reduced social isolation-induced aggressiveness with the same stereospecificity as detected in their action on 3alpha,5alpha-THP brain content, while their ex vivo inhibition of serotonin reuptake occurred at high micromolar doses and lacked stereospecificity. From these results we infer that the brain 3alpha,5alpha-THP content physiologically upregulates GABA(A) receptor responsiveness to GABA and that social isolation induces a reduction of brain 3alpha,5alpha-THP content that is probably causally related to the onset of aggression.     

Characteristics of body excursion during a static upright posture in elderly people with central nervous system disorders and with other disorders from the viewpoint of body-excursion parameters

This study aimed to compare characteristics of body excursion of healthy elderly and elderly people with disorders. The participants were 38 healthy elderly who were at home (Healthy Elderly group) and 24 elderly people with disorders. The latter consisted of two groups: 12 in the Central Nervous System Disorders group with vestibular organ or central nervous system disorders, and 12 in the Other Disorders group with other system disorders. 34 parameters were selected from six domains: distance, distribution of amplitude, area, velocity, power spectrum, and vector. When compared with the Healthy Elderly group, the Central Nervous System Disorders group was judged abnormal on many parameters and showed large and quick body excursion characteristics, particularly in left-right excursion. The Other Disorders group showed different characteristics in the size of the left-right excursion and velocity of the front-back excursion. However, compared with the Central Nervous System Disorders group, very few people in the Other Disorders group were judged abnormal, and they showed slower velocity for front-back excursion.     

Effects of maternal stress on development and behaviour in rat offspring

Retrospective studies suggest that gestational stress in humans can delay the attainment of developmental milestones, increase the incidence of allergic reactions and respiratory infections and cause behavioural abnormalities in the children. Our studies and others have shown that prenatal stress in rats can mimic several of these developmental and behavioural alterations. These include a suppression of immune function, but also enhanced sensitivity to allergens. Prenatally-stressed rats, like children, show a reduced propensity for social interaction and increased anxiety in intimidating or novel situations. They have physiological and behavioural alterations consistent with depressive symptoms, including a phase-shift in their circadian rhythm for corticosterone, sleep abnormalities, and greater acquisition of learned helplessness under appropriate conditions. Prenatally-stressed male rats also show demasculinisation and feminisation of their sexual behaviour. The developmental and behavioural abnormalities in prenatally-stressed offspring may be mediated by alterations in the activity of endogenous opioids or neurosteroids, since several of them can be corrected by maternal administration of an opioid antagonist or by drugs like diazepam and allopregnanolone that modulate GABA transmission.     

Critical flicker fusion in normal elderly subjects; a cross-sectional community study

Critical Flicker Fusion Thresholds (CFFTs) were measured in 644 elderly people identified from community-based general practice records, and the relationship of CFFT with age was investigated. The CFFT was measured using the method of limits with mean scores for three ascending (flicker/fusion) and three descending (fusion/flicker) presentations being recorded. The difference between the ascending and descending means was found to be significantly correlated with age (r=−0.131,P<0.001) and may reflect a reduced sensitivity of the Central Nervous System to suprathreshold flicker with increasing age. The results suggest that CFFT measurement has an important role to play in gerontological research as an objective measure of cognitive aspects of the ageing process.     

Muscle fatigue as an investigative tool in motor control: A review with new insights on internal models and posture–movement coordination

Muscle fatigue is a common phenomenon experienced in everyday life which affects both our force capacity and movement production. In this paper, we review works dealing with muscle fatigue and motor control and we attempt to demonstrate how the Central Nervous System deals with this particular state. We especially focus on how internal models – neural substrates which can estimate the current state as well as the future state of the body – face this internal perturbation. Moreover, we show that muscle fatigue is an interesting investigative tool in understanding the mechanisms involved in posture–movement coordination.     

Human placental corticotropin-releasing factor (CRF) in the adaptive response to pregnancy

Several findings suggest a role of placental hormones in the regulation of maternal and fetal physiology during pregnancy. The placenta and its accessory membranes, amnion and chorion, although of fetal origin, actually undertake the role of intermediary barriers and active messengers in the maternal-fetal dialogue. They synthesize, metabolize and serve as targets for numerous hormones and cytokines which control all aspects of pregnancy and parturition. Among these, corticotropin-releasing factor (CRF) has been one of the most investigated in the last decade. The secretion of placental CRF is autonomous, but increasing evidence indicates that maternal or fetal physiological and pathological conditions may influence such secretion. In the event of acute or chronic metabolic, physical or infection stress, the placenta takes part in a stress syndrome by releasing CRF, which may contribute to restore local blood flow, and to influence the timing of delivery. Placental CRF and cytokines produced in case of intrauterine infection may activate labour, thereby helping the fetus to escape from a hostile environment.On the background of maternal and/or fetal stress elicited by a number of pathological conditions, CRF appears to play a role in coordinating adaptive changes in uterine perfusion,maternal metabolism, fluid balance and possibly uterine contractility.     

Steroid Hormone Modulation of Hippocampal Dependent Spatial Memory

Recent studies show that the adult CNS is capable of considerable re-structuring and re-growth, a property previously thought limited to the developmental period. Hormones play an important role in many of these plastic processes, and the hippocampus, as a target for all the major classes of steroid hormones, undergoes considerable remodeling. Since it is critical for mediating tasks requiring spatial memory, the hippocampus can serve as an important model for understanding not only the mechanisms underlying plasticity of brain circuits but also how these changes impact on a higher order function, spatial memory. In this review, the effects of steroid hormones on hippocampal remodeling are discussed, and the ability of estradiol to enhance spatial memory as well as the ability of both excessive or diminished corticosteroid levels to impair spatial memory are described. The neural mechanisms for these effects, as well as previous and current contributions of McEwen and colleagues to this expanding area of research, are discussed.     

汉字笔迹与个性测评研究

本文采用汉字笔迹测量法和80－8神经类型量表法对大、中、小学生共计2153人进行了团体测验,各项测量指标所得到的数据,经统计检验,其主要结论如下：1．笔迹特征表现为年龄越小,以直笔、重笔、慢速、光边占的比例越大,13岁以后,笔迹特征出现明显分化,这表明,个性在13、14岁年龄阶段开始加速形成与发展．2．笔迹书写形式、书写速度、书写压力及稳定性等心理特征指标与其神经类型特征有密切的关系．3．根据笔迹书写形式、速度、压力及稳定性等基本特征指标的不同组合,划分为8种气质类型,并在实际应用中获得较为满意的效果．     

Critical flicker fusion in primary degenerative dementia of the alzheimer’s type (PDDAT): Clinical implications (II)

Critical Flicker Fusion Threshold (CFFT) and the difference between fusion and flicker thresholds were examined in 23 female and three male patients with Primary Degenerative Dementia of the Alzheimer’s type (PDDAT). The control group consisted of age, sex, and occupational class-matched, normal volunteers. Patients had a mean age of 81.7 years ±6.05 (range 67–89); diagnosis was based on DSM-IIIR criteria. The psychophysical method of limits was used to measure three ascending (fusion) and three descending (flicker) means the average being the CFFT. Both the CFFT and the flicker thresholds were able to distinguish between patients and volunteers at a high level of statistical significance (t=2.054, df=50, p<0.0018 and t=?4.903, df=50, p<0.0000 respectively). Sixty-five percent of patients had CFFT scores below 1.96 SD of the volunteer CFFT mean and 85 percent of patients had flicker thresholds below 1.96 SD of the volunteer flicker mean. The fusion thresholds were not significantly different in the two groups but the fusion thresholds were significantly greater than the flicker thresholds in patients (t=5.617, df=25, p<0.0000). One interpretation of the results in that patients with PDDAT have a significant reduction in the sensitivity of the Central Nervous System to suprathreshold flicker. Accurate diagnosis of early PDDAT (probable Alzheimer’s disease) continues to remain one of the most difficult areas in dementia research. The use of simple quantitative measures such as CFFT may have an important role to play in the overall assessment of patients with PDDAT.     

Effect of catatoxic steroids upon lidocaine intoxication

Various steroids have been shown to influence the activity of psychotropic hormones and drugs. Among these, we distinguish “syntoxic” steroids which act by inhibiting excessive reactions to various agents and “catatoxic” steroids which actually destroy certain toxicants and hormones often through the induction of hepatic microsomal enzymes. Thus, the liver can play a decisive role in psychosomatic interrelations by regulating the blood clearance of agents affecting the nervous system. To illustrate these principles, new observations are presented which show that certain catatoxic steroids offer considerable protection against lidocaine, an anesthetic, analgesic drug. These findings may serve as an example showing how modern research techniques may help us to analyze the possible relationships between the liver and the mind, which were intuitively suspected since Hippocrates created the term “melancholia.”     

The Effect of Boundaries on Space Estimation

C. U. Ariëns Kappers, G. C. Huber, &; E. C. Crosby. The Comparative Anatomy of the Nervous System of Vertebrates, Including Man. Two volumes. New York: Macmillan, 1936. Pp. xvii+864; xi+981. $16.00. Reviewed by Morton A. Rubin.     

Primary melanoblastoma as a cause of occlusive hydrocephalus

Primary melanoblastomas of the Central Nervous System are comparatively rare tumors. Lumpy or diffuse forms may occur either alone or in combination. On the basis of actual case histories, diffuse cerebral and medullary melanoblastoma is presented as a rare cause of occlusive hydrocephalus.     

A Multicriteria Spatial Decision Support System Development for Siting a Landfill in the Province of Torino (Italy)

The present paper proposes a spatial multicriteria approach for supporting Decision‐Makers in the siting process of a Municipal Solid Waste landfill in the Province of Torino (Italy). In particular, the contribution illustrates the development of a Multicriteria‐Spatial Decision Support System based on the integration of Geographic Information Systems and a specific Multicriteria Decision Analysis technique, named Analytic Network Process (ANP). This technique, which represents the generalization of the more well‐known Analytic Hierarchy Process to dependences and feedbacks, is particularly suitable for dealing with complex decision problems which are characterized by inter‐relationships among the elements at stake. The application allows the dependence relationships among the criteria to be assessed, and the relative importance of all the elements that play an influence on the final choice to be evaluated. The purpose of the study is to generate a suitability map of the area under analysis for locating a waste landfill, paying particular attention to the contribution that the spatial ANP offers to sustainability assessments of undesirable facilities. To this end, the simple network structure has been used and both exclusionary and non‐exclusionary criteria have been identified and grouped into clusters. The results are obtained in the form of suitability maps analysed through ilwis 3.3 software (52North, ITC, Enschede, The Netherlands) and have been further verified through a sensitivity analysis with reference to the clusters priorities in order to test the robustness of the proposed model. The main findings of this research have proved that the spatial ANP is a useful tool to help technicians to make their decision process traceable and reliable. Moreover, this approach helps Decision‐Makers to undertake a sound reflection of the siting problem. Finally, the implementation of the spatial ANP technique gives an originality value to the present research because it represents one of the first applications at both the national and international level. Copyright © 2011 John Wiley & Sons, Ltd.     

Stress management effects on psychological, endocrinological, and immune functioning in men with HIV infection: empirical support for a psychoneuroimmunological model

We present a psychoneuroimmunologic (PNI) model for Human Immunodeficiency Virus (HIV) infection, describe a 10-week group-based cognitive behavioral stress management (CBSM) intervention and summarize research demonstrating the effects of this intervention on mood, neuroendocrine (Hypothalamic Pituitary Adrenal [HPA], Hypothalamic Pituitary Gonadal [HPG] and Sympathetic Nervous System [SNS] hormones) and immune system status (lymphocyte subsets, anti-viral immune function) in HIV-infected persons. This work demonstrates that changes in relaxation skills, cognitive coping strategies and social support may mediate the mood effects of CBSM, and that these mood changes may mediate adrenal hormone regulation indicated by reductions in 24-h urinary cortisol (with reduced depressed mood) and norepinephrine (with reduced anxiety) and increases in serum DHEA-S and testosterone levels (with reduced depressed mood). Results also suggest that CBSM-related changes in production of these hormones may explain, in part, the effects of this intervention on short-term changes in IgG antibody titers to herpesviruses (with increased DHEA-S-to-cortisol ratio), and longer-term changes in lymphocyte subpopulations such as CD8 suppressor/cytotoxic cells (with reductions in urinary noradrenaline output) and transitional na?ve CD4 cells (with reductions in urinary cortisol output). Thus a multi-modal CBSM intervention is associated with alterations in mood, neuroendocrine functioning and immunologic status that may have health implications for HIV infection.     

Loss aversion in the eye and in the heart: The autonomic nervous system's responses to losses

The common view in psychology and neuroscience is that losses loom larger than gains, leading to a negativity bias in behavioral responses and Autonomic Nervous System (ANS) activation. However, evidence has accumulated that in decisions under risk and uncertainty individuals often impart similar weights to negative and positive outcomes. We examine the role of the ANS in decisions under uncertainty, and its consistency with the behavioral responses. In three studies, we show that losses lead to heightened autonomic responses, compared to equivalent gains (as indicated by pupil dilation and increased heart rate) even in situations where the average decision maker exhibits no loss aversion. Moreover, in the studied tasks autonomic responses were not associated with risk taking propensities. These results are interpreted by the hypothesis that losses signal the subjective importance of global outcome patterns. Copyright © 2010 John Wiley & Sons, Ltd.     

Ovarian hormones, aging and stress on hippocampal synaptic plasticity

The ovarian steroid hormones estradiol and progesterone regulate a wide variety of non-reproductive functions in the central nervous system by interacting with molecular and cellular processes. A growing literature from studies using rodent models suggests that 17β-estradiol, the most potent of the biologically relevant estrogens, enhances synaptic transmission and the magnitude of long-term potentiation recorded from in vitro hippocampal slices. In contrast, progesterone has been shown to decrease synaptic transmission and reduce hippocampal long-term potentiation in this model system. Hippocampal long-term depression, another form of synaptic plasticity, occurs more prominently in slices from aged rats. A decrease in long-term potentiation magnitude has been recorded in hippocampal slices from both adult and aged rats behaviorally stressed just prior to hippocampal slice tissue preparation and electrophysiological recording. 17β-estradiol modifies synaptic plasticity in both adult and aged rats, whether behaviorally stressed or not by enhancing long-term potentiation and attenuating long-term depression. The studies discussed in this review provide an understanding of new approaches used to investigate the protective effects of ovarian hormones against aging and stress, and how these hormones impact age and stress-related learning and memory dysfunction.