Humanized substitutions of Vmat1 in mice induce changes in amygdala-dependent behaviors associated with the evolution of anxiety in humans

The human vesicular monoamine transporter 1 (VMAT1) harbors unique substitutions (Asn136Thr/Ile) that alter monoamine uptake into synaptic vesicles. These substitutions are absent in all known mammals, suggesting their contributions to distinct aspects of human behavior modulated by monoaminergic transmission, such as emotion and cognition. To directly test the impact of these human-specific mutations, we introduced the humanized residues into mouse Vmat1 via CRISPR/Cas9-mediated genome editing and examined changes at the behavioral, neurophysiological and molecular levels. Behavioral tests revealed reduced anxiety-related traits of Vmat1Ile mice, consistent with human studies, and electrophysiological recordings showed altered oscillatory activity in the amygdala under anxiogenic conditions. Transcriptome analyses further identified amygdala-specific changes in the expression of genes involved in neurodevelopment and emotional regulation, which may corroborate the observed phenotypes. This knock-in mouse model hence provides compelling evidence that the mutations affecting monoaminergic signaling and amygdala circuits have contributed to the evolution of human socio-emotional behaviors.

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Report1: Impact of Covid-19 on young people aged 13-24 in the UK- preliminary findings

10.31234/osf.io/uq4rn ◽

2020 ◽

Cited By ~ 1

Author(s):

Liat Levita ◽

Jilly Gibson Miller ◽

Todd K. Hartman ◽

Jamie Murphy ◽

Mark Shevlin ◽

...

Keyword(s):

Mental Health ◽

Young People ◽

Emotional Regulation ◽

Health Anxiety ◽

Self Control ◽

Social Risk ◽

Need For Support ◽

The Uk ◽

Social Recovery ◽

The Impact

COVID-19 has led to an unprecedented disruption of normal social relationships and activities, which are so important during the teen years and young adulthood, and to education and economic activity worldwide. The impact of this on young people’s mental health and future prospects may affect their need for support and services, and the speed of the nation’s social recovery afterwards. This study focused on the unique challenges facing young people at different points during adolescent development, which spans from the onset of puberty until the mid-twenties. Although this is an immensely challenging time and there is a potential risk for long term trauma, adolescence can be a period of opportunity, where the teenagers’ brain enjoys greater capacity for change. Hence, the focus on young people is key for designing age-specific interventions and public policies, which can offer new strategies for instilling resilience, emotional regulation, and self-control. In fact, adolescents might be assisted to not only cope, but excel, in spite of the challenges imposed by this pandemic. Our work will feed into the larger societal response that utilizes the discoveries about adolescence in the way we raise, teach, and treat young people during this time of crisis. Wave 1 data has already been collected from 2,002 young people aged 13-24, measuring their mental health (anxiety, depression, trauma), family functioning, social networks, and resilience, and social risk-taking at the time of the pandemic. Here we present a preliminary report of our findings, (Report 1). Data collected 21/4/20- 29/4/20 - a month after the lockdown started).

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Intraoperative localization of spatially and spectrally distinct resting-state networks in Parkinson’s disease

Journal of Neurosurgery ◽

10.3171/2018.11.jns181684 ◽

2020 ◽

Vol 132 (4) ◽

pp. 1234-1242 ◽

Cited By ~ 1

Author(s):

Paolo Belardinelli ◽

Ramin Azodi-Avval ◽

Erick Ortiz ◽

Georgios Naros ◽

Florian Grimm ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Network Effects ◽

Brain Activity ◽

Dynamic Imaging ◽

Oscillatory Activity ◽

Network Information ◽

Novel Approach ◽

Electrophysiological Recordings ◽

Intraoperative Localization

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for symptomatic Parkinson’s disease (PD); the clinical benefit may not only mirror modulation of local STN activity but also reflect consecutive network effects on cortical oscillatory activity. Moreover, STN-DBS selectively suppresses spatially and spectrally distinct patterns of synchronous oscillatory activity within cortical-subcortical loops. These STN-cortical circuits have been described in PD patients using magnetoencephalography after surgery. This network information, however, is currently not available during surgery to inform the implantation strategy.The authors recorded spontaneous brain activity in 3 awake patients with PD (mean age 67 ± 14 years; mean disease duration 13 ± 7 years) during implantation of DBS electrodes into the STN after overnight withdrawal of dopaminergic medication. Intraoperative propofol was discontinued at least 30 minutes prior to the electrophysiological recordings. The authors used a novel approach for performing simultaneous recordings of STN local field potentials (LFPs) and multichannel electroencephalography (EEG) at rest. Coherent oscillations between LFP and EEG sensors were computed, and subsequent dynamic imaging of coherent sources was performed.The authors identified coherent activity in the upper beta range (21–35 Hz) between the STN and the ipsilateral mesial (pre)motor area. Coherence in the theta range (4–6 Hz) was detected in the ipsilateral prefrontal area.These findings demonstrate the feasibility of detecting frequency-specific and spatially distinct synchronization between the STN and cortex during DBS surgery. Mapping the STN with this technique may disentangle different functional loops relevant for refined targeting during DBS implantation.

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Impact of Environmental Stressors on Gene Expression in the Embryo of the Italian Wall Lizard

Applied Sciences ◽

10.3390/app11114723 ◽

2021 ◽

Vol 11 (11) ◽

pp. 4723

Author(s):

Rosaria Scudiero ◽

Chiara Maria Motta ◽

Palma Simoniello

Keyword(s):

Gene Expression ◽

Protein Interactions ◽

Membrane Trafficking ◽

Translational Regulation ◽

Cellular Protection ◽

Terrestrial Vertebrate ◽

Expression Of Genes ◽

Stress Changes ◽

Probable Consequence ◽

The Impact

The cleidoic eggs of oviparous reptiles are protected from the external environment by membranes and a parchment shell permeable to water and dissolved molecules. As a consequence, not only physical but also chemical insults can reach the developing embryos, interfering with gene expression. This review provides information on the impact of the exposure to cadmium contamination or thermal stress on gene expression during the development of Italian wall lizards of the genus Podarcis. The results obtained by transcriptomic analysis, although not exhaustive, allowed to identify some stress-reactive genes and, consequently, the molecular pathways in which these genes are involved. Cadmium-responsive genes encode proteins involved in cellular protection, metabolism and proliferation, membrane trafficking, protein interactions, neuronal transmission and plasticity, immune response, and transcription regulatory factors. Cold stress changes the expression of genes involved in transcriptional/translational regulation and chromatin remodeling and inhibits the transcription of a histone methyltransferase with the probable consequence of modifying the epigenetic control of DNA. These findings provide transcriptome-level evidence of how terrestrial vertebrate embryos cope with stress, giving a key to use in population survival and environmental change studies. A better understanding of the genes contributing to stress tolerance in vertebrates would facilitate methodologies and applications aimed at improving resistance to unfavourable environments.

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Neuromodulation of Astrocytic K+ Clearance

International Journal of Molecular Sciences ◽

10.3390/ijms22052520 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2520

Author(s):

Alba Bellot-Saez ◽

Rebecca Stevenson ◽

Orsolya Kékesi ◽

Evgeniia Samokhina ◽

Yuval Ben-Abu ◽

...

Keyword(s):

Oscillatory Behavior ◽

Network Activity ◽

Oscillatory Activity ◽

Extracellular Potassium ◽

Uptake Mechanism ◽

Kir Channels ◽

Neuronal Network Activity ◽

Clearance Process ◽

Spatial Buffering ◽

The Impact

Potassium homeostasis is fundamental for brain function. Therefore, effective removal of excessive K+ from the synaptic cleft during neuronal activity is paramount. Astrocytes play a key role in K+ clearance from the extracellular milieu using various mechanisms, including uptake via Kir channels and the Na+-K+ ATPase, and spatial buffering through the astrocytic gap-junction coupled network. Recently we showed that alterations in the concentrations of extracellular potassium ([K+]o) or impairments of the astrocytic clearance mechanism affect the resonance and oscillatory behavior of both the individual and networks of neurons. These results indicate that astrocytes have the potential to modulate neuronal network activity, however, the cellular effectors that may affect the astrocytic K+ clearance process are still unknown. In this study, we have investigated the impact of neuromodulators, which are known to mediate changes in network oscillatory behavior, on the astrocytic clearance process. Our results suggest that while some neuromodulators (5-HT; NA) might affect astrocytic spatial buffering via gap-junctions, others (DA; Histamine) primarily affect the uptake mechanism via Kir channels. These results suggest that neuromodulators can affect network oscillatory activity through parallel activation of both neurons and astrocytes, establishing a synergistic mechanism to maximize the synchronous network activity.

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Minor Changes in Erythrocyte Osmotic Fragility in Trace Amine-Associated Receptor 5 (TAAR5) Knockout Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22147307 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7307

Author(s):

Ilya S. Zhukov ◽

Larisa G. Kubarskaya ◽

Inessa V. Karpova ◽

Anastasia N. Vaganova ◽

Marina N. Karpenko ◽

...

Keyword(s):

Knockout Mice ◽

Emotional Regulation ◽

Complete Blood Count ◽

Gene Knockout ◽

Hematological Parameters ◽

Osmotic Fragility ◽

Erythrocyte Osmotic Fragility ◽

Trace Amine ◽

Socially Relevant ◽

The Impact

Trace amine-associated receptors (TAARs) are a group of G protein-coupled receptors that are expressed in the olfactory epithelium, central nervous system, and periphery. TAAR family generally consists of nine types of receptors (TAAR1-9), which can detect biogenic amines. During the last 5 years, the TAAR5 receptor became one of the most intriguing receptors in this subfamily. Recent studies revealed that TAAR5 is involved not only in sensing socially relevant odors but also in the regulation of dopamine and serotonin transmission, emotional regulation, and adult neurogenesis by providing significant input from the olfactory system to the limbic brain areas. Such results indicate that future antagonistic TAAR5-based therapies may have high pharmacological potential in the field of neuropsychiatric disorders. TAAR5 is known to be expressed in leucocytes as well. To evaluate potential hematological side effects of such future treatments we analyzed several hematological parameters in mice lacking TAAR5. In these mutants, we observed minor but significant changes in the osmotic fragility test of erythrocytes and hematocrit levels. At the same time, analysis of other parameters including complete blood count and reticulocyte levels showed no significant alterations in TAAR5 knockout mice. Thus, TAAR5 gene knockout leads to minor negative changes in the erythropoiesis or eryptosis processes, and further research in that field is needed. The impact of TAAR5 deficiency on other hematological parameters seems minimal. Such negative, albeit minor, effects of TAAR5 deficiency should be taken into account during future TAAR5-based therapy development.

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The Impact of Mobile Application Systems Use on Mental Health Outcomes: A Secondary Analysis of the Effect of Systems Usage on Anxiety, Worry, & Emotional Reactivity Among Participants in the Unwinding Anxiety Program (Preprint)

10.2196/preprints.33696 ◽

2021 ◽

Author(s):

William Nardi ◽

Alexandra Roy ◽

Shira Dunsiger ◽

Judson Brewer

Keyword(s):

Mental Health ◽

Health Outcomes ◽

Emotional Regulation ◽

Mobile Application ◽

Secondary Analysis ◽

Health Behavior Change ◽

Mental Health Outcomes ◽

Interoceptive Awareness ◽

Point Increase ◽

The Impact

BACKGROUND Mobile health applications provide a promising avenue to help mitigate the burden on mental health services by complimenting therapist-led treatments for anxiety. However, it remains unclear how specific systems' use of application components (i.e., tools) may be associated with changes in clinical symptomatology (i.e., anxiety, worry). OBJECTIVE This study was a secondary analysis of systems usage data from the Stage I randomized controlled trial testing the impact of the Unwinding Anxiety mobile application among adults with GAD. This secondary analysis was conducted to assess how using specific application tools may be associated with improvements in anxiety, worry, emotional regulation, and interoceptive awareness. METHODS We present analyses of the intervention group (i.e., those who received the Unwinding Anxiety program) during the Stage 1 trial. Total use of specific mobile application tools (i.e., ecological tools, meditation practices, educational modules) as well use specific to each tool (e.g., stress meter, lovingkindness meditation practice) were calculated. We utilized multivariate linear models to investigate the effect of total use of these tools on anxiety, worry, interoceptive awareness, emotional regulation at 2-months post-program initiation controlling for baseline scores, age, and education level. In addition, associations between systems usage metrics and baseline participant characteristics were assessed for differences in usage groupings. RESULTS The sample was primarily female (n=25; 92.6%) and the average age was 42.9 years old (SD=15.6) and educational module completion, the central intervention component, averaged 20.2 + 11.4 modules out of XXX for the total sample. Multivariate models revealed that completing >75% of the program was associated with an average 22.6-point increase in interoceptive awareness (SE=8.32, p=0.013) and an 11.6-point decrease in worry (SE=4.12, p=0.009). In addition, a single log unit change in total number of meditations was associated with a 0.95-point reduction in GAD-7 scores (SE=0.27, p=0.005) while a single log unit use of the stress meter was associated with an average of a 0.5-point increase in emotional regulation scores (FFMQ) (SE=0.21, p=0.027). CONCLUSIONS The work presented offers a clearer understanding of the impact of specific mobile app systems use on mental health outcomes. In addition, this research lays the groundwork for future comprehensive investigations of systems usage in dosing studies for health behavior change. CLINICALTRIAL Developing a Novel Digital Therapeutic for the Treatment of Generalized Anxiety Disorder (NCT03683472).

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The Impact of MNRI Therapy on the Levels of Neurotransmitters Associated with Inflammatory Processes

International Journal of Molecular Sciences ◽

10.3390/ijms21041358 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1358 ◽

Cited By ~ 1

Author(s):

Tatiana V. Tatarinova ◽

Trina Deiss ◽

Lorri Franckle ◽

Susan Beaven ◽

Jeffrey Davis

Keyword(s):

Attention Deficit ◽

Attention Deficit Disorder ◽

Emotional Regulation ◽

Cognitive Skills ◽

Developmental Disorders ◽

Negative Impact ◽

Autism Spectrum ◽

Post Traumatic Stress ◽

Compulsive Disorder ◽

The Impact

The neurotransmitter levels of representatives from five different diagnosis groups were tested before and after participation in the MNRI®—Masgutova Neurosensorimotor Reflex Intervention. The purpose of this study was to ascertain neurological impact on (1) Developmental disorders, (2) Anxiety disorders/OCD (Obsessive Compulsive Disorder), PTSD (Post-Traumatic Stress disorder), (3) Palsy/Seizure disorders, (4) ADD/ADHD (Attention Deficit Disorder/Attention Deficit Disorder Hyperactive Disorder), and (5) ASD (Autism Spectrum Disorder) disorders. Each participant had a form of neurological dysregulation and typical symptoms respective to their diagnosis. These diagnoses have a severe negative impact on the quality of life, immunity, stress coping, cognitive skills, and social assimilation. This study showed a trend towards optimization and normalization of neurological and immunological functioning, thus supporting the claim that the MNRI method is an effective non-pharmacological neuromodulation treatment of neurological disorders. The effects of MNRI on inflammation have not yet been assessed. The resulting post-MNRI changes in participants’ neurotransmitters show significant adjustments in the regulation of the neurotransmitter resulting in being calmer, a decrease of hypervigilance, an increase in stress resilience, behavioral and emotional regulation improvements, a more positive emotional state, and greater control of cognitive processes. In this paper, we demonstrate that the MNRI approach is an intervention that reduces inflammation. It is also likely to reduce oxidative stress and encourage homeostasis of excitatory neurotransmitters. MNRI may facilitate neurodevelopment, build stress resiliency, neuroplasticity, and optimal learning opportunity. There have been no reported side effects of MNRI treatments.

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Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice

eLife ◽

10.7554/elife.01098 ◽

2013 ◽

Vol 2 ◽

Cited By ~ 76

Author(s):

Liou Y Sun ◽

Adam Spong ◽

William R Swindell ◽

Yimin Fang ◽

Cristal Hill ◽

...

Keyword(s):

Growth Hormone ◽

Caloric Restriction ◽

Stress Resistance ◽

Growth Hormone Releasing Hormone ◽

Somatotropic Axis ◽

Releasing Hormone ◽

Xenobiotic Detoxification ◽

Expression Of Genes ◽

Extended Longevity ◽

The Impact

We examine the impact of targeted disruption of growth hormone-releasing hormone (GHRH) in mice on longevity and the putative mechanisms of delayed aging. GHRH knockout mice are remarkably long-lived, exhibiting major shifts in the expression of genes related to xenobiotic detoxification, stress resistance, and insulin signaling. These mutant mice also have increased adiponectin levels and alterations in glucose homeostasis consistent with the removal of the counter-insulin effects of growth hormone. While these effects overlap with those of caloric restriction, we show that the effects of caloric restriction (CR) and the GHRH mutation are additive, with lifespan of GHRH-KO mutants further increased by CR. We conclude that GHRH-KO mice feature perturbations in a network of signaling pathways related to stress resistance, metabolic control and inflammation, and therefore provide a new model that can be used to explore links between GHRH repression, downregulation of the somatotropic axis, and extended longevity.

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Investigation of GSTP1 and epigenetic regulators expression pattern in a population of Iranian patients with prostate cancer

Human Antibodies ◽

10.3233/hab-200424 ◽

2020 ◽

Vol 28 (4) ◽

pp. 327-334

Author(s):

Mahan Mohammadi ◽

Shiva Irani ◽

Iman Salahshourifar ◽

Jalil Hosseini ◽

Afshin Moradi ◽

...

Keyword(s):

Prostate Cancer ◽

High Efficiency ◽

Rna Extraction ◽

P Value ◽

Prostate Hyperplasia ◽

Expression Of Genes ◽

Elevated Expression ◽

Epigenetic Regulators ◽

The Impact ◽

Iranian Patients

BACKGROUND AND AIM: Prostate cancer is the leading cause of death in many countries. It is important to diagnose the disease in the early stages. Current methods detect the disease with low specificity. Examining the expression of genes responsible for disease and their epigenetic regulators are good tools in this regard. MATERIAL AND METHODS: In this prospective case-control study, 40 Iranian patients with cancer, 40 Iranian patients with prostate hyperplasia, and 40 control samples were examined. After blood sampling from each individual, RNA extraction and cDNA synthesis, GSTP1, HDAC, DNMT3A, and DNMT3B expressions were measured in three understudy groups using specific primers and Real-Time PCR method. RESULTS: A reverse correlation was identified between loss of GSTP1 expression and overexpression of HDAC, DNMT3A, and DNMT3B (P value < 0.0001) with a beneficial pattern of cancer development with high efficiency. The significant decrease of GSTP1 expression in patients in comparison to the healthy controls and the elevated expression levels of the studied epigenetic regulators in PCA and BPH samples indicate the impact of the regulators on GSTP1 expression activity. CONCLUSION: This study showed that the measurement of combined GSTP1 and its epigenetic regulators’ expression could be used as suitable genetic markers for the detection and separation of healthy individuals from prostatic patient groups in the Iranian population. However, a similar study in a larger population of case and control could help us to distinguish between normal, benign, and malignant conditions.

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CNGA3 achromatopsia-associated mutation potentiates the phosphoinositide sensitivity of cone photoreceptor CNG channels by altering intersubunit interactions

AJP Cell Physiology ◽

10.1152/ajpcell.00037.2013 ◽

2013 ◽

Vol 305 (2) ◽

pp. C147-C159 ◽

Cited By ~ 7

Author(s):

Gucan Dai ◽

Michael D. Varnum

Keyword(s):

Leucine Zipper ◽

Sensory Transduction ◽

Cone Photoreceptor ◽

Electrophysiological Recordings ◽

Retinal Photoreceptors ◽

Functional Consequences ◽

Interdomain Interaction ◽

Channel Assembly ◽

Intersubunit Interactions ◽

The Impact

Cyclic nucleotide-gated (CNG) channels are critical for sensory transduction in retinal photoreceptors and olfactory receptor cells; their activity is modulated by phosphoinositides (PIPn) such as phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). An achromatopsia-associated mutation in cone photoreceptor CNGA3, L633P, is located in a carboxyl (COOH)-terminal leucine zipper domain shown previously to be important for channel assembly and PIPn regulation. We determined the functional consequences of this mutation using electrophysiological recordings of patches excised from cells expressing wild-type and mutant CNG channel subunits. CNGA3-L633P subunits formed functional channels with or without CNGB3, producing an increase in apparent cGMP affinity. Surprisingly, L633P dramatically potentiated PIPn inhibition of apparent cGMP affinity for these channels. The impact of L633P on PIPn sensitivity depended on an intact amino (NH2) terminal PIPn regulation module. These observations led us to hypothesize that L633P enhances PIPn inhibition by altering the coupling between NH2- and COOH-terminal regions of CNGA3. A recombinant COOH-terminal fragment partially restored normal PIPn sensitivity to channels with COOH-terminal truncation, but L633P prevented this effect. Furthermore, coimmunoprecipitation of channel fragments, and thermodynamic linkage analysis, also provided evidence for NH2-COOH interactions. Finally, tandem dimers of CNGA3 subunits that specify the arrangement of subunits containing L633P and other mutations indicated that the putative interdomain interaction occurs between channel subunits (intersubunit) rather than exclusively within the same subunit (intrasubunit). Collectively, these studies support a model in which intersubunit interactions control the sensitivity of cone CNG channels to regulation by phosphoinositides. Aberrant channel regulation may contribute to disease progression in patients with the L633P mutation.

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