Noradrenergic modulation of identified, potentially energy homeostasis regulating neurons in the paraventricular nucleus of the hypothalamus
Final Report Abstract
The paraventricular hypothalamus (PVH) is a central regulator of neuroendocrine and autonomic functions, integrating signals from various pathways, including noradrenergic inputs from the locus coeruleus, to maintain processes like energy homeostasis. Our long-term goal is understanding how the noradrenergic system influences feeding behavior by modulating PVH neurons. Here, we characterized the intrinsic electrophysiological properties of PVH neurons using perforated patch-clamp recordings in mice, aligning our findings with previous studies in rats. Three distinct neuron types were identified: Type I neurons, corresponding to magnocellular neurosecretory neurons, displayed delayed spike onset after hyperpolarization and slow spike-frequency adaptation. Type II neurons (putative parvocellular neurosecretory) fired repetitive spikes without delay, while Type III neurons (putative preautonomic) showed spike bursts after hyperpolarization and rapid adaptation. Type III neurons had more complex dendritic structures, while Type I had the largest somata. These distinct neuron types were distributed differently across PVH regions, with Type I neurons located more anteriorly and Type III neurons more posteriorly. Noradrenaline (NA) differentially modulated the activity of these neuron types. In Type I neurons, around 80% showed increased firing in response to NA, while the remaining 20% were inhibited. Type II neurons mainly decreased their firing (60%), although 35% showed excitation. In Type III neurons, 65% were inhibited, and 17% were excited by NA. This demonstrates that NA modulates PVH neurons in a cell-type-specific manner. To explore the molecular basis of these effects, we conducted transcriptomic analyses to assess adrenergic receptor (AR) expression in PVH neuron populations. Oxytocin (Oxt)- neurons (predominantly Type I) expressed predominantly α1a-ARs, while argininevasopressin (AVP)-neurons (predominantly Type I) showed high α1a- and α2c-AR expression. Thyrotropin-releasing hormone (TRH)-neurons (predominantly Type II) were characterized by α2a-AR dominance, and corticotropin-releasing hormone (CRH)-neurons (constituted by all three types) expressed α1b-, α2a-, α2c-, and β1-ARs. These findings indicate that different PVH neuron populations have distinct AR expression profiles. We substantiated the functional relevance of these AR subtypes using pharmacological methods. In conclusion, our results reveal cell type-specific AR inventories that mediate the excitatory and inhibitory effects of NA across different neuron types, showing how NA differentially modulates PVH neurons. These findings suggest complex regulatory mechanisms for autonomic processes such as energy balance.
Publications
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Analysis of neuronal Ca2+ handling properties by combining perforated patch clamp recordings and the added buffer approach. Cell Calcium, 97, 102411.
Hess, Simon; Pouzat, Christophe; Paeger, Lars; Pippow, Andreas & Kloppenburg, Peter
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Datasets for calcium dynamics comparison between the whole-cell and a β-escin based perforated patch configuration in brain slices from adult mice. Data in Brief, 39, 107494.
Hess, Simon; Pouzat, Christophe & Kloppenburg, Peter
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Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting. Nature Neuroscience, 24(7), 913-929.
Biglari, Nasim; Gaziano, Isabella; Schumacher, Jonas; Radermacher, Jan; Paeger, Lars; Klemm, Paul; Chen, Weiyi; Corneliussen, Svenja; Wunderlich, Claudia M.; Sue, Michael; Vollmar, Stefan; Klöckener, Tim; Sotelo-Hitschfeld, Tamara; Abbasloo, Amin; Edenhofer, Frank; Reimann, Frank; Gribble, Fiona M.; Fenselau, Henning; Kloppenburg, Peter ... & Brüning, Jens C.
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Perforated Patch Clamp Recordings in ex vivo Brain Slices from Adult Mice. BIO-PROTOCOL, 13(16).
Hess, Simon; Wratil, Helmut & Kloppenburg, Peter
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Deficiency of Orexin Receptor Type 1 in Dopaminergic Neurons Increases Novelty-Induced Locomotion and Exploration. eLife Sciences Publications, Ltd.
Xiao, Xing; Yeghiazaryan, Gagik; Eggersmann, Fynn; Cremer, Anna L.; Backes, Heiko; Kloppenburg, Peter & Hausen, A. Christine
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Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release. Nature Communications, 15(1).
Zhou, Xuehan; Stine, Carrie; Prada, Patricia Oliveira; Fusca, Debora; Assoumou, Kevin; Dernic, Jan; Bhat, Musadiq A.; Achanta, Ananya S.; Johnson, Joseph C.; Pasqualini, Amanda Loren; Jadhav, Sanjana; Bauder, Corinna A.; Steuernagel, Lukas; Ravotto, Luca; Benke, Dietmar; Weber, Bruno; Suko, Azra; Palmiter, Richard D.; Stoeber, Miriam ... & Patriarchi, Tommaso
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Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism. Nature Metabolism, 6(3), 473-493.
De Solis, Alain J.; Del Río-Martín, Almudena; Radermacher, Jan; Chen, Weiyi; Steuernagel, Lukas; Bauder, Corinna A.; Eggersmann, Fynn R.; Morgan, Donald A.; Cremer, Anna-Lena; Sué, Michael; Germer, Maximilian; Kukat, Christian; Vollmar, Stefan; Backes, Heiko; Rahmouni, Kamal; Kloppenburg, Peter & Brüning, Jens C.
