Similar Datasets
Project description:Preclinical work has long focused on male animals, though biological sex clearly influences risk for certain diseases, including many psychiatric disorders. Such disorders are often treated by drugs targeting the CNS norepinephrine system. Despite roles for noradrenergic neurons in behavior and neuropsychiatric disease models, their molecular characterization has lagged. We profiled mouse noradrenergic neurons in vivo, defining over 3,000 high-confidence transcripts expressed therein, including druggable receptors. We uncovered remarkable sex differences in gene expression, including elevated expression of the EP3 receptor in females-which we leverage to illustrate the behavioral and pharmacologic relevance of these findings-and of Slc6a15 and Lin28b, both major depressive disorder (MDD)-associated genes. Broadly, we present a means of transcriptionally profiling locus coeruleus under baseline and experimental conditions. Our findings underscore the need for preclinical work to include both sexes and suggest that sex differences in noradrenergic neurons may underlie behavioral differences relevant to disease.
| S-EPMC6070358 | biostudies-literature
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:Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus
| PRJNA390307 | ENA
Project description:The locus coeruleus (LC), the origin of noradrenergic modulation of cognitive and behavioral function, may play an important role healthy ageing and in neurodegenerative conditions. We investigated the functional significance of age-related differences in mean normalized LC signal intensity values (LC-CR) in magnetization-transfer (MT) images from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort - an open-access, population-based dataset. Using structural equation modelling, we tested the pre-registered hypothesis that putatively noradrenergic (NA)-dependent functions would be more strongly associated with LC-CR in older versus younger adults. A unidimensional model (within which LC-CR related to a single factor representing all cognitive and behavioral measures) was a better fit with the data than the a priori two-factor model (within which LC-CR related to separate NA-dependent and NA-independent factors). Our findings support the concept that age-related reduction of LC structural integrity is associated with impaired cognitive and behavioral function.
| S-EPMC7136271 | biostudies-literature
Project description:Noradrenergic neurons in the locus coeruleus (LC) release noradrenaline (NA) that acts via volume transmission to activate extrasynaptic G-protein coupled receptors (GPCRs) in target cells throughout the brain. As the closest projection, the dorsal LC laterally adjoins the mesencephalic trigeminal nucleus (MTN), in which proprioceptive primary sensory neurons innervating muscle spindles of jaw-closing muscles are exceptionally located. MTN neurons express α2-adrenergic receptors (α2-ARs) and display hyperpolarization-activated cyclic nucleotide-gated (HCN) currents (Ihs), which is downregulated by α2-AR activation. To quantify the activity-dependent outcome of volume transmission of NA from LC to MTN, we investigated how direct LC activation inhibits Ih in MTN neurons by performing dual whole-cell recordings from LC and MTN neurons. Repetition of 20 Hz spike-train evoked with 1-s current-pulse in LC neurons every 30 s resulted in a gradual decrease in Ih evoked every 30 s, revealing a Hill-type relationship between the number of spike-trains in LC neurons and the degree of Ih inhibition in MTN neurons. On the other hand, when microstimulation was applied in LC every 30 s, an LC neuron repeatedly displayed a transient higher-frequency firing followed by a tonic firing at 5-10 Hz for 30 s. This subsequently caused a similar Hill-type inhibition of Ih in the simultaneously recorded MTN neuron, but with a smaller Hill coefficient, suggesting a lower signal transduction efficacy. In contrast, 20 Hz activity induced by a 1-s pulse applied every 5-10 s caused only a transient facilitation of Ih inhibition followed by a forced termination of Ih inhibition. Thus, the three modes of LC activities modulated the volume transmission to activate α2-adrenergic GPCR to differentially inhibit Ih in MTN neurons.
| S-EPMC9087804 | biostudies-literature
Project description:Dysfunction of the noradrenergic (NE) neurons is implicated in the pathogenesis of bipolar disorder (BPD). ErbB4 is highly expressed in NE neurons, and its genetic variation has been linked to BPD; however, how ErbB4 regulates NE neuronal function and contributes to BPD pathogenesis is unclear. Here we find that conditional deletion of ErbB4 in locus coeruleus (LC) NE neurons increases neuronal spontaneous firing through NMDA receptor hyperfunction, and elevates catecholamines in the cerebrospinal fluid (CSF). Furthermore, Erbb4-deficient mice present mania-like behaviors, including hyperactivity, reduced anxiety and depression, and increased sucrose preference. These behaviors are completely rescued by the anti-manic drug lithium or antagonists of catecholaminergic receptors. Our study demonstrates the critical role of ErbB4 signaling in regulating LC-NE neuronal function, reinforcing the view that dysfunction of the NE system may contribute to the pathogenesis of mania-associated disorder.
| S-EPMC6185106 | biostudies-literature
Project description:To investigate the changes in the firing activity of noradrenergic neurons in the locus coeruleus (LC) in a rat model of Parkinson disease (PD).2 and 4 weeks after unilateral lesion of the nigrostriatal pathway in the rat by local injection of 6-hydroxydopamine (6-OHDA) into the right substantia nigra pars compacta (SNc), the firing activity of noradrenergic neurons in LC was recorded by extracellular single unit recording.The firing rate of LC noradrenergic neurons increased significantly 2 and 4 weeks after 6-OHDA lesions compared to normal rats, respectively (P < 0.05). The percentage of irregularly firing neurons was obviously higher than that of normal rats during the fourth week after SNc lesion (P < 0.05).LC noradrenergic neurons are overactive and more irregular in 6-OHDA-lesioned rats. These changes suggest an implication of the LC in the pathophysiological mechanism of PD.
| S-EPMC5552494 | biostudies-other
Project description:As the most important organ in our bodies, the brain plays a critical role in deciding sex-related differential features; however, the underlying neural circuitry basis remains unclear. Here, we used a cell-type-specific rabies virus-mediated monosynaptic tracing system to generate a sex differences-related whole-brain input atlas of locus coeruleus noradrenaline (LC-NE) neurons. We developed custom pipelines for brain-wide comparisons of input sources in both sexes with the registration of the whole-brain data set to the Allen Mouse Brain Reference Atlas. Among 257 distinct anatomical regions, we demonstrated the differential proportions of inputs to LC-NE neurons in male and female mice at different levels. Locus coeruleus noradrenaline neurons of two sexes showed general similarity in the input patterns, but with differentiated input proportions quantitatively from major brain regions and diverse sub-regions. For instance, inputs to male LC-NE neurons were found mainly in the cerebrum, interbrain, and cerebellum, whereas inputs to female LC-NE neurons were found in the midbrain and hindbrain. We further found that specific subsets of nuclei nested within sub-regions contributed to overall sex-related differences in the input circuitry. Furthermore, among the totaled 123 anatomical regions with proportion of inputs >0.1%, we also identified 11 sub-regions with significant statistical differences of total inputs between male and female mice, and seven of them also showed such differences in ipsilateral hemispheres. Our study not only provides a structural basis to facilitate our understanding of sex differences at a circuitry level but also provides clues for future sexually differentiated functional studies related to LC-NE neurons.
| S-EPMC7541090 | biostudies-literature
Project description:Locus coeruleus (LC) neurons regulate breathing by sensing CO2/pH. Neurons within the vertebrate LC are the main source of norepinephrine within the brain. However, they also use glutamate and GABA for fast neurotransmission. Although the amphibian LC is recognized as a site involved in central chemoreception for the control of breathing, the neurotransmitter phenotype of these neurons is unknown. To address this question, we combined electrophysiology and single-cell quantitative PCR to detect mRNA transcripts that define norepinephrinergic, glutamatergic, and GABAergic phenotypes in LC neurons activated by hypercapnic acidosis (HA) in American bullfrogs. Most LC neurons activated by HA had overlapping expression of noradrenergic and glutamatergic markers but did not show strong support for GABAergic transmission. Genes that encode the pH-sensitive K+ channel, TASK2, and acid-sensing cation channel, ASIC2, were most abundant, while Kir5.1 was present in 1/3 of LC neurons. The abundance of transcripts related to norepinephrine biosynthesis linearly correlated with those involved in pH sensing. These results suggest that noradrenergic neurons in the amphibian LC also use glutamate as a neurotransmitter and that CO2/pH sensitivity may be linkedto the noradrenergic cell identity.
| S-EPMC10492231 | biostudies-literature