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Learning & Memory (Cold Spring Harbor,... Dec 2022Empirical and computational methods were combined to examine whether individual or dual-drug treatments can restore the deficit in long-term synaptic facilitation (LTF)...
Empirical and computational methods were combined to examine whether individual or dual-drug treatments can restore the deficit in long-term synaptic facilitation (LTF) of the sensorimotor synapse observed in a cellular model of Coffin-Lowry syndrome (CLS). The model was produced by pharmacological inhibition of p90 ribosomal S6 kinase (RSK) activity. In this model, coapplication of an activator of the mitogen-activated protein kinase (MAPK) isoform ERK and an activator of protein kinase A (PKA) resulted in enhanced phosphorylation of RSK and enhanced LTF to a greater extent than either drug alone and also greater than their additive effects, which is termed synergism. The extent of synergism appeared to depend on another MAPK isoform, p38 MAPK. Inhibition of p38 MAPK facilitated serotonin (5-HT)-induced RSK phosphorylation, indicating that p38 MAPK inhibits activation of RSK. Inhibition of p38 MAPK combined with activation of PKA synergistically activated both ERK and RSK. Our results suggest that cellular models of disorders that affect synaptic plasticity and learning, such as CLS, may constitute a useful strategy to identify candidate drug combinations, and that combining computational models with empirical tests of model predictions can help explain synergism of drug combinations.
Topics: Humans; Coffin-Lowry Syndrome; Cyclic AMP-Dependent Protein Kinases; Mitogen-Activated Protein Kinases; Neuronal Plasticity; p38 Mitogen-Activated Protein Kinases; Serotonin
PubMed: 36446603
DOI: 10.1101/lm.053625.122 -
Bioorganic & Medicinal Chemistry Dec 2022A photo-clickable analog of adenosine was devised and synthesized in which the photoactive functional group (8-azidoadenosine) and the click moiety...
A photo-clickable analog of adenosine was devised and synthesized in which the photoactive functional group (8-azidoadenosine) and the click moiety (2'-O-propargyl-ether) were compactly combined within the structure of the adenosine nucleoside itself. We synthesized 8-N-2'-O-propargyl adenosine in four steps starting from adenosine. This photo-clickable adenosine was 5'-phosphorylated and coupled to nicotinamide mononucleotide to form the NAD analog 8-N-2'-O-propargyl-NAD. This NAD analog was recognized by Aplysia californica ADP-ribosyl cyclase and enzymatically cyclized producing 8-N-2'-O-propargyl cyclic ADP-ribose. Photo-clickable cyclic-ADP-ribose analog was envisioned as a probe to label cyclic ADP-ribose binding proteins. The monofunctional 8-N-cADPR has previously been shown to be an antagonist of cADPR-induced calcium release [T.F. Walseth et. al., J. Biol. Chem (1993) 268, 26686-26691]. 2'-O-propargyl-cADPR was recognized as an agonist which elicited Ca release when added at low concentration to sea urchin egg homogenates. The bifunctional 8-N-2'-O-propargyl cyclic ADP-ribose did not elicit Ca release at low concentration or impact cyclic ADP-ribose mediated Ca release either when added to sea urchin egg homogenates or when microinjected into cultured human U2OS cells. The photo-clickable adenosine will none-the-less be a useful scaffold for synthesizing photo-clickable probes for identifying proteins that interact with a variety of adenosine nucleotides.
Topics: Humans; Cyclic ADP-Ribose; NAD; Adenosine
PubMed: 36446271
DOI: 10.1016/j.bmc.2022.117099 -
Frontiers in Behavioral Neuroscience 2022Learning to identify and predict threats is a basic skill that allows animals to avoid harm. Studies in invertebrates like , and have revealed that the basic mechanisms... (Review)
Review
Learning to identify and predict threats is a basic skill that allows animals to avoid harm. Studies in invertebrates like , and have revealed that the basic mechanisms of learning and memory are conserved. We will summarize these studies and highlight the common pathways and mechanisms in invertebrate fear-associated behavioral changes. Fear conditioning studies utilizing electric shock in and have demonstrated that serotonin or dopamine are typically involved in relaying aversive stimuli, leading to changes in intracellular calcium levels and increased presynaptic neurotransmitter release and short-term changes in behavior. Long-term changes in behavior typically require multiple, spaced trials, and involve changes in gene expression. studies have demonstrated these basic aversive learning principles as well; however, fear conditioning has yet to be explicitly demonstrated in this model due to stimulus choice. Because predator-prey relationships can be used to study learned fear in a naturalistic context, this review also summarizes what is known about predator-induced behaviors in these three organisms, and their potential applications for future investigations into fear conditioning.
PubMed: 36439964
DOI: 10.3389/fnbeh.2022.1008818 -
Scientific Reports Nov 2022Nowadays, there is a huge gap between autonomous vehicles and mankind in terms of the decision response against some dangerous scenarios, which would has stressed the...
Nowadays, there is a huge gap between autonomous vehicles and mankind in terms of the decision response against some dangerous scenarios, which would has stressed the potential users out and even made them nervous. To efficiently identify the possible sensitivity scenarios, a new neural network configuration, named sensitive non-associative learning network (SNAL), is proposed. In such structure, the modulated interneurons, excited by abnormal scene stimulation for scene processing, are well processed and utilized to improve the training structure which refers to the sensitization mechanism in non-associative learning in neurobiology and the neural structure of Aplysia. When encountering the sensitivity scenes that the automatic driving agent is not good at or has not seen, the modulated interneuron facilitates the full connection layer neurons for the decision-making process, so as to change the final automatic driving strategy. In the process of constructing the model, a method to measure the similarity of the convolution feature map is proposed, which provides a new investigation tool for the properties of convolution networks after the feature extraction. Based on the Morris-Lecar equation in neurobiology, the dynamic model of modulating interneurons in the network is constructed. The automatic control optimization of the model is carried out by imitating the biological properties. The optimization method provides a reference for introducing neurobiological mechanism into deep learning and automatic control. To validate the effectiveness of the proposed method, the simulation test are executed and the existing methods are compared accordingly. The results show that the proposed SNAL algorithm can effectively recognize the sensitivity mechanism. Furthermore, compared with the existing algorithms, such as CNN, LSTM, ViT, the proposed algorithm can make better defensive strategies for potentially dangerous scenes rarely seen or not seen in the training stage. This sensitivity mechanism is more in line with the human driving intuition when dealing with abnormal driving scenes, and makes the decision more interpretable, significantly improving the traffic ability of autonomous vehicles under the sensitive scenes. In addition, this configuration can be easily combined with the existing mainstream neural network models and has good expansibility.
Topics: Humans; Neural Networks, Computer; Algorithms; Automobile Driving; Computer Simulation
PubMed: 36414644
DOI: 10.1038/s41598-022-24674-9 -
Biological Cybernetics Dec 2022Motor systems show an overall robustness, but because they are highly nonlinear, understanding how they achieve robustness is difficult. In many rhythmic systems,...
Motor systems show an overall robustness, but because they are highly nonlinear, understanding how they achieve robustness is difficult. In many rhythmic systems, robustness against perturbations involves response of both the shape and the timing of the trajectory. This makes the study of robustness even more challenging. To understand how a motor system produces robust behaviors in a variable environment, we consider a neuromechanical model of motor patterns in the feeding apparatus of the marine mollusk Aplysia californica (Shaw et al. in J Comput Neurosci 38(1):25-51, 2015; Lyttle et al. in Biol Cybern 111(1):25-47, 2017). We established in (Wang et al. in SIAM J Appl Dyn Syst 20(2):701-744, 2021. https://doi.org/10.1137/20M1344974 ) the tools for studying combined shape and timing responses of limit cycle systems under sustained perturbations and here apply them to study robustness of the neuromechanical model against increased mechanical load during swallowing. Interestingly, we discover that nonlinear biomechanical properties confer resilience by immediately increasing resistance to applied loads. In contrast, the effect of changed sensory feedback signal is significantly delayed by the firing rates' hard boundary properties. Our analysis suggests that sensory feedback contributes to robustness in swallowing primarily by shifting the timing of neural activation involved in the power stroke of the motor cycle (retraction). This effect enables the system to generate stronger retractor muscle forces to compensate for the increased load, and hence achieve strong robustness. The approaches that we are applying to understanding a neuromechanical model in Aplysia, and the results that we have obtained, are likely to provide insights into the function of other motor systems that encounter changing mechanical loads and hard boundaries, both due to mechanical and neuronal firing properties.
Topics: Animals; Aplysia; Feedback, Sensory; Gravitation
PubMed: 36396795
DOI: 10.1007/s00422-022-00951-8 -
The FEBS Journal Feb 2023So far one gene for Hv1 has been detected in studied species. The work presented by Chaves et al. in The FEBS Journal reported an 'Unexpected expansion of the...
So far one gene for Hv1 has been detected in studied species. The work presented by Chaves et al. in The FEBS Journal reported an 'Unexpected expansion of the voltage-gated proton channel family'. They searched for proton channel candidates and found three sequences in the genome of Aplysia californica (Ac), which were named AcHv1, AcHv2 and AcHv3. Based on electrophysiological experiments, AcHv1 and AcHv2 are voltage-gated channels. While AcHv1 behaves like Hv1 in other species, that is, it is voltage and pH-dependent, it can be inhibited by zinc and conducts protons outwardly, AcHv2 conducts protons inwards at symmetrical pH. AcHv3 constantly leaks protons, and its C-terminal part contains several cytoplasmic retention motifs. Through carefully designed and carried out electrophysiological experiments, Chaves et al. determined the biophysical parameters of all three proton channels, such as the voltage and the pH dependence, the threshold-voltage, the gating charge and the time constants of activation and inactivation. Comment on: https://doi.org/10.1111/febs.16617.
Topics: Protons; Ion Channel Gating; Ion Channels; Zinc
PubMed: 36315610
DOI: 10.1111/febs.16670 -
Proceedings of the National Academy of... Oct 2022Two-trial learning in reveals nonlinear interactions between training trials: A single trial has no effect, but two precisely spaced trials induce long-term memory....
Two-trial learning in reveals nonlinear interactions between training trials: A single trial has no effect, but two precisely spaced trials induce long-term memory. Extracellularly regulated kinase (ERK) activity is essential for intertrial interactions, but the mechanism remains unresolved. A combination of immunochemical and optogenetic tools reveals unexpected complexity of ERK signaling during the induction of long-term synaptic facilitation by two spaced pulses of serotonin (5-hydroxytryptamine, 5HT). Specifically, dual ERK phosphorylation at its activating TxY motif is accompanied by dephosphorylation at the pT position, leading to a buildup of inactive, singly phosphorylated pY-ERK. Phosphorylation and dephosphorylation occur concurrently but scale differently with varying 5HT concentrations, predicting that mixed two-trial protocols involving both "strong" and "weak" 5HT pulses should be sensitive to the precise order and timing of trials. Indeed, long-term synaptic facilitation is induced only when weak pulses precede strong, not vice versa. This may represent a physiological mechanism to prioritize memory of escalating threats.
Topics: Animals; Aplysia; Extracellular Signal-Regulated MAP Kinases; Memory, Long-Term; Optogenetics; Phosphorylation; Repetition Priming; Serotonin; Time Factors
PubMed: 36161885
DOI: 10.1073/pnas.2210478119 -
Scandinavian Journal of Pain Apr 2023Although neurobiological research has shown that interoception plays a role in the perception of pain and its chronification, the relationship between interoceptive...
Can interoceptive sensitivity provide information on the difference in the perceptual mechanisms of recurrent and chronic pain? Part I. A retrospective clinical study related to multidimensional pain assessment.
OBJECTIVES
Although neurobiological research has shown that interoception plays a role in the perception of pain and its chronification, the relationship between interoceptive sensitivity and pain has not been definitively confirmed by clinical studies. The aim of this study was therefore to better understand the relationship between interoceptive sensitivity, somatization, and clinical pain, and to identify any differences in the interoceptive sensitivity of patients with recurrent vs. chronic pain.
METHODS
Scores from 43 Chronic pain subjects, assessed using ICD-11 Criteria; 42 healthy subjects (without pain or psychiatric disorders); and 38 recurrent pain subjects on the Multidimensional Assessment of Interoceptive Awareness (MAIA), Body Perception Questionnaire (BPQ-SF), Somatosensory amplification scale (SSAS), Patient Health Questionnaire (PHQ-15), Symptom Checklist-Revised (SCL-90-R), and Italian Pain Questionnaire (IPQ) were compared.
RESULTS
Negative attention to the body was indicated by higher scores of psychosomatic dimensions as SSAS, SCL90R somatization, and PHQ-15 in recurrent, but especially chronic pain (p<0.000 for all). An increase in psychosomatic dimension scores (i.e., somatization, somatosensory amplification) was associated with an increase in both autonomic nervous system reactivity (ANSR) dimension scores and the negative influence of the Not-worrying, attention regulation and trusting of the MAIA. In contrast, the presence of pain and scores for its dimensions with associated with lower supra-diaphragmatic activity as per the BPQ.
CONCLUSIONS
Pain chronification might depend on both the impairment of interoceptive sensitivity and an increase on psychosomatic dimensions via modification of ANSR hyperactivity and a reduction of the MAIA Not-worrying dimension.
Topics: Humans; Awareness; Chronic Pain; Retrospective Studies; Pain Measurement; Anxiety
PubMed: 36131533
DOI: 10.1515/sjpain-2022-0040 -
Journal of Comparative Physiology. A,... Nov 2022Anorexia due to aging is recognized as a syndrome of animal feeding behavior. Age-related functional disorders of the brain often cause behavioral changes. We used...
An age-related decline in the cholinergic synaptic response may cause the firing pattern in the jaw-closing motor neurons, which resembles the aversive taste response in the feeding behavior of old Aplysia kurodai.
Anorexia due to aging is recognized as a syndrome of animal feeding behavior. Age-related functional disorders of the brain often cause behavioral changes. We used Aplysia kurodai to study this neural mechanism, following our previous study on food preference behaviors. The age of each wild animal was defined by a previously described method, and a significant age-related decline in food intake was observed. In this study, we explored the effects of aging on a specific inhibitory synaptic response in jaw-closing (JC) motor neurons produced by cholinergic multiaction (MA) neurons, the size of which determines the delay between MA and JC firings and this delay is reduced during aversive taste responses; in our analyses, we found a significant age-related decline in the synaptic response. Thereafter, we further explored whether such functional decline affects the JC firing pattern during the normal feeding response. During the feeding-like rhythmic responses induced by electrical nerve stimulation, the firing of the JC motor neurons advanced toward that of the MA burst, which typically happens during aversive taste responses. These results suggest that the age-related decline in the cholinergic synaptic response may partly cause the JC firing patterns that resemble the aversive taste response in old animals.
Topics: Animals; Aplysia; Motor Neurons; Feeding Behavior; Brain; Cholinergic Agents
PubMed: 36104576
DOI: 10.1007/s00359-022-01573-y -
The FEBS Journal Feb 2023Voltage-gated ion channels, whose first identified function was to generate action potentials, are divided into subfamilies with numerous members. The family of...
Voltage-gated ion channels, whose first identified function was to generate action potentials, are divided into subfamilies with numerous members. The family of voltage-gated proton channels (H ) is tiny. To date, all species found to express H have exclusively one gene that codes for this unique ion channel. Here we report the discovery and characterization of three proton channel genes in the classical model system of neural plasticity, Aplysia californica. The three channels (AcH 1, AcH 2, and AcH 3) are distributed throughout the whole animal. Patch-clamp analysis confirmed proton selectivity of these channels but they all differed markedly in gating. AcH 1 gating resembled H in mammalian cells where it is responsible for proton extrusion and charge compensation. AcH 2 activates more negatively and conducts extensive inward proton current, properties likely to acidify the cytosol. AcH 3, which differs from AcH 1 and AcH 2 in lacking the first arginine in the S4 helix, exhibits proton selective leak currents and weak voltage dependence. We report the expansion of the proton channel family, demonstrating for the first time the expression of three functionally distinct proton channels in a single species.
Topics: Animals; Ion Channel Gating; Protons; Ion Channels; Arginine; Cytosol; Mammals
PubMed: 36062330
DOI: 10.1111/febs.16617