Histone acetylation rescues contextual fear conditioning in nNOS KO mice and accelerates extinction of cued fear conditioning in wild type mice

Epigenetic regulation of chromatin structure is an essential molecular mechanism that contributes to the formation of synaptic plasticity and long-term memory (LTM). An important regulatory process of chromatin structure is acetylation and deacetylation of histone proteins. Inhibition of histone deacetylase (HDAC) increases acetylation of histone proteins and facilitate learning and memory. Nitric oxide (NO) signaling pathway has a role in synaptic plasticity, LTM and regulation of histone acetylation. We have previously shown that NO signaling pathway is required for contextual fear conditioning. The present study investigated the effects of systemic administration of the HDAC inhibitor sodium butyrate (NaB) on fear conditioning in neuronal nitric oxide synthase (nNOS) knockout (KO) and wild type (WT) mice. The effect of single administration of NaB on total H3 and H4 histone acetylation in hippocampus and amygdala was also investigated. A single administration of NaB prior to fear conditioning (a) rescued contextual fear conditioning of nNOS KO mice and (b) had long-term (weeks) facilitatory effect on the extinction of cued fear memory of WT mice. The facilitatory effect of NaB on extinction of cued fear memory of WT mice was confirmed in a study whereupon NaB was administered during extinction. Results suggest that (a) the rescue of contextual fear conditioning in nNOS KO mice is associated with NaB-induced increase in H3 histone acetylation and (b) the accelerated extinction of cued fear memory in WT mice is associated with NaB-induced increase in H4 histone acetylation. Hence, a single administration of HDAC inhibitor may rescue NO-dependent cognitive deficits and afford a long-term accelerating effect on extinction of fear memory of WT mice.     

Percepts to recollections: insights from single neuron recordings in the human brain

Transformation of experience into memories that can guide future behavior is a common ability across species. However, only humans can declare their perceptions and memories of experienced events (episodes). The medial temporal lobe (MTL) is central to episodic memory, yet the neuronal code underlying the translation from sensory information to memory remains unclear. Recordings from neurons within the brain in patients who have electrodes implanted for clinical reasons provide an opportunity to bridge physiology with cognitive theories. Recent evidence illustrates several striking response properties of MTL neurons. Responses are selective yet invariant, associated with conscious perception, can be internally generated and modulated, and spontaneously retrieved. Representation of information by these neurons is highly explicit, suggesting abstraction of information for future conscious recall.     

Impairments in fear conditioning in mice lacking the nNOS gene

The fear conditioning paradigm is used to investigate the roles of various genes, neurotransmitters, and substrates in the formation of fear learning related to contextual and auditory cues. In the brain, nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) functions as a retrograde neuronal messenger that facilitates synaptic plasticity, including the late phase of long-term potentiation (LTP) and formation of long-term memory (LTM). Evidence has implicated NO signaling in synaptic plasticity and LTM formation following fear conditioning, yet little is known about the role of the nNOS gene in fear learning. Using knockout (KO) mice with targeted mutation of the nNOS gene and their wild-type (WT) counterparts, the role of NO signaling in fear conditioning was investigated. Plasma levels of the stress hormone corticosterone were measured to determine the relationship between physiological and behavioral response to fear conditioning. Contextual fear learning was severely impaired in male and female nNOS KO mice compared with WT counterparts; cued fear learning was slightly impaired in nNOS KO mice. Sex-dependent differences in both contextual and cued fear learning were not observed in either genotype. Deficits in contextual fear learning in nNOS KO mice were partially overcome by multiple trainings. A relationship between increase in plasma corticosterone levels following footshock administration and the magnitude of contextual, but not cued freezing was also observed. Results suggest that the nNOS gene contributes more to optimal contextual fear learning than to cued fear learning, and therefore, inhibition of the nNOS enzyme may ameliorate context-dependent fear response.Anxiety disorders, such as post-traumatic stress disorder (PTSD), constitute the most prevalent mental illnesses in the United States, costing nearly one-third of the country''s total health bill (Greenberg et al. 1999). The treatment of these disorders requires overcoming complications such as reluctance to seek mental health treatment and an extremely high comorbidity rate with other affective disorders, reaching 80% (Brady 1997; Solomon and Davidson 1997). Emerging evidence suggests that dysfunctions underlying acquired anxiety and PTSD include an abnormal reaction to stress, which is mediated by specific neurochemical and neuroanatomical substrates (Yehuda and McFarlane 1995; Adamec 1997). Pharmacotherapies that target neuronal signaling molecules, such as nitric oxide (NO), may play a role in the treatment of these disorders.In the brain, N-methyl-d-aspartate receptor (NMDAR) activation and calcium influx into the cell activates the neuronal nitric oxide synthase (nNOS) enzyme to produce NO, which has the role of retrograde messenger (Snyder 1992). NO is involved in memory formation and synaptic plastic events such as late-phase long-term potentiation (LTP) (Lu et al. 1999; Arancio et al. 2001; Puzzo et al. 2006). Behavioral evidence in invertebrates (Lewin and Walters 1999; Muller 2000; Kemenes et al. 2002; Matsumoto et al. 2006) and vertebrates (Medina and Izquierdo 1995; Rickard et al. 1998; Ota et al. 2008) suggest that NO has a major role in consolidation of long-term memory (LTM). Recently, studies have shown that site-specific pharmacological blockade of NO signaling in rats impairs contextual (Resstel et al. 2008) and cued (Schafe et al. 2005) fear learning. However, the role of the nNOS gene in fear conditioning has not been investigated.In the present study, fear conditioning was investigated in homozygous nNOS knockout (KO) and wild-type (WT) mice. In the fear-conditioning paradigm, the association of a footshock (unconditioned stimulus; US), with a specific context and a neutral stimulus (auditory cue) results in learned fear. Re-exposure to the conditioning context and to the previously neutral auditory cue (conditioned stimulus; CS) elicits a freezing response in the absence of the aversive US. Thus, the fear-conditioning paradigm includes both contextual and cued fear learning components, which can be measured in separate tests. Fear conditioning recruits both the amygdala (emotional cue learning) and the hippocampus (spatial/contextual learning) (Phillips and LeDoux 1992; Goosens and Maren 2004; Mei et al. 2005). The involvement of these brain regions in fear learning and anxiety has been confirmed by animal and human imaging studies (LeDoux 1998; Rauch et al. 2006).We report that nNOS KO mice showed a severe deficiency in contextual fear learning and a less marked deficit in cued fear learning compared with WT mice after a single fear-conditioning session. This deficiency was partially improved by multiple (four) fear-conditioning sessions. In addition, we observed that plasma levels of corticosterone, the primary stress hormone in rodents, are related to contextual fear learning ability.     

The five-factor personality model in applied settings

Two studies of the Revised NEO-Personality Inventory (NEO-PI-R) conducted on two different applicant samples (one consisting of 539 female subjects and the other consisting of 396 male subjects) are reported. Factor analysis of the female sample yielded a five-factor solution, highly congruent with the factors presented by Costa, McCrae and Dye (1991). Results of the male data were less clear-cut, yielding four to five factors which were moderately congruent with the American data. The combined male and female sample showed again high congruence coefficients. Various minor deviations in the location of the facet variables are discussed.     

Life stress and psychopathology: Progress on research begun with Barbara Snell Dohrenwend

This is a progress report on some of the research that was planned and begun with Barbara Dohrenwend before she died in 1982. The main focus is on two of the studies. One was conducted in New York City; the other is still underway in Israel. The New York study is a retrospective case/control study of social and psychological factors that may put people at risk for developing schizophrenic episodes and episodes of major depression. The Israel research consists of epidemiological, case/control, and family studies of these two disorders together with other types of psychopathology that are inversely related to social class. Preliminary findings from both studies are reported, and their implications for primary prevention are discussed.     

The gulf war: Distressful reactions to scud missiles attacks

This study investigated the relationships among coping strategies, trait anxiety and distressful reactions (State anxiety and fears and symptoms) of Israeli civilians under missile attack during the 1991 Gulf war. During the war sixty-six subjects (46 females and 20 males) completed a questionnaire that measured their distressful reactions and included fears in various situations (e.g., during the night, in the sealed room) and various symptoms (e.g., sleep disturbances, sensitivity to noise). In addition each subject completed the Coping Inventory for Stressful Situations (CISS, Endler & Parker, 1990a), a multidimensional self-report measure of coping which measures three major coping strategies: task-oriented, emotion-oriented and avoidance-oriented. Subjects also completed the State and Trait anxiety scales of the Endler Multidimensional Anxiety Scales (EMAS, Endler, Edwards, & Vitelli, 1991). The state anxiety scales measure two components of the individual's state anxiety, cognitive worry and autonomic emotional reactions. The trait anxiety scales measure the individual's predisposition to experience anxiety in four different situations: social evaluation, physical danger, ambiguous situations and daily routines. The results showed that individuals who used emotion-oriented coping more frequently, experienced more state anxiety and symptoms and fears, (i.e., experienced greater distress) during the war. Task-oriented and avoidance-oriented coping were not related to the distressful reactions. It was further found that subjects high on physical danger trait anxiety and social evaluation trait anxiety experienced greater fears and more symptoms (i.e., experienced greater distress) during the war. Persons high on social evaluation trait anxiety also experienced great cognitive-worry state anxiety. The results are discussed within the framework of the multidimensional model of stress, anxiety and coping (Endler, 1988; Endler & Parker, 1990a, 1990b) and the special characteristics of the Gulf war situation.     

Retracted: The Indirect Relationship Between Learning Climate and Employees’ Creativity and Adaptivity: The Role of Employee Engagement

This study examines the indirect relationship between learning climate and employees’ creativity and adaptivity. Utilizing multi‐level modeling analysis techniques and data from a sample of 625 employees from 12 different organizations in Israel, we tested the proposed relationship as mediated by employee engagement and moderated by sector of employment (business versus public). Results were generally consistent with the hypothesized conceptual model in that we found the indirect relationship between learning climate and employees’ creativity and adaptivity to be mediated by employee engagement. In addition, we found that this mediation through engagement is moderated by sector of employment. We conclude that the relationship between learning climate and employee performance behaviors is more complex than previously argued in the learning climate literature. Implications for theory and practice are discussed. This article is protected by copyright. All rights reserved