Specific plasticity loci and their synergism mediate operant conditioning

AbstractDespite numerous studies examining the mechanisms of operant conditioning (OC), the diversity of plasticity loci and their synergism have not been examined sufficiently. In the well-characterized feeding neural circuit of Aplysia, appetitive OC increases neuronal excitability and electrical coupling among several neurons. Here we found OC decreased the intrinsic excitability of B4 and the strength of its inhibitory connection to a key decision-making neuron, B51. The OC-induced changes were specific without affecting the B4-to-B8 inhibitory connection or excitability of another neuron critical for feeding behavior, B8. A conductance-based circuit model indicated certain sites of plasticity mediated the OC phenotype more effectively and that plasticity loci acted synergistically. This synergy was specific in that only certain combinations of loci synergistically enhanced feeding. Taken together, these results suggest modifications of diverse loci work synergistically to mediate OC.Significance StatementThe diversity and synergism of plasticity loci mediating operant conditioning (OC) is poorly understood. Here we found that OC decreased the intrinsic excitability of a critical neuron mediating Aplysia feeding behavior and specifically reduced the strength of one of its inhibitory connections to a key decision-making neuron. A conductance-based computational model indicated that the known plasticity loci showed a surprising level of synergism to mediate the behavioral changes associated with OC. These results highlight the importance of understanding the diversity, specificity and synergy among different types of plasticity that encode memory. Also, because OC in Aplysia is mediated by dopamine (DA), the present study provides insights into specific and synergistic mechanisms of DA-mediated reinforcement of behaviors.

Download Full-text

GABAergic motor neurons bias locomotor decision-making in C. elegans

Nature Communications ◽

10.1038/s41467-020-18893-9 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Ping Liu ◽

Bojun Chen ◽

Zhao-Wen Wang

Keyword(s):

Decision Making ◽

Motor Neurons ◽

Gaba Receptor ◽

Single Neuron ◽

Neural Circuit ◽

Electrical Coupling ◽

C Elegans ◽

Sensory Modalities ◽

Motor Information ◽

Molecular Bases

Abstract Proper threat-reward decision-making is critical to animal survival. Emerging evidence indicates that the motor system may participate in decision-making but the neural circuit and molecular bases for these functions are little known. We found in C. elegans that GABAergic motor neurons (D-MNs) bias toward the reward behavior in threat-reward decision-making by retrogradely inhibiting a pair of premotor command interneurons, AVA, that control cholinergic motor neurons in the avoidance neural circuit. This function of D-MNs is mediated by a specific ionotropic GABA receptor (UNC-49) in AVA, and depends on electrical coupling between the two AVA interneurons. Our results suggest that AVA are hub neurons where sensory inputs from threat and reward sensory modalities and motor information from D-MNs are integrated. This study demonstrates at single-neuron resolution how motor neurons may help shape threat-reward choice behaviors through interacting with other neurons.

Download Full-text

An epitope specific patient-derived LGI1-autoantibody enhances neuronal excitability by modulating the Kv1.1 channel.

10.1101/2021.12.10.471894 ◽

2021 ◽

Author(s):

Johanna Extrémet ◽

Oussama El Far ◽

Sarosh R Irani ◽

Dominique Debanne ◽

Michael Russier

Keyword(s):

Neuronal Excitability ◽

Pyramidal Neurons ◽

Channel Blocker ◽

Intrinsic Excitability ◽

Excitatory Synapses ◽

Loss Of Function ◽

Specific Patient ◽

Domain Specific ◽

Ca3 Pyramidal Neurons ◽

Induced Changes

Leucine-rich Glioma Inactivated protein 1 (LGI1) is expressed in the central nervous and genetic loss of function is associated with epileptic disorders. Also, patients with LGI1-directed autoantibodies have frequent focal seizures as a key feature of their disease. LGI1 is composed of a Leucine Rich Repeat (LRR) and an Epitempin (EPTP) domain. These domains are reported to interact with different aspects of the transsynaptic complex formed by LGI1 at excitatory synapses, including presynaptic Kv1 potassium channels. Patient-derived monoclonal antibodies (mAbs) are ideal reagents to study whether domain-specific LGI1-autoantibodies induce epileptiform activities in neurons, and their downstream mechanisms. To address this question, we measured the intrinsic excitability of CA3 pyramidal neurons in organotypic cultures from rat hippocampus treated with either a LRR- or an EPTP- reactive patient-derived mAb. The antibodies induced changes in neuronal intrinsic excitability which led us to measure their effects on Kv1-type potassium currents. We found an increase of intrinsic excitability correlated with a reduction of the sensitivity to a selective Kv1.1-channel blocker in neurons treated with the LRR mAb compared to the control, but not in neurons treated with the EPTP mAb. Our findings suggest LRR mAbs are able to modulate neuronal excitability that could account for epileptiform activities observed in patients.

Download Full-text

PKA-RIIβ autophosphorylation modulates PKA activity and seizure phenotypes in mice

Communications Biology ◽

10.1038/s42003-021-01748-4 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Jingliang Zhang ◽

Chenyu Zhang ◽

Xiaoling Chen ◽

Bingwei Wang ◽

Weining Ma ◽

...

Keyword(s):

Therapeutic Target ◽

Neurological Disorders ◽

Neuronal Excitability ◽

Granule Cells ◽

Critical Role ◽

Intrinsic Excitability ◽

Seizure Susceptibility ◽

Seizure Onset ◽

Potential Therapeutic Target ◽

Seizure Model

AbstractTemporal lobe epilepsy (TLE) is one of the most common and intractable neurological disorders in adults. Dysfunctional PKA signaling is causally linked to the TLE. However, the mechanism underlying PKA involves in epileptogenesis is still poorly understood. In the present study, we found the autophosphorylation level at serine 114 site (serine 112 site in mice) of PKA-RIIβ subunit was robustly decreased in the epileptic foci obtained from both surgical specimens of TLE patients and seizure model mice. The p-RIIβ level was negatively correlated with the activities of PKA. Notably, by using a P-site mutant that cannot be autophosphorylated and thus results in the released catalytic subunit to exert persistent phosphorylation, an increase in PKA activities through transduction with AAV-RIIβ-S112A in hippocampal DG granule cells decreased mIPSC frequency but not mEPSC, enhanced neuronal intrinsic excitability and seizure susceptibility. In contrast, a reduction of PKA activities by RIIβ knockout led to an increased mIPSC frequency, a reduction in neuronal excitability, and mice less prone to experimental seizure onset. Collectively, our data demonstrated that the autophosphorylation of RIIβ subunit plays a critical role in controlling neuronal and network excitabilities by regulating the activities of PKA, providing a potential therapeutic target for TLE.

Download Full-text

Conflict Resolution as Near-Threshold Decision-Making: A Spiking Neural Circuit Model with Two-Stage Competition for Antisaccadic Task

PLoS Computational Biology ◽

10.1371/journal.pcbi.1005081 ◽

2016 ◽

Vol 12 (8) ◽

pp. e1005081 ◽

Cited By ~ 12

Author(s):

Chung-Chuan Lo ◽

Xiao-Jing Wang

Keyword(s):

Decision Making ◽

Conflict Resolution ◽

Neural Circuit ◽

Circuit Model ◽

Two Stage ◽

Near Threshold

Download Full-text

Major Role For Tonic GABAA Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

Journal of Neurophysiology ◽

10.1152/jn.00223.2004 ◽

2004 ◽

Vol 92 (3) ◽

pp. 1658-1667 ◽

Cited By ~ 86

Author(s):

Mark C. Bieda ◽

M. Bruce MacIver

Keyword(s):

Synaptic Transmission ◽

Neuronal Excitability ◽

Brain Slices ◽

Pyramidal Cells ◽

Intrinsic Excitability ◽

High Potassium ◽

Ca1 Neurons ◽

Adult Rat ◽

Adult Rat Brain ◽

Sites Of Action

Anesthetics appear to produce neurodepression by altering synaptic transmission and/or intrinsic neuronal excitability. Propofol, a widely used anesthetic, has proposed effects on many targets, ranging from sodium channels to GABAA inhibition. We examined effects of propofol on the intrinsic excitability of hippocampal CA1 neurons (primarily interneurons) recorded from adult rat brain slices. Propofol strongly depressed action potential production induced by DC injection, synaptic stimulation, or high-potassium solutions. Propofol-induced depression of intrinsic excitability was completely reversed by bicuculline and picrotoxin but was strychnine-insensitive, implicating GABAA but not glycine receptors. Propofol strongly enhanced inhibitory postsynaptic currents (IPSCs) and induced a tonic GABAA-mediated current. We pharmacologically differentiated tonic and phasic (synaptic) GABAA-mediated inhibition using the GABAA receptor antagonist SR95531 (gabazine). Gabazine (20 μM) completely blocked both evoked and spontaneous IPSCs but failed to block the propofol-induced depression of intrinsic excitability, implicating tonic, but not phasic, GABAA inhibition. Glutamatergic synaptic responses were not altered by propofol (≤30 μM). Similar results were found in both interneurons and pyramidal cells and with the chemically unrelated anesthetic thiopental. These results suggest that suppression of CA1 neuron intrinsic excitability, by these anesthetics, is largely due to activation of tonic GABAA conductances; although other sites of action may play important roles in affecting synaptic transmission, which also can produce strong neurodepression. We propose that for some anesthetics, suppression of intrinsic excitability, mediated by tonic GABAA conductances, operates in conjunction with effects on synaptic transmission, mediated by other mechanisms, to depress hippocampal function during anesthesia.

Download Full-text

A neural circuit linking two sugar sensors regulates satiety-dependent fructose drive in Drosophila

10.1101/2021.04.08.439043 ◽

2021 ◽

Author(s):

Pierre-Yves Musso ◽

Pierre Junca ◽

Michael D Gordon

Keyword(s):

Feeding Behavior ◽

Synaptic Input ◽

Neural Circuit ◽

Internal State ◽

Calcium Activity ◽

Shaped Body ◽

Body Activity ◽

The Brain

ABSTRACTIngestion of certain sugars leads to activation of fructose sensors within the brain of flies, which then sustain or terminate feeding behavior depending on internal state. Here, we describe a three-part neural circuit that links satiety with fructose sensing. We show that AB-FBl8 neurons of the Fan-shaped body display oscillatory calcium activity when hemolymph glycemia is high, and that these oscillations require synaptic input from SLP-AB neurons projecting from the protocerebrum to the asymmetric body. Suppression of activity in this circuit, either by starvation or genetic silencing, promotes specific drive for fructose ingestion. Moreover, neuropeptidergic signaling by tachykinin bridges fan-shaped body activity and Gr43a-mediated fructose sensing. Together, our results demonstrate how a three-layer neural circuit links the detection of two sugars to impart precise satiety-dependent control over feeding behavior.

Download Full-text

Rem2 stabilizes intrinsic excitability and spontaneous firing in visual circuits

eLife ◽

10.7554/elife.33092 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 5

Author(s):

Anna R Moore ◽

Sarah E Richards ◽

Katelyn Kenny ◽

Leandro Royer ◽

Urann Chan ◽

...

Keyword(s):

Neuronal Excitability ◽

Ocular Dominance ◽

Sensory Experience ◽

Cellular Level ◽

Synaptic Function ◽

Intrinsic Excitability ◽

Spontaneous Firing ◽

Circuit Function

Sensory experience plays an important role in shaping neural circuitry by affecting the synaptic connectivity and intrinsic properties of individual neurons. Identifying the molecular players responsible for converting external stimuli into altered neuronal output remains a crucial step in understanding experience-dependent plasticity and circuit function. Here, we investigate the role of the activity-regulated, non-canonical Ras-like GTPase Rem2 in visual circuit plasticity. We demonstrate that Rem2-/- mice fail to exhibit normal ocular dominance plasticity during the critical period. At the cellular level, our data establish a cell-autonomous role for Rem2 in regulating intrinsic excitability of layer 2/3 pyramidal neurons, prior to changes in synaptic function. Consistent with these findings, both in vitro and in vivo recordings reveal increased spontaneous firing rates in the absence of Rem2. Taken together, our data demonstrate that Rem2 is a key molecule that regulates neuronal excitability and circuit function in the context of changing sensory experience.

Download Full-text

Changes in the Activity of a CPG Neuron After the Reinforcement of an Operantly Conditioned Behavior in Lymnaea

Journal of Neurophysiology ◽

10.1152/jn.2002.88.4.1915 ◽

2002 ◽

Vol 88 (4) ◽

pp. 1915-1923 ◽

Cited By ~ 38

Author(s):

Gaynor E. Spencer ◽

Mustapha H. Kazmi ◽

Naweed I. Syed ◽

Ken Lukowiak

Keyword(s):

Operant Conditioning ◽

Sensory Input ◽

Lymnaea Stagnalis ◽

Training Stimulus ◽

Rhythmic Activity ◽

Neural Correlates ◽

Behavioral Changes ◽

Conditioned Behavior ◽

Before And After ◽

Respiratory Behavior

We have previously shown that the aerial respiratory behavior of the mollusk Lymnaea stagnalis can be operantly conditioned, and the central pattern generating (CPG) neurons underlying this behavior have been identified. As neural correlates of operant conditioning remain poorly defined in both vertebrates and invertebrates, we have used the Lymnaea respiratory CPG to investigate neuronal changes associated with the change in behavior after conditioning. After operant conditioning of the intact animals, semi-intact preparations were dissected, so that changes in the respiratory behavior (pneumostome openings) and underlying activity of the identified CPG neuron, right pedal dorsal 1 (RPeD1), could be monitored simultaneously. RPeD1 was studied because it initiates the rhythmic activity of the CPG and receives chemo-sensory input from the pneumostome area. Pneumostome openings and RPeD1 activity were monitored both before and after a reinforcing training stimulus applied to the open pneumostome of operantly conditioned and yoked control preparations. After presentation of the reinforcing stimulus, there was a significant reduction in both breathing behavior and RPeD1 activity in operant preparations but not in yoked and naı̈ve controls. Furthermore these changes were only significant in the subgroup of operantly conditioned animals described as good learners and not in poor learners. These data strongly suggest that changes in RPeD1 activity may underlie the behavioral changes associated with the reinforcement of operant conditioning of the respiratory behavior.

Download Full-text

Response to coincident inputs in electrically coupled primary afferents is heterogeneous and is enhanced by H-current (IH) modulation

Journal of Neurophysiology ◽

10.1152/jn.00029.2019 ◽

2019 ◽

Vol 122 (1) ◽

pp. 151-175

Author(s):

Federico Davoine ◽

Sebastian Curti

Keyword(s):

Neuronal Excitability ◽

Signal To Noise Ratio ◽

Electrical Coupling ◽

Primary Afferents ◽

Coincidence Detection ◽

Mammalian Brain ◽

Electrical Transmission ◽

Electrical Synapses ◽

Electrophysiological Properties ◽

Cationic Current

Electrical synapses represent a widespread modality of interneuronal communication in the mammalian brain. These contacts, by lowering the effectiveness of random or temporally uncorrelated inputs, endow circuits of coupled neurons with the ability to selectively respond to simultaneous depolarizations. This mechanism may support coincidence detection, a property involved in sensory perception, organization of motor outputs, and improvement signal-to-noise ratio. While the role of electrical coupling is well established, little is known about the contribution of the cellular excitability and its modulations to the susceptibility of groups of neurons to coincident inputs. Here, we obtained dual whole cell patch-clamp recordings of pairs of mesencephalic trigeminal (MesV) neurons in brainstem slices from rats to evaluate coincidence detection and its determinants. MesV neurons are primary afferents involved in the organization of orofacial behaviors whose cell bodies are electrically coupled mainly in pairs through soma-somatic gap junctions. We found that coincidence detection is highly heterogeneous across the population of coupled neurons. Furthermore, combined electrophysiological and modeling approaches reveal that this heterogeneity arises from the diversity of MesV neuron intrinsic excitability. Consistently, increasing these cells’ excitability by upregulating the hyperpolarization-activated cationic current ( IH) triggered by cGMP results in a dramatic enhancement of the susceptibility of coupled neurons to coincident inputs. In conclusion, the ability of coupled neurons to detect coincident inputs is critically shaped by their intrinsic electrophysiological properties, emphasizing the relevance of neuronal excitability for the many functional operations supported by electrical transmission in mammals. NEW & NOTEWORTHY We show that the susceptibility of pairs of coupled mesencephalic trigeminal (MesV) neurons to coincident inputs is highly heterogenous and depends on the interaction between electrical coupling and neuronal excitability. Additionally, upregulating the hyperpolarization-activated cationic current ( IH) by cGMP results in a dramatic increase of this susceptibility. The IH and electrical synapses have been shown to coexist in many neuronal populations, suggesting that modulation of this conductance could represent a common strategy to regulate circuit operation supported by electrical coupling.

Download Full-text