Background
Interferon (IFN)-alpha is an innate immune cytokine that causes high rates of depression in humans and therefore has been used to study the impact of cytokines on the brain and behavior. To establish a non-human primate model of cytokine-induced depression, we examined the effects of IFN-alpha on rhesus monkeys.
Methods
Eight rhesus monkeys were administered recombinant human (rHu)-IFN-alpha (20 MIU/m2) or saline for 4 weeks in counterbalanced fashion, and videotaped behavior, as well as plasma and cerebrospinal fluid (CSF), were obtained at regular intervals to assess behavioral, neuroendocrine, immune and neurotransmitter parameters. Additionally, expression and activity of IFN-alpha/beta receptors in monkey peripheral blood mononuclear cells (PBMCs) were assessed.
Results
Compared to saline treatment, IFN-alpha administration was associated with persistent increases in anxiety-like behaviors and decreases in environmental exploration. In addition, IFN-alpha induced significant increases in plasma concentrations of ACTH, cortisol, and interleukin-6 that tended to diminish after chronic administration, especially in dominant animals. Interestingly, in 3 animals, depressive-like, huddling behavior was observed. Monkeys that displayed huddling behavior exhibited significantly higher plasma concentrations of ACTH and lower CSF concentrations of the dopamine metabolite, homovanillic acid. Rhesus monkey PBMCs were found to express mRNA and protein for the IFN-alpha/beta receptor. Moreover, treatment of PBMCs with rHu-IFN-alpha led to induction of STAT1, one of the primary IFN-alpha-induced signaling molecules.
Conclusions
IFN-alpha evoked behavioral, neuroendocrine and immune responses in rhesus monkeys that are similar to humans. Moreover, alterations in hypothalamic-pituitary-adrenal axis responses and dopamine metabolism may contribute to IFN-alpha-induced depressive-like huddling behavior.
Building on interpersonal theories of depression, the current study sought to explore whether early childhood social withdrawal serves as a risk factor for depressive symptoms and diagnoses in young adulthood. The researchers hypothesized that social impairment at age 15 would mediate the association between social withdrawal at age 5 and depression by age 20. This mediational model was tested in a community sample of 702 Australian youth followed from mother's pregnancy to youth age 20. Structural equation modeling analyses found support for a model in which childhood social withdrawal predicted adolescent social impairment, which, in turn, predicted depression in young adulthood. Additionally, gender was found to moderate the relationship between adolescent social impairment and depression in early adulthood, with females exhibiting a stronger association between social functioning and depression at the symptom and diagnostic level. This study illuminates one potential pathway from early developing social difficulties to later depressive symptoms and disorders.
Considerable animal research and available human studies suggest that psychological distress experienced by mothers during gestation is associated with later neurodevelopmental deficits in offspring; however, little research has examined potential protective factors that might mitigate this risk. The current study examined the impact of maternal prenatal psychological distress during pregnancy on cognitive outcomes in preschoolers (ages 2.5–5 years) and positive parenting as a potential protective factor. Mother-child dyads (N = 162, mean child age = 44 months, 49 % female) were recruited from a longitudinal cohort of women who had previously participated in a study of maternal mood disorders during pregnancy. Maternal prenatal distress was assessed with multiple measures collected throughout pregnancy. During a follow-up visit, mothers were interviewed about their psychological symptoms since the birth of the child, parenting behaviors were recorded during a parent-child interaction, and children’s cognitive abilities were measured using the Differential Ability Scales, 2nd Edition. Maternal prenatal distress significantly predicted lower general cognitive abilities; however, this relationship was strongest for children whose mothers exhibited low levels of positive engagement and not significant when mothers exhibited high levels of positive engagement. Results suggest that positive parental engagement can protect against the detrimental effects of maternal prenatal distress on preschoolers’ cognitive abilities.
by
Paula Frew;
Kimberly Parker;
Linda Vo;
Danielle Haley;
Ann O'Leary;
Dazon Dixon Diallo;
Carol E. Golin;
Irene Kuo;
Lydia Soto-Torres;
Jing Wang;
Adaora A. Adimora;
Laura A. Randall;
Carlos Del Rio;
Sally Hodder
Background: We sought to understand the multilevel syndemic factors that are concurrently contributing to the HIV epidemic among women living in the US. We specifically examined community, network, dyadic, and individual factors to explain HIV vulnerability within a socioecological framework. Methods: We gathered qualitative data (120 interviews and 31 focus groups) from a subset of women ages 18-44 years (N = 2,099) enrolled in the HPTN 064 HIV seroincidence estimation study across 10 US communities. We analyzed data from 4 diverse locations: Atlanta, New York City (the Bronx), Raleigh, and Washington, DC. Data were thematically coded using grounded theory methodology. Intercoder reliability was assessed to evaluate consistency of team-based coding practices. Results: The following themes were identified at 4 levels including 1) exosystem (community): poverty prevalence, discrimination, gender imbalances, community violence, and housing challenges; 2) mesosystem (network): organizational social support and sexual concurrency; 3) microsystem (dyadic): sex exchange, interpersonal social support, intimate partner violence; and 4) individual: HIV/STI awareness, risk taking, and substance use. A strong theme emerged with over 80 % of responses linked to the fundamental role of financial insecurity underlying risk-taking behavioral pathways. Conclusions: Multilevel syndemic factors contribute to women's vulnerability to HIV in the US. Financial insecurity is a predominant theme, suggesting the need for tailored programming for women to reduce HIV risk. Trial registration: Clinicaltrials.gov, NCT00995176
by
Robert D. Latzman;
Laura E. Drislane;
Lisa K. Hecht;
Sarah J. Brislin;
Christopher J. Patrick;
Scott Lilienfeld;
Hani J. Freeman;
Steven J. Schapiro;
William D. Hopkins
The current work sought to operationalize constructs of the triarchic model of psychopathy in chimpanzees (Pan troglodytes), a species well-suited for investigations of basic biobehavioral dispositions relevant to psychopathology. Across three studies, we generated validity evidence for scale measures of the triarchic model constructs in a large sample (N=238) of socially-housed chimpanzees. Using a consensus-based rating approach, we first identified candidate items for the chimpanzee triarchic (CHMP-Tri) scales from an existing primate personality instrument and refined these into scales. In Study 2, we collected data for these scales from human informants (N=301), and examined their convergent and divergent relations with scales from another triarchic inventory developed for human use. In Study 3, we undertook validation work examining associations between CHMP-Tri scales and task measures of approach-avoidance behavior (N=73) and ability to delay gratification (N=55). Current findings provide support for a chimpanzee model of core dispositions relevant to psychopathy and other forms of psychopathology.
Virtual organisms animated by a selectionist theory of behavior dynamics worked on concurrent random interval schedules where both the rate and magnitude of reinforcement were varied. The selectionist theory consists of a set of simple rules of selection, recombination, and mutation that act on a population of potential behaviors by means of a genetic algorithm. An extension of the power function matching equation, which expresses behavior allocation as a joint function of exponentiated reinforcement rate and reinforcer magnitude ratios, was fitted to the virtual organisms' data, and over a range of moderate mutation rates was found to provide an excellent description of their behavior without residual trends. The mean exponents in this range of mutation rates were 0.83 for the reinforcement rate ratio and 0.68 for the reinforcer magnitude ratio, which are values that are comparable to those obtained in experiments with live organisms. These findings add to the evidence supporting the selectionist theory, which asserts that the world of behavior we observe and measure is created by evolutionary dynamics.
Affective spectrum and anxiety disorders have come to be recognized as the most prevalently diagnosed psychiatric disorders. Among a suite of potential causes, changes in mitochondrial energy metabolism and function have been associated with such disorders. Thus, proteins that specifically change mitochondrial functionality could be identified as molecular targets for drugs related to treatment for affective spectrum disorders. Here, we report generation of transgenic mice overexpressing the scaffolding and mitophagy related protein Sequestosome1 (SQSTM1/p62) or a single point mutant (P392L) in the UBA domain of SQSTM1/p62. We show that overexpression of SQSTM1/p62 increases mitochondrial energy output and improves transcription factor import into the mitochondrial matrix. These elevated levels of mitochondrial functionality correlate directly with discernible improvements in mouse behaviors related to affective spectrum and anxiety disorders. We also describe how overexpression of SQSTM1/p62 improves spatial learning and long term memory formation in these transgenic mice. These results suggest that SQSTM1/p62 provides an attractive target for therapeutic agents potentially suitable for the treatment of anxiety and affective spectrum disorders.
Background and Purpose: Diffusion-weighted imaging (DWI) and perfusion MRI were used to examine the spatiotemporal evolution of stroke lesions in adult macaques with ischemic occlusion. Methods: Permanent MCA occlusion was induced with silk sutures through an interventional approach via the femoral artery in adult rhesus monkeys (n = 8, 10-21 years old). The stroke lesions were examined with high-resolution DWI and perfusion MRI, and T2-weighted imaging (T2W) on a clinical 3T scanner at 1-6, 48, and 96 hours post occlusion and validated with H&E staining. Results: The stroke infarct evolved via a natural logarithmic pattern with the mean infarct growth rate = 1.38 ± 1.32 ml per logarithmic time scale (hours) (n = 7) in the hyperacute phase (1-6 hours). The mean infarct volume after 6 hours post occlusion was 3.6±2.8 ml (n = 7, by DWI) and increased to 3.9±2.9 ml (n = 5, by T2W) after 48 hours, and to 4.7±2.2ml (n = 3, by T2W) after 96 hours post occlusion. The infarct volumes predicted by the natural logarithmic function were correlated significantly with the T2W-derived lesion volumes (n = 5, r = 0.92, p = 0.01) at 48 hours post occlusion. The final infarct volumes derived from T2W were correlated significantly with those from H&E staining (r = 0.999, p < 0.0001, n = 4). In addition, the diffusion-perfusion mismatch was visible generally at 6 hours but nearly diminished at 48 hours post occlusion. Conclusion: The infarct evolution follows a natural logarithmic pattern in the hyperacute phase of stroke. The logarithmic pattern of evolution could last up to 48 hours after stroke onset and may be used to predict the infarct volume growth during the acute phase of ischemic stroke. The nonhuman primate model, MRI protocols, and post data processing strategy may provide an excellent platform for characterizing the evolution of acute stroke lesion in mechanistic studies and therapeutic interventions of stroke disease.
Causal composition allows people to generate new causal relations by combining existing causal knowledge. We introduce a new computational model of such reasoning, the force theory, which holds that people compose causal relations by simulating the processes that join forces in the world, and compare this theory with the mental model theory (Khemlani et al., 2014) and the causal model theory (Sloman et al., 2009), which explain causal composition on the basis of mental models and structural equations, respectively. In one experiment, the force theory was uniquely able to account for people's ability to compose causal relationships from complex animations of real-world events. In three additional experiments, the force theory did as well as or better than the other two theories in explaining the causal compositions people generated from linguistically presented causal relations. Implications for causal learning and the hierarchical structure of causal knowledge are discussed.
Rationale
There is significant interest in the NMDA-receptor antagonist ketamine due to its efficacy in treating depressive disorders and its induction of psychotic-like symptoms that make it a useful tool for modeling psychosis.
Objective
The present study extends the successful development of an apparatus and methodology to conduct pharmacological MRI studies in awake rhesus monkeys in order to evaluate the CNS effects of ketamine.
Methods
Functional MRI scans were conducted in four awake adult female rhesus monkeys during sub-anesthetic i.v. infusions of ketamine (0.345 mg/kg bolus followed by 0.256 mg/kg/hr constant infusion) with and without risperidone pretreatment (0.06mg/kg). Statistical parametric maps of ketamine-induced BOLD activation were obtained with appropriate GLM models incorporating motion and hemodynamics of ketamine infusion.
Results
Ketamine infusion induced and sustained robust BOLD activation in a number of cortical and subcortical regions, including the thalamus, cingulate gyrus, and supplementary motor area. Pretreatment with the antipsychotic drug risperidone markedly blunted ketamine-induced activation in many brain areas.
Conclusions
The results are remarkably similar to human imaging studies showing ketamine-induced BOLD activation in many of the same brain areas, and pretreatment with risperidone or another antipsychotic blunting the ketamine response to a similar extent. The strong concordance of the functional imaging data in humans with these results from nonhuman primates highlights the translational value of the model and provides an excellent avenue for future research examining the CNS effects of ketamine. This model may also be a useful tool for evaluating the efficacy of novel antipsychotic drugs.