Command Neurons Research Articles

InVivo Ca(2+) Imaging Reveals that Decreased Dendritic Excitability Drives Startle Habituation.

Exposure to repetitive startling stimuli induces habitation, a simple form of learning. Despite its simplicity, the precise cellular mechanisms by which repeated stimulation converts a robust behavioral response to behavioral indifference are unclear. Here, we use head-restrained zebrafish larvae to monitor subcellular Ca(2+) dynamics in Mauthner neurons, the startle command neurons, during startle habituation in vivo. Using the Ca(2+) reporter GCaMP6s, we find that the amplitude of Ca(2+) signals in the lateral dendrite of the Mauthner neuron determines startle probability and that depression of this dendritic activity rather than downstream inhibition mediates glycine and N-methyl-D-aspartate (NMDA)-receptor-dependent short-term habituation. Combined, our results suggest a model for habituation learning in which increased inhibitory drive from feedforward inhibitory neurons combined with decreased excitatory input from auditory afferents decreases dendritic and Mauthner neuron excitability.

Experimental observation of multistability and dynamic attractors in silicon central pattern generators.

We report on the multistability of chaotic networks of silicon neurons and demonstrate how spatiotemporal sequences of voltage oscillations are selected with timed current stimuli. A three neuron central pattern generator was built by interconnecting Hodgkin-Huxley neurons with mutually inhibitory links mimicking gap junctions. By systematically varying the timing of current stimuli applied to individual neurons, we generate the phase lag maps of neuronal oscillators and study their dependence on the network connectivity. We identify up to six attractors consisting of triphasic sequences of unevenly spaced pulses propagating clockwise and anticlockwise. While confirming theoretical predictions, our experiments reveal more complex oscillatory patterns shaped by the ratio of the pulse width to the oscillation period. Our work contributes to validating the command neuron hypothesis.

Excitation and inhibition onto central courtship neurons biases Drosophila mate choice.

The ability to distinguish males from females is essential for productive mate selection and species propagation. Recent studies in Drosophila have identified different classes of contact chemosensory neurons that detect female or male pheromones and influence courtship decisions. Here, we examine central neural pathways in the male brain that process female and male pheromones using anatomical, calcium imaging, optogenetic, and behavioral studies. We find that sensory neurons that detect female pheromones, but not male pheromones, activate a novel class of neurons in the ventral nerve cord to cause activation of P1 neurons, male-specific command neurons that trigger courtship. In addition, sensory neurons that detect male pheromones, as well as those that detect female pheromones, activate central mAL neurons to inhibit P1. These studies demonstrate that the balance of excitatory and inhibitory drives onto central courtship-promoting neurons controls mating decisions.

Coordinated autonomic and respiratory responses evoked by alerting stimuli: Role of the midbrain colliculi

Threatening stimuli trigger rapid and coordinated behavioral responses supported by cardiorespiratory changes. The midbrain colliculi can generate coordinated orienting or defensive behavioral responses, and it has been proposed that collicular neurons also generate appropriate cardiovascular and respiratory responses to support such behaviors. We have shown previously that under conditions where collicular neurons are disinhibited, coordinated cardiovascular, somatomotor and respiratory responses can be evoked independently of the cortex by auditory, visual and somatosensory stimuli. Here we report that these natural stimuli effectively increase inspiratory time most likely though phase switching. As a result the pattern of phrenic and sympathetic coupling is an inspiratory-related sympathoexcitation. We propose that blockade of tonic GABAergic input in the midbrain colliculi permits alerting stimuli to drive command neurons that generate coordinated cardiovascular, respiratory and motor outputs. The outputs of these command neurons likely interact with the central respiratory pattern generator, however the precise output pathways mediating the coordinated autonomic and respiratory responses remain to be determined.

Descending Command Neurons in the Brainstem that Halt Locomotion

The episodic nature of locomotion is thought to be controlled by descending inputs from the brainstem. Most studies have largely attributed this control to initiating excitatory signals, but little is known about putative commands that may specifically determine locomotor offset. To link identifiable brainstem populations to a potential locomotor stop signal, we used developmental genetics and considered a discrete neuronal population in the reticular formation: the V2a neurons. We find that those neurons constitute a major excitatory pathway to locomotor areas of the ventral spinal cord. Selective activation of V2a neurons of the rostral medulla stops ongoing locomotor activity, owing to an inhibition of premotor locomotor networks in the spinal cord. Moreover, inactivation of such neurons decreases spontaneous stopping in vivo. Therefore, the V2a "stop neurons" represent a glutamatergic descending pathway that favors immobility and may thus help control the episodic nature of locomotion.

Neuronal control of walking: studies on insects

The control of walking in insects is to a substantial amount a function of neuronal networks in the thoracic ganglia. While descending signals from head ganglia provide general commands such as for walking direction and velocity, it is the thoracic central nervous system that controls movements of individual joints and legs. The coordination pattern of legs is velocity dependent. However, a clear stereotypic coordination pattern appears only at high velocities. In accordance with the unit burst oscillator concept, oscillatory networks (central pattern generators (CPGs)) interlocked with movement and load sensors control the timing and amplitude of joint movements. For a leg’s movements different joint CPGs of a leg are mainly coupled by proprioceptors. Differential processing of proprioceptive signals allows a task specific modulation of leg movements, for example, for changing movement direction. A switch between walking and searching movements of a leg is under local control. When stepping into a gap missing sensory input and the activation of a local command neuron evokes stereotypic searching movements of the leg.

A Subset of Serotonergic Neurons Evokes Hunger in Adult Drosophila

Hunger is a complex motivational state that drives multiple behaviors. The sensation of hunger is caused by an imbalance between energy intake and expenditure. One immediate response to hunger is increased food consumption. Hunger also modulates behaviors related to food seeking such as increased locomotion and enhanced sensory sensitivity in both insects and vertebrates. In addition, hunger can promote the expression of food-associated memory. Although progress is being made, how hunger is represented in the brain and how it coordinates these behavioral responses is not fully understood in any system. Here, we use Drosophila melanogaster to identify neurons encoding hunger. We found a small group of neurons that, when activated, induced a fed fly to eat as though it were starved, suggesting that these neurons are downstream of the metabolic regulation of hunger. Artificially activating these neurons also promotes appetitive memory performance in sated flies, indicating that these neurons are not simply feeding command neurons but likely play a more general role in encoding hunger. We determined that the neurons relevant for the feeding effect are serotonergic and project broadly within the brain, suggesting a possible mechanism for how various responses to hunger are coordinated. These findings extend our understanding of the neural circuitry that drives feeding and enable future exploration of how state influences neural activity within this circuit.

Habituation-Like Decrease of Acetylcholine-Induced Inward Current in Helix Command Neurons: Role of Microtubule Motor Proteins.

The role of kinesin and dynein microtubule-associated molecular motors in the cellular mechanism of depression of acetylcholine-induced inward chloride current (ACh-current) was examined in command neurons of land snails (Helix lucorum) in response to repeated applications of ACh to neuronal soma. This pharmacological stimulation imitated the protocol of tactile stimulation evoking behavioural habituation of the defensive reaction. In this system, a dynein inhibitor (erythro-9-(2-hydroxy-3-nonyl)adenine, 50 µM) decreased the ACh-current depression rate. Kinesin Eg5 inhibitors (Eg5 inhibitor III, 10 µM and Eg5 inhibitor V, trans-24, 15 µM) reduced the degree of current depression, and Eg5 inhibitor V also reduced the initial rate of depression. The results of electrophysiological experiments in combination with mathematical modelling provided evidence of the participation of dyneins and kinesin Eg5 proteins in the radial transport of acetylcholine receptors in command neurons of H. lucorum in the cellular analogue of habituation. Furthermore, these results suggest that the reciprocal interaction between dynein and kinesin proteins located on the same vesicle can lead to reverse their usual direction of transport (dyneins-in exocytosis and kinesin Eg5-in endocytosis).

Differences in the Molecular Mechanisms of Long-Term Synaptic Facilitation in Associative Learning and Sensitization

Studies on defensive behavior command neurons Lpl1 and Rpl1 in common snails addressed the involvement of translation and transcription processes in the mechanisms of synaptic plasticity during acquisition of conditioned taste aversion. In control snails, combinations of the taste stimulus (carrot juice) and the reinforcing stimulus (concentrated quinine solution) led to changes in neuron responses characteristic for both conditioning and concomitant sensitization. Facilitation of responses to a sensory chemical stimulus (dilute quinine solution) occurred 1 h after training started, with facilitation of reactions to the conditioned food stimulus occurring at 1.5 h. Application of the protein synthesis inhibitor cycloheximide during conditioning suppressed facilitation of responses to both dilute quinine solution and the conditioned food stimulus. However, application of the RNA synthesis inhibitor actinomycin D to neurons produced selective suppression of synaptic facilitation in responses to sensory stimulation with dilute quinine solution, but had no effect on synaptic facilitation in responses to the conditioned stimulus. It is suggested that the acquisition of conditioned taste aversion in snails induces long-term synaptic facilitation in nerve cells Lpl1 and Rpl1 typical of conditioning and sensitization processes, whose induction requires different molecular-genetic mechanisms.

Efficacy of the Omega-3 Index in predicting NAFLD in overweight and obese adults: A pilot study

ral pathways directed to WAT, BAT and brite/beige fat. Specifically, pseudorabies virus (PRV Bartha) was injected into inguinal WAT (iWAT), interscapular BAT (iBAT) and iWAT transformed to include brite/beige fat cells by exposure of rats to 8 ◦C for 7 days. After injection of PRV with different fluorescent reporters (PRV-red/PRV-green) into the various fat pads, rats were allowed to survive for 5 days to allow transport through the autonomic neuraxis before sacrifice and subsequent histolological analysis to assess the distribution of transynaptically viral-infected neurons. After injection of PRV-red or PRV-green into each of the fat depots in the same animal, distinct labelling patterns were observed in 1st, 2nd, 3rd and 4th order neurons in paravertebral ganglia, spinal cord, brain stem, midbrain and hypothalamus. In addition to these ‘‘private lines’’ of communication to various fat pads, populations of ‘‘command neurons’’ were identified which had collateral axonal projections to different fat pads including those to both brown and white fat. Moreover, the relative percentage of these ‘‘command’’ neurons projecting to iBAT and beiged iWAT increased under conditions of cold exposure. These data including the unique identification of ‘‘command’’ controllers of fat involved with both storage and burning of energy provide a neuroanatomical basis for differentiating the central neural control of white, brown and white fat transferred into brite/beige fat.

The Role of Myosins in Depression of Neuron Sensitivity to Acetylcholine in a Cellular Analog of Habituation in the Common Snail

The involvement of cytoskeletal motor proteins, i.e., myosins, in the molecular mechanism of depression of the acetylcholine sensitivity of defensive behavior command neurons was studied in the common snail. Thus, the effects of compounds impairing myosin functioning on ACh-evoked current depression curves in neurons were studied – the myosin light chain kinase blockers ML-7 and MLCK-IP-18, the non-muscle myosin II inhibitor blebbistatin, and the ROCK-I and ROCK-II kinase (which mainly activate non-muscle myosin II) inhibitor Y-27632. ML-7 and MLCK-IP-18 were found to weaken depression of the current, while blebbistatin and Y-27632 had no effect on depression. The experimental results and mathematical models of the effects of these blockers on the number of membrane-bound cholinoreceptors suggest the involvement of myosins (except non-muscle myosin II) in the endo- and exocytosis of cholinoreceptors and the resultant depression of the cholinosensitivity of the somatic membranes of neurons in a cellular analog of habituation.

Disinhibition of the midbrain colliculi unmasks coordinated autonomic, respiratory, and somatomotor responses to auditory and visual stimuli.

The midbrain superior and inferior colliculi have critical roles in generating coordinated orienting or defensive behavioral responses to environmental stimuli, and it has been proposed that neurons within the colliculi can also generate appropriate cardiovascular and respiratory responses to support such behavioral responses. We have previously shown that activation of neurons within a circumscribed region in the deep layers of the superior colliculus and in the central and external nuclei of the inferior colliculus can evoke a response characterized by intense and highly synchronized bursts of renal sympathetic nerve activity and phrenic nerve activity. In this study, we tested the hypothesis that, under conditions in which collicular neurons are disinhibited, coordinated cardiovascular, somatomotor, and respiratory responses can be evoked by natural environmental stimuli. In response to natural auditory, visual, or somatosensory stimuli, powerful synchronized increases in sympathetic, respiratory, and somatomotor activity were generated following blockade of GABAA receptors in a specific region in the midbrain colliculi of anesthetized rats, but not under control conditions. Such responses still occurred after removal of most of the forebrain, including the amygdala and hypothalamus, indicating that the essential pathways mediating these coordinated responses were located within the brain stem. The temporal relationships between the different outputs suggest that they are driven by a common population of "command neurons" within the colliculi.

The Role of Serine/Threonine and Tyrosine Protein Phosphatases in Common Snail Command Neurons in a Cellular Analog of Habituation

The effects of inhibitors of a series of serine-threonine phosphatases, i.e., okadaic acid (which suppresses PP1 and PP2A phosphatase activities), endothall (PP2A), cyclosporin A and cypermethrin (PP2B), CCT007093 (PPM1D), and dephostatin (blocks tyrosine phosphatases), on the depression and spontaneous recovery of the ACh-induced influx current in defensive behavior command neurons in the common snail were studied in a cellular analog of habituation. All the inhibitors used here altered the dynamics of depression of the current, while endothall also slowed spontaneous recovery of the ACh current. The results obtained here provide evidence of the relationship between changes in defensive behavior command neuron membrane cholinosensitivity in the common snail in a cellular analog of habituation on the one hand and the activities of all the protein phosphatases studied on the other. Application of a mathematical model addressing the possibility that receptors have different cellular locations suggested that these phosphatases are involved in the mobility (endocytosis and exocytosis) of the membrane cholinoreceptors responsible for changes in the ACh current in the cellular analog of habituation. Comparison of the experimental data and simulation-derived calculated curves of changes in the ACh current showed that the main target of protein phosphatases is the neuron’s transport system, i.e., the cytoskeleton and motor proteins.

Changes in Intracellular Calcium Ion Concentrations during Generation of High-Amplitude EPSP in Neurons in the Common Snail

Changes in intracellular calcium ion concentrations are the main trigger for most physiological processes in neurons, including changes in gene expression and the processes of synaptic plasticity. Our experiments showed that high-amplitude EPSP in common snail command neurons, like action potentials, are accompanied by marked increases in intracellular calcium ion concentrations. The amplitude of calcium signals accompanying high-amplitude EPSP in command neurons was found to depend linearly on the strength of synaptic stimulation, while the dynamics of changes in the amplitude of EPSP themselves showed marked saturation as stimulus strength increased. This means that over a certain range of changes of membrane potential, calcium signals transmit stimulus strength more adequately than the level of depolarization of the postsynaptic neuron. We suggest that calcium signals evoked by high-amplitude EPSP can induce biochemical changes in neurons, thus mediating cellular responses in the range subthreshold for action potentials.

Gating of steering signals through phasic modulation of reticulospinal neurons during locomotion

The neural control of movements in vertebrates is based on a set of modules, like the central pattern generator networks (CPGs) in the spinal cord coordinating locomotion. Sensory feedback is not required for the CPGs to generate the appropriate motor pattern and neither a detailed control from higher brain centers. Reticulospinal neurons in the brainstem activate the locomotor network, and the same neurons also convey signals from higher brain regions, such as turning/steering commands from the optic tectum (superior colliculus). A tonic increase in the background excitatory drive of the reticulospinal neurons would be sufficient to produce coordinated locomotor activity. However, in both vertebrates and invertebrates, descending systems are in addition phasically modulated because of feedback from the ongoing CPG activity. We use the lamprey as a model for investigating the role of this phasic modulation of the reticulospinal activity, because the brainstem-spinal cord networks are known down to the cellular level in this phylogenetically oldest extant vertebrate. We describe how the phasic modulation of reticulospinal activity from the spinal CPG ensures reliable steering/turning commands without the need for a very precise timing of on- or offset, by using a biophysically detailed large-scale (19,600 model neurons and 646,800 synapses) computational model of the lamprey brainstem-spinal cord network. To verify that the simulated neural network can control body movements, including turning, the spinal activity is fed to a mechanical model of lamprey swimming. The simulations also predict that, in contrast to reticulospinal neurons, tectal steering/turning command neurons should have minimal frequency adaptive properties, which has been confirmed experimentally.

Synaptic polarity of the command interneurons for Caenorhabditis Elegans directional motion

Event Abstract Back to Event Synaptic polarity of the command interneurons for Caenorhabditis Elegans directional motion Franciszek M. Rakowski1* and Jan Karbowski2 1 University of Warsaw, Interdisciplinary Centre for Mathematical and Computational Modeling, Poland 2 University of Warsaw, Institute of Applied Mathematics and Mechanics, Poland The command interneuron circuit for Caenorhabditis Elegans locomotion has been known for a long time [1,2]. However, synaptic polarities of these interneurons, and thus, the circuit functioning is largely unknown. Additionally, nematode command neurons express both glutamate-gated chloride channels and glutamate-gated cation channels, which causes that each synapse, even when belonging to the same neuron, might be either inhibitory or excitatory. We use an experimental behavioral data set: eighteen different neural ablations were performed and times spent in the forward and reverse motions were registered. Therefore one can consider eighteen different command neuron network structures where each one as a whole, controls the behavior of the nematode, and results with one of the eighteen different behavioral patterns. In order to decipher the particular polarities of each neuron we have constructed a theoretical (inter)neuron network model, in which neural activities are represented by a set of differential equations and searched all possible synaptic polarity combinations in the circuit to find the best match to the timing data [3,4]. Here, we present the extension of this model, where we explicitly incorporate calcium concentration dynamics as the regulatory factor and detailed connectivity diagram based on the transmission type of each synapse. Since the parameter space spanned by the morphological and regulatory factors is huge, we have applied an evolutionary strategy for finding the parameters of the mathematical model, for which the theoretical results and the experimental data fit the best. The overall model output consists of the averaged values: neuron activities, calcium concentration levels, input signal (the upstream neurons activity pattern) and of the resolved detailed connectivity diagram. The deciphered list of the types of synapses states that most of the synapses, including strongest connections, e.g. ASH -> “backward” motoneurons, PVC -> “forward” motoneurons, AVD -> AVA, in the command neuron circuit are inhibitory.

Possibility of “Comet-Like” Transport of Acetylcholine Receptors in Command <i>Helix</i> Neurons in Cellular Analog of Habituation

The presence of "comet-like" radial transport of acetylcholine receptors by actin microfilaments without the participation of myosin motors in the depression of acetylcholine-induced inward chloric current (ACh-current) in command neurons of defensive behavior of the land snail, Helix lucorum, in a cellular analog of habituation was investigated. For that purpose the effects of CK548, CK-636 (inhibitors of actin-related protein complex Arp2/3, whose activation triggers rapid actin polymerization and the formation of the "comet-like" tail on the actinic filament) and wiskostatin (an N-WASP protein inhibitor, activating Arp2/3) on the depression of ACh-current were studied. The attenuation of ACh-current depression was observed upon the addition of CK548. At the same time, CK-636 and wiskostatin irreversibly strengthened the depression of this current and suppressed its spontaneous recovery. The results of CK-548 action and its mathematical modeling allow suggesting the presence of "comet-like" transport of acetylcholine receptors, initiated by Arp2/3 protein complex in receptor endo and exocytosis in command neurons of Helix lucorum in a cellular analog of habituation. Irreversible inhibition of vital metabolic processes of the neuron by wiskostatin and CK-636, which lead to the decrease in the level of ATP, could have caused irreversible effects of these blockers on current depression.

Neuromodulators, stress and plasticity: a role for endocannabinoid signalling

Any unanticipated threat to survival triggers an immediate sequence of events in the brain that culminate in a coordinated neural, endocrine and behavioural response. There is increasing evidence that stress itself modifies neural circuits. In other words, neural stress circuits learn from stress. This self-teaching is surprising as one might expect these essential circuits to be hard-wired. Our recent findings, however, indicate that repeated homotypic stress in rats causes functional changes in neural circuitry in the hypothalamus. In particular, we focus on signalling via endocannabinoids and describe plasticity in this system that impacts fast retrograde signalling at synapses on to the stress command neurons in the brain. Interestingly, this plasticity appears to be limited to early adolescence, hinting at unique modes of control of neural circuits by stress during different developmental stages.

The psychophysiology of consciousness

Table of Contents E.N. Sokolov (1920-2008) Preface Introduction Part 1. The spherical model of cognitive processing Chapter 1. Vector encoding in perception 1.1. The detector neuron 1.2. The neuronal structure of color space 1.3. Detectors of orientation and spatial frequency 1.4. Detectors of orientation and direction of lines in motion 1.5. Computation of perceptual differences: the perceptual evoked potential Chapter 2. From detector map to maps of memory and semantic units 2.1. The vector code in mismatch negativity 2.2. Recognition memory: vector transformation in neural networks 2.3. Association of memory traces based on time and similarity 2.4. Correlation between percepts and semantics 2.5. Computation of semantic differences in neural networks Chapter 3. Vector encoding in response conditioning 3.1. Synaptic mechanisms of the conditional response 3.2. Corticofugal and centripetal modulation of detector maps 3.3. Fluctuation of the pacemaker potential 3.4. The pacemaker potential in receptors, detectors and command neurons Part 2. The Neural Screen of Consciousness Chapter 4. The modular organization of the brain 4.1. The modular organization of cortical neurons. 4.2. Are all neurons associated with consciousness? 4.3. Consciousness and sleep Chapter 5. The mosaic nature of consciousness 5.1. The concept of distributed consciousness 5.2. Perception 5.3. Memory and semantics 5.4. Emotions 5.5. Subjective mosaics Chapter 6. Varieties of consciousness 6.1. Global and focal changes of consciousness 6.2. Special states of neurons in global and focal loss of consciousness 6.3. Filling-in and assimilation 6.4. Contrast 6.5. Masking 6.6. Supersensitivity Chapter 7. The neurophysiology of consciousness 7.1. Introspective and neuroconceptual models of consciousness 7.2. Re-entry 7.3. Consciousness and rhythmic brain activity 7.4. The gamma-rhythm and consciousness 7.5. Semantic evoked potentials 7.6. Consciousness neurons 7.7. Neurocomputation on dendrites 7.8. The intracellular mechanism of consciousness Conclusion: the spherical model of consciousness Bibliography

Central control of cardiovascular function during sleep

There is increasing evidence that cardiovascular control during sleep is relevant for cardiovascular risk. This evidence warrants increased experimental efforts to understand the physiological mechanisms of such control. This review summarizes current knowledge on autonomic features of sleep states [non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS)] and proposes some testable hypotheses concerning the underlying neural circuits. The physiological reduction of blood pressure (BP) during the night (BP dipping phenomenon) is mainly caused by generalized cardiovascular deactivation and baroreflex resetting during NREMS, which, in turn, are primarily a consequence of central autonomic commands. Central commands during NREMS may involve the hypothalamic ventrolateral preoptic area, central thermoregulatory and central baroreflex pathways, and command neurons in the pons and midbrain. During REMS, opposing changes in vascular resistance in different regional beds have the net effect of increasing BP compared with that of NREMS. In addition, there are transient increases in BP and baroreflex suppression associated with bursts of brain and skeletal muscle activity during REMS. These effects are also primarily a consequence of central autonomic commands, which may involve the midbrain periaqueductal gray, the sublaterodorsal and peduncular pontine nuclei, and the vestibular and raphe obscurus medullary nuclei. A key role in permitting physiological changes in BP during sleep may be played by orexin peptides released by hypothalamic neurons, which target the postulated neural pathways of central autonomic commands during NREMS and REMS. Experimental verification of these hypotheses may help reveal which central neural pathways and mechanisms are most essential for sleep-related changes in cardiovascular function.