Biology subjects

Masri, R.

Publications and source records attributed to Masri, R..

9 recordsLinked to original sources

bioRxiv2026

Sex Differences in Bed Nucleus of the Stria Terminalis Response to Calcitonin Gene-Related Peptide

Women are disproportionately affected by chronic pain, yet the neural mechanisms underlying sex differences in affective pain processing remain incompletely understood. The bed nucleus of the stria terminalis (BNST), a sexually dimorphic structure implicated in aversion and chronic pain, receives dense input from aversive calcitonin gene-related peptide (CGRP)-expressing neurons arising from the parabrachial nucleus (PBN). Although CGRP signaling has been implicated in sex differences in clinical pain conditions, whether CGRP transmission within the PBN[->]BNST pathway is sexually dimorphic has not been determined. Here, we tested the hypothesis that CGRP signaling in the BNST differs between sexes. Contrary to our prediction, PBN CGRP neurotransmitter release in the BNST was sex-independent. However, CGRP neuromodulation of BNST excitability exhibited sex-dependent features. While CGRP potentiated PBN[->]BNST glutamatergic signaling in both sexes, spontaneous inhibitory signaling was selectively increased in males. Together, these findings indicate that sex differences in this circuit arise not from differential peptide release, but from downstream modulation of inhibitory tone, biasing female BNST neurons toward greater excitation. Such circuit-specific sex differences may contribute to the enhanced susceptibility of females to affective components of chronic pain and highlight targets for sex-informed therapeutic interventions.

neuroscience↗

bioRxiv2025

In-silico molecular enrichment and clearance of the human intracranial space

The mechanisms of intracranial solute transport are fundamental to human brain health, with alterations often linked to disease and functional impairment, and with distinct opportunities for personalized diagnostics and treatment. However, our understanding of these mechanisms and their interplay remains incomplete, in part due to the complexity of integrating insights across scales, between species and from different modalities. Here, we combine mixed-dimensional modelling, multi-modal magnetic resonance images, and high performance computing to construct and explore a high-fidelity in-silico model of human intracranial molecular enrichment. This model predicts the temporo-spatial spreading of a solute within an image-derived geometric representation of the subarachnoid space, ventricular system and brain parenchyma, including networks of surface perivascular spaces (PVSs). Our findings highlight the significant impact of cerebrospinal fluid (CSF) production and intracranial pulsatility on molecular enrichment following intrathecal tracer injection. We demonstrate that low-frequency vasomotion induces moderate CSF flow in surface PVS networks which substantially enhances tracer enrichment, and that impaired enrichment is a direct natural consequence of enlarged PVSs. This openly available technology platform thus provides an opportunity for integrating separate observations on diffusion in neuropil, vascular dynamics, intracranial pulsatility, CSF production, and efflux, and for exploring drug delivery and clearance in the human brain.

neuroscience↗

bioRxiv2024

Sex differences in central amygdala glutamate responses to calcitonin gene-related peptide

Women are disproportionately affected by chronic pain compared to men. While societal and environmental factors contribute to this disparity, sex-based biological differences in the processing of pain are also believed to play significant roles. The central lateral nucleus of the amygdala (CeLC) is a key region for the emotional-affective dimension of pain, and a prime target for exploring sex differences in pain processing since a recent study demonstrated sex differences in CGRP actions in this region. Inputs to CeLC from the parabrachial nucleus (PB) play a causal role in aversive processing, and release both glutamate and calcitonin gene-related peptide (CGRP). CGRP is thought to play a crucial role in chronic pain by potentiating glutamatergic signaling in CeLC. However, it is not known if this CGRP-mediated synaptic plasticity occurs similarly in males and females. Here, we tested the hypothesis that female CeLC neurons experience greater potentiation of glutamatergic signaling than males following endogenous CGRP exposure. Using trains of optical stimuli to evoke transient CGRP release from PB terminals in CeLC, we find that subsequent glutamatergic responses are preferentially potentiated in CeLC neurons from female mice. This potentiation was CGRP-dependent and involved a postsynaptic mechanism. This sex difference in CGRP sensitivity may explain sex differences in affective pain processing. Significance statementThe central lateral nucleus of the amygdala (CeLC) receives a dense projection from parabrachial nucleus (PB) neurons that corelease calcitonin gene-related peptide (CGRP) and glutamate following aversive stimuli. This PBCGRP[->]CeLC projection plays a causal role in chronic pain. We show that endogenous CGRP release potentiates glutamate signaling in female, but not male, CeLC neurons. In the context of previous work in male CeLC, this suggests that that females are more sensitive to even transient CGRP release events. Understanding how this sex difference in CGRP sensitivity arises could enhance strategies for treating chronic pain in both women and men.

neuroscience↗

bioRxiv2023

Elevated serotonin in mouse spinal dorsal horn is pronociceptive

Serotonergic neurons in the rostral ventral medulla (RVM) contribute to bidirectional control of pain through modulation of spinal and trigeminal nociceptive networks. Deficits in this pathway are believed to contribute to pathological pain states, but whether changes in serotonergic mechanisms are pro or anti-nociceptive are debated. We used a combination of optogenetics and fiber photometry to examine these mechanisms more closely. We find that optogenetic activation of RVM serotonergic afferents in the spinal cord of naive mice produces mechanical hypersensitivity and conditioned place aversion. Neuropathic pain, produced by chronic constriction injury of the infraorbital nerve (CCI-ION), evoked a tonic increase in serotonin concentrations within the spinal trigeminal nucleus caudalis (SpVc), measured with liquid chromatography-tandem mass spectroscopy (LC-MS/MS). By contract, CCI-ION had no effect on the phasic serotonin transients in SpVc, evoked by noxious pinch, and measured with fiber photometry of a serotonin sensor. These findings suggest that serotonin release in the spinal cord is pronociceptive and that an increase is sustained serotonin signaling, rather than phasic or event driven increases, potentiate nociception in models of chronic pain. Significance StatementSerotonergic neurons of the rostral ventral medulla participate in descending pain modulation by regulating spinal and trigeminal nociceptive circuits. Whether changes in serotonergic mechanisms are pro or anti-nociceptive is debated. We show that serotonin release within the spinal trigeminal nucleus is pronociceptive and that enhanced tonic, but not phasic serotonin release may contribute to sensitization in mouse models of chronic pain. These results further clarify the role of serotonin in nociception and suggest that local inhibition of serotonin release or increase of uptake may be a viable therapeutic approach in treating chronic pain.

neuroscience↗

bioRxiv2023

Sex differences in the role of parabrachial in nociception and pain in awake mice

The parabrachial nuclear complex (PBN) is a nexus for aversion, and for the sensory and affective components of pain perception. We have previously shown that, during chronic pain, PBN neurons in anesthetized rodents have amplified activity. We report a method to record from PBN neurons of behaving, head-restrained mice, while applying reproducible noxious stimuli. We find that both spontaneous and evoked activity are higher in awake animals, compared to urethane anesthetized mice. Fiber photometry of calcium responses from CGRP-expressing PBN neurons demonstrates that these neurons respond to nociceptive stimuli. In both males and females with neuropathic or inflammatory pain, responses of PBN neurons remain amplified for at least 5 weeks, in parallel with increased pain metrics. We also show that PBN neurons can be rapidly conditioned to respond to innocuous stimuli, after pairing with nociceptive stimuli. Finally, we demonstrate that changes in PBN neuronal activity are correlated with changes in arousal, measured as changes in pupil diameter. Significance StatementThe parabrachial complex is a nexus of aversion, including pain. We report a method to record from parabrachial nucleus neurons of behaving mice, while applying reproducible noxious stimuli. This allowed, for the first time, tracking the activity of these neurons over time in animals with neuropathic or inflammatory pain. It also allowed us to show that the activity of these neurons correlates with arousal states, and that these neurons can be conditioned to respond to innocuous stimuli.

neuroscience↗

bioRxiv2022

Noradrenergic input from nucleus of the solitary tract regulates parabrachial activity in mice

The parabrachial complex (PB) is critically involved in aversive processes, and chronic pain is associated with amplified activity of PB neurons in rodent models of neuropathic pain. Here we demonstrate that catecholaminergic input from the caudal nucleus of the solitary tract (cNTScat)--a stress responsive region that integrates intero- and exteroceptive signals--causes amplification of PB activity and their sensory afferents. We used a virally mediated expression of a norepinephrine (NE) sensor, NE2h, fiber photometry, and extracellular recordings in anesthetized mice to show that noxious mechanical and thermal stimuli activate cNTS neurons. These stimuli also produce prolonged NE transients in PB that far outlast the noxious stimuli. Similar NE transients can be evoked by focal electrical stimulation of cNTS, a region that contains the noradrenergic A2 cell group that projects densely upon PB. In vitro, optical stimulation of cNTScat terminals depolarized PB neurons and caused a prolonged increase the frequency of excitatory synaptic activity. A dual opsin approach showed that sensory afferents from the caudal spinal trigeminal nucleus are potentiated by cNTScat terminal activation. This potentiation was coupled with a decrease in the paired pulse ratio, consistent with an cNTScat - mediated increase in the probability of release at SpVc synapses. Together, these data suggest that A2 neurons of the cNTS generate long lasting NE transients in PB which increase excitability and potentiate responses of PB neurons to sensory inputs. These reveal a mechanism through which stressors from multiple modalities may potentiate the aversiveness of nociceptive stimuli. Significance StatementIncreased excitability of the parabrachial nucleus (PB), a key integrative hub for aversive stimuli, is linked to amplified pain behaviors. We show that prolonged norepinephrine (NE) transients in PB following noxious stimulation in mice. These NE transients potentiate sensory input to PB and arise, at least in part, from catecholaminergic projections from the caudal nucleus of the solitary tract (cNTScat). We propose that activity this cNTScat to PB pathway may potentiate the aversiveness of pain.

neuroscience↗

bioRxiv2020

Parabrachial complex processes dura inputs through a direct trigeminal ganglion-to-parabrachial connection

Migraines cause significant disability and contribute heavily to healthcare costs. Irritation of the meninges outermost layer (the dura mater), and trigeminal ganglion activation contribute to migraine initiation. Maladaptive changes in central pain-processing regions are also important in maintaining pain. The parabrachial complex (PB) is a central region that mediates chronic pain. PB receives diverse sensory information, including a direct input from the trigeminal ganglion. We hypothesized that PB processes inputs from the dura. Using in vivo electrophysiology recordings from single units in anesthetized rats we identified 58 neurons in lateral PB that respond reliably and with short latency to electrical dura stimulation. After injecting tracer into PB, anatomical examination reveals retrogradely labeled cell bodies in the trigeminal ganglion. Neuroanatomical tract-tracing revealed a population of neurons in the trigeminal ganglion that innervate the dura and project directly to PB. These findings indicate that PB is strategically placed to process dura inputs, and suggest that it is directly involved in the pathogenesis of migraine headaches.

neuroscience↗

bioRxiv2020

Improved reference genome of the arboviral vector Aedes albopictus

The Asian tiger mosquito Aedes albopictus is globally expanding and has become the main vector for human arboviruses in Europe. Here we present AalbF2, a dramatically improved assembly of the Ae. albopictus genome that has revealed widespread viral insertions, novel microRNAs and piRNA clusters, the sex determining locus, new immunity genes, and has enabled genome-wide studies of geographically diverse Ae. albopictus populations and analyses of the developmental and stage-dependent network of expression data. Additionally, we built the first physical map for this species with 75% of the assembled genome anchored to the chromosomes. These up-to-date resources of the genome provide a foundation to improve understanding of the adaptation potential and the epidemiological relevance of this species and foster the development of innovative control measures. One Sentence SummaryLong-read and Hi-C-based de novo assembly of the arboviral vector Aedes albopictus genome fosters deeper understanding of its biological features.

genomics↗

bioRxiv2020

An amygdalo-parabrachial pathway regulates pain perception and chronic pain

The parabrachial (PB) complex mediates both ascending nociceptive signaling and descending pain modulatory information in the affective/emotional pain pathway. We have recently reported that chronic pain is associated with amplified activity of PB neurons in a rat model of neuropathic pain. Here we demonstrate that similar activity amplification occurs in mice, and that this is related to suppressed inhibition to PB neurons from the central nucleus of the amygdala (CeA). Animals with pain after chronic constriction injury of the infraorbital nerve (CCI-Pain) displayed higher spontaneous and evoked activity in PB neurons, and a dramatic increase in after-discharges--responses that far outlast the stimulus--compared to controls. PB neurons in CCI-Pain animals showed a reduction in inhibitory, GABAergic inputs. We show that--in both rats and mice--PB contains few GABAergic neurons, and that most of its GABAergic inputs arise from CeA. These CeA GABA neurons express dynorphin, somatostatin and/or corticotropin releasing hormone. We find that the efficacy of this CeA-LPB pathway is suppressed in chronic pain. Further, optogenetically stimulating this pathway suppresses acute pain, and inhibiting it, in naive animals, evokes pain behaviors. These findings demonstrate that the CeA-LPB pathway is critically involved in pain regulation, and in the pathogenesis of chronic pain. Significance StatementWe describe a novel pathway, consisting of inhibition by dynorphin, somatostatin and corticotropin-releasing hormone expressing neurons in the central nucleus of the amygdala that project to the parabrachial nucleus (PB). We show that this pathway regulates the activity of pain-related neurons in PB, and that, in chronic pain, this inhibitory pathway is suppressed, and that this suppression is causally related to pain perception. We propose that this amygdalo-parabrachial pathway is a key regulator of both chronic and acute pain, and a novel target for pain relief.

neuroscience↗