Upregulations of α1 adrenergic receptors and noradrenaline synthases in the medial prefrontal cortex are associated with emotional and cognitive dysregulation induced by post-weaning social isolation in male rats.

Early-life social isolation induces emotional and cognitive dysregulation, such as increased aggression and anxiety, and decreases neuron excitability in the medial prefrontal cortex (mPFC). The noradrenergic system in the mPFC regulates emotion and cognitive function via α1 or α2A adrenergic receptors, depending on noradrenaline levels. However, social isolation-induced changes in the mPFC noradrenergic system have not been reported. Here, male Wistar rats received post-weaning social isolation for nine consecutive weeks and were administered behavioral tests (novel object recognition, elevated plus maze, aggression, and forced swimming, sequentially). Protein expression levels in the mPFC noradrenergic system (α1 and α2A adrenergic receptors, tyrosine hydroxylase, and dopamine-ß-hydroxylase used as indices of noradrenaline synthesis and release) were examined through western blotting. Social isolation caused cognitive dysfunction, anxiety-like behavior, and aggression, but not behavioral despair. Socially-isolated rats exhibited increased protein levels of the α1 adrenergic receptor, tyrosine hydroxylase, and dopamine-ß-hydroxylase in the mPFC; there was no significant difference between the groups in the α2A adrenergic receptor expression levels. Preferential activation of the α1 adrenergic receptor caused by high noradrenaline concentration in the mPFC may be involved in social isolation-induced emotional and cognitive regulation impairments. Targeting the α1 adrenergic receptor signaling pathway is a potential therapeutic strategy for psychiatric disorders with symptomatic features such as emotional and cognitive dysregulation.

Reconsidering the role of sex hormones in psychopathy development: Estrogen and psychopathy among male justice-involved youth.

Prominent theory suggests that factor one psychopathic traits may develop from increased input from hormones in the hypothalamic pituitary gonadal axis (HPG; i.e., testosterone) and decreased input from the hypothalamic pituitary adrenal axis (HPA; i.e., cortisol). Although there are extensive findings connecting low cortisol to psychopathy, less support has emerged for high levels of testosterone. This study examined whether incorporating the HPG hormone, estradiol, into this model would reveal relationships in line with theory: high levels of estradiol and testosterone in combination with low levels of cortisol would inform psychopathic traits. Baseline and reactive hormone levels were measured and compared to Psychopathy Checklist-Youth Version (PCL-YV) interviews among 66 male justice-involved youth (M age = 15.73) in a Southeastern juvenile detention center. The primary findings of this study were relationships between interacting HPA and HPG axis hormones with facet one and facet two psychopathic traits. Specifically, psychopathy total scores, interpersonal traits, and affective traits related to estradiol and testosterone reactivity, in that psychopathy scores were more likely with decreases in hormone reactivity (i.e., change in hormone level) following a stressor. Moreover, affective traits related to reactivity in all three hormones. These findings support inclusion of estradiol in neurobiological models of psychopathy and consideration of the individual components of psychopathy. This study adds to the growing body of research supporting interactions between variations in functioning of the HPA and HPG axes in relation to psychopathy.

Effects of Omega 3 Fatty Acids on Main Dimensions of Psychopathology.

The usefulness of polyunsaturated fatty acids on inflammatory, cardiovascular, and the nervous system was studied in the last decades, but the mechanisms underlying their benefic properties are still partially unknown. These agents seem to express their action on the membrane phospholipid composition and permeability and modulation of second messenger cascades. In psychiatry, the efficacy and tolerability of omega-3 fatty acids were investigated in several psychiatric disorders, including major depression, bipolar disorder, personality disorders, high-risk conditions to develop psychosis, attention-deficit hyperactivity disorder, and autism spectrum disorders. Initial findings in this field are promising, and some relevant questions need to be addressed. In particular, the effects of these agents on the main symptom dimensions have to be investigated in a trans-diagnostic perspective. The present systematic review is aimed to examine the available data on the efficacy of omega-3 fatty acids on domains of psychotic symptoms, affective symptoms, impulsivity, and aggressiveness, and harmful behaviors, and suicide risk.

Paroxetine ameliorates prodromal emotional dysfunction and late-onset memory deficit in Alzheimer's disease mice.

BACKGROUND: Neuropsychiatric symptoms (NPS) such as depression, anxiety, apathy, and irritability occur in prodromal phases of clinical Alzheimer's disease (AD), which might be an increased risk for later developing AD. Here we treated young APP/PS1 AD model mice prophylactically with serotonin-selective re-uptake inhibitor (SSRI) paroxetine and investigated the protective role of anti-depressant agent in emotional abnormalities and cognitive defects during disease progress. METHODS: To investigate the protective role of paroxetine in emotional abnormalities and cognitive defects during disease progress, we performed emotional behaviors of 3 months old APP/PS1 mouse following oral administration of paroxetine prophylactically starting at 1 month of age. Next, we tested the cognitive, biochemical and pathological, effects of long term administration of paroxetine at 6 months old. RESULTS: Our results showed that AD mice displayed emotional dysfunction in the early stage. Prophylactic administration of paroxetine ameliorated the initial emotional abnormalities and preserved the eventual memory function in AD mice. CONCLUSION: Our data indicate that prophylactic administration of paroxetine ameliorates the emotional dysfunction and memory deficit in AD mice. These neuroprotective effects are attributable to functional restoration of glutamate receptor (GluN2A) in AD mice.

Stress-induced cortisol reactivity as a predictor of success in treatment for affective dimensions.

BACKGROUND: Response rates to first-line treatments for depression and anxiety remain unsatisfactory. Identification of predictors or moderators that can optimize treatment matching is of scientific and clinical interest. This study examined the role of prolonged laboratory-induced stress cortisol reactivity as a predictor of outcome for a treatment of affective dimensions (TAD). Patients received 15-sessions of a treatment targeting reductions in negative affect or increases in positive affect (Craske et al., 2019). A second aim was to examine whether treatment type would moderate the association between cortisol reactivity and treatment outcome. METHODS: Thirty-five participants underwent a 36-minute intermittent stress induction task composed of a mental arithmetic task and a fear-potentiated startle task one week before treatment initiation. Cortisol was collected at five-time points with reactivity being quantified as peak during the task minus basal level of cortisol the evening before the assessment. Using multilevel modeling, we examined the associations between cortisol reactivity and slopes of symptom improvement. RESULTS: Cortisol reactivity was related to treatment outcome, with average and higher levels of stress-induced cortisol response predicting greater decreases in symptoms throughout treatment and 6-month follow-up. Treatment condition differences (moderation) were not observed in the effect of cortisol reactivity on symptoms. CONCLUSION: Our findings demonstrate the impact of greater cortisol stress reactivity on treatment outcome. Future studies should investigate how to enhance this therapeutic benefit through capitalizing on endogenous diurnal fluctuations or exogenous cortisol manipulation.

Prenatal maternal hair cortisol concentrations are related to maternal prenatal emotion dysregulation but not neurodevelopmental or birth outcomes.

Hair cortisol concentrations measured during pregnancy have emerged as a novel biomarker for prenatal stress exposure. However, associations between prenatal stress and distress, broadly defined, and hair cortisol concentrations during pregnancy are inconsistent. We examined relations among hair cortisol concentrations during the third trimester with (a) emotion dysregulation and (b) detailed measures of maternal prenatal stress. We also examined the predictive validity of maternal hair cortisol during pregnancy for adverse newborn health outcomes. Cortisol concentrations were derived from 6 cm of hair during the third trimester of pregnancy. Mothers reported on their emotion dysregulation and stress at this time. A standardized newborn neurobehavioral exam was conducted shortly after birth and newborn birth weight and gestational age were assessed from medical records. All hypotheses were preregistered on the Open Science Framework (osf.io/279ng). High levels of emotion dysregulation, but not stress, were predictive of high hair cortisol concentrations. Maternal prenatal BMI mediated the relation between maternal prenatal emotion dysregulation and hair cortisol concentrations. There was no association between hair cortisol and infant birth outcomes. This research supports the notion that transdiagnostic markers of psychopathology are important correlates of hair cortisol concentrations during pregnancy.

Impaired cognitive self-awareness mediates the association between alexithymia and excitation/inhibition balance in the pgACC.

BACKGROUND: Previous research showed that automatic emotion regulation is associated with activation of subcortical areas and subsequent feedforward processes to cortical areas. In contrast, cognitive awareness of emotions is mediated by negative feedback from cortical to subcortical areas. Pregenual anterior cingulate cortex (pgACC) is essential in the modulation of both affect and alexithymia. We considered the interplay between these two mechanisms in the pgACC and their relationship with alexithymia. METHOD: In 68 healthy participants (30 women, age = 26.15 ± 4.22) we tested associations of emotion processing and alexithymia with excitation/inhibition (E/I) balance represented as glutamate (Glu)/GABA in the pgACC measured via magnetic resonance spectroscopy in 7 T. RESULTS: Alexithymia was positively correlated with the Glu/GABA ratio (N = 41, p = 0.0393). Further, cognitive self-awareness showed an association with Glu/GABA (N = 52, p = 0.003), which was driven by a correlation with GABA. In contrast, emotion regulation was only correlated with glutamate levels in the pgACC (N = 49, p = 0.008). CONCLUSION: Our results corroborate the importance of the pgACC as a mediating region of alexithymia, reflected in an altered E/I balance. Furthermore, we could specify that this altered balance is linked to a GABA-related modulation of cognitive self-awareness of emotions.

Sleep and pain: recent insights, mechanisms, and future directions in the investigation of this relationship.

Sleep disturbances and chronic pain are considered public health concerns. They are frequently associated, and the direction of its relationship and possible mechanisms underlying it are frequently debated. The exploration of the sleep-pain association is of great clinical interest to explore in order to steer potential therapeutic avenues, accommodate the patient's experience, and adapt the common practice of health professionals. In this review, the direction between sleep-pain in adult and pediatric populations will be discussed. Moreover, the possible mechanisms contributing to this relationship as endogenous pain modulation, inflammation, affect, mood and other states, the role of different endogenous substances (dopamine, orexin, melatonin, vitamin D) as well as other lesser known such as cyclic alternating pattern among others, will be explored. Finally, directions for future studies on this area will be discussed, opening up to the addition of tools such as brain imaging (e.g., fMRI), electrophysiology and non-invasive brain stimulation techniques. Such resources paired with artificial intelligence are key to personalized medicine management for patients facing pain and sleep interacting conditions.

Use of an estradiol-based combined oral contraceptives has no influence on attentional bias or depressive symptoms in healthy women.

Combined oral contraceptive (COC) use is associated with small, albeit significant, increases in mental symptom scores, predominantly irritability, depressed mood, and anxiety. Yet, randomized prospective trials are needed to better characterize the women at risk for COC-induced negative mood change. Thus, the primary aim of this sub-study to a placebo-controlled randomized trial was to determine whether COC use influences emotional interference by negative and positive stimuli. Secondly, we wanted to evaluate what factors would predict depressive symptoms at the end of the trial, taking personality factors, history of mental disorders and other demographic factors into account. Sixty-nine women were included, randomized to three cycles of treatment with a COC (1.5 mg estradiol and 2.5 mg nomegestrolacetate) or placebo. An emotional verbal Stroop task was used to measure interference of emotional stimuli, in which participants were asked to only name the color of a presented word, while ignoring the meaning of the word. Four different word categories were used; neutral, positive, depression, and anxiety. For the second aim of the study, rating on the Montgomery-Åsberg Depression Rating Scale during the final days of the trial was used as outcome. We found no interaction between emotional verbal Stroop word category and treatment, indicating that COC treatment did not evoke any differences in emotional interference to the three word categories. Significant predictors for depressive symptoms at the end of the trial were trait anxiety at baseline and prior adverse mood effects by hormonal contraceptive use. Treatment (i.e. whether women had been treated with the COC or placebo) did not play a role in predicting depression scores at the end of the trial. In conclusion, we found no evidence that combined oral contraceptive use is associated with impaired cognitive-emotional processing. Instead, the main predictors of self-rated depression at the end of the trial were baseline trait anxiety and previous mental symptoms during hormonal contraceptive use.

Elucidating the putative link between prefrontal neurotransmission, functional connectivity, and affective symptoms in irritable bowel syndrome.

Altered neural mechanisms are well-acknowledged in irritable bowel syndrome (IBS), a disorder of brain-gut-communication highly comorbid with anxiety and depression. As a key hub in corticolimbic inhibition, medial prefrontal cortex (mPFC) may be involved in disturbed emotion regulation in IBS. However, aberrant mPFC excitatory and inhibitory neurotransmission potentially contributing to psychological symptoms in IBS remains unknown. Using quantitative magnetic resonance spectroscopy (qMRS), we compared mPFC glutamate + glutamine (Glx) and γ-aminobutyric acid (GABA+) concentrations in 64 women with IBS and 32 age-matched healthy women (HCs) and investigated their association with anxiety and depression in correlational and subgroup analyses. Applying functional magnetic resonance imaging (fMRI), we explored whether altered neurotransmission was paralleled by aberrant mPFC resting-state functional connectivity (FC). IBS patients did not differ from HCs with respect to mPFC GABA+ or Glx levels. Anxiety was positively associated with mPFC GABA+ concentrations in IBS, whereas Glx was unrelated to psychological or gastrointestinal symptoms. Subgroup comparisons of patients with high or low anxiety symptom severity and HCs revealed increased GABA+ in patients with high symptom severity, and lower mPFC FC with adjacent anterior cingulate cortex (ACC), a crucial region of emotion modulation. Our findings provide novel evidence that altered prefrontal inhibitory neurotransmission may be linked to anxiety in IBS.

Anxiety in transition: Neuroendocrine mechanisms supporting the development of anxiety pathology in adolescence and young adulthood.

Adolescence marks a key developmental window during which emotion dysregulation increases, along with risk for the onset of anxiety and other affect-related pathologies. Although emotion dysregulation and related pathologies normatively decline during the transition into adulthood, this does not occur for a sizable minority of individuals. Finally, sex differences in anxiety emerge during adolescence, with females developing a 2-fold increase in risk relative to males. Unfortunately, a neurobiological model of the mechanisms that cause these changes during adolescence has yet to be proposed. In the present work, we first provide brief reviews of relevant literature. Next, we outline a dual-mechanism model focused on (i) the influence of pubertal testosterone on key emotion-regulation circuitry (i.e., orbitofrontal cortex-amygdala coupling) and (ii) myelination of the fiber bundles connecting such circuitry (i.e., uncinate fasciculus). The proposed model offers a set of specific, testable hypotheses that will hopefully spur much needed cross-disciplinary research.

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition.

Chronic stress-induced emotional disorders like anxiety and depression involve imbalances between the excitatory glutamatergic system and the inhibitory GABAergic system in the prefrontal cortex (PFC). However, the precise nature and trajectory of excitatory/inhibitory (E/I) imbalances in these conditions is not clear, with the literature reporting glutamatergic and GABAergic findings that are at times contradictory and inconclusive. Here we propose and discuss the hypothesis that chronic stress-induced emotional dysfunction involves hypoactivity of the PFC due to increased inhibition. We will also discuss E/I imbalances in the context of sex differences. In this review, we will synthesize research about how glutamatergic and GABAergic systems are perturbed by chronic stress and in related emotional disorders like anxiety and depression and propose ideas for reconciling contradictory findings in support of the hypothesis of over-inhibition. We will also discuss evidence for how aspects of the GABAergic system such as parvalbumin (PV) cells can be targeted therapeutically for reinstating activity and plasticity in the PFC and treating stress-related disorders.

Limbic neurochemical changes in patients with functional motor symptoms.

OBJECTIVE: To assess by magnetic resonance spectroscopy (MRS) the N-acetylaspartate, myo-inositol, choline, sum of glutamate and glutamine (Glx), and creatine (Cr) content in the anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC) and in the occipital cortex (OCC) (control region) in patients with functional motor symptoms (FMS) and healthy controls, and to determine whether neurochemical limbic changes as estimated by MRS correlate with FMS-related motor symptom severity, alexithymia, anxiety, depression, and quality of life. METHODS: This case-control study enrolled 10 patients with FMS and 10 healthy controls. Participants underwent MRS and were tested with the Mini-Mental State Examination, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, 20-Item Toronto Alexithymia Scale, and EuroQol 5D. RESULTS: In patients with FMS, MRS showed increased Glx/Cr in the ACC/mPFC but normal content in the control OCC. All the other metabolites tested were normal in both regions. The increased Glx/Cr content in the ACC/mPFC correlated with alexithymia, anxiety, and severity of symptoms. CONCLUSIONS: The abnormal limbic Glx increase could have a crucial pathophysiologic role in FMS, possibly by altering limbic-motor interactions, ultimately leading to abnormal movements.

Role of the endocannabinoid and endovanilloid systems in an animal model of schizophrenia-related emotional processing/cognitive deficit.

Studies suggest that the endocannabinoid and endovanilloid systems are implicated in the pathophysiology of schizophrenia. The Spontaneously Hypertensive Rats (SHR) strain displays impaired contextual fear conditioning (CFC) attenuated by antipsychotic drugs and worsened by pro-psychotic manipulations. Therefore, SHR strain is used to study emotional processing/associative learning impairments associated with schizophrenia and effects of potential antipsychotic drugs. Here, we evaluated the expression of CB1 and TRPV1 receptors in some brain regions related to the pathophysiology of schizophrenia. We also assessed the effects of drugs that act on the endocannabinoid/endovanilloid systems on the CFC task in SHRs and control animals (Wistar rats - WRs). The following drugs were used: AM404 (anandamide uptake/metabolism inhibitor), WIN55-212,2 (non-selective CB1 agonist), capsaicin (TRPV1 agonist), and capsazepine (TRPV1 antagonist). SHRs displayed increased CB1 expression in prelimbic cortex and cingulate cortex area 1 and in CA3 region of the dorsal hippocampus. Conversely, SHRs exhibited decreases in TRPV1 expression in prelimbic and CA1 region of dorsal hippocampus and increases in the basolateral amygdala. AM404, WIN 55,212-2 and capsaicin attenuated SHRs CFC deficit, although WIN 55,212-2 worsened SHRs CFC deficit in higher doses. WRs and SHRs CFC were modulated by distinct doses, suggesting that these strains display different responsiveness to cannabinoid and vanilloid drugs. Treatment with capsazepine did not modify CFC in either strains. The effects of AM404 on SHRs CFC deficit was not blocked by pretreatment with rimonabant (CB1 antagonist) or capsazepine. These results reinforce the involvement of the endocannabinoid/endovanilloid systems in the SHRs CFC deficit and point to these systems as targets to treat the emotional processing/cognitive symptoms of schizophrenia.

The impact of sugar consumption on stress driven, emotional and addictive behaviors.

In 2016 the World Health Organization reported 39% of the world's adult population (over 18 y) was overweight, with western countries such as Australia and the United States of America at 64.5% and 67.9% respectively. Overconsumption of high fat/sugar containing food and beverages contribute to the development of obesity. Neural plasticity that occurs as a result of long term sugar consumption has been shown to reduce impulse control and therefore lower the ability to resist the high fat/sugar foods contributing to the obesity epidemic. There is significant overlap between the neural pathways involved in emotions that guide behavioural responses to survival situations with those regulating overconsumption of highly palatable food. This suggests that having a clearer understanding of the role of stress and emotions in the development of obesity will lead to the development of novel therapeutic strategies. Sucrose consumption activates the mesocorticolimbic system in a manner synonymous with substances of abuse. There is overwhelming evidence to support the hypothesis that sucrose consumption results in pathophysiological consequences such as morphological neuronal changes, altered emotional processing and modified behaviour in rodent and human models. In this comprehensive review, we examined >300 studies investigating the interaction between sugar consumption, stress and emotions. Preclinical and clinical trials investigating highly palatable foods and stress, anxiety, depression and fear are reviewed. Importantly, the synergy between sugar consumption and neurobiology is addressed. This review summarizes the neurochemical changes and neural adaptations ö including changes in the dopaminergic system ö that influence emotion and behaviour following sugar consumption.

Longitudinal proton spectroscopy study of the prefrontal cortex in youth at risk for bipolar disorder before and after their first mood episode.

OBJECTIVES: To investigate neurochemical abnormalities in the left and right ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) of youth at risk for bipolar disorder using proton magnetic resonance spectroscopy before and after their first mood episode. METHODS: Children and adolescents offspring of parents with bipolar I disorder (at-risk group, n = 117) and matched healthy controls (HC group, n = 61) were recruited at the University of Cincinnati. At-risk subjects had no lifetime major mood and psychotic disorders at baseline, and were followed up every 4 months to monitor for development of a major depressive, manic, hypomanic, or mixed mood episode. Levels of N-acetyl-aspartate (NAA), phosphocreatine plus creatine (PCr + Cr), choline-containing compounds, myo-inositol, and glutamate were determined using LCModel and corrected for partial volume effects. RESULTS: There were no baseline differences in metabolite levels for any of the brain regions between at-risk and HC youth. Nineteen at-risk subjects developed a first mood episode during follow-up. Survival analyses showed that baseline PCr + Cr levels in the left VLPFC significantly predicted a mood episode during follow-up in the at-risk group (HR: 0.47, 95% CI: 0.27-0.82, P = 0.008). There were no longitudinal changes in metabolites levels in the VLPFC and ACC before and after a mood episode in at-risk subjects. CONCLUSIONS: We found no evidence for abnormal proton spectroscopy metabolite levels in the VLPFC and ACC of at-risk youth, prior and after the development of their first mood episode. Preliminary findings of association between baseline PCr + Cr levels in the left VLPFC and risk to develop a mood episode warrant further investigation.

High-fructose diet initiated during adolescence does not affect basolateral amygdala excitability or affective-like behavior in Sprague Dawley rats.

Patients with type-2 diabetes, obesity, and metabolic syndrome have a significantly increased risk of developing depression. Dysregulated metabolism may contribute to the etiology of depression by affecting neuronal activity in key limbic areas. The basolateral amygdala (BLA) acts as a critical emotional valence detector in the brain's limbic circuit, and shows hyperactivity and abnormal glucose metabolism in depressed patients. Furthermore, administering a periadolescent high-fructose diet (HFrD; a model of metabolic syndrome) to male Wistar rats increases anxiety- and depressive-like behavior. Repeated shock stress in Sprague Dawley rats similarly increases anxiety-like behavior and increases BLA excitability. We therefore investigated whether a metabolic stressor (HFrD) would have similar effects as shock stress on BLA excitability in Sprague Dawley rats. We found that a HFrD did not affect the intrinsic excitability of BLA neurons. Fructose-fed Sprague Dawley rats had elevated body fat mass, but did not show increases in metabolic efficiency and fasting blood glucose relative to control. Finally unlike Wistar rats, fructose-fed Sprague Dawley rats did not show increased anxiety- and depressive-like behavior. These results suggest that genetic differences between rat strains may affect susceptibility to a metabolic insult. Collectively, these data show that a periadolescent HFrD disrupts metabolism, but does not change affective behavior or BLA excitability in Sprague Dawley rats.

Endocannabinoid control of the insular-bed nucleus of the stria terminalis circuit regulates negative affective behavior associated with alcohol abstinence.

Negative affect is a core symptom domain associated with an array of neurological and psychiatric disorders and is only partially targeted by current therapies, highlighting the need for better, more targeted treatment options. This study focuses on negative affective symptoms associated with prolonged alcohol abstinence, one of the leading causes of relapse. Using a mouse model of chronic alcohol consumption followed by forced abstinence (CDFA), prolonged alcohol abstinence increased c-fos expression and spontaneous glutamatergic neurotransmission in the dorsal bed nucleus of the stria terminalis (dBNST), a region heavily implicated in negative affect in both humans and rodents. Further, pharmacologically enhancing endogenous cannabinoids (eCB) with JZL184 prevents abstinence-induced increases in dBNST neuronal activity, underscoring the therapeutic potential of drugs targeting the brain's eCB system. Next, we used a channelrhodopsin-assisted mapping strategy to identify excitatory inputs to the dBNST that could contribute to CDFA-induced negative affect. We identified the insular cortex (insula), a region involved in regulating interoception, as a dense, functional, eCB-sensitive input to the dBNST. Using a chemogenetic strategy to locally mimic eCB signaling, we demonstrate that the insula strongly influences the CDFA behavioral phenotype and dBNST neuronal activity. Lastly, we used an anterograde strategy for transynaptic targeting of Cre expression in combination with a Gq-DREADD to selectively recruit dBNST neurons receiving insula projections. Chemogenetic recruitment of these neurons mimicked behavioral and c-fos responses observed in CDFA. Collectively, this study supports a role for the insula-BNST neural circuit in negative affective disturbances and highlights the therapeutic potential of the eCB system for treating negative affective disorders.

The Neurobiology of Reduced Autobiographical Memory Specificity.

There has been a recent growth in investigations into the neural mechanisms underlying the problems recalling specific autobiographical events that are a core feature of emotional disorders. In this review we provide the first synthesis of this literature, taking into account brain as well as cognitive mechanisms. We suggest that these problems are driven by idiosyncratic activation in areas of the brain associated with assigning salience and self-relevance to emotional memories. Other areas associated with inhibiting distraction and constructing vivid memory representations are also important. Each of these mechanisms may work independently or in concert with one another. Importantly, this interaction between mechanisms may differ between diagnostic and demographic groups such that similar problems in specificity may be characterised by different mechanisms. Given this challenge, neuroimaging may prove useful in identifying patient-specific biomarkers for interventions.

Microarray Analysis of Gene Expression Changes in Neuroplastin 65-Knockout Mice: Implications for Abnormal Cognition and Emotional Disorders.

Neuroplastin 65 (Np65) is an immunoglobulin superfamily cell adhesion molecule involved in synaptic formation and plasticity. Our recent study showed that Np65-knockout (KO) mice exhibit abnormal cognition and emotional disorders. However, the underlying mechanisms remain unclear. In this study, we found 588 differentially-expressed genes in Np65-KO mice by microarray analysis. RT-PCR analysis also revealed the altered expression of genes associated with development and synaptic structure, such as Cdh1, Htr3a, and Kcnj9. In addition, the expression of Wnt-3, a Wnt protein involved in development, was decreased in Np65-KO mice as evidenced by western blotting. Surprisingly, MRI and DAPI staining showed a significant reduction in the lateral ventricular volume of Np65-KO mice. Together, these findings suggest that ablation of Np65 influences gene expression, which may contribute to abnormal brain development. These results provide clues to the mechanisms underlying the altered brain functions of Np65-deficient mice.