Biology subjects

Rastoldo, G.

Publications and source records attributed to Rastoldo, G..

5 recordsLinked to original sources

bioRxiv2026

Sex-dependent Aβ RA-Low threshold mechanoreceptors alteration in diabetic conditions

Diabetic peripheral neuropathy (DPN) is a major complication of diabetes that profoundly affects quality of life, yet its cellular mechanisms remain poorly defined. Neuropathic pain and sensory loss in DPN are thought to arise from progressive alterations in peripheral nerves usually described as a glove-stocking distribution, but the specific contribution of sensory neuron subtypes has received little attention. Here, we focused on A{beta} rapidly adapting low-threshold mechanoreceptors (A{beta} RA-LTMRs), a large-diameter sensory neuron subtype best known for mediating touch and vibratory sensation. Using an intersectional genetic approach, we generated AdvillinCre; MafAFlpO; Ai65 mice, allowing us to selectively label MafA-expressing sensory neuronal populations, which we identified as A{beta} RA-LTMRs. We provide the first detailed characterization of how diet-induced type 2 diabetes alters A{beta} RA-LTMRs. After 16 weeks of high-fat diet (HFD), we observed striking sex-dependent effects. Male mice developed impaired glucose tolerance, mechanical hypoalgesia, and thermal hyperalgesia, which correlated with a decrease of A{beta} RA-LTMR central projections in the dorsal horn. By contrast, female mice showed no changes in either their glycemic status or their sensory sensitivity. These findings demonstrate that A{beta} RA-LTMRs are vulnerable to early diabetes-induced alterations in a sex-dependent manner and highlight distinct peripheral versus central mechanisms contributing to sensory dysfunction.

neuroscience↗

bioRxiv2026

High-Frequency Focused Ultrasound targeting the midbrain in the Guinea Pig Induces Activation and Plasticity of the Efferent System, and Protection Against Noise-Induced Hearing Loss

Focused ultrasound (FUS) is a promising noninvasive neuromodulation approach, but whether it can directly activate central auditory neurons in vivo remains unresolved. We applied high-frequency FUS (20 MHz) to the central nucleus of the inferior colliculus (CNIC) in anesthetized guinea pigs while recording electrophysiological responses from the auditory pathway and cochlea. FUS evoked cortical activity through indirect cochlear activation, possibly via skull-mediated mechanical coupling, rather than direct inferior colliculus activation, with ultrasound-evoked compound action potentials predominating in the ipsilateral cochlea. More interestingly, FUS stimulation of the CNIC induced activation of neurons and glial cells in the CNIC and auditory cortex as demonstrated by c-Fos expression, suggesting that FUS stimulation activated the afferent pathway. We also show that FUS engaged the auditory efferent system, likely via medial olivocochlear neurons, producing reduced compound action potential amplitudes, enhanced cochlear microphonics, and persistent effects lasting at least two hours, consistent with long-lasting efferent plasticity. Strikingly, FUS administered before acoustic trauma almost completely prevented noise-induced hearing loss, limiting auditory brainstem response threshold shifts to <10 dB versus ~60 dB in controls. Gentamicin abolished these physiological and protective effects, implicating medial olivocochlear activation. These findings identify FUS as a potent noninvasive strategy for engaging auditory efferent circuits and protecting against acoustic injury.

neuroscience↗

bioRxiv2024

Alteration of nociceptive Schwann cells in a mouse model of peripheral neuropathy in prediabetic condition

Diabetic peripheral neuropathy (DPN) is characterized by progressive and symmetrical sensory abnormalities and constitutes one of the earliest and main complications of diabetes. DPN is characterized by heterogeneous sensory symptoms such as chronic pain, tingling, burning or loss of sensation. Nociceptive Schwann cells (nSCs), a recently identified subtypes of dermal Schwann cells support terminal nerve fibers in mouse skin and contribute to mechanical sensation and neuropathic pain. While terminal nerve fibers density is evaluated in DPN models, there is currently no data about nSCs number and integrity during the early stages of the disease. In the present study, we determined the quantitative differences in terminal nerve fiber density as well as nSCs number and cellular extensions between control and high-fat diet (HFD) induced diabetic mice presenting with a neuropathic phenotype. We also characterized L1CAM as a reliable and specific marker of nSCs, a cell type previously assessed by the expression of S100{beta} and Sox10. Interestingly, we observed a decrease in intraepidermal nerve fiber density (IENFD) associated with a significant reduction of nSCs in the glabrous foot skin of neuropathic mice. Overall, this study identifies L1CAM as a new marker of nSCs and indicates that these cells are impacted in diabetic peripheral neuropathy.

neuroscience↗

bioRxiv2024

PCSK9 deficiency promotes the development of peripheral neuropathy

PCSK9 best-known and studied function is to induce the hepatic degradation of the low-density lipoprotein receptor (LDLR), thereby increasing the concentration of LDL-cholesterol (LDL-C) in the blood. Beyond its effects on LDL, recent studies have reported pleiotropic effects of PCSK9 notably in septic shock, vascular inflammation, viral infection, and cancer. While the functional and structural integrity of peripheral nerves are critically influenced by circulating lipids, the impact of PCSK9 in the peripheral nervous system is unknown. In this study, we investigated the consequences of PCSK9 deficiency on peripheral nerves. We found that PCSK9 deletion in mice leads to peripheral neuropathy characterized by a reduction of thermal and mechanical pain sensations. PCSK9 deficient mice also presented skin structural changes with a reduction of number of terminal nociceptive Schwann cells, Remak fiber axonal swelling, as well as hypomyelination of small nerve fibers. Interestingly, peripheral nerves of PCSK9 deficient mice presented an upregulation of the fatty acid transporter CD36 expression which correlated with an increase in nerve lipid contents and structural mitochondrial abnormalities. Our findings demonstrate that PCSK9 plays a critical role in the peripheral nerves by regulating lipid homeostasis, and its deficiency could lead to the development of symptoms related to peripheral neuropathy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/583154v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1469ef8org.highwire.dtl.DTLVardef@16ebcd9org.highwire.dtl.DTLVardef@1305cbborg.highwire.dtl.DTLVardef@181758_HPS_FORMAT_FIGEXP M_FIG C_FIG PCSK9 modulates nerve energy metabolism and health. Created with BioRender.com.

neuroscience↗

bioRxiv2021

L-Thyroxine improves vestibular compensation in a rat model of acute peripheral vestibulopathy

Unilateral vestibular lesions induce a vestibular syndrome, which recovers over time due to vestibular compensation. The therapeutic effect of L-Thyroxine (L-T4) on vestibular compensation was investigated by behavioral testing and immunohistochemical analysis in a rat model of unilateral vestibular neurectomy (UVN). We demonstrated that an acute L-T4 treatment reduced the vestibular syndrome and significantly promoted vestibular compensation. Thyroid hormone receptors (TR and TR{beta}) and type II iodothyronine deiodinase (DIO2) were present in the vestibular nuclei (VN), supporting a local action of L-T4. We confirmed the T4-induced metabolic effects by demonstrating an increase in the number of cytochrome oxidase-labelled neurons in the VN three days after the lesion. L-T4 treatment modulated glial reaction by decreasing both microglia and oligodendrocytes in the deafferented VN three days after UVN and increased cell proliferation. The survival of newly generated cells was not affected, but neuronal differentiation was altered by the L-T4 treatment.

neuroscience↗