Diversity of ancestral brainstem noradrenergic neurons across species and multiple biological factors

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

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Norepinephrine depletion in the brain sex-dependently modulates aspects of spatial learning and memory in female and male rats

Psychopharmacology, Journal Year: 2023, Volume and Issue: 240(12), P. 2585 - 2595

Published: Sept. 2, 2023

Language: Английский

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Locus coeruleus integrity and left frontoparietal connectivity provide resilience against attentional decline in preclinical alzheimer’s disease

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: May 31, 2024

Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline dementia. Recent neuroimaging and pharmacological studies left frontoparietal network functional connectivity (LFPN-FC) confers resilience beta-amyloid (Aβ)-related preclinical sporadic autosomal dominant Alzheimer's disease (AD), as well LC-related changes. Given LFPN LC play important roles attention, attention deficits have been observed early process, we examined whether LFPN-FC structural health attenuate attentional context of AD pathology. 142 participants from Harvard Aging Brain Study who underwent resting-state MRI, imaging, PiB(Aβ)-PET, up to 5 years follow-ups were included (mean age = 74.5 ± 9.9 years, 89 women). Cross-sectional robust linear regression associated integrity (measured average five continuous voxels with highest intensities images) or Digit Symbol Substitution Test (DSST) performance at baseline. Longitudinal mixed effect analyses associations between DSST (i) two-way interactions baseline (or LFPN-FC) PiB (ii) three-way interaction integrity, LFPN-FC, PiB. Baseline age, sex, education covariates. At baseline, lower but not was related worse performance. Longitudinally, a faster decline, especially > 10.38 CL. Lower steeper on independent elevated levels (> 46 CL), higher an attenuated DSST, despite presence integrity. Our findings demonstrate can provide Aβ-related decline. However, when Aβ accumulates LC's resources may be depleted, functioning cortical target regions LC, such additional sustain AD. These results critical insights into correlates contributing individual variability risk versus

Language: Английский

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The effects of locus coeruleus ablation on mouse brain volume and microstructure evaluated by high-field MRI

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

Published: Dec. 11, 2024

The locus coeruleus (LC) produces most of the brain's noradrenaline (NA). Among its many roles, NA is often said to be neuroprotective and important for brain upkeep. For this reason, loss LC integrity thought impact volume microstructure as well plasticity broadly. dysfunction also a suspected driver in development neurodegenerative diseases. Nevertheless, on gross structure normal brains not well-studied. We employed high-field ex vivo magnetic resonance imaging (MRI) investigate volumetrics control (CON) mice with ablation (LCA) at two ages, representing developing fully matured brain. These whole-brain methods are known capable detecting subtle morphological changes microstructural remodeling. found behavior consistent histologically confirmed ablation. However, MRI showed no difference between CON LCA groups regard size, relative regional volumes, or indices. Our findings suggest that LC-NA needed postnatal maturation growth mice. Nor it required maintenance adult mouse brain, atrophy aberration detected after weeks dysfunction. This adds clarity often-encountered notion "trophic support" shows such effects likely relevant mechanisms related neuroprotection (pre)diseased

Language: Английский

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

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

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Locus coeruleus injury modulates ventral midbrain neuroinflammation during DSS-induced colitis

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: March 12, 2024

Parkinson's disease (PD) is characterized by a decades-long prodrome, consisting of collection non-motor symptoms that emerges prior to the motor manifestation disease. Of these symptoms, gastrointestinal dysfunction and deficits attributed central norepinephrine (NE) loss, including mood changes sleep disturbances, are frequent in PD population emerge early Evidence mounting injury inflammation gut locus coeruleus (LC), respectively, underlie systems progression PD. In this study, we generate novel two-hit mouse model captures both features, using dextran sulfate sodium (DSS) induce N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesion LC. We first confirmed specificity DSP-4 for NE neurochemical methods fluorescence light-sheet microscopy cleared tissue, established DSS-induced outcomes periphery, weight gross indices systemic inflammation, loss tight junction proteins colonic epithelium, markers were unaffected with pre-administration. then measured alterations neuroimmune gene expression ventral midbrain response DSS treatment alone as well extent which LC modified response. observed colitis activates key cytokines chemokines only presence typical DSS-associated blunted pre-LC lesioning DSP-4. all, study supports growing appreciation neuroprotective against inflammation-induced brain draws attention potential NEergic interventions exert disease-modifying effects under conditions where peripheral may compromise dopaminergic neurons increase risk development

Language: Английский

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Functional Regrowth of Norepinephrine Axons in the Adult Mouse Brain Following Injury

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

Published: Aug. 20, 2024

Abstract It is widely believed that axons in the central nervous system of adult mammals do not regrow following injury. This failure thought, at least part, to underlie limited recovery function injury brain or spinal cord. Some studies fixed tissue have suggested that, counter dogma, norepinephrine (NE) Here, we used vivo two-photon microscopy layer 1 primary somatosensory cortex transgenic mice harboring a fluorophore selectively expressed NE neurons. protocol allowed us explore dynamic nature with selective axon toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). Following DSP4 treatment, were massively depleted and then slowly partially recovered their density over period weeks. regrowth was dominated by new entering imaged volume. There almost no contribution from local sprouting spared axons. Regrown did appear use either paths previously lesioned nor survived treatment as guide. To measure release, GCaMP8s neocortical astrocytes startle-evoked, receptor-mediated Ca 2+ transients measured. These abolished soon after lesion but returned pre-lesion values 3-5 weeks, roughly coincident regrowth, suggesting regrown are competent release response physiological stimulus awake mouse. Significance Statement (CNS) incapable Counter this notion, describe structural functional results extend previous describing regenerative capacity serotonin CNS demonstrating another neuronal subtype these respond normally an external stimulus. Taken together, findings suggest monoaminergic neurons share common program for regrowth. Elucidation molecular genetic could inform therapies promote CNS.

Language: Английский

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tDCS Cranial Nerve Co-Stimulation: Unveiling Brainstem Pathways Involved in Trigeminal Nerve Direct Current Stimulation in Rats

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

Published: Oct. 12, 2024

Abstract The effects of transcranial direct current stimulation (tDCS) are typically attributed to the polarization cortical neurons by weak electric fields it generates in cortex. However, emerging evidence indicates that certain tDCS may be mediated through co-stimulation peripheral or cranial nerves, particularly trigeminal nerve (TN), which projects critical brainstem nuclei regulate release various neurotransmitters throughout central nervous system. Despite this, specific pathways involved remain inadequately characterized. In this study, we examined acute transcutaneous TN (TN-DCS) on tonic (i.e. mean spike rate and over time) phasic (number bursts, per burst, burst duration, inter-burst interval) activities while simultaneously recording single-neuron activity across three rats: locus coeruleus (LC), dorsal raphe nucleus (DRN), median (MnRN). We found TN-DCS significantly modulated LC, with notable interactions between amplitude, polarity, time epoch affecting rates. Similar were observed DRN regarding activity. Further, LC was influenced TN-DCS, changes number, intervals linked parameters. Conversely, MnRN following remained unchanged. Importantly, xylocaine administration block abolished both DRN. These results suggest partially arise from indirect modulation TN, leading altered neuronal LC. Besides, differential underscore their complementary roles mediating higher regions. This research bears significant translational implications, providing mechanistic insights could enhance efficacy applications deepen our understanding its neurophysiological effects.

Language: Английский

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Progressive noradrenergic degeneration and motor cortical dysfunction in Parkinson’s disease

Acta Pharmacologica Sinica, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 26, 2024

Abstract The locus coeruleus norepinephrine (LC-NE) system plays an important role in regulating brain function, and its neuronal loss has been well-documented Parkinson’s disease (PD). LC-NE neurodegeneration is believed to underlie various nonmotor symptoms people with PD, including neuropsychiatric deficits, sleep disruptions, cognitive impairments. Of particular interest, neurons send intensive axonal projections the motor regions of cerebral cortex. However, how NE depletion cortex contributes PD pathophysiology remains poorly understood. In addition, recent studies provided increasing mechanistic insights into secondary changes as degenerates, which might involve interaction dopaminergic signaling during chronic course disease. present article, we briefly discuss clinical preclinical that support critical roles cortical dysfunction both deficits Parkinsonian states. We focus our discussion on potential impact function subsequent symptom manifestation. Last, propose future research directions can advance understanding by integrating noradrenergic degeneration.

Language: Английский

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Functional Regrowth of Norepinephrine Axons in the Adult Mouse Brain Following Injury

eNeuro, Journal Year: 2024, Volume and Issue: unknown, P. ENEURO.0418 - 24.2024

Published: Dec. 26, 2024

It is widely believed that axons in the central nervous system of adult mammals do not regrow following injury. This failure thought, at least part, to underlie limited recovery function injury brain or spinal cord. Some studies fixed tissue have suggested that, counter dogma, norepinephrine (NE) Here, we used vivo two-photon microscopy layer 1 primary somatosensory cortex transgenic mice harboring a fluorophore selectively expressed NE neurons. protocol allowed us explore dynamic nature with selective axon toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). Following DSP4, were massively depleted and then slowly partially recovered their density over period weeks. regrowth was dominated by new entering imaged volume. There almost no contribution from local sprouting spared axons. Regrown did appear use either paths previously lesioned nor survived DSP4 as guide. To measure release, GCaMP8s neocortical astrocytes startle-evoked, receptor-mediated Ca 2+ transients measured. These abolished soon after lesion but returned pre-lesion values 3-5 weeks, roughly coincident regrowth, suggesting regrown are competent release response physiological stimulus awake mouse. Significance Statement (CNS) incapable Counter this notion, describe structural functional results extend previous describing regenerative capacity serotonin CNS demonstrating another neuronal subtype these respond normally an external stimulus. Taken together, findings suggest monoaminergic neurons share common program for regrowth. Elucidation molecular genetic could inform therapies promote CNS.

Language: Английский

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