Haplotype-resolved diverse human genomes and integrated analysis of structural variation

Science, Journal Year: 2021, Volume and Issue: 372(6537)

Published: Feb. 25, 2021

Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% genome: 26 million base pairs) integrate all forms genetic variation, even across complex loci. identified 107,590 structural variants (SVs), which 68% were not discovered with short-read sequencing, 278 SV hotspots (spanning megabases gene-rich sequence). characterized 130 most active mobile element source elements found that 63% SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping short reads up 50,340 SVs, resulting in identification 1526 expression quantitative trait loci as well candidates for adaptive selection within population.

Language: Английский

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The transition to compulsion in addiction

Nature reviews. Neuroscience, Journal Year: 2020, Volume and Issue: 21(5), P. 247 - 263

Published: March 30, 2020

Language: Английский

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Volitional social interaction prevents drug addiction in rat models

Nature Neuroscience, Journal Year: 2018, Volume and Issue: 21(11), P. 1520 - 1529

Published: Oct. 11, 2018

Language: Английский

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Addiction is driven by excessive goal-directed drug choice under negative affect: translational critique of habit and compulsion theory

Neuropsychopharmacology, Journal Year: 2020, Volume and Issue: 45(5), P. 720 - 735

Published: Jan. 6, 2020

Drug addiction may be a goal-directed choice driven by excessive drug value in negative affective states, habit strong stimulus-response associations, or compulsion insensitivity to costs imposed on seeking. Laboratory animal and human evidence for these three theories is evaluated. Excessive goal theory supported dependence severity being associated with greater choice/economic demand. demonstrably (driven the expected of drug) can augmented stress/negative mood induction withdrawal-effects amplified those psychiatric symptoms use coping motives. Furthermore, confer risk dependence, motives mediate this risk. Habit has weaker support. Habitual behaviour seen drug-exposed animals often does not occur complex decision scenarios, where responding rewarded, so unlikely explain most addictive conditions apply. studies have found propensity habitual users as function severity, minority that explained task disengagement producing impaired explicit contingency knowledge. Compulsion also weak The persistence punished seeking better (evinced association economic demand) than costs. provided discount cost severity. These data suggest primarily under affect, less compulsion. Addiction pathological because states powerfully increase acutely outweighing abstinence goals.

Language: Английский

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Addiction as a brain disease revised: why it still matters, and the need for consilience

Neuropsychopharmacology, Journal Year: 2021, Volume and Issue: 46(10), P. 1715 - 1723

Published: Feb. 22, 2021

The view that substance addiction is a brain disease, although widely accepted in the neuroscience community, has become subject to acerbic criticism recent years. These criticisms state disease deterministic, fails account for heterogeneity remission and recovery, places too much emphasis on compulsive dimension of addiction, specific neural signature not been identified. We acknowledge some these have merit, but assert foundational premise neurobiological basis fundamentally sound. also emphasize denying harmful standpoint since it contributes reducing access healthcare treatment, consequences which are catastrophic. Here, we therefore address criticisms, doing so provide contemporary update addiction. arguments support this view, discuss why apparently spontaneous does negate it, how seemingly behaviors can co-exist with sensitivity alternative reinforcement Most importantly, argue biological substrate from both capacity behavior change arise, arguing an intensified neuroscientific study recovery. More broadly, propose disagreements reveal need multidisciplinary research integrates neuroscientific, behavioral, clinical, sociocultural perspectives.

Language: Английский

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Food addiction: a valid concept?

Neuropsychopharmacology, Journal Year: 2018, Volume and Issue: 43(13), P. 2506 - 2513

Published: Sept. 6, 2018

Can food be addictive? What does it mean to a addict? Do common underlying neurobiological mechanisms contribute drug and addiction? These vexing questions have been the subject of considerable interest debate in recent years, driven large part by major health concerns associated with dramatically increasing body weights rates obesity United States, Europe, other regions developed economies. No clear consensus has yet emerged on validity concept addiction whether some individuals who struggle control their intake can considered addicts. Some, including Fletcher, argued that is unsupported, as many defining features are not seen context feeding behaviors. Others, Kenny included, share similar may reflect neural mechanisms. Here, Fletcher argue merits these opposing positions addiction.

Language: Английский

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Improving translation of animal models of addiction and relapse by reverse translation

Nature reviews. Neuroscience, Journal Year: 2020, Volume and Issue: 21(11), P. 625 - 643

Published: Oct. 6, 2020

Language: Английский

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Influence of glutamate and GABA transport on brain excitatory/inhibitory balance

Experimental Biology and Medicine, Journal Year: 2021, Volume and Issue: 246(9), P. 1069 - 1083

Published: Feb. 7, 2021

An optimally functional brain requires both excitatory and inhibitory inputs that are regulated balanced. A perturbation in the excitatory/inhibitory balance-as is case some neurological disorders/diseases (e.g. traumatic injury Alzheimer's disease, stroke, epilepsy substance abuse) disorders of development schizophrenia, Rhett syndrome autism spectrum disorder)-leads to dysfunctional signaling, which can result impaired cognitive motor function, if not frank neuronal injury. At cellular level, transmission glutamate GABA, principle neurotransmitters central nervous system control balance. Herein, we review synthesis, release, signaling GABA followed by a focused discussion on importance their transport systems maintenance

Language: Английский

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Hazardous drinking and alcohol use disorders

Nature Reviews Disease Primers, Journal Year: 2022, Volume and Issue: 8(1)

Published: Dec. 22, 2022

Language: Английский

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The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission

JCI Insight, Journal Year: 2023, Volume and Issue: 8(12)

Published: May 16, 2023

Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in neurobiology of addictive behaviors, and GLP-1 analogues may be used for treatment alcohol use disorder (AUD). Here, we examined effects semaglutide, a long-acting analogue, on biobehavioral correlates rodents. A drinking-in-the-dark procedure was to test semaglutide binge-like drinking male female mice. We also tested dependence-induced rats, as well acute spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced mice; similar effect observed intake other caloric/noncaloric solutions. rats. increased sIPSC frequency CeA ILC neurons alcohol-naive suggesting enhanced GABA release, but had no overall transmission alcohol-dependent In conclusion, analogue decreased across different models species modulated neurotransmission, providing support clinical testing potentially novel pharmacotherapy AUD.

Language: Английский

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