Release Of Neuromodulators Research Articles

Precisely Timed Nicotinic Activation Drives SST Inhibition in Neocortical Circuits

Sleep, waking, locomotion, and attention are associated with cell-type-specific changes in neocortical activity. The effect of brain state on circuit output requires understanding of how neuromodulators influence specific neuronal classes and their synapses, with normal patterns of neuromodulator release from endogenous sources. We investigated the state-dependent modulation of a ubiquitous feedforward inhibitory motif in mouse sensory cortex, local pyramidal (Pyr) inputs onto somatostatin (SST)-expressinginterneurons. Paired whole-cell recordings in acute brain slices and invivo showed that Pyr-to-SST synapses are remarkably weak, with failure rates approaching 80%. Pharmacological screening revealed that cholinergic agonists uniquely enhance synaptic efficacy. Brief, optogenetically gated acetylcholine release dramatically enhanced Pyr-to-SST input, via nicotinic receptors and presynaptic PKA signaling. Importantly, endogenous acetylcholine release preferentially activated nicotinic, not muscarinic, receptors, thus differentiating drug effects from endogenous neurotransmission. Brain state- and synapse-specific unmasking of synapses may be a powerful way to functionally rewire cortical circuits dependent on behavioral demands.

Differential release of dopamine in the nucleus accumbens evoked by low-versus high-frequency medial prefrontal cortex stimulation

The medial prefrontal cortex (mPFC) coordinates goal-directed behaviors, which may be mediated through mPFC regulation of dopamine release in the nucleus accumbens (NAc). Furthermore, frequency-specific oscillatory activity between the frontal cortex and downstream structures may facilitate inter-region communication. Although high-frequency (e.g., 60 Hz) mPFC stimulation is known to increase basal dopamine levels in the NAc, little is known about how phasic dopamine release is affected by mPFC stimulation. Understanding the frequency-specific control of phasic dopamine release by mPFC stimulation could elucidate mechanisms by which the mPFC modulates other regions. It could also inform optimization of deep brain stimulation for treatment of neurological disorders. ObjectiveThe goal of this work was to characterize the frequency response of NAc dopamine release resultant from mPFC stimulation. We hypothesized that the magnitude of dopamine release in the NAc would increase with increasing stimulation frequency. MethodsElectrical stimulation of the mPFC of anesthetized rats was delivered at 4–60 Hz and at varying durations while measuring NAc dopamine release with fast-scan cyclic voltammetry. ResultsmPFC stimulation resulted in phasic dopamine release in the NAc. Furthermore, 20 Hz stimulation evoked the largest peak response for stimulation intervals >5 s when compared to higher or lower frequencies. ConclusionsActivation of the mPFC drives dopamine release in the NAc in a complex frequency- and duration-dependent manner. This has implications for the use of deep brain stimulation treatment of disorders marked by dopaminergic dysregulation, and suggest that mPFC may exert more specialized control over neuromodulator release than previously understood.

The special relationship: glia-neuron interactions in the neuroendocrine hypothalamus.

Natural fluctuations in physiological conditions require adaptive responses involving rapid and reversible structural and functional changes in the hypothalamic neuroendocrine circuits that control homeostasis. Here, we discuss the data that implicate hypothalamic glia in the control of hypothalamic neuroendocrine circuits, specifically neuron-glia interactions in the regulation of neurosecretion as well as neuronal excitability. Mechanistically, the morphological plasticity displayed by distal processes of astrocytes, pituicytes and tanycytes modifies the geometry and diffusion properties of the extracellular space. These changes alter the relationship between glial cells of the hypothalamus and adjacent neuronal elements, especially at specialized intersections such as synapses and neurohaemal junctions. The structural alterations in turn lead to functional plasticity that alters the release and spread of neurotransmitters, neuromodulators and gliotransmitters, as well as the activity of discrete glial signalling pathways that mediate feedback by peripheral signals to the hypothalamus. An understanding of the contributions of these and other non-neuronal cell types to hypothalamic neuroendocrine function is thus critical both to understand physiological processes such as puberty, the maintenance of bodily homeostasis and ageing and to develop novel therapeutic strategies for dysfunctions of these processes, such as infertility and metabolic disorders.

(Invited) Light up the Brain with Genetically Encoded Indicators of Neural Activity

To study the neural circuitry, the action of one cells under the context of others, one would precisely measure and perturb specific neuronal populations and molecules in behaving animals who are specifically engaged in performing the computation or function of interest. The dataset of millions of neurons firing together underlying a behavior are required to develop and refine theories (hypotheses) explaining animal behavior in terms of brain physiology. A key challenge has been difficulty of assessing the synaptic transmission with optical methods. My lab has developed a new suite of genetically encoded indicators that would enable one to 1) specifically highlight the structure of single spines and axonal termini in densely labeled neurons and record glutamate activity; 2) simultaneously record synaptic connectivity and glutamate activity to identify active synapses; 3) direct record the release of neuromodulators. We demonstrate the utility of these indicators in cells, rat hippocampal neurons and in vivo. We expect that applications of these imaging tools will contribute to a dynamic and comprehensive view of synaptic transmission in action to decipher the codes for transferring information across neural circuitry and systems.

(Invited) New Platforms for Multiplexing Electrochemical Measurements In Vivo

Complex behaviors depend on the coordination of the activities of ensembles of neurons and the release of neuromodulators such as dopamine. The mechanisms underlying such coordination are not well-understood due to a lack of instrumentation for combined and real-time monitoring of neuromodulator release and the activities of large ensembles of neurons. Here I describe a measurement platform that allows for the combined monitoring of electrophysiology from a high-density electrode array and dopamine dynamics from a carbon-fiber microelectrode. Integration of these two measurement systems was achieved through modification of the existing instrumentation. A shared grounded reference electrode was used in both systems to minimize electrical interference. Further, an optional solid-state-relay array positioned between the electrophysiological electrode array and amplifiers was added to provide additional electrical isolation. The capacity of the integrated measurement platform, termed DANA (Dopamine And Neural Activity), to measure action potentials (high frequency) and local-field oscillations (low frequency) was characterized in vitro using an artificial cerebral spinal fluid gelatin. In vivo recordings from the DANA platform in anesthetized rats demonstrated the ability of the system for near-simultaneous measurement of dopamine release and activity from multiple neurons both in distant brain regions (striatum and hippocampus) and within the same brain region (striatum). Furthermore, this system was shown to be sufficiently compact to measure activity in freely moving animals through recording of single-neuron activity, high-frequency local-field oscillations, and dopamine release. Fast scan cyclic voltammetry has been used extensively to monitor dynamic changes in neurotransmitters (e.g. dopamine, serotonin, norepinephrine) in real time. However, these measurements are limited in terms of the number of implantable sensors. This does not allow the coordinated chemical communication and interactions between groups of neurons to be mapped in the same animal. Additioanally, we present arrays of electrodes with biocompatible conducting polymers capable of measuring biogenic amines. Metal wires are coated with the electrochemical polymerization of the monomer 3,4-ethylenedioxythiophene (EDOT). After baking and rinsing, a film with a positively charged polymer backbone balanced by negatively charged tosylate ions is formed. These electrodes can then be easily integrated in mass-producible arrays, brining voltammetry on par with multiple probe recordings common in electrophysiology. These voltammetric recordings also require custom instrumentation that integrates low-noise operational amplifiers with high-performance data acquisition cards and software. The system presented is capable of recording from eight channels (with appropriate instrumentation). By electrically isolating each channel, they can be independently addressed and a different neurotransmitter can be measured at each sensor. This greatly increases the ability to map neurotransmitter release in the brain of animals in real time. Data measuring both dopamine and serotonin in different brain regions is presented.

Ventilation and neurochemical changes during µ-opioid receptor activation or blockade of excitatory receptors in the hypoglossal motor nucleus of goats.

Neuromodulator interdependence posits that changes in one or more neuromodulators are compensated by changes in other modulators to maintain stability in the respiratory control network. Herein, we studied compensatory neuromodulation in the hypoglossal motor nucleus (HMN) after chronic implantation of microtubules unilaterally ( n = 5) or bilaterally ( n = 5) into the HMN. After recovery, receptor agonists or antagonists in mock cerebrospinal fluid (mCSF) were dialyzed during the awake and non-rapid eye movement (NREM) sleep states. During day studies, dialysis of the µ-opioid inhibitory receptor agonist [d-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO; 100 µM) decreased pulmonary ventilation (V̇i), breathing frequency ( f), and genioglossus (GG) muscle activity but did not alter neuromodulators measured in the effluent mCSF. However, neither unilateral dialysis of a broad spectrum muscarinic receptor antagonist (atropine; 50 mM) nor unilateral or bilateral dialysis of a mixture of excitatory receptor antagonists altered V̇i or GG activity, but all of these did increase HMN serotonin (5-HT) levels. Finally, during night studies, DAMGO and excitatory receptor antagonist decreased ventilatory variables during NREM sleep but not during wakefulness. These findings contrast with previous dialysis studies in the ventral respiratory column (VRC) where unilateral DAMGO or atropine dialysis had no effects on breathing and bilateral DAMGO or unilateral atropine increased V̇i and f and decreased GABA or increased 5-HT, respectively. Thus we conclude that the mechanisms of compensatory neuromodulation are less robust in the HMN than in the VRC under physiological conditions in adult goats, possibly because of site differences in the underlying mechanisms governing neuromodulator release and consequently neuronal activity, and/or responsiveness of receptors to compensatory neuromodulators. NEW & NOTEWORTHY Activation of inhibitory µ-opioid receptors in the hypoglossal motor nucleus decreased ventilation under physiological conditions and did not affect neurochemicals in effluent dialyzed mock cerebral spinal fluid. These findings contrast with studies in the ventral respiratory column where unilateral [d-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO) had no effects on ventilation and bilateral DAMGO or unilateral atropine increased ventilation and decreased GABA or increased serotonin, respectively. Our data support the hypothesis that mechanisms that govern local compensatory neuromodulation within the brain stem are site specific under physiological conditions.

Long-Term Recordings of Arcuate Nucleus Kisspeptin Neurons Reveal Patterned Activity That Is Modulated by Gonadal Steroids in Male Mice.

Pulsatile release of gonadotropin-releasing hormone (GnRH) is key to fertility. Pulse frequency is modulated by gonadal steroids and likely arises subsequent to coordination of GnRH neuron firing activity. The source of rhythm generation and the site of steroid feedback remain critical unanswered questions. Arcuate neurons that synthesize kisspeptin, neurokinin B, and dynorphin (KNDy) may be involved in both of these processes. We tested the hypotheses that action potential firing in KNDy neurons is episodic and that gonadal steroids regulate this pattern. Targeted extracellular recordings were made of green fluorescent protein-identified KNDy neurons in brain slices from adult male mice that were intact, castrated, or castrated and treated with estradiol or dihydrotestosterone (DHT). KNDy neurons exhibited marked peaks and nadirs in action potential firing activity during recordings lasting 1 to 3.5 hours. Peaks, identified by Cluster analysis, occurred more frequently in castrated than intact mice, and either estradiol or DHT in vivo or blocking neurokinin type 3 receptor in vitro restored peak frequency to intact levels. The frequency of peaks in firing rate and estradiol regulation of this frequency is similar to that observed for GnRH neurons, whereas DHT suppressed firing in KNDy but not GnRH neurons. We further examined the patterning of action potentials to identify bursts that may be associated with increased neuromodulator release. Burst frequency and duration are increased in castrated compared with intact and steroid-treated mice. The observation that KNDy neurons fire in an episodic manner that is regulated by steroid feedback is consistent with a role for these neurons in GnRH pulse generation and regulation.

Three-dimensional fine structure of the organization of microtubules in neurite varicosities by ultra-high voltage electron microscope tomography.

Neurite varicosities are highly specialized compartments that are involved in neurotransmitter/ neuromodulator release and provide a physiological platform for neural functions. However, it remains unclear how microtubule organization contributes to the form of varicosity. Here, we examine the three-dimensional structure of microtubules in varicosities of a differentiated PC12 neural cell line using ultra-high voltage electron microscope tomography. Three-dimensional imaging showed that a part of the varicosities contained an accumulation of organelles that were separated from parallel microtubule arrays. Further detailed analysis using serial sections and whole-mount tomography revealed microtubules running in a spindle shape of swelling in some other types of varicosities. These electron tomographic results showed that the structural diversity and heterogeneity of microtubule organization supported the form of varicosities, suggesting that a different distribution pattern of microtubules in varicosities is crucial to the regulation of varicosities development.

Models of Acetylcholine and Dopamine Signals Differentially Improve Neural Representations.

Biological and artificial neural networks (ANNs) represent input signals as patterns of neural activity. In biology, neuromodulators can trigger important reorganizations of these neural representations. For instance, pairing a stimulus with the release of either acetylcholine (ACh) or dopamine (DA) evokes long lasting increases in the responses of neurons to the paired stimulus. The functional roles of ACh and DA in rearranging representations remain largely unknown. Here, we address this question using a Hebbian-learning neural network model. Our aim is both to gain a functional understanding of ACh and DA transmission in shaping biological representations and to explore neuromodulator-inspired learning rules for ANNs. We model the effects of ACh and DA on synaptic plasticity and confirm that stimuli coinciding with greater neuromodulator activation are over represented in the network. We then simulate the physiological release schedules of ACh and DA. We measure the impact of neuromodulator release on the network's representation and on its performance on a classification task. We find that ACh and DA trigger distinct changes in neural representations that both improve performance. The putative ACh signal redistributes neural preferences so that more neurons encode stimulus classes that are challenging for the network. The putative DA signal adapts synaptic weights so that they better match the classes of the task at hand. Our model thus offers a functional explanation for the effects of ACh and DA on cortical representations. Additionally, our learning algorithm yields performances comparable to those of state-of-the-art optimisation methods in multi-layer perceptrons while requiring weaker supervision signals and interacting with synaptically-local weight updates.

Platform to Enable Combined Measurement of Dopamine and Neural Activity.

Complex behaviors depend on the coordination of the activities of ensembles of neurons and the release of neuromodulators such as dopamine. The mechanisms underlying such coordination are not well-understood due to a lack of instrumentation for combined and real-time monitoring of neuromodulator release and the activities of large ensembles of neurons. Here we describe a measurement platform that allows for the combined monitoring of electrophysiology from a high-density electrode array and dopamine dynamics from a carbon-fiber microelectrode. Integration of these two measurement systems was achieved through modification of the existing instrumentation. A shared grounded reference electrode was used in both systems to minimize electrical interference. Further, an optional solid-state-relay array positioned between the electrophysiological electrode array and amplifiers was added to provide additional electrical isolation. The capacity of the integrated measurement platform, termed DANA (Dopamine And Neural Activity), to measure action potentials (high frequency) and local-field oscillations (low frequency) was characterized in vitro using an artificial cerebral spinal fluid gelatin. In vivo recordings from the DANA platform in anesthetized rats demonstrated the ability of the system for near-simultaneous measurement of dopamine release and activity from multiple neurons both in distant brain regions (striatum and hippocampus) and within the same brain region (striatum). Furthermore, this system was shown to be sufficiently compact to measure activity in freely moving animals through recording of single-neuron activity, high-frequency local-field oscillations, and dopamine release.

Physiologische Mechanismen der analgetischen Akupunkturwirkung – ein Update im klinischen Kontext

BackgroundPhysiological mechanisms of pain relief achieved by acupuncture are subject to three decades of intensive research. ObjectiveTo give an overview about the current knowledge on mechanism underlying acupuncture induced analgesia MethodsAn extensive literature search based on significant reviews of the last years was performed. Secondary literature was reviewed and Medline searches using respective keywords were carried out. Results were summarized in the following sections: 1Importance of endogenous opioids and descending pain inhibitory circuits2Effects on the autonomous nervous system3Impacts on central pain processing4Segmental inhibition5Local mechanisms ResultsThere is substantial evidence for the release of endorphins as a central anti-nociceptive mechanism of acupuncture. With regard to electroacupuncture (EA) it has been suggested that stimulation frequency impacts on treatment outcome. The decisive role of further neuromodulators of the descending pain inhibitory circuits, primarily serotonin and norepinephrine, is well established. Effects of acupuncture on the autonomous nervous system seem likely, but remain largely unclear. In contrast, the impact of acupuncture on central pain processing is well characterized, as well as the activation of segmental inhibition occurring in the spinal cord. The peripheral release of various neuromodulators is also fairly well described as a potential mechanism contributing to acupuncture analgesia. ConclusionAcupuncture induced analgesia is based on a complex interplay of peripheral, spinal and central mechanisms. A large number of basic science and clinical studies support this notion. However it remains largely unclear how these different mechanisms are interwoven and how their contributions to the analgesic acupuncture effect compare to each other. Future studies need to address the specificity of acupuncture points or point regimens and the impact of different types and intensities of needle stimulation. In addition, it needs to be clarified whether the mechanisms identified through animal studies apply to acupuncture in humans as well.

Nonparalytic botulinum molecules for the control of pain.

Local injections of botulinum toxins have been reported to be useful not only for the treatment of peripheral neuropathic pain and migraine but also to cause long-lasting muscle paralysis, a potentially serious side effect. Recently, a botulinum A-based molecule ("BiTox") has been synthesized that retains neuronal silencing capacity without triggering muscle paralysis. In this study, we examined whether BiTox delivered peripherally was able to reduce or prevent the increased nociceptive sensitivity found in animal models of inflammatory, surgical, and neuropathic pain. Plasma extravasation and edema were also measured as well as keratinocyte proliferation. No motor deficits were seen and acute thermal and mechanical nociceptive thresholds were unimpaired by BiTox injections. We found reduced plasma extravasation and inflammatory edema as well as lower levels of keratinocyte proliferation in cutaneous tissue after local BiTox injection. However, we found no evidence that BiTox was transported to the dorsal root ganglia or dorsal horn and no deficits in formalin-elicited behaviors or capsaicin or formalin-induced c-Fos expression within the dorsal horn. In contrast, Bitox treatment strongly reduced A-nociceptor-mediated secondary mechanical hyperalgesia associated with either complete Freund's adjuvant (CFA)-induced joint inflammation or capsaicin injection and the hypersensitivity associated with spared nerve injury. These results imply that although local release of neuromodulators from C-fibers was inhibited by BiTox injection, C-nociceptive signaling function was not impaired. Taken together with recent clinical data the results suggest that BiTox should be considered for treatment of pain conditions in which A-nociceptors are thought to play a significant role.

The anatomical basis for modulatory convergence in the antennal lobe of Manduca sexta.

The release of neuromodulators by widely projecting neurons often allows sensory systems to alter how they process information based on the physiological state of an animal. Neuromodulators alter network function by changing the biophysical properties of individual neurons and the synaptic efficacy with which individual neurons communicate. However, most, if not all, sensory networks receive multiple neuromodulatory inputs, and the mechanisms by which sensory networks integrate multiple modulatory inputs are not well understood. Here we characterized the relative glomerular distribution of two extrinsic neuromodulators associated with distinct physiological states, serotonin (5-HT) and dopamine (DA), in the antennal lobe (AL) of the moth Manduca sexta. By using immunocytochemistry and mass dye fills, we characterized the innervation patterns of both 5-HT- and tyrosine hydroxylase-immunoreactive processes relative to each other, to olfactory receptor neurons (ORNs), to projection neurons (PNs), and to several subsets of local interneurons (LNs). 5-HT immunoreactivity had nearly complete overlap with PNs and LNs, yet no overlap with ORNs, suggesting that 5-HT may modulate PNs and LNs directly but not ORNs. TH immunoreactivity overlapped with PNs, LNs, and ORNs, suggesting that dopamine has the potential to modulate all three cell types. Furthermore, the branching density of each neuromodulator differed, with 5-HT exhibiting denser arborizations and TH-ir processes being sparser. Our results suggest that 5-HT and DA extrinsic neurons target partially overlapping glomerular regions, yet DA extends further into the region occupied by ORNs.

Ventilatory and Neurochemical Effects of Microdialysis of a µ‐opioid Receptor Agonist (DAMGO) into the Region of the Ventral Respiratory Column in Awake Goats

Prior studies (J.appl Phisiol. 114, 694‐647, 2012., Respir Phisiol 205: 7‐15 2014.) have shown that dialysis of antagonists of excitatory neuromodulator receptors in the ventral respiratory column (VRC) resulted in changes in the release of other excitatory neuromodulators with no net change in ventilation. In the present study, we tested the hypothesis that agonists of inhibitory receptors in the VRC will also increase excitatory neuromodulator release by dialyzing DAMGO ([D‐Ala2, N‐MePhe4, Gly‐ol]‐enkephalin), a µ‐opioid receptor agonist, in chronically cannulated awake goats. In five goats we dialyzed mock cerebral spinal fluid (mCSF) with or without DAMGO (10, 50, or 100µM concentrations). Dialysis of 100µM DAMGO resulted in a decrease in tidal volume which was followed by an increase in frequency to maintain ventilation. The concentrations of serotonin, substance P, GABA and glycine in the effluent mCSF were not altered by DAMGO dialysis. We conclude that increased inhibition of VRC respiratory neurons is not compensated for by the same mechanism as during decreased excitation. This work was funded by the National Heart, Lung, and Blood Institute grants HL‐25739, HL‐112996, HL‐007852, and by the Department of Veterans Affairs.

Systemic lipopolysaccharide-mediated alteration of cortical neuromodulation involves increases in monoamine oxidase-A and acetylcholinesterase activity.

BackgroundLipopolysaccharide (LPS)-mediated sickness behaviour is known to be a result of increased inflammatory cytokines in the brain. Inflammatory cytokines have been shown to mediate increases in brain excitation by loss of GABAA-mediated inhibition through receptor internalization or inactivation. Inflammatory pathways, reactive oxygen species and stress are also known to increase monoamine oxidase-A (MAO-A) and acetylcholinesterase (ACh-E) activity. Given that neuromodulator actions on neural circuits largely depend on inhibitory pathways and are sensitive to alteration in corresponding catalytic enzyme activities, we assessed the impact of systemic LPS on neuromodulator-mediated shaping of a simple cortical network.MethodsExtracellular field recordings of evoked postsynaptic potentials in adult mouse somatosensory cortical slices were used to evaluate effects of a single systemic LPS challenge on neuromodulator function 1 week later. Neuromodulators were administered transiently as a bolus (100 μl) to the bath perfusate immediately upstream of the recording site to mimic phasic release of neuromodulators and enable assessment of response temporal dynamics.ResultsSystemic LPS administration resulted in loss of both spontaneous and evoked inhibition as well as alterations in the temporal dynamics of neuromodulator effects on a paired-pulse paradigm. The effects on neuromodulator temporal dynamics were sensitive to the Monoamine oxidase-A (MAO-A) antagonist clorgyline (for norepinephrine and serotonin) and the ACh-E inhibitor donepezil (for acetylcholine). This is consistent with significant increases in total MAO and ACh-E activity found in hemi-brain samples from the LPS-treated group, supporting the notion that systemic LPS administration may lead to longer-lasting changes in inhibitory network function and enzyme (MAO/ACh-E) activity responsible for reduced neuromodulator actions.ConclusionsGiven the significant role of neuromodulators in behavioural state and cognitive processes, it is possible that an inflammatory-mediated change in neuromodulator action plays a role in LPS-induced cognitive effects and could help define the link between infection and neuropsychiatric/degenerative conditions.

Neural reflex regulation of systemic inflammation: potential new targets for sepsis therapy.

Sepsis progresses to multiple organ dysfunction due to the uncontrolled release of inflammatory mediators, and a growing body of evidence shows that neural signals play a significant role in modulating the immune response. Thus, similar toall other physiological systems, the immune system is both connected to and regulated by the central nervous system. The efferent arc consists of the activation of the hypothalamic–pituitary–adrenal axis, sympathetic activation, the cholinergic anti-inflammatory reflex, and the local release of physiological neuromodulators. Immunosensory activity is centered on the production of pro-inflammatory cytokines, signals that are conveyed to the brain through different pathways. The activation of peripheral sensory nerves, i.e., vagal paraganglia by the vagus nerve, and carotid body (CB) chemoreceptors by the carotid/sinus nerve are broadly discussed here. Despite cytokine receptor expression in vagal afferent fibers, pro-inflammatory cytokines have no significant effect on vagus nerve activity. Thus, the CB may be the source of immunosensory inputs and incoming neural signals and, in fact, sense inflammatory mediators, playing a protective role during sepsis. Considering that CB stimulation increases sympathetic activity and adrenal glucocorticoids release, the electrical stimulation of arterial chemoreceptors may be suitable therapeutic approach for regulating systemic inflammation.

Intrinsic motivations and open-ended development in animals, humans, and robots: an overview.

Intrinsic motivations and open-ended development in animals, humans, and robots: an overview.

The P600-as-P3 hypothesis revisited: Single-trial analyses reveal that the late EEG positivity following linguistically deviant material is reaction time aligned

The P600, a late positive ERP component following linguistically deviant stimuli, is commonly seen as indexing structural, high-level processes, e.g. of linguistic (re)analysis. It has also been identified with the P3 (P600-as-P3 hypothesis), which is thought to reflect a systemic neuromodulator release facilitating behavioural shifts and is usually response time aligned. We investigated single-trial alignment of the P600 to response, a critical prediction of the P600-as-P3 hypothesis. Participants heard sentences containing morphosyntactic and semantic violations and responded via a button press. The elicited P600 was perfectly response aligned, while an N400 following semantic deviations was stimulus aligned. This is, to our knowledge, the first single-trial analysis of language processing data using within-sentence behavioural responses as temporal covariates. Results support the P600-as-P3 perspective and thus constitute a step towards a neurophysiological grounding of language-related ERPs.

The Right Dorsal Habenula Limits Attraction to an Odor in Zebrafish

The habenula consists of an evolutionarily conserved set of nuclei that control neuromodulator release. In lower vertebrates, the dorsal habenula receives innervation from sensory regions, but the significance of this is unclear. Here, we address the role of the habenula in olfaction by imaging neural activity in larval zebrafish expressing GCaMP3 throughout the habenula and by carrying out behavioral assays. Activity in several hundred neurons throughout the habenula was recorded using wide-field fluorescence microscopy, fast focusing, and deconvolution. This enabled the creation of 4D maps of odor-evoked activity. Odors activated the habenula in two broad spatiotemporal patterns. Increasing concentrations of a putative social cue (a bile salt) evoked a corresponding increase in neuronal activity in the right dorsal habenula. In behavioral assays, fish were attracted to intermediate concentration of this cue but avoided higher concentration. Increasing cholinergic activity through nicotine exposure rendered the intermediate concentration aversive in a habenula-dependent manner. Pharmacologically blocking nicotinic receptors or lesioning the right dorsal habenula attenuated avoidance. These data provide physiological and functional evidence that the habenula functions as a higher center in zebrafish olfaction and suggest that activity in the right dorsal subdomain gates innate attraction to specific odors.

Chapter Eight - Seizure Termination

A better understanding of the mechanisms by which most focal epileptic seizures stop spontaneously within a few minutes would be of highest importance, because they could potentially help to improve existing and develop novel therapeutic measures for seizure control. Studies devoted to unraveling mechanisms of seizure termination often take one of the two following approaches. The first approach focuses on metabolic mechanisms such as ionic concentrations, acidity, or neuromodulator release, studying how they are dependent on, and in turn affect changes of neuronal activity. The second approach uses quantitative tools to derive functional networks from electrophysiological recordings and analyzes these networks with mathematical methods, without focusing on actual details of cell biology. In this chapter, we summarize key results obtained by both of these approaches and attempt to show that they are complementary and equally necessary in our aim to gain a better understanding of seizure termination.