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Redox Biology Nov 2023The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased...
The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the α-ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the affected regions of the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the existing oxidative phosphorylation (OXPHOS) ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.
Topics: Mice; Animals; Humans; Ketoglutarate Dehydrogenase Complex; Citric Acid Cycle; Mitochondria; Mice, Knockout; Oxidative Phosphorylation; Adenosine Triphosphate
PubMed: 37883842
DOI: 10.1016/j.redox.2023.102932 -
IScience Nov 2023The mouse olfactory system regenerates constantly throughout life. While genes critical for the initial projection of olfactory sensory neurons (OSNs) to the olfactory...
The mouse olfactory system regenerates constantly throughout life. While genes critical for the initial projection of olfactory sensory neurons (OSNs) to the olfactory bulb have been identified, what genes are important for maintaining the olfactory map during regeneration are still unknown. Here we show a mutation in (), a cell adhesion molecule and member of the cadherin superfamily, leads to defects in OSN coalescence during regeneration. Surprisingly, lateral glomeruli were more affected and males in particular showed a more severe phenotype. Single cell analysis unexpectedly showed OSNs expressing the MOR28 odorant receptor could be subdivided into two major clusters. We showed that at least one protocadherin is differentially expressed between OSNs coalescing on the medial and lateral glomeruli. Moreover, females expressed a slightly different complement of genes from males. These features may explain the differential effects of mutating on medial and lateral glomeruli in males and females.
PubMed: 37965156
DOI: 10.1016/j.isci.2023.108220 -
Nature Communications Aug 2023Olfactory cues are vital for prey animals like rodents to perceive and evade predators. Stress-induced hyperthermia, via brown adipose tissue (BAT) thermogenesis, boosts...
Olfactory cues are vital for prey animals like rodents to perceive and evade predators. Stress-induced hyperthermia, via brown adipose tissue (BAT) thermogenesis, boosts physical performance and facilitates escape. However, many aspects of this response, including thermogenic control and sex-specific effects, remain enigmatic. Our study unveils that the predator odor trimethylthiazoline (TMT) elicits BAT thermogenesis, suppresses feeding, and drives glucocorticoid release in female mice. Chemogenetic stimulation of olfactory bulb (OB) mitral cells recapitulates the thermogenic output of this response and associated stress hormone corticosterone release in female mice. Neuronal projections from OB to medial amygdala (MeA) and dorsomedial hypothalamus (DMH) exhibit female-specific cFos activity toward odors. Cell sorting and single-cell RNA-sequencing of DMH identify cholecystokinin (CCK)-expressing neurons as recipients of predator odor cues. Chemogenetic manipulation and neuronal silencing of DMH neurons further implicate these neurons in the propagation of predator odor-associated thermogenesis and food intake suppression, highlighting their role in female stress-induced hyperthermia.
Topics: Male; Mice; Female; Animals; Smell; Cholecystokinin; Thermogenesis; Neurons; Hypothalamus
PubMed: 37582805
DOI: 10.1038/s41467-023-40484-7 -
The Journal of Neuroscience : the... Nov 2023Fragile X syndrome (FXS) is the single most common monogenetic cause of autism spectrum disorders (ASDs) in humans. FXS is caused by loss of expression of the fragile X...
Fragile X syndrome (FXS) is the single most common monogenetic cause of autism spectrum disorders (ASDs) in humans. FXS is caused by loss of expression of the fragile X mental retardation protein (FMRP), an mRNA-binding protein encoded on the X chromosome involved in suppressing protein translation. Sensory processing deficits have been a major focus of studies of FXS in both humans and rodent models of FXS, but olfactory deficits remain poorly understood. Here, we conducted experiments in wild-type (WT) and knock-out (KO; ) mice (males) that lack expression of the gene encoding FMRP to assess olfactory circuit and behavioral abnormalities. In patch-clamp recordings conducted in slices of the olfactory bulb, output mitral cells (MCs) in KO mice displayed greatly enhanced excitation under baseline conditions, as evidenced by a much higher rate of occurrence of spontaneous network-level events known as long-lasting depolarizations (LLDs). The higher probability of spontaneous LLDs (sLLDs), which appeared to be because of a decrease in GABAergic synaptic inhibition in glomeruli leading to more feedforward excitation, caused a reduction in the reliability of stimulation-evoked responses in MCs. In addition, in a go/no-go operant discrimination paradigm, we found that KO mice displayed impaired discrimination of odors in difficult tasks that involved odor mixtures but not altered discrimination of monomolecular odors. We suggest that the KO-induced reduction in MC response reliability is one plausible mechanism for the impaired fine odor discrimination. Fragile X syndrome (FXS) in humans is associated with a range of debilitating deficits including aberrant sensory processing. One sensory system that has received comparatively little attention in studies in animal models of FXS is olfaction. Here, we report the first comprehensive physiological analysis of circuit defects in the olfactory bulb in the commonly-used knock-out (KO) mouse model of FXS. Our studies indicate that KO alters the local excitation/inhibition balance in the bulb, similar to what KO does in other brain circuits, but through a novel mechanism that involves enhanced feedforward excitation. Furthermore, KO mice display behavioral impairments in fine odor discrimination, an effect that may be explained by changes in neural response reliability.
Topics: Humans; Male; Animals; Mice; Olfactory Bulb; Fragile X Syndrome; Mice, Knockout; Odorants; Reproducibility of Results; Fragile X Mental Retardation Protein; Disease Models, Animal
PubMed: 37788940
DOI: 10.1523/JNEUROSCI.0584-23.2023 -
Acta Physiologica (Oxford, England) Sep 2023General anesthesia can induce cognitive deficits in both humans and rodents, correlating with pathological alterations in the hippocampus. However, whether general...
AIM
General anesthesia can induce cognitive deficits in both humans and rodents, correlating with pathological alterations in the hippocampus. However, whether general anesthesia affects olfactory behaviors remains controversial as clinical studies have produced inconsistent results. Therefore, we aimed to investigate how olfactory behaviors and neuronal activity are affected by isoflurane exposure in adult mice.
METHODS
The olfactory detection test, olfactory sensitivity test, and olfactory preference/avoidance test were used to examine olfactory function. In vivo electrophysiology was performed in awake, head-fixed mice to record single-unit spiking and local field potentials in the olfactory bulb (OB). We also performed patch-clamp recordings of mitral cell activity. For morphological studies, immunofluorescence and Golgi-Cox staining were applied.
RESULTS
Repeated exposure to isoflurane impaired olfactory detection in adult mice. The main olfactory epithelium, the first region exposed to anesthetics, displayed increased proliferation of basal stem cells. In the OB, a crucial hub for olfactory processing, repeated isoflurane exposure increased the odor responses of mitral/tufted cells. Furthermore, the odor-evoked high gamma response was decreased after isoflurane exposure. Whole-cell recordings further indicated that repeated isoflurane exposure increased the excitability of mitral cells, which may be due to weakened inhibitory input in isoflurane-exposed mice. In addition, elevated astrocyte activation and glutamate transporter-1 expression in the OB were observed in isoflurane-exposed mice.
CONCLUSIONS
Our findings indicate that repeated isoflurane exposure impairs olfactory detection by increasing neuronal activity in the OB in adult mice.
Topics: Humans; Mice; Animals; Smell; Olfactory Bulb; Isoflurane; Neurons; Odorants
PubMed: 37330999
DOI: 10.1111/apha.14009 -
Scientific Data Sep 2023Axolotl (Ambystoma mexicanum) is an excellent model for investigating regeneration, the interaction between regenerative and developmental processes, comparative...
Axolotl (Ambystoma mexicanum) is an excellent model for investigating regeneration, the interaction between regenerative and developmental processes, comparative genomics, and evolution. The brain, which serves as the material basis of consciousness, learning, memory, and behavior, is the most complex and advanced organ in axolotl. The modulation of transcription factors is a crucial aspect in determining the function of diverse regions within the brain. There is, however, no comprehensive understanding of the gene regulatory network of axolotl brain regions. Here, we utilized single-cell ATAC sequencing to generate the chromatin accessibility landscapes of 81,199 cells from the olfactory bulb, telencephalon, diencephalon and mesencephalon, hypothalamus and pituitary, and the rhombencephalon. Based on these data, we identified key transcription factors specific to distinct cell types and compared cell type functions across brain regions. Our results provide a foundation for comprehensive analysis of gene regulatory programs, which are valuable for future studies of axolotl brain development, regeneration, and evolution, as well as on the mechanisms underlying cell-type diversity in vertebrate brains.
Topics: Animals; Ambystoma mexicanum; Ascomycota; Brain; Chromatin; Learning; Mesencephalon; Single-Cell Gene Expression Analysis
PubMed: 37709774
DOI: 10.1038/s41597-023-02533-0 -
Brain, Behavior, and Immunity Nov 2023Approximately 20-68% of traumatic brain injury (TBI) patients exhibit trauma-associated olfactory deficits (OD) which can compromise not only the quality of life but...
Approximately 20-68% of traumatic brain injury (TBI) patients exhibit trauma-associated olfactory deficits (OD) which can compromise not only the quality of life but also cognitive and neuropsychiatric functions. However, few studies to date have examined the impact of experimental TBI on OD. The present study examined inflammation and neuronal dysfunction in the olfactory bulb (OB) and the underlying mechanisms associated with OD in male mice using a controlled cortical impact (CCI) model. TBI caused a rapid inflammatory response in the OB as early as 24 h post-injury, including elevated mRNA levels of proinflammatory cytokines, increased numbers of microglia and infiltrating myeloid cells, and increased IL1β and IL6 production in these cells. These changes were sustained for up to 90 days after TBI. Moreover, we observed significant upregulation of the voltage-gated proton channel Hv1 and NOX2 expression levels, which were predominantly localized in microglia/macrophages and accompanied by increased reactive oxygen species production. In vivo OB neuronal firing activities showed early neuronal hyperexcitation and later hypo-neuronal activity in both glomerular layer and mitral cell layer after TBI, which were improved in the absence of Hv1. In a battery of olfactory behavioral tests, WT/TBI mice displayed significant OD. In contrast, neither Hv1 KO/TBI nor NOX2 KO/TBI mice showed robust OD. Finally, seven days of intranasal delivery of a NOX2 inhibitor (NOX2ds-tat) ameliorated post-traumatic OD. Collectively, these findings highlight the importance of OB neuronal networks and its role in TBI-mediated OD. Thus, targeting Hv1/NOX2 may be a potential intervention for improving post-traumatic anosmia.
Topics: Humans; Male; Mice; Animals; Olfactory Bulb; Quality of Life; Brain Injuries, Traumatic; Smell; Microglia; Olfaction Disorders; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37557959
DOI: 10.1016/j.bbi.2023.08.004 -
Nigerian Journal of Physiological... Dec 2023The African giant rat, AGR (Cricetomys gambianus) is a unique rodent known for its keen sense of smell which has enabled its use in the diagnosis of tuberculosis and...
The African giant rat, AGR (Cricetomys gambianus) is a unique rodent known for its keen sense of smell which has enabled its use in the diagnosis of tuberculosis and demining activities in war torn countries. This keen sense of smell and the ability to navigate tight spaces are skills modulated by the olfactory bulb and cerebellum. While the brain is generally susceptible to environmental pollutants such as heavy metals, vanadium has predilection for these two brain regions. This work was thus designed to investigate the probable neurotoxic effect of vanadium on the neuronal cytoarchitecture of the cerebellum and olfactory bulb in this rodent. To achieve this, twelve adults male AGRs were divided into two groups (vanadium and control groups) and were given intraperitoneal injections of 3mg/kg body weight sodium metavanadate and normal saline respectively for 14 days. After which they were sacrificed, and brains harvested for histological investigations using Nissl and Golgi staining techniques. Results from our experiment revealed Purkinje cell degeneration and pyknosis as revealed by a lower intact-pyknotic cell (I-P) ratio, higher pyknotic Purkinje cell density and poor dendritic arborizations in the molecular layer of the cerebellum in the vanadium treated group. In the olfactory bulb, neuronal loss in the glomerular layer was observed as shrunken glomeruli. These neuronal changes have been linked to deficits in motor function and disruption of odor transduction in the olfactory bulb. This work has further demonstrated the neurotoxic effects of vanadium on the cerebellum and olfactory bulb of the AGR and the likely threat it may pose to the translational potentials of this rodent. We therefore propose the use of this rodent as a suitable model for better understanding vanadium induced olfactory and cerebellar dysfunctions.
Topics: Animals; Olfactory Bulb; Male; Vanadium; Cerebellum; Neurotoxicity Syndromes; Rats; Purkinje Cells
PubMed: 38696691
DOI: 10.54548/njps.v38i2.3 -
Frontiers in Neuroscience 2023Alzheimer's disease (AD) is the leading cause of dementia, with over 45 million patients worldwide, and poses significant economic and emotional burdens to both patients... (Review)
Review
Alzheimer's disease (AD) is the leading cause of dementia, with over 45 million patients worldwide, and poses significant economic and emotional burdens to both patients and caregivers, significantly raising the number of those affected. Unfortunately, much of the existing research on the disease only addresses a small subset of associated symptomologies and pathologies. In this review, we propose to target the earliest stages of the disease, when symptomology first arises. In these stages, before the onset of hallmark symptoms of AD such as cognitive impairments and memory loss, circadian and olfactory disruptions arise and are detectable. Functional similarities between circadian and olfactory systems provide a basis upon which to seek out common mechanisms in AD which may target them early on in the disease. Existing studies of interactions between these systems, while intriguing, leave open the question of the neural substrates underlying them. Potential substrates for such interactions are proposed in this review, such as indirect projections that may functionally connect the two systems and dopaminergic signaling. These substrates may have significant implications for mechanisms underlying disruptions to circadian and olfactory function in early stages of AD. In this review, we propose early detection of AD using a combination of circadian and olfactory deficits and subsequent early treatment of these deficits may provide profound benefits to both patients and caregivers. Additionally, we suggest that targeting research toward the intersection of these two systems in AD could uncover mechanisms underlying the broader set of symptoms and pathologies that currently elude researchers.
PubMed: 38094003
DOI: 10.3389/fnins.2023.1295998 -
Parkinsonism & Related Disorders May 2024We recently proposed a new disease model of Parkinson's disease - the a-Synuclein Origin site and Connectome model. The model posits that the initial pathology starts... (Review)
Review
We recently proposed a new disease model of Parkinson's disease - the a-Synuclein Origin site and Connectome model. The model posits that the initial pathology starts either in the olfactory bulb or amygdala leading to a brain-first subtype, or in the enteric nervous system leading to a body-first subtype. These subtypes should be distinguishable early in the disease course on a range of imaging, clinical, and neuropathological markers. Here, we review recent original human studies, which tested the predictions of the model. Molecular imaging studies were generally in agreement with the model, whereas structural imaging studies, such as MRI volumetry, showed conflicting findings. Most large-scale clinical studies were supportive, reporting clustering of relevant markers of the body-first subtype, including REM-sleep behavior disorder, constipation, autonomic dysfunction, neuropsychiatric symptoms, and cognitive impairment. Finally, studies of a-synuclein deposition in antemortem and postmortem tissues revealed distribution of pathology, which generally supports the model.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Brain; Connectome; Enteric Nervous System
PubMed: 38519273
DOI: 10.1016/j.parkreldis.2024.106101