Locus coeruleus ablation in mice: protocol optimization, stereology and behavioral impact DOI Creative Commons

Nanna Bertin Markussen,

Rasmus West Knopper, Stine Hasselholt

et al.

Frontiers in Cellular Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: April 27, 2023

The Locus Coeruleus (LC) is in the brainstem and supplies key brain structures with noradrenaline, including forebrain hippocampus. LC impacts specific behaviors such as anxiety, fear, motivation, well physiological phenomena that impact functions general, sleep, blood flow regulation, capillary permeability. Nevertheless, short- long-term consequences of dysfunction remain unclear. among first affected patients suffering from neurodegenerative diseases Parkinson’s disease Alzheimer’s Disease, hinting may play a central role development progression. Animal models modified or disrupted function are essential to further our understanding normal brain, dysfunction, its putative roles development. For this, well-characterized animal needed. Here, we establish optimal dose selective neurotoxin N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP-4) for ablation. Using histology stereology, compare volume neuron number ablated (LCA) mice controls assess efficacy ablation different numbers DSP-4 injections. All LCA groups show consistent decrease cell count volume. We then proceed characterize behavior using light-dark box test, Barnes maze non-invasive sleep-wakefulness monitoring. Behaviorally, differ subtly control mice, generally being more curious less anxious compared known projections. note an interesting contrast have varying size but whereas (as expected) consistently sized erratic behavior. Our study provides thorough characterization model, firmly consolidating it valid model system dysfunction.

Language: Английский

Biomedical knowledge graph learning for drug repurposing by extending guilt-by-association to multiple layers DOI Creative Commons
Dongmin Bang, Sangsoo Lim, Sangseon Lee

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 15, 2023

Abstract Computational drug repurposing aims to identify new indications for existing drugs by utilizing high-throughput data, often in the form of biomedical knowledge graphs. However, learning on graphs can be challenging due dominance genes and a small number disease entities, resulting less effective representations. To overcome this challenge, we propose “semantic multi-layer guilt-by-association" approach that leverages principle guilt-by-association - “similar share similar functions", at drug-gene-disease level. Using approach, our model DREAMwalk: Drug Repurposing through Exploring Associations using Multi-layer random walk uses semantic information-guided generate disease-populated node sequences, allowing mapping both diseases unified embedding space. Compared state-of-the-art link prediction models, improves drug-disease association accuracy up 16.8%. Moreover, exploration space reveals well-aligned harmony between biological contexts. We demonstrate effectiveness case studies breast carcinoma Alzheimer’s disease, highlighting potential perspective

Language: Английский

Citations

54
Noradrenergic and cholinergic systems take centre stage in neuropsychiatric diseases of ageing DOI Creative Commons
Isabella F. Orlando, James M. Shine, Trevor W. Robbins

et al.

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 149, P. 105167 - 105167

Published: April 11, 2023

Noradrenergic and cholinergic systems are among the most vulnerable brain in neuropsychiatric diseases of ageing, including Alzheimer's disease, Parkinson's Lewy body dementia, progressive supranuclear palsy. As these fail, they contribute directly to many characteristic cognitive psychiatric symptoms. However, their contribution symptoms is not sufficiently understood, pharmacological interventions targeting noradrenergic have met with mixed success. Part challenge complex neurobiology systems, operating across multiple timescales, non-linear changes adult lifespan disease course. We address challenges a detailed review outlining roles cognition behaviour, how influence disease. By bridging levels analysis, we highlight opportunities for improving drug therapies pursuing personalised medicine strategies.

Language: Английский

Citations

33
The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance DOI Creative Commons
Martin J. Dahl, Shelby L. Bachman, Shubir Dutt

et al.

Nature Aging, Journal Year: 2023, Volume and Issue: 3(9), P. 1128 - 1143

Published: Aug. 31, 2023

Abstract Changes in dopaminergic neuromodulation play a key role adult memory decline. Recent research has also implicated noradrenaline shaping late-life memory. However, it is unclear whether these two neuromodulators have distinct roles age-related cognitive changes. Here, combining longitudinal MRI of the substantia nigra–ventral tegmental area (SN-VTA) and noradrenergic locus coeruleus (LC) younger ( n = 69) older 251) adults, we found that integrity are differentially associated with performance. While LC was related to better episodic across several tasks, SN-VTA linked working Longitudinally, age more negative change integrity. Notably, changes reliably predicted future These differential associations nuclei decline potential clinical utility, given their degeneration age-associated diseases.

Language: Английский

Citations

32
Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease DOI Creative Commons
Michael A. Kelberman, Jacki M. Rorabaugh,

Claire R. Anderson

et al.

Neurobiology of Aging, Journal Year: 2023, Volume and Issue: 125, P. 98 - 108

Published: Feb. 1, 2023

Language: Английский

Citations

27
Declining locus coeruleus–dopaminergic and noradrenergic modulation of long-term memory in aging and Alzheimer’s disease DOI Creative Commons
Martin J. Dahl, Agnieszka Kulesza, Markus Werkle‐Bergner

et al.

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 153, P. 105358 - 105358

Published: Aug. 17, 2023

Language: Английский

Citations

22
Digging into the intrinsic capacity concept: Can it be applied to Alzheimer’s disease? DOI
Susana López‐Ortiz, Giuseppe Caruso, Enzo Emanuele

et al.

Progress in Neurobiology, Journal Year: 2024, Volume and Issue: 234, P. 102574 - 102574

Published: Jan. 22, 2024

Language: Английский

Citations

6
Apathy and Motivation: Biological Basis and Drug Treatment DOI Open Access
Harry Costello, Masud Husain, Jonathan P. Roiser

et al.

The Annual Review of Pharmacology and Toxicology, Journal Year: 2023, Volume and Issue: 64(1), P. 313 - 338

Published: Aug. 16, 2023

Apathy is a disabling syndrome associated with poor functional outcomes that common across broad range of neurological and psychiatric conditions. Currently, there are no established therapies specifically for the condition, safe effective treatments urgently needed. Advances in understanding motivation goal-directed behavior humans animals have shed light on cognitive neurobiological mechanisms contributing to apathy, providing an important foundation development new treatments. Here, we review components, neural circuitry, pharmacology apathy motivation, highlighting converging evidence shared transdiagnostic mechanisms. Though pharmacological yet been licensed, summarize trials existing novel compounds date, identifying several promising candidates clinical use avenues future drug development.

Language: Английский

Citations

13
Noradrenergic neuromodulation in ageing and disease DOI Creative Commons

Friedrich Krohn,

Elisa Lancini, Mareike Ludwig

et al.

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 152, P. 105311 - 105311

Published: July 10, 2023

The locus coeruleus (LC) is a small brainstem structure located in the lower pons and main source of noradrenaline (NA) brain. Via its phasic tonic firing, it modulates cognition autonomic functions involved brain's immune response. extent degeneration to LC healthy ageing remains unclear, however, noradrenergic dysfunction may contribute pathogenesis Alzheimer's (AD) Parkinson's disease (PD). Despite their differences progression at later stages, early involvement lead comparable behavioural symptoms such as preclinical sleep problems neuropsychiatric result AD PD pathology. In this review, we draw attention mechanisms that underlie ageing, PD. We aim motivate future research investigate how system play pivotal role which also be relevant other neurodegenerative diseases.

Language: Английский

Citations

12
State‐of‐the‐art therapy for Down syndrome DOI
Nicola Lorenzón,

Juanluis Musoles‐Lleó,

Federica Turrisi

et al.

Developmental Medicine & Child Neurology, Journal Year: 2023, Volume and Issue: 65(7), P. 870 - 884

Published: Jan. 24, 2023

In the last decade, an important effort was made in field of Down syndrome to find new interventions that improve cognition. These therapies have added traditional symptomatic treatments and drugs for treating Alzheimer disease general population repurposed syndrome. Defining next-generation therapeutics will involve biomarker-based therapeutic decision-making, preventive multimodal interventions. However, translation specific findings into effective strategies has been disappointingly slow failed many cases at clinical level, leading reduced credibility mouse studies. This is aggravated by a tendency favour large-magnitude effects highly significant findings, high expectations but also biased view complex pathophysiology Here, we review some most recent promising ameliorating cognitive state individuals with We studied landscape preclinical studies conducted thorough literature search on PubMed ClinicalTrials.gov articles published between June 2012 August 2022 function critically assess current approaches, why fail trials syndrome, what could be path forward. discuss intrinsic difficulties translational research, need framework improves detection drug efficacy avoid discarding compounds too early from companies' pipelines.

Language: Английский

Citations

11
Non-coding RNAs involved in the molecular pathology of Alzheimer’s disease: a systematic review DOI Creative Commons
Reynand Jay Canoy,

J Sy,

Christian Deo T. Deguit

et al.

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: June 28, 2024

Alzheimer's disease (AD) is the leading cause of dementia globally, having a pathophysiology that complex and multifactorial. Recent findings highlight significant role non-coding RNAs (ncRNAs), specifically microRNAs (miRNAs), long (lncRNAs), circular (circRNAs), piwi-interacting (piRNAs) in molecular mechanisms underlying AD. These ncRNAs are involved critical biological processes such as cell proliferation, apoptosis, oxidative stress, amyloid-beta aggregation, tau phosphorylation, neuroinflammation, autophagy, which pivotal AD development progression. This systematic review aims to consolidate current scientific knowledge on AD, making it first encompass four types associated with disease. Our comprehensive search analysis reveal not only play crucial roles pathogenesis but also hold potential biomarkers for its early detection novel therapeutic targets. Specifically, underscore significance miRNAs regulating genes key pathways activin receptor signaling pathway, actomyosin contractile ring organization, advanced glycation endproducts-receptor endproducts (AGE-RAGE) pathway. highlights unveiling diagnostic strategies, emphasizing need further research validate their clinical utility. exploration provides foundation future bioinformatic analyses ncRNA-based precision medicine approaches offering new insights into disease's pathology paving way innovative treatment strategies.

Language: Английский

Citations

4