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Neuroscience Jan 2020Kainate receptors (KARs) are glutamate receptors with ionotropic and metabotropic activity composed of the GluK1-GluK5 subunits. We previously reported that KARs...
Kainate receptors (KARs) are glutamate receptors with ionotropic and metabotropic activity composed of the GluK1-GluK5 subunits. We previously reported that KARs modulate excitatory and inhibitory transmission in the olfactory bulb (OB). Zinc, which is highly concentrated in the OB, also appears to modulate OB synaptic transmission via actions at other ionotropic glutamate receptors (i.e., AMPA, NMDA). However, few reports of effects of zinc on recombinant and/or native KARs exist and none have involved the OB. In the present study, we investigated the effects of exogenously applied zinc on OB KARs expressed by mitral/tufted (M/T) cells. We found that 100 µM zinc inhibits currents evoked by various combinations of KAR agonists (kainate or SYM 2081) and the AMPA receptor antagonist SYM 2206. The greatest degree of zinc-mediated inhibition was observed with coapplication of zinc with the GluK1- and GluK2-preferring agonist SYM 2081 plus SYM 2206. This finding is consistent with prior reports of zinc's inhibitory effects on some recombinant (homomeric GluK1 and GluK2 and heteromeric GluK2/GluK4 and GluK2/GluK5) KARs, although potentiation of other (GluK3, GluK2/3) KARs has also been described. It is also of potential importance given our previously reported molecular data suggesting that OB neurons express relatively high levels of GluK1 and GluK2. Our present findings suggest that a physiologically relevant concentration of zinc modulates KARs expressed by M/T cells. As M/T cells are targets of zinc-containing olfactory sensory neurons, synaptically released zinc may influence odor information-encoding synaptic circuits in the OB via actions at KARs.
Topics: Animals; Glutamic Acid; Neurons; Olfactory Bulb; Protein Multimerization; Protein Subunits; Rats, Sprague-Dawley; Receptors, Kainic Acid; Synapses; Synaptic Transmission; Zinc
PubMed: 31874243
DOI: 10.1016/j.neuroscience.2019.11.041 -
Journal of Neurophysiology Oct 2017Synaptic inhibition critically influences sensory processing throughout the mammalian brain, including the main olfactory bulb (MOB), the first station of sensory... (Review)
Review
Synaptic inhibition critically influences sensory processing throughout the mammalian brain, including the main olfactory bulb (MOB), the first station of sensory processing in the olfactory system. Decades of research across numerous laboratories have established a central role for granule cells (GCs), the most abundant GABAergic interneuron type in the MOB, in the precise regulation of principal mitral and tufted cell (M/TC) firing rates and synchrony through lateral and recurrent inhibitory mechanisms. In addition to GCs, however, the MOB contains a vast diversity of other GABAergic interneuron types, and recent findings suggest that, while fewer in number, these oft-ignored interneurons are just as important as GCs in shaping odor-evoked M/TC activity. Here I challenge the prevailing centrality of GCs. In this review, I first outline the specific properties of each GABAergic interneuron type in the rodent MOB, with particular emphasis placed on direct interneuron recordings and cell type-selective manipulations. On the basis of these properties, I then critically reevaluate the contribution of GCs vs. other interneuron types to the regulation of odor-evoked M/TC firing rates and synchrony via lateral, recurrent, and other inhibitory mechanisms. This analysis yields a novel model in which multiple interneuron types with distinct abundances, connectivity patterns, and physiologies complement one another to regulate M/TC activity and sensory processing.
Topics: Animals; GABAergic Neurons; Interneurons; Mammals; Olfactory Bulb
PubMed: 28724776
DOI: 10.1152/jn.00109.2017 -
Seminars in Cell & Developmental Biology Sep 2022Olfactory dysfunction is often the earliest indicator of disease in a range of neurological and psychiatric disorders. One tempting working hypothesis is that... (Review)
Review
Olfactory dysfunction is often the earliest indicator of disease in a range of neurological and psychiatric disorders. One tempting working hypothesis is that pathological changes in the peripheral olfactory system where the body is exposed to many adverse environmental stressors may have a causal role for the brain alteration. Whether and how the peripheral pathology spreads to more central brain regions may be effectively studied in rodent models, and there is successful precedence in experimental models for Parkinson's disease. It is of interest to study whether a similar mechanism may underlie the pathology of psychiatric illnesses, such as schizophrenia. However, direct comparison between rodent models and humans includes challenges under light of comparative neuroanatomy and experimental methodologies used in these two distinct species. We believe that neuroimaging modality that has been the main methodology of human brain studies may be a useful viewpoint to address and fill the knowledge gap between rodents and humans in this scientific question. Accordingly, in the present review article, we focus on brain imaging studies associated with olfaction in healthy humans and patients with neurological and psychiatric disorders, and if available those in rodents. We organize this review article at three levels: 1) olfactory bulb (OB) and peripheral structures of the olfactory system, 2) primary olfactory cortical and subcortical regions, and 3) associated higher-order cortical regions. This research area is still underdeveloped, and we acknowledge that further validation with independent cohorts may be needed for many studies presented here, in particular those with human subjects. Nevertheless, whether and how peripheral olfactory disturbance impacts brain function is becoming even a hotter topic in the ongoing COVID-19 pandemic, given the risk of long-term changes of mental status associated with olfactory infection of SARS-CoV-2. Together, in this review article, we introduce this underdeveloped but important research area focusing on its implications in neurological and psychiatric disorders, with several pioneered publications.
Topics: COVID-19; Humans; Neuroimaging; Olfaction Disorders; Olfactory Bulb; Pandemics; SARS-CoV-2; Smell
PubMed: 34462249
DOI: 10.1016/j.semcdb.2021.08.009 -
Experimental Gerontology Aug 2017In the anterior forebrain, along the lateral wall of the lateral ventricles, a neurogenic stem cell niche is found in a region referred to as the... (Review)
Review
In the anterior forebrain, along the lateral wall of the lateral ventricles, a neurogenic stem cell niche is found in a region referred to as the ventricular-subventricular zone (V-SVZ). In rodents, robust V-SVZ neurogenesis provides new neurons to the olfactory bulb throughout adulthood; however, with increasing age stem cell numbers are reduced and neurogenic capacity is significantly diminished, but new olfactory bulb neurons continue to be produced even in old age. Humans, in contrast, show little to no new neurogenesis after two years of age and whether V-SVZ neural stem cells persist in the adult human brain remains unclear. Here, we review functional and organizational differences in the V-SVZ stem cell niche of mice and humans, and examine how aging affects the V-SVZ niche and its associated functions.
Topics: Age Factors; Aging; Animals; Cell Movement; Cell Proliferation; Humans; Lateral Ventricles; Neural Stem Cells; Neurogenesis; Olfactory Bulb; Prosencephalon; Species Specificity; Stem Cell Niche
PubMed: 27867091
DOI: 10.1016/j.exger.2016.11.007 -
Frontiers in Neural Circuits 2021Our sensory systems such as the olfactory and visual systems are the target of neuromodulatory regulation. This neuromodulation starts at the level of sensory receptors... (Review)
Review
Our sensory systems such as the olfactory and visual systems are the target of neuromodulatory regulation. This neuromodulation starts at the level of sensory receptors and extends into cortical processing. A relatively new group of neuromodulators includes cannabinoids. These form a group of chemical substances that are found in the cannabis plant. Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the main cannabinoids. THC acts in the brain and nervous system like the chemical substances that our body produces, the endogenous cannabinoids or endocannabinoids, also nicknamed the brain's own cannabis. While the function of the endocannabinoid system is understood fairly well in limbic structures such as the hippocampus and the amygdala, this signaling system is less well understood in the olfactory pathway and the visual system. Here, we describe and compare endocannabinoids as signaling molecules in the early processing centers of the olfactory and visual system, the olfactory bulb, and the retina, and the relevance of the endocannabinoid system for synaptic plasticity.
Topics: Animals; Cannabinoids; Humans; Neuronal Plasticity; Olfactory Bulb; Receptor, Cannabinoid, CB1; Retina; Smell; Visual Pathways; Visual Perception
PubMed: 34305536
DOI: 10.3389/fncir.2021.662349 -
Seminars in Cell & Developmental Biology Nov 2014Recent studies using molecular genetics, electrophysiology, in vivo imaging, and behavioral analyses have elucidated detailed connectivity and function of the mammalian... (Review)
Review
Recent studies using molecular genetics, electrophysiology, in vivo imaging, and behavioral analyses have elucidated detailed connectivity and function of the mammalian olfactory circuits. The olfactory bulb is the first relay station of olfactory perception in the brain, but it is more than a simple relay: olfactory information is dynamically tuned by local olfactory bulb circuits and converted to spatiotemporal neural code for higher-order information processing. Because the olfactory bulb processes ∼1000 discrete input channels from different odorant receptors, it serves as a good model to study neuronal wiring specificity, from both functional and developmental aspects. This review summarizes our current understanding of the olfactory bulb circuitry from functional standpoint and discusses important future studies with particular focus on its development and plasticity.
Topics: Animals; Humans; Models, Neurological; Nerve Net; Neuronal Plasticity; Neurons; Odorants; Olfactory Bulb; Olfactory Pathways; Smell
PubMed: 25084319
DOI: 10.1016/j.semcdb.2014.07.012 -
ENeuro 2019Glutamatergic transmission in the brain typically occurs at well-defined synaptic connections, but increasing evidence indicates that neural excitation can also occur...
Glutamatergic transmission in the brain typically occurs at well-defined synaptic connections, but increasing evidence indicates that neural excitation can also occur through activation of "extrasynaptic" glutamate receptors. Here, we investigated the underlying mechanisms and functional properties of extrasynaptic signals that are part of a feedforward path of information flow in the olfactory bulb. This pathway involves glutamatergic interneurons, external tufted cells (eTCs), that are excited by olfactory sensory neurons (OSNs) and in turn excite output mitral cells (MCs) extrasynaptically. Using pair-cell and triple-cell recordings in rat bulb slices (of either sex), combined with ultrastructural approaches, we first present evidence that eTC-to-MC signaling results from "spillover" of glutamate released at eTC synapses onto GABAergic periglomerular (PG) cells in glomeruli. Thus, feedforward excitation is an indirect result of and must cooccur with activation of inhibitory circuitry. Next, to examine the dynamics of the competing signals, we assayed the relationship between the number of spikes in eTCs and excitation of MCs or PG cells in pair-cell recordings. This showed that extrasynaptic excitation in MCs is very weak due to single spikes but rises sharply and supralinearly with increasing spikes, differing from sublinear behavior for synaptic excitation of PG cells. Similar dynamics leading to a preference for extrasynaptic excitation were also observed during recordings of extrasynaptic and inhibitory currents in response to OSN input of increasing magnitude. The observed alterations in the balance between extrasynaptic excitation and inhibition in glomeruli with stimulus strength could underlie an intraglomerular mechanism for olfactory contrast enhancement.
Topics: Animals; Female; Glutamic Acid; Interneurons; Male; Neural Inhibition; Neurons; Olfactory Bulb; Olfactory Receptor Neurons; Rats, Sprague-Dawley; Synapses
PubMed: 31345999
DOI: 10.1523/ENEURO.0247-19.2019 -
PloS One 2016The changes in olfactory bulb (OB) volume in Parkinson's disease (PD) patients have not yet been comprehensively evaluated. The purpose of this meta-analysis was to... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The changes in olfactory bulb (OB) volume in Parkinson's disease (PD) patients have not yet been comprehensively evaluated. The purpose of this meta-analysis was to explore whether the OB volume was significantly different between PD patients and healthy controls.
METHODS
PubMed and Embase were searched up to March 6, 2015 with no language restrictions. Two independent reviewers screened eligible studies and extracted data on study characteristics and OB volume. Additionally, a systematic review and meta-analysis using a random-effects model were conducted. Publication bias was determined by using funnel plots and Begg's and Egger's tests. Subgroup analyses were performed to assess possible sources of heterogeneity.
RESULTS
Six original case-control studies of 216 PD patients and 175 healthy controls were analyzed. The pooled weighted mean difference (WMD) in the OB volume between the PD patients and the healthy participants was -8.071 for the right OB and -10.124 for the left OB; these values indicated a significant difference among PD patients compared with healthy controls. In addition, a significant difference in the lateralized OB volume was observed in PD patients, with a pooled WMD of 1.618; these results indicated a larger right OB volume than left OB volume in PD patients. In contrast, no difference in the lateralized OB volume was found in healthy controls. No statistical evidence of publication bias among studies was found based on Egger's or Begg's tests. Sensitivity analyses revealed that the results were consistent and robust.
CONCLUSIONS
Overall, both the left and the right OB volume were significantly smaller in PD patients than in healthy controls. However, significant heterogeneity and an insufficient number of studies underscore the need for further observational research.
Topics: Humans; Olfactory Bulb; Organ Size; Parkinson Disease
PubMed: 26900958
DOI: 10.1371/journal.pone.0149286 -
International Journal of Environmental... Oct 2018A major step in our understanding of brain function is to determine how neural circuits are altered in their function by signaling molecules or neuromodulators.... (Review)
Review
A major step in our understanding of brain function is to determine how neural circuits are altered in their function by signaling molecules or neuromodulators. Neuromodulation is the neurochemical process that modifies the computations performed by a neuron or network based on changing the functional needs or behavioral state of the subject. These modulations have the effect of altering the responsivity to synaptic inputs. Early sensory processing areas, such as the main olfactory bulb, provide an accessible window for investigating how neuromodulation regulates the functional states of neural networks and influences how we process sensory information. Olfaction is an attractive model system in this regard because of its relative simplicity and because it links primary olfactory sensory neurons to higher olfactory and associational networks. Likewise, centrifugal fibers from higher order brain centers target neurons in the main olfactory bulb to regulate synaptic processing. The neuromodulatory systems that provide regulatory inputs and play important roles in olfactory sensory processing and behaviors include the endocannabinoid system, the dopaminergic system, the cholinergic system, the noradrenergic system and the serotonergic system. Here, we present a brief survey of neuromodulation of olfactory signals in the main olfactory bulb with an emphasis on the endocannabinoid system.
Topics: Brain; Humans; Neurotransmitter Agents; Olfactory Bulb; Smell; Synaptic Transmission
PubMed: 30297631
DOI: 10.3390/ijerph15102194 -
The Journal of Comparative Neurology Aug 2022Olfactory epithelium (OE) is capable of lifelong regeneration due to presence of basal progenitor cells that respond to injury or neuronal loss with increased activity....
Olfactory epithelium (OE) is capable of lifelong regeneration due to presence of basal progenitor cells that respond to injury or neuronal loss with increased activity. However, this capability diminishes with advancing age and a decrease in odor perception in older individuals is well established. To characterize changes associated with age in the peripheral olfactory system, an in-depth analysis of the OE and its neuronal projections onto the olfactory bulb (OB) as a function of age was performed. Human olfactory tissue autopsy samples from 36 subjects with an average age of 74.1 years were analyzed. Established cell type-specific antibodies were used to identify OE component cells in whole mucosal sheets and epithelial sections as well as glomeruli and periglomerular structures in OB sections. With age, a reduction in OE area occurs across the mucosa progressing in a posterior-dorsal direction. Deterioration of the olfactory system is accompanied with diminution of neuron-containing OE, mature olfactory sensory neurons (OSNs) and OB innervation. On an individual level, the neuronal density within the epithelium appears to predict synapse density within the OB. The innervation of the OB is uneven with higher density at the ventral half that decreases with age as opposed to stable innervation at the dorsal half. Respiratory metaplasia, submucosal cysts, and neuromata, were commonly identified in aged OE. The finding of respiratory metaplasia and aneuronal epithelium with reduction in global basal cells suggests a progression of stem cell quiescence as an underlying pathophysiology of age-related smell loss in humans. KEY POINTS: A gradual loss of olfactory sensory neurons with age in human olfactory epithelium is also reflected in a reduction in glomeruli within the olfactory bulb. This gradual loss of neurons and synaptic connections with age occurs in a specific, spatially inhomogeneous manner. Decreasing mitotically active olfactory epithelium basal cells may contribute to age-related neuronal decline and smell loss in humans.
Topics: Aged; Anosmia; Humans; Metaplasia; Olfactory Bulb; Olfactory Mucosa; Olfactory Receptor Neurons
PubMed: 35397118
DOI: 10.1002/cne.25325