Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus
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ABSTRACT:
PROVIDER: PRJNA390307 | ENA |
REPOSITORIES: ENA
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Project description:Preclinical work has long focused only on male animals, even though sexual divergence in both baseline behaviors and drug responses clearly impact treatment outcomes in patients. Psychiatric disorders are notably divergent, with males showing higher prevalence of ADHD and ASD, and females GAD and MDD. This divergence is reflected in quantitative differences in subclincal behaviors. The Noradrenergic neurotransmitter system is targeted by many psychiatric drugs, but is relatively uncharacterized at a molecular level. We developed a mouse to profile these neurons, defining their both a baseline transcriptome, including druggable receptors, and their molecular response to stimulation. We also discovered a remarkable sexual divergence in their gene expression, including functionally increased expression of the EP3 receptor in females – a difference that can be used to modulate stress-induced anxiety in a sex specific manner. These findings underscore the need to conduct preclinical studies in a manner balanced for sex, and suggest that baseline differences in noradrenergic neurons could underlay sexually divergent behaviors.
2018-04-30 | GSE100004 | GEO
Project description:Preclinical work has long focused only on male animals, even though sexual divergence in both baseline behaviors and drug responses clearly impact treatment outcomes in patients. Psychiatric disorders are notably divergent, with males showing higher prevalence of ADHD and ASD, and females GAD and MDD. This divergence is reflected in quantitative differences in subclincal behaviors. The Noradrenergic neurotransmitter system is targeted by many psychiatric drugs, but is relatively uncharacterized at a molecular level. We developed a mouse to profile these neurons, defining their both a baseline transcriptome, including druggable receptors, and their molecular response to stimulation. We also discovered a remarkable sexual divergence in their gene expression, including functionally increased expression of the EP3 receptor in females – a difference that can be used to modulate stress-induced anxiety in a sex specific manner. These findings underscore the need to conduct preclinical studies in a manner balanced for sex, and suggest that baseline differences in noradrenergic neurons could underlay sexually divergent behaviors.
2018-04-30 | GSE100002 | GEO
Project description:Aims: This study aimed to identify and characterize the intrinsic properties of locus coeruleus (LC) noradrenergic neurons in male and female mice using a genetic approach. We also sought to investigate sex-specific differences in membrane properties, action potential generation, and protein expression profiles to understand the mechanisms underlying neuronal excitability variations. Methods: Utilizing a genetic mouse model by crossing Dbhcre knock-in mice with tdTomato Ai14 transgenic mice, LC neurons were identified using fluorescence microscopy. Neuronal properties, including capacitance, action potential frequency, and rheobase, were assessed using patch-clamp recordings. Spontaneous and evoked activity between sexes was compared. Proteomic analyses of individual LC neuron soma was conducted using mass-spectrometry to discern protein expression profiles. Results: Female LC noradrenergic neurons displayed greater membrane capacitance than those in male mice. Male LC neurons demonstrated greater spontaneous and evoked action potential generation compared to females. Male LC neurons exhibited a lower rheobase and achieved higher peak frequencies with similar current injections. Proteomic analysis revealed inherent differences in protein expression profiles between sexes, with male mice displaying a notably larger unique protein set compared to females. Notably, pathways pertinent to protein synthesis, degradation, and recycling, such as EIF2 and glucocorticoid receptor signaling, showed reduced expression in females. Conclusions: Male LC noradrenergic neurons exhibit higher intrinsic excitability compared to those from females. The discernible sex-based differences in excitability could be ascribed to varying protein expression profiles, especially within pathways that regulate protein synthesis and degradation. This study lays the groundwork for future studies focusing on the interplay between proteomics and neuronal function examined in individual cells.
2024-05-24 | PXD045844 | Pride
Project description: Not available
| S-EPMC6070358 | biostudies-literature
Project description:Alzheimer's disease (AD) often begins with non-cognitive symptoms such as olfactory deficits, which can predict later cognitive decline, though the mechanisms remain unclear. Pathologically, the brainstem locus coeruleus (LC), the main source of the neurotransmitter noradrenalin (NA) modulating olfactory information processing is affected ealy. Here we show early and distinct loss of noradrenergic input to the olfactory bulb (OB) coinciding with impaired olfaction in an AD mouse model, before appearance of amyloid plaques. Mechanistically, OB microglia recognize and phagocytose LC axons. Reducing phagocytosis genetically preserves LC axons and olfaction. Importantly, patients with prodromal AD display elevated TSPO-PET signals in the OB, similarly to AppNL-G-F mice. We further confirm early LC axon degeneration in post-mortem OBs in patients with early AD. Our findings reveal a mechanism linking early LC damage to hyposmia in AD, suggesting olfactory testing and neurocircuit imaging for early diagnosis and enable timely therapeutic intervention for Alzheimer's disease.
2025-07-21 | GSE302245 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-04-30 | GSE100005 | GEO
Project description:Post-mortem investigations indicate that the locus coeruleus (LC) is the initial site of hyperphosphorylated pretangle tau, a precursor to neurofibrillary tangles (NFTs) found in Alzheimer's disease (AD). The presence of pretangle tau and NFTs in the LC correlates with AD progression. LC neuron integrity and quantity are linked to cognitive states, with degeneration associated with AD. However, the mechanisms of pretangle tau-induced LC degeneration are unclear. This study examined the transcriptomic and mitochondrial profiles of LC noradrenergic neurons after transduction with pseudophosphorylated human tau. Tau hyperphosphorylation increased the somatic expression of the L-type calcium channel (LTCC), impaired mitochondria health, and led to deficits in spatial and olfactory learning. Sex-dependent alterations in gene expression were observed in rats transduced with pretangle tau. Chronic LTCC blockade prevented behavioral deficits and altered mitochondrial mRNA expression, suggesting a potential link between LTCC hyperactivity and mitochondrial dysfunction. Our research provides insights into the consequences of tau pathology in the originating structure of AD.
2024-11-16 | GSE272794 | GEO
Project description:The locus coeruleus (LC) is the earliest site of tau pathology in Alzheimer’s disease (AD), yet how modifiable environmental factors influence its vulnerability, particularly in a sex-specific manner, remains unclear. Using a rat model expressing pseudophosphorylated human tau (htauE14) in the LC, we show that tau accumulation induces anxiety-like behavior, cognitive deficits, and tau spread, shaped by sex and life history. Early-life enrichment attenuated tau propagation, reduced neuroinflammation, and increased hippocampal BDNF expression, while late enrichment reduced anxiety and improved learning. In contrast, late-life stress exacerbated LC degeneration. Single-nucleus RNA sequencing revealed female-biased transcriptional dysregulation in hippocampal excitatory neurons and glia cells following htauE14 expression. Environmental exposures drove distinct cell type-specific transcriptomic signatures: early stress further disrupted mitochondrial and synaptic programs, whereas early enrichment conferred transcriptional stability. These findings position the LC as a sexually dimorphic and environmentally sensitive node of early AD vulnerability and highlight the preventive potential of early-life interventions.
2026-03-18 | GSE306235 | GEO
Project description:Sex and life experience shape locus coeruleus pretangle tau pathology
| PRJNA1309729 | ENA
Project description: Not available
| S-EPMC9183949 | biostudies-literature