Adolescent but not adult-born neurons are critical for susceptibility to chronic social defeat

Recent evidence implicates adult hippocampal neurogenesis in regulating behavioral and physiologic responses to stress. Hippocampal neurogenesis occurs across the lifespan, however the rate of cell birth is up to 300% higher in adolescent mice compared to adults. Adolescence is a sensitive period in development where emotional circuitry and stress reactivity undergo plasticity establishing life-long set points. Therefore neurogenesis occurring during adolescence may be particularly important for emotional behavior. However, little is known about the function of hippocampal neurons born during adolescence. In order to assess the contribution of neurons born in adolescence to the adult stress response and depression-related behavior, we transiently reduced cell proliferation either during adolescence, or during adulthood in GFAP-Tk mice. We found that the intervention in adolescence did not change adult baseline behavioral response in the forced swim test, sucrose preference test or social affiliation test, and did not change adult corticosterone responses to an acute stressor. However following chronic social defeat, adult mice with reduced adolescent neurogenesis showed a resilient phenotype. A similar transient reduction in adult neurogenesis did not affect depression-like behaviors or stress induced corticosterone. Our study demonstrates that hippocampal neurons born during adolescence, but not in adulthood are important to confer susceptibility to chronic social defeat

Response Assessment of NovoTTF-100A Versus Best Physician\u27s Choice Chemotherapy in Recurrent Glioblastoma

The NovoTTF-100A device emits frequency-tuned alternating electric fields that interfere with tumor cell mitosis. In phase III trial for recurrent glioblastomas, NovoTTF-100A was shown to have equivalent efficacy and less toxicity when compared to Best Physician\u27s Choice (BPC) chemotherapy. We analyzed the characteristics of responders and nonresponders in both cohorts to determine the characteristics of response and potential predictive factors. Tumor response and progression were determined by Macdonald criteria. Time to response, response duration, progression-free survival (PFS) ± Simon-Makuch correction, overall survival (OS), prognostic factors, and relative hazard rates were compared between responders and nonresponders. Median response duration was 7.3 versus 5.6 months for NovoTTF-100A and BPC chemotherapy, respectively (P = 0.0009). Five of 14 NovoTTF-100A responders but none of seven BPC responders had prior low-grade histology. Mean cumulative dexamethasone dose was 35.9 mg for responders versus 485.6 mg for nonresponders in the NovoTTF-100A cohort (P \u3c 0.0001). Hazard analysis showed delayed tumor progression in responders compared to nonresponders. Simon-Makuch-adjusted PFS was longer in responders than in nonresponders treated with NovoTTF-100A (P = 0.0007) or BPC chemotherapy (P = 0.0222). Median OS was longer for responders than nonresponders treated with NovoTTF-100A (P \u3c 0.0001) and BPC chemotherapy (P = 0.0235). Pearson analysis showed strong correlation between response and OS in NovoTTF-100A (P = 0.0002) but not in BPC cohort (P = 0.2900). Our results indicate that the response characteristics favor NovoTTF-100A and data on prior low-grade histology and dexamethasone suggest potential genetic and epigenetic determinants of NovoTTF-100A response

Perceptual Other-Race Training Reduces Implicit Racial Bias

Background: Implicit racial bias denotes socio-cognitive attitudes towards other-race groups that are exempt from conscious awareness. In parallel, other-race faces are more difficult to differentiate relative to own-race faces – the ‘‘Other-Race Effect.’ ’ To examine the relationship between these two biases, we trained Caucasian subjects to better individuate other-race faces and measured implicit racial bias for those faces both before and after training. Methodology/Principal Findings: Two groups of Caucasian subjects were exposed equally to the same African American faces in a training protocol run over 5 sessions. In the individuation condition, subjects learned to discriminate between African American faces. In the categorization condition, subjects learned to categorize faces as African American or not. For both conditions, both pre- and post-training we measured the Other-Race Effect using old-new recognition and implicit racial biases using a novel implicit social measure – the ‘‘Affective Lexical Priming Score’ ’ (ALPS). Subjects in the individuation condition, but not in the categorization condition, showed improved discrimination of African American faces with training. Concomitantly, subjects in the individuation condition, but not the categorization condition, showed a reduction in their ALPS. Critically, for the individuation condition only, the degree to which an individual subject’s ALPS decreased was significantly correlated with the degree of improvement that subject showed in their ability to differentiate African American faces

The dopamine D2/D3 receptor agonist quinpirole increases checking-like behaviour in an operant observing response task with uncertain reinforcement: a novel possible model of OCD.

Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours. We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty. In the ORT, rats pressed an 'observing' lever for information about the location of an 'active' lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes. Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be beneficial

Deficits in Implicit Attention to Social Signals in Schizophrenia and High Risk Groups: Behavioural Evidence from a New Illusion

Background An increasing body of evidence suggests that the apparent social impairments observed in schizophrenia may arise from deficits in social cognitive processing capacities. The ability to process basic social cues, such as gaze direction and biological motion, effortlessly and implicitly is thought to be a prerequisite for establishing successful social interactions and for construing a sense of "social intuition." However, studies that address the ability to effortlessly process basic social cues in schizophrenia are lacking. Because social cognitive processing deficits may be part of the genetic vulnerability for schizophrenia, we also investigated two groups that have been shown to be at increased risk of developing schizophrenia-spectrum pathology: first-degree relatives of schizophrenia patients and men with Klinefelter syndrome (47,XXY). Results We compared 28 patients with schizophrenia, 29 siblings of patients with schizophrenia, and 29 individuals with Klinefelter syndrome with 46 matched healthy control subjects on a new paradigm. This paradigm measures one's susceptibility for a bias in distance estimation between two agents that is induced by the implicit processing of gaze direction and biological motion conveyed by these agents. Compared to control subjects, patients with schizophrenia, as well as siblings of patients and Klinefelter men, showed a lack of influence of social cues on their distance judgments. Conclusions We suggest that the insensitivity for social cues is a cognitive aspect of schizophrenia that may be seen as an endophenotype as it appears to be present both in relatives who are at increased genetic risk and in a genetic disorder at risk for schizophrenia-spectrum psychopathology. These social cue-processing deficits could contribute, in part, to the difficulties in higher order social cognitive tasks and, hence, to decreased social competence that has been observed in these groups

The Earth BioGenome Project 2020: Starting the clock

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The Earth BioGenome Project 2020: Starting the clock.

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Lewin, H. A., Richards, S., Lieberman Aiden, E., Allende, M. L., Archibald, J. M., Bálint, M., Barker, K. B., Baumgartner, B., Belov, K., Bertorelle, G., Blaxter, Mark L., Cai, J., Caperello, N. D., Carlson, K., Castilla-Rubio, J. C., Chaw, S-M., Chen, L., Childers, A. K., Coddington, J. A., Conde, D. A., Corominas, M., Crandall, K. A., Crawford, A. J., DiPalma, F., Durbin, R., Ebenezer, T. E., Edwards, S. V., Fedrigo, O., Flicek, P., Formenti, G., Gibbs, R. A., Gilbert, M. Thomas P., Goldstein, M. M., Graves, J. M., Greely, H. T., Grigoriev, I. V., Hackett, K. J., Hall, N., Haussler, D., Helgen, K. M., Hogg, C. J., Isobe, S., Jakobsen, K. S., Janke, A., Jarvis, E. D., Johnson, W. E., Jones, S. J. M., Karlsson, E. K., Kersey, P. J., Kim, J-H., Kress, W. J., Kuraku, S., Lawniczak, M. K. N., Leebens-Mack, J. H., Li, X., Lindblad-Toh, K., Liu, X., Lopez, J. V., Marques-Bonet, T., Mazard, S., Mazet, J. A. K., Mazzoni, C. J., Myers, E. W., O’Neill, R. J., Paez, S., Park, H., Robinson, G. E., Roquet, C., Ryder, O. A., Sabir, J. S. M., Shaffer, H. B., Shank, T. M., Sherkow, J. S., Soltis, P. S., Tang, B., Tedersoo, L., Uliano-Silva, M., Wang, K., Wei, X., Wetzer, R., Wilson, J. L., Xu, X., Yang, H., Yoder, A. D., Zhang, G. The Earth BioGenome Project 2020: starting the clock. Proceedings of the National Academy of Sciences of the United States of America, 119(4), (2022): e2115635118, https://doi.org/10.1073/pnas.2115635118.November 2020 marked 2 y since the launch of the Earth BioGenome Project (EBP), which aims to sequence all known eukaryotic species in a 10-y timeframe. Since then, significant progress has been made across all aspects of the EBP roadmap, as outlined in the 2018 article describing the project’s goals, strategies, and challenges (1). The launch phase has ended and the clock has started on reaching the EBP’s major milestones. This Special Feature explores the many facets of the EBP, including a review of progress, a description of major scientific goals, exemplar projects, ethical legal and social issues, and applications of biodiversity genomics. In this Introduction, we summarize the current status of the EBP, held virtually October 5 to 9, 2020, including recent updates through February 2021. References to the nine Perspective articles included in this Special Feature are cited to guide the reader toward deeper understanding of the goals and challenges facing the EBP

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination