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Schizophrenia is conceptualized as a neurodevelopmental disorder and pre-morbid differences in social function and cognition have been well-established. Less is known about pre-morbid temperament and personality. Inhibited temperament-the predisposition to respond to novelty with wariness, fear, or caution-is a premorbid risk factor for anxiety, depression, and substance use but is understudied in schizophrenia. Participants were patients with schizophrenia spectrum disorders (n = 166) and healthy controls (n = 180). Patients completed measures of childhood inhibited temperament, clinical symptoms (anxiety, depression, PANSS factors), and quality of life. Patients had significantly higher levels of inhibited temperament relative to healthy controls. In patients with schizophrenia, higher inhibited temperament was significantly associated with co-morbid anxiety disorders, greater anxiety and depression symptoms, higher PANSS Distress scores, lower PANSS Excitement scores, and lower quality of life. The current findings replicate and extend previous research with a larger sample and are consistent with vulnerability in an affective path to psychosis. In schizophrenia, higher inhibited temperament was associated with a cluster of mood and anxiety symptoms. Inhibited temperament was not associated with psychosis symptoms. Patients with high inhibited temperament may especially benefit from treatments that specifically target anxiety and depression.
Copyright © 2019. Published by Elsevier B.V.
Stress contributes to numerous psychiatric disorders. Corticotropin releasing factor (CRF) signaling and CRF neurons in the bed nucleus of the stria terminalis (BNST) drive negative affective behaviors, thus agents that decrease activity of these cells may be of therapeutic interest. Here, we show that acute restraint stress increases cFos expression in CRF neurons in the mouse dorsal BNST, consistent with a role for these neurons in stress-related behaviors. We find that activation of α-adrenergic receptors (ARs) by the agonist guanfacine reduced cFos expression in these neurons both in stressed and unstressed conditions. Further, we find that α- and β-ARs differentially regulate excitatory drive onto these neurons. Pharmacological and channelrhodopsin-assisted mapping experiments suggest that α-ARs specifically reduce excitatory drive from parabrachial nucleus (PBN) afferents onto CRF neurons. Given that the α-AR is a G-linked GPCR, we assessed the impact of activating the G-coupled DREADD hM4Di in the PBN on restraint stress regulation of BNST CRF neurons. CNO activation of PBN hM4Di reduced stress-induced in BNST neurons. Further, using as an additional marker of BNST neuronal identity, we uncovered a female-specific upregulation of the coexpression of in BNST neurons following stress, which was prevented by ovariectomy. These findings show that stress activates BNST CRF neurons, and that α-AR activation suppresses the activity of these cells, at least in part by suppressing excitatory drive from PBN inputs onto CRF neurons. Stress is a major variable contributing to mood disorders. Here, we show that stress increases activation of BNST CRF neurons that drive negative affective behavior. We find that the clinically well tolerated α-AR agonist guanfacine reduces activity of these cells , and reduces excitatory PBN inputs onto these cells Additionally, we uncover a novel sex-dependent coexpression of with in female BNST neurons after stress, an effect abolished by ovariectomy. These results demonstrate input-specific interactions between norepinephrine and CRF, and point to an action by which guanfacine may reduce negative affective responses.
Copyright © 2019 the authors 0270-6474/19/390472-13$15.00/0.
Police maltreatment, whether experienced personally or indirectly through one's family or friends, represents a structurally rooted public health problem that disproportionately affects minorities. Researchers, however, know little about the physiological mechanisms connecting unfair treatment by police (UTBP) to poor health. Shortened telomeres due to exposure to this stressor represent one plausible mechanism. Using data from a community sample of black (n = 262) and white (n = 252) men residing in Nashville-Davidson County, we test four hypotheses: (1) Black men will be more likely to report UTBP than white men, (2) those reporting UTBP will have shorter telomeres than those not reporting UTBP, (3) this association will be more pronounced among black men, and (4) these hypotheses will extend to those who report vicarious UTBP. Results reveal support for all hypotheses. The implications for our findings are discussed as they pertain to debates on policing practices and health disparities research.
Stress is a precipitating agent in neuropsychiatric disease and initiates relapse to drug-seeking behavior in addicted patients. Targeting the stress system in protracted abstinence from drugs of abuse with anxiolytics may be an effective treatment modality for substance use disorders. α-adrenergic receptors (α-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α-AR agonist guanfacine reduces overall craving and uncouples craving from stress, yet minimally affects relapse, potentially due to competing actions in the brain. Here, we show that heteroceptor α-ARs postsynaptically enhance dorsal bed nucleus of the stria terminalis (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation channels because inhibition of these channels is necessary and sufficient for excitatory actions. Finally, this excitatory action is mimicked by clozapine--oxide activation of the G-coupled DREADD hM4Di in dBNST neurons and its activation elicits anxiety-like behavior in the elevated plus maze. Together, these data provide a framework for elucidating cell-specific actions of GPCR signaling and provide a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction. Stress affects the development of neuropsychiatric disorders including anxiety and addiction. Guanfacine is an α2A-adrenergic receptor (α2A-AR) agonist with actions in the bed nucleus of the stria terminalis (BNST) that produces antidepressant actions and uncouples stress from reward-related behaviors. Here, we show that guanfacine increases dorsal BNST neuronal activity through actions at postsynaptic α2A-ARs via a mechanism that involves hyperpolarization-activated cyclic nucleotide gated cation channels. This action is mimicked by activation of the designer receptor hM4Di expressed in the BNST, which also induces anxiety-like behaviors. Together, these data suggest that postsynaptic α2A-ARs in BNST have excitatory actions on BNST neurons and that these actions can be phenocopied by the so-called "inhibitory" DREADDs, suggesting that care must be taken regarding interpretation of data obtained with these tools.
Copyright © 2018 the authors 0270-6474/18/388923-21$15.00/0.
BACKGROUND - Late-life depression (LLD) is associated with a fragile antidepressant response and high recurrence risk. This study examined what measures predict recurrence in remitted LLD.
METHODS - Individuals of age 60 years or older with a Diagnostic and Statistical Manual - IV (DSM-IV) diagnosis of major depressive disorder were enrolled in the neurocognitive outcomes of depression in the elderly study. Participants received manualized antidepressant treatment and were followed longitudinally for an average of 5 years. Study analyses included participants who remitted. Measures included demographic and clinical measures, medical comorbidity, disability, life stress, social support, and neuropsychological testing. A subset underwent structural magnetic resonance imaging (MRI).
RESULTS - Of 241 remitted elders, approximately over 4 years, 137 (56.8%) experienced recurrence and 104 (43.2%) maintained remission. In the final model, greater recurrence risk was associated with female sex (hazard ratio [HR] = 1.536; confidence interval [CI] = 1.027-2.297), younger age of onset (HR = 0.990; CI = 0.981-0.999), higher perceived stress (HR = 1.121; CI = 1.022-1.229), disability (HR = 1.060; CI = 1.005-1.119), and less support with activities (HR = 0.885; CI = 0.812-0.963). Recurrence risk was also associated with higher Montgomery-Asberg Depression Rating Scale (MADRS) scores prior to censoring (HR = 1.081; CI = 1.033-1.131) and baseline symptoms of suicidal thoughts by MADRS (HR = 1.175; CI = 1.002-1.377) and sadness by Center for Epidemiologic Studies-Depression (HR = 1.302; CI, 1.080-1.569). Sex, age of onset, and suicidal thoughts were no longer associated with recurrence in a model incorporating report of multiple prior episodes (HR = 2.107; CI = 1.252-3.548). Neither neuropsychological test performance nor MRI measures of aging pathology were associated with recurrence.
CONCLUSIONS - Over half of the depressed elders who remitted experienced recurrence, mostly within 2 years. Multiple clinical and environmental measures predict recurrence risk. Work is needed to develop instruments that stratify risk.
© 2018 Wiley Periodicals, Inc.
Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light-dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.
Major depressive disorder (MDD) is considered a 'circuitopathy', and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal dysfunction. It is unknown whether stimulation of upstream hippocampal circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in mice and humans. Here we show that molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemogenetic stimulation of Ent neurons induce antidepressive-like effects in mice. Mechanistically, we show that Ent-stimulation-induced antidepressive-like behavior relies on the generation of new hippocampal neurons. Thus, controlled stimulation of Ent hippocampal afferents is antidepressive via increased hippocampal neurogenesis. These findings emphasize the power and potential of Ent glutamatergic afferent stimulation-previously well-known for its ability to influence learning and memory-for MDD treatment.
Over 4 million children in the United States suffer from chronic health conditions, including cancer, sickle cell disease, and diabetes. Because of major advances in the early identification and treatment of these conditions, survival rates for these children continue to rise, and the majority now lives into adulthood. However, increases in survival have come with costs related to long-term effects of disease processes and treatments. Foremost among these consequences is impairment in brain development and neurocognitive function that may affect a substantial portion of children with chronic health conditions and follow many into adulthood. Impaired cognitive function may contribute to impairment in educational and occupational attainment, mental health, and quality of life for children with chronic conditions. Despite the significance and scope of this problem, advances in the identification and understanding of neurocognitive problems and the delivery of effective clinical care have been hindered in part because research has been "siloed"-conducted on each chronic condition in isolation. This review examines, for the first time, neurocognitive problems in a selected set of 6 chronic pediatric health conditions-leukemia, brain tumors, sickle cell disease, congenital heart disease, Type 1 diabetes, and traumatic brain injury-to define the magnitude of the problem and identify directions for future research and clinical care. Psychologists from many areas of specialization, including pediatric psychology, educational and school psychology, neuropsychology, behavioral medicine, and adult primary care, are uniquely positioned to contribute to every phase of this work, including research, identification, and intervention. (PsycINFO Database Record
(c) 2017 APA, all rights reserved).
Stress is a ubiquitous risk factor for the exacerbation and development of affective disorders including major depression and posttraumatic stress disorder. Understanding the neurobiological mechanisms conferring resilience to the adverse consequences of stress could have broad implications for the treatment and prevention of mood and anxiety disorders. We utilize laboratory mice and their innate inter-individual differences in stress-susceptibility to demonstrate a critical role for the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) in stress-resilience. Specifically, systemic 2-AG augmentation is associated with a stress-resilient phenotype and enhances resilience in previously susceptible mice, while systemic 2-AG depletion or CB1 receptor blockade increases susceptibility in previously resilient mice. Moreover, stress-resilience is associated with increased phasic 2-AG-mediated synaptic suppression at ventral hippocampal-amygdala glutamatergic synapses and amygdala-specific 2-AG depletion impairs successful adaptation to repeated stress. These data indicate amygdala 2-AG signalling mechanisms promote resilience to adverse effects of acute traumatic stress and facilitate adaptation to repeated stress exposure.
BACKGROUND - Childhood early life stress (ELS) increases risk of adulthood major depressive disorder (MDD) and is associated with altered brain structure and function. It is unclear whether specific ELSs affect depression risk, cognitive function and brain structure.
METHOD - This cross-sectional study included 64 antidepressant-free depressed and 65 never-depressed individuals. Both groups reported a range of ELSs on the Early Life Stress Questionnaire, completed neuropsychological testing and 3T magnetic resonance imaging (MRI). Neuropsychological testing assessed domains of episodic memory, working memory, processing speed and executive function. MRI measures included cortical thickness and regional gray matter volumes, with a priori focus on the cingulate cortex, orbitofrontal cortex (OFC), amygdala, caudate and hippocampus.
RESULTS - Of 19 ELSs, only emotional abuse, sexual abuse and severe family conflict independently predicted adulthood MDD diagnosis. The effect of total ELS score differed between groups. Greater ELS exposure was associated with slower processing speed and smaller OFC volumes in depressed subjects, but faster speed and larger volumes in non-depressed subjects. In contrast, exposure to ELSs predictive of depression had similar effects in both diagnostic groups. Individuals reporting predictive ELSs exhibited poorer processing speed and working memory performance, smaller volumes of the lateral OFC and caudate, and decreased cortical thickness in multiple areas including the insula bilaterally. Predictive ELS exposure was also associated with smaller left hippocampal volume in depressed subjects.
CONCLUSIONS - Findings suggest an association between childhood trauma exposure and adulthood cognitive function and brain structure. These relationships appear to differ between individuals who do and do not develop depression.