No description available.

The ability of the brain to store information and adapt to changes in the sensory environment stems from the capability of neurons to change their communication with other neurons (“synaptic plasticity”). However, the ability of synapses to change (e.g., strengthen) is profoundly influenced by various chemical signals released in the nervous system (neuromodulators). Such modulatory effects may be preferential for different types of synapses. For example, cortical acetylcholine (ACh) has been shown to result in a relative enhancement of thalamocortical over intracortical synapses. Here, I tested the hypothesis that field postsynaptic potentials (fPSPs) in the rat primary visual cortex (V1) evoked by single pulse stimulation of the lateral geniculate nucleus (LGN) can be potentiated when LGN stimulation is paired with short bursts of stimuli applied to the basal forebrain (BF), the major source of ACh released in the cortex. Stimulation of the ipsi- and contralateral LGN elicited fPSPs in V1, with fPSPs triggered from the contralateral LGN exhibiting longer latencies and smaller amplitudes relative to fPSPs in ipsilateral projections. Stimulation bursts applied to the BF, paired with single, delayed LGN pulses, resulted in an enhancement of fPSP amplitude (~25%) for contralateral inputs at short (130 ms), but not longer (200-1000 ms) pairing intervals, while ipsilateral fPSPs failed to show significant potentiation over these intervals. The enhancement of the contralateral LGN-V1 fiber system induced by BF pairings was abolished by systemic or V1 application of the muscarinic receptor antagonist scopolamine, while systemic nicotinic receptor blockade was ineffective. These data suggest that there is a differential capacity for plasticity induction between strong, ipsilateral and weaker, contralateral fiber inputs to V1, with weaker inputs exhibiting greater synaptic enhancement following pairing with BF stimulation to elicit cortical ACh release. This preferential readiness for synaptic potentiation in normally weaker, non-dominant fiber inputs to V1 may facilitate the detection and integration of separate sensory signals originating in thalamic sensory nuclei. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2009-03-31 08:49:23.896

The nervous system copes with variability in the external and internal environment by using neuromodulators to adjust the efficacy of neural circuits. The role of serotonin (5HT) as a neuromodulator of olfactory processing in the antennal lobe (AL) of Manduca sexta was examined. Serotonin has been hypothesized as a circadian modulator of sensitivity of AL neurons, so the coding of odor concentration in the AL was first examined without the manipulation of 5HT levels. Reponses of the AL to different concentrations of odors were recorded using multi-electrode extracellular arrays. As odor concentration increased, more AL units responded and the AL was best able to discriminate odors at high concentrations, a finding that was replicated in matched behavioral assays. Multi-electrode recordings were then used to examine the effects of 5HT on responses to stimuli that varied in chemical structure and concentration. Serotonin enhanced AL unit responses by increasing response duration and firing rate, which in turn increased the amount of coincident firing between units. Due to the increased activation of units as concentration increased, and the greater effect of 5HT on stronger responses, serotonin had the greatest effect on overall ensemble activation at higher odor concentrations. Additionally, response thresholds shifted to lower odor concentrations for some units, suggesting that 5HT increases the sensitivity of AL units. Serotonin enhanced AL discrimination of single odors at different concentrations and structurally dissimilar odors at a single concentration. In order to predict which insects share a similar role for 5HT in the AL, immunocytochemistry was used to compare the ALs of different insects. All holometabolous insects (except the Euhymenoptera) had 5HT-immunoreactive AL neurons that were morphologically similar to those of M. sexta. These combined studies implicate 5HT as a modulator of sensitivity and efficacy in the AL of M. sexta and suggest that 5HT may play this role for most of the Holometabola. This proposed role of 5HT in the AL of the Holometabola is reminiscent of the hypothesized involvement of serotonergic neurons from the Raphe nucleus in vertebrates that seem to gate activity in the olfactory bulb in the context of behavioral arousal.

This study uses a conductance-based computer simulation to test the feasibility of a mechanism underlying a newly-described dynamic form of neuromodulation, called spike-timing dependent neuromodulation (STDN). In the mollusc, Tritonia diomedea, it was recently found that a serotonergic neuron (called DSI) alters the synaptic strength of another neuron (VSI-B) in a temporally biphasic-bidirectional manner, with an initial potentiation followed by prolonged synaptic depression (Sakurai and Katz 2003). Physiological evidence suggested that the depression phase is due to serotonin enhancing the A-current in VSI-B, thereby causing spike-narrowing or a decrease in spike amplitude, and thus a decrease in transmitter release. We sought to test the feasibility of this mechanism by developing a conductance-based model of VSI-B using a Hodgkin-Huxley style simulation with a minimal number of ion conductances: A-current, delayed rectifier potassium, fast sodium, and leak channels. From our model, we conducted simulations in order to study how the spike shape of the VSI-B action potential changes as the A-current conductance is enhanced, from which we are able to predict the amount of depression in the post-synaptic cell. Our model indicates that the depression due to the narrowing of the spike with A-current enhancement is sufficient to account for the empirically observed depression during STDN, although it suggests a greater effect of serotonin at the terminals than is observed in the soma. Additionally, the model suggested that the slow inactivation kinetics of the A-current cannot explain the dynamics of the depression phase of STDN. These modeling results suggest that serotonergic modulation of the A-current plays a role in STDN but does not account for its dynamics.

Modulation of network state is a ubiquitous feature of nervous systems. A major challenge in understanding the physiological flexibility of neural circuits is linking molecules that regulate behaviour to changes in the properties of individual neurons. Here, we use a defined neural circuit in C. elegans to frame this universal problem. By genetic dissection of the behavioural state that sustains escape of 21% O2, we identify novel neuronal functions for several highly conserved genes, including a caspase-like molecule, a calcium-sensitive transcription factor, and two translation initiation factors. These molecules have been implicated in diverse forms of human disease, but their role in the nervous system is either unexplored or poorly understood. Using in vivo Ca2+ imaging techniques to investigate neuron physiology in immobilized and behaving animals, we demonstrate their effect on the properties of individual neurons. The activity of RMG hub neurons is associated with the switch in behavioural state induced by 21% O2. Recently it has been shown that the input-output relationship of RMG is controlled by cytokine signaling, an increasingly appreciated form of neuromodulation. Here I present biochemical and genetic evidence that characterize a novel signaling component downstream of IL-17 receptors in RMG. Our data suggest that, reminiscent of its role in the immune system, it performs both scaffolding and enzymatic functions in neurons. Additionally, we show that RMG responsiveness is controlled by widely expressed, putative regulators of gene expression. Our analyses of these proteins elucidate their function within the URX-RMG circuit, but also raise hypotheses that can be tested more generally in the nervous system. We propose that a calmodulin-binding protein regulates adaptation to ambient O2 conditions, which may reflect a widespread requirement for controlling homeostatic plasticity. Two translation factors that have been shown to be dispensable for general translation are important for regulation of the response to stress. Our study raises the possibility that their role in promoting the activity of all, or some subset of, neurons might underlie this contextual requirement. Together, our findings provide mechanistic insight into the regulation of a behavioural state associated with a specific environmental context.

Manipulation of brain circuits is a critical to understanding how brain controls behaviors under normal physiological conditions and how its dysfunction causes diseases. Ultrasound stimulation is an emerging neuromodulation modality that allows activation of neurons with acoustic waves. However, the piezo based transcranial ultrasound stimulation offers poor spatial resolution, which hinders the understanding of its mechanism as well as application in region specific activation in small animals. To address this limitation, we developed a series of neuromodulation techniques utilizing the photon to sound conversion capability offered by the optoacoustic effect. In chapter 2, we developed a fiber based optoacoustic converter th-at allows neural stimulation at submillimeter spatial precision both in vitro and in vivo. In chapter 3, the spatial resolution was further improved by tapered fiber optoacoustic emitter to achieve stimulation of single neurons and even subcellular structures in culture. In chapter 4, we developed photoacoustic nanoparticle based neural stimulation that allows direct activation of neurons through optoacoustic waves generated by nanoparticles bonded to the neuronal membrane. Finally, in chapter 5, in an effort to improve penetration depth, a split ring resonator based microwave neuromodulation was developed that allows wireless stimulation and inhibition of neurons with subwavelength spatial resolution. Together, these methods offer an enabling platform with opportunities to understand the mechanism of acoustic neural stimulation as well as potential for treatment of neurological diseases with high precision neuromodulation.

archives@tulane.edu / 1 / Xin Fu

No description available.

Previous work has demonstrated that rhythmic motor outputs, such as locomotion and scratch induce a hyperpolarization of the voltage threshold (Vth) for action potential initiation in spinal motoneurons, enhancing their excitability. Descending monoamines were implicated in mediating this effect; however, the recent observation that changes in Vth persist during fictive scratch in cats following acute cervical transection revealed that intraspinal systems, of unknown neuromodulatory identity, also have the ability to regulate motoneuron excitability during motor behaviour. This thesis addresses: 1) whether acetylcholine (ACh) is able to modulate spinal motoneuron Vth, and 2) whether endogenous ACh modulates motoneuron excitability during motor activity without intact descending modulation. Our first study investigates whether ACh from exogenous and/or endogenous sources alters motoneuron Vth. We made intracellular recordings of lumbar motoneurons from neonatal rats to pharmacologically manipulate muscarinic and nicotinic receptor activity. Results show that ACh induces either Vth hyperpolarization, Vth depolarization or no change in Vth depending on the activity state of the network, the ACh concentration, and influences from other systems. Our second study investigates whether intraspinal cholinergic inputs induce Vth hyperpolarization during rhythmic motor output when descending projections are disrupted. For this we developed an in vitro neonatal rat spinal cord preparation to elicit rhythmic activity independently of brainstem or lumbar cord stimulation. Intracellular recordings from motoneurons allowed comparison of the Vth prior to and during rhythmic output, both in the absence and presence of cholinergic antagonists in the lumbar cord. Results show that intraspinal cholinergic mechanisms are active and importantly contribute to modulation of motoneuron Vth during motor output. We suggest that in addition to descending modulation, the spinal cholinergic system regulates motoneuron Vth to either facilitate or inhibit recruitment according to the motor network state. Motoneuron excitability regulation by modification of distinct membrane properties resulting from separate modulatory systems activation during diverse motor behaviours is discussed. This work is the first to demonstrate the role of cholinergic mechanisms in regulating motoneuron excitability through modulation of Vth in an activity based context, and therefore outlines a spinal modulatory system that would contribute to motor control in both normal and pathological states. / May 2016

An open question in contemporary neuroscience is how neuromodulators coregulate multiple conductances to maintain functional neuronal activity. Neuromodulators enact changes to properties of biophysical characteristics, such as the maximal conductance or voltage of half-activation of an ionic current, which determine the type and properties of neuronal activity. We apply dynamical systems theory to study the changes to neuronal activity that arise from neuromodulation. Neuromulators can act on multiple targets within a cell. The coregulation of mulitple ionic currents extends the scope of dynamic control on neuronal activity. Different aspects of neuronal activity can be independently controlled by different currents. The coregulation of multiple ionic currents provides precise control over the temporal characteristics of neuronal activity. Compensatory changes in multiple ionic currents could be used to avoid dangerous dynamics or maintain some aspect of neuronal activity. The coregulation of multiple ionic currents can be used as bifurcation control to ensure robust dynamics or expand the range of coexisting regimes. Multiple ionic currents could be involved in increasing the range of dynamic control over neuronal activity. The coregulation of multiple ionic currents in neuromodulation expands the range over which biophysical parameters support functional activity.