Perturbation of in vivo Neural Activity Following α-Synuclein Seeding in the Olfactory Bulb

Background: Parkinson’s disease (PD) neuropathology is characterized by intraneuronal protein aggregates composed of misfolded α-Synuclein (α-Syn), as well as degeneration of substantia nigra dopamine neurons. Deficits in olfactory perception and aggregation of α-Syn in the olfactory bulb (OB) are observed during early stages of PD, and have been associated with the PD prodrome, before onset of the classic motor deficits. α-Syn fibrils injected into the OB of mice cause progressive propagation of α-Syn pathology throughout the olfactory system and are coupled to olfactory perceptual deficits. Objective: We hypothesized that accumulation of pathogenic α-Syn in the OB impairs neural activity in the olfactory system. Methods: To address this, we monitored spontaneous and odor-evoked local field potential dynamics in awake wild type mice simultaneously in the OB and piriform cortex (PCX) one, two, and three months following injection of pathogenic preformed α-Syn fibrils in the OB. Results: We detected α-Syn pathology in both the OB and PCX. We also observed that α-Syn fibril injections influenced odor-evoked activity in the OB. In particular, α-Syn fibril-injected mice displayed aberrantly high odor-evoked power in the beta spectral range. A similar change in activity was not detected in the PCX, despite high levels of α-Syn pathology. Conclusion: Together, this work provides evidence that synucleinopathy impacts in vivo neural activity in the olfactory system at the network-level.

Download Full-text

Perturbation of in vivo neural activity following α-Synuclein seeding in the olfactory bulb

10.1101/2020.04.17.045013 ◽

2020 ◽

Author(s):

Aishwarya S. Kulkarni ◽

Maria del Mar Cortijo ◽

Elizabeth R. Roberts ◽

Tamara L. Suggs ◽

Heather B. Stover ◽

...

Keyword(s):

Olfactory Bulb ◽

Neural Activity ◽

Olfactory System ◽

Piriform Cortex ◽

Field Potential ◽

Dopamine Neurons ◽

Motor Deficits ◽

Wild Type ◽

Evoked Activity

AbstractBACKGROUNDParkinson’s disease (PD) neuropathology is characterized by intraneuronal protein aggregates composed of misfolded α-Synuclein (α-Syn), as well as degeneration of substantia nigra dopamine neurons. Deficits in olfactory perception and aggregation of α-Syn in the olfactory bulb (OB) are observed during early stages of PD, and have been associated with the PD prodrome, before onset of the classic motor deficits. α-Syn fibrils injected into the OB of mice cause progressive propagation of α-Syn pathology throughout the olfactory system and are coupled to olfactory perceptual deficits.OBJECTIVEWe hypothesized that accumulation of pathogenic α-Syn in the OB impairs neural activity in the olfactory system.METHODSTo address this, we monitored spontaneous and odor-evoked local field potential dynamics in awake wild type mice simultaneously in the OB and piriform cortex (PCX) one, two, and three months following injection of pathogenic preformed α-Syn fibrils in the OB.RESULTSWe detected α-Syn pathology in both the OB and PCX. We also observed that α-Syn fibril injections influenced odor-evoked activity in the OB. In particular, α-Syn fibril-injected mice displayed aberrantly high odor-evoked power in the beta spectral range. A similar change in activity was not detected in the PCX, despite high levels of α-Syn pathology.CONCLUSIONSTogether, this work provides evidence that synucleinopathy impacts in vivo neural activity in the olfactory system at the network-level.

Download Full-text

Chemical Factors Determine Olfactory System Beta Oscillations in Waking Rats

Journal of Neurophysiology ◽

10.1152/jn.00124.2007 ◽

2007 ◽

Vol 98 (1) ◽

pp. 394-404 ◽

Cited By ~ 47

Author(s):

Catherine A. Lowry ◽

Leslie M. Kay

Keyword(s):

Olfactory Bulb ◽

Vapor Pressure ◽

Vapor Phase ◽

Local Field ◽

Olfactory System ◽

Piriform Cortex ◽

Field Potential ◽

Gamma Oscillations ◽

Beta Oscillations ◽

Phase Concentration

Recent studies have pointed to olfactory system beta oscillations of the local field potential (15–30 Hz) and their roles both in learning and as specific responses to predator odors. To describe odorant physical properties, resultant behavioral responses and changes in the central olfactory system that may induce these oscillations without associative learning, we tested rats with 26 monomolecular odorants spanning 6 log units of theoretical vapor pressure (estimate of relative vapor phase concentration) and 10 different odor mixtures. We found odorant vapor phase concentration to be inversely correlated with investigation time on the first presentation, after which investigation times were brief and not different across odorants. Analysis of local field potentials from the olfactory bulb and anterior piriform cortex shows that beta oscillations in waking rats occur specifically in response to the class of volatile organic compounds with vapor pressures of 1–120 mmHg. Beta oscillations develop over the first three to four presentations and are weakly present for some odorants in anesthetized rats. Gamma oscillations show a smaller effect that is not restricted to the same range of odorants. Olfactory bulb theta oscillations were also examined as a measure of effective afferent input strength, and the power of these oscillations did not vary systematically with vapor pressure, suggesting that it is not olfactory bulb drive strength that determines the presence of beta oscillations. Theta band coherence analysis shows that coupling strength between the olfactory bulb and piriform cortex increases linearly with vapor phase concentration, which may facilitate beta oscillations above a threshold.

Download Full-text

Neuroprotective Potential of a Small Molecule RET Agonist in Cultured Dopamine Neurons and Hemiparkinsonian Rats

Journal of Parkinson s Disease ◽

10.3233/jpd-202400 ◽

2021 ◽

pp. 1-24

Author(s):

Juho-Matti Renko ◽

Arun Kumar Mahato ◽

Tanel Visnapuu ◽

Konsta Valkonen ◽

Mati Karelson ◽

...

Keyword(s):

Mapk Signaling ◽

Dopamine Neurons ◽

Dopamine Depletion ◽

Wild Type ◽

Disease Modifying Therapy ◽

Immortalized Cells ◽

Midbrain Dopamine ◽

6 Hydroxydopamine

Background: Parkinson’s disease (PD) is a progressive neurological disorder where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor symptoms. Currently, no treatment is able to halt the progression of PD. Glial cell line-derived neurotrophic factor (GDNF) rescues degenerating dopamine neurons both in vitro and in animal models of PD. When tested in PD patients, however, the outcomes from intracranial GDNF infusion paradigms have been inconclusive, mainly due to poor pharmacokinetic properties. Objective: We have developed drug-like small molecules, named BT compounds that activate signaling through GDNF’s receptor, the transmembrane receptor tyrosine kinase RET, both in vitro and in vivo and are able to penetrate through the blood-brain barrier. Here we evaluated the properties of BT44, a second generation RET agonist, in immortalized cells, dopamine neurons and rat 6-hydroxydopamine model of PD. Methods: We used biochemical, immunohistochemical and behavioral methods to evaluate the effects of BT44 on dopamine system in vitro and in vivo. Results: BT44 selectively activated RET and intracellular pro-survival AKT and MAPK signaling pathways in immortalized cells. In primary midbrain dopamine neurons cultured in serum-deprived conditions, BT44 promoted the survival of the neurons derived from wild-type, but not from RET knockout mice. BT44 also protected cultured wild-type dopamine neurons from MPP +-induced toxicity. In a rat 6-hydroxydopamine model of PD, BT44 reduced motor imbalance and could have protected dopaminergic fibers in the striatum. Conclusion: BT44 holds potential for further development into a novel, possibly disease-modifying therapy for PD.

Download Full-text

In vivo electrophysiology of nigral and thalamic neurons in alpha-synuclein-overexpressing mice highlights differences from toxin-based models of parkinsonism

Journal of Neurophysiology ◽

10.1152/jn.00441.2013 ◽

2013 ◽

Vol 110 (12) ◽

pp. 2792-2805 ◽

Cited By ~ 10

Author(s):

C. J. Lobb ◽

A. K. Zaheer ◽

Y. Smith ◽

D. Jaeger

Keyword(s):

Primary Motor Cortex ◽

Alpha Synuclein ◽

Motor Dysfunction ◽

Motor Deficits ◽

Dopamine Depletion ◽

Wild Type ◽

Beta Oscillations ◽

Nigrostriatal Dopamine ◽

6 Hydroxydopamine

Numerous studies have suggested that alpha-synuclein plays a prominent role in both familial and idiopathic Parkinson's disease (PD). Mice in which human alpha-synuclein is overexpressed (ASO) display progressive motor deficits and many nonmotor features of PD. However, it is unclear what in vivo pathophysiological mechanisms drive these motor deficits. It is also unknown whether previously proposed pathophysiological features (i.e., increased beta oscillations, bursting, and synchronization) described in toxin-based, nigrostriatal dopamine-depletion models are also present in ASO mice. To address these issues, we first confirmed that 5- to 6-mo-old ASO mice have robust motor dysfunction, despite the absence of significant nigrostriatal dopamine degeneration. In the same animals, we then recorded simultaneous single units and local field potentials (LFPs) in the substantia nigra pars reticulata (SNpr), the main basal ganglia output nucleus, and one of its main thalamic targets, the ventromedial nucleus, as well as LFPs in the primary motor cortex in anesthetized ASO mice and their age-matched, wild-type littermates. Neural activity was examined during slow wave activity and desynchronized cortical states, as previously described in 6-hydroxydopamine-lesioned rats. In contrast to toxin-based models, we found a small decrease, rather than an increase, in beta oscillations in the desynchronized state. Similarly, synchronized burst firing of nigral neurons observed in toxin-based models was not observed in ASO mice. Instead, we found more subtle changes in pauses of SNpr firing compared with wild-type control mice. Our results suggest that the pathophysiology underlying motor dysfunction in ASO mice is distinctly different from striatal dopamine-depletion models of parkinsonism.

Download Full-text

Stimulation of the Parasubiculum Modulates Entorhinal Cortex Responses to Piriform Cortex Inputs In Vivo

Journal of Neurophysiology ◽

10.1152/jn.00038.2004 ◽

2004 ◽

Vol 92 (2) ◽

pp. 1226-1235 ◽

Cited By ~ 12

Author(s):

Douglas A. Caruana ◽

C. Andrew Chapman

Keyword(s):

Entorhinal Cortex ◽

Hippocampal Formation ◽

Piriform Cortex ◽

Current Source ◽

Field Potential ◽

Implanted Electrodes ◽

Deep Layers ◽

Negative Field ◽

Stimulation Of

Although a major output of the hippocampal formation is from the subiculum to the deep layers of the entorhinal cortex, the parasubiculum projects to the superficial layers of the entorhinal cortex and may therefore modulate how the entorhinal cortex responds to sensory inputs from other cortical regions. Recordings at multiple depths in the entorhinal cortex were first used to characterize field potentials evoked by stimulation of the parasubiculum in urethan-anesthetized rats. Current source density analysis showed that a prominent surface-negative field potential component is generated by synaptic activation in layer II. The surface-negative field potential was also observed in rats with chronically implanted electrodes. The response was maintained during short stimulation trains of ≤125 Hz, suggesting that it is generated by activation of monosynaptic inputs to the entorhinal cortex. The piriform cortex also projects to layer II of the entorhinal cortex, and interactions between parasubicular and piriform cortex inputs were investigated using double-site stimulation tests. Simultaneous activation of parasubicular and piriform cortex inputs with high-intensity pulses resulted in smaller synaptic potentials than were expected on the basis of summing the individual responses, consistent with the termination of both pathways onto a common population of neurons. Paired-pulse tests were then used to assess the effect of parasubicular stimulation on responses to piriform cortex stimulation. Responses of the entorhinal cortex to piriform cortex inputs were inhibited when the parasubiculum was stimulated 5 ms earlier and were enhanced when the parasubiculum was stimulated 20–150 ms earlier. These results indicate that excitatory inputs to the entorhinal cortex from the parasubiculum may enhance the propagation of neuronal activation patterns into the hippocampal circuit by increasing the responsiveness of the entorhinal cortex to appropriately timed inputs.

Download Full-text

Comprehensive mapping of whisker-evoked responses reveals broad, sharply tuned thalamocortical input to layer 4 of barrel cortex

Journal of Neurophysiology ◽

10.1152/jn.00939.2010 ◽

2011 ◽

Vol 105 (5) ◽

pp. 2421-2437 ◽

Cited By ~ 14

Author(s):

Noah C. Roy ◽

Thomas Bessaih ◽

Diego Contreras

Keyword(s):

Cortical Neurons ◽

Barrel Cortex ◽

Current Source ◽

Field Potential ◽

Fundamental Information ◽

Layer 4 ◽

Density Analysis ◽

Evoked Activity ◽

Rats And Mice

Cortical neurons are organized in columns, distinguishable by their physiological properties and input-output organization. Columns are thought to be the fundamental information-processing modules of the cortex. The barrel cortex of rats and mice is an attractive model system for the study of cortical columns, because each column is defined by a layer 4 (L4) structure called a barrel, which can be clearly visualized. A great deal of information has been collected regarding the connectivity of neurons in barrel cortex, but the nature of the input to a given L4 barrel remains unclear. We measured this input by making comprehensive maps of whisker-evoked activity in L4 of rat barrel cortex using recordings of multiunit activity and current source density analysis of local field potential recordings of animals under light isoflurane anesthesia. We found that a large number of whiskers evoked a detectable response in each barrel (mean of 13 suprathreshold, 18 subthreshold) even after cortical activity was abolished by application of muscimol, a GABAA agonist. We confirmed these findings with intracellular recordings and single-unit extracellular recordings in vivo. This constitutes the first direct confirmation of the hypothesis that subcortical mechanisms mediate a substantial multiwhisker input to a given cortical barrel.

Download Full-text

A transformation from temporal to ensemble coding in a model of piriform cortex

10.1101/118364 ◽

2017 ◽

Cited By ~ 1

Author(s):

Merav Stern ◽

Kevin A. Bolding ◽

L.F. Abbott ◽

Kevin M. Franks

Keyword(s):

Olfactory Bulb ◽

Olfactory System ◽

Feedback Inhibition ◽

Piriform Cortex ◽

Odor Coding ◽

System A ◽

Coding Strategies ◽

Concentration Changes ◽

Recurrent Collateral ◽

The Impact

ABSTRACTDifferent coding strategies are used to represent odor information at various stages of the mammalian olfactory system. A temporal latency code represents odor identity in olfactory bulb (OB), but this temporal information is discarded in piriform cortex (PCx) where odor identity is instead encoded through ensemble membership. We developed a spiking PCx network model to understand how this transformation is implemented. In the model, the impact of OB inputs activated earliest after inhalation is amplified within PCx by diffuse recurrent collateral excitation, which then recruits strong, sustained feedback inhibition that suppresses the impact of later-responding glomeruli. Simultaneous OB-PCx recordings indicate that indeed, over a single sniff, the earliest-active OB inputs are most effective at driving PCx activity. We model increasing odor concentrations by decreasing glomerulus onset latencies while preserving their activation sequences. This produces a multiplexed cortical odor code in which activated ensembles are robust to concentration changes while concentration information is encoded through population synchrony. Our model demonstrates how PCx circuitry can implement multiplexed ensemble-identity/temporal-concentration odor coding.

Download Full-text

In vivo beta and gamma subthreshold oscillations in rat mitral cells: origin and gating by respiratory dynamics

Journal of Neurophysiology ◽

10.1152/jn.00053.2017 ◽

2018 ◽

Vol 119 (1) ◽

pp. 274-289 ◽

Cited By ~ 1

Author(s):

Nicolas Fourcaud-Trocmé ◽

Virginie Briffaud ◽

Marc Thévenet ◽

Nathalie Buonviso ◽

Corine Amat

Keyword(s):

Membrane Potential ◽

Olfactory Bulb ◽

Local Field ◽

Local Field Potential ◽

Respiratory Rhythm ◽

Field Potential ◽

Synaptic Activity ◽

Spike Discharge ◽

Subthreshold Oscillations

In mammals, olfactory bulb (OB) dynamics are paced by slow and fast oscillatory rhythms at multiple levels: local field potential, spike discharge, and/or membrane potential oscillations. Interactions between these levels have been well studied for the slow rhythm linked to animal respiration. However, less is known regarding rhythms in the fast beta (10–35 Hz) and gamma (35–100 Hz) frequency ranges, particularly at the membrane potential level. Using a combination of intracellular and extracellular recordings in the OB of freely breathing rats, we show that beta and gamma subthreshold oscillations (STOs) coexist intracellularly and are related to extracellular local field potential (LFP) oscillations in the same frequency range. However, they are differentially affected by changes in cell excitability and by odor stimulation. This leads us to suggest that beta and gamma STOs may rely on distinct mechanisms: gamma STOs would mainly depend on mitral cell intrinsic resonance, while beta STOs could be mainly driven by synaptic activity. In a second study, we find that STO occurrence and timing are constrained by the influence of the slow respiratory rhythm on mitral and tufted cells. First, respiratory-driven excitation seems to favor gamma STOs, while respiratory-driven inhibition favors beta STOs. Second, the respiratory rhythm is needed at the subthreshold level to lock gamma and beta STOs in similar phases as their LFP counterparts and to favor the correlation between STO frequency and spike discharge. Overall, this study helps us to understand how the interaction between slow and fast rhythms at all levels of OB dynamics shapes its functional output. NEW & NOTEWORTHY In the mammalian olfactory bulb of a freely breathing anesthetized rat, we show that both beta and gamma membrane potential fast oscillation ranges exist in the same mitral and tufted (M/T) cell. Importantly, our results suggest they have different origins and that their interaction with the slow subthreshold oscillation (respiratory rhythm) is a key mechanism to organize their dynamics, favoring their functional implication in olfactory bulb information processing.

Download Full-text

Odour Retrieval Processing in Mice: Cholinergic Modulation of Oscillatory Coupling in Olfactory Bulb-Piriform Networks

Neuropsychobiology ◽

10.1159/000513511 ◽

2021 ◽

pp. 1-19

Author(s):

Abdallah Ahnaou ◽

Lucile Chave ◽

Nikolay V. Manyakov ◽

Wilhelmus H.I.M. Drinkenburg

Keyword(s):

Olfactory Bulb ◽

Piriform Cortex ◽

Field Potential ◽

Reference Memory ◽

Valuable Insight ◽

Olfactory Pathway ◽

Cholinergic Modulation ◽

Coupling Index ◽

Phase Amplitude

Background/Aims: Olfactory dysfunction can provide valuable insight into early pathophysiological processes of brain disorders. Olfactory processing of chemosensory and odour sensitivity relies on segregating salient odours from background odours cues. Odour-evoked fast oscillations in the olfactory bulb (OB) are hypothesized to be an important index of odour quality coding. The present preclinical work aimed at better understanding connectivity associated with odour coding and behavioural odour discrimination. Methods: Network oscillations and functional connectivity (FC) were measured in C57BL/6 mice performing the olfactory associative odour learning (OL) test, using multichannel local field potential recordings in key olfactory networks. Cholinergic modulation of odour processing was investigated using the muscarinic antagonist scopolamine. Results: At the behavioural level, olfactory memory, which refers to the acquisition and recollection of a reference odour by reduced exploration time, was observed in animals that correctly learned the task. Significant decrease in mean investigation and retrieval time of the associated odour-food reward was observed between trials. At the network level, the associated odour during sniffing behaviour was associated with enhanced coherence in the β and γ frequency oscillations across the olfactory pathway, with marked changes observed between the OB and anterior piriform cortex (PC). The enhanced phase-amplitude cross-frequency coupling in the OB and the weak coupling index in the hippocampal CA1 suggests a role of the OB network in olfaction encoding and processing. Scopolamine impaired behavioural and FC underlying recall and retrieval of the associated odour. Conclusion: The results suggest that the acquisition and formation of odour reference memory rely primarily on FC at the OB-PC network and confirm the role of muscarinic receptors in olfactory retrieval processing.

Download Full-text

Pharmacological manipulation of olfactory bulb granule cell excitability modulates beta oscillations: Testing a model

10.1101/234625 ◽

2017 ◽

Author(s):

Boleslaw L. Osinski ◽

Alex Kim ◽

Wenxi Xiao ◽

Nisarg Mehta ◽

Leslie M. Kay

Keyword(s):

Olfactory Bulb ◽

Granule Cell ◽

Piriform Cortex ◽

Field Potential ◽

Gamma Oscillations ◽

List Type ◽

Muscarinic Agonist ◽

Beta Oscillations ◽

Cell Excitability ◽

Beta Power

AbstractThe mammalian olfactory bulb (OB) generates gamma (40 – 100 Hz) and beta (15 – 30 Hz) oscillations of the local field potential (LFP). Gamma oscillations arise at the peak of inhalation supported by dendrodendritic interactions between glutamatergic mitral cells (MCs) and GABAergic granule cells (GCs). Beta oscillations occur in response to odorants in learning or odor sensitization paradigms, but their generation mechanism and function are still poorly understood. When centrifugal inputs to the OB are blocked, beta oscillations disappear, but gamma oscillations persist. Centrifugal input targets primarily GABAergic interneurons in the GC layer (GCL) and regulates GC excitability, which suggests a causal link between beta oscillations and GC excitability. Previous modeling work from our laboratory predicted that convergence of excitatory/inhibitory inputs onto MCs and centrifugal inputs onto GCs can increase GC excitability sufficiently to drive beta oscillations primarily through voltage dependent calcium channel (VDCC) mediated GABA release, independently of NMDA channels. We test this model by examining the influence of NMDA and muscarinic acetylcholine receptors on GC excitability and beta oscillations. Intrabulbar scopolamine (muscarinic antagonist) infusion decreased or completely suppressed odor-evoked beta in response to a strong stimulus, but increased beta power in response to a weak stimulus, as predicted by our model. Piriform cortex (PC) beta power was unchanged. Oxotremorine (muscarinic agonist) tended to suppress all oscillations, probably from over-inhibition. APV, an NMDA receptor antagonist, suppressed gamma oscillations selectively (in OB and PC), lending support to the model’s prediction that beta oscillations can be supported by VDCC mediated currents.New and Noteworthy:Olfactory bulb beta oscillations rely on granule cell excitability.Reducing granule cell excitability with scopolamine reduces high volatilityinduced beta power but increases low volatility-induced beta power.Piriform cortex beta oscillations maintain power when olfactory bulb beta power is low, and the system maintains beta band coherence.

Download Full-text