Effects of Age and Atomoxetine on Olfactory Perception and Learning and Underlying Plasticity Mechanisms in Rats DOI Open Access

Ruhuf Abu‐Labdeh,

Tamunotonye Omoluabi,

Qi Yuan

et al.

European Journal of Neuroscience, Journal Year: 2024, Volume and Issue: 61(1)

Published: Dec. 26, 2024

The locus coeruleus (LC) plays a vital role in cognitive function through norepinephrine release. Impaired LC neuronal health and is linked to decline during ageing Alzheimer's disease. This study investigates age-related alterations olfactory detection discrimination learning, along with its reversal, Long-Evans rats, examines the effects of atomoxetine (ATM), uptake inhibitor, on these processes. Adult (6-9 months) aged (22-24 rats underwent odour threshold experiments saline two doses ATM (0.3 1 mg/kg). Reward-based learning included simple, difficult reversal tasks. neuron density, dopamine beta-hydroxylase transporter expression piriform cortex (PC) orbitofrontal were measured. Reversal threat extinction used measure behavioural flexibility. Immunohistochemistry western blotting analyse phosphorylated cAMP response element binding protein (pCREB) cFos ex vivo electrophysiology assessed long-term depression (LTD) PC. Whereas adult cohorts showed similar fewer acquired successfully. improved reward-based adults but hindered reversal. A delayed CREB phosphorylation posterior PC associated administration possibly underlies enhancement. resulted less freezing behaviour conditioning paradigm at moderate, not higher doses. prevented LTD. These findings highlight intricate atomoxetine, influenced by target structures, suggest potential interactions other neurotransmitters. Our results contribute understanding impact enhancers

Language: Английский

Effects of social isolation on locus coeruleus opioid receptor expression and affective behavior. DOI Creative Commons

John A. Tkaczynski,

Jordan Riser,

Maya Patel

et al.

Neurobiology of Stress, Journal Year: 2025, Volume and Issue: unknown, P. 100717 - 100717

Published: March 1, 2025

Language: Английский

Citations

0
Loss of excitatory inputs and decreased tonic and evoked activity of locus coeruleus neurons in aged P301S mice DOI Creative Commons
Anthony M. Downs,

Gracianne Kmiec,

Christina M. Catavero

et al.

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106883 - 106883

Published: March 1, 2025

Tau pathology in the locus coeruleus (LC) is associated with several neurodegenerative conditions including Alzheimer's disease and frontotemporal dementia. Phosphorylated tau accumulates LC results inflammation, synaptic loss, eventually cell death as progresses. Loss of neurons noradrenergic innervation thought to contribute symptoms cognitive decline later disease. While loss degeneration has been well studied, less known about changes physiology at advanced stages that precedes neurodegeneration. In this study, we investigated ex vivo electrophysiological properties male female mice from P301S mouse model tauopathy 9 months age, a time-point when significant accumulation, death, impairments are observed. We found reduction excitatory inputs post-synaptic current kinetics P301S. There was also decrease spontaneous discharge an increase AP threshold both sexes. Finally, observed excitability rheobase mice. Despite activity slices, did not identify differences total tissue norepinephrine (NE) or NE metabolites prefrontal cortex hippocampus. Together these findings demonstrate reductions late accumulation. However, compensatory mechanisms may maintain normal levels projection regions vivo.

Language: Английский

Citations

0
Atrophy links lower novelty‐related locus coeruleus connectivity to cognitive decline in preclinical AD DOI Creative Commons
Christoph Schneider, Prokopis C. Prokopiou, Kathryn V. Papp

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(6), P. 3958 - 3971

Published: April 27, 2024

Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to medial temporal lobe (MTL), atrophy, and cognitive impairment. We investigated contribution of LC-MTL functional connectivity (FC

Language: Английский

Citations

3
Structural and functional remodeling of neural networks in β-amyloid driven hippocampal hyperactivity DOI
Jinquan Li, Yanjun Liu,

Chuhui Yin

et al.

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 101, P. 102468 - 102468

Published: Aug. 31, 2024

Language: Английский

Citations

3
Diversity of ancestral brainstem noradrenergic neurons across species and multiple biological factors DOI Creative Commons
Michael A. Kelberman, Ellen M. Rodberg, Ehsan Arabzadeh

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 16, 2024

Abstract The brainstem region, locus coeruleus (LC), has been remarkably conserved across vertebrates. Evolution woven the LC into wide-ranging neural circuits that influence functions as broad autonomic systems, stress response, nociception, sleep, and high-level cognition among others. Given this conservation, there is a strong possibility activity inherently similar species, furthermore age, sex, brain state similarly species. degree to which homogenous these factors, however, never assessed due small sample size of individual studies. Here, we pool data from 20 laboratories (1,855 neurons) show diversity both intrinsic extrinsic factors such sex state. We use negative binomial regression model compare male monkeys, rats mice sexes were recorded states slices ex vivo or under different anesthetics during wakefulness in . differed complex interactions became more active aging, independent sex. Finally, contrast foundational principle all species express two distinct firing modes (“tonic” “phasic”), discovered great within spontaneous patterns. Different associated with higher incidence some modes. conclude evolutionarily-ancient not conserved. Inherent differences age species-sex-brain have implications for understanding role species-specific naturalistic behavior, well psychiatric disorders, cardiovascular disease, immunology, metabolic disorders.

Language: Английский

Citations

3
Tyrosinase-induced neuromelanin accumulation triggers rapid dysregulation and degeneration of the mouse locus coeruleus DOI Creative Commons

Alexa F. Iannitelli,

Leslie Hassenein,

Bernard Mulvey

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 10, 2023

Abstract The locus coeruleus (LC), the major source of norepinephrine (NE) in brain, is an early site pathology both Alzheimer’s disease (AD) and Parkinson’s (PD), it undergoes catastrophic degeneration later disorders. Dysregulation LC thought to contribute prodromal symptoms AD PD such as anxiety sleep disturbances, while frank LC-NE loss promotes cognitive decline. However, mechanisms responsible for its selective vulnerability are unknown. among only structures brain that produces appreciable amounts neuromelanin (NM), a dark cytoplasmic pigment. It has been proposed NM initially plays protective role by sequestering toxic catecholamine metabolites heavy metals, but may become harmful during aging overwhelms cellular machinery released neurodegeneration. Rodents do not naturally produce NM, limiting study causal relationships between pathology. Adapting viral-mediated approach expression human tyrosinase, enzyme peripheral melanin production, we successfully promoted pigmentation mouse neurons recapitulates key ultrastructural features endogenous found primates. Pigment results neuron hyperactivity, reduced tissue NE levels, transcriptional changes, novelty-induced phenotypes 1-week post-injection. By 6-10 weeks, accumulation associated with severe neurodegeneration microglial engulfment pigment granules, anxiety-like behavior abated. These reminiscent dysfunction cell death PD, validating this model studying consequences relates neurodegenerative disease.

Language: Английский

Citations

8
Anxiety and Alzheimer’s disease pathogenesis: focus on 5-HT and CRF systems in 3xTg-AD and TgF344-AD animal models DOI Creative Commons
Nicole C. Reyna, Benjamin J. Clark, Derek A. Hamilton

et al.

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: Nov. 10, 2023

Dementia remains one of the leading causes morbidity and mortality in older adults. Alzheimer’s disease (AD) is most common type dementia, affecting over 55 million people worldwide. AD characterized by distinct neurobiological changes, including amyloid-beta protein deposits tau neurofibrillary tangles, which cause cognitive decline subsequent behavioral such as distress, insomnia, depression, anxiety. Recent literature suggests a strong connection between stress systems progression. This presents promising direction for future research. In this review, two involved regulating pathogenesis will be highlighted: serotonin (5-HT) corticotropin releasing factor (CRF). Throughout we summarize critical findings field while discussing limitations with animal models (3xTg-AD TgF344-AD), novel pharmacotherapies, potential early-intervention treatment options. We conclude highlighting pharmacotherapies translational

Language: Английский

Citations

8
Examining resilience to Alzheimer’s disease through the lens of monoaminergic neuromodulator systems DOI
Jennifer L. Crawford, Anne S. Berry

Trends in Neurosciences, Journal Year: 2024, Volume and Issue: 47(11), P. 892 - 903

Published: Oct. 4, 2024

Language: Английский

Citations

1
VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction DOI Creative Commons
Harris E. Blankenship,

Kelsey A Carter,

Kevin D. Pham

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 8, 2024

Abstract Alzheimer’s disease (AD) patients exhibit neuropsychiatric symptoms that extend beyond classical cognitive deficits, suggesting involvement of subcortical areas. Here, we investigated the role midbrain dopamine (DA) neurons in AD using amyloid + tau-driven 3xTg-AD mouse model. We found deficits reward-based operant learning mice, possible VTA DA neuron dysregulation. Physiological assessment revealed hyperexcitability and disrupted firing caused by reduced activity small-conductance calcium-activated potassium (SK) channels. RNA sequencing from contents single patch-clamped (Patch-seq) identified up-regulation SK channel modulator casein kinase 2 (CK2), which corroborated immunohistochemical protein analysis. Pharmacological inhibition CK2 restored normal patterns mice. These findings identify a mechanism ion dysregulation could contribute to behavioral abnormalities AD, paving way for novel treatment strategies.

Language: Английский

Citations

1
Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology DOI Open Access
Annie M Goettemoeller, Emmie Banks, Prateek Kumar

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 6, 2023

Preventative treatment for Alzheimer's Disease is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in remain unknown. In human patients with Disease, one the earliest observed pathophysiological correlates to cognitive decline hyperexcitability. mouse models, hyperexcitability has been shown entorhinal cortex, first cortical region impacted by Disease. The origin early-stage disease why it preferentially emerges specific regions unclear. Using cortical-region cell-type-specific proteomics coupled

Language: Английский

Citations

3