Biology subjects

Sterm, J. E.

Publications and source records attributed to Sterm, J. E..

6 recordsLinked to original sources

bioRxiv2026

SOMATODENDRITIC VASOPRESSIN RELEASE COUPLES INTRINSIC EXCITABILITY TO POPULATION-LEVEL ACTIVITY

The transition from single-neuron excitability to organized population firing is a fundamental feature of neural circuits, yet the mechanisms that govern this transition remain poorly understood. Magnocellular vasopressin (VP) and oxytocin neurons are intermingled within the hypothalamus, yet display strikingly different population dynamics, with VP output sustained by a distributed, largely asynchronous activity. Here, we identify a local mechanism by which somatodendritically released VP acts as a diffusible signal that converts an intrinsic excitability mechanism into spatially and temporally organized feedback across the VP population. Activity-dependent somatodendritic VP release recruited a rapid autocrine feedback that transiently potentiated the slow afterhyperpolarization (sAHP) through V1aR signaling which in turn strengthened spike-frequency adaptation and restrained firing. The same signal also acted in a diffusible, paracrine manner on neighboring VP neurons, producing distance- and time-dependent sAHP modulation, with rapid potentiation at short range and delayed inhibition at greater distances. Focal VP uncaging further revealed preferential engagement of somatic over dendritic signaling. Together, these findings show how a diffusible neuropeptide can convert an intrinsic excitability mechanism into spatially structured intercellular feedback, providing a candidate mechanism for sustaining distributed, asynchronous VP population output during prolonged homeostatic demand.

neuroscience↗

bioRxiv2025

Microglial Purinergic Signaling Underlies Salt-Induced Neurovascular Polarity Reversal in the Hypothalamus During Heart Failure

BackgroundNeurovascular coupling (NVC) is essential for matching cerebral blood flow (CBF) to neuronal activity. While cortical NVC has been studied extensively, particularly in the context of sensory processing, little is known about NVC dynamics in deep brain regions, such as the hypothalamus, especially under disease conditions like heart failure (HF), where impaired cortical NVC has been linked to cognitive decline. Our goal in this study was to investigate salt-induced NVC responses in the hypothalamic supraoptic nucleus (SON) of rats with HF, and to determine the role of microglial purinergic signaling in modulating these responses. MethodsUsing in vivo two-photon imaging and real-time oxygen measurements in the SON, we assessed neurovascular responses to a systemic salt challenge in a well-established HF rat model that mimics clinical outcomes observed in the human population. Pharmacological and biosensor approaches were employed to dissect the contribution of key vasoactive mediators. ResultsContrary to our original hypothesis, that HF would exacerbate salt-evoked inverse NVC (iNVC; vasoconstriction and hypoxia) as previously reported by our group in healthy rats, in HF, the NVC response was reversed. Here, salt-induced neuronal activation triggered vasodilation and increased SON pO2, restoring oxygen levels to those of sham controls. This vasodilation was mediated by adenosine acting on A2A receptors and originated from a putative microglial source. Importantly, a masked, enhanced AVP-mediated vasoconstrictive component was still present, as revealed by biosensor assays, indicating a complex interplay between opposing vasoactive signals during HF. ConclusionsThese findings reveal a previously unrecognized microglia-driven purinergic mechanism that overrides AVP-mediated vasoconstriction to restore SON oxygenation during salt challenges in HF. The polarity switch in hypothalamic NVC suggests a region- and disease-specific adaptation with potential relevance to neurohumoral dysregulation in HF.

physiology↗

bioRxiv2023

Impaired oxytocin signaling in the central amygdala in rats with chronic heart failure

AimsHeart failure (HF) patients often suffer from cognitive decline, depression, and mood impairments, but the molecular signals and brain circuits underlying these effects remain elusive. The hypothalamic neuropeptide oxytocin (OT) is critically involved in the regulation of mood, and OTergic signaling in the central amygdala (CeA) is a key mechanism controlling emotional responses including anxiety-like behaviors. Based on this, we used in this study a well-established ischemic rat HF model and aimed to study alterations in the hypothalamus-to-CeA OTergic circuit. Methods and ResultsTo study potential HF-induced changes in the hypothalamus-to-CeA OTertic circuit, we combined patch-clamp electrophysiology, immunohistochemical analysis, RNAScope assessment of OTR mRNA, brain region-specific stereotaxic injections of viral vectors and retrograde tracing, optogenetic stimulation and OT biosensors in the ischemic HF model. We found that most of OTergic innervation of the central amygdala (CeA) originated from the hypothalamic supraoptic nucleus (SON). While no differences in the numbers of SONCeA OTertic neurons (or their OT content) was observed between sham and HF rats, we did observe a blunted content and release of OT from axonal terminals within the CeA. Moreover, we report downregulation of neuronal and astrocytic OT receptors, and impaired OTR-driven GABAergic synaptic activity within the CeA microcircuit of rats with HF. ConclusionsOur study provides first evidence that HF rats display various perturbations in the hypothalamus-to-amygdala OTergic circuit, and lays the foundation for future translational studies targeting either the OT system or GABAergic amygdala GABA microcircuit to ameliorate depression or mood impairments in rats or patients with chronic HF.

neuroscience↗

bioRxiv2023

A vasopressin circuit that modulates sex-specific social interest and anxiety-like behavior in mice

One of the largest sex differences in brain neurochemistry is the male-biased expression of the neuropeptide arginine vasopressin (AVP) within the vertebrate social brain. Despite the long-standing implication of AVP in social and anxiety-like behavior, the precise circuitry and anatomical substrate underlying its control are still poorly understood. By employing optogenetic manipulation of AVP cells within the bed nucleus of the stria terminalis (BNST), we have unveiled a central role for these cells in promoting social investigation, with a more pronounced role in males relative to females. These cells facilitate male social investigation and anxiety-like behavior through their projections to the lateral septum (LS), an area with the highest density of sexually-dimorphic AVP fibers. Blocking the vasopressin 1a receptor (V1aR) in the LS eliminated stimulation-mediated increases in these behaviors. Together, these findings establish a distinct BNST AVP [->] LS V1aR circuit that modulates sex-specific social interest and anxiety-like behavior. Significance StatementThe function of sex differences in the brain is poorly understood. Here we test the function of one of the most consistently found sex differences in vertebrate brains, the male-biased vasopressin projections from the bed nucleus of the stria terminalis. Using optogenetic techniques, we demonstrate that these cells and their projection to the lateral septum are much more important in driving male than female social investigation. These studies make a strong contribution to understanding how sexually dimorphic circuitry controls social behavior.

neuroscience↗

bioRxiv2022

A novel analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray

The hypothalamic neuropeptide, oxytocin (OT), exerts prominent analgesic effects via central and peripheral action. Here we discovered a novel subset of OT neurons whose projections preferentially terminate on OT receptor (OTR)-expressing neurons in the ventrolateral periaqueductal gray (vlPAG). Using a newly generated line of transgenic rats (OTR-IRES-Cre), we determined that most of the vlPAG OTR expressing cells being targeted by OT projections are GABAergic in nature. Both optogenetically-evoked axonal OT release in the vlPAG as well as chemogenetic activation of OTR vlPAG neurons results in a long-lasting overall increase of vlPAG neuronal activity. This then leads to an indirect suppression of sensory neuron activity in the spinal cord and strong analgesia. Finally, we describe a novel OT[->]vlPAG[->]spinal cord circuit that seems critical for analgesia in the context of both inflammatory and neuropathic pain. Highlights- We generated a new transgenic knock-in rat line (OTR-IRES-Cre) - A distinct parvOT neuronal population projects to vlPAG but not the SON or spinal cord - OT excites vlPAG OTR neurons which indirectly inhibit SC WDR neurons - This novel parvOT[->]vlPAG[->]SC pathway alleviates nociception but not the affective component of pain

neuroscience↗

bioRxiv2019

Functional coupling between NMDA receptors and SK channels in rat hypothalamic magnocellular neurons: altered mechanisms during heart failure.

Glutamatergic NMDA receptors (NMDAR) and small conductance Ca2+-activated K+ channels (SK) are critical synaptic and intrinsic mechanisms that regulate the activity of hypothalamic magnocellular neurosecretory neurons (MNNs) under physiological and pathological states, including lactation and heart failure (HF). Still, whether NMDARs and SK channels in MNNs are functionally coupled, and whether changes in this coupling contribute to exacerbated neuronal activity during HF is at present unknown. In the present study, we addressed these questions using patch-clamp electrophysiology and confocal Ca2+ imaging in a rat model of ischaemic HF. We found that in MNNs of sham rats, blockade of SK channels with apamin (200 nM) significantly increased the magnitude of an NMDAR-evoked current (INMDA). We also observed that blockade of SK channels potentiated NMDAR-evoked firing, and abolished spike frequency adaptation in MNNs from sham, but not HF rats. Importantly, a larger INMDA-{Delta}Ca2+response was observed under basal conditions in HF compared to sham rats. Finally, we found that dialyzing recorded cells with the Ca2+ chelator BAPTA (10 mM) increased the magnitude of INMDA in MNNs from both sham and HF rats, and occluded the effects of apamin in the former. Together, our studies demonstrate that in MNNs, NMDARs and SK channels are functionally coupled, forming a local negative feedback loop that restrains the excitatory effect evoked by NMDAR activation. Moreover, our studies also support a blunted NMDAR-SK channel coupling in MNNs of HF rats, standing thus as a pathophysiological mechanism contributing to exacerbated hypothalamic neuronal activity during this prevalent neurogenic cardiovascular disease.

neuroscience↗