scholarly journals Cholinergic modulation of distinct inhibitory domains in granule cells of the olfactory bulb

2021 ◽  
Author(s):  
Pablo S Villar ◽  
Ruilong Hu ◽  
Batya Teitz ◽  
Ricardo C Araneda
Keyword(s):  
Olfactory Bulb ◽  
Acetylcholine Receptors ◽  
Granule Cells ◽  
Large Population ◽  
Brain Slices ◽  
Proximal Region ◽  
Muscarinic Acetylcholine Receptors ◽  
Inhibitory Neurons ◽  
Local Inhibition ◽  
Opposing Effects

Early olfactory processing relies on a large population of inhibitory neurons in the olfactory bulb (OB), the granule cells (GCs). GCs inhibit the OB output neurons, the mitral and tufted cells (M/TCs), shaping their responses to odors both in the spatial and temporal domains, therefore, the activity of GCs is finely tuned by local and centrifugal excitatory and inhibitory inputs. While the circuit substrates underlying regulatory inputs onto GCs are well-established, how they are locally modulated remains unclear. Here, we examine the regulation of GABAergic inhibition onto GCs by acetylcholine, a main neuromodulatory transmitter released in the OB, by basal forebrain (BF) neurons. In acute brain slices from male and female mice, we show that activation of muscarinic acetylcholine receptors (mAChRs) produces opposing effects on local and centrifugal inhibition onto GCs. By using electrophysiology, laser uncaging and optogenetics we show that the kinetics of GABAergic currents in GCs could be correlated with distal and proximal spatial domains from where they originate, along the GC somatodendritic axis. Proximal inhibition from BF afferents, is suppressed by activation of M2/M4-mAChRs. In contrast, distal local inhibition from deep short axon cells (dSACs) is enhanced by activation of M3-mAChRs. Furthermore, we show that the cholinergic enhancement of distal inhibition in GCs reduces the extent of dendrodendritic inhibition in MCs. Interestingly, the excitatory cortical feedback, which also targets the proximal region of GCs, was not modulated by acetylcholine, suggesting that muscarinic activation shifts the synaptic balance towards excitation in GCs. Together, these results suggest that BF cholinergic inputs to the OB fine tune GC-mediated inhibition of M/TCs by differentially modulating the proximal and distal domains of inhibition in GCs.

scholarly journals Knockouts reveal overlapping functions of M2 and M4 muscarinic receptors and evidence for a local glutamatergic circuit within the laterodorsal tegmental nucleus

2012 ◽  
Vol 108 (10) ◽  
pp. 2751-2766 ◽  
Author(s):  
Kristi A. Kohlmeier ◽  
Masaru Ishibashi ◽  
Jürgen Wess ◽  
Martha E. Bickford ◽  
Christopher S. Leonard
Keyword(s):  
Acetylcholine Receptors ◽  
Brain Slices ◽  
Cholinergic Neurons ◽  
Muscarinic Acetylcholine Receptors ◽  
Feedback Signal ◽  
Laterodorsal Tegmental Nucleus ◽  
Membrane Hyperpolarization ◽  
Whole Cell ◽  
Whole Cell Recording ◽  
Cell Recording

Cholinergic neurons in the laterodorsal tegmental (LDT) and peduncolopontine tegmental (PPT) nuclei regulate reward, arousal, and sensory gating via major projections to midbrain dopamine regions, the thalamus, and pontine targets. Muscarinic acetylcholine receptors (mAChRs) on LDT neurons produce a membrane hyperpolarization and inhibit spike-evoked Ca2+ transients. Pharmacological studies suggest M2 mAChRs are involved, but the role of these and other localized mAChRs (M1--M4) has not been definitively tested. To identify the underlying receptors and to circumvent the limited receptor selectivity of available mAChR ligands, we used light- and electron-immunomicroscopy and whole cell recording with Ca2+ imaging in brain slices from knockout mice constitutively lacking either M2, M4, or both mAChRs. Immunomicroscopy findings support a role for M2 mAChRs, since cholinergic and noncholinergic LDT and pedunculopontine tegmental neurons contain M2-specific immunoreactivity. However, whole cell recording revealed that the presence of either M2 or M4 mAChRs was sufficient, and that the presence of at least one of these receptors was required for these carbachol actions. Moreover, in the absence of M2 and M4 mAChRs, carbachol elicited both direct excitation and barrages of spontaneous excitatory postsynaptic potentials (sEPSPs) in cholinergic LDT neurons mediated by M1 and/or M3 mAChRs. Focal carbachol application to surgically reduced slices suggest that local glutamatergic neurons are a source of these sEPSPs. Finally, neither direct nor indirect excitation were knockout artifacts, since each was detected in wild-type slices, although sEPSP barrages were delayed, suggesting M2 and M4 receptors normally delay excitation of glutamatergic inputs. Collectively, our findings indicate that multiple mAChRs coordinate cholinergic outflow from the LDT in an unexpectedly complex manner. An intriguing possibility is that a local circuit transforms LDT muscarinic inputs from a negative feedback signal for transient inputs into positive feedback for persistent inputs to facilitate different firing patterns across behavioral states.

scholarly journals Classifying neuronal subclasses of the cerebellum through constellation pharmacology

2016 ◽  
Vol 115 (2) ◽  
pp. 1031-1042 ◽  
Author(s):  
Kigen J. Curtice ◽  
Lee S. Leavitt ◽  
Kevin Chase ◽  
Shrinivasan Raghuraman ◽  
Martin P. Horvath ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Gaba Receptors ◽  
Acetylcholine Receptors ◽  
Granule Cells ◽  
Functional Expression ◽  
Muscarinic Acetylcholine Receptors ◽  
Receptor Subtypes ◽  
Mouse Cerebellum ◽  
The Brain

A pressing need in neurobiology is the comprehensive identification and characterization of neuronal subclasses within the mammalian nervous system. To this end, we used constellation pharmacology as a method to interrogate the neuronal and glial subclasses of the mouse cerebellum individually and simultaneously. We then evaluated the data obtained from constellation-pharmacology experiments by cluster analysis to classify cells into neuronal and glial subclasses, based on their functional expression of glutamate, acetylcholine, and GABA receptors, among other ion channels. Conantokin peptides were used to identify N-methyl-d-aspartate (NMDA) receptor subtypes, which revealed that neurons of the young mouse cerebellum expressed NR2A and NR2B NMDA receptor subunits. Additional pharmacological tools disclosed differential expression of α-amino-3-hydroxy-5-methyl-4-isoxazloepropionic, nicotinic acetylcholine, and muscarinic acetylcholine receptors in different neuronal and glial subclasses. Certain cell subclasses correlated with known attributes of granule cells, and we combined constellation pharmacology with genetically labeled neurons to identify and characterize Purkinje cells. This study illustrates the utility of applying constellation pharmacology to classify neuronal and glial subclasses in specific anatomical regions of the brain.

scholarly journals Sniff-Like Patterned Input Results in Long-Term Plasticity at the Rat Olfactory Bulb Mitral and Tufted Cell to Granule Cell Synapse

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Mahua Chatterjee ◽  
Fernando Perez de los Cobos Pallares ◽  
Alex Loebel ◽  
Michael Lukas ◽  
Veronica Egger
Keyword(s):  
Olfactory Bulb ◽  
Granule Cells ◽  
Brain Slices ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Term Potentiation ◽  
Presynaptic Release ◽  
Extra Activity ◽  
Hippocampal Theta

During odor sensing the activity of principal neurons of the mammalian olfactory bulb, the mitral and tufted cells (MTCs), occurs in repetitive bursts that are synchronized to respiration, reminiscent of hippocampal theta-gamma coupling. Axonless granule cells (GCs) mediate self- and lateral inhibitory interactions between the excitatory MTCs via reciprocal dendrodendritic synapses. We have explored long-term plasticity at this synapse by using a theta burst stimulation (TBS) protocol and variations thereof. GCs were excited via glomerular stimulation in acute brain slices. We find that TBS induces exclusively long-term depression in the majority of experiments, whereas single bursts (“single-sniff paradigm”) can elicit both long-term potentiation and depression. Statistical analysis predicts that the mechanism underlying this bidirectional plasticity involves the proportional addition or removal of presynaptic release sites. Gamma stimulation with the same number of APs as in TBS was less efficient in inducing plasticity. Both TBS- and “single-sniff paradigm”-induced plasticity depend on NMDA receptor activation. Since the onset of plasticity is very rapid and requires little extra activity, we propose that these forms of plasticity might play a role already during an ongoing search for odor sources. Our results imply that components of both short-term and long-term olfactory memory may be encoded at this synapse.

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.

scholarly journals Long-range GABAergic inhibition modulates spatiotemporal dynamics of the output neurons in the olfactory bulb

2020 ◽  
Author(s):  
Pablo S. Villar ◽  
Ruilong Hu ◽  
Ricardo C. Araneda
Keyword(s):  
Olfactory Bulb ◽  
Long Range ◽  
Granule Cells ◽  
Brain Slices ◽  
Gabaergic Neurons ◽  
Gabaergic Inhibition ◽  
Top Down ◽  
Local Interneurons ◽  
Output Neurons ◽  
Tufted Cells

SUMMARYLocal interneurons of the olfactory bulb (OB) are densely innervated by long-range GABAergic neurons from the basal forebrain (BF), suggesting that this top-down inhibition regulates early processing in the olfactory system. However, how GABAergic inputs modulate the OB output neurons, the mitral/tufted cells, is unknown. Here, in acute brain slices, we show that optogenetic activation of BF GABAergic inputs produced distinct local circuit effects that can influence the activity of mitral/tufted cells in the spatiotemporal domains. Activation of the GABAergic axons produced a fast disinhibition of mitral/tufted cells consistent with a rapid and synchronous release of GABA onto local interneurons in the glomerular and inframitral circuits of the OB, which also reduced the spike precision of mitral/tufted cells in response to simulated stimuli. In addition, BF GABAergic inhibition modulated local oscillations in a layer-specific manner. The intensity of locally evoked θ oscillations was decreased upon activation of top-down inhibition in the glomerular circuit, while evoked γ oscillations were reduced by inhibition of granule cells. Furthermore, BF GABAergic input reduced dendrodendritic inhibition in mitral/tufted cells. Together, these results suggest that long-range GABAergic neurons from the BF are well suited to influence temporal and spatial aspects of processing by OB circuits.

SK Channel Regulation of Dendritic Excitability and Dendrodendritic Inhibition in the Olfactory Bulb

2005 ◽  
Vol 94 (6) ◽  
pp. 3743-3750 ◽  
Author(s):  
Brady J. Maher ◽  
Gary L. Westbrook
Keyword(s):  
Olfactory Bulb ◽  
Granule Cells ◽  
Brain Slices ◽  
Mitral Cell ◽  
Mitral Cells ◽  
Sk Channels ◽  
Action Potential Firing ◽  
Sk Channel ◽  
Dendritic Excitability ◽  
Potential Firing

Small-conductance calcium-activated potassium channels (SK) regulate dendritic excitability in many neurons. In the olfactory bulb, regulation of backpropagating action potentials and dendrodendritic inhibition depend on the dendritic excitability of mitral cells. We report here that SK channel currents are present in mitral cells but are not detectable in granule cells in the olfactory bulb. In brain slices from PND 14–21 mice, long step depolarizations (100 ms) in the mitral cell soma evoked a cadmium- and apamin-sensitive outward SK current lasting several hundred milliseconds. Block of the SK current unmasked an inward N-methyl-d-aspartate (NMDA) autoreceptor current due to glutamate released from mitral cell dendrites. In low extracellular Mg2+ (100 μM), brief step depolarizations (2 ms) evoked an apamin-sensitive current that was reduced by d,l-2-amino-5-phosphonopentanoic acid. In current- clamp, block of SK channels increased action potential firing in mitral cells as well as dendrodendritic inhibition. Our results indicate that SK channels can be activated either by calcium channels or NMDA channels in mitral cell dendrites, providing a mechanism for local control of dendritic excitability.

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