Biology subjects

Luebke, A. E.

Publications and source records attributed to Luebke, A. E..

10 recordsLinked to original sources

bioRxiv2024

Loss of Calcitonin gene-related Related Receptor component protein (RCP) in nervous system can bias gepant antagonism

We examined calcitonin gene-related peptide (CGRP)s effects on behavioral surrogates for motion-induced nausea and static imbalance in the nestinRCP (-/-), a novel mouse model that loses expression of receptor component protein (RCP) in the nervous system after tamoxifen induction. The assays used were the motion-induced thermoregulation and center of pressure (CoP) assays. Findings suggest CGRPs affects behavioral measures in the nestinRCP (-/-) similarly to littermate controls, since CGRP was observed to increase female sway and diminishes tail vasodilations to provocative motion in both sexes. However, the CGRP-receptor antagonist olcegepant did not antagonize CGRPs effects in the nestinRCP (-/-), whereas it was effective in littermate controls. Findings suggest RCP loss may change the sensitivity of the CGRP receptor and affect the efficacy of receptor antagonists. Significance StatementResearch in calcitonin gene-related peptide (CGRP) has primarily focused on ligand- receptor interactions at the calcitonin-like receptor (CLR) and receptor activity-modifying unit 1 (RAMP1) subunits. However, the role of receptor component protein (RCP), which mediates signaling via the G-stimulatory pathway, is less understood. A novel tamoxifen-inducible mouse model, nestinRCP (-/-), was generated to study loss of RCP in CGRP signaling in the nervous system, and behavioral changes to motion-induced nausea and postural sway were studied after systemic injections of CGRP or CGRP co-delivered with migraine drugs. Findings from this study suggest the loss of CGRP-RCP can bias "gepant" antagonists like olcegepant, and may promote development of therapies to inhibit the RCP-CLR interactions.

neuroscience↗

bioRxiv2024

Systemic CGRP and PACAP-38's Effects on Motion-Induced Nausea and Balance Behaviors in C57BL/6J Mice: A Comparison

Pituitary adenylate-cyclase-activating polypeptide (PACAP), particularly its dominant isoform PACAP-38, is implicated in migraine and represents a promising therapeutic target. We investigated if intraperitoneally delivered (IP) PACAP-38 impacts motion-induced nausea, postural sway, and imbalance in C57BL/6J wildtype mice using the motion-induced thermoregulation, center of pressure (CoP), rotarod, and balance beam assays. We also assessed systemic Calcitonin Gene-Related Peptides (CGRP) effects on these behaviors in parallel. Our findings indicate that IP PACAP-38 significantly disrupts motion-induced thermoregulation in mice, with notable blunting of tail vasodilation responses in both sexes. Additionally, PACAP-38 administration increased postural sway in female mice only and caused balance beam imbalances. Contrary to IP CGRP, IP PACAP-38 did not affect rotarod performance when mice were trained on a dowel with 1.5 cm radius. Our findings provide preclinical evidence supporting a potential role of PACAP-38 in vestibular migraine pathophysiology. Future research will explore if PACAP antagonism can protect against PACAP-38s effects on nausea and balance behaviors, relevant to treatment of vestibular migraine (VM), especially for patients unresponsive to triptans or CGRP-targeting therapies.

neuroscience↗

bioRxiv2024

Musical training does not enhance neural sound encoding at early stages of the auditory system: A large-scale multisite investigation

Musical training has been associated with enhanced neural processing of sounds, as measured via the frequency following response (FFR), implying the potential for human subcortical neural plasticity. We conducted a large-scale multi-site preregistered study (n > 260) to replicate and extend the findings underpinning this important relationship. We failed to replicate any of the major findings published previously in smaller studies. Musical training was related neither to enhanced spectral encoding strength of a speech stimulus (/da/) in babble nor to a stronger neural-stimulus correlation. Similarly, the strength of neural tracking of a speech sound with a time-varying pitch was not related to either years of musical training or age of onset of musical training. Our findings provide no evidence for plasticity of early auditory responses based on musical training and exposure.

neuroscience↗

bioRxiv2023

Human RAMP1-overexpressing mice are resistant to migraine therapies for motion sensitivity: a mouse model of vestibular migraine

Both enhanced motion-induced nausea and increased static imbalance are observed symptoms in migraine and especially vestibular migraine (VM). Motion-induced nausea and static imbalance were investigated in a mouse model, nestin/hRAMP1, expressing elevated levels of human RAMP1 which enhances CGRP signaling in the nervous system, and compared to non-affected littermate controls. Behavioral surrogates such as the motion- induced thermoregulation and postural sway center of pressure (CoP) assays were used to assess motion sensitivity. Nausea readouts revealed that the nestin/hRAMP1 mouse exhibit an increased sensitivity to CGRPs effects at lower doses compared to unaffected controls. In addition, the nestin/hRAMP1 mice exhibit a higher dynamic range in postural sway than their wildtype counterparts, along with increased sway observed in nestin/hRAMP1 male mice that was not present in male unaffected controls. Results from migraine blocker experiments were challenging to interpret, but the data suggests that olcegepant is incapable of reversing CGRP-induced or endogenous alterations in the nestin/hRAMP1 mice, while rizatriptan was ineffective in both the nestin/hRAMP1 and control mice. The results indicate that overexpression of hRAMP1 leads to heightened endogenous CGRP signaling. Results also suggest that both olcegepant and rizatriptan are ineffective in reducing nausea and sway in this hypersensitive CGRP mouse model. This study suggests that the hypersensitive nestin/hRAMP1 mouse may serve as a model for difficult to treat cases of migraine that exhibit increased motion sensitivity.

neuroscience↗

bioRxiv2023

SARS-CoV-2 induces acute neurological signs while Calcitonin Gene-Related Peptide (CGRP) signaling blockade reduces interleukin 6 (IL-6) release and weight loss in mouse models

COVID-19 can result in neurological symptoms such as fever, headache, dizziness, and nausea. However, neurological signs of SARS-CoV-2 infection have been hardly assessed in mouse models. Here, we infected two commonly used wildtype mice lines (C57BL/6 and 129S) with mouse-adapted SARS-CoV-2 and demonstrated neurological signs including motion- related dizziness. We then evaluated whether the Calcitonin Gene-Related Peptide (CGRP) receptor antagonist, olcegepant, used in migraine treatment could mitigate acute neuroinflammatory and neurological responses to SARS-COV-2 infection. We infected wildtype C57BL/6J and 129/SvEv mice, and a 129 CGRP-null mouse line with a mouse-adapted SARS- CoV-2 virus, and evaluated the effect of CGRP receptor antagonism on the outcome of that infection. First, we determined that CGRP receptor antagonism provided protection from permanent weight loss in older (>12 m) C57BL/6J and 129 SvEv mice. We also observed acute fever and motion-induced dizziness in all older mice, regardless of treatment. However, in both wildtype mouse lines, CGRP antagonism reduced acute interleukin 6 (IL-6) levels by half, with virtually no IL-6 release in mice lacking CGRP. These findings suggest that migraine inhibitors such as those blocking CGRP signaling protect against acute IL-6 release and subsequent inflammatory events after SARS-CoV-2 infection, which may have repercussions for related pandemic and/or endemic coronaviruses. ImportanceCOVID-19 can cause neurological symptoms such as fever, headache, dizziness, and nausea. However, such neurological symptoms of SARS-CoV-2 infection have been hardly assessed in mouse models. Here, we first infected two commonly used wildtype mice lines (C57BL/6 and 129S) with mouse-adapted SARS-CoV-2 and demonstrated neurological signs including motion-related dizziness. Further, we showed that migraine treatment drug olcegepant could reduce long-term weight loss and IL-6 release associated with SARS-CoV-2 infection. These findings suggest that a migraine blocker can be protective for at least some acute SARS-CoV-2 infection signs and raise the possibility that it may also impact long-term outcomes of infection.

neuroscience↗

bioRxiv2023

Both systemic Calcitonin Gene Related Peptide (CGRP) and a vestibular challenge promote anxiety-related behaviors and dynamic imbalance in mice

Motion-induced anxiety and agoraphobia are more frequent symptoms in patients with vestibular migraine than migraine without vertigo. The neuropeptide calcitonin gene-related peptide (CGRP) is a therapeutic target for migraine and vestibular migraine, but the link between motion hypersensitivity, anxiety, and CGRP is relatively unexplored, especially in preclinical mouse models. To further examine this link, we tested the effects of systemic CGRP and off-vertical axis rotation (OVAR) on elevated plus maze (EPM) and rotarod performance in male and female C57BL/6J mice. Rotarod ability was assessed using two different dowel diameters: mouse dowel (r = 1.5 cm) versus rat dowel (r = 3.5 cm). EPM results indicate CGRP increased anxiety indexes and time spent in the closed arms in females but not males, while OVAR increased anxiety indexes and time spent in the closed arms in both sexes. The combination of CGRP and OVAR elicited even greater anxiety-like behavior. On the rotarod, CGRP reduced performance in both sexes on a mouse dowel but had no effect on a rat dowel, whereas OVAR had a significant effect on the rat dowel. Rotarod performance is influenced by dowel diameter, with larger dowels presenting greater challenges on balance function. These results suggest that both CGRP and vestibular stimulation induce anxiety-like behavior and that CGRP affects dynamic balance function in mice depending on the type of challenge presented. Findings highlight the potential translation of anti-CGRP receptor signaling therapeutics for treating motion hypersensitivity and motion-induced anxiety that manifests in vestibular migraine. Significance statementAnxiety is very common in patients with dizziness and vestibular migraine (VM). Elevated CGRP levels have been linked to migraine symptoms of increased light and touch sensitivity in mice and humans and we wondered if a systemic injection of CGRP into mice would increase anxiety and imbalance; and if mice further exposed to a vestibular stimulus would have their anxiety measures sharpened. We observed a female preponderance in both CGRP and motion-induced anxiety-like behaviors, suggesting that the role of CGRP in migraines anxiety symptoms can be recapitulated in the mouse. Our findings suggest that CGRP signaling has a pertinent role in motion-induced anxiety and dynamic imbalance, and warrants the potential use of anti-CGRP therapies for the treatment of these symptoms.

neuroscience↗

bioRxiv2023

Age-Related Balance Problems in Mice Are Sharpened by the Loss of Calcitonin Gene-Related Peptide (CGRP) and a Vestibular Challenge

Aging impacts the vestibular system and contributes to imbalance. In fact, in the elderly balance deficits often precede changes in cognition. However, imbalance research is limited in assessing aging mouse models that are deficient in neuromodulators like Calcitonin Gene-Related Peptide (CGRP). We studied the loss of CGRP and its effects in the aging mouse, namely its effect on both static and dynamic imbalances. In addition, postural sway and rotarod testing were performed before and after a vestibular challenge (VC) in the 129S wildtype and the CGRP (-/-) null mice. Four age groups were tested that correspond to young adulthood, late adulthood, middle age, and senescence in humans. Our results suggest wildtype mice experience a decline in rotarod ability with increased age, while the CGRP (-/-) null mice perform poorly on rotarod early in life and do not improve. Our postural sway study suggests that a vestibular challenge can lead to significantly reduced CoP ellipse areas (freezing behaviors) in older mice, and this change occurs earlier in the CGRP (-/-) null mouse. These results indicate that CGRP is an important component of static and dynamic balance; and that the loss of CGRP can contribute to balance complications that may compound with aging.

neuroscience↗

bioRxiv2022

Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonism Reduces Motion Sickness Indicators in Mouse Models of Vestibular Migraine

Structured AbstractO_ST_ABSBackgroundC_ST_ABSMigraine and especially vestibular migraine are associated with enhanced motion sickness and motion-induced nausea. Murine models of migraine have used injections of Calcitonin Gene-Related Peptide (CGRP) or other migraine triggers [i.e., sodium nitroprusside (SNP)] to induce migraine sensitivities to touch and light. Yet, there is limited research on whether these triggers increase motion-induced nausea, and if migraine blockers can reduce these migraine symptoms. We hypothesized that systemic delivery of CGRP or SNP will increase motion sickness susceptibility and motion-induced nausea in mouse models, and that migraine blockers can block these changes induced by systemically delivered CGRP or SNP. MethodsWe investigated two measures of motion sickness assessment [motion sickness index (MSI) scoring and motion-induced thermoregulation] after intraperitoneal injections of either CGRP or SNP in C57B6/J mice. The drugs olcegepant, sumatriptan, and rizatriptan were used to assess the efficacy of migraine blockers. ResultsMSI measures were confounded by CGRPs effect on gastric distress. However, analysis of tail vasodilations as a surrogate for motion-induced nausea was robust for both migraine triggers. Only olcegepant treatment rescued tail vasodilations. ConclusionThese preclinical findings support the use of small molecule CGRP receptor antagonists for the treatment of motion-induced nausea of migraine, and show that triptan therapeutics are ineffective against motion-induced nausea of migraine.

neuroscience↗

bioRxiv2022

Role of Calcitonin Gene-Related Peptide (CGRP) in Auditory, Static, and Dynamic Imbalance Behaviors: Implications for Vestibular Migraine

Migraine is a severe and chronic neurological disorder that affects [~]18% of people worldwide, the majority being female (3:1). It is characterized by recurrent, debilitating headaches and heightened sensory sensitivities. People with migraine may develop vestibular migraine (VM), characterized by a heightened motion sensitivity and preponderance for spontaneous vertigo attacks and balance problems such as postural instability. Calcitonin gene-related peptide (CGRP) is implicated in migraine and is believed to act on brain meninges or in subcortical central nervous system (CNS) structures, and CGRP-based antagonists have shown efficacy for migraine treatment. CGRP also signals at efferent synapses of the cochlea and vestibular end organs, but it is unclear if exogenous CGRP can modulate inner ear function at the end organ level and cause heightened behavioral responses consistent with VM. We tested if intraperitoneally (IP) delivered CGRP to wildtype mice can modulate end organ potentials to sound [via auditory brainstem responses (ABRs)] and jerk stimuli [via vestibular sensory evoked potentials (VsEPs)]. We also assessed behavioral measures of phonophobia [acoustic startle reflex (ASR)] and static imbalance [postural sway-center of pressure (CoP)] after IP CGRP, and observed female mice exhibited heightened sensitivities to IP CGRP in all assays. Male mice showed similar auditory sensitivity and end organ effects to CGRP, but systemic CGRP did not modify male postural sway as it did in females. In conclusion, we show that intraperitoneally delivered CGRP affects ABRs and VsEPs, and elicits behaviors suggestive of auditory hypersensitivity and postural instability in mice related to the phonophobia and postural instability seen in VM patients. Significance StatementCalcitonin Gene-Related Peptide (CGRP) has been implicated in migraine, and CGRP-based therapeutics have shown efficacy in the treatment of migraine headaches. CGRP is also present in efferent synapses of the inner ear, so we questioned if increases in systemic CGRP can act directly on inner ear end organs and modify corresponding behavioral responses. In this study, we determined systemic CGRP changes cochlear and vestibular end organ potentials and produces migraine behaviors similar to phonophobia and postural control deficits. Peripheral changes in auditory and vestibular compound action potentials following systemic CGRP administration suggest CGRP can act directly on the inner ear, which provides one site of action for CGRPs involvement in hypersensitivity to sound and movement in migraine.

neuroscience↗

bioRxiv2020

Rescuing auditory temporal processing with a novel augmented acoustic environment in an animal model of congenital hearing loss

Congenital sensorineural hearing loss (SNHL) affects thousands of infants each year and results in significant delays in speech and language development. Previous studies have shown that early exposure to a simple augmented acoustic environment (AAE) can limit the effects of progressive SNHL on hearing sensitivity. However, SNHL is also accompanied by "hidden hearing loss" that is not assessed on standard audiological exams, such as reduced temporal processing acuity. To assess whether sound therapy may improve these hidden deficits, a mouse model of congenital SNHL was exposed to simple or temporally complex AAE. Peripheral function and sound sensitivity in auditory midbrain neurons improved following exposure to both types of AAE. However, only exposure to a novel, temporally complex AAE significantly improved a measure of temporal processing acuity, neural gap-in-noise detection in the auditory midbrain. These experiments suggest that targeted sound therapy may improve hearing outcomes for children suffering from congenital SNHL.

neuroscience↗