Perinatal High Fat Diet Exposure Alters Oxytocin and Corticotropin Releasing Factor Inputs onto Vagal Neurocircuits Controlling Gastric Motility

Carson, Kaitlin E.; Alvarez, Jared; Mackley, Jasmine; Travagli, Alberto; Browning, Kirsteen N.

doi:10.1101/2022.11.28.517564

Cited by 6 publications

(7 citation statements)

References 74 publications

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“…Receptors for CRH, OXT, PENK, and SST were present, as well as the receptor for TRH to a lesser extent. This receptor expression profile is consistent with literature on PVN‐DMV neurons, which reports the expression of AVP, OXT, PENK, SST, and CRH in preparasympathetic neurons 8,49 . The presence of TRH receptor might indicate relevance for this neuropeptide in PVN‐DMV circuitry as well, though TRH projections could also originate from brain regions other than the PVN.…”

Section: Discussionsupporting

confidence: 91%

“…This receptor expression profile is consistent with literature on PVN-DMV neurons, which reports the expression of AVP, OXT, PENK, SST, and CRH in preparasympathetic neurons. 8,49 The presence of TRH receptor might indicate relevance for this neuropeptide in PVN-DMV circuitry as well, though TRH projections could also originate from brain regions other than the PVN. As the DMV-projecting AVP and OXT neurons were reportedly parvocellular, we can infer that the Avp-Adarb2 and Oxt-Adarb2 populations are the most likely candidates for the vasopressinergic and oxytocinergic PVN-DMV connections.…”

Section: Discussionmentioning

confidence: 99%

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An integrated single‐cell RNA‐seq atlas of the mouse hypothalamic paraventricular nucleus links transcriptomic and functional types

Berkhout,

Poormoghadam,

et al. 2024

J Neuroendocrinology

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The hypothalamic paraventricular nucleus (PVN) is a highly complex brain region that is crucial for homeostatic regulation through neuroendocrine signaling, outflow of the autonomic nervous system, and projections to other brain areas. In the past years, single‐cell datasets of the hypothalamus have contributed immensely to the current understanding of the diverse hypothalamic cellular composition. While the PVN has been adequately classified functionally, its molecular classification is currently still insufficient. To address this, we created a detailed atlas of PVN transcriptomic cell types by integrating various PVN single‐cell datasets into a recently published hypothalamus single‐cell transcriptome atlas. Furthermore, we functionally profiled transcriptomic cell types, based on relevant literature, existing retrograde tracing data, and existing single‐cell data of a PVN‐projection target region. Finally, we validated our findings with immunofluorescent stainings. In our PVN atlas dataset, we identify the well‐known different neuropeptide types, each composed of multiple novel subtypes. We identify Avp‐Tac1, Avp‐Th, Oxt‐Foxp1, Crh‐Nr3c1, and Trh‐Nfib as the most important neuroendocrine subtypes based on markers described in literature. To characterize the preautonomic functional population, we integrated a single‐cell retrograde tracing study of spinally projecting preautonomic neurons into our PVN atlas. We identify these (presympathetic) neurons to cocluster with the Adarb2+ clusters in our dataset. Further, we identify the expression of receptors for Crh, Oxt, Penk, Sst, and Trh in the dorsal motor nucleus of the vagus, a key region that the pre‐parasympathetic PVN neurons project to. Finally, we identify Trh‐Ucn3 and Brs3‐Adarb2 as some centrally projecting populations. In conclusion, our study presents a detailed overview of the transcriptomic cell types of the murine PVN and provides a first attempt to resolve functionality for the identified populations.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

An integrated single‐cell RNA‐seq atlas of the mouse hypothalamic paraventricular nucleus links transcriptomic and functional types

Berkhout,

Poormoghadam,

et al. 2024

J Neuroendocrinology

View full text Add to dashboard Cite

show abstract

“…Receptors for CRH, OXT, PENK and SST were present, as well as the receptor for TRH to a lesser extent. This receptor expression profile is consistent with literature on PVN-DMV neurons, which reports expression of AVP, OXT, PENK, SST, and CRH [23,5]. The presence of TRH receptor might indicate relevance for this neuropeptide in PVN-DMV circuitry, though TRH projections could originate from brain regions other than the PVN as well.…”

Section: Discussionsupporting

confidence: 91%

An integrated single-cell RNA-seq atlas of the mouse hypothalamic paraventricular nucleus links transcriptional and functional types

Berkhout

Poormoghadam

et al. 2023

Preprint

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The hypothalamic paraventricular nucleus (PVN) is a highly complex brain region that is crucial for homeostatic regulation through neuroendocrine signalling, outflow of the autonomic nervous system, and projections to other brain areas. The past years, single-cell datasets of the hypothalamus have contributed immensely to the current understanding of the diverse hypothalamic cellular composition. While the PVN has been adequately classified functionally, its molecular classification is currently still insufficient. To address this, we created a detailed atlas of PVN transcriptional cell types by integrating various PVN single-cell datasets into a recently published hypothalamus single-cell transcriptome atlas. Furthermore, we functionally profiled transcriptional cell types, based on relevant literature, existing retrograde tracing data and existing single-cell data of a PVN-projection target region. In our PVN atlas dataset, we identify the well-known different neuropeptide types, each composed of multiple novel subtypes. We identify Avp-Tac1, Avp-Th, Oxt-Foxp1, Crh-Nr3c1 and Trh-Nfib as the most important neuroendocrine subtypes based on markers described in literature. To characterize the pre-autonomic functional population, we integrated a single-cell retrograde tracing study of spinally-projecting pre-autonomic neurons into our PVN atlas. We identify these (pre-sympathetic) neurons to co-cluster with the Adarb2+ clusters in our dataset. Finally, we identify expression of receptors for Crh, Oxt, Penk, Sst, and Trh in the dorsal motor nucleus of the vagus, a key region that pre-parasympathetic PVN neurons project to. Concluding, our study present a detailed overview of the transcriptional cell types of the murine PVN, and provides a first attempt to resolve functionality for the identified populations.

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“…Oxytocin neurons in caudal regions of the PVH coordinate various aspects of ingestive behavior and autonomic regulation (15)(16)(17)(18)(19)(20)(21)(22)(23). Oxytocin neural circuits mature relatively late in development, as mature oxytocin peptide is not detected until after birth, and axon outgrowth progressively increases during the first few weeks of postnatal life (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

AgRP neurons mediate activity-dependent development of oxytocin connectivity and autonomic regulation

Biddinger,

Elson,

Fathi

et al. 2024

Preprint

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During postnatal life, the adipocyte-derived hormone leptin is required for proper targeting of neural inputs to the paraventricular nucleus of the hypothalamus (PVH) and impacts the activity of neurons containing agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Activity-dependent developmental mechanisms are known to play a defining role during postnatal organization of neural circuits, but whether leptin-mediated postnatal neuronal activity specifies neural projections to the PVH or impacts downstream connectivity is largely unexplored. Here, we blocked neuronal activity of AgRP neurons during a discrete postnatal period and evaluated development of AgRP inputs to defined regions in the PVH, as well as descending projections from PVH oxytocin neurons to the dorsal vagal complex (DVC) and assessed their dependence on leptin or postnatal AgRP neuronal activity. In leptin-deficient mice, AgRP inputs to PVH neurons were significantly reduced, as well as oxytocin-specific neuronal targeting by AgRP. Moreover, downstream oxytocin projections from the PVH to the DVC were also impaired, despite the lack of leptin receptors found on PVH oxytocin neurons. Blocking AgRP neuron activity specifically during early postnatal life reduced the density of AgRP inputs to the PVH, as well as the density of projections from PVH oxytocin neurons to the DVC, and these innervation deficits were associated with dysregulated autonomic function. These findings suggest that postnatal targeting of descending PVH oxytocin projections to the DVC requires leptin-mediated AgRP neuronal activity, and represents a novel activity-dependent mechanism for hypothalamic specification of metabolic circuitry, with consequences for autonomic regulation.Significance statementHypothalamic neural circuits maintain homeostasis by coordinating endocrine signals with autonomic responses and behavioral outputs to ensure that physiological responses remain in tune with environmental demands. The paraventricular nucleus of the hypothalamus (PVH) plays a central role in metabolic regulation, and the architecture of its neural inputs and axonal projections is a defining feature of how it receives and conveys neuroendocrine information. In adults, leptin regulates multiple aspects of metabolic physiology, but it also functions during development to direct formation of circuits controlling homeostatic functions. Here we demonstrate that leptin acts to specify the input-output architecture of PVH circuits through an activity-dependent, transsynaptic mechanism, which represents a novel means of sculpting neuroendocrine circuitry, with lasting effects on how the brain controls energy balance.

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Perinatal High Fat Diet Exposure Alters Oxytocin and Corticotropin Releasing Factor Inputs onto Vagal Neurocircuits Controlling Gastric Motility

Cited by 6 publications

References 74 publications

An integrated single‐cell RNA‐seq atlas of the mouse hypothalamic paraventricular nucleus links transcriptomic and functional types

An integrated single‐cell RNA‐seq atlas of the mouse hypothalamic paraventricular nucleus links transcriptomic and functional types

An integrated single-cell RNA-seq atlas of the mouse hypothalamic paraventricular nucleus links transcriptional and functional types

AgRP neurons mediate activity-dependent development of oxytocin connectivity and autonomic regulation

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