scholarly journals α-Synuclein aggregation in the olfactory bulb induces olfactory deficits by perturbing granule cells and granular–mitral synaptic transmission

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Fengjiao Chen ◽  
Wei Liu ◽  
Penglai Liu ◽  
Zhen Wang ◽  
You Zhou ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
Neural Circuit ◽  
Granule Cells ◽  
Gamma Oscillations ◽  
Olfactory Dysfunction ◽  
Synaptic Function ◽  
Neural Mechanisms ◽  
Motor Symptom ◽  
High Gamma

AbstractOlfactory dysfunction is an early pre-motor symptom of Parkinson’s disease (PD) but the neural mechanisms underlying this dysfunction remain largely unknown. Aggregation of α-synuclein is observed in the olfactory bulb (OB) during the early stages of PD, indicating a relationship between α-synuclein pathology and hyposmia. Here we investigate whether and how α-synuclein aggregates modulate neural activity in the OB at the single-cell and synaptic levels. We induced α-synuclein aggregation specifically in the OB via overexpression of double-mutant human α-synuclein by an adeno-associated viral (AAV) vector. We found that α-synuclein aggregation in the OB decreased the ability of mice to detect odors and to perceive attractive odors. The spontaneous activity and odor-evoked firing rates of single mitral/tufted cells (M/Ts) were increased by α-synuclein aggregates with the amplitude of odor-evoked high-gamma oscillations increased. Furthermore, the decreased activity in granule cells (GCs) and impaired inhibitory synaptic function were responsible for the observed hyperactivity of M/Ts induced by α-synuclein aggregates. These results provide direct evidences of the role of α-synuclein aggregates on PD-related olfactory dysfunction and reveal the neural circuit mechanisms by which olfaction is modulated by α-synuclein pathology.

scholarly journals Superimposed gratings induce diverse response patterns of gamma oscillations in primary visual cortex

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bin Wang ◽  
Chuanliang Han ◽  
Tian Wang ◽  
Weifeng Dai ◽  
Yang Li ◽  
...  
Keyword(s):  
Visual Cortex ◽  
Primary Visual Cortex ◽  
Field Potential ◽  
Gamma Oscillations ◽  
Neural Mechanisms ◽  
Model Parameters ◽  
Response Patterns ◽  
Region Difference ◽  
High Gamma ◽  
Spiking Activity

AbstractStimulus-dependence of gamma oscillations (GAMMA, 30–90 Hz) has not been fully understood, but it is important for revealing neural mechanisms and functions of GAMMA. Here, we recorded spiking activity (MUA) and the local field potential (LFP), driven by a variety of plaids (generated by two superimposed gratings orthogonal to each other and with different contrast combinations), in the primary visual cortex of anesthetized cats. We found two distinct narrow-band GAMMAs in the LFPs and a variety of response patterns to plaids. Similar to MUA, most response patterns showed that the second grating suppressed GAMMAs driven by the first one. However, there is only a weak site-by-site correlation between cross-orientation interactions in GAMMAs and those in MUAs. We developed a normalization model that could unify the response patterns of both GAMMAs and MUAs. Interestingly, compared with MUAs, the GAMMAs demonstrated a wider range of model parameters and more diverse response patterns to plaids. Further analysis revealed that normalization parameters for high GAMMA, but not those for low GAMMA, were significantly correlated with the discrepancy of spatial frequency between stimulus and sites’ preferences. Consistent with these findings, normalization parameters and diversity of high GAMMA exhibited a clear transition trend and region difference between area 17 to 18. Our results show that GAMMAs are also regulated in the form of normalization, but that the neural mechanisms for these normalizations might differ from those of spiking activity. Normalizations in different brain signals could be due to interactions of excitation and inhibitions at multiple stages in the visual system.

scholarly journals Granule cell excitability regulates gamma and beta oscillations in a model of the olfactory bulb dendrodendritic microcircuit

2016 ◽  
Vol 116 (2) ◽  
pp. 522-539 ◽  
Author(s):  
Bolesław L. Osinski ◽  
Leslie M. Kay
Keyword(s):  
Olfactory Bulb ◽  
Granule Cells ◽  
Field Potential ◽  
Gamma Oscillations ◽  
Causal Link ◽  
Beta Oscillations ◽  
Gamma Frequency ◽  
Voltage Dependent ◽  
Nmda Channels ◽  
Beta Frequency

Odors evoke gamma (40–100 Hz) and beta (20–30 Hz) oscillations in the local field potential (LFP) of the mammalian olfactory bulb (OB). Gamma (and possibly beta) oscillations arise from interactions in the dendrodendritic microcircuit between excitatory mitral cells (MCs) and inhibitory granule cells (GCs). When cortical descending inputs to the OB are blocked, beta oscillations are extinguished whereas gamma oscillations become larger. Much of this centrifugal input targets inhibitory interneurons in the GC layer and regulates the excitability of GCs, which suggests a causal link between the emergence of beta oscillations and GC excitability. We investigate the effect that GC excitability has on network oscillations in a computational model of the MC-GC dendrodendritic network with Ca2+-dependent graded inhibition. Results from our model suggest that when GC excitability is low, the graded inhibitory current mediated by NMDA channels and voltage-dependent Ca2+ channels (VDCCs) is also low, allowing MC populations to fire in the gamma frequency range. When GC excitability is increased, the activation of NMDA receptors and other VDCCs is also increased, allowing the slow decay time constants of these channels to sustain beta-frequency oscillations. Our model argues that Ca2+ flow through VDCCs alone could sustain beta oscillations and that the switch between gamma and beta oscillations can be triggered by an increase in the excitability state of a subpopulation of GCs.

scholarly journals Developmental synaptic regulator, TWEAK/Fn14 signaling, is a determinant of synaptic function in models of stroke and neurodegeneration

2021 ◽  
Vol 118 (6) ◽  
pp. e2001679118
Author(s):  
Dávid Nagy ◽  
Katelin A. Ennis ◽  
Ru Wei ◽  
Susan C. Su ◽  
Christopher A. Hinckley ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Neural Circuit ◽  
Hippocampal Slices ◽  
Visual Development ◽  
Synaptic Function ◽  
Synaptic Physiology ◽  
Mature Brain ◽  
Circuit Development ◽  
Basal Synaptic Transmission

Identifying molecular mediators of neural circuit development and/or function that contribute to circuit dysfunction when aberrantly reengaged in neurological disorders is of high importance. The role of the TWEAK/Fn14 pathway, which was recently reported to be a microglial/neuronal axis mediating synaptic refinement in experience-dependent visual development, has not been explored in synaptic function within the mature central nervous system. By combining electrophysiological and phosphoproteomic approaches, we show that TWEAK acutely dampens basal synaptic transmission and plasticity through neuronal Fn14 and impacts the phosphorylation state of pre- and postsynaptic proteins in adult mouse hippocampal slices. Importantly, this is relevant in two models featuring synaptic deficits. Blocking TWEAK/Fn14 signaling augments synaptic function in hippocampal slices from amyloid-beta–overexpressing mice. After stroke, genetic or pharmacological inhibition of TWEAK/Fn14 signaling augments basal synaptic transmission and normalizes plasticity. Our data support a glial/neuronal axis that critically modifies synaptic physiology and pathophysiology in different contexts in the mature brain and may be a therapeutic target for improving neurophysiological outcomes.

scholarly journals The role of calretinin-expressing granule cells in olfactory bulb functions and odor behavior

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Delphine Hardy ◽  
Sarah Malvaut ◽  
Vincent Breton-Provencher ◽  
Armen Saghatelyan
Keyword(s):  
Olfactory Bulb ◽  
Granule Cells

scholarly journals Dendritic integration in olfactory bulb granule cells: Thresholds for lateral inhibition and role of active conductances upon simultaneous activation

2020 ◽  
Author(s):  
Max Müller ◽  
Veronica Egger
Keyword(s):  
Olfactory Bulb ◽  
Lateral Inhibition ◽  
Granule Cells ◽  
Brain Slices ◽  
Dendritic Integration ◽  
Two Photon ◽  
Channel Inactivation ◽  
Cell Recording ◽  
Simultaneous Activation

AbstractThe inhibitory axonless olfactory bulb granule cells (GCs) form reciprocal dendrodendritic synapses with mitral and tufted cells via large spines, mediating recurrent and lateral inhibition. Rat GC dendrites are excitable by local Na+ spine spikes and global Ca2+- and Na+-spikes. To investigate the transition from local to global signaling without Na+ channel inactivation we performed simultaneous holographic two-photon uncaging in acute brain slices, along with whole-cell recording and dendritic Ca2+ imaging. Less than 10 coactive reciprocal spines were sufficient to generate diverse regional and global signals that also included local dendritic Ca2+- and Na+-spikes (D-spikes). Individual spines could sense the respective signal transitions as increments in Ca2+ entry. Dendritic integration was mostly linear until a few spines below global Na+-spike threshold, where often D-spikes set in. NMDARs strongly contributed to active integration, whereas morphological parameters barely mattered. In summary, thresholds for GC-mediated bulbar lateral inhibition are low.

Disruption of GABAA Receptors on GABAergic Interneurons Leads to Increased Oscillatory Power in the Olfactory Bulb Network

2001 ◽  
Vol 86 (6) ◽  
pp. 2823-2833 ◽  
Author(s):  
Zoltan Nusser ◽  
Leslie M. Kay ◽  
Gilles Laurent ◽  
Gregg E. Homanics ◽  
Istvan Mody
Keyword(s):  
Olfactory Bulb ◽  
Granule Cells ◽  
Fold Increase ◽  
Network Activity ◽  
Gabaergic Interneurons ◽  
Synaptic Inhibition ◽  
Principal Cells ◽  
Network Oscillations

Synchronized neural activity is believed to be essential for many CNS functions, including neuronal development, sensory perception, and memory formation. In several brain areas GABAA receptor–mediated synaptic inhibition is thought to be important for the generation of synchronous network activity. We have used GABAA receptor β3 subunit deficient mice (β3−/−) to study the role of GABAergic inhibition in the generation of network oscillations in the olfactory bulb (OB) and to reveal the role of such oscillations in olfaction. The expression of functional GABAA receptors was drastically reduced (>93%) in β3−/− granule cells, the local inhibitory interneurons of the OB. This was revealed by a large reduction of muscimol-evoked whole-cell current and the total current mediated by spontaneous, miniature inhibitory postsynaptic currents (mIPSCs). In β3−/− mitral/tufted cells (principal cells), there was a two-fold increase in mIPSC amplitudes without any significant change in their kinetics or frequency. In parallel with the altered inhibition, there was a significant increase in the amplitude of theta (80% increase) and gamma (178% increase) frequency oscillations in β3−/− OBs recorded in vivo from freely moving mice. In odor discrimination tests, we found β3−/− mice to be initially the same as, but better with experience than β3+/+ mice in distinguishing closely related monomolecular alcohols. However, β3−/− mice were initially better and then worse with practice than control mice in distinguishing closely related mixtures of alcohols. Our results indicate that the disruption of GABAAreceptor–mediated synaptic inhibition of GABAergic interneurons and the augmentation of IPSCs in principal cells result in increased network oscillations in the OB with complex effects on olfactory discrimination, which can be explained by an increase in the size or effective power of oscillating neural cell assemblies among the mitral cells of β3−/− mice.

scholarly journals Connectivity and dynamics in the olfactory bulb

2021 ◽  
Author(s):  
David EC Kersen ◽  
Gaia Tavoni ◽  
Vijay Balasubramanian
Keyword(s):  
Olfactory Bulb ◽  
Lateral Inhibition ◽  
Large Scale ◽  
Computational Models ◽  
Granule Cells ◽  
Cell Activity ◽  
Gamma Oscillations ◽  
Scale Model ◽  
Mitral Cells ◽  
Cortical Feedback

Dendrodendritic interactions between excitatory mitral cells and inhibitory granule cells in the olfactory bulb create a dense interaction network, reorganizing sensory representations of odors and, consequently, perception. Large-scale computational models are needed for revealing how the collective behavior of this network emerges from its global architecture. We propose an approach where we summarize anatomical information through dendritic geometry and density distributions which we use to calculate the probability of synapse between mitral and granule cells, while capturing activity patterns of each cell type in the neural dynamical systems theory of Izhikevich. In this way, we generate an efficient, anatomically and physiologically realistic large-scale model of the olfactory bulb network. Our model reproduces known connectivity between sister vs. non-sister mitral cells; measured patterns of lateral inhibition; and theta, beta, and gamma oscillations. It in turn predicts testable relations between network structure, lateral inhibition, and odor pattern decorrelation; between the density of granule cell activity and LFP oscillation frequency; how cortical feedback to granule cells affects mitral cell activity; and how cortical feedback to mitral cells is modulated by the network embedding. Additionally, the methodology we describe here provides a tractable tool for other researchers.

scholarly journals Excitability of Neural Activity is Enhanced, but Neural Discrimination of Odors is Slightly Decreased, in the Olfactory Bulb of Fasted Mice

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 433 ◽  
Author(s):  
Jing Wu ◽  
Penglai Liu ◽  
Fengjiao Chen ◽  
Lingying Ge ◽  
Yifan Lu ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
Neural Activity ◽  
Neural Circuit ◽  
Field Potential ◽  
Gamma Oscillations ◽  
Odor Processing ◽  
Fasted State ◽  
New Information ◽  
Tufted Cells ◽  
Olfactory Abilities

Olfaction and satiety status influence each other: cues from the olfactory system modulate eating behavior, and satiety affects olfactory abilities. However, the neural mechanisms governing the interactions between olfaction and satiety are unknown. Here, we investigate how an animal’s nutritional state modulates neural activity and odor representation in the mitral/tufted cells of the olfactory bulb, a key olfactory center that plays important roles in odor processing and representation. At the single-cell level, we found that the spontaneous firing rate of mitral/tufted cells and the number of cells showing an excitatory response both increased when mice were in a fasted state. However, the neural discrimination of odors slightly decreased. Although ongoing baseline and odor-evoked beta oscillations in the local field potential in the olfactory bulb were unchanged with fasting, the amplitude of odor-evoked gamma oscillations significantly decreased in a fasted state. These neural changes in the olfactory bulb were independent of the sniffing pattern, since both sniffing frequency and mean inhalation duration did not change with fasting. These results provide new information toward understanding the neural circuit mechanisms by which olfaction is modulated by nutritional status.

scholarly journals Age-dependent adrenergic actions in the main olfactory bulb that could underlie an olfactory-sensitive period

2012 ◽  
Vol 108 (7) ◽  
pp. 1999-2007 ◽  
Author(s):  
Sruthi Pandipati ◽  
Nathan E. Schoppa
Keyword(s):  
Olfactory Bulb ◽  
Neural Plasticity ◽  
Granule Cells ◽  
Gamma Oscillations ◽  
Sensitive Period ◽  
Loss Of Function ◽  
Main Olfactory Bulb ◽  
Cellular Mechanisms ◽  
Gamma Frequency ◽  
Age Dependent

Many sensory systems are endowed with mechanisms of neural plasticity that are restricted to a sensitive period in the young developing animal. In this study, we performed experiments in slices of the main olfactory bulb (OB) from rats to examine possible age-dependent cellular mechanisms of plasticity in the olfactory system. We focused on the neurotransmitter norepinephrine (NE), shown to be important in different forms of olfactory learning, examining whether two specific cellular effects of NE previously observed in rats less than P14 extended to older animals. These included an acute reduction in GABAergic synaptic transmission from granule cells (GCs) onto output mitral cells (MCs) and an enhancement in gamma frequency (30–70 Hz) oscillations that persists long after removal of NE. We found that NE failed to reduce GC-to-MC transmission or enhance gamma oscillations in older rats at P18–23. The loss of NE actions on both phenomena appeared to reflect an age-dependent loss of function of α2-adrenergic receptors. In addition, we found that NE induced an age-dependent enhancement of transient excitation in MCs, providing a mechanism to link the acute decrease in GC-to-MC inhibition to the long-term increase in gamma oscillations through increases in intracellular calcium. The age-dependent cellular mechanisms that we describe could underlie an olfactory-sensitive period in newborn rodents.

scholarly journals Enhancing GABAergic signaling ameliorates aberrant gamma oscillations of olfactory bulb in AD mouse models

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Ming Chen ◽  
Yunan Chen ◽  
Qingwei Huo ◽  
Lei Wang ◽  
Shuyi Tan ◽  
...  
Keyword(s):  
T Cells ◽  
Olfactory Bulb ◽  
Field Potential ◽  
Gamma Oscillations ◽  
Synaptic Function ◽  
Gaba Uptake ◽  
Olfactory Behavior ◽  
Olfactory Pathway

Abstract Background Before the deposition of amyloid-beta plaques and the onset of learning memory deficits, patients with Alzheimer’s disease (AD) experience olfactory dysfunction, typified by a reduced ability to detect, discriminate, and identify odors. Rodent models of AD, such as the Tg2576 and APP/PS1 mice, also display impaired olfaction, accompanied by aberrant in vivo or in vitro gamma rhythms in the olfactory pathway. However, the mechanistic relationships between the electrophysiological, biochemical and behavioral phenomena remain unclear. Methods To address the above issues in AD models, we conducted in vivo measurement of local field potential (LFP) with a combination of in vitro electro-olfactogram (EOG), whole-cell patch and field recordings to evaluate oscillatory and synaptic function and pharmacological regulation in the olfactory pathway, particularly in the olfactory bulb (OB). Levels of protein involved in excitation and inhibition of the OB were investigated by western blotting and fluorescence staining, while behavioral studies assessed olfaction and memory function. Results LFP measurements demonstrated an increase in gamma oscillations in the OB accompanied by altered olfactory behavior in both APP/PS1 and 3xTg mice at 3–5 months old, i.e. an age before the onset of plaque formation. Fewer olfactory sensory neurons (OSNs) and a reduced EOG contributed to a decrease in the excitatory responses of M/T cells, suggesting a decreased ability of M/T cells to trigger interneuron GABA release indicated by altered paired-pulse ratio (PPR), a presynaptic parameter. Postsynaptically, there was a compensatory increase in levels of GABAAR α1 and β3 subunits and subsequent higher amplitude of inhibitory responses. Strikingly, the GABA uptake inhibitor tiagabine (TGB) ameliorated abnormal gamma oscillations and levels of GABAAR subunits, suggesting a potential therapeutic strategy for early AD symptoms. These findings reveal increased gamma oscillations in the OB as a core indicator prior to onset of AD and uncover mechanisms underlying aberrant gamma activity in the OB. Conclusions This study suggests that the concomitant dysfunction of both olfactory behavior and gamma oscillations have important implications for early AD diagnosis: in particular, awareness of aberrant GABAergic signaling mechanisms might both aid diagnosis and suggest therapeutic strategies for olfactory damage in AD.

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