Biology subjects

Reisert, J.

Publications and source records attributed to Reisert, J..

7 recordsLinked to original sources

bioRxiv2025

Neurodegeneration in the olfactory system in Niemann Pick type C1 disease

Niemann-Pick type C1 (NPC1) disease is a rare neurodegenerative disorder linked to defective cholesterol biosynthesis and altered lipid regulation. In patients, the most common variant in the Npc1 gene is a missense mutation that leads to a misfolded and non-functional NPC1 protein. We used a mouse model carrying this mutation (I1061T, Npc1tm(I1061T)Dso) to investigate the olfactory system since olfaction is often negatively impacted in many neurodegenerative disorders, with olfactory decline frequently preceding other neurodegenerative symptoms. We characterized cell types in the olfactory epithelium (OE) in wild-type, heterozygous, and homozygous Npc1tm(I1061T)Dso mice to analyze neurodegeneration at two time points, namely 36 and 60 days after birth. In homozygous Npc1tm(I1061T)Dso mice the density of olfactory sensory neurons (OSNs) at 36 days after birth is decreased compared to wild type and heterozygous mice while the density of immature OSNs and the stem cell niche seems to not be affected. In the OE of the homozygous Npc1tm(I1061T)Dso mice we found an increased density of apoptotic cells and clear sign of neuroinflammation in macrophage/microglia infiltrating the OE. We analyzed the lipid profile of OE by positive MALDI-TOF and found increased markers of neuroinflammation homozygous Npc1tm(I1061T)Dso mice. These structural changes affected the functionality of the OE since we found reduced odorant responses in Npc1tm(I1061T)Dso mice compared to wild type. Additionally, our olfactory behavioral tests revealed deficits in odor-guided food-seeking tests in Npc1tm(I1061T)Dso but not in the wild type and heterozygous mice. We also analyzed the olfactory abilities of a family of three with the parents carrying two different mutations of the Npc1 gene, with the child carrying both mutations and being diagnosed with NPC1 disease. Using the Sniffin Sticks olfactory test, we found that all three were hyposmic with the child having severe hyposmia. Our work extensively characterized the OE structurally and functionally proposing it as a sentinel to monitor disease progression. We are the first to show that NPC1 patients are affected by severe hyposmia and that heterozygous parents could be monitored for olfactory abilities since it could be a biomarker for future neurological disorders.

neuroscience↗

bioRxiv2024

The Ca2+-activated Cl- channel TMEM16B shapes the response time course of olfactory sensory neurons

Mammalian olfactory sensory neurons (OSNs) generate an odorant-induced response by sequentially activating two ion channels, which are in their ciliary membranes. First, a cationic, Ca2+-permeable cyclic nucleotide-gated channel is opened following odorant stimulation via a G protein-coupled transduction cascade and an ensuing raise in cAMP. Second, the increase in ciliary Ca2+ opens the excitatory Ca2+-activated Cl- channel TMEM16B that carries most of the odorant-induced receptor current. While the role of TMEM16B in amplifying the response has been well established, it is less understood how this secondary ion channel contributes to response kinetics and action potential generation during single as well as repeated stimulation and, on the other hand, which response properties the CNG channel determines. We first demonstrate that basic membrane properties such as input resistance, resting potential and voltage-gated currents remained unchanged in OSNs that lack TMEM16B. The CNG channel predominantly determines the response delay and adaptation during odorant exposure, while the absence of the Cl- channels shortens both the time the response requires to reach its maximum as well as to terminate after odorant stimulation. This faster response termination in Tmem16b knockout OSNs allows them, somewhat counterintuitively, to fire action potentials more reliably when stimulated repeatedly in rapid succession, a phenomenon that occurs both in isolated OSNs as well as in OSNs within epithelial slices. Thus, while the two olfactory ion channels act in concert to generate the overall response, each one controls specific aspects of the odorant-induced response.

physiology↗

bioRxiv2023

Short-term consumption of ultra-processed semi-synthetic diets impairs the sense of smell and brain metabolism in mice

The prevalence of highly-palatable, ultra-processed food in our modern diet has exacerbated obesity rates and contributed to a global health crisis. While accumulating evidence suggests that chronic consumption of ultra-processed semi-synthetic food is detrimental to sensory and neural physiology, it is unclear whether its short-term intake has adverse effects. Here, we assessed how short-term consumption (<2 months) of three ultra-processed diets (one grain-based diet, and two semi-synthetic) influence olfaction and brain metabolism in mice. Our results demonstrate that short-term consumption of semi-synthetic diets, regardless of macronutrient composition, adversely affect odor-guided behaviors, physiological responses to odorants, transcriptional profiles in the olfactory mucosa and brain regions, and brain glucose metabolism and mitochondrial respiration. These findings reveal that even short periods of ultra-processed semi-synthetic food consumption are sufficient to cause early olfactory and brain abnormalities, which has the potential to alter food choices and influence the risk of developing metabolic disease.

neuroscience↗

bioRxiv2023

Quantifying peripheral modulation of olfaction by trigeminal agonists

In the mammalian nose, two chemosensory systems, the trigeminal and the olfactory mediate the detection of volatile chemicals. Most odorants in fact are able to activate the trigeminal system, and vice versa, most trigeminal agonists activate the olfactory system as well. Although these two systems constitute two separate sensory modalities, trigeminal activation modulates the neural representation of an odor. The mechanisms behind the modulation of olfactory response by trigeminal activation are still poorly understood. In this study, we addressed this question by looking at the olfactory epithelium, where olfactory sensory neurons and trigeminal sensory fibers co-localize and where the olfactory signal is generated. We characterize the trigeminal activation in response to five different odorants by measuring intracellular Ca2+ changes from primary cultures of trigeminal neurons (TGNs). We also measured responses from mice lacking TRPA1 and TRPV1 channels known to mediate some trigeminal responses. Next, we tested how trigeminal activation affects the olfactory response in the olfactory epithelium using electro-olfactogram (EOG) recordings from WT and TRPA1/V1-KO mice. The trigeminal modulation of the olfactory response was determined by measuring responses to the odorant, 2-phenylethanol (PEA), an odorant with little trigeminal potency after stimulation with a trigeminal agonist. Trigeminal agonists induced a decrease in the EOG response to PEA, which depended on the level of TRPA1 and TRPV1 activation induced by the trigeminal agonist. This suggests that trigeminal activation can alter odorant responses even at the earliest stage of the olfactory sensory transduction. Significance StatementMost odorants reaching the olfactory epithelium can simultaneously activate olfactory and trigeminal systems. Although these two systems constitute two separate sensory modalities, trigeminal activation can alter odor perception. Here, we analyzed the trigeminal activity induced by different odorants proposing an objective quantification of their trigeminal potency independent from human perception. We show that trigeminal activation by odorants reduces the olfactory response in the olfactory epithelium and that such modulation correlates with the trigeminal potency of the trigeminal agonist. These results show that the trigeminal system impacts the olfactory response from its earliest stage.

neuroscience↗

bioRxiv2021

The anatomical logic of smell

The sense of smell helps us navigate the environment, but its molecular architecture and underlying logic remain unknown. The spatial location of odorant receptor genes (Olfrs) in the nose is widely thought to be independent of the structural diversity of the odorants they detect. Using spatial transcriptomics, we created a genome-wide 3D atlas of the mouse olfactory mucosa (OM). Topographic maps of genes differentially expressed in space reveal that both Olfrs and non-Olfrs are distributed in a continuous and overlapping fashion over five broad zones in the OM. The spatial locations of Olfrs correlate with the mucus solubility of the odorants they recognize, providing direct evidence for the chromatographic theory of olfaction. This resource resolved the molecular architecture of the mouse OM, and will inform future studies on mechanisms underlying Olfr gene choice, axonal pathfinding, patterning of the nervous system, and basic logic for the peripheral representation of smell.

neuroscience↗

bioRxiv2021

Insulin-dependent maturation of newly generated olfactory sensory neurons after injury

Loss of olfactory sensory neurons (OSNs) after injury to the olfactory epithelium (OE) triggers the generation of OSNs that are incorporated into olfactory circuits to restore olfactory sensory perception. This study addresses how insulin receptor-mediated signaling affects the functional recovery of OSNs after OE injury. Insulin levels were reduced in mice by ablating the pancreatic beta cells via streptozotocin injections. These streptozotocin-induced diabetic and control mice were then intraperitoneally injected with the olfactotoxic drug methimazole to selectively ablate OSNs. The OE of diabetic and control mice regenerated similarly until day 14 after injury. Thereafter, the OE of diabetic mice contained fewer mature and more apoptotic OSNs than control mice. Functionally, diabetic mice showed reduced electro-olfactogram responses and their olfactory bulbs had fewer c-Fos-active cells following odor stimulation, as well as performed worse in an odor-guided task compared to control mice. Insulin administered intranasally during day 8 to 13 after injury was sufficient to rescue recovery of OSNs in diabetic mice compared to control levels, while insulin administration between days 1 - 6 did not. During this critical time window on day 8 - 13 after injury, insulin receptors are highly expressed and intranasal application of insulin receptor antagonist inhibits regeneration. Furthermore, an insulin-enriched environment could facilitate regeneration even in non-diabetic mice. These results indicate that insulin facilitates the regeneration of OSNs after injury and suggest a critical stage during recovery (8 - 13 days after injury) during which the maturation of newly generated OSNs is highly dependent on and promoted by insulin. Significance StatementAlthough insulin receptor signaling is known to influence on cellular processes such as proliferation and apoptosis, it is poorly understood whether the insulin influences the regeneration of olfactory sensory neurons (OSNs) after injury. We compared the maturation processes of new OSNs after the methimazole-induced loss of pre-existing OSNs between diabetic and control mice. The results show that the regeneration of new OSNs depend on sufficient insulin levels during a specific temporal window, when insulin receptor expression is highly upregulated. Furthermore, an insulin-enriched environment via nasal insulin application during the critical period facilitates OSNs regeneration even in non-diabetic mice. The present results have implications for intranasal application of insulin as potential clinical therapeutics to facilitate OSNs regeneration after the injury.

neuroscience↗

bioRxiv2018

The Ca2+-activated Cl- current ensures robust and reliable signal amplification in vertebrate olfactory receptor neurons

Activation of most primary sensory neurons results in transduction currents that are carried by cations. One notable exception is the vertebrate olfactory receptor neuron (ORN), where the transduction current is carried largely by the anion Cl-. However, it remains unclear why ORNs use an anionic current for signal amplification. We have sought to provide clarification on this topic by studying the so far neglected dynamics of Na+, Ca2+, K+ and Cl- in the small space of olfactory cilia during an odorant response. Using computational modeling and simulations we compared the outcomes of signal amplification based on either Cl- or Na+ currents. We found that amplification produced by Na+ influx instead of a Cl- efflux is problematic due to several reasons: First, the Na+ current amplitude varies greatly depending on mucosal ion concentration changes. Second, a Na+ current leads to a large increase in the ciliary Na+ concentration during an odorant response. This increase inhibits and even reverses Ca2+ clearance by Na+/Ca2+/K+ exchange, which is essential for response termination. Finally, a Na+ current increases the ciliary osmotic pressure, which could cause swelling to damage the cilia. By contrast, a transduction pathway based on Cl- efflux circumvents these problems and renders the odorant response robust and reliable.

neuroscience↗