Beyond the Medial Regions of Prefrontal Cortex in the Regulation of Fear and Anxiety.

Fear and anxiety are adaptive responses but if left unregulated, or inappropriately regulated, they become biologically and socially maladaptive. Dysregulated emotions are manifest in a wide variety of psychiatric and neurological conditions but the external expression gives little indication of the underlying causes, which are inevitably multi-determined. To go beyond the overt phenotype and begin to understand the causal mechanisms leading to conditions characterized by anxiety and disorders of mood, it is necessary to identify the base psychological processes that have become dysregulated, and map them on to their associated neural substrates. So far, attention has been focused primarily on the medial regions of prefrontal cortex (PFC) and in particular their contribution to the expression and extinction of conditioned fear. However, functional neuroimaging studies have shown that the sphere of influence within the PFC is not restricted to its medial regions, but extends into dorsal, ventrolateral (vlPFC) and orbitofrontal (OFC) regions too; although the causal role of these other areas in the regulation of fear and anxiety remains to be determined and in the case of the OFC, existing findings are conflicting. Here, we review the evidence for the contribution of these other regions in negative emotion regulation in rodents and old world and new world monkeys. We consider a variety of different contexts, including conditioned and innate fear, learned and unlearned anxiety and cost-benefit decision-making, and a range of physiological and behavioral measures of emotion. It is proposed that both the OFC and vlPFC contribute to emotion regulation via their involvement, respectively, in the prediction of future outcomes and higher-order attentional control. The fractionation of these neurocognitive and neurobehavioral systems that regulate fear and anxiety opens up new opportunities for diagnostic stratification and personalized treatment strategies.This research was supported by a Medical Research Programme Grant (G0901884) from the Medical Research Council (MRC), UK to ACR and carried out within the Behavioral and Clinical Neurosciences Institute supported by a consortium award from the Wellcome Trust and the MRC.This is the final version of the article. It first appeared from Frontiers via http://dx.doi.org/10.3389/fnsys.2016.0001

Lesions of either anterior orbitofrontal cortex or ventrolateral prefrontal cortex in marmoset monkeys heighten innate fear and attenuate active coping behaviors to predator threat.

The ventral prefrontal cortex is an integral part of the neural circuitry that is dysregulated in mood and anxiety disorders. However, the contribution of its distinct sub-regions to the regulation of negative emotion are poorly understood. Recently we implicated both the ventrolateral prefrontal cortex (vlPFC) and anterior orbitofrontal cortex (antOFC) in the regulation of conditioned fear and anxiety responses to a social stimulus, i.e., human intruder, in the marmoset monkey. In the present study we extend our investigations to determine the role of these two regions in regulating innate responses and coping strategies to a predator stimulus, i.e., a model snake. Both the vlPFC and antOFC lesioned groups exhibited enhanced anxiety-related responses to the snake in comparison to controls. Both groups also showed a reduction in active coping behavior. These results indicate that the vlPFC and antOFC contribute independently to the regulation of both innate fear and, as previously reported, conditioned fear, and highlight the importance of these regions in producing stimulus-appropriate coping responses. The finding that dysregulation in two distinct prefrontal regions produces the apparently similar behavioral phenotype of heightened negative emotion provides insight into the varied etiology that may underlie this symptom across a wide variety of neuropsychiatric conditions with implications for personalized treatment strategies.This research was supported by a Medical Research Programme Grant (G0901884) from the Medical Research Council (MRC), UK to Angela C. Roberts. Yoshiro Shiba was supported by the Long Term Student Support Program provided by Osaka University and the Ministry of Education, Culture, Sports, Science and Technology of Japan and currently by the MRC Programme grant (G0901884). Andrea M. Santangelo, until October 2011, by a J. S. McDonnell Foundation grant (Principle Investigators; E. Phelps, T. W. Robbins, co-investigators; J. E. LeDoux, and Angela C. Roberts) and currently by the MRC Programme grant (G0901884). Work was carried out within the Behavioral and Clinical Neurosciences Institute supported by a consortium award from the Wellcome Trust and the MRC. We thank Dr. Carmen Agustín-Pavón for conducting the lesion surgeries, Dr. Katrin Braesicke for help with statistical analyses and Dr. Mercedes Arroyo for the preparation of histological material.This is the final published version of the paper, which first appeared in Frontiers Systems Neuroscience, 21 January 2015, doi: 10.3389/fnsys.2014.0025

Avoidant Coping Style to High Imminence Threat Is Linked to Higher Anxiety-Like Behavior.

Human studies with self-reported measures have suggested a link between an avoidant coping style and high anxiety. Here, using the common marmoset as a model, we characterize the latent factors underlying behavioral responses of these monkeys towards low and high imminence threat and investigate if a predominantly avoidant behavioral response to high imminence threat is associated with greater anxiety-like behavior in a context of low imminence threat. Exploratory factor analysis (EFA) of the human intruder test of low imminence threat revealed a single factor in which a combination of active vigilance and avoidance responses underpinned anxiety-like behavior. In contrast, two negatively-associated factors were revealed in the model snake test reflecting active and avoidant coping to high imminence threat. Subsequent analysis showed that animals with a predominantly avoidant coping style on the model snake test displayed higher anxiety-like behavior on the human intruder test, findings consistent with those described in humans. Together they illustrate the richness of the behavioral repertoire displayed by marmosets in low and high imminence threatening contexts and the additional insight that factor analysis can provide by identifying the latent factors underlying these complex behavioral datasets. They also highlight the translational value of this approach when studying the neural circuits underlying complex anxiety-like states in this primate model

Ancient Exaptation of a CORE-SINE Retroposon into a Highly Conserved Mammalian Neuronal Enhancer of the Proopiomelanocortin Gene

The proopiomelanocortin gene (POMC) is expressed in the pituitary gland and the ventral hypothalamus of all jawed vertebrates, producing several bioactive peptides that function as peripheral hormones or central neuropeptides, respectively. We have recently determined that mouse and human POMC expression in the hypothalamus is conferred by the action of two 5′ distal and unrelated enhancers, nPE1 and nPE2. To investigate the evolutionary origin of the neuronal enhancer nPE2, we searched available vertebrate genome databases and determined that nPE2 is a highly conserved element in placentals, marsupials, and monotremes, whereas it is absent in nonmammalian vertebrates. Following an in silico paleogenomic strategy based on genome-wide searches for paralog sequences, we discovered that opossum and wallaby nPE2 sequences are highly similar to members of the superfamily of CORE-short interspersed nucleotide element (SINE) retroposons, in particular to MAR1 retroposons that are widely present in marsupial genomes. Thus, the neuronal enhancer nPE2 originated from the exaptation of a CORE-SINE retroposon in the lineage leading to mammals and remained under purifying selection in all mammalian orders for the last 170 million years. Expression studies performed in transgenic mice showed that two nonadjacent nPE2 subregions are essential to drive reporter gene expression into POMC hypothalamic neurons, providing the first functional example of an exapted enhancer derived from an ancient CORE-SINE retroposon. In addition, we found that this CORE-SINE family of retroposons is likely to still be active in American and Australian marsupial genomes and that several highly conserved exonic, intronic and intergenic sequences in the human genome originated from the exaptation of CORE-SINE retroposons. Together, our results provide clear evidence of the functional novelties that transposed elements contributed to their host genomes throughout evolution

A Transgenic Marker for Newly Born Granule Cells in Dentate Gyrus

Neurogenesis in the dentate gyrus continues into adulthood, yet little is known about the function of newly born neurons or how they integrate into an existing network of mature neurons. We made transgenic mice that selectively and transiently express enhanced green fluorescent protein (EGFP) in newly born granule cells of the dentate gyrus under the transcriptional control of proopiomelanocortin (POMC) genomic sequences. Analysis of transgenic pedigrees with truncation or deletion mutations indicated that EGFP expression in the dentate gyrus required cryptic POMC promoter regions dispensable for arcuate hypothalamic or pituitary expression. Unlike arcuate neurons, dentate granule cells did not express the endogenous POMC gene. EGFP-positive neurons had immature properties, including short spineless dendrites and small action potentials. Colocalization with bromodeoxyuridine indicated that EGFP-labeled granule cells were 2 weeks postmitotic. EGFP-labeled cells expressed markers for immature granule cells but not the glial marker GFAP. The number of EGFP-labeled neurons declined with age and increased with exercise, paralleling neurogenesis. Our results indicate that POMC-EGFP marks immature granule cells and that adult-generated granule cells integrate quite slowly into the hippocampal circuitry

A dimensional approach to modeling symptoms of neuropsychiatric disorders in the marmoset monkey.

Some patients suffering from the same neuropsychiatric disorder may have no overlapping symptoms whilst others may share symptoms common to other distinct disorders. Therefore, the Research Domain Criteria initiative recognises the need for better characterisation of the individual symptoms on which to focus symptom-based treatment strategies. Many of the disorders involve dysfunction within the prefrontal cortex (PFC) and so the marmoset, due to their highly developed PFC and small size, is an ideal species for studying the neurobiological basis of the behavioural dimensions that underlie these symptoms.Here we focus on a battery of tests that address dysfunction spanning the cognitive (cognitive inflexibility and working memory), negative valence (fear generalisation and negative bias) and positive valence (anhedonia) systems pertinent for understanding disorders such as ADHD, Schizophrenia, Anxiety, Depression and OCD. Parsing the separable prefrontal and striatal circuits and identifying the selective neurochemical modulation (serotonin vs dopamine) that underlie cognitive dysfunction have revealed counterparts in the clinical domain. Aspects of the negative valence system have been explored both at individual- (trait anxiety and genetic variation in serotonin transporter) and circuit-based levels enabling the understanding of generalisation processes, negative biases and differential responsiveness to SSRIs. Within the positive valence system, the combination of cardiovascular and behavioural measures provides a framework for understanding motivational, anticipatory and consummatory aspects of anhedonia and their neurobiological mechanisms. Together, the direct comparison of experimental findings in marmosets with clinical studies is proving an excellent translational model to address the behavioural dimensions and neurobiology of neuropsychiatric symptoms. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 328-353, 2017.This work was supported by long term funding from the MRC (ACR) and the Wellcome Trust (TWR) and was performed within the Behavioural and Clinical Neuroscience Institute, University of Cambridge, funded jointly by the Wellcome Trust and MRC. LO is supported by an MRC studentship.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/dneu.2244

Dense matter with eXTP

In this White Paper we present the potential of the Enhanced X-ray Timing and Polarimetry (eXTP) mission for determining the nature of dense matter; neutron star cores host an extreme density regime which cannot be replicated in a terrestrial laboratory. The tightest statistical constraints on the dense matter equation of state will come from pulse profile modelling of accretion-powered pulsars, burst oscillation sources, and rotation-powered pulsars. Additional constraints will derive from spin measurements, burst spectra, and properties of the accretion flows in the vicinity of the neutron star. Under development by an international Consortium led by the Institute of High Energy Physics of the Chinese Academy of Science, the eXTP mission is expected to be launched in the mid 2020s.Comment: Accepted for publication on Sci. China Phys. Mech. Astron. (2019

Detecting ultra-high energy cosmic rays from space with unprecedented acceptance: objectives and design of the JEM-EUSO mission

The Extreme Universe Space Observatory on the Japanese Experiment Module (JEM-EUSO) of the Interna- tional Space Station (ISS) is the first mission that will study from space Ultra High-Energy Cosmic Rays (UHECR). JEM-EUSO will observe Extensive Air Showers (EAS) pro- duced by UHECRs traversing the Earth's atmosphere from above. For each event, the detector will make accurate mea- surements of the energy, arrival direction and nature of the primary particle using a target volume far greater than what is achievable from ground. The corresponding increase in statistics will help to clarify the origin and sources of UHE- CRs as well as the environment traversed during production and propagation. Possibly this will bring new light onto par- ticle physics mechanisms operating at energies well beyond those achievable by man-made accelerators. The spectrum of scientific goals of the JEM-EUSO mission includes as ex- ploratory objectives the detection of high-energy gamma ray

Multi-Wavelength Properties of the 2021 Periastron Passage of PSR B1259-63

PSR B1259-63 is a gamma-ray binary system hosting a radio pulsar orbiting around a O9.5Ve star, LS 2883, with a period of similar to 3.4 years. The interaction of the pulsar wind with the LS 2883 outflow leads to unpulsed broadband emission in the radio, X-ray, GeV, and TeV domains. One of the most unusual features of the system is an outburst of GeV energies around the periastron, during which the energy release substantially exceeds the spin down luminosity under the assumption of the isotropic emission. In this paper, we present the first results of a recent multi-wavelength campaign (radio, optical, and X-ray bands) accompanied by the analysis of publicly available GeV Fermi/LAT data. The campaign covered a period of more than 100 days around the 2021 periastron and revealed substantial differences from previously observed passages. We report a major delay of the GeV flare, weaker X-ray flux during the peaks, which are typically attributed to the times when the pulsar crosses the disk, and the appearance of a third X-ray peak never observed before. We argue that these features are consistent with the emission cone model proposed by us previously, in the case of a sparser and clumpier disk of the Be star