Musings on the wanderer: what's new in our understanding of vago-vagal reflexes? III. Activity-dependent plasticity in vago-vagal reflexes controlling the stomach

Vago-vagal reflex circuits modulate digestive functions from the oral cavity to the transverse colon. Previous articles in this series have described events at the level of the sensory receptors encoding the peripheral stimuli, the transmission of information in the afferent vagus, and the conversion of this data within the dorsal vagal complex (DVC) to impulses in the preganglionic efferents. The control by vagal efferents of the postganglionic neurons impinging on the glands and smooth muscles of the target organs has also been illustrated. Here we focus on some of the mechanisms by which these apparently static reflex circuits can be made quite plastic as a consequence of the action of modulatory inputs from other central nervous system sources. A large body of evidence has shown that the neuronal elements that constitute these brain stem circuits have nonuniform properties and function differently according to status of their target organs and the level of activity in critical modulatory inputs. We propose that DVC circuits undergo a certain amount of short-term plasticity that allows the brain stem neuronal elements to act in harmony with neural systems that control behavioral and physiological homeostasis.     

Spinal and supraspinal effects of activity in ligament afferents.

In this paper available knowledge on effects from joint and ligament afferents on spinal neurones and pathways are briefly reviewed, and possible functional implications discussed. Ligament afferents may contribute to joint stability, muscle coordination and proprioception through direct polysynaptic reflex effects onto ascending pathways and skeletomotoneurones, and/or indirectly via reflex actions on the gamma-muscle spindle system. Theoretical and experimental evidence indicate that ligament afferents, together with afferents from other joint structures, muscles and the skin, provide the CNS with information on movements and posture through ensemble coding mechanisms, rather than via modality specific private pathways. The existence and functional relevance of ligamentomuscular protective reflexes, that are triggered when the ligament is threatened by potentially harmful loads, has been seriously questioned. It seems more likely that peripheral sensory inputs from ligament afferents participate in a continuous control of the muscle activity through feedforward, or preprogramming, mechanisms. In line with these ideas it has been suggested that ligament mechanoreceptors have an important role in muscle coordination and in the reflex regulation of the functional joint stability, by contributing to the preprogramming of the muscle stiffness through reflex modulation of the gamma-muscle spindle system.     

A test of a dual central pattern generator hypothesis for subcortical control of locomotion.

This study was designed to examine the nature of neural circuits involved in subcortical inter-limb coordination and reflex modulation mechanisms of locomotion. These circuits, called central pattern generators (CPGs), are believed to receive tonic input and generate rhythmically alternating sets of commands. Although CPGs have been theorized to exist in humans, their potential dual role in inter-limb coordination and reflex modulation is unclear. In the present study, nine participants walked on a treadmill, timing their heel-strikes to a metronome which varied the phase lag from 0.5 to 1.0 pi radians (0.1 pi intervals). A stimulus was delivered to the sural nerve and reflexes were measured in the ipsilateral and contralateral lower extremities through electromyography. The similarity between phase lag conditions for both temporal coordination (i.e., relative timing aspects between muscles and/or limbs) and reflex intensities suggested that they may be controlled by the same subcortical circuitry. Two plausible explanations exist: (1) a single CPG coordinates muscular contractions and phasically alters proprioceptive reflex modulation, as well as cutaneous input, using feed-forward control; (2) two separate circuits are strongly entrained, producing synchronous outputs for inter-limb coordination and reflex modulation. The out-of-phase task used in this study was limited in discerning such a difference, if it exists.     

Escape behavior — brainstem and spinal cord circuitry and function

Recent work has demonstrated that the neural circuits mediating escape reactions in lower vertebrates and mammals have a common framework, with only two excitatory central synapses in the reflex arc. This relatively direct linkage from sense organs to muscles and the fact that segments of the network also transmit other motor commands help guarantee that escape always has priority over ongoing behaviors. Yet, modulation and plasticity contribute some variability to the expression of escape and, therefore, to the adequacy of its survival function.     

Synapses and Memory Storage

The synapse is the functional unit of the brain. During the last several decades we have acquired a great deal of information on its structure, molecular components, and physiological function. It is clear that synapses are morphologically and molecularly diverse and that this diversity is recruited to different functions. One of the most intriguing findings is that the size of the synaptic response in not invariant, but can be altered by a variety of homo- and heterosynaptic factors such as past patterns of use or modulatory neurotransmitters. Perhaps the most difficult challenge in neuroscience is to design experiments that reveal how these basic building blocks of the brain are put together and how they are regulated to mediate the information flow through neural circuits that is necessary to produce complex behaviors and store memories. In this review we will focus on studies that attempt to uncover the role of synaptic plasticity in the regulation of whole-animal behavior by learning and memory.The idea that learning results from changes in the strength of the synapse was first suggested by Santiago Ramon y Cajal (1894) based on insights from his anatomical studies. That modulation of synaptic connectivity is a critical mechanism of learning was incorporated into more refined models by Hebb in the 1940s and 1950s. The experimental investigation of these intriguing conjectures required the development of behavioral systems in which one could examine changes in the neuronal components of a specific behavior during or after the modification of that behavior with learning (Kandel and Spencer 1968).     

Brain stem excitatory and inhibitory signaling pathways regulating bronchoconstrictive responses.

This review summarizes recent work on two basic processes of central nervous system (CNS) control of cholinergic outflow to the airways: 1) transmission of bronchoconstrictive signals from the airways to the airway-related vagal preganglionic neurons (AVPNs) and 2) regulation of AVPN responses to excitatory inputs by central GABAergic inhibitory pathways. In addition, the autocrine-paracrine modulation of AVPNs is briefly discussed. CNS influences on the tracheobronchopulmonary system are transmitted via AVPNs, whose discharge depends on the balance between excitatory and inhibitory impulses that they receive. Alterations in this equilibrium may lead to dramatic functional changes. Recent findings indicate that excitatory signals arising from bronchopulmonary afferents and/or the peripheral chemosensory system activate second-order neurons within the nucleus of the solitary tract (NTS), via a glutamate-AMPA signaling pathway. These neurons, using the same neurotransmitter-receptor unit, transmit information to the AVPNs, which in turn convey the central command to airway effector organs: smooth muscle, submucosal secretory glands, and the vasculature, through intramural ganglionic neurons. The strength and duration of reflex-induced bronchoconstriction is modulated by GABAergic-inhibitory inputs and autocrine-paracrine controlling mechanisms. Downregulation of GABAergic inhibitory influences may result in a shift from inhibitory to excitatory drive that may lead to increased excitability of AVPNs, heightened airway responsiveness, and sustained narrowing of the airways. Hence a better understanding of these normal and altered central neural circuits and mechanisms could potentially improve the design of therapeutic interventions and the treatment of airway obstructive diseases.     

The role of the thalamus in the flow of information to the cortex

The lateral geniculate nucleus is the best understood thalamic relay and serves as a model for all thalamic relays. Only 5-10% of the input to geniculate relay cells derives from the retina, which is the driving input. The rest is modulatory and derives from local inhibitory inputs, descending inputs from layer 6 of the visual cortex, and ascending inputs from the brainstem. These modulatory inputs control many features of retinogeniculate transmission. One such feature is the response mode, burst or tonic, of relay cells, which relates to the attentional demands at the moment. This response mode depends on membrane potential, which is controlled effectively by the modulator inputs. The lateral geniculate nucleus is a first-order relay, because it relays subcortical (i.e. retinal) information to the cortex for the first time. By contrast, the other main thalamic relay of visual information, the pulvinar region, is largely a higher-order relay, since much of it relays information from layer 5 of one cortical area to another. All thalamic relays receive a layer-6 modulatory input from cortex, but higher-order relays in addition receive a layer-5 driver input. Corticocortical processing may involve these corticothalamocortical 're-entry' routes to a far greater extent than previously appreciated. If so, the thalamus sits at an indispensable position for the modulation of messages involved in corticocortical processing.     

A single functional model of drivers and modulators in cortex

A distinction is commonly made between synaptic connections capable of evoking a response (“drivers”) and those that can alter ongoing activity but not initiate it (“modulators”). Here it is proposed that, in cortex, both drivers and modulators are an emergent property of the perceptual inference performed by cortical circuits. Hence, it is proposed that there is a single underlying computational explanation for both forms of synaptic connection. This idea is illustrated using a predictive coding model of cortical perceptual inference. In this model all synaptic inputs are treated identically. However, functionally, certain synaptic inputs drive neural responses while others have a modulatory influence. This model is shown to account for driving and modulatory influences in bottom-up, lateral, and top-down pathways, and is used to simulate a wide range of neurophysiological phenomena including surround suppression, contour integration, gain modulation, spatio-temporal prediction, and attention. The proposed computational model thus provides a single functional explanation for drivers and modulators and a unified account of a diverse range of neurophysiological data.     

Top-Down Modulation on Perceptual Decision with Balanced Inhibition through Feedforward and Feedback Inhibitory Neurons

Recent physiological studies have shown that neurons in various regions of the central nervous systems continuously receive noisy excitatory and inhibitory synaptic inputs in a balanced and covaried fashion. While this balanced synaptic input (BSI) is typically described in terms of maintaining the stability of neural circuits, a number of experimental and theoretical studies have suggested that BSI plays a proactive role in brain functions such as top-down modulation for executive control. Two issues have remained unclear in this picture. First, given the noisy nature of neuronal activities in neural circuits, how do the modulatory effects change if the top-down control implements BSI with different ratios between inhibition and excitation? Second, how is a top-down BSI realized via only excitatory long-range projections in the neocortex? To address the first issue, we systematically tested how the inhibition/excitation ratio affects the accuracy and reaction times of a spiking neural circuit model of perceptual decision. We defined an energy function to characterize the network dynamics, and found that different ratios modulate the energy function of the circuit differently and form two distinct functional modes. To address the second issue, we tested BSI with long-distance projection to inhibitory neurons that are either feedforward or feedback, depending on whether these inhibitory neurons do or do not receive inputs from local excitatory cells, respectively. We found that BSI occurs in both cases. Furthermore, when relying on feedback inhibitory neurons, through the recurrent interactions inside the circuit, BSI dynamically and automatically speeds up the decision by gradually reducing its inhibitory component in the course of a trial when a decision process takes too long.     

Neurotransmitters are regulators for the migration of tumor cells and leukocytes

Neurotransmitters are signal substances that have traditionally been regarded as mere mediators of signal states between cells in the nervous system. Whereas the mechanisms of this "classic" neurotransmitter regulation are well understood, only recently has new evidence come to light elucidating the modulatory role of neurotransmitters in immune function, and in the regulation of migration of leukocytes and tumor cells. The migration of leukocytes is, among other things, of primary importance for an anti-tumor immune response, whereas the migration of tumor cells is a prerequisite for invasion and the development of metastases. We here clarify and consolidate the latest tumor biological findings on the role of these neurotransmitters, which bind to serpentine receptors, and which are involved in leukocyte migration, tumor growth, invasion and metastasis. This review thus accentuates the complex, interactive involvement of neurotransmitters in the regulation of migration of both leukocytes and tumor cells.     

Widespread anatomical projections of the serotonergic modulatory neuron,CB1, inAplysia

Although sensitization-related changes in the neural circuitry of withdrawal reflexes inAplysia are well studied, relatively few studies address the organization of the modulatory components of sensitization. In particular, it is not known whether individual modulatory loci can simultaneously influence multiple reflex circuits. There is, however, evidence that a single modulatory transmitter, serotonin, plays a pivotal role in facilitating different reflex circuits during sensitization. Furthermore, it is known that activation of a pair of serotonergic neurons, the CB1s, produces heterosynaptic facilitation of the sensorimotor connections of one of these reflex circuits. These data together raise the possibility that the CB1s may produce sensitizing changes in the neural elements of multiple reflex systems simultaneously. In the present study, we utilized immunocytochemistry and intracellular labeling to obtain anatomical evidence of CB1's possible role in modulating multiple reflex circuits. We found that two distinct neurons satisfy previously published physiological criteria for CB1. One of these, CB1, is immunoreactive to serotonin. The second cell, here named CB2, has a different neuroanatomy and is not serotonin immunoreactive. Focusing on CB1, we found (1) profuse fine processes given off by its axons in the posterior neuropil of the cerebral ganglion, (2) extensive branching and fine processes in the pleural ganglion, and (3) a branch of CB1 that projects into the pedal ganglion. These three observations are consistent with the hypothesis that, in addition to its already established role in modulating the siphon withdrawal circuit, CB1 may also modulate synaptic connections between (1) the sensory and motor neurons of the tentacle withdrawal reflex (2) the sensory neurons and interneurons of the tail and tail-elicited siphon withdrawal reflex, and (3) the sensory and motor neurons of the tail withdrawal reflex. These observations support further physiological investigations of a possible global role of CB1 in modulating the tail and tentacle withdrawal reflexes.     

Octopamine-containing (OC) interneurons enhance central pattern generator activity in sucrose-induced feeding in the snail <Emphasis Type="Italic">Lymnaea</Emphasis>

In the pond snail Lymnaea stagnalis octopamine-containing (OC) interneurons trigger and reconfigure the feeding pattern in isolated CNS by excitation of the central pattern generator. In semi-intact (lip–mouth—CNS) preparations, this central pattern generator is activated by chemosensory inputs. We now test if sucrose application to the lips activates the OC neurons independently of the rest of the feeding central pattern generator, or if the OC interneuron is activated by inputs from the feeding network. In 66% of experiments, sucrose stimulated feeding rhythms and OC interneurons received regular synaptic inputs. Only rarely (14%) did the OC interneuron fire action potentials, proving that firing of OC interneurons is not necessary for the sucrose-induced feeding. Prestimulation of OC neurons increased the intensity and duration of the feeding rhythm evoked by subsequent sucrose presentations. One micromolar octopamine in the CNS bath mimicked the effect of OC interneuron stimulation, enhancing the feeding response when sucrose is applied to the lips. We conclude that the modulatory OC neurons are not independently excited by chemosensory inputs to the lips, but rather from the buccal central pattern generator network. However, when OC neurons fire, they release modulatory octopamine, which provides a positive feedback to the network to enhance the sucrose-activated central pattern generator rhythm.     

Plasticity in the nucleus tractus solitarius and its influence on lung and airway reflexes.

The nucleus tractus solitarius (NTS) is the first central nervous system (CNS) site for synaptic contact of the primary afferent fibers from the lungs and airways. The signal processing at these synapses will determine the output of the sensory information from the lungs and airways to all downstream synapses in the reflex pathways. The second-order NTS neurons bring to bear their own intrinsic and synaptic properties to temporally and spatially integrate the sensory information with inputs from local networks, higher brain regions, and circulating mediators, to orchestrate a coherent reflex output. There is growing evidence that NTS neurons share the rich repertoire of forms of plasticity demonstrated throughout the CNS. This review focuses on existing evidence for plasticity in the NTS, potential targets for plasticity in the NTS, and the impact of this plasticity on lung and airway reflexes.     

Modulation of excitatory neurotransmission by neuronal/glial signalling molecules: interplay between purinergic and glutamatergic systems

Glutamate is the main excitatory neurotransmitter of the central nervous system (CNS), released both from neurons and glial cells. Acting via ionotropic (NMDA, AMPA, kainate) and metabotropic glutamate receptors, it is critically involved in essential regulatory functions. Disturbances of glutamatergic neurotransmission can be detected in cognitive and neurodegenerative disorders. This paper summarizes the present knowledge on the modulation of glutamate-mediated responses in the CNS. Emphasis will be put on NMDA receptor channels, which are essential executive and integrative elements of the glutamatergic system. This receptor is crucial for proper functioning of neuronal circuits; its hypofunction or overactivation can result in neuronal disturbances and neurotoxicity. Somewhat surprisingly, NMDA receptors are not widely targeted by pharmacotherapy in clinics; their robust activation or inhibition seems to be desirable only in exceptional cases. However, their fine-tuning might provide a promising manipulation to optimize the activity of the glutamatergic system and to restore proper CNS function. This orchestration utilizes several neuromodulators. Besides the classical ones such as dopamine, novel candidates emerged in the last two decades. The purinergic system is a promising possibility to optimize the activity of the glutamatergic system. It exerts not only direct and indirect influences on NMDA receptors but, by modulating glutamatergic transmission, also plays an important role in glia-neuron communication. These purinergic functions will be illustrated mostly by depicting the modulatory role of the purinergic system on glutamatergic transmission in the prefrontal cortex, a CNS area important for attention, memory and learning.     

The contribution of sensory inputs to the pattern generation of breathing

Current concepts of the basic neural control system and its modulation by afferent inputs are reviewed. It is emphasized that, in analogy with locomotion, the central pattern generator (CPG) for automatic metabolic respiration does not depend on any afferent feedback from receptors sensitive to the movements of the "pump," or the streams of pumped air, for its production of a rhythmic motor output provides the CPG receives some "drive" inputs above threshold and adequate bias. The operation for a variety of reflexes and feedback loops is of fundamental importance, however, for adapting the breathing pattern to the varying requirements for gas exchange to the many behavioural, nonmetabolic demands on the breathing apparatus which are competing with its primary metabolic control functions. The presentation is focussed also on available evidence that the respiratory CPG exerts powerful modulations on the transmission in these reflex pathways controlling the pattern of breathing and adjusting it to the various metabolic and behavioural demands. Mechanisms for "gating," "phasic gain changes," and "phase-dependent reflex reversal" are exemplified.     

Neuropeptide Regulation of Signaling and Behavior in the BNST

Recent technical developments have transformed how neuroscientists can probe brain function. What was once thought to be difficult and perhaps impossible, stimulating a single set of long range inputs among many, is now relatively straight-forward using optogenetic approaches. This has provided an avalanche of data demonstrating causal roles for circuits in a variety of behaviors. However, despite the critical role that neuropeptide signaling plays in the regulation of behavior and physiology of the brain, there have been remarkably few studies demonstrating how peptide release is causally linked to behaviors. This is likely due to both the different time scale by which peptides act on and the modulatory nature of their actions. For example, while glutamate release can effectively transmit information between synapses in milliseconds, peptide release is potentially slower [See the excellent review by Van Den Pol on the time scales and mechanisms of release (van den Pol, 2012)] and it can only tune the existing signals via modulation. And while there have been some studies exploring mechanisms of release, it is still not as clearly known what is required for efficient peptide release. Furthermore, this analysis could be complicated by the fact that there are multiple peptides released, some of which may act in contrast. Despite these limitations, there are a number of groups making progress in this area. The goal of this review is to explore the role of peptide signaling in one specific structure, the bed nucleus of the stria terminalis, that has proven to be a fertile ground for peptide action.     

A Feedback Model of Attention Explains the Diverse Effects of Attention on Neural Firing Rates and Receptive Field Structure

Visual attention has many effects on neural responses, producing complex changes in firing rates, as well as modifying the structure and size of receptive fields, both in topological and feature space. Several existing models of attention suggest that these effects arise from selective modulation of neural inputs. However, anatomical and physiological observations suggest that attentional modulation targets higher levels of the visual system (such as V4 or MT) rather than input areas (such as V1). Here we propose a simple mechanism that explains how a top-down attentional modulation, falling on higher visual areas, can produce the observed effects of attention on neural responses. Our model requires only the existence of modulatory feedback connections between areas, and short-range lateral inhibition within each area. Feedback connections redistribute the top-down modulation to lower areas, which in turn alters the inputs of other higher-area cells, including those that did not receive the initial modulation. This produces firing rate modulations and receptive field shifts. Simultaneously, short-range lateral inhibition between neighboring cells produce competitive effects that are automatically scaled to receptive field size in any given area. Our model reproduces the observed attentional effects on response rates (response gain, input gain, biased competition automatically scaled to receptive field size) and receptive field structure (shifts and resizing of receptive fields both spatially and in complex feature space), without modifying model parameters. Our model also makes the novel prediction that attentional effects on response curves should shift from response gain to contrast gain as the spatial focus of attention drifts away from the studied cell.     

Modulation of NMDA-receptor efficiency by intracellular agents

Glutamate in one of the principle transmitters in the CNS. Ionotropic receptors of glutamate selectively activated by N-methyl-d-aspartate (NMDA) play an important role in the processes of development, learning, memory etc. Hyperactivation of these receptors is responsible for a number of pathological processes. Due to their importance, the NMDA receptors are subjected to strong modulatory influences of different modulatory systems of the brain. Modulation of the NMDA receptor efficiency by extracellular factors is well known and described in a number of reviews, while their modulation by intracellular factors is less known and has not yet been reviewed. This review presents the experimental data concerning a modulatory control of the NMDA receptors by intracellular factors. Some of these factors are: phosphorylation by protein kinases (PK) C, A, Ca2+/calmodulin-dependent PK II, tyrosine kinases; dephosphorylation by protein phosphatases 1, 2A, 2B; interaction with regulatory peptides and cytoskeleton; influence of surrounding lipids etc. Interaction between these factors creates a labile intracellular system, which efficiently modulates activity of the NMDA receptors mediating the activity of different extracellular active compounds (neurotransmitters, neurotoxins, drugs etc.). A cheme summarizing different intracellular pathways of modulation of the NMDA receptor efficiency is described.     

fMRI reveals how pain modulates visual object processing in the ventral visual stream

It is well known that pain attracts attention and interferes with cognition. Given that the mechanisms behind this phenomenon are largely unknown, we used functional magnetic resonance imaging and presented visual objects with or without concomitant pain stimuli. To test for the specificity of pain, we compared this modulatory effect with a previously established modulatory effect of working memory on visual object processing. Our data showed a comparable behavioral effect of both types of modulation and identified the lateral occipital complex (LOC) as the site of modulation in the ventral visual stream, for both pain and working memory. However, the sources of these modulatory effects differed for the two processes. Whereas the source of modulation for working memory could be attributed to the parietal cortex, the modulatory effect of pain was observed in the rostral anterior cingulate cortex (rACC), an area ideally suited to link pain perception and attentional control.