Neuromodulatory State Research Articles

Neural and physiological state dependency of opioid induced respiratory depression

Opioid induced respiratory depression (OIRD) is the major cause of death associated with opioid overdose. Within the brainstem, respiratory activity is generated within the ventrolateral medulla in an opioid-sensitive region known as the PreBötzinger Complex (PreBötC). Within the PreBötC a heterogenous network of neurons under continuous influence by excitatory and inhibitory neuromodulators culminate to form synchronized bursting that results in inspiratory activity. Additionally, the PreBötC network dynamically interacts with the physiological processes that give rise to ventilation. Understanding the interplay between neural and physiological states of the in-vivo system will be key to overcoming OIRD. Here, we tested whether increasing the excitatory state of the PreBötC in-vivo by non-specific K + channel inhibition, or elevated norepinephrine destabilizes breathing, but creates a network state resistant to OIRD. Further, we tested whether the state of upper airway patency following opioid administration influences sensitivity of the PreBötC to OIRD. Following microdialysis into the PreBötC of the non-specific K + channel antagonist, tetraethylammonium (TEA)(10mM), or 1mM norepinephrine ventilation increased and breathing became erratic with variable frequency and tidal volume. However, following 150mg/kg morphine, breathing re-stabilized and returned to near control levels. These results demonstrate that determining the neuromodulatory state of excitability within the PreBötC prior to opioid administration may help to better predict and prevent OIRD. To determine whether the physiological state of the upper-airway following opioid administration can affect sensitivity of the PreBötC to OIRD we tested the ventilatory response to opioids in both airway-intact and tracheostomized mice in-vivo. For these experiments we utilized fentanyl, due to it’s known effects on disrupting upper airway function. Following administration of 500μg/kg fentanyl airway in-tact mice displayed increased upper airway resistance with regular periods of obstructive apnea, severe hypoxemia and reduced breathing frequency that eventually resulted in complete cessation of respiratory activity. Conversely, mice receiving 500μg/kg fentanyl following tracheostomy showed significantly less respiratory suppression and no apneic periods, compared to airway in-tact mice. However, following administration of a hypoxic gas mixture (10% O2) tracheostomized mice experienced terminal apnea in the presence of 500μg/Kg fentanyl. These results demonstrate that hypoxemia experienced following fentanyl administration, which is exacerbated by upper airway constriction may increase the risk of fatal OIRD in-vivo. Together our data suggest that understanding OIRD within the in-vivo system requires the careful investigation of integrative mechanisms between the neural and physiological processes that give rise to overall ventilation. This work was supported by NIH grants: HL154558 (NJB), HL145004 (NEB), HL126523 (JMR), HL144801 (JMR) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dopaminergic and Cholinergic Modulation of Large Scale Networks in silico Using Snudda.

Neuromodulation is present throughout the nervous system and serves a critical role for circuit function and dynamics. The computational investigations of neuromodulation in large scale networks require supportive software platforms. Snudda is a software for the creation and simulation of large scale networks of detailed microcircuits consisting of multicompartmental neuron models. We have developed an extension to Snudda to incorporate neuromodulation in large scale simulations. The extended Snudda framework implements neuromodulation at the level of single cells incorporated into large-scale microcircuits. We also developed Neuromodcell, a software for optimizing neuromodulation in detailed multicompartmental neuron models. The software adds parameters within the models modulating the conductances of ion channels and ionotropic receptors. Bath application of neuromodulators is simulated and models which reproduce the experimentally measured effects are selected. In Snudda, we developed an extension to accommodate large scale simulations of neuromodulation. The simulator has two modes of simulation – denoted replay and adaptive. In the replay mode, transient levels of neuromodulators can be defined as a time-varying function which modulates the receptors and ion channels within the network in a cell-type specific manner. In the adaptive mode, spiking neuromodulatory neurons are connected via integrative modulating mechanisms to ion channels and receptors. Both modes of simulating neuromodulation allow for simultaneous modulation by several neuromodulators that can interact dynamically with each other. Here, we used the Neuromodcell software to simulate dopaminergic and muscarinic modulation of neurons from the striatum. We also demonstrate how to simulate different neuromodulatory states with dopamine and acetylcholine using Snudda. All software is freely available on Github, including tutorials on Neuromodcell and Snudda-neuromodulation.

Shouting strengthens maximal voluntary force and is associated with augmented pupillary dilation

Previous research has demonstrated that human maximal voluntary force is generally limited by neural inhibition. Producing a shout during maximal exertion effort enhances the force levels of maximal voluntary contraction. However, the mechanisms underlying this enhancement effect on force production remain unclear. We investigated the influence of producing a shout on the pupil-linked neuromodulatory system state by examining pupil size. We also examined its effects on the motor system state by examining motor evoked potentials in response to transcranial magnetic stimulation applied over the contralateral primary motor cortex, and by evaluating handgrip maximal voluntary force. Analysis revealed that producing a shout significantly increased handgrip maximal voluntary force, followed by an increase in pupil size and a reduction of the cortical silent period. Our results indicate that producing a shout increased handgrip maximal voluntary force through the enhancement of motor cortical excitability, possibly via the enhancement of noradrenergic system activity. This study provides evidence that the muscular force-enhancing effect of shouting during maximal force exertion is related to both the motor system state and the pupil-linked neuromodulatory system state.

Adaptive Neural Decoder for Prosthetic Hand Control.

The overarching goal was to resolve a major barrier to real-life prosthesis usability—the rapid degradation of prosthesis control systems, which require frequent recalibrations. Specifically, we sought to develop and test a motor decoder that provides (1) highly accurate, real-time movement response, and (2) unprecedented adaptability to dynamic changes in the amputee’s biological state, thereby supporting long-term integrity of control performance with few recalibrations. To achieve that, an adaptive motor decoder was designed to auto-switch between algorithms in real-time. The decoder detects the initial aggregate motoneuron spiking activity from the motor pool, then engages the optimal parameter settings for decoding the motoneuron spiking activity in that particular state. “Clear-box” testing of decoder performance under varied physiological conditions and post-amputation complications was conducted by comparing the movement output of a simulated prosthetic hand as driven by the decoded signal vs. as driven by the actual signal. Pearson’s correlation coefficient and Normalized Root Mean Square Error were used to quantify the accuracy of the decoder’s output. Our results show that the decoder algorithm extracted the features of the intended movement and drove the simulated prosthetic hand accurately with real-time performance (<10 ms) (Pearson’s correlation coefficient >0.98 to >0.99 and Normalized Root Mean Square Error <13–5%). Further, the decoder robustly decoded the spiking activity of multi-speed inputs, inputs generated from reversed motoneuron recruitment, and inputs reflecting substantial biological heterogeneity of motoneuron properties, also in real-time. As the amputee’s neuromodulatory state changes throughout the day and the electrical properties and ratio of slower vs. faster motoneurons shift over time post-amputation, the motor decoder presented here adapts to such changes in real-time and is thus expected to greatly enhance and extend the usability of prostheses.

A quiescent state following mild sensory arousal in Caenorhabditis elegans is potentiated by stress

An animal’s behavioral and physiological response to stressors includes changes to its responses to stimuli. How such changes occur is not well understood. Here we describe a Caenorhabditis elegans quiescent behavior, post-response quiescence (PRQ), which is modulated by the C. elegans response to cellular stressors. Following an aversive mechanical or blue light stimulus, worms respond first by briefly moving, and then become more quiescent for a period lasting tens of seconds. PRQ occurs at low frequency in unstressed animals, but is more frequent in animals that have experienced cellular stress due to ultraviolet light exposure as well as in animals following overexpression of epidermal growth factor (EGF). PRQ requires the function of the carboxypeptidase EGL-21 and the calcium-activated protein for secretion (CAPS) UNC-31, suggesting it has a neuropeptidergic mechanism. Although PRQ requires the sleep-promoting neurons RIS and ALA, it is not accompanied by decreased arousability, and does not appear to be homeostatically regulated, suggesting that it is not a sleep state. PRQ represents a simple, tractable model for studying how neuromodulatory states like stress alter behavioral responses to stimuli.

Neuromodulation in circuits of aversive emotional learning.

Emotional learning and memory are functionally and dysfunctionally regulated by the neuromodulatory state of the brain. While the role of excitatory and inhibitory neural circuits mediating emotional learning and its control have been the focus of much research, we are only now beginning to understand the more diffuse role of neuromodulation in these processes. Recent experimental studies of the acetylcholine, noradrenaline and dopamine systems in fear learning and extinction of fear responding provide surprising answers to key questions in neuromodulation. One area of research has revealed how modular organization, coupled with context-dependent coding modes, allows for flexible brain-wide or targeted neuromodulation. Other work has shown how these neuromodulators act in downstream targets to enhance signal-to-noise ratios and gain, as well as to bind distributed circuits through neuronal oscillations. These studies elucidate how different neuromodulatory systems regulate aversive emotional processing and reveal fundamental principles of neuromodulatory function.

The Mechanistic Basis for Successful Spinal Cord Stimulation to Generate Steady Motor Outputs.

Electrical stimulation of the spinal cord is a promising rehabilitation intervention to restore/augment motor function after spinal cord injury (SCI). Combining sensory feedback with stimulation of remaining motor circuits has been shown to be a prerequisite for the functional improvement of SCI patients. However, little is known about the cellular mechanisms potentially underlying this functional benefit in the injured spinal cord. Here, we combine computer simulations with an isolated whole-tissue adult mouse spinal cord preparation to examine synaptic, cellular, and system potentials measured from single motoneurons and ventral roots. The stimulation protocol included separate and combined activation of the sensory inputs (evoked by dorsal root stimulation) and motor inputs (evoked by stimulation of spinal cord tissue) at different frequencies, intensities, and neuromodulatory states. Our data show that, while sensory inputs exhibit short-term depression in response to a train of stimulation, motor inputs exhibit short-term facilitation. However, the concurrent activation of both inputs elicits a stronger and steadier motor output. This effect is enhanced by the application of pharmacological neuromodulators. Furthermore, sensorimotor excitatory postsynaptic potentials (EPSPs) summate sublinearly (i.e., their combination produces an excitatory potential smaller than the sum of the excitatory potentials they would individually produce). However, ventral root compound action potentials (CoAPs) summate supralinearly generating much higher outputs. Computer simulations revealed that the contrasting summation and disproportionality in plasticity between the excitatory postsynaptic potentials (EPSPs) and CoAPs result from the motoneuronal firing threshold acting as an amplitude-selective filter. Together, these results provide the mechanistic basis for the cellular processes contributing to the generation of steady motor outputs using spinal stimulation. This data has great potential to guide the design of more effective stimulation protocols in SCI patients.

Substance P Reshapes Inspiratory and Postinspiratory Activity Generated in Horizontal Brainstem Slices

The triple oscillator hypothesis posits that breathing is generated by three rhythmogenic microcircuits contained within the ventrolateral medulla. The preBötzinger Complex (preBötC) generates the inexorable inspiratory phase of breathing, whereas the conditional postinspiratory and active expiratory phases of breathing are generated by the Postinspiratory Complex (PiCo) and lateral parafacial respiratory group (PFL), respectively. Neuromodulators including norepinephrine, opioids, and somatostatin are known to differentially modulate the activity of each rhythmic circuit, likely contributing to the independence of each breathing phase and the flexibility of the respiratory rhythm. However, whether the functional boundaries of each of these microcircuits are static or can change dynamically based on the neuromodulatory state of the network is unknown. The neuromodulator Substance P (SP) facilitates breathing frequency in vivo and also in medullary slices that isolate the preBötC in vitro. Using a neonatal mouse horizontal brainstem slice preparation that preserves the rostrocaudal extent of the ventral medulla, we tested the hypothesis that SP differentially modulates bursting activity in the preBötC and PiCo and explored how SP may reshape the distribution of inspiratory activity within the wider medullary network. Rhythmic bursting activity was simultaneously recorded from the preBötC and PiCo (n=5). As expected, recordings from the PiCo, located ~500μm rostral to the preBötC, revealed a slow postinspiratory rhythm with robust bursts occurring after only ~1/12 preBötC bursts under control conditions. Following introduction of 0.5–1.0μM SP into the bath superfusion solution, PiCo bursts decreased in amplitude (~40%) and accelerated such that they occurred 1:1 with preBötC bursts without changing the time interval between peak preBötC and PiCo activity. In some PiCo recordings, we noted a small amount of inspiratory activity synchronized with preBötC bursts that was eliminated in the presence of SP. To test whether SP alters the spatial distribution of inspiratory activity along the ventral medulla, we simultaneously recorded inspiratory population activity generated at the preBötC and 400–600μm rostral (n=8). Following application of 1μM SP frequency was increased (~90%) and inspiratory burst amplitude was reduced by ~20% at the preBötC, whereas burst amplitude decreased by ~50% in rostral recordings. Based on these preliminary experiments, we hypothesize that SP reshapes breathing activity generated within the medulla by facilitating postinspiratory activity and reducing the extent of inspiratory activity rostral of the preBötC to shrink the size of the active inspiratory network. Differential neuromodulatory properties and dynamic functional boundaries of the rhythmogenic circuits that generate breathing may contribute to the remarkable flexibility and robustness of this vital physiological behavior.Support or Funding InformationNIH F32 HL134207NIH R01 HL126523This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Control of entropy in neural models of environmental state.

Humans and animals construct internal models of their environment in order to select appropriate courses of action. The representation of uncertainty about the current state of the environment is a key feature of these models that controls the rate of learning as well as directly affecting choice behaviour. To maintain flexibility, given that uncertainty naturally decreases over time, most theoretical inference models include a dedicated mechanism to drive up model uncertainty. Here we probe the long-standing hypothesis that noradrenaline is involved in determining the uncertainty, or entropy, and thus flexibility, of neural models. Pupil diameter, which indexes neuromodulatory state including noradrenaline release, predicted increases (but not decreases) in entropy in a neural state model encoded in human medial orbitofrontal cortex, as measured using multivariate functional MRI. Activity in anterior cingulate cortex predicted pupil diameter. These results provide evidence for top-down, neuromodulatory control of entropy in neural state models.

Causal Evidence for a Neural Component of Spatially Global Hemodynamic Signals

In this issue of Neuron, Turchi etal. (2018) reversibly inactivate the basal forebrain to show that this region magnifies global neocortical signal fluctuations without altering the topography of canonical resting-state networks. Thus, spatially diffuse signals measurable via functional neuroimaging may track large-scale neuromodulatory state changes in the primate brain.

An integrative model of the intrinsic hippocampal theta rhythm.

Hippocampal theta oscillations (4–12 Hz) are consistently recorded during memory tasks and spatial navigation. Despite several known circuits and structures that generate hippocampal theta locally in vitro, none of them were found to be critical in vivo, and the hippocampal theta rhythm is severely attenuated by disruption of external input from medial septum or entorhinal cortex. We investigated these discrepancies that question the sufficiency and robustness of hippocampal theta generation using a biophysical spiking network model of the CA3 region of the hippocampus that included an interconnected network of pyramidal cells, inhibitory basket cells (BC) and oriens-lacunosum moleculare (OLM) cells. The model was developed by matching biological data characterizing neuronal firing patterns, synaptic dynamics, short-term synaptic plasticity, neuromodulatory inputs, and the three-dimensional organization of the hippocampus. The model generated theta power robustly through five cooperating generators: spiking oscillations of pyramidal cells, recurrent connections between them, slow-firing interneurons and pyramidal cells subnetwork, the fast-spiking interneurons and pyramidal cells subnetwork, and non-rhythmic structured external input from entorhinal cortex to CA3. We used the modeling framework to quantify the relative contributions of each of these generators to theta power, across different cholinergic states. The largest contribution to theta power was that of the divergent input from the entorhinal cortex to CA3, despite being constrained to random Poisson activity. We found that the low cholinergic states engaged the recurrent connections in generating theta activity, whereas high cholinergic states utilized the OLM-pyramidal subnetwork. These findings revealed that theta might be generated differently across cholinergic states, and demonstrated a direct link between specific theta generators and neuromodulatory states.

The Role of Neuromodulators in Cortical Plasticity. A Computational Perspective.

Neuromodulators play a ubiquitous role across the brain in regulating plasticity. With recent advances in experimental techniques, it is possible to study the effects of diverse neuromodulatory states in specific brain regions. Neuromodulators are thought to impact plasticity predominantly through two mechanisms: the gating of plasticity and the upregulation of neuronal activity. However, the consequences of these mechanisms are poorly understood and there is a need for both experimental and theoretical exploration. Here we illustrate how neuromodulatory state affects cortical plasticity through these two mechanisms. First, we explore the ability of neuromodulators to gate plasticity by reshaping the learning window for spike-timing-dependent plasticity. Using a simple computational model, we implement four different learning rules and demonstrate their effects on receptive field plasticity. We then compare the neuromodulatory effects of upregulating learning rate versus the effects of upregulating neuronal activity. We find that these seemingly similar mechanisms do not yield the same outcome: upregulating neuronal activity can lead to either a broadening or a sharpening of receptive field tuning, whereas upregulating learning rate only intensifies the sharpening of receptive field tuning. This simple model demonstrates the need for further exploration of the rich landscape of neuromodulator-mediated plasticity. Future experiments, coupled with biologically detailed computational models, will elucidate the diversity of mechanisms by which neuromodulatory state regulates cortical plasticity.

Neuromodulation to the Rescue: Compensation of Temperature-Induced Breakdown of Rhythmic Motor Patterns via Extrinsic Neuromodulatory Input.

Stable rhythmic neural activity depends on the well-coordinated interplay of synaptic and cell-intrinsic conductances. Since all biophysical processes are temperature dependent, this interplay is challenged during temperature fluctuations. How the nervous system remains functional during temperature perturbations remains mostly unknown. We present a hitherto unknown mechanism of how temperature-induced changes in neural networks are compensated by changing their neuromodulatory state: activation of neuromodulatory pathways establishes a dynamic coregulation of synaptic and intrinsic conductances with opposing effects on neuronal activity when temperature changes, hence rescuing neuronal activity. Using the well-studied gastric mill pattern generator of the crab, we show that modest temperature increase can abolish rhythmic activity in isolated neural circuits due to increased leak currents in rhythm-generating neurons. Dynamic clamp-mediated addition of leak currents was sufficient to stop neuronal oscillations at low temperatures, and subtraction of additional leak currents at elevated temperatures was sufficient to rescue the rhythm. Despite the apparent sensitivity of the isolated nervous system to temperature fluctuations, the rhythm could be stabilized by activating extrinsic neuromodulatory inputs from descending projection neurons, a strategy that we indeed found to be implemented in intact animals. In the isolated nervous system, temperature compensation was achieved by stronger extrinsic neuromodulatory input from projection neurons or by augmenting projection neuron influence via bath application of the peptide cotransmitter Cancer borealis tachykinin-related peptide Ia (CabTRP Ia). CabTRP Ia activates the modulator-induced current IMI (a nonlinear voltage-gated inward current) that effectively acted as a negative leak current and counterbalanced the temperature-induced leak to rescue neuronal oscillations. Computational modelling revealed the ability of IMI to reduce detrimental leak-current influences on neuronal networks over a broad conductance range and indicated that leak and IMI are closely coregulated in the biological system to enable stable motor patterns. In conclusion, these results show that temperature compensation does not need to be implemented within the network itself but can be conditionally provided by extrinsic neuromodulatory input that counterbalances temperature-induced modifications of circuit-intrinsic properties.

Editorial: The role of glia in plasticity and behavior.

Editorial: The role of glia in plasticity and behavior.

GABAA receptor-mediated feedforward and feedback inhibition differentially modulate the gain and the neural code transformation in hippocampal CA1 pyramidal cells

Diverse variety of hippocampal interneurons exists in the CA1 area, which provides either feedforward (FF) or feedback (FB) inhibition to CA1 pyramidal cell (PC). However, how the two different inhibitory network architectures modulate the computational mode of CA1 PC is unknown. By investigating the CA3 PC rate-driven input–output function of CA1 PC using in vitro electrophysiology, in vitro-simulation of inhibitory network, and in silico computational modeling, we demonstrated for the first time that GABAA receptor-mediated FF and FB inhibition differentially modulate the gain, the spike precision, the neural code transformation and the information capacity of CA1 PC. Recruitment of FF inhibition buffered the CA1 PC spikes to theta-frequency regardless of the input frequency, abolishing the gain and making CA1 PC insensitive to its inputs. Instead, temporal variability of the CA1 PC spikes was increased, promoting the rate-to-temporal code transformation to enhance the information capacity of CA1 PC. In contrast, the recruitment of FB inhibition sub-linearly transformed the input rate to spike output rate with high gain and low spike temporal variability, promoting the rate-to-rate code transformation. These results suggest that GABAA receptor-mediated FF and FB inhibitory circuits could serve as network mechanisms for differentially modulating the gain of CA1 PC, allowing CA1 PC to switch between different computational modes using rate and temporal codes ad hoc. Such switch will allow CA1 PC to efficiently respond to spatio-temporally dynamic inputs and expand its computational capacity during different behavioral and neuromodulatory states in vivo.

Activity-Dependent Feedback Regulates Correlated Ion Channel mRNA Levels in Single Identified Motor Neurons

Neurons generate cell-specific outputs via interactions of conductances carried by ion channel proteins that are homeostatically regulated to maintain key quantitative relationships among subsets of conductances. Given the challenges of both normal channel protein turnover and short-term plasticity, how is the balance of membrane conductances maintained over long-term timescales to ensure stable electrophysiological phenotype? One possible mechanism is to dynamically regulate production of channel protein via feedback that constrains relationships at the channel mRNA level. Recent modeling work has postulated that such mRNA relationships could emerge as a result of activity-dependent homeostatic tuning rules that ensure an appropriate ratio of mRNA for key ion channels is maintained to preserve robust cellular output. Yet, this has never been demonstrated in biological neurons. In this study, we quantified multiple ion channel mRNAs from single identified motor neurons of the stomatogastric ganglion to determine whether correlations among channel mRNAs are actively maintained, and, if so, by what form of feedback. In these neurons, we identified correlations among mRNAs for voltage-gated calcium and potassium channels. By performing experiments that decoupled activity, synaptic connectivity, and neuromodulatory state, we determined that correlated channel mRNAs are maintained by an activity-dependent process. This is the first study to demonstrate that distinct relationships across channel mRNAs are dynamically maintained in an activity-dependent manner. This feedback from cellular activity to coordinated transcriptome-level interactions represents a novel aspect of regulation of neuronal output with implications for long-term stability of neuron function.

A Neocortical Delta Rhythm Facilitates Reciprocal Interlaminar Interactions via Nested Theta Rhythms

Delta oscillations (1-4 Hz) associate with deep sleep and are implicated in memory consolidation and replay of cortical responses elicited during wake states. A potent local generator has been characterized in thalamus, and local generators in neocortex have been suggested. Here we demonstrate that isolated rat neocortex generates delta rhythms in conditions mimicking the neuromodulatory state during deep sleep (low cholinergic and dopaminergic tone). The rhythm originated in an NMDA receptor-driven network of intrinsic bursting (IB) neurons in layer 5, activating a source of GABAB receptor-mediated inhibition. In contrast, regular spiking (RS) neurons in layer 5 generated theta-frequency outputs. In layer 2/3 principal cells, outputs from IB cells associated with IPSPs, whereas those from layer 5 RS neurons related to nested bursts of theta-frequency EPSPs. Both interlaminar spike and field correlations revealed a sequence of events whereby sparse spiking in layer 2/3 was partially reflected back from layer 5 on each delta period. We suggest that these reciprocal, interlaminar interactions may represent a "Helmholtz machine"-like process to control synaptic rescaling during deep sleep.

Neuromodulatory State and Sex Specify Alternative Behaviors through Antagonistic Synaptic Pathways in C. elegans

Pheromone responses are highly context dependent. For example, the C. elegans pheromone ascaroside C9 (ascr#3) is repulsive to wild-type hermaphrodites, attractive to wild-type males, and usually neutral to "social" hermaphrodites with reduced activity of the npr-1 neuropeptide receptor gene. We show here that these distinct behavioral responses arise from overlapping push-pull circuits driven by two classes of pheromone-sensing neurons. The ADL sensory neurons detect C9 and, in wild-type hermaphrodites, drive C9 repulsion through their chemical synapses. In npr-1 mutant hermaphrodites, C9 repulsion is reduced by the recruitment of a gap junction circuit that antagonizes ADL chemical synapses. In males, ADL sensory responses are diminished; in addition, a second pheromone-sensing neuron, ASK, antagonizes C9 repulsion. The additive effects of these antagonistic circuit elements generate attractive, repulsive, or neutral pheromone responses. Neuronal modulation by circuit state and sex, and flexibility in synaptic output pathways, may permit small circuits to maximize their adaptive behavioral outputs.

A Core Circuit Module for Cost/Benefit Decision

A simple circuit for cost-benefit decision derived from behavioral and neural studies of the predatory sea-slug Pleurobranchaea may closely resemble that upon which the more complex valuation and decision processes of the social vertebrates are built. The neuronal natures of the pathways in the connectionist model comprise classic central pattern generators, bipolar switch mechanisms, and neuromodulatory state regulation. Marked potential exists for exploring more complex neuroeconomic behavior by appending appropriate circuitry in simulo.

Flexibility of Motor Pattern Generation Across Stimulation Conditions by the Neonatal Rat Spinal Cord

Previous studies have demonstrated that "locomotor-like" rhythmic patterns can be evoked in the isolated neonatal rat spinal cord by several means, including pharmacological neuromodulation and electrical stimulation of various pathways. Recent studies have used stimulation of afferent pathways to evoke rhythmic patterns, relying on synaptic activation of interneuronal systems rather than global imposition of neuromodulatory state by pharmacological agents. We use the in vitro neonatal rat spinal cord with attached hindlimb to examine the muscle activation patterns evoked by stimulation of these different pathways and evaluate whether stimulation of these pathways all evoke the same patterns. We find that the patterns evoked by bath application of serotonin (5-HT) and N-methyl-D-aspartic acid (NMDA) consisted of alternation between hip flexors and extensors and similar alternation was observed in the patterns evoked by electrical stimulation of the cauda equina (CE) or contralateral fifth lumbar (L(5)) dorsal nerve root. In contrast, the knee extensor/hip flexor rectus femoris (RF) and knee flexor/hip extensor semitendinosus (ST) were activated differentially across stimulation conditions. In 5-HT/NMDA patterns, RF was active in late flexion and ST in late extension. In CE patterns, these two muscles switched places with RF typically active in late extension and ST active in flexion. In L(5) patterns, ST was activated in extension and RF was silent or weakly active during flexion. There were also systematic differences in the consistency of rhythms evoked by each stimulation method: patterns evoked by electrical stimulation of CE or L(5) were less consistently modulated with the rhythm when compared with 5-HT/NMDA-evoked patterns. All differences were preserved following deafferentation, demonstrating that they reflect intrinsic properties of spinal systems. These results highlight the intrinsic flexibility of motor pattern generation by spinal motor circuitry which is present from birth and provides important information to many studies examining spinal pattern generating networks.