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Edinger-Westphal peptidergic neurons enable maternal preparatory nesting.

ABSTRACT: Optimizing reproductive fitness in mammalians requires behavioral adaptations during pregnancy. Maternal preparatory nesting is an essential behavior for the survival of the upcoming litter. Brain-wide immediate early gene mapping in mice evoked by nesting sequences revealed that phases of nest construction strongly activate peptidergic neurons of the Edinger-Westphal nucleus in pregnant mice. Genetic ablation, bidirectional neuromodulation, and in vitro and in vivo activity recordings demonstrated that these neurons are essential to modulate arousal before sleep to promote nesting specifically. We show that these neurons enable the behavioral effects of progesterone on preparatory nesting by modulating a broad network of downstream targets. Our study deciphers the role of midbrain CART+ neurons in behavioral adaptations during pregnancy vital for reproductive fitness.

SUBMITTER: Topilko T

PROVIDER: S-EPMC9090132 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Edinger-Westphal peptidergic neurons enable maternal preparatory nesting.

Topilko Thomas T Diaz Silvina L SL Pacheco Catarina M CM Verny Florine F Rousseau Charly V CV Kirst Christoph C Deleuze Charlotte C Gaspar Patricia P Renier Nicolas N

Neuron 20220204 8

Optimizing reproductive fitness in mammalians requires behavioral adaptations during pregnancy. Maternal preparatory nesting is an essential behavior for the survival of the upcoming litter. Brain-wide immediate early gene mapping in mice evoked by nesting sequences revealed that phases of nest construction strongly activate peptidergic neurons of the Edinger-Westphal nucleus in pregnant mice. Genetic ablation, bidirectional neuromodulation, and in vitro and in vivo activity recordings demonstra ...[more]

PMID: 35123655

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Project description:Introduction: The centrally projecting Edinger-Westphal nucleus (EWcp) contributes to the control of alcohol consumption by its urocortin 1 (UCN1) and cocaine- and amphetamine-regulated transcript (CART) co-expressing peptidergic neurons. Our group recently showed that the urocortinergic centrally projecting EWcp is the primary seat of central nervous system transient receptor potential ankyrin 1 (TRPA1) cation channel mRNA expression. Here, we hypothesized that alcohol and its metabolites, that pass through the blood-brain barrier, may influence the function of urocortinergic cells in centrally projecting EWcp by activating TRPA1 ion channels. We aimed to examine the functional activity of TRPA1 in centrally projecting EWcp and its possible role in a mouse model of acute alcohol exposure. Methods: Electrophysiological measurements were performed on acute brain slices of C57BL/6J male mice containing the centrally projecting EWcp to prove the functional activity of TRPA1 using a selective, potent, covalent agonist JT010. Male TRPA1 knockout (KO) and wildtype (WT) mice were compared with each other in the morphological studies upon acute alcohol treatment. In both genotypes, half of the animals was treated intraperitoneally with 1 g/kg 6% ethanol vs. physiological saline-injected controls. Transcardial perfusion was performed 2 h after the treatment. In the centrally projecting EWcp area, FOS immunohistochemistry was performed to assess neuronal activation. TRPA1, CART, and urocortin 1 mRNA expression as well as urocortin 1 and CART peptide content was semi-quantified by RNAscope in situ hybridization combined with immunofluorescence. Results: JT010 activated TRPA1 channels of the urocortinergic cells in acute brain slices. Alcohol treatment resulted in a significant FOS activation in both genotypes. Alcohol decreased the Trpa1 mRNA expression in WT mice. The assessment of urocortin 1 peptide immunoreactivity revealed lower basal urocortin 1 in KO mice compared to WTs. The urocortin 1 peptide content was affected genotype-dependently by alcohol: the peptide content decreased in WTs while it increased in KO mice. Alcohol exposure influenced neither CART and urocortin 1 mRNA expression nor the centrally projecting EWcp/CART peptide content. Conclusion: We proved the presence of functional TRPA1 receptors on urocortin 1 neurons of the centrally projecting EWcp. Decreased Trpa1 mRNA expression upon acute alcohol treatment, associated with reduced neuronal urocortin 1 peptide content suggesting that this cation channel may contribute to the regulation of the urocortin 1 release.

Project description:BackgroundTransient receptor potential ankyrin 1 (TRPA1), a cation channel, is expressed predominantly in primary sensory neurons, but its central distribution and role in mood control are not well understood. We investigated whether TRPA1 is expressed in the urocortin 1 (UCN1)-immunoreactive centrally projecting Edinger-Westphal nucleus (EWcp), and we hypothesized that chronic variable mild stress (CVMS) would reduce its expression in mice. We anticipated that TRPA1 mRNA would be present in the human EWcp, and that it would be downregulated in people who died by suicide.MethodsWe exposed Trpa1 knockout and wild-type mice to CVMS or no-stress control conditions. We then performed behavioural tests for depression and anxiety, and we evaluated physical and endocrinological parameters of stress. We assessed EWcp Trpa1 and Ucn1 mRNA expression, as well as UCN1 peptide content, using RNA-scope in situ hybridization and immunofluorescence. We tested human EWcp samples for TRPA1 using reverse transcription polymerase chain reaction.ResultsTrpa1 mRNA was colocalized with EWcp/UCN1 neurons. Non-stressed Trpa1 knockout mice expressed higher levels of Ucn1 mRNA, had less body weight gain and showed greater immobility in the forced swim test than wild-type mice. CVMS downregulated EWcp/Trpa1 expression and increased immobility in the forced swim test only in wild-type mice. We confirmed that TRPA1 mRNA expression was downregulated in the human EWcp in people who died by suicide.LimitationsDevelopmental compensations and the global lack of TRPA1 may have influenced our findings. Because experimental data came from male brains only, we have no evidence for whether findings would be similar in female brains. Because a TRPA1-specific antibody is lacking, we have provided mRNA data only. Limited access to high-quality human tissues restricted sample size.ConclusionTRPA1 in EWcp/UCN1 neurons might contribute to the regulation of depression-like behaviour and stress adaptation response in mice. In humans, TRPA1 might contribute to mood control via EWcp/UCN1 neurons.

Project description:BackgroundThe neuropathological background of major depression and anxiety as non-motor symptoms of Parkinson's disease is much less understood than classical motor symptoms. Although, neurodegeneration of the Edinger-Westphal nucleus in human Parkinson's disease is a known phenomenon, its possible significance in mood status has never been elucidated. In this work we aimed at investigating whether neuron loss and alpha-synuclein accumulation in the urocortin 1 containing (UCN1) cells of the centrally-projecting Edinger-Westphal (EWcp) nucleus is associated with anxiety and depression-like state in the rat.MethodsSystemic chronic rotenone administration as well as targeted leptin-saporin-induced lesions of EWcp/UCN1 neurons were conducted. Rotarod, open field and sucrose preference tests were performed to assess motor performance and mood status. Multiple immunofluorescence combined with RNAscope were used to reveal the functional-morphological changes. Two-sample Student's t test, Spearman's rank correlation analysis and Mann-Whitney U tests were used for statistics.ResultsIn the rotenone model, besides motor deficit, an anxious and depression-like phenotype was detected. Well-comparable neuron loss, cytoplasmic alpha-synuclein accumulation as well as astro- and microglial activation were observed both in the substantia nigra pars compacta and EWcp. Occasionally, UCN1-immunoreactive neuronal debris was observed in phagocytotic microglia. UCN1 peptide content of viable EWcp cells correlated with dopaminergic substantia nigra cell count. Importantly, other mood status-related dopaminergic (ventral tegmental area), serotonergic (dorsal and median raphe) and noradrenergic (locus ceruleus and A5 area) brainstem centers did not show remarkable morphological changes. Targeted partial selective EWcp/UCN1 neuron ablation induced similar mood status without motor symptoms.ConclusionsOur findings collectively suggest that neurodegeneration of urocortinergic EWcp contributes to the mood-related non-motor symptoms in toxic models of Parkinson's disease in the rat.

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Edinger-Westphal peptidergic neurons enable maternal preparatory nesting.

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Edinger-Westphal peptidergic neurons enable maternal preparatory nesting.

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