Blockade of IP3-mediated SK channel signaling in the rat medial prefrontal cortex improves spatial working memory

Planning and directing thought and behavior require the working memory (WM) functions of prefrontal cortex. WM is compromised by stress, which activates phosphatidylinositol (PI)-mediated IP3-PKC intracellular signaling. PKC overactivation impairs WM operations and in vitro studies indicate that IP3 receptor (IP3R)-evoked calcium release results in SK channel-dependent hyperpolarization of prefrontal neurons. However, the effects of IP3R signaling on prefrontal function have not been investigated. The present findings demonstrate that blockade of IP3R or SK channels in the prefrontal cortex enhances WM performance in rats, suggesting that both arms of the PI cascade influence prefrontal cognitive function.     

Catecholamine modulation of prefrontal cortical cognitive function

The prefrontal cortex (PFC) utilizes working memory to guide behavior and to release the organism from dependence on environmental cues and is commonly disrupted in neuropsychiatric disorders, normal aging, or exposure to uncontrollable stress. This review posits that the PFC is very sensitive to changes in the neuromodulatory inputs it receives from norepinephrine (NE) and dopamine (DA) systems and that this sensitivity can lead to marked changes in the working-memory functions of the PFC. While NE and DA have important beneficial influences on processing in this area, very high levels of catecholamine release, for example, during exposure to uncontrollable stress, disrupt the cognitive functions of the PFC. This fresh understanding of the neurochemical influences on PFC function has led to new treatments for cognitive disorders such as Attention Deficit Hyperactivity Disorder (ADHD), and may help to elucidate the prevalence of PFC dysfunction in other mental disorders.     

Alpha2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals

The working-memory functions of the prefrontal cortex (PFC) are improved by stimulation of postsynaptic, alpha2A-adrenoceptors, especially in aged animals with PFC cognitive deficits. Thus, the alpha2A-adrenoceptor agonist, guanfacine, greatly improves working-memory performance in monkeys and rats following systemic administration or intra-PFC infusion. Alpha2A-adrenoceptors are generally coupled to Gi, which can inhibit adenylyl cyclases and reduce the production of cAMP. However, no study has directly examined whether the working-memory enhancement observed with guanfacine or other alpha2A-adrenoceptor agonists results from cAMP inhibition. The current study confirmed this hypothesis in both rats and monkeys, showing that treatments that increase cAMP-mediated signaling block guanfacine's beneficial effects. In aged rats, guanfacine was infused directly into the prelimbic PFC and was challenged with co-infusions of the cAMP analog, Sp-cAMPS. In aging monkeys, systemically administered guanfacine was challenged with the phosphodiesterase 4 inhibitor, rolipram, using intramuscular doses known to have no effect on their own. In both studies, agents that mimicked the actions of cAMP (rats) or increased endogenous cAMP (monkeys) completely blocked the enhancing effects of guanfacine on working-memory performance. These results are consistent with alpha2A-adrenoceptor stimulation enhancing PFC working-memory function via inhibition of cAMP-mediated signaling.     

Vulnerability of conditional NCAM-deficient mice to develop stress-induced behavioral alterations

Previous studies in rodents showed that chronic stress induces structural and functional alterations in several brain regions, including shrinkage of the hippocampus and the prefrontal cortex, which are accompanied by cognitive and emotional disturbances. Reduced expression of the neural cell adhesion molecule (NCAM) following chronic stress has been proposed to be crucially involved in neuronal retraction and behavioral alterations. Since NCAM gene polymorphisms and altered expression of alternatively spliced NCAM isoforms have been associated with bipolar depression and schizophrenia in humans, we hypothesized that reduced expression of NCAM renders individuals more vulnerable to the deleterious effects of stress on behavior. Here, we specifically questioned whether mice in which the NCAM gene is inactivated in the forebrain by cre-recombinase under the control of the calcium-calmodulin-dependent kinase II promoter (conditional NCAM-deficient mice), display increased vulnerability to stress. We assessed the evolving of depressive-like behaviors and spatial learning and memory impairments following a subchronic stress protocol (2 weeks) that does not result in behavioral dysfunction, nor in altered NCAM expression, in wild-type mice. Indeed, while no behavioral alterations were detected in wild-type littermates after subchronic stress, conditional NCAM-deficient mice showed increased immobility in the tail suspension test and deficits in reversal spatial learning in the water maze. These findings indicate that diminished NCAM expression might be a critical vulnerability factor for the development of behavioral alterations by stress and further support a functional involvement of NCAM in stress-induced cognitive and emotional disturbances.     

Hemispheric asymmetry in stress processing in rat prefrontal cortex and the role of mesocortical dopamine

The prefrontal cortex (PFC) is known to play an important role not only in the regulation of emotion, but in the integration of affective states with appropriate modulation of autonomic and neuroendocrine stress regulatory systems. The present review highlights findings in the rat which helps to elucidate the complex nature of prefrontal involvement in emotion and stress regulation. The medial PFC is particularly important in this regard and while dorsomedial regions appear to play a suppressive role in such regulation, the ventromedial (particularly infralimbic) region appears to activate behavioral, neuroendocrine and sympathetic autonomic systems in response to stressful situations. This may be especially true of spontaneous stress-related behavior or physiological responses to relatively acute stressors. The role of the medial PFC is somewhat more complex in conditions involving learned adjustments to stressful situations, such as the extinction of conditioned fear responses, but it is clear that the medial PFC is important in incorporating stressful experience for future adaptive behavior. It is also suggested that mesocortical dopamine plays an important adaptive role in this region by preventing excessive behavioral and physiological stress reactivity. The rat brain shows substantial hemispheric specialization in many respects, and while the right PFC is normally dominant in the activation of stress-related systems, the left may play a role in countering this activation through processes of interhemispheric inhibition. This proposed basic template for the lateralization of stress regulatory systems is suggested to be associated with efficient stress and emotional self-regulation, and also to be shaped by both early postnatal experience and gender differences.     

Molecular activity underlying working memory

The prefrontal cortex is necessary for directing thought and planning action. Working memory, the active, transient maintenance of information in mind for subsequent monitoring and manipulation, lies at the core of many simple, as well as high-level, cognitive functions. Working memory has been shown to be compromised in a number of neurological and psychiatric conditions and may contribute to the behavioral and cognitive deficits associated with these disorders. It has been theorized that working memory depends upon reverberating circuits within the prefrontal cortex and other cortical areas. However, recent work indicates that intracellular signals and protein dephosphorylation are critical for working memory. The present article will review recent research into the involvement of the modulatory neurotransmitters and their receptors in working memory. The intracellular signaling pathways activated by these receptors and evidence that indicates a role for G(q)-initiated PI-PLC and calcium-dependent protein phosphatase calcineurin activity in working memory will be discussed. Additionally, the negative influence of calcium- and cAMP-dependent protein kinase (i.e., calcium/calmodulin-dependent protein kinase II (CaMKII), calcium/diacylglycerol-activated protein kinase C (PKC), and cAMP-dependent protein kinase A (PKA)) activities on working memory will be reviewed. The implications of these experimental findings on the observed inverted-U relationship between D(1) receptor stimulation and working memory, as well as age-associated working memory dysfunction, will be presented. Finally, we will discuss considerations for the development of clinical treatments for working memory disorders.     

Using fMRI to investigate

Using fMRI, we investigated the functional organization of prefrontal cortex (PFC) as participants briefly thought of a single just-experienced item (i.e., refreshed an active representation). The results of six studies, and a meta-analysis including previous studies, identified regions in left dorsolateral, anterior, and ventrolateral PFC associated in varying degrees with refreshing different types of information (visual and auditory words, drawings, patterns, people, places, or locations). In addition, activity increased in anterior cingulate with selection demands and in orbitofrontal cortex when a nonselected item was emotionally salient, consistent with a role for these areas in cognitive control (e.g., overcoming “mental rubbernecking”). We also found evidence that presenting emotional information disrupted an anterior component of the refresh circuit. We suggest that refreshing accounts for some neural activity observed in more complex tasks, such as working memory, long-term memory, and problem solving, and that its disruption (e.g., from aging or emotion) could have a broad impact.     

Sexual coercion among women living with a severe and persistent mental illness: Review of the literature and recommendations for mental health providers

Women with severe and persistent mental illness (e.g., schizophrenia, bipolar disorder) are at enhanced risk for sexual coercion and several resulting sexual health complications. We examine the prevalence and types of sexual coercion encountered by women with severe and persistent mental illness and provide recommendations for interventions to reduce the prevalence of sexual coercion. Mental health professionals working with this population need to provide increased attention to the problem of sexual coercion and can take measures to intervene safely and effectively.     

Measuring Stigma Toward Mental Illness: Development and Application of the Mental Illness Stigma Scale1

Guided by theory on stigma, a Likert‐type scale was developed to measure 7 factors of attitudes toward people with mental illness: interpersonal anxiety, relationship disruption, poor hygiene, visibility, treatability, professional efficacy, and recovery. The scale was validated among college students and community members, measuring attitudes toward people with mental illness, depression, bipolar disorder, and schizophrenia. In a second application, college students completed the scale from their own perspective, then from an imagined perspective of someone with mental illness, while psychiatric patients completed the scale from their own perspective, then from an imagined viewpoint of someone without mental illness. Psychiatric patients assumed that they were stigmatized to a greater extent than was admitted by the student sample.     

Sex differences in prenatal epigenetic programming of stress pathways

Maternal stress experience is associated with neurodevelopmental disorders including schizophrenia and autism. Recent studies have examined mechanisms by which changes in the maternal milieu may be transmitted to the developing embryo and potentially translated into programming of the epigenome. Animal models of prenatal stress have identified important sex- and temporal-specific effects on offspring stress responsivity. As dysregulation of stress pathways is a common feature in most neuropsychiatric diseases, molecular and epigenetic analyses at the maternal-embryo interface, especially in the placenta, may provide unique insight into identifying much-needed predictive biomarkers. In addition, as most neurodevelopmental disorders present with a sex bias, examination of sex differences in the inheritance of phenotypic outcomes may pinpoint gene targets and specific windows of vulnerability in neurodevelopment, which have been disrupted. This review discusses the association and possible contributing mechanisms of prenatal stress in programming offspring stress pathway dysregulation and the importance of sex.     

Narcolepsy: differential diagnosis or etiology in some cases of bipolar disorder and schizophrenia?

Does narcolepsy, a neurological disease, need to be considered when diagnosing major mental illness? Clinicians have reported cases of narcolepsy with prominent hypnagogic hallucinations that were mistakenly diagnosed as schizophrenia. In some bipolar disorder patients with narcolepsy, the HH resulted in their receiving a more severe diagnosis (ie, bipolar disorder with psychotic features or schizoaffective disorder). The role of narcolepsy in psychiatric patients has remained obscure and problematic, and it may be more prevalent than commonly believed. Classical narcolepsy patients display the clinical "tetrad"--cataplexy, hypnagogic hallucinations, daytime sleep attacks, and sleep paralysis. Over 85% also display the human leukocyte antigen marker DQB1*0602 (subset of DQ6). Since 1998, discoveries in neuroanatomy and neurophysiology have greatly advanced the understanding of narcolepsy, which involves a nearly total loss of the recently discovered orexin/hypocretin (hypocretin) neurons of the hypothalamus, likely by an autoimmune mechanism. Hypocretin neurons normally supply excitatory signals to brainstem nuclei producing norepinephrine, serotonin, histamine, and dopamine, with resultant suppression of sleep. They also project to basal forebrain areas and cortex. A literature review regarding the differential diagnosis of narcolepsy, affective disorder, and schizophrenia is presented. Furthermore, it is now possible to rule out classical narcolepsy in difficult psychiatric cases. Surprisingly, psychotic patients with narcolepsy will likely require stimulants to fully recover. Many conventional antipsychotic drugs would worsen their symptoms and make them appear to become a "chronic psychotic," while in fact they can now be properly diagnosed and treated.     

Stability of formal thought disorder and referential communication disturbances in schizophrenia

This study examined the degree to which different types of communication disturbances in the speech of 48 schizophrenia patients and 28 controls were variable and state related versus stable and traitlike. Clinically rated formal thought disorder and 5 types of referential disturbance showed substantial stability within participants over time. The sixth type of referential disturbance, the vague reference, was not stable over time. Formal thought disorder was associated with the severity of core psychotic symptoms in patients. whereas referential disturbances showed little or no association with positive or negative symptom severity. Furthermore, changes in psychotic symptoms over time were accompanied by corresponding changes in formal thought disorder but not referential disturbances. These results support the idea that some types of referential disturbances are traitlike and may be reflective of vulnerability as well as manifest illness.     

Behavioural characteristics of offenders with mental health disorders in a South African prison population

This exploratory study profiled behavioural characteristics of a non-random sample of 91 offenders with mental illness in a South African correctional facility. The sample is directly related to diagnosed cases from the correctional psychiatrist's case load. The most prevalent mental disorders diagnosed amongst the research participants of this sample specific profile were schizophrenia (33%), major depressive (27.5%), bipolar mood (12.1%) and psychotic disorders (11%).     

前额叶在老年阶段的可塑性及相关机制

大量研究表明, 前额叶的结构和功能更容易受年老化影响; 然而, 近年来的研究发现, 前额叶的结构和功能在老年阶段具有一定的可塑性。对老年人进行认知训练, 能够延缓前额叶皮层厚度的萎缩, 提高白质完整性, 改善神经网络的功能连接和分化, 并可能通过调节多巴胺系统的活动改变前额叶皮质和皮质下结构的功能激活模式。有氧锻炼能够改善心脑血管功能, 保护和促进神经元的存活和生长, 引起前额叶灰质、白质体积的增加及功能激活的变化。认知训练与有氧锻炼等相结合的整合性训练不仅引起前额叶及相关认知功能的改变, 而且具有更好的生态学效度, 使老年人日常认知能力和生活质量得到提高。未来研究应采用多种技术手段, 从多个层面理解老年阶段前额叶的可塑性及相关机制; 加强对与前额叶关系密切的多种认知功能可塑性神经机制的研究; 并重视与整合性训练有关的前额叶可塑性。     

Schizophrenia, ketamine and cannabis: evidence of overlapping memory deficits

Drug models of mental illness are considered useful if they provoke its characteristic symptoms. In this respect, ketamine and tetrahydrocannabinol (cannabis) are coming under increasing scrutiny as models for schizophrenia. However, although both undoubtedly produce psychotic symptoms characteristic of the disorder, we argue here that, because schizophrenia is also accompanied by cognitive deficits, a full understanding of the impact of these drugs on cognition will be crucial in taking these models further. Memory deficits are pronounced in schizophrenia and we focus upon patterns of working and episodic memory impairment produced by ketamine and cannabis, identifying overlaps between drug and illness. We suggest that close attention to these deficits can offer insights into core pathophysiology of schizophrenia.     

Performance of schizophrenia and bipolar patients on verbal and figural working memory tasks

Working memory (WM) was studied in 82 healthy volunteers, 43 schizophrenia patients, and 81 bipolar patients. Schizophrenia patients were impaired on verbal and figural WM tasks that possessed similar test discriminating power. Bipolar patients performed similarly to healthy volunteers. A mathematical model of WM performance revealed a primary role for reduced WM span in accounting for the impaired verbal WM of schizophrenia patients and a primary role for diminished attention in accounting for impaired figural WM. Although WM impairment in schizophrenia is due neither to the general effects of severe mental illness nor to the specific type of material studied, the microarchitecture of abnormal WM in schizophrenia may depend on the stimulus material presented.     

前额皮层肾上腺素能受体在工作记忆中的作用

前额皮层去甲肾上腺素能神经支配主要来自脑干蓝斑核。前额皮层存在不同类型的肾上腺素能受体。其中突触后α2及β2肾上腺素能受体的激活提高工作记忆;α1及β1肾上腺素能受体的激活损害工作记忆。不同受体是通过激活不同的信号通路发挥对工作记忆的调节作用。来自人类被试的研究结果与对动物的研究结果之间尚存在不一致。了解前额皮层不同肾上腺素受体的作用为开发治疗与前额皮层功能失调相关疾病的药物提供了新的方向。     

Integrative neuropsychological characteristics of subcortical-frontal brain regions as a schizophrenia liability factor

In order to study neuropsychological characteristics of subcortical-frontal brain regions function and assessment of their relation with vulnerability to schizophrenia 59 patients and 23 controls were investigated using Luria's neuropsychological methods. The analysis established bilateral abnormalities of the function of prefrontal and profound frontal lobe zones in patients as compared with controls. These abnormalities were more predominate in the left hemisphere. Point biserial correlation coefficients of determined integrative neuropsychological indicators with liability to schizophrenia were 0.39 +/- 0.11 and 0.28 +/- 0.09, for the left and right brain zones respectively. The obtained data permits discussion of the integrative neuropsychological indicators of subcortical-frontal brain regions as potential markers of liability to schizophrenia and confirms the role of structural and functional brain asymmetry in the pathogenesis of schizophrenia.     

Can functional emotion regulation protect children's mental health from war trauma? A Palestinian study

Effective emotion regulation (ER) is expected to protect mental health in traumatic stress. We first analysed the protective (moderator) function of different ER strategies and the associations between ER and mental health. Second, we tested gender differences in the protective function of ER and the associations between ER strategies and mental health. Participants were 482 Palestinian children (girls 49.4%; 10–13 years, M = 11.29, SD = .68) whose ER was assessed by the Emotion Regulation Questionnaire and mental health by post‐traumatic stress (Children's Impact Event Scale), depressive, and psychological distress (Strengths and Difficulties Questionnaire) symptoms, and by psychosocial well‐being (Mental Health Continuum‐Short Form). War trauma involved 42 events. Results showed, first, that none of the ER strategies could protect a child's mental health from negative impact of war trauma, but self‐focused ER was associated with low depressive symptoms, and other‐facilitated ER with high psychological well‐being. However, controlling of emotions formed a comprehensive risk for children's mental health. Second, gender differences were found in the protective role of ER, as self‐focused and distractive ER formed a vulnerability among boys. The results are discussed in the context of emotional and regulative demands of war and life‐threat.