Addiction: decreased reward sensitivity and increased expectation sensitivity conspire to overwhelm the brain's control circuit.

PubMed

Volkow, Nora D; Wang, Gene-Jack; Fowler, Joanna S; Tomasi, Dardo; Telang, Frank; Baler, Ruben

2010-09-01

Based on brain imaging findings, we present a model according to which addiction emerges as an imbalance in the information processing and integration among various brain circuits and functions. The dysfunctions reflect (a) decreased sensitivity of reward circuits, (b) enhanced sensitivity of memory circuits to conditioned expectations to drugs and drug cues, stress reactivity, and (c) negative mood, and a weakened control circuit. Although initial experimentation with a drug of abuse is largely a voluntary behavior, continued drug use can eventually impair neuronal circuits in the brain that are involved in free will, turning drug use into an automatic compulsive behavior. The ability of addictive drugs to co-opt neurotransmitter signals between neurons (including dopamine, glutamate, and GABA) modifies the function of different neuronal circuits, which begin to falter at different stages of an addiction trajectory. Upon exposure to the drug, drug cues or stress this results in unrestrained hyperactivation of the motivation/drive circuit that results in the compulsive drug intake that characterizes addiction.

Functional territories in primate substantia nigra pars reticulata separately signaling stable and flexible values

PubMed Central

Hikosaka, Okihide

2014-01-01

Gaze is strongly attracted to visual objects that have been associated with rewards. Key to this function is a basal ganglia circuit originating from the caudate nucleus (CD), mediated by the substantia nigra pars reticulata (SNr), and aiming at the superior colliculus (SC). Notably, subregions of CD encode values of visual objects differently: stably by CD tail [CD(T)] vs. flexibly by CD head [CD(H)]. Are the stable and flexible value signals processed separately throughout the CD-SNr-SC circuit? To answer this question, we identified SNr neurons by their inputs from CD and outputs to SC and examined their sensitivity to object values. The direct input from CD was identified by SNr neuron's inhibitory response to electrical stimulation of CD. We found that SNr neurons were separated into two groups: 1) neurons inhibited by CD(T) stimulation, located in the caudal-dorsal-lateral SNr (cdlSNr), and 2) neurons inhibited by CD(H) stimulation, located in the rostral-ventral-medial SNr (rvmSNr). Most of CD(T)-recipient SNr neurons encoded stable values, whereas CD(H)-recipient SNr neurons tended to encode flexible values. The output to SC was identified by SNr neuron's antidromic response to SC stimulation. Among the antidromically activated neurons, many encoded only stable values, while some encoded only flexible values. These results suggest that CD(T)-cdlSNr-SC circuit and CD(H)-rvmSNr-SC circuit transmit stable and flexible value signals, largely separately, to SC. The speed of signal transmission was faster through CD(T)-cdlSNr-SC circuit than through CD(H)-rvmSNr-SC circuit, which may reflect automatic and controlled gaze orienting guided by these circuits. PMID:25540224

VAV-1 acts in a single interneuron to inhibit motor circuit activity in Caenorhabditis elegans.

PubMed

Fry, Amanda L; Laboy, Jocelyn T; Norman, Kenneth R

2014-11-21

The complex molecular and cellular mechanisms underlying neuronal control of animal movement are not well understood. Locomotion of Caenorhabditis elegans is mediated by a neuronal circuit that produces coordinated sinusoidal movement. Here we utilize this simple, yet elegant, behaviour to show that VAV-1, a conserved guanine nucleotide exchange factor for Rho-family GTPases, negatively regulates motor circuit activity and the rate of locomotion. While vav-1 is expressed in a small subset of neurons, we find that VAV-1 function is required in a single interneuron, ALA, to regulate motor neuron circuit activity. Furthermore, we show by genetic and optogenetic manipulation of ALA that VAV-1 is required for the excitation and activation of this neuron. We find that ALA signalling inhibits command interneuron activity by abrogating excitatory signalling in the command interneurons, which is responsible for promoting motor neuron circuit activity. Together, our data describe a novel neuromodulatory role for VAV-1-dependent signalling in the regulation of motor circuit activity and locomotion.

Selective Manipulation of Neural Circuits.

PubMed

Park, Hong Geun; Carmel, Jason B

2016-04-01

Unraveling the complex network of neural circuits that form the nervous system demands tools that can manipulate specific circuits. The recent evolution of genetic tools to target neural circuits allows an unprecedented precision in elucidating their function. Here we describe two general approaches for achieving circuit specificity. The first uses the genetic identity of a cell, such as a transcription factor unique to a circuit, to drive expression of a molecule that can manipulate cell function. The second uses the spatial connectivity of a circuit to achieve specificity: one genetic element is introduced at the origin of a circuit and the other at its termination. When the two genetic elements combine within a neuron, they can alter its function. These two general approaches can be combined to allow manipulation of neurons with a specific genetic identity by introducing a regulatory gene into the origin or termination of the circuit. We consider the advantages and disadvantages of both these general approaches with regard to specificity and efficacy of the manipulations. We also review the genetic techniques that allow gain- and loss-of-function within specific neural circuits. These approaches introduce light-sensitive channels (optogenetic) or drug sensitive channels (chemogenetic) into neurons that form specific circuits. We compare these tools with others developed for circuit-specific manipulation and describe the advantages of each. Finally, we discuss how these tools might be applied for identification of the neural circuits that mediate behavior and for repair of neural connections.

Functional imaging of hippocampal place cells at cellular resolution during virtual navigation

PubMed Central

Dombeck, Daniel A.; Harvey, Christopher D.; Tian, Lin; Looger, Loren L.; Tank, David W.

2010-01-01

Spatial navigation is a widely employed behavior in rodent studies of neuronal circuits underlying cognition, learning and memory. In vivo microscopy combined with genetically-encoded indicators provides important new tools to study neuronal circuits, but has been technically difficult to apply during navigation. We describe methods to image the activity of hippocampal CA1 neurons with sub-cellular resolution in behaving mice. Neurons expressing the genetically encoded calcium indicator GCaMP3 were imaged through a chronic hippocampal window. Head-fixed mice performed spatial behaviors within a setup combining a virtual reality system and a custom built two-photon microscope. Populations of place cells were optically identified, and the correlation between the location of their place fields in the virtual environment and their anatomical location in the local circuit was measured. The combination of virtual reality and high-resolution functional imaging should allow for a new generation of studies to probe neuronal circuit dynamics during behavior. PMID:20890294

Cholecystokinin: A multi-functional molecular switch of neuronal circuits

PubMed Central

Lee, Soo Yeun; Soltesz, Ivan

2010-01-01

Cholecystokinin (CCK), a peptide originally discovered in the gastrointestinal tract, is one of the most the abundant and widely distributed neuropeptides in the brain. In spite of its abundance, recent data indicate that that CCK modulates intrinsic neuronal excitability and synaptic transmission in a surprisingly cell-type specific manner, acting as a key molecular switch to regulate the functional output of neuronal circuits. The central importance of CCK in neuronal networks is also reflected in its involvement in a variety of neuropsychiatric and neurological disorders including panic attacks and epilepsy. PMID:21154912

Large-scale, high-density (up to 512 channels) recording of local circuits in behaving animals

PubMed Central

Berényi, Antal; Somogyvári, Zoltán; Nagy, Anett J.; Roux, Lisa; Long, John D.; Fujisawa, Shigeyoshi; Stark, Eran; Leonardo, Anthony; Harris, Timothy D.

2013-01-01

Monitoring representative fractions of neurons from multiple brain circuits in behaving animals is necessary for understanding neuronal computation. Here, we describe a system that allows high-channel-count recordings from a small volume of neuronal tissue using a lightweight signal multiplexing headstage that permits free behavior of small rodents. The system integrates multishank, high-density recording silicon probes, ultraflexible interconnects, and a miniaturized microdrive. These improvements allowed for simultaneous recordings of local field potentials and unit activity from hundreds of sites without confining free movements of the animal. The advantages of large-scale recordings are illustrated by determining the electroanatomic boundaries of layers and regions in the hippocampus and neocortex and constructing a circuit diagram of functional connections among neurons in real anatomic space. These methods will allow the investigation of circuit operations and behavior-dependent interregional interactions for testing hypotheses of neural networks and brain function. PMID:24353300

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow, N.D.; Wang, G.; Volkow, N.D.

Based on brain imaging findings, we present a model according to which addiction emerges as an imbalance in the information processing and integration among various brain circuits and functions. The dysfunctions reflect (a) decreased sensitivity of reward circuits, (b) enhanced sensitivity of memory circuits to conditioned expectations to drugs and drug cues, stress reactivity, and (c) negative mood, and a weakened control circuit. Although initial experimentation with a drug of abuse is largely a voluntary behavior, continued drug use can eventually impair neuronal circuits in the brain that are involved in free will, turning drug use into an automatic compulsivemore » behavior. The ability of addictive drugs to co-opt neurotransmitter signals between neurons (including dopamine, glutamate, and GABA) modifies the function of different neuronal circuits, which begin to falter at different stages of an addiction trajectory. Upon exposure to the drug, drug cues or stress this results in unrestrained hyperactivation of the motivation/drive circuit that results in the compulsive drug intake that characterizes addiction.« less

Electrical Hyperexcitation of Lateral Ventral Pacemaker Neurons Desynchronizes Downstream Circadian Oscillators in the Fly Circadian Circuit and Induces Multiple Behavioral Periods

PubMed Central

Nitabach, Michael N.; Wu, Ying; Sheeba, Vasu; Lemon, William C.; Strumbos, John; Zelensky, Paul K.; White, Benjamin H.; Holmes, Todd C.

2008-01-01

Coupling of autonomous cellular oscillators is an essential aspect of circadian clock function but little is known about its circuit requirements. Functional ablation of the pigment-dispersing factor-expressing lateral ventral subset (LNV ) of Drosophila clock neurons abolishes circadian rhythms of locomotor activity. The hypothesis that LNVs synchronize oscillations in downstream clock neurons was tested by rendering the LNVs hyperexcitable via transgenic expression of a low activation threshold voltage-gated sodium channel. When the LNVs are made hyperexcitable, free-running behavioral rhythms decompose into multiple independent superimposed oscillations and the clock protein oscillations in the dorsal neuron 1 and 2 subgroups of clock neurons are phase-shifted. Thus, regulated electrical activity of the LNVs synchronize multiple oscillators in the fly circadian pacemaker circuit. PMID:16407545

The Topographical Mapping in Drosophila Central Complex Network and Its Signal Routing

PubMed Central

Chang, Po-Yen; Su, Ta-Shun; Shih, Chi-Tin; Lo, Chung-Chuan

2017-01-01

Neural networks regulate brain functions by routing signals. Therefore, investigating the detailed organization of a neural circuit at the cellular levels is a crucial step toward understanding the neural mechanisms of brain functions. To study how a complicated neural circuit is organized, we analyzed recently published data on the neural circuit of the Drosophila central complex, a brain structure associated with a variety of functions including sensory integration and coordination of locomotion. We discovered that, except for a small number of “atypical” neuron types, the network structure formed by the identified 194 neuron types can be described by only a few simple mathematical rules. Specifically, the topological mapping formed by these neurons can be reconstructed by applying a generation matrix on a small set of initial neurons. By analyzing how information flows propagate with or without the atypical neurons, we found that while the general pattern of signal propagation in the central complex follows the simple topological mapping formed by the “typical” neurons, some atypical neurons can substantially re-route the signal pathways, implying specific roles of these neurons in sensory signal integration. The present study provides insights into the organization principle and signal integration in the central complex. PMID:28443014

Mouse Visual Neocortex Supports Multiple Stereotyped Patterns of Microcircuit Activity

PubMed Central

Sadovsky, Alexander J.

2014-01-01

Spiking correlations between neocortical neurons provide insight into the underlying synaptic connectivity that defines cortical microcircuitry. Here, using two-photon calcium fluorescence imaging, we observed the simultaneous dynamics of hundreds of neurons in slices of mouse primary visual cortex (V1). Consistent with a balance of excitation and inhibition, V1 dynamics were characterized by a linear scaling between firing rate and circuit size. Using lagged firing correlations between neurons, we generated functional wiring diagrams to evaluate the topological features of V1 microcircuitry. We found that circuit connectivity exhibited both cyclic graph motifs, indicating recurrent wiring, and acyclic graph motifs, indicating feedforward wiring. After overlaying the functional wiring diagrams onto the imaged field of view, we found properties consistent with Rentian scaling: wiring diagrams were topologically efficient because they minimized wiring with a modular architecture. Within single imaged fields of view, V1 contained multiple discrete circuits that were overlapping and highly interdigitated but were still distinct from one another. The majority of neurons that were shared between circuits displayed peri-event spiking activity whose timing was specific to the active circuit, whereas spike times for a smaller percentage of neurons were invariant to circuit identity. These data provide evidence that V1 microcircuitry exhibits balanced dynamics, is efficiently arranged in anatomical space, and is capable of supporting a diversity of multineuron spike firing patterns from overlapping sets of neurons. PMID:24899701

"The developmental and functional logic of neuronal circuits": commentary on the Kavli Prize in Neuroscience.

PubMed

Glover, J C

2009-11-10

The first Kavli Prize in Neuroscience recognizes a confluence of career achievements that together provide a fundamental understanding of how brain and spinal cord circuits are assembled during development and function in the adult. The members of the Kavli Neuroscience Prize Committee have decided to reward three scientists (Sten Grillner, Thomas Jessell, and Pasko Rakic) jointly "for discoveries on the developmental and functional logic of neuronal circuits". Pasko Rakic performed groundbreaking studies of the developing cerebral cortex, including the discovery of how radial glia guide the neuronal migration that establishes cortical layers and for the radial unit hypothesis and its implications for cortical connectivity and evolution. Thomas Jessell discovered molecular principles governing the specification and patterning of different neuron types and the development of their synaptic interconnection into sensorimotor circuits. Sten Grillner elucidated principles of network organization in the vertebrate locomotor central pattern generator, along with its command systems and sensory and higher order control. The discoveries of Rakic, Jessell and Grillner provide a framework for how neurons obtain their identities and ultimate locations, establish appropriate connections with each other, and how the resultant neuronal networks operate. Their work has significantly advanced our understanding of brain development and function and created new opportunities for the treatment of neurological disorders. Each has pioneered an important area of neuroscience research and left a legacy of exceptional scientific achievement, insight, communication, mentoring and leadership.

Spike timing precision of neuronal circuits.

PubMed

Kilinc, Deniz; Demir, Alper

2018-06-01

Spike timing is believed to be a key factor in sensory information encoding and computations performed by the neurons and neuronal circuits. However, the considerable noise and variability, arising from the inherently stochastic mechanisms that exist in the neurons and the synapses, degrade spike timing precision. Computational modeling can help decipher the mechanisms utilized by the neuronal circuits in order to regulate timing precision. In this paper, we utilize semi-analytical techniques, which were adapted from previously developed methods for electronic circuits, for the stochastic characterization of neuronal circuits. These techniques, which are orders of magnitude faster than traditional Monte Carlo type simulations, can be used to directly compute the spike timing jitter variance, power spectral densities, correlation functions, and other stochastic characterizations of neuronal circuit operation. We consider three distinct neuronal circuit motifs: Feedback inhibition, synaptic integration, and synaptic coupling. First, we show that both the spike timing precision and the energy efficiency of a spiking neuron are improved with feedback inhibition. We unveil the underlying mechanism through which this is achieved. Then, we demonstrate that a neuron can improve on the timing precision of its synaptic inputs, coming from multiple sources, via synaptic integration: The phase of the output spikes of the integrator neuron has the same variance as that of the sample average of the phases of its inputs. Finally, we reveal that weak synaptic coupling among neurons, in a fully connected network, enables them to behave like a single neuron with a larger membrane area, resulting in an improvement in the timing precision through cooperation.

Neural circuitry coordinating male copulation

PubMed Central

Pavlou, Hania J; Lin, Andrew C; Neville, Megan C; Nojima, Tetsuya; Diao, Fengqiu; Chen, Brian E; White, Benjamin H; Goodwin, Stephen F

2016-01-01

Copulation is the goal of the courtship process, crucial to reproductive success and evolutionary fitness. Identifying the circuitry underlying copulation is a necessary step towards understanding universal principles of circuit operation, and how circuit elements are recruited into the production of ordered action sequences. Here, we identify key sex-specific neurons that mediate copulation in Drosophila, and define a sexually dimorphic motor circuit in the male abdominal ganglion that mediates the action sequence of initiating and terminating copulation. This sexually dimorphic circuit composed of three neuronal classes – motor neurons, interneurons and mechanosensory neurons – controls the mechanics of copulation. By correlating the connectivity, function and activity of these neurons we have determined the logic for how this circuitry is coordinated to generate this male-specific behavior, and sets the stage for a circuit-level dissection of active sensing and modulation of copulatory behavior. DOI: http://dx.doi.org/10.7554/eLife.20713.001 PMID:27855059

Antidromic-rectifying gap junctions amplify chemical transmission at functionally mixed electrical-chemical synapses

PubMed Central

Liu, Ping; Chen, Bojun; Mailler, Roger; Wang, Zhao-Wen

2017-01-01

Neurons communicate through chemical synapses and electrical synapses (gap junctions). Although these two types of synapses often coexist between neurons, little is known about whether they interact, and whether any interactions between them are important to controlling synaptic strength and circuit functions. By studying chemical and electrical synapses between premotor interneurons (AVA) and downstream motor neurons (A-MNs) in the Caenorhabditis elegans escape circuit, we found that disrupting either the chemical or electrical synapses causes defective escape response. Gap junctions between AVA and A-MNs only allow antidromic current, but, curiously, disrupting them inhibits chemical transmission. In contrast, disrupting chemical synapses has no effect on the electrical coupling. These results demonstrate that gap junctions may serve as an amplifier of chemical transmission between neurons with both electrical and chemical synapses. The use of antidromic-rectifying gap junctions to amplify chemical transmission is potentially a conserved mechanism in circuit functions. PMID:28317880

A modeling framework for deriving the structural and functional architecture of a short-term memory microcircuit.

PubMed

Fisher, Dimitry; Olasagasti, Itsaso; Tank, David W; Aksay, Emre R F; Goldman, Mark S

2013-09-04

Although many studies have identified neural correlates of memory, relatively little is known about the circuit properties connecting single-neuron physiology to behavior. Here we developed a modeling framework to bridge this gap and identify circuit interactions capable of maintaining short-term memory. Unlike typical studies that construct a phenomenological model and test whether it reproduces select aspects of neuronal data, we directly fit the synaptic connectivity of an oculomotor memory circuit to a broad range of anatomical, electrophysiological, and behavioral data. Simultaneous fits to all data, combined with sensitivity analyses, revealed complementary roles of synaptic and neuronal recruitment thresholds in providing the nonlinear interactions required to generate the observed circuit behavior. This work provides a methodology for identifying the cellular and synaptic mechanisms underlying short-term memory and demonstrates how the anatomical structure of a circuit may belie its functional organization. Copyright © 2013 Elsevier Inc. All rights reserved.

Sequencing the Connectome

PubMed Central

Zador, Anthony M.; Dubnau, Joshua; Oyibo, Hassana K.; Zhan, Huiqing; Cao, Gang; Peikon, Ian D.

2012-01-01

Connectivity determines the function of neural circuits. Historically, circuit mapping has usually been viewed as a problem of microscopy, but no current method can achieve high-throughput mapping of entire circuits with single neuron precision. Here we describe a novel approach to determining connectivity. We propose BOINC (“barcoding of individual neuronal connections”), a method for converting the problem of connectivity into a form that can be read out by high-throughput DNA sequencing. The appeal of using sequencing is that its scale—sequencing billions of nucleotides per day is now routine—is a natural match to the complexity of neural circuits. An inexpensive high-throughput technique for establishing circuit connectivity at single neuron resolution could transform neuroscience research. PMID:23109909

Canonical Organization of Layer 1 Neuron-Led Cortical Inhibitory and Disinhibitory Interneuronal Circuits

PubMed Central

Lee, Alice J.; Wang, Guangfu; Jiang, Xiaolong; Johnson, Seraphina M.; Hoang, Elizabeth T.; Lanté, Fabien; Stornetta, Ruth L.; Beenhakker, Mark P.; Shen, Ying; Julius Zhu, J.

2015-01-01

Interneurons play a key role in cortical function and dysfunction, yet organization of cortical interneuronal circuitry remains poorly understood. Cortical Layer 1 (L1) contains 2 general GABAergic interneuron groups, namely single bouquet cells (SBCs) and elongated neurogliaform cells (ENGCs). SBCs predominantly make unidirectional inhibitory connections (SBC→) with L2/3 interneurons, whereas ENGCs frequently form reciprocal inhibitory and electric connections (ENGC↔) with L2/3 interneurons. Here, we describe a systematic investigation of the pyramidal neuron targets of L1 neuron-led interneuronal circuits in the rat barrel cortex with simultaneous octuple whole-cell recordings and report a simple organizational scheme of the interneuronal circuits. Both SBCs→ and ENGC ↔ L2/3 interneuronal circuits connect to L2/3 and L5, but not L6, pyramidal neurons. SBC → L2/3 interneuronal circuits primarily inhibit the entire dendritic–somato–axonal axis of a few L2/3 and L5 pyramidal neurons located within the same column. In contrast, ENGC ↔ L2/3 interneuronal circuits generally inhibit the distal apical dendrite of many L2/3 and L5 pyramidal neurons across multiple columns. Finally, L1 interneuron-led circuits target distinct subcellular compartments of L2/3 and L5 pyramidal neurons in a L2/3 interneuron type-dependent manner. These results suggest that L1 neurons form canonical interneuronal circuits to control information processes in both supra- and infragranular cortical layers. PMID:24554728

Motor Neurons Tune Premotor Activity in a Vertebrate Central Pattern Generator

PubMed Central

2017-01-01

Central patterns generators (CPGs) are neural circuits that drive rhythmic motor output without sensory feedback. Vertebrate CPGs are generally believed to operate in a top-down manner in which premotor interneurons activate motor neurons that in turn drive muscles. In contrast, the frog (Xenopus laevis) vocal CPG contains a functionally unexplored neuronal projection from the motor nucleus to the premotor nucleus, indicating a recurrent pathway that may contribute to rhythm generation. In this study, we characterized the function of this bottom-up connection. The X. laevis vocal CPG produces a 50–60 Hz “fast trill” song used by males during courtship. We recorded “fictive vocalizations” in the in vitro CPG from the laryngeal nerve while simultaneously recording premotor activity at the population and single-cell level. We show that transecting the motor-to-premotor projection eliminated the characteristic firing rate of premotor neurons. Silencing motor neurons with the intracellular sodium channel blocker QX-314 also disrupted premotor rhythms, as did blockade of nicotinic synapses in the motor nucleus (the putative location of motor neuron-to-interneuron connections). Electrically stimulating the laryngeal nerve elicited primarily IPSPs in premotor neurons that could be blocked by a nicotinic receptor antagonist. Our results indicate that an inhibitory signal, activated by motor neurons, is required for proper CPG function. To our knowledge, these findings represent the first example of a CPG in which precise premotor rhythms are tuned by motor neuron activity. SIGNIFICANCE STATEMENT Central pattern generators (CPGs) are neural circuits that produce rhythmic behaviors. In vertebrates, motor neurons are not commonly known to contribute to CPG function, with the exception of a few spinal circuits where the functional significance of motor neuron feedback is still poorly understood. The frog hindbrain vocal circuit contains a previously unexplored connection from the motor to premotor region. Our results indicate that motor neurons activate this bottom-up connection, and blocking this signal eliminates normal premotor activity. These findings may promote increased awareness of potential involvement of motor neurons in a wider range of CPGs, perhaps clarifying our understanding of network principles underlying motor behaviors in numerous organisms, including humans. PMID:28219984

The autism associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain

PubMed Central

Peng, Yun; Lu, Zhongming; Li, Guohui; Piechowicz, Mariel; Anderson, Miranda; Uddin, Yasin; Wu, Jie; Qiu, Shenfeng

2015-01-01

The human MET gene imparts a replicated risk for autism spectrum disorder (ASD), and is implicated in the structural and functional integrity of brain. MET encodes a receptor tyrosine kinase, MET, which plays a pleiotropic role in embryogenesis and modifies a large number of neurodevelopmental events. Very little is known, however, on how MET signaling engages distinct cellular events to collectively affect brain development in ASD-relevant disease domains. Here, we show that MET protein expression is dynamically regulated and compartmentalized in developing neurons. MET is heavily expressed in neuronal growth cones at early developmental stages and its activation engages small GTPase Cdc42 to promote neuronal growth, dendritic arborization, and spine formation. Genetic ablation of MET signaling in mouse dorsal pallium leads to altered neuronal morphology indicative of early functional maturation. In contrast, prolonged activation of MET represses the formation and functional maturation of glutamatergic synapses. Moreover, manipulating MET signaling levels in vivo in the developing prefrontal projection neurons disrupts the local circuit connectivity made onto these neurons. Therefore, normal time-delimited MET signaling is critical in regulating the timing of neuronal growth, glutamatergic synapse maturation and cortical circuit function. Dysregulated MET signaling may lead to pathological changes in forebrain maturation and connectivity, and thus contribute to the emergence of neurological symptoms associated with ASD. PMID:26728565

Local Circuits of V1 Layer 4B Neurons Projecting to V2 Thick Stripes Define Distinct Cell Classes and Avoid Cytochrome Oxidase Blobs

PubMed Central

Yarch, Jeff; Federer, Frederick

2017-01-01

Decades of anatomical studies on the primate primary visual cortex (V1) have led to a detailed diagram of V1 intrinsic circuitry, but this diagram lacks information about the output targets of V1 cells. Understanding how V1 local processing relates to downstream processing requires identification of neuronal populations defined by their output targets. In primates, V1 layers (L)2/3 and 4B send segregated projections to distinct cytochrome oxidase (CO) stripes in area V2: neurons in CO blob columns project to thin stripes while neurons outside blob columns project to thick and pale stripes, suggesting functional specialization of V1-to-V2 CO streams. However, the conventional diagram of V1 shows all L4B neurons, regardless of their soma location in blob or interblob columns, as projecting selectively to CO blobs in L2/3, suggesting convergence of blob/interblob information in L2/3 blobs and, possibly, some V2 stripes. However, it is unclear whether all L4B projection neurons show similar local circuitries. Using viral-mediated circuit tracing, we have identified the local circuits of L4B neurons projecting to V2 thick stripes in macaque. Consistent with previous studies, we found the somata of this L4B subpopulation to reside predominantly outside blob columns; however, unlike previous descriptions of local L4B circuits, these cells consistently projected outside CO blob columns in all layers. Thus, the local circuits of these L4B output neurons, just like their extrinsic projections to V2, preserve CO streams. Moreover, the intra-V1 laminar patterns of axonal projections identify two distinct neuron classes within this L4B subpopulation, including a rare novel neuron type, suggestive of two functionally specialized output channels. SIGNIFICANCE STATEMENT Conventional diagrams of primate primary visual cortex (V1) depict neuronal connections within and between different V1 layers, but lack information about the cells' downstream targets. This information is critical to understanding how local processing in V1 relates to downstream processing. We have identified the local circuits of a population of cells in V1 layer (L)4B that project to area V2. These cells' local circuits differ from classical descriptions of L4B circuits in both the laminar and functional compartments targeted by their axons, and identify two neuron classes. Our results demonstrate that both local intra-V1 and extrinsic V1-to-V2 connections of L4B neurons preserve CO-stream segregation, suggesting that across-stream integration occurs downstream of V1, and that output targets dictate local V1 circuitry. PMID:28077720

Clique of Functional Hubs Orchestrates Population Bursts in Developmentally Regulated Neural Networks

PubMed Central

Luccioli, Stefano; Ben-Jacob, Eshel; Barzilai, Ari; Bonifazi, Paolo; Torcini, Alessandro

2014-01-01

It has recently been discovered that single neuron stimulation can impact network dynamics in immature and adult neuronal circuits. Here we report a novel mechanism which can explain in neuronal circuits, at an early stage of development, the peculiar role played by a few specific neurons in promoting/arresting the population activity. For this purpose, we consider a standard neuronal network model, with short-term synaptic plasticity, whose population activity is characterized by bursting behavior. The addition of developmentally inspired constraints and correlations in the distribution of the neuronal connectivities and excitabilities leads to the emergence of functional hub neurons, whose stimulation/deletion is critical for the network activity. Functional hubs form a clique, where a precise sequential activation of the neurons is essential to ignite collective events without any need for a specific topological architecture. Unsupervised time-lagged firings of supra-threshold cells, in connection with coordinated entrainments of near-threshold neurons, are the key ingredients to orchestrate population activity. PMID:25255443

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

PubMed Central

Wang, Cheng-Te; Lee, Chung-Ting; Wang, Xiao-Jing; Lo, Chung-Chuan

2013-01-01

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. PMID:23626812

Top-down modulation on perceptual decision with balanced inhibition through feedforward and feedback inhibitory neurons.

PubMed

Wang, Cheng-Te; Lee, Chung-Ting; Wang, Xiao-Jing; Lo, Chung-Chuan

2013-01-01

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.

Transsynaptic Mapping of Second-Order Taste Neurons in Flies by trans-Tango.

PubMed

Talay, Mustafa; Richman, Ethan B; Snell, Nathaniel J; Hartmann, Griffin G; Fisher, John D; Sorkaç, Altar; Santoyo, Juan F; Chou-Freed, Cambria; Nair, Nived; Johnson, Mark; Szymanski, John R; Barnea, Gilad

2017-11-15

Mapping neural circuits across defined synapses is essential for understanding brain function. Here we describe trans-Tango, a technique for anterograde transsynaptic circuit tracing and manipulation. At the core of trans-Tango is a synthetic signaling pathway that is introduced into all neurons in the animal. This pathway converts receptor activation at the cell surface into reporter expression through site-specific proteolysis. Specific labeling is achieved by presenting a tethered ligand at the synapses of genetically defined neurons, thereby activating the pathway in their postsynaptic partners and providing genetic access to these neurons. We first validated trans-Tango in the Drosophila olfactory system and then implemented it in the gustatory system, where projections beyond the first-order receptor neurons are not fully characterized. We identified putative second-order neurons within the sweet circuit that include projection neurons targeting known neuromodulation centers in the brain. These experiments establish trans-Tango as a flexible platform for transsynaptic circuit analysis. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetically identified spinal interneurons integrating tactile afferents for motor control

PubMed Central

Panek, Izabela; Farah, Carl

2015-01-01

Our movements are shaped by our perception of the world as communicated by our senses. Perception of sensory information has been largely attributed to cortical activity. However, a prior level of sensory processing occurs in the spinal cord. Indeed, sensory inputs directly project to many spinal circuits, some of which communicate with motor circuits within the spinal cord. Therefore, the processing of sensory information for the purpose of ensuring proper movements is distributed between spinal and supraspinal circuits. The mechanisms underlying the integration of sensory information for motor control at the level of the spinal cord have yet to be fully described. Recent research has led to the characterization of spinal neuron populations that share common molecular identities. Identification of molecular markers that define specific populations of spinal neurons is a prerequisite to the application of genetic techniques devised to both delineate the function of these spinal neurons and their connectivity. This strategy has been used in the study of spinal neurons that receive tactile inputs from sensory neurons innervating the skin. As a result, the circuits that include these spinal neurons have been revealed to play important roles in specific aspects of motor function. We describe these genetically identified spinal neurons that integrate tactile information and the contribution of these studies to our understanding of how tactile information shapes motor output. Furthermore, we describe future opportunities that these circuits present for shedding light on the neural mechanisms of tactile processing. PMID:26445867

Genetic Feedback Regulation of Frontal Cortical Neuronal Ensembles Through Activity-Dependent Arc Expression and Dopaminergic Input.

PubMed

Mastwal, Surjeet; Cao, Vania; Wang, Kuan Hong

2016-01-01

Mental functions involve coordinated activities of specific neuronal ensembles that are embedded in complex brain circuits. Aberrant neuronal ensemble dynamics is thought to form the neurobiological basis of mental disorders. A major challenge in mental health research is to identify these cellular ensembles and determine what molecular mechanisms constrain their emergence and consolidation during development and learning. Here, we provide a perspective based on recent studies that use activity-dependent gene Arc/Arg3.1 as a cellular marker to identify neuronal ensembles and a molecular probe to modulate circuit functions. These studies have demonstrated that the transcription of Arc is activated in selective groups of frontal cortical neurons in response to specific behavioral tasks. Arc expression regulates the persistent firing of individual neurons and predicts the consolidation of neuronal ensembles during repeated learning. Therefore, the Arc pathway represents a prototypical example of activity-dependent genetic feedback regulation of neuronal ensembles. The activation of this pathway in the frontal cortex starts during early postnatal development and requires dopaminergic (DA) input. Conversely, genetic disruption of Arc leads to a hypoactive mesofrontal dopamine circuit and its related cognitive deficit. This mutual interaction suggests an auto-regulatory mechanism to amplify the impact of neuromodulators and activity-regulated genes during postnatal development. Such a mechanism may contribute to the association of mutations in dopamine and Arc pathways with neurodevelopmental psychiatric disorders. As the mesofrontal dopamine circuit shows extensive activity-dependent developmental plasticity, activity-guided modulation of DA projections or Arc ensembles during development may help to repair circuit deficits related to neuropsychiatric disorders.

COMPENSATION FOR VARIABLE INTRINSIC NEURONAL EXCITABILITY BY CIRCUIT-SYNAPTIC INTERACTIONS

PubMed Central

Grashow, Rachel; Brookings, Ted; Marder, Eve

2010-01-01

Recent theoretical and experimental work indicates that neurons tune themselves to maintain target levels of excitation by modulating ion channel expression and synaptic strengths. As a result, functionally equivalent circuits can produce similar activity despite disparate underlying network and cellular properties. To experimentally test the extent to which synaptic and intrinsic conductances can produce target activity in the presence of variability in neuronal intrinsic properties, we used the dynamic clamp to create hybrid two-cell circuits built from four types of stomatogastric (STG) neurons coupled to the same model Morris-Lecar neuron by reciprocal inhibition. We measured six intrinsic properties (input resistance, minimum membrane potential, firing rate in response to +1nA of injected current, slope of the FI curve, spike height and spike voltage threshold) of Dorsal Gastric (DG), Gastric Mill (GM), Lateral Pyloric (LP) and Pyloric Dilator (PD) neurons from male crabs, Cancer borealis. The intrinsic properties varied two to seven-fold in each cell type. We coupled each biological neuron to the Morris-Lecar model with seven different values of inhibitory synaptic conductance, and also used the dynamic clamp to add seven different values of an artificial h-conductance, thus creating 49 different circuits for each biological neuron. Despite the variability in intrinsic excitability, networks formed from each neuron produced similar circuit performance at some values of synaptic and h-conductances. This work experimentally confirms results from previous modeling studies; tuning synaptic and intrinsic conductances can yield similar circuit output from neurons with variable intrinsic excitability. PMID:20610748

Matrix Metalloproteinase-9 regulates neuronal circuit development and excitability

PubMed Central

Murase, Sachiko; Lantz, Crystal; Kim, Eunyoung; Gupta, Nitin; Higgins, Richard; Stopfer, Mark; Hoffman, Dax A.; Quinlan, Elizabeth M.

2015-01-01

In early postnatal development, naturally occurring cell death, dendritic outgrowth and synaptogenesis sculpt neuronal ensembles into functional neuronal circuits. Here we demonstrate that deletion of the extracellular proteinase MMP-9 affects each of these processes, resulting in maladapted neuronal circuitry. MMP-9 deletion increases the number of CA1 pyramidal neurons, but decreases dendritic length and complexity while dendritic spine density is unchanged. Parallel changes in neuronal morphology are observed in primary visual cortex, and persist into adulthood. Individual CA1 neurons in MMP-9−/− mice have enhanced input resistance and a significant increase in the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs). Additionally, deletion of MMP-9 significant increases spontaneous neuronal activity in awake MMP-9−/− mice and enhances response to acute challenge by the excitotoxin kainate. Thus MMP-9-dependent proteolysis regulates several aspects of circuit maturation to constrain excitability throughout life. PMID:26093382

Genetic strategies to investigate neuronal circuit properties using stem cell-derived neurons

PubMed Central

Garcia, Isabella; Kim, Cynthia; Arenkiel, Benjamin R.

2012-01-01

The mammalian brain is anatomically and functionally complex, and prone to diverse forms of injury and neuropathology. Scientists have long strived to develop cell replacement therapies to repair damaged and diseased nervous tissue. However, this goal has remained unrealized for various reasons, including nascent knowledge of neuronal development, the inability to track and manipulate transplanted cells within complex neuronal networks, and host graft rejection. Recent advances in embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) technology, alongside novel genetic strategies to mark and manipulate stem cell-derived neurons, now provide unprecedented opportunities to investigate complex neuronal circuits in both healthy and diseased brains. Here, we review current technologies aimed at generating and manipulating neurons derived from ESCs and iPSCs toward investigation and manipulation of complex neuronal circuits, ultimately leading to the design and development of novel cell-based therapeutic approaches. PMID:23264761

A neural command circuit for grooming movement control.

PubMed

Hampel, Stefanie; Franconville, Romain; Simpson, Julie H; Seeds, Andrew M

2015-09-07

Animals perform many stereotyped movements, but how nervous systems are organized for controlling specific movements remains unclear. Here we use anatomical, optogenetic, behavioral, and physiological techniques to identify a circuit in Drosophila melanogaster that can elicit stereotyped leg movements that groom the antennae. Mechanosensory chordotonal neurons detect displacements of the antennae and excite three different classes of functionally connected interneurons, which include two classes of brain interneurons and different parallel descending neurons. This multilayered circuit is organized such that neurons within each layer are sufficient to specifically elicit antennal grooming. However, we find differences in the durations of antennal grooming elicited by neurons in the different layers, suggesting that the circuit is organized to both command antennal grooming and control its duration. As similar features underlie stimulus-induced movements in other animals, we infer the possibility of a common circuit organization for movement control that can be dissected in Drosophila.

Inter-progenitor pool wiring: An evolutionarily conserved strategy that expands neural circuit diversity.

PubMed

Suzuki, Takumi; Sato, Makoto

2017-11-15

Diversification of neuronal types is key to establishing functional variations in neural circuits. The first critical step to generate neuronal diversity is to organize the compartmental domains of developing brains into spatially distinct neural progenitor pools. Neural progenitors in each pool then generate a unique set of diverse neurons through specific spatiotemporal specification processes. In this review article, we focus on an additional mechanism, 'inter-progenitor pool wiring', that further expands the diversity of neural circuits. After diverse types of neurons are generated in one progenitor pool, a fraction of these neurons start migrating toward a remote brain region containing neurons that originate from another progenitor pool. Finally, neurons of different origins are intermingled and eventually form complex but precise neural circuits. The developing cerebral cortex of mammalian brains is one of the best examples of inter-progenitor pool wiring. However, Drosophila visual system development has revealed similar mechanisms in invertebrate brains, suggesting that inter-progenitor pool wiring is an evolutionarily conserved strategy that expands neural circuit diversity. Here, we will discuss how inter-progenitor pool wiring is accomplished in mammalian and fly brain systems. Copyright © 2017 Elsevier Inc. All rights reserved.

Memory formation orchestrates the wiring of adult-born hippocampal neurons into brain circuits.

PubMed

Petsophonsakul, Petnoi; Richetin, Kevin; Andraini, Trinovita; Roybon, Laurent; Rampon, Claire

2017-08-01

During memory formation, structural rearrangements of dendritic spines provide a mean to durably modulate synaptic connectivity within neuronal networks. New neurons generated throughout the adult life in the dentate gyrus of the hippocampus contribute to learning and memory. As these neurons become incorporated into the network, they generate huge numbers of new connections that modify hippocampal circuitry and functioning. However, it is yet unclear as to how the dynamic process of memory formation influences their synaptic integration into neuronal circuits. New memories are established according to a multistep process during which new information is first acquired and then consolidated to form a stable memory trace. Upon recall, memory is transiently destabilized and vulnerable to modification. Using contextual fear conditioning, we found that learning was associated with an acceleration of dendritic spines formation of adult-born neurons, and that spine connectivity becomes strengthened after memory consolidation. Moreover, we observed that afferent connectivity onto adult-born neurons is enhanced after memory retrieval, while extinction training induces a change of spine shapes. Together, these findings reveal that the neuronal activity supporting memory processes strongly influences the structural dendritic integration of adult-born neurons into pre-existing neuronal circuits. Such change of afferent connectivity is likely to impact the overall wiring of hippocampal network, and consequently, to regulate hippocampal function.

Interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in minimal hepatic encephalopathy.

PubMed

Llansola, Marta; Montoliu, Carmina; Agusti, Ana; Hernandez-Rabaza, Vicente; Cabrera-Pastor, Andrea; Gomez-Gimenez, Belen; Malaguarnera, Michele; Dadsetan, Sherry; Belghiti, Majedeline; Garcia-Garcia, Raquel; Balzano, Tiziano; Taoro, Lucas; Felipo, Vicente

2015-09-01

The cognitive and motor alterations in hepatic encephalopathy (HE) are the final result of altered neurotransmission and communication between neurons in neuronal networks and circuits. Different neurotransmitter systems cooperate to modulate cognitive and motor function, with a main role for glutamatergic and GABAergic neurotransmission in different brain areas and neuronal circuits. There is an interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in HE. This interplay may occur: (a) in different brain areas involved in specific neuronal circuits; (b) in the same brain area through cross-modulation of glutamatergic and GABAergic neurotransmission. We will summarize some examples of the (1) interplay between glutamatergic and GABAergic neurotransmission alterations in different areas in the basal ganglia-thalamus-cortex circuit in the motor alterations in minimal hepatic encephalopathy (MHE); (2) interplay between glutamatergic and GABAergic neurotransmission alterations in cerebellum in the impairment of cognitive function in MHE through altered function of the glutamate-nitric oxide-cGMP pathway. We will also comment the therapeutic implications of the above studies and the utility of modulators of glutamate and GABA receptors to restore cognitive and motor function in rats with hyperammonemia and hepatic encephalopathy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Conserved neural circuit structure across Drosophila larval development revealed by comparative connectomics.

PubMed

Gerhard, Stephan; Andrade, Ingrid; Fetter, Richard D; Cardona, Albert; Schneider-Mizell, Casey M

2017-10-23

During postembryonic development, the nervous system must adapt to a growing body. How changes in neuronal structure and connectivity contribute to the maintenance of appropriate circuit function remains unclear. Previously , we measured the cellular neuroanatomy underlying synaptic connectivity in Drosophila (Schneider-Mizell et al., 2016). Here, we examined how neuronal morphology and connectivity change between first instar and third instar larval stages using serial section electron microscopy. We reconstructed nociceptive circuits in a larva of each stage and found consistent topographically arranged connectivity between identified neurons. Five-fold increases in each size, number of terminal dendritic branches, and total number of synaptic inputs were accompanied by cell type-specific connectivity changes that preserved the fraction of total synaptic input associated with each pre-synaptic partner. We propose that precise patterns of structural growth act to conserve the computational function of a circuit, for example determining the location of a dangerous stimulus.

Linking Neurons to Network Function and Behavior by Two-Photon Holographic Optogenetics and Volumetric Imaging.

PubMed

Dal Maschio, Marco; Donovan, Joseph C; Helmbrecht, Thomas O; Baier, Herwig

2017-05-17

We introduce a flexible method for high-resolution interrogation of circuit function, which combines simultaneous 3D two-photon stimulation of multiple targeted neurons, volumetric functional imaging, and quantitative behavioral tracking. This integrated approach was applied to dissect how an ensemble of premotor neurons in the larval zebrafish brain drives a basic motor program, the bending of the tail. We developed an iterative photostimulation strategy to identify minimal subsets of channelrhodopsin (ChR2)-expressing neurons that are sufficient to initiate tail movements. At the same time, the induced network activity was recorded by multiplane GCaMP6 imaging across the brain. From this dataset, we computationally identified activity patterns associated with distinct components of the elicited behavior and characterized the contributions of individual neurons. Using photoactivatable GFP (paGFP), we extended our protocol to visualize single functionally identified neurons and reconstruct their morphologies. Together, this toolkit enables linking behavior to circuit activity with unprecedented resolution. Copyright © 2017 Elsevier Inc. All rights reserved.

Pubertally born neurons and glia are functionally integrated into limbic and hypothalamic circuits of the male Syrian hamster.

PubMed

Mohr, Margaret A; Sisk, Cheryl L

2013-03-19

During puberty, the brain goes through extensive remodeling, involving the addition of new neurons and glia to brain regions beyond the canonical neurogenic regions (i.e., dentate gyrus and olfactory bulb), including limbic and hypothalamic cell groups associated with sex-typical behavior. Whether these pubertally born cells become functionally integrated into neural circuits remains unknown. To address this question, we gave male Syrian hamsters daily injections of the cell birthdate marker bromodeoxyuridine throughout puberty (postnatal day 28-49). Half of the animals were housed in enriched environments with access to a running wheel to determine whether enrichment increased the survival of pubertally born cells compared with the control environment. At 4 wk after the last BrdU injection, animals were allowed to interact with a receptive female and were then killed 1 h later. Triple-label immunofluorescence for BrdU, the mature neuron marker neuronal nuclear antigen, and the astrocytic marker glial fibrillary acidic protein revealed that a proportion of pubertally born cells in the medial preoptic area, arcuate nucleus, and medial amygdala differentiate into either mature neurons or astrocytes. Double-label immunofluorescence for BrdU and the protein Fos revealed that a subset of pubertally born cells in these regions is activated during sociosexual behavior, indicative of their functional incorporation into neural circuits. Enrichment affected the survival and activation of pubertally born cells in a brain region-specific manner. These results demonstrate that pubertally born cells located outside of the traditional neurogenic regions differentiate into neurons and glia and become functionally incorporated into neural circuits that subserve sex-typical behaviors.

Carotid chemoreceptors tune breathing via multipath routing: reticular chain and loop operations supported by parallel spike train correlations.

PubMed

Morris, Kendall F; Nuding, Sarah C; Segers, Lauren S; Iceman, Kimberly E; O'Connor, Russell; Dean, Jay B; Ott, Mackenzie M; Alencar, Pierina A; Shuman, Dale; Horton, Kofi-Kermit; Taylor-Clark, Thomas E; Bolser, Donald C; Lindsey, Bruce G

2018-02-01

We tested the hypothesis that carotid chemoreceptors tune breathing through parallel circuit paths that target distinct elements of an inspiratory neuron chain in the ventral respiratory column (VRC). Microelectrode arrays were used to monitor neuronal spike trains simultaneously in the VRC, peri-nucleus tractus solitarius (p-NTS)-medial medulla, the dorsal parafacial region of the lateral tegmental field (FTL-pF), and medullary raphe nuclei together with phrenic nerve activity during selective stimulation of carotid chemoreceptors or transient hypoxia in 19 decerebrate, neuromuscularly blocked, and artificially ventilated cats. Of 994 neurons tested, 56% had a significant change in firing rate. A total of 33,422 cell pairs were evaluated for signs of functional interaction; 63% of chemoresponsive neurons were elements of at least one pair with correlational signatures indicative of paucisynaptic relationships. We detected evidence for postinspiratory neuron inhibition of rostral VRC I-Driver (pre-Bötzinger) neurons, an interaction predicted to modulate breathing frequency, and for reciprocal excitation between chemoresponsive p-NTS neurons and more downstream VRC inspiratory neurons for control of breathing depth. Chemoresponsive pericolumnar tonic expiratory neurons, proposed to amplify inspiratory drive by disinhibition, were correlationally linked to afferent and efferent "chains" of chemoresponsive neurons extending to all monitored regions. The chains included coordinated clusters of chemoresponsive FTL-pF neurons with functional links to widespread medullary sites involved in the control of breathing. The results support long-standing concepts on brain stem network architecture and a circuit model for peripheral chemoreceptor modulation of breathing with multiple circuit loops and chains tuned by tegmental field neurons with quasi-periodic discharge patterns. NEW & NOTEWORTHY We tested the long-standing hypothesis that carotid chemoreceptors tune the frequency and depth of breathing through parallel circuit operations targeting the ventral respiratory column. Responses to stimulation of the chemoreceptors and identified functional connectivity support differential tuning of inspiratory neuron burst duration and firing rate and a model of brain stem network architecture incorporating tonic expiratory "hub" neurons regulated by convergent neuronal chains and loops through rostral lateral tegmental field neurons with quasi-periodic discharge patterns.

Comparative mapping of GABA-immunoreactive neurons in the central nervous systems of nudibranch molluscs.

PubMed

Gunaratne, Charuni A; Sakurai, Akira; Katz, Paul S

2014-03-01

The relative simplicity of certain invertebrate nervous systems, such as those of gastropod molluscs, allows behaviors to be dissected at the level of small neural circuits composed of individually identifiable neurons. Elucidating the neurotransmitter phenotype of neurons in neural circuits is important for understanding how those neural circuits function. In this study, we examined the distribution of γ-aminobutyric-acid;-immunoreactive (GABA-ir) neurons in four species of sea slugs (Mollusca, Gastropoda, Opisthobranchia, Nudibranchia): Tritonia diomedea, Melibe leonina, Dendronotus iris, and Hermissenda crassicornis. We found consistent patterns of GABA immunoreactivity in the pedal and cerebral-pleural ganglia across species. In particular, there were bilateral clusters in the lateral and medial regions of the dorsal surface of the cerebral ganglia as well as a cluster on the ventral surface of the pedal ganglia. There were also individual GABA-ir neurons that were recognizable across species. The invariant presence of these individual neurons and clusters suggests that they are homologous, although there were interspecies differences in the numbers of neurons in the clusters. The GABAergic system was largely restricted to the central nervous system, with the majority of axons confined to ganglionic connectives and commissures, suggesting a central, integrative role for GABA. GABA was a candidate inhibitory neurotransmitter for neurons in central pattern generator (CPG) circuits underlying swimming behaviors in these species, however none of the known swim CPG neurons were GABA-ir. Although the functions of these GABA-ir neurons are not known, it is clear that their presence has been strongly conserved across nudibranchs. Copyright © 2013 Wiley Periodicals, Inc.

Altered Excitability and Local Connectivity of mPFC-PAG Neurons in a Mouse Model of Neuropathic Pain.

PubMed

Cheriyan, John; Sheets, Patrick L

2018-05-16

The medial prefrontal cortex (mPFC) plays a major role in both sensory and affective aspects of pain. There is extensive evidence that chronic pain produces functional changes within the mPFC. However, our understanding of local circuit changes to defined subpopulations of mPFC neurons in chronic pain models remains unclear. A major subpopulation of mPFC neurons project to the periaqueductal gray (PAG), which is a key midbrain structure involved in endogenous pain suppression and facilitation. Here, we used laser scanning photostimulation of caged glutamate to map cortical circuits of retrogradely labeled cortico-PAG (CP) neurons in layer 5 (L5) of mPFC in brain slices prepared from male mice having undergone chronic constriction injury (CCI) of the sciatic nerve. Whole-cell recordings revealed a significant reduction in excitability for L5 CP neurons contralateral to CCI in the prelimbic (PL), but not infralimbic (IL), region of mPFC. Circuit mapping showed that excitatory inputs to L5 CP neurons in both PL and IL arose primarily from layer 2/3 (L2/3) and were significantly reduced in CCI mice. Glutamate stimulation of L2/3 and L5 elicited inhibitory inputs to CP neurons in both PL and IL, but only L2/3 input was significantly reduced in CP neurons of CCI mice. We also observed significant reduction in excitability and L2/3 inhibitory input to CP neurons ipsilateral to CCI. These results demonstrating region and laminar specific changes to mPFC-PAG neurons suggest that a unilateral CCI bilaterally alters cortical circuits upstream of the endogenous analgesic network, which may contribute to persistence of chronic pain. SIGNIFICANCE STATEMENT Chronic pain is a significant unresolved medical problem that is refractory to traditional analgesics and can negatively affect emotional health. The role of central circuits in mediating the persistent nature of chronic pain remains unclear. Local circuits within the medial prefrontal cortex (mPFC) process ascending pain inputs and can modulate endogenous analgesia via direct projections to the periaqueductal gray (PAG). However, the mechanisms by which chronic pain alters intracortical circuitry of mPFC-PAG neurons are unknown. Here, we report specific changes to local circuits of mPFC-PAG neurons in mice displaying chronic pain behavior after nerve injury. These findings provide evidence for a neural mechanism by which chronic pain disrupts the descending analgesic system via functional changes to cortical circuits. Copyright © 2018 the authors 0270-6474/18/384829-11$15.00/0.

Two cell circuits of oriented adult hippocampal neurons on self-assembled monolayers for use in the study of neuronal communication in a defined system.

PubMed

Edwards, Darin; Stancescu, Maria; Molnar, Peter; Hickman, James J

2013-08-21

In this study, we demonstrate the directed formation of small circuits of electrically active, synaptically connected neurons derived from the hippocampus of adult rats through the use of engineered chemically modified culture surfaces that orient the polarity of the neuronal processes. Although synaptogenesis, synaptic communication, synaptic plasticity, and brain disease pathophysiology can be studied using brain slice or dissociated embryonic neuronal culture systems, the complex elements found in neuronal synapses makes specific studies difficult in these random cultures. The study of synaptic transmission in mature adult neurons and factors affecting synaptic transmission are generally studied in organotypic cultures, in brain slices, or in vivo. However, engineered neuronal networks would allow these studies to be performed instead on simple functional neuronal circuits derived from adult brain tissue. Photolithographic patterned self-assembled monolayers (SAMs) were used to create the two-cell "bidirectional polarity" circuit patterns. This pattern consisted of a cell permissive SAM, N-1[3-(trimethoxysilyl)propyl] diethylenetriamine (DETA), and was composed of two 25 μm somal adhesion sites connected with 5 μm lines acting as surface cues for guided axonal and dendritic regeneration. Surrounding the DETA pattern was a background of a non-cell-permissive poly(ethylene glycol) (PEG) SAM. Adult hippocampal neurons were first cultured on coverslips coated with DETA monolayers and were later passaged onto the PEG-DETA bidirectional polarity patterns in serum-free medium. These neurons followed surface cues, attaching and regenerating only along the DETA substrate to form small engineered neuronal circuits. These circuits were stable for more than 21 days in vitro (DIV), during which synaptic connectivity was evaluated using basic electrophysiological methods.

Emergence of binocular functional properties in a monocular neural circuit

PubMed Central

Ramdya, Pavan; Engert, Florian

2010-01-01

Sensory circuits frequently integrate converging inputs while maintaining precise functional relationships between them. For example, in mammals with stereopsis, neurons at the first stages of binocular visual processing show a close alignment of receptive-field properties for each eye. Still, basic questions about the global wiring mechanisms that enable this functional alignment remain unanswered, including whether the addition of a second retinal input to an otherwise monocular neural circuit is sufficient for the emergence of these binocular properties. We addressed this question by inducing a de novo binocular retinal projection to the larval zebrafish optic tectum and examining recipient neuronal populations using in vivo two-photon calcium imaging. Notably, neurons in rewired tecta were predominantly binocular and showed matching direction selectivity for each eye. We found that a model based on local inhibitory circuitry that computes direction selectivity using the topographic structure of both retinal inputs can account for the emergence of this binocular feature. PMID:19160507

A Point-process Response Model for Spike Trains from Single Neurons in Neural Circuits under Optogenetic Stimulation

PubMed Central

Luo, X.; Gee, S.; Sohal, V.; Small, D.

2015-01-01

Optogenetics is a new tool to study neuronal circuits that have been genetically modified to allow stimulation by flashes of light. We study recordings from single neurons within neural circuits under optogenetic stimulation. The data from these experiments present a statistical challenge of modeling a high frequency point process (neuronal spikes) while the input is another high frequency point process (light flashes). We further develop a generalized linear model approach to model the relationships between two point processes, employing additive point-process response functions. The resulting model, Point-process Responses for Optogenetics (PRO), provides explicit nonlinear transformations to link the input point process with the output one. Such response functions may provide important and interpretable scientific insights into the properties of the biophysical process that governs neural spiking in response to optogenetic stimulation. We validate and compare the PRO model using a real dataset and simulations, and our model yields a superior area-under-the- curve value as high as 93% for predicting every future spike. For our experiment on the recurrent layer V circuit in the prefrontal cortex, the PRO model provides evidence that neurons integrate their inputs in a sophisticated manner. Another use of the model is that it enables understanding how neural circuits are altered under various disease conditions and/or experimental conditions by comparing the PRO parameters. PMID:26411923

Multimodal Chemosensory Circuits Controlling Male Courtship in Drosophila.

PubMed

Clowney, E Josephine; Iguchi, Shinya; Bussell, Jennifer J; Scheer, Elias; Ruta, Vanessa

2015-09-02

Throughout the animal kingdom, internal states generate long-lasting and self-perpetuating chains of behavior. In Drosophila, males instinctively pursue females with a lengthy and elaborate courtship ritual triggered by activation of sexually dimorphic P1 interneurons. Gustatory pheromones are thought to activate P1 neurons but the circuit mechanisms that dictate their sensory responses to gate entry into courtship remain unknown. Here, we use circuit mapping and in vivo functional imaging techniques to trace gustatory and olfactory pheromone circuits to their point of convergence onto P1 neurons and reveal how their combined input underlies selective tuning to appropriate sexual partners. We identify inhibition, even in response to courtship-promoting pheromones, as a key circuit element that tunes and tempers P1 neuron activity. Our results suggest a circuit mechanism in which balanced excitation and inhibition underlie discrimination of prospective mates and stringently regulate the transition to courtship in Drosophila. Copyright © 2015 Elsevier Inc. All rights reserved.

Multimodal chemosensory circuits controlling male courtship in Drosophila

PubMed Central

Clowney, E. Josephine; Iguchi, Shinya; Bussell, Jennifer J.; Scheer, Elias; Ruta, Vanessa

2015-01-01

Summary Throughout the animal kingdom, internal states generate long-lasting and self-perpetuating chains of behavior. In Drosophila, males instinctively pursue females with a lengthy and elaborate courtship ritual triggered by activation of sexually dimorphic P1 interneurons. Gustatory pheromones are thought to activate P1 neurons but the circuit mechanisms that dictate their sensory responses to gate entry into courtship remain unknown. Here, we use circuit mapping and in vivo functional imaging techniques to trace gustatory and olfactory pheromone circuits to their point of convergence onto P1 neurons and reveal how their combined input underlies selective tuning to appropriate sexual partners. We identify inhibition, even in response to courtship-promoting pheromones, as a key circuit element that tunes and tempers P1 neuron activity. Our results suggest a circuit mechanism in which balanced excitation and inhibition underlie discrimination of prospective mates and stringently regulate the transition to courtship in Drosophila. PMID:26279475

Functional Interactions between Mammalian Respiratory Rhythmogenic and Premotor Circuitry

PubMed Central

Song, Hanbing; Hayes, John A.; Vann, Nikolas C.; Wang, Xueying; LaMar, M. Drew

2016-01-01

Breathing in mammals depends on rhythms that originate from the preBötzinger complex (preBötC) of the ventral medulla and a network of brainstem and spinal premotor neurons. The rhythm-generating core of the preBötC, as well as some premotor circuits, consist of interneurons derived from Dbx1-expressing precursors (Dbx1 neurons), but the structure and function of these networks remain incompletely understood. We previously developed a cell-specific detection and laser ablation system to interrogate respiratory network structure and function in a slice model of breathing that retains the preBötC, the respiratory-related hypoglossal (XII) motor nucleus and XII premotor circuits. In spontaneously rhythmic slices, cumulative ablation of Dbx1 preBötC neurons decreased XII motor output by ∼50% after ∼15 cell deletions, and then decelerated and terminated rhythmic function altogether as the tally increased to ∼85 neurons. In contrast, cumulatively deleting Dbx1 XII premotor neurons decreased motor output monotonically but did not affect frequency nor stop XII output regardless of the ablation tally. Here, we couple an existing preBötC model with a premotor population in several topological configurations to investigate which one may replicate the laser ablation experiments best. If the XII premotor population is a “small-world” network (rich in local connections with sparse long-range connections among constituent premotor neurons) and connected with the preBötC such that the total number of incoming synapses remains fixed, then the in silico system successfully replicates the in vitro laser ablation experiments. This study proposes a feasible configuration for circuits consisting of Dbx1-derived interneurons that generate inspiratory rhythm and motor pattern. SIGNIFICANCE STATEMENT To produce a breathing-related motor pattern, a brainstem core oscillator circuit projects to a population of premotor interneurons, but the assemblage of this network remains incompletely understood. Here we applied network modeling and numerical simulation to discover respiratory circuit configurations that successfully replicate photonic cell ablation experiments targeting either the core oscillator or premotor network, respectively. If premotor neurons are interconnected in a so-called “small-world” network with a fixed number of incoming synapses balanced between premotor and rhythmogenic neurons, then our simulations match their experimental benchmarks. These results provide a framework of experimentally testable predictions regarding the rudimentary structure and function of respiratory rhythm- and pattern-generating circuits in the brainstem of mammals. PMID:27383596

An Adenosine-Mediated Glial-Neuronal Circuit for Homeostatic Sleep.

PubMed

Bjorness, Theresa E; Dale, Nicholas; Mettlach, Gabriel; Sonneborn, Alex; Sahin, Bogachan; Fienberg, Allen A; Yanagisawa, Masashi; Bibb, James A; Greene, Robert W

2016-03-30

Sleep homeostasis reflects a centrally mediated drive for sleep, which increases during waking and resolves during subsequent sleep. Here we demonstrate that mice deficient for glial adenosine kinase (AdK), the primary metabolizing enzyme for adenosine (Ado), exhibit enhanced expression of this homeostatic drive by three independent measures: (1) increased rebound of slow-wave activity; (2) increased consolidation of slow-wave sleep; and (3) increased time constant of slow-wave activity decay during an average slow-wave sleep episode, proposed and validated here as a new index for homeostatic sleep drive. Conversely, mice deficient for the neuronal adenosine A1 receptor exhibit significantly decreased sleep drive as judged by these same indices. Neuronal knock-out of AdK did not influence homeostatic sleep need. Together, these findings implicate a glial-neuronal circuit mediated by intercellular Ado, controlling expression of homeostatic sleep drive. Because AdK is tightly regulated by glial metabolic state, our findings suggest a functional link between cellular metabolism and sleep homeostasis. The work presented here provides evidence for an adenosine-mediated regulation of sleep in response to waking (i.e., homeostatic sleep need), requiring activation of neuronal adenosine A1 receptors and controlled by glial adenosine kinase. Adenosine kinase acts as a highly sensitive and important metabolic sensor of the glial ATP/ADP and AMP ratio directly controlling intracellular adenosine concentration. Glial equilibrative adenosine transporters reflect the intracellular concentration to the extracellular milieu to activate neuronal adenosine receptors. Thus, adenosine mediates a glial-neuronal circuit linking glial metabolic state to neural-expressed sleep homeostasis. This indicates a metabolically related function(s) for this glial-neuronal circuit in the buildup and resolution of our need to sleep and suggests potential therapeutic targets more directly related to sleep function. Copyright © 2016 the authors 0270-6474/16/363709-13$15.00/0.

Fragile X Mental Retardation Protein is Required for Programmed Cell Death and Clearance of Developmentally-Transient Peptidergic Neurons

PubMed Central

Gatto, Cheryl L.; Broadie, Kendal

2011-01-01

Fragile X syndrome (FXS), caused by loss of fragile X mental retardation 1 (FMR1) gene function, is the most common heritable cause of intellectual disability and autism spectrum disorders. The FMR1 product (FMRP) is an RNA-binding protein best established to function in activity-dependent modulation of synaptic connections. In the Drosophila FXS disease model, loss of functionally-conserved dFMRP causes synaptic overgrowth and overelaboration in pigment dispersing factor (PDF) peptidergic neurons in the adult brain. Here, we identify a very different component of PDF neuron misregulation in dfmr1 mutants: the aberrant retention of normally developmentally-transient PDF tritocerebral (PDF-TRI) neurons. In wild-type animals, PDF-TRI neurons in the central brain undergo programmed cell death and complete, processive clearance within days of eclosion. In the absence of dFMRP, a defective apoptotic program leads to constitutive maintenance of these peptidergic neurons. We tested whether this apoptotic defect is circuit-specific by examining crustacean cardioactive peptide (CCAP) and bursicon circuits, which are similarly developmentally-transient and normally eliminated immediately post-eclosion. In dfmr1 null mutants, CCAP/bursicon neurons also exhibit significantly delayed clearance dynamics, but are subsequently eliminated from the nervous system, in contrast to the fully persistent PDF-TRI neurons. Thus, the requirement of dFMRP for the retention of transitory peptidergic neurons shows evident circuit specificity. The novel defect of impaired apoptosis and aberrant neuron persistence in the Drosophila FXS model suggests an entirely new level of “pruning” dysfunction may contribute to the FXS disease state. PMID:21596027

Fragile X Mental Retardation Protein Restricts Small Dye Iontophoresis Entry into Central Neurons

PubMed Central

2017-01-01

Fragile X mental retardation protein (FMRP) loss causes Fragile X syndrome (FXS), a major disorder characterized by autism, intellectual disability, hyperactivity, and seizures. FMRP is both an RNA- and channel-binding regulator, with critical roles in neural circuit formation and function. However, it remains unclear how these FMRP activities relate to each other and how dysfunction in their absence underlies FXS neurological symptoms. In testing circuit level defects in the Drosophila FXS model, we discovered a completely unexpected and highly robust neuronal dye iontophoresis phenotype in the well mapped giant fiber (GF) circuit. Controlled dye injection into the GF interneuron results in a dramatic increase in dye uptake in neurons lacking FMRP. Transgenic wild-type FMRP reintroduction rescues the mutant defect, demonstrating a specific FMRP requirement. This phenotype affects only small dyes, but is independent of dye charge polarity. Surprisingly, the elevated dye iontophoresis persists in shaking B mutants that eliminate gap junctions and dye coupling among GF circuit neurons. We therefore used a wide range of manipulations to investigate the dye uptake defect, including timed injection series, pharmacology and ion replacement, and optogenetic activity studies. The results show that FMRP strongly limits the rate of dye entry via a cytosolic mechanism. This study reveals an unexpected new phenotype in a physical property of central neurons lacking FMRP that could underlie aspects of FXS disruption of neural function. SIGNIFICANCE STATEMENT FXS is a leading heritable cause of intellectual disability and autism spectrum disorders. Although researchers established the causal link with FMRP loss >;25 years ago, studies continue to reveal diverse FMRP functions. The Drosophila FXS model is key to discovering new FMRP roles, because of its genetic malleability and individually identified neuron maps. Taking advantage of a well characterized Drosophila neural circuit, we discovered that neurons lacking FMRP take up dramatically more current-injected small dye. After examining many neuronal properties, we determined that this dye defect is cytoplasmic and occurs due to a highly elevated dye iontophoresis rate. We also report several new factors affecting neuron dye uptake. Understanding how FMRP regulates iontophoresis should reveal new molecular factors underpinning FXS dysfunction. PMID:28887386

A novel function for Wnt signaling modulating neuronal firing activity and the temporal structure of spontaneous oscillation in the entorhinal-hippocampal circuit.

PubMed

Oliva, Carolina A; Inestrosa, Nibaldo C

2015-07-01

During early and late postnatal developments, the establishment of functional neuronal connectivity depends on molecules like Wnt that help the recently formed synapses to establish and consolidate their new cellular interactions. However, unlike other molecules, whether Wnt can modulate the firing properties of cells is unknown. Here, for the first time we explore the physiological effect of the canonical and non-canonical Wnt pathways on a circuit that is currently generating oscillatory activity, the entorhinal cortex-hippocampal circuit. Our results indicate that Wnt pathways have strong influence in the circuital and cellular properties depending on the Wnt protein isoforms, concentration, and type of neuronal circuit. Antibodies against canonical and non-canonical ligands, as well as WASP-1 and sFRP-2, demonstrate that constitutive release of Wnts contributes to the maintenance of the network and intrinsic properties of the circuit. Furthermore, we found that the excess of Wnt3a or the permanent intracellular activation of the pathway with BIO-6 accelerates the period of the oscillation by disrupting the oscillatory units (Up states) in short units, presumably by affecting the synaptic mechanisms that couples neurons into the oscillatory cycle, but without affecting the spike generation. Instead, low doses of Wnt5a increase the period of the oscillation in EC by incorporating new cells into the network activity, probably modifying firing activity in other places of the circuit. Moreover, we found that Wnt signaling operates under different principles in the hippocampus. Using pyrvinium pamoate, a Wnt/β-catenin dependent pathway inhibitor, we demonstrated that this pathway is essential to keep the firing activity in the circuit CA3, and in less degree of CA1 circuit. However, CA1 circuit possesses homeostatic mechanisms to up-regulate the firing activity when it has been suppressed in CA3, and to down-modulate the cellular excitability when exacerbated circuital activity has dominated. In summary, the amount of Wnt that is being released can exert a fine tuning of the physiological output, modulating firing activity, improving reliability of communication between neurons, and maintaining a continuous self-regulatory cycle of synaptic structure-function that can be present during all postnatal life. Copyright © 2015 Elsevier Inc. All rights reserved.

Dendritic nonlinearities are tuned for efficient spike-based computations in cortical circuits.

PubMed

Ujfalussy, Balázs B; Makara, Judit K; Branco, Tiago; Lengyel, Máté

2015-12-24

Cortical neurons integrate thousands of synaptic inputs in their dendrites in highly nonlinear ways. It is unknown how these dendritic nonlinearities in individual cells contribute to computations at the level of neural circuits. Here, we show that dendritic nonlinearities are critical for the efficient integration of synaptic inputs in circuits performing analog computations with spiking neurons. We developed a theory that formalizes how a neuron's dendritic nonlinearity that is optimal for integrating synaptic inputs depends on the statistics of its presynaptic activity patterns. Based on their in vivo preynaptic population statistics (firing rates, membrane potential fluctuations, and correlations due to ensemble dynamics), our theory accurately predicted the responses of two different types of cortical pyramidal cells to patterned stimulation by two-photon glutamate uncaging. These results reveal a new computational principle underlying dendritic integration in cortical neurons by suggesting a functional link between cellular and systems--level properties of cortical circuits.

Temperature and neuronal circuit function: compensation, tuning and tolerance.

PubMed

Robertson, R Meldrum; Money, Tomas G A

2012-08-01

Temperature has widespread and diverse effects on different subcellular components of neuronal circuits making it difficult to predict precisely the overall influence on output. Increases in temperature generally increase the output rate in either an exponential or a linear manner. Circuits with a slow output tend to respond exponentially with relatively high Q(10)s, whereas those with faster outputs tend to respond in a linear fashion with relatively low temperature coefficients. Different attributes of the circuit output can be compensated by virtue of opposing processes with similar temperature coefficients. At the extremes of the temperature range, differences in the temperature coefficients of circuit mechanisms cannot be compensated and the circuit fails, often with a reversible loss of ion homeostasis. Prior experience of temperature extremes activates conserved processes of phenotypic plasticity that tune neuronal circuits to be better able to withstand the effects of temperature and to recover more rapidly from failure. Copyright © 2012 Elsevier Ltd. All rights reserved.

A conserved juxtacrine signal regulates synaptic partner recognition in Caenorhabditis elegans

PubMed Central

2011-01-01

Background An essential stage of neural development involves the assembly of neural circuits via formation of inter-neuronal connections. Early steps in neural circuit formation, including cell migration, axon guidance, and the localization of synaptic components, are well described. However, upon reaching their target region, most neurites still contact many potential partners. In order to assemble functional circuits, it is critical that within this group of cells, neurons identify and form connections only with their appropriate partners, a process we call synaptic partner recognition (SPR). To understand how SPR is mediated, we previously developed a genetically encoded fluorescent trans-synaptic marker called NLG-1 GRASP, which labels synaptic contacts between individual neurons of interest in dense cellular environments in the genetic model organism Caenorhabditis elegans. Results Here, we describe the first use of NLG-1 GRASP technology, to identify SPR genes that function in this critical process. The NLG-1 GRASP system allows us to assess synaptogenesis between PHB sensory neurons and AVA interneurons instantly in live animals, making genetic analysis feasible. Additionally, we employ a behavioral assay to specifically test PHB sensory circuit function. Utilizing this approach, we reveal a new role for the secreted UNC-6/Netrin ligand and its transmembrane receptor UNC-40/Deleted in colorectal cancer (DCC) in SPR. Synapses between PHB and AVA are severely reduced in unc-6 and unc-40 animals despite normal axon guidance and subcellular localization of synaptic components. Additionally, behavioral defects indicate a complete disruption of PHB circuit function in unc-40 mutants. Our data indicate that UNC-40 and UNC-6 function in PHB and AVA, respectively, to specify SPR. Strikingly, overexpression of UNC-6 in postsynaptic neurons is sufficient to promote increased PHB-AVA synaptogenesis and to potentiate the behavioral response beyond wild-type levels. Furthermore, an artificially membrane-tethered UNC-6 expressed in the postsynaptic neurons promotes SPR, consistent with a short-range signal between adjacent synaptic partners. Conclusions These results indicate that the conserved UNC-6/Netrin-UNC-40/DCC ligand-receptor pair has a previously unknown function, acting in a juxtacrine manner to specify recognition of individual postsynaptic neurons. Furthermore, they illustrate the potential of this new approach, combining NLG-1 GRASP and behavioral analysis, in gene discovery and characterization. PMID:21663630

Region-specific spike frequency acceleration in Layer 5 pyramidal neurons mediated by Kv1 subunits

PubMed Central

Miller, Mark N; Okaty, Benjamin W; Nelson, Sacha B

2009-01-01

Separation of the cortical sheet into functionally distinct regions is a hallmark of neocortical organization. Cortical circuit function emerges from afferent and efferent connectivity, local connectivity within the cortical microcircuit, and the intrinsic membrane properties of neurons that comprise the circuit. While localization of functions to particular cortical areas can be partially accounted for by regional differences in both long range and local connectivity, it is unknown whether the intrinsic membrane properties of cortical cell-types differ between cortical regions. Here we report the first example of a region-specific firing type in layer 5 pyramidal neurons, and show that the intrinsic membrane and integrative properties of a discrete subtype of layer 5 pyramidal neurons differ between primary motor and somatosensory cortices due to region and cell-type-specific Kv1 subunit expression. PMID:19091962

A hypothalamic circuit for the circadian control of aggression.

PubMed

Todd, William D; Fenselau, Henning; Wang, Joshua L; Zhang, Rong; Machado, Natalia L; Venner, Anne; Broadhurst, Rebecca Y; Kaur, Satvinder; Lynagh, Timothy; Olson, David P; Lowell, Bradford B; Fuller, Patrick M; Saper, Clifford B

2018-05-01

'Sundowning' in dementia and Alzheimer's disease is characterized by early-evening agitation and aggression. While such periodicity suggests a circadian origin, whether the circadian clock directly regulates aggressive behavior is unknown. We demonstrate that a daily rhythm in aggression propensity in male mice is gated by GABAergic subparaventricular zone (SPZ GABA ) neurons, the major postsynaptic targets of the central circadian clock, the suprachiasmatic nucleus. Optogenetic mapping revealed that SPZ GABA neurons receive input from vasoactive intestinal polypeptide suprachiasmatic nucleus neurons and innervate neurons in the ventrolateral part of the ventromedial hypothalamus (VMH), which is known to regulate aggression. Additionally, VMH-projecting dorsal SPZ neurons are more active during early day than early night, and acute chemogenetic inhibition of SPZ GABA transmission phase-dependently increases aggression. Finally, SPZ GABA -recipient central VMH neurons directly innervate ventrolateral VMH neurons, and activation of this intra-VMH circuit drove attack behavior. Altogether, we reveal a functional polysynaptic circuit by which the suprachiasmatic nucleus clock regulates aggression.

Genetic Approaches to Reveal the Connectivity of Adult-Born Neurons

PubMed Central

Arenkiel, Benjamin R.

2011-01-01

Much has been learned about the environmental and molecular factors that influence the division, migration, and programmed cell death of adult-born neurons in the mammalian brain. However, detailed knowledge of the mechanisms that govern the formation and maintenance of functional circuit connectivity via adult neurogenesis remains elusive. Recent advances in genetic technologies now afford the ability to precisely target discrete brain tissues, neuronal subtypes, and even single neurons for vital reporter expression and controlled activity manipulations. Here, I review current viral tracing methods, heterologous receptor expression systems, and optogenetic technologies that hold promise toward elucidating the wiring diagrams and circuit properties of adult-born neurons. PMID:21519388

Neural Representation of a Target Auditory Memory in a Cortico-Basal Ganglia Pathway

PubMed Central

Bottjer, Sarah W.

2013-01-01

Vocal learning in songbirds, like speech acquisition in humans, entails a period of sensorimotor integration during which vocalizations are evaluated via auditory feedback and progressively refined to achieve an imitation of memorized vocal sounds. This process requires the brain to compare feedback of current vocal behavior to a memory of target vocal sounds. We report the discovery of two distinct populations of neurons in a cortico-basal ganglia circuit of juvenile songbirds (zebra finches, Taeniopygia guttata) during vocal learning: (1) one in which neurons are selectively tuned to memorized sounds and (2) another in which neurons are selectively tuned to self-produced vocalizations. These results suggest that neurons tuned to learned vocal sounds encode a memory of those target sounds, whereas neurons tuned to self-produced vocalizations encode a representation of current vocal sounds. The presence of neurons tuned to memorized sounds is limited to early stages of sensorimotor integration: after learning, the incidence of neurons encoding memorized vocal sounds was greatly diminished. In contrast to this circuit, neurons known to drive vocal behavior through a parallel cortico-basal ganglia pathway show little selective tuning until late in learning. One interpretation of these data is that representations of current and target vocal sounds in the shell circuit are used to compare ongoing patterns of vocal feedback to memorized sounds, whereas the parallel core circuit has a motor-related role in learning. Such a functional subdivision is similar to mammalian cortico-basal ganglia pathways in which associative-limbic circuits mediate goal-directed responses, whereas sensorimotor circuits support motor aspects of learning. PMID:24005299

Glutamatergic Preoptic Area Neurons That Express Leptin Receptors Drive Temperature-Dependent Body Weight Homeostasis.

PubMed

Yu, Sangho; Qualls-Creekmore, Emily; Rezai-Zadeh, Kavon; Jiang, Yanyan; Berthoud, Hans-Rudolf; Morrison, Christopher D; Derbenev, Andrei V; Zsombok, Andrea; Münzberg, Heike

2016-05-04

The preoptic area (POA) regulates body temperature, but is not considered a site for body weight control. A subpopulation of POA neurons express leptin receptors (LepRb(POA) neurons) and modulate reproductive function. However, LepRb(POA) neurons project to sympathetic premotor neurons that control brown adipose tissue (BAT) thermogenesis, suggesting an additional role in energy homeostasis and body weight regulation. We determined the role of LepRb(POA) neurons in energy homeostasis using cre-dependent viral vectors to selectively activate these neurons and analyzed functional outcomes in mice. We show that LepRb(POA) neurons mediate homeostatic adaptations to ambient temperature changes, and their pharmacogenetic activation drives robust suppression of energy expenditure and food intake, which lowers body temperature and body weight. Surprisingly, our data show that hypothermia-inducing LepRb(POA) neurons are glutamatergic, while GABAergic POA neurons, originally thought to mediate warm-induced inhibition of sympathetic premotor neurons, have no effect on energy expenditure. Our data suggest a new view into the neurochemical and functional properties of BAT-related POA circuits and highlight their additional role in modulating food intake and body weight. Brown adipose tissue (BAT)-induced thermogenesis is a promising therapeutic target to treat obesity and metabolic diseases. The preoptic area (POA) controls body temperature by modulating BAT activity, but its role in body weight homeostasis has not been addressed. LepRb(POA) neurons are BAT-related neurons and we show that they are sufficient to inhibit energy expenditure. We further show that LepRb(POA) neurons modulate food intake and body weight, which is mediated by temperature-dependent homeostatic responses. We further found that LepRb(POA) neurons are stimulatory glutamatergic neurons, contrary to prevalent models, providing a new view on thermoregulatory neural circuits. In summary, our study significantly expands our current understanding of central circuits and mechanisms that modulate energy homeostasis. Copyright © 2016 the authors 0270-6474/16/365034-13$15.00/0.

Glutamatergic Preoptic Area Neurons That Express Leptin Receptors Drive Temperature-Dependent Body Weight Homeostasis

PubMed Central

Qualls-Creekmore, Emily; Rezai-Zadeh, Kavon; Jiang, Yanyan; Berthoud, Hans-Rudolf; Morrison, Christopher D.; Derbenev, Andrei V.; Zsombok, Andrea

2016-01-01

The preoptic area (POA) regulates body temperature, but is not considered a site for body weight control. A subpopulation of POA neurons express leptin receptors (LepRbPOA neurons) and modulate reproductive function. However, LepRbPOA neurons project to sympathetic premotor neurons that control brown adipose tissue (BAT) thermogenesis, suggesting an additional role in energy homeostasis and body weight regulation. We determined the role of LepRbPOA neurons in energy homeostasis using cre-dependent viral vectors to selectively activate these neurons and analyzed functional outcomes in mice. We show that LepRbPOA neurons mediate homeostatic adaptations to ambient temperature changes, and their pharmacogenetic activation drives robust suppression of energy expenditure and food intake, which lowers body temperature and body weight. Surprisingly, our data show that hypothermia-inducing LepRbPOA neurons are glutamatergic, while GABAergic POA neurons, originally thought to mediate warm-induced inhibition of sympathetic premotor neurons, have no effect on energy expenditure. Our data suggest a new view into the neurochemical and functional properties of BAT-related POA circuits and highlight their additional role in modulating food intake and body weight. SIGNIFICANCE STATEMENT Brown adipose tissue (BAT)-induced thermogenesis is a promising therapeutic target to treat obesity and metabolic diseases. The preoptic area (POA) controls body temperature by modulating BAT activity, but its role in body weight homeostasis has not been addressed. LepRbPOA neurons are BAT-related neurons and we show that they are sufficient to inhibit energy expenditure. We further show that LepRbPOA neurons modulate food intake and body weight, which is mediated by temperature-dependent homeostatic responses. We further found that LepRbPOA neurons are stimulatory glutamatergic neurons, contrary to prevalent models, providing a new view on thermoregulatory neural circuits. In summary, our study significantly expands our current understanding of central circuits and mechanisms that modulate energy homeostasis. PMID:27147656

Role of Non-Neuronal Cells in Body Weight and Appetite Control

PubMed Central

Argente-Arizón, Pilar; Freire-Regatillo, Alejandra; Argente, Jesús; Chowen, Julie A.

2015-01-01

The brain is composed of neurons and non-neuronal cells, with the latter encompassing glial, ependymal and endothelial cells, as well as pericytes and progenitor cells. Studies aimed at understanding how the brain operates have traditionally focused on neurons, but the importance of non-neuronal cells has become increasingly evident. Once relegated to supporting roles, it is now indubitable that these diverse cell types are fundamental for brain development and function, including that of metabolic circuits, and they may play a significant role in obesity onset and complications. They participate in processes of neurogenesis, synaptogenesis, and synaptic plasticity of metabolic circuits both during development and in adulthood. Some glial cells, such as tanycytes and astrocytes, transport circulating nutrients and metabolic factors that are fundamental for neuronal viability and activity into and within the hypothalamus. All of these cell types express receptors for a variety of metabolic factors and hormones, suggesting that they participate in metabolic function. They are the first line of defense against any assault to neurons. Indeed, microglia and astrocytes participate in the hypothalamic inflammatory response to high fat diet (HFD)-induced obesity, with this process contributing to inflammatory-related insulin and leptin resistance. Moreover, HFD-induced obesity and hyperleptinemia modify hypothalamic astroglial morphology, which is associated with changes in the synaptic inputs to neuronal metabolic circuits. Astrocytic contact with the microvasculature is increased by HFD intake and this could modify nutrient/hormonal uptake into the brain. In addition, progenitor cells in the hypothalamus are now known to have the capacity to renew metabolic circuits, and this can be affected by HFD intake and obesity. Here, we discuss our current understanding of how non-neuronal cells participate in physiological and physiopathological metabolic control. PMID:25859240

Integrating anatomy and function for zebrafish circuit analysis.

PubMed

Arrenberg, Aristides B; Driever, Wolfgang

2013-01-01

Due to its transparency, virtually every brain structure of the larval zebrafish is accessible to light-based interrogation of circuit function. Advanced stimulation techniques allow the activation of optogenetic actuators at different resolution levels, and genetically encoded calcium indicators report the activity of a large proportion of neurons in the CNS. Large datasets result and need to be analyzed to identify cells that have specific properties-e.g., activity correlation to sensory stimulation or behavior. Advances in three-dimensional (3D) functional mapping in zebrafish are promising; however, the mere coordinates of implicated neurons are not sufficient. To comprehensively understand circuit function, these functional maps need to be placed into the proper context of morphological features and projection patterns, neurotransmitter phenotypes, and key anatomical landmarks. We discuss the prospect of merging functional and anatomical data in an integrated atlas from the perspective of our work on long-range dopaminergic neuromodulation and the oculomotor system. We propose that such a resource would help researchers to surpass current hurdles in circuit analysis to achieve an integrated understanding of anatomy and function.

Functional compatibility between Purkinje cell axon branches and their target neurons in the cerebellum.

PubMed

Yang, Zhilai; Chen, Na; Ge, Rongjing; Qian, Hao; Wang, Jin-Hui

2017-09-22

A neuron sprouts an axon, and its branches to innervate many target neurons that are divergent in their functions. In order to efficiently regulate the diversified cells, the axon branches should differentiate functionally to be compatible with their target neurons, i.e., a function compatibility between presynaptic and postsynaptic partners. We have examined this hypothesis by using electrophysiological method in the cerebellum, in which the main axon of Purkinje cell projected to deep nucleus cells and the recurrent axons innervated the adjacent Purkinje cells. The fidelity of spike propagation is superior in the recurrent branches than the main axon. The capabilities of encoding spikes and processing GABAergic inputs are advanced in Purkinje cells versus deep nucleus cells. The functional differences among Purkinje's axonal branches and their postsynaptic neurons are preset by the variable dynamics of their voltage-gated sodium channels. In addition, activity strengths between presynaptic and postsynaptic partners are proportionally correlated, i.e., active axonal branches innervate active target neurons, or vice versa. The physiological impact of the functional compatibility is to make the neurons in their circuits to be activated appropriately. In conclusion, each cerebellar Purkinje cell sprouts the differentiated axon branches to be compatible with the diversified target cells in their functions, in order to construct the homeostatic and efficient units for their coordinated activity in neural circuits.

Functional compatibility between Purkinje cell axon branches and their target neurons in the cerebellum

PubMed Central

Qian, Hao; Wang, Jin-Hui

2017-01-01

A neuron sprouts an axon, and its branches to innervate many target neurons that are divergent in their functions. In order to efficiently regulate the diversified cells, the axon branches should differentiate functionally to be compatible with their target neurons, i.e., a function compatibility between presynaptic and postsynaptic partners. We have examined this hypothesis by using electrophysiological method in the cerebellum, in which the main axon of Purkinje cell projected to deep nucleus cells and the recurrent axons innervated the adjacent Purkinje cells. The fidelity of spike propagation is superior in the recurrent branches than the main axon. The capabilities of encoding spikes and processing GABAergic inputs are advanced in Purkinje cells versus deep nucleus cells. The functional differences among Purkinje's axonal branches and their postsynaptic neurons are preset by the variable dynamics of their voltage-gated sodium channels. In addition, activity strengths between presynaptic and postsynaptic partners are proportionally correlated, i.e., active axonal branches innervate active target neurons, or vice versa. The physiological impact of the functional compatibility is to make the neurons in their circuits to be activated appropriately. In conclusion, each cerebellar Purkinje cell sprouts the differentiated axon branches to be compatible with the diversified target cells in their functions, in order to construct the homeostatic and efficient units for their coordinated activity in neural circuits. PMID:29069799

Beadex Function in the Motor Neurons Is Essential for Female Reproduction in Drosophila melanogaster

PubMed Central

Kairamkonda, Subhash; Nongthomba, Upendra

2014-01-01

Drosophila melanogaster has served as an excellent model system for understanding the neuronal circuits and molecular mechanisms regulating complex behaviors. The Drosophila female reproductive circuits, in particular, are well studied and can be used as a tool to understand the role of novel genes in neuronal function in general and female reproduction in particular. In the present study, the role of Beadex, a transcription co-activator, in Drosophila female reproduction was assessed by generation of mutant and knock down studies. Null allele of Beadex was generated by transposase induced excision of P-element present within an intron of Beadex gene. The mutant showed highly compromised reproductive abilities as evaluated by reduced fecundity and fertility, abnormal oviposition and more importantly, the failure of sperm release from storage organs. However, no defect was found in the overall ovariole development. Tissue specific, targeted knock down of Beadex indicated that its function in neurons is important for efficient female reproduction, since its neuronal knock down led to compromised female reproductive abilities, similar to Beadex null females. Further, different neuronal class specific knock down studies revealed that Beadex function is required in motor neurons for normal fecundity and fertility of females. Thus, the present study attributes a novel and essential role for Beadex in female reproduction through neurons. PMID:25396431

AgRP to Kiss1 neuron signaling links nutritional state and fertility

PubMed Central

Padilla, Stephanie L.; Qiu, Jian; Nestor, Casey C; Zhang, Chunguang; Smith, Arik W.; Whiddon, Benjamin B.; Rønnekleiv, Oline K.; Kelly, Martin J.; Palmiter, Richard D.

2017-01-01

Mammalian reproductive function depends upon a neuroendocrine circuit that evokes the pulsatile release of gonadotropin hormones (luteinizing hormone and follicle-stimulating hormone) from the pituitary. This reproductive circuit is sensitive to metabolic perturbations. When challenged with starvation, insufficient energy reserves attenuate gonadotropin release, leading to infertility. The reproductive neuroendocrine circuit is well established, composed of two populations of kisspeptin-expressing neurons (located in the anteroventral periventricular hypothalamus, Kiss1AVPV, and arcuate hypothalamus, Kiss1ARH), which drive the pulsatile activity of gonadotropin-releasing hormone (GnRH) neurons. The reproductive axis is primarily regulated by gonadal steroid and circadian cues, but the starvation-sensitive input that inhibits this circuit during negative energy balance remains controversial. Agouti-related peptide (AgRP)-expressing neurons are activated during starvation and have been implicated in leptin-associated infertility. To test whether these neurons relay information to the reproductive circuit, we used AgRP-neuron ablation and optogenetics to explore connectivity in acute slice preparations. Stimulation of AgRP fibers revealed direct, inhibitory synaptic connections with Kiss1ARH and Kiss1AVPV neurons. In agreement with this finding, Kiss1ARH neurons received less presynaptic inhibition in the absence of AgRP neurons (neonatal toxin-induced ablation). To determine whether enhancing the activity of AgRP neurons is sufficient to attenuate fertility in vivo, we artificially activated them over a sustained period and monitored fertility. Chemogenetic activation with clozapine N-oxide resulted in delayed estrous cycles and decreased fertility. These findings are consistent with the idea that, during metabolic deficiency, AgRP signaling contributes to infertility by inhibiting Kiss1 neurons. PMID:28196880

Viral-genetic tracing of the input-output organization of a central noradrenaline circuit.

PubMed

Schwarz, Lindsay A; Miyamichi, Kazunari; Gao, Xiaojing J; Beier, Kevin T; Weissbourd, Brandon; DeLoach, Katherine E; Ren, Jing; Ibanes, Sandy; Malenka, Robert C; Kremer, Eric J; Luo, Liqun

2015-08-06

Deciphering how neural circuits are anatomically organized with regard to input and output is instrumental in understanding how the brain processes information. For example, locus coeruleus noradrenaline (also known as norepinephrine) (LC-NE) neurons receive input from and send output to broad regions of the brain and spinal cord, and regulate diverse functions including arousal, attention, mood and sensory gating. However, it is unclear how LC-NE neurons divide up their brain-wide projection patterns and whether different LC-NE neurons receive differential input. Here we developed a set of viral-genetic tools to quantitatively analyse the input-output relationship of neural circuits, and applied these tools to dissect the LC-NE circuit in mice. Rabies-virus-based input mapping indicated that LC-NE neurons receive convergent synaptic input from many regions previously identified as sending axons to the locus coeruleus, as well as from newly identified presynaptic partners, including cerebellar Purkinje cells. The 'tracing the relationship between input and output' method (or TRIO method) enables trans-synaptic input tracing from specific subsets of neurons based on their projection and cell type. We found that LC-NE neurons projecting to diverse output regions receive mostly similar input. Projection-based viral labelling revealed that LC-NE neurons projecting to one output region also project to all brain regions we examined. Thus, the LC-NE circuit overall integrates information from, and broadcasts to, many brain regions, consistent with its primary role in regulating brain states. At the same time, we uncovered several levels of specificity in certain LC-NE sub-circuits. These tools for mapping output architecture and input-output relationship are applicable to other neuronal circuits and organisms. More broadly, our viral-genetic approaches provide an efficient intersectional means to target neuronal populations based on cell type and projection pattern.

Functional Characterization of a Vesicular Glutamate Transporter in an Interneuron That Makes Excitatory and Inhibitory Synaptic Connections in a Molluscan Neural Circuit

PubMed Central

Alexeeva, Vera; Chen, Song-an; Yu, Ke; Due, Michael R.; Tan, Li-nuo; Chen, Ting-ting; Liu, Dan-dan; Cropper, Elizabeth C.; Vilim, Ferdinand S.; Weiss, Klaudiusz R.

2015-01-01

Understanding circuit function requires the characterization of component neurons and their neurotransmitters. Previous work on radula protraction in the Aplysia feeding circuit demonstrated that critical neurons initiate feeding via cholinergic excitation. In contrast, it is less clear how retraction is mediated at the interneuronal level. In particular, glutamate involvement was suggested, but was not directly confirmed. Here we study a suspected glutamatergic retraction interneuron, B64. We used the representational difference analysis (RDA) method to successfully clone an Aplysia vesicular glutamate transporter (ApVGLUT) from B64 and from a glutamatergic motor neuron B38. Previously, RDA was used to characterize novel neuropeptides. Here we demonstrate its utility for characterizing other types of molecules. Bioinformatics suggests that ApVGLUT is more closely related to mammalian VGLUTs than to Drosophila and Caenorhabditis elegans VGLUTs. We expressed ApVGLUT in a cell line, and demonstrated that it indeed transports glutamate in an ATP and proton gradient-dependent manner. We mapped the ApVGLUT distribution in the CNS using in situ hybridization and immunocytochemistry. Further, we demonstrated that B64 is ApVGLUT positive, supporting the idea that it is glutamatergic. Although glutamate is primarily an excitatory transmitter in the mammalian CNS, B64 elicits inhibitory PSPs in protraction neurons to terminate protraction and excitatory PSPs in retraction neurons to maintain retraction. Pharmacological data indicated that both types of PSPs are mediated by glutamate. Thus, glutamate mediates the dual function of B64 in Aplysia. More generally, our systematic approaches based on RDA may facilitate analyses of transmitter actions in small circuits with identifiable neurons. PMID:26085636

Strategies for targeting primate neural circuits with viral vectors

PubMed Central

El-Shamayleh, Yasmine; Ni, Amy M.

2016-01-01

Understanding how the brain works requires understanding how different types of neurons contribute to circuit function and organism behavior. Progress on this front has been accelerated by optogenetics and chemogenetics, which provide an unprecedented level of control over distinct neuronal types in small animals. In primates, however, targeting specific types of neurons with these tools remains challenging. In this review, we discuss existing and emerging strategies for directing genetic manipulations to targeted neurons in the adult primate central nervous system. We review the literature on viral vectors for gene delivery to neurons, focusing on adeno-associated viral vectors and lentiviral vectors, their tropism for different cell types, and prospects for new variants with improved efficacy and selectivity. We discuss two projection targeting approaches for probing neural circuits: anterograde projection targeting and retrograde transport of viral vectors. We conclude with an analysis of cell type-specific promoters and other nucleotide sequences that can be used in viral vectors to target neuronal types at the transcriptional level. PMID:27052579

Frank Beach Award Winner: Steroids as Neuromodulators of Brain Circuits and Behavior

PubMed Central

Remage-Healey, Luke

2014-01-01

Neurons communicate primarily via action potentials that transmit information on the timescale of milliseconds. Neurons also integrate information via alterations in gene transcription and protein translation that are sustained for hours to days after initiation. Positioned between these two signaling timescales are the minute-by-minute actions of neuromodulators. Over the course of minutes, the classical neuromodulators (such as serotonin, dopamine, octopamine, and norepinephrine) can alter and/or stabilize neural circuit patterning as well as behavioral states. Neuromodulators allow many flexible outputs from neural circuits and can encode information content into the firing state of neural networks. The idea that steroid molecules can operate as genuine behavioral neuromodulators - synthesized by and acting within brain circuits on a minute-by-minute timescale - has gained traction in recent years. Evidence for brain steroid synthesis at synaptic terminals has converged with evidence for the rapid actions of brain-derived steroids on neural circuits and behavior. The general principle emerging from this work is that the production of steroid hormones within brain circuits can alter their functional connectivity and shift sensory representations by enhancing their information coding. Steroids produced in the brain can therefore change the information content of neuronal networks to rapidly modulate sensory experience and sensorimotor functions. PMID:25110187

Neuronal substrates of sleep homeostasis; lessons from flies, rats and mice.

PubMed

Donlea, Jeffrey M; Alam, Md Noor; Szymusiak, Ronald

2017-06-01

Sleep homeostasis is a fundamental property of vigilance state regulation that is highly conserved across species. Neuronal systems and circuits that underlie sleep homeostasis are not well understood. In Drosophila, a neuronal circuit involving neurons in the ellipsoid body and in the dorsal Fan-shaped body is a candidate for both tracing sleep need during waking and translating it to increased sleep drive and expression. Sleep homeostasis in rats and mice involves multiple neuromodulators acting on multiple wake- and sleep-promoting neuronal systems. A functional central homeostat emerges from A 1 receptor mediated actions of adenosine on wake-promoting neurons in the basal forebrain and hypothalamus, and A 2A adenosine receptor-mediated actions on sleep-promoting neurons in the preoptic hypothalamus and nucleus accumbens. Copyright © 2017. Published by Elsevier Ltd.

Adult-born neurons modify excitatory synaptic transmission to existing neurons

PubMed Central

Adlaf, Elena W; Vaden, Ryan J; Niver, Anastasia J; Manuel, Allison F; Onyilo, Vincent C; Araujo, Matheus T; Dieni, Cristina V; Vo, Hai T; King, Gwendalyn D; Wadiche, Jacques I; Overstreet-Wadiche, Linda

2017-01-01

Adult-born neurons are continually produced in the dentate gyrus but it is unclear whether synaptic integration of new neurons affects the pre-existing circuit. Here we investigated how manipulating neurogenesis in adult mice alters excitatory synaptic transmission to mature dentate neurons. Enhancing neurogenesis by conditional deletion of the pro-apoptotic gene Bax in stem cells reduced excitatory postsynaptic currents (EPSCs) and spine density in mature neurons, whereas genetic ablation of neurogenesis increased EPSCs in mature neurons. Unexpectedly, we found that Bax deletion in developing and mature dentate neurons increased EPSCs and prevented neurogenesis-induced synaptic suppression. Together these results show that neurogenesis modifies synaptic transmission to mature neurons in a manner consistent with a redistribution of pre-existing synapses to newly integrating neurons and that a non-apoptotic function of the Bax signaling pathway contributes to ongoing synaptic refinement within the dentate circuit. DOI: http://dx.doi.org/10.7554/eLife.19886.001 PMID:28135190

Investigation of synapse formation and function in a glutamatergic-GABAergic two-neuron microcircuit.

PubMed

Chang, Chia-Ling; Trimbuch, Thorsten; Chao, Hsiao-Tuan; Jordan, Julia-Christine; Herman, Melissa A; Rosenmund, Christian

2014-01-15

Neural circuits are composed of mainly glutamatergic and GABAergic neurons, which communicate through synaptic connections. Many factors instruct the formation and function of these synapses; however, it is difficult to dissect the contribution of intrinsic cell programs from that of extrinsic environmental effects in an intact network. Here, we perform paired recordings from two-neuron microculture preparations of mouse hippocampal glutamatergic and GABAergic neurons to investigate how synaptic input and output of these two principal cells develop. In our reduced preparation, we found that glutamatergic neurons showed no change in synaptic output or input regardless of partner neuron cell type or neuronal activity level. In contrast, we found that glutamatergic input caused the GABAergic neuron to modify its output by way of an increase in synapse formation and a decrease in synaptic release efficiency. These findings are consistent with aspects of GABAergic synapse maturation observed in many brain regions. In addition, changes in GABAergic output are cell wide and not target-cell specific. We also found that glutamatergic neuronal activity determined the AMPA receptor properties of synapses on the partner GABAergic neuron. All modifications of GABAergic input and output required activity of the glutamatergic neuron. Because our system has reduced extrinsic factors, the changes we saw in the GABAergic neuron due to glutamatergic input may reflect initiation of maturation programs that underlie the formation and function of in vivo neural circuits.

A structural and a functional aspect of stable information processing by the brain

PubMed Central

2007-01-01

Brain is an expert in producing the same output from a particular set of inputs, even from a very noisy environment. In this article a model of neural circuit in the brain has been proposed which is composed of cyclic sub-circuits. A big loop has been defined to be consisting of a feed forward path from the sensory neurons to the highest processing area of the brain and feed back paths from that region back up to close to the same sensory neurons. It has been mathematically shown how some smaller cycles can amplify signal. A big loop processes information by contrast and amplify principle. How a pair of presynaptic and postsynaptic neurons can be identified by an exact synchronization detection method has also been mentioned. It has been assumed that the spike train coming out of a firing neuron encodes all the information produced by it as output. It is possible to extract this information over a period of time by Fourier transforms. The Fourier coefficients arranged in a vector form will uniquely represent the neural spike train over a period of time. The information emanating out of all the neurons in a given neural circuit over a period of time can be represented by a collection of points in a multidimensional vector space. This cluster of points represents the functional or behavioral form of the neural circuit. It has been proposed that a particular cluster of vectors as the representation of a new behavior is chosen by the brain interactively with respect to the memory stored in that circuit and the amount of emotion involved. It has been proposed that in this situation a Coulomb force like expression governs the dynamics of functioning of the circuit and stability of the system is reached at the minimum of all the minima of a potential function derived from the force like expression. The calculations have been done with respect to a pseudometric defined in a multidimensional vector space. PMID:19003500

Dendritic nonlinearities are tuned for efficient spike-based computations in cortical circuits

PubMed Central

Ujfalussy, Balázs B; Makara, Judit K; Branco, Tiago; Lengyel, Máté

2015-01-01

Cortical neurons integrate thousands of synaptic inputs in their dendrites in highly nonlinear ways. It is unknown how these dendritic nonlinearities in individual cells contribute to computations at the level of neural circuits. Here, we show that dendritic nonlinearities are critical for the efficient integration of synaptic inputs in circuits performing analog computations with spiking neurons. We developed a theory that formalizes how a neuron's dendritic nonlinearity that is optimal for integrating synaptic inputs depends on the statistics of its presynaptic activity patterns. Based on their in vivo preynaptic population statistics (firing rates, membrane potential fluctuations, and correlations due to ensemble dynamics), our theory accurately predicted the responses of two different types of cortical pyramidal cells to patterned stimulation by two-photon glutamate uncaging. These results reveal a new computational principle underlying dendritic integration in cortical neurons by suggesting a functional link between cellular and systems--level properties of cortical circuits. DOI: http://dx.doi.org/10.7554/eLife.10056.001 PMID:26705334

Sleep Drive Is Encoded by Neural Plastic Changes in a Dedicated Circuit.

PubMed

Liu, Sha; Liu, Qili; Tabuchi, Masashi; Wu, Mark N

2016-06-02

Prolonged wakefulness leads to an increased pressure for sleep, but how this homeostatic drive is generated and subsequently persists is unclear. Here, from a neural circuit screen in Drosophila, we identify a subset of ellipsoid body (EB) neurons whose activation generates sleep drive. Patch-clamp analysis indicates these EB neurons are highly sensitive to sleep loss, switching from spiking to burst-firing modes. Functional imaging and translational profiling experiments reveal that elevated sleep need triggers reversible increases in cytosolic Ca(2+) levels, NMDA receptor expression, and structural markers of synaptic strength, suggesting these EB neurons undergo "sleep-need"-dependent plasticity. Strikingly, the synaptic plasticity of these EB neurons is both necessary and sufficient for generating sleep drive, indicating that sleep pressure is encoded by plastic changes within this circuit. These studies define an integrator circuit for sleep homeostasis and provide a mechanism explaining the generation and persistence of sleep drive. Copyright © 2016 Elsevier Inc. All rights reserved.

Fragile X Mental Retardation Protein Restricts Small Dye Iontophoresis Entry into Central Neurons.

PubMed

Kennedy, Tyler; Broadie, Kendal

2017-10-11

Fragile X mental retardation protein (FMRP) loss causes Fragile X syndrome (FXS), a major disorder characterized by autism, intellectual disability, hyperactivity, and seizures. FMRP is both an RNA- and channel-binding regulator, with critical roles in neural circuit formation and function. However, it remains unclear how these FMRP activities relate to each other and how dysfunction in their absence underlies FXS neurological symptoms. In testing circuit level defects in the Drosophila FXS model, we discovered a completely unexpected and highly robust neuronal dye iontophoresis phenotype in the well mapped giant fiber (GF) circuit. Controlled dye injection into the GF interneuron results in a dramatic increase in dye uptake in neurons lacking FMRP. Transgenic wild-type FMRP reintroduction rescues the mutant defect, demonstrating a specific FMRP requirement. This phenotype affects only small dyes, but is independent of dye charge polarity. Surprisingly, the elevated dye iontophoresis persists in shaking B mutants that eliminate gap junctions and dye coupling among GF circuit neurons. We therefore used a wide range of manipulations to investigate the dye uptake defect, including timed injection series, pharmacology and ion replacement, and optogenetic activity studies. The results show that FMRP strongly limits the rate of dye entry via a cytosolic mechanism. This study reveals an unexpected new phenotype in a physical property of central neurons lacking FMRP that could underlie aspects of FXS disruption of neural function. SIGNIFICANCE STATEMENT FXS is a leading heritable cause of intellectual disability and autism spectrum disorders. Although researchers established the causal link with FMRP loss >;25 years ago, studies continue to reveal diverse FMRP functions. The Drosophila FXS model is key to discovering new FMRP roles, because of its genetic malleability and individually identified neuron maps. Taking advantage of a well characterized Drosophila neural circuit, we discovered that neurons lacking FMRP take up dramatically more current-injected small dye. After examining many neuronal properties, we determined that this dye defect is cytoplasmic and occurs due to a highly elevated dye iontophoresis rate. We also report several new factors affecting neuron dye uptake. Understanding how FMRP regulates iontophoresis should reveal new molecular factors underpinning FXS dysfunction. Copyright © 2017 the authors 0270-6474/17/379844-15$15.00/0.

Neuron Bifurcations in an Analog Electronic Burster

NASA Astrophysics Data System (ADS)

Savino, Guillermo V.; Formigli, Carlos M.

2007-05-01

Although bursting electrical activity is typical in some brain neurons and biological excitable systems, its functions and mechanisms of generation are yet unknown. In modeling such complex oscillations, analog electronic models are faster than mathematical ones, whether phenomenologically or theoretically based. We show experimentally that bursting oscillator circuits can be greatly simplified by using the nonlinear characteristics of two bipolar transistors. Since our circuit qualitatively mimics Hodgkin and Huxley model neurons bursting activity, and bifurcations originating neuro-computational properties, it is not only a caricature but a realistic model.

The basic circuit of the IC: tectothalamic neurons with different patterns of synaptic organization send different messages to the thalamus

PubMed Central

Ito, Tetsufumi; Oliver, Douglas L.

2012-01-01

The inferior colliculus (IC) in the midbrain of the auditory system uses a unique basic circuit to organize the inputs from virtually all of the lower auditory brainstem and transmit this information to the medial geniculate body (MGB) in the thalamus. Here, we review the basic circuit of the IC, the neuronal types, the organization of their inputs and outputs. We specifically discuss the large GABAergic (LG) neurons and how they differ from the small GABAergic (SG) and the more numerous glutamatergic neurons. The somata and dendrites of LG neurons are identified by axosomatic glutamatergic synapses that are lacking in the other cell types and exclusively contain the glutamate transporter VGLUT2. Although LG neurons are most numerous in the central nucleus of the IC (ICC), an analysis of their distribution suggests that they are not specifically associated with one set of ascending inputs. The inputs to ICC may be organized into functional zones with different subsets of brainstem inputs, but each zone may contain the same three neuron types. However, the sources of VGLUT2 axosomatic terminals on the LG neuron are not known. Neurons in the dorsal cochlear nucleus, superior olivary complex, intermediate nucleus of the lateral lemniscus, and IC itself that express the gene for VGLUT2 only are the likely origin of the dense VGLUT2 axosomatic terminals on LG tectothalamic neurons. The IC is unique since LG neurons are GABAergic tectothalamic neurons in addition to the numerous glutamatergic tectothalamic neurons. SG neurons evidently target other auditory structures. The basic circuit of the IC and the LG neurons in particular, has implications for the transmission of information about sound through the midbrain to the MGB. PMID:22855671

Pathological circuit function underlying addiction and anxiety disorders.

PubMed

Lüthi, Andreas; Lüscher, Christian

2014-12-01

Current models of addiction and anxiety stem from the idea that aberrant function and remodeling of neural circuits cause the pathological behaviors. According to this hypothesis, a disease-defining experience (for example, drug reward or stress) would trigger specific forms of synaptic plasticity, which in susceptible subjects would become persistent and lead to the disease. While the notion of synaptic diseases has received much attention, no candidate disorder has been sufficiently investigated to yield new, rational therapies that could be tested in the clinic. Here we review the arguments in favor of abnormal neuronal plasticity underlying addiction and anxiety disorders, with a focus on the functional diversity of neurons that make up the circuits involved. We argue that future research must strive to obtain a comprehensive description of the relevant functional anatomy. This will allow identification of molecular mechanisms that govern the induction and expression of disease-relevant plasticity in identified neurons. To establish causality, one will have to test whether normalization of function can reverse pathological behavior. With these elements in hand, it will be possible to propose blueprints for manipulations to be tested in translational studies. The challenge is daunting, but new techniques, above all optogenetics, may enable decisive advances.

A Review on Locomotor Training after Spinal Cord Injury: Reorganization of Spinal Neuronal Circuits and Recovery of Motor Function

PubMed Central

2016-01-01

Locomotor training is a classic rehabilitation approach utilized with the aim of improving sensorimotor function and walking ability in people with spinal cord injury (SCI). Recent studies have provided strong evidence that locomotor training of persons with clinically complete, motor complete, or motor incomplete SCI induces functional reorganization of spinal neuronal networks at multisegmental levels at rest and during assisted stepping. This neuronal reorganization coincides with improvements in motor function and decreased muscle cocontractions. In this review, we will discuss the manner in which spinal neuronal circuits are impaired and the evidence surrounding plasticity of neuronal activity after locomotor training in people with SCI. We conclude that we need to better understand the physiological changes underlying locomotor training, use physiological signals to probe recovery over the course of training, and utilize established and contemporary interventions simultaneously in larger scale research studies. Furthermore, the focus of our research questions needs to change from feasibility and efficacy to the following: what are the physiological mechanisms that make it work and for whom? The aforementioned will enable the scientific and clinical community to develop more effective rehabilitation protocols maximizing sensorimotor function recovery in people with SCI. PMID:27293901

Targeting neuronal dysfunction in schizophrenia with nicotine: Evidence from neurophysiology to neuroimaging

PubMed Central

Smucny, Jason; Tregellas, Jason R

2018-01-01

Patients with schizophrenia self-administer nicotine at rates higher than is self-administered for any other psychiatric illness. Although the reasons are unclear, one hypothesis suggests that nicotine is a form of ‘self-medication’ in order to restore normal levels of nicotinic signaling and target abnormalities in neuronal function associated with cognitive processes. This brief review discusses evidence from neurophysiological and neuroimaging studies in schizophrenia patients that nicotinic agonists may effectively target dysfunctional neuronal circuits in the illness. Evidence suggests that nicotine significantly modulates a number of these circuits, although relatively few studies have used modern neuroimaging techniques (e.g. functional magnetic resonance imaging (fMRI)) to examine the effects of nicotinic drugs on disease-related neurobiology. The neuronal effects of nicotine and other nicotinic agonists in schizophrenia remain a priority for psychiatry research. PMID:28441884

Somatostatin-Expressing Inhibitory Interneurons in Cortical Circuits

PubMed Central

Yavorska, Iryna; Wehr, Michael

2016-01-01

Cortical inhibitory neurons exhibit remarkable diversity in their morphology, connectivity, and synaptic properties. Here, we review the function of somatostatin-expressing (SOM) inhibitory interneurons, focusing largely on sensory cortex. SOM neurons also comprise a number of subpopulations that can be distinguished by their morphology, input and output connectivity, laminar location, firing properties, and expression of molecular markers. Several of these classes of SOM neurons show unique dynamics and characteristics, such as facilitating synapses, specific axonal projections, intralaminar input, and top-down modulation, which suggest possible computational roles. SOM cells can be differentially modulated by behavioral state depending on their class, sensory system, and behavioral paradigm. The functional effects of such modulation have been studied with optogenetic manipulation of SOM cells, which produces effects on learning and memory, task performance, and the integration of cortical activity. Different classes of SOM cells participate in distinct disinhibitory circuits with different inhibitory partners and in different cortical layers. Through these disinhibitory circuits, SOM cells help encode the behavioral relevance of sensory stimuli by regulating the activity of cortical neurons based on subcortical and intracortical modulatory input. Associative learning leads to long-term changes in the strength of connectivity of SOM cells with other neurons, often influencing the strength of inhibitory input they receive. Thus despite their heterogeneity and variability across cortical areas, current evidence shows that SOM neurons perform unique neural computations, forming not only distinct molecular but also functional subclasses of cortical inhibitory interneurons. PMID:27746722

Cadherin-8 expression, synaptic localization, and molecular control of neuronal form in prefrontal corticostriatal circuits.

PubMed

Friedman, Lauren G; Riemslagh, Fréderike W; Sullivan, Josefa M; Mesias, Roxana; Williams, Frances M; Huntley, George W; Benson, Deanna L

2015-01-01

Neocortical interactions with the dorsal striatum support many motor and executive functions, and such underlying functional networks are particularly vulnerable to a variety of developmental, neurological, and psychiatric brain disorders, including autism spectrum disorders, Parkinson's disease, and Huntington's disease. Relatively little is known about the development of functional corticostriatal interactions, and in particular, virtually nothing is known of the molecular mechanisms that control generation of prefrontal cortex-striatal circuits. Here, we used regional and cellular in situ hybridization techniques coupled with neuronal tract tracing to show that Cadherin-8 (Cdh8), a homophilic adhesion protein encoded by a gene associated with autism spectrum disorders and learning disability susceptibility, is enriched within striatal projection neurons in the medial prefrontal cortex and in striatal medium spiny neurons forming the direct or indirect pathways. Developmental analysis of quantitative real-time polymerase chain reaction and western blot data show that Cdh8 expression peaks in the prefrontal cortex and striatum at P10, when cortical projections start to form synapses in the striatum. High-resolution immunoelectron microscopy shows that Cdh8 is concentrated at excitatory synapses in the dorsal striatum, and Cdh8 knockdown in cortical neurons impairs dendritic arborization and dendrite self-avoidance. Taken together, our findings indicate that Cdh8 delineates developing corticostriatal circuits where it is a strong candidate for regulating the generation of normal cortical projections, neuronal morphology, and corticostriatal synapses. © 2014 Wiley Periodicals, Inc.

Optogenetic Activation of Zebrafish Somatosensory Neurons using ChEF-tdTomato

PubMed Central

Palanca, Ana Marie S.; Sagasti, Alvaro

2013-01-01

Larval zebrafish are emerging as a model for describing the development and function of simple neural circuits. Due to their external fertilization, rapid development, and translucency, zebrafish are particularly well suited for optogenetic approaches to investigate neural circuit function. In this approach, light-sensitive ion channels are expressed in specific neurons, enabling the experimenter to activate or inhibit them at will and thus assess their contribution to specific behaviors. Applying these methods in larval zebrafish is conceptually simple but requires the optimization of technical details. Here we demonstrate a procedure for expressing a channelrhodopsin variant in larval zebrafish somatosensory neurons, photo-activating single cells, and recording the resulting behaviors. By introducing a few modifications to previously established methods, this approach could be used to elicit behavioral responses from single neurons activated up to at least 4 days post-fertilization (dpf). Specifically, we created a transgene using a somatosensory neuron enhancer, CREST3, to drive the expression of the tagged channelrhodopsin variant, ChEF-tdTomato. Injecting this transgene into 1-cell stage embryos results in mosaic expression in somatosensory neurons, which can be imaged with confocal microscopy. Illuminating identified cells in these animals with light from a 473 nm DPSS laser, guided through a fiber optic cable, elicits behaviors that can be recorded with a high-speed video camera and analyzed quantitatively. This technique could be adapted to study behaviors elicited by activating any zebrafish neuron. Combining this approach with genetic or pharmacological perturbations will be a powerful way to investigate circuit formation and function. PMID:23407374

The Role of Glia in Sleep Regulation and Function.

PubMed

Frank, Marcos G

2018-01-28

The cellular mechanisms governing the expression, regulation, and function of sleep are not entirely understood. The traditional view is that these mechanisms are neuronal. An alternative view is that glial brain cells may play important roles in these processes. Their ubiquity in the central nervous system makes them well positioned to modulate neuronal circuits that gate sleep and wake. Their ability to respond to chemical neuronal signals suggests that they form feedback loops with neurons that may globally regulate neuronal activity. Their potential role in detoxifying the brain, regulating neuronal metabolism, and promoting synaptic plasticity raises the intriguing possibility that glia mediate important functions ascribed to sleep.

A scalable neural chip with synaptic electronics using CMOS integrated memristors.

PubMed

Cruz-Albrecht, Jose M; Derosier, Timothy; Srinivasa, Narayan

2013-09-27

The design and simulation of a scalable neural chip with synaptic electronics using nanoscale memristors fully integrated with complementary metal-oxide-semiconductor (CMOS) is presented. The circuit consists of integrate-and-fire neurons and synapses with spike-timing dependent plasticity (STDP). The synaptic conductance values can be stored in memristors with eight levels, and the topology of connections between neurons is reconfigurable. The circuit has been designed using a 90 nm CMOS process with via connections to on-chip post-processed memristor arrays. The design has about 16 million CMOS transistors and 73 728 integrated memristors. We provide circuit level simulations of the entire chip performing neuronal and synaptic computations that result in biologically realistic functional behavior.

Role of mechanical cues in shaping neuronal morphology and connectivity.

PubMed

Gangatharan, Girisaran; Schneider-Maunoury, Sylvie; Breau, Marie Anne

2018-06-01

Neuronal circuits, the functional building blocks of the nervous system, assemble during development through a series of dynamic processes including the migration of neurons to their final position, the growth and navigation of axons and their synaptic connection with target cells. While the role of chemical cues in guiding neuronal migration and axonal development has been extensively analysed, the contribution of mechanical inputs, such as forces and stiffness, has received far less attention. In this article, we review the in vitro and more recent in vivo studies supporting the notion that mechanical signals are critical for multiple aspects of neuronal circuit assembly, from the emergence of axons to the formation of functional synapses. By combining live imaging approaches with tools designed to measure and manipulate the mechanical environment of neurons, the emerging field of neuromechanics will add a new paradigm in our understanding of neuronal development and potentially inspire novel regenerative therapies. © 2018 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.

Dopaminergic neurons encode a distributed, asymmetric representation of temperature in Drosophila.

PubMed

Tomchik, Seth M

2013-01-30

Dopaminergic circuits modulate a wide variety of innate and learned behaviors in animals, including olfactory associative learning, arousal, and temperature-preference behavior. It is not known whether distinct or overlapping sets of dopaminergic neurons modulate these behaviors. Here, I have functionally characterized the dopaminergic circuits innervating the Drosophila mushroom body with in vivo calcium imaging and conditional silencing of genetically defined subsets of neurons. Distinct subsets of PPL1 dopaminergic neurons innervating the vertical lobes of the mushroom body responded to decreases in temperature, but not increases, with rapidly adapting bursts of activity. PAM neurons innervating the horizontal lobes did not respond to temperature shifts. Ablation of the antennae and maxillary palps reduced, but did not eliminate, the responses. Genetic silencing of dopaminergic neurons innervating the vertical mushroom body lobes substantially reduced behavioral cold avoidance, but silencing smaller subsets of these neurons had no effect. These data demonstrate that overlapping dopaminergic circuits encode a broadly distributed, asymmetric representation of temperature that overlays regions implicated previously in learning, memory, and forgetting. Thus, diverse behaviors engage overlapping sets of dopaminergic neurons that encode multimodal stimuli and innervate a single anatomical target, the mushroom body.

Scalable, Lightweight, Integrated and Quick-to-Assemble (SLIQ) Hyperdrives for Functional Circuit Dissection.

PubMed

Liang, Li; Oline, Stefan N; Kirk, Justin C; Schmitt, Lukas Ian; Komorowski, Robert W; Remondes, Miguel; Halassa, Michael M

2017-01-01

Independently adjustable multielectrode arrays are routinely used to interrogate neuronal circuit function, enabling chronic in vivo monitoring of neuronal ensembles in freely behaving animals at a single-cell, single spike resolution. Despite the importance of this approach, its widespread use is limited by highly specialized design and fabrication methods. To address this, we have developed a Scalable, Lightweight, Integrated and Quick-to-assemble multielectrode array platform. This platform additionally integrates optical fibers with independently adjustable electrodes to allow simultaneous single unit recordings and circuit-specific optogenetic targeting and/or manipulation. In current designs, the fully assembled platforms are scalable from 2 to 32 microdrives, and yet range 1-3 g, light enough for small animals. Here, we describe the design process starting from intent in computer-aided design, parameter testing through finite element analysis and experimental means, and implementation of various applications across mice and rats. Combined, our methods may expand the utility of multielectrode recordings and their continued integration with other tools enabling functional dissection of intact neural circuits.

Modulation of short-term plasticity in the corticothalamic circuit by group III metabotropic glutamate receptors.

PubMed

Kyuyoung, Christine L; Huguenard, John R

2014-01-08

Recurrent connections in the corticothalamic circuit underlie oscillatory behavior in this network and range from normal sleep rhythms to the abnormal spike-wave discharges seen in absence epilepsy. The propensity of thalamic neurons to fire postinhibitory rebound bursts mediated by low-threshold calcium spikes renders the circuit vulnerable to both increased excitation and increased inhibition, such as excessive excitatory cortical drive to thalamic reticular (RT) neurons or heightened inhibition of thalamocortical relay (TC) neurons by RT. In this context, a protective role may be played by group III metabotropic receptors (mGluRs), which are uniquely located in the presynaptic active zone and typically act as autoreceptors or heteroceptors to depress synaptic release. Here, we report that these receptors regulate short-term plasticity at two loci in the corticothalamic circuit in rats: glutamatergic cortical synapses onto RT neurons and GABAergic synapses onto TC neurons in somatosensory ventrobasal thalamus. The net effect of group III mGluR activation at these synapses is to suppress thalamic oscillations as assayed in vitro. These findings suggest a functional role of these receptors to modulate corticothalamic transmission and protect against prolonged activity in the network.

Optogenetic dissection of neural circuits underlying emotional valence and motivated behaviors

PubMed Central

Nieh, Edward H.; Kim, Sung-Yon; Namburi, Praneeth; Tye, Kay M.

2014-01-01

The neural circuits underlying emotional valence and motivated behaviors are several synapses away from both defined sensory inputs and quantifiable motor outputs. Electrophysiology has provided us with a suitable means for observing neural activity during behavior, but methods for controlling activity for the purpose of studying motivated behaviors have been inadequate: electrical stimulation lacks cellular specificity and pharmacological manipulation lacks temporal resolution. The recent emergence of optogenetic tools provides a new means for establishing causal relationships between neural activity and behavior. Optogenetics, the use of genetically-encodable light-activated proteins, permits the modulation of specific neural circuit elements with millisecond precision. The ability to control individual cell types, and even projections between distal regions, allows us to investigate functional connectivity in a causal manner. The greatest consequence of controlling neural activity with finer precision has been the characterization of individual neural circuits within anatomical brain regions as defined functional units. Within the mesolimbic dopamine system, optogenetics has helped separate subsets of dopamine neurons with distinct functions for reward, aversion and salience processing, elucidated GABA neuronal effects on behavior, and characterized connectivity with forebrain and cortical structures. Within the striatum, optogenetics has confirmed the opposing relationship between direct and indirect pathway medium spiny neurons (MSNs), in addition to characterizing the inhibition of MSNs by cholinergic interneurons. Within the hypothalamus, optogenetics has helped overcome the heterogeneity in neuronal cell-type and revealed distinct circuits mediating aggression and feeding. Within the amygdala, optogenetics has allowed the study of intra-amygdala microcircuitry as well as interconnections with distal regions involved in fear and anxiety. In this review, we will present the body of optogenetic studies that has significantly enhanced our understanding of emotional valence and motivated behaviors. PMID:23142759

Distinct Thalamic Reticular Cell Types Differentially Modulate Normal and Pathological Cortical Rhythms.

PubMed

Clemente-Perez, Alexandra; Makinson, Stefanie Ritter; Higashikubo, Bryan; Brovarney, Scott; Cho, Frances S; Urry, Alexander; Holden, Stephanie S; Wimer, Matthew; Dávid, Csaba; Fenno, Lief E; Acsády, László; Deisseroth, Karl; Paz, Jeanne T

2017-06-06

Integrative brain functions depend on widely distributed, rhythmically coordinated computations. Through its long-ranging connections with cortex and most senses, the thalamus orchestrates the flow of cognitive and sensory information. Essential in this process, the nucleus reticularis thalami (nRT) gates different information streams through its extensive inhibition onto other thalamic nuclei, however, we lack an understanding of how different inhibitory neuron subpopulations in nRT function as gatekeepers. We dissociated the connectivity, physiology, and circuit functions of neurons within rodent nRT, based on parvalbumin (PV) and somatostatin (SOM) expression, and validated the existence of such populations in human nRT. We found that PV, but not SOM, cells are rhythmogenic, and that PV and SOM neurons are connected to and modulate distinct thalamocortical circuits. Notably, PV, but not SOM, neurons modulate somatosensory behavior and disrupt seizures. These results provide a conceptual framework for how nRT may gate incoming information to modulate brain-wide rhythms. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Signal transfer within a cultured asymmetric cortical neuron circuit

NASA Astrophysics Data System (ADS)

Isomura, Takuya; Shimba, Kenta; Takayama, Yuzo; Takeuchi, Akimasa; Kotani, Kiyoshi; Jimbo, Yasuhiko

2015-12-01

Objective. Simplified neuronal circuits are required for investigating information representation in nervous systems and for validating theoretical neural network models. Here, we developed patterned neuronal circuits using micro fabricated devices, comprising a micro-well array bonded to a microelectrode-array substrate. Approach. The micro-well array consisted of micrometre-scale wells connected by tunnels, all contained within a silicone slab called a micro-chamber. The design of the micro-chamber confined somata to the wells and allowed axons to grow through the tunnels bidirectionally but with a designed, unidirectional bias. We guided axons into the point of the arrow structure where one of the two tunnel entrances is located, making that the preferred direction. Main results. When rat cortical neurons were cultured in the wells, their axons grew through the tunnels and connected to neurons in adjoining wells. Unidirectional burst transfers and other asymmetric signal-propagation phenomena were observed via the substrate-embedded electrodes. Seventy-nine percent of burst transfers were in the forward direction. We also observed rapid propagation of activity from sites of local electrical stimulation, and significant effects of inhibitory synapse blockade on bursting activity. Significance. These results suggest that this simple, substrate-controlled neuronal circuit can be applied to develop in vitro models of the function of cortical microcircuits or deep neural networks, better to elucidate the laws governing the dynamics of neuronal networks.

Signal transfer within a cultured asymmetric cortical neuron circuit.

PubMed

Isomura, Takuya; Shimba, Kenta; Takayama, Yuzo; Takeuchi, Akimasa; Kotani, Kiyoshi; Jimbo, Yasuhiko

2015-12-01

Simplified neuronal circuits are required for investigating information representation in nervous systems and for validating theoretical neural network models. Here, we developed patterned neuronal circuits using micro fabricated devices, comprising a micro-well array bonded to a microelectrode-array substrate. The micro-well array consisted of micrometre-scale wells connected by tunnels, all contained within a silicone slab called a micro-chamber. The design of the micro-chamber confined somata to the wells and allowed axons to grow through the tunnels bidirectionally but with a designed, unidirectional bias. We guided axons into the point of the arrow structure where one of the two tunnel entrances is located, making that the preferred direction. When rat cortical neurons were cultured in the wells, their axons grew through the tunnels and connected to neurons in adjoining wells. Unidirectional burst transfers and other asymmetric signal-propagation phenomena were observed via the substrate-embedded electrodes. Seventy-nine percent of burst transfers were in the forward direction. We also observed rapid propagation of activity from sites of local electrical stimulation, and significant effects of inhibitory synapse blockade on bursting activity. These results suggest that this simple, substrate-controlled neuronal circuit can be applied to develop in vitro models of the function of cortical microcircuits or deep neural networks, better to elucidate the laws governing the dynamics of neuronal networks.

In vitro large-scale experimental and theoretical studies for the realization of bi-directional brain-prostheses.

PubMed

Bonifazi, Paolo; Difato, Francesco; Massobrio, Paolo; Breschi, Gian L; Pasquale, Valentina; Levi, Timothée; Goldin, Miri; Bornat, Yannick; Tedesco, Mariateresa; Bisio, Marta; Kanner, Sivan; Galron, Ronit; Tessadori, Jacopo; Taverna, Stefano; Chiappalone, Michela

2013-01-01

Brain-machine interfaces (BMI) were born to control "actions from thoughts" in order to recover motor capability of patients with impaired functional connectivity between the central and peripheral nervous system. The final goal of our studies is the development of a new proof-of-concept BMI-a neuromorphic chip for brain repair-to reproduce the functional organization of a damaged part of the central nervous system. To reach this ambitious goal, we implemented a multidisciplinary "bottom-up" approach in which in vitro networks are the paradigm for the development of an in silico model to be incorporated into a neuromorphic device. In this paper we present the overall strategy and focus on the different building blocks of our studies: (i) the experimental characterization and modeling of "finite size networks" which represent the smallest and most general self-organized circuits capable of generating spontaneous collective dynamics; (ii) the induction of lesions in neuronal networks and the whole brain preparation with special attention on the impact on the functional organization of the circuits; (iii) the first production of a neuromorphic chip able to implement a real-time model of neuronal networks. A dynamical characterization of the finite size circuits with single cell resolution is provided. A neural network model based on Izhikevich neurons was able to replicate the experimental observations. Changes in the dynamics of the neuronal circuits induced by optical and ischemic lesions are presented respectively for in vitro neuronal networks and for a whole brain preparation. Finally the implementation of a neuromorphic chip reproducing the network dynamics in quasi-real time (10 ns precision) is presented.

Optogenetics in a transparent animal: circuit function in the larval zebrafish.

PubMed

Portugues, Ruben; Severi, Kristen E; Wyart, Claire; Ahrens, Misha B

2013-02-01

Optogenetic tools can be used to manipulate neuronal activity in a reversible and specific manner. In recent years, such methods have been applied to uncover causal relationships between activity in specified neuronal circuits and behavior in the larval zebrafish. In this small, transparent, genetic model organism, noninvasive manipulation and monitoring of neuronal activity with light is possible throughout the nervous system. Here we review recent work in which these new tools have been applied to zebrafish, and discuss some of the existing challenges of these approaches. Copyright © 2012. Published by Elsevier Ltd.

Making sense out of spinal cord somatosensory development

PubMed Central

Seal, Rebecca P.

2016-01-01

The spinal cord integrates and relays somatosensory input, leading to complex motor responses. Research over the past couple of decades has identified transcription factor networks that function during development to define and instruct the generation of diverse neuronal populations within the spinal cord. A number of studies have now started to connect these developmentally defined populations with their roles in somatosensory circuits. Here, we review our current understanding of how neuronal diversity in the dorsal spinal cord is generated and we discuss the logic underlying how these neurons form the basis of somatosensory circuits. PMID:27702783

Homology and homoplasy of swimming behaviors and neural circuits in the Nudipleura (Mollusca, Gastropoda, Opisthobranchia)

PubMed Central

Newcomb, James M.; Sakurai, Akira; Lillvis, Joshua L.; Gunaratne, Charuni A.; Katz, Paul S.

2012-01-01

How neural circuit evolution relates to behavioral evolution is not well understood. Here the relationship between neural circuits and behavior is explored with respect to the swimming behaviors of the Nudipleura (Mollusca, Gastropoda, Opithobranchia). Nudipleura is a diverse monophyletic clade of sea slugs among which only a small percentage of species can swim. Swimming falls into a limited number of categories, the most prevalent of which are rhythmic left–right body flexions (LR) and rhythmic dorsal–ventral body flexions (DV). The phylogenetic distribution of these behaviors suggests a high degree of homoplasy. The central pattern generator (CPG) underlying DV swimming has been well characterized in Tritonia diomedea and in Pleurobranchaea californica. The CPG for LR swimming has been elucidated in Melibe leonina and Dendronotus iris, which are more closely related. The CPGs for the categorically distinct DV and LR swimming behaviors consist of nonoverlapping sets of homologous identified neurons, whereas the categorically similar behaviors share some homologous identified neurons, although the exact composition of neurons and synapses in the neural circuits differ. The roles played by homologous identified neurons in categorically distinct behaviors differ. However, homologous identified neurons also play different roles even in the swim CPGs of the two LR swimming species. Individual neurons can be multifunctional within a species. Some of those functions are shared across species, whereas others are not. The pattern of use and reuse of homologous neurons in various forms of swimming and other behaviors further demonstrates that the composition of neural circuits influences the evolution of behaviors. PMID:22723353

Creation of defined single cell resolution neuronal circuits on microelectrode arrays

NASA Astrophysics Data System (ADS)

Pirlo, Russell Kirk

2009-12-01

The way cell-cell organization of neuronal networks influences activity and facilitates function is not well understood. Microelectrode arrays (MEAs) and advancing cell patterning technologies have enabled access to and control of in vitro neuronal networks spawning much new research in neuroscience and neuroengineering. We propose that small, simple networks of neurons with defined circuitry may serve as valuable research models where every connection can be analyzed, controlled and manipulated. Towards the goal of creating such neuronal networks we have applied microfabricated elastomeric membranes, surface modification and our unique laser cell patterning system to create defined neuronal circuits with single-cell precision on MEAs. Definition of synaptic connectivity was imposed by the 3D physical constraints of polydimethylsiloxane elastomeric membranes. The membranes had 20mum clear-through holes and 2-3mum deep channels which when applied to the surface of the MEA formed microwells to confine neurons to electrodes connected via shallow tunnels to direct neurite outgrowth. Tapering and turning of channels was used to influence neurite polarity. Biocompatibility of the membranes was increased by vacuum baking, oligomer extraction, and autoclaving. Membranes were bound to the MEA by oxygen plasma treatment and heated pressure. The MEA/membrane surface was treated with oxygen plasma, poly-D-lysine and laminin to improve neuron attachment, survival and neurite outgrowth. Prior to cell patterning the outer edge of culture area was seeded with 5x10 5 cells per cm and incubated for 2 days. Single embryonic day 7 chick forebrain neurons were then patterned into the microwells and onto the electrodes using our laser cell patterning system. Patterned neurons successfully attached to and were confined to the electrodes. Neurites extended through the interconnecting channels and connected with adjacent neurons. These results demonstrate that neuronal circuits can be created with clearly defined circuitry and a one-to-one neuron-electrode ratio. The techniques and processes described here may be used in future research to create defined neuronal circuits to model in vivo circuits and study neuronal network processing.

The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors

PubMed Central

Root, David H.; Melendez, Roberto I.; Zaborszky, Laszlo; Napier, T. Celeste

2015-01-01

The ventral pallidum (VP) plays a critical role in the processing and execution of motivated behaviors. Yet this brain region is often overlooked in published discussions of the neurobiology of mental health (e.g., addiction, depression). This contributes to a gap in understanding the neurobiological mechanisms of psychiatric disorders. This review is presented to help bridge the gap by providing a resource for current knowledge of VP anatomy, projection patterns and subregional circuits, and how this organization relates to the function of VP neurons and ultimately behavior. For example, ventromedial (VPvm) and dorsolateral (VPdl) VP subregions receive projections from nucleus accumbens shell and core, respectively. Inhibitory GABAergic neurons of the VPvm project to mediodorsal thalamus, lateral hypothalamus, and ventral tegmental area, and this VP subregion helps discriminate the appropriate conditions to acquire natural rewards or drugs of abuse, consume preferred foods, and perform working memory tasks. GABAergic neurons of the VPdl project to subthalamic nucleus and substantia nigra pars reticulata, and this VP subregion is modulated by, and is necessary for, drug-seeking behavior. Additional circuits arise from nonGABAergic neuronal phenotypes that are likely to excite rather than inhibit their targets. These subregional and neuronal phenotypic circuits place the VP in a unique position to process motivationally-relevant stimuli and coherent adaptive behaviors. PMID:25857550

Deconstruction of a neural circuit for hunger.

PubMed

Atasoy, Deniz; Betley, J Nicholas; Su, Helen H; Sternson, Scott M

2012-08-09

Hunger is a complex behavioural state that elicits intense food seeking and consumption. These behaviours are rapidly recapitulated by activation of starvation-sensitive AGRP neurons, which present an entry point for reverse-engineering neural circuits for hunger. Here we mapped synaptic interactions of AGRP neurons with multiple cell populations in mice and probed the contribution of these distinct circuits to feeding behaviour using optogenetic and pharmacogenetic techniques. An inhibitory circuit with paraventricular hypothalamus (PVH) neurons substantially accounted for acute AGRP neuron-evoked eating, whereas two other prominent circuits were insufficient. Within the PVH, we found that AGRP neurons target and inhibit oxytocin neurons, a small population that is selectively lost in Prader-Willi syndrome, a condition involving insatiable hunger. By developing strategies for evaluating molecularly defined circuits, we show that AGRP neuron suppression of oxytocin neurons is critical for evoked feeding. These experiments reveal a new neural circuit that regulates hunger state and pathways associated with overeating disorders.

Deconstruction of a neural circuit for hunger

PubMed Central

Atasoy, Deniz; Betley, J. Nicholas; Su, Helen H.; Sternson, Scott M.

2012-01-01

Hunger is a complex behavioural state that elicits intense food seeking and consumption. These behaviours are rapidly recapitulated by activation of starvation-sensitive AGRP neurons, which present an entry point for reverse-engineering neural circuits for hunger. We mapped synaptic interactions of AGRP neurons with multiple cell populations and probed the contribution of these distinct circuits to feeding behaviour using optogenetic and pharmacogenetic techniques. An inhibitory circuit with paraventricular hypothalamus (PVH) neurons substantially accounted for acute AGRP neuron-evoked eating, whereas two other prominent circuits were insufficient. Within the PVH, we found that AGRP neurons target and inhibit oxytocin neurons, a small population that is selectively lost in Prader-Willi syndrome, a condition involving insatiable hunger. By developing strategies for evaluating molecularly-defined circuits, we show that AGRP neuron suppression of oxytocin neurons is critical for evoked feeding. These experiments reveal a new neural circuit that regulates hunger state and pathways associated with overeating disorders. PMID:22801496

Integrated neuron circuit for implementing neuromorphic system with synaptic device

NASA Astrophysics Data System (ADS)

Lee, Jeong-Jun; Park, Jungjin; Kwon, Min-Woo; Hwang, Sungmin; Kim, Hyungjin; Park, Byung-Gook

2018-02-01

In this paper, we propose and fabricate Integrate & Fire neuron circuit for implementing neuromorphic system. Overall operation of the circuit is verified by measuring discrete devices and the output characteristics of the circuit. Since the neuron circuit shows asymmetric output characteristic that can drive synaptic device with Spike-Timing-Dependent-Plasticity (STDP) characteristic, the autonomous weight update process is also verified by connecting the synaptic device and the neuron circuit. The timing difference of the pre-neuron and the post-neuron induce autonomous weight change of the synaptic device. Unlike 2-terminal devices, which is frequently used to implement neuromorphic system, proposed scheme of the system enables autonomous weight update and simple configuration by using 4-terminal synapse device and appropriate neuron circuit. Weight update process in the multi-layer neuron-synapse connection ensures implementation of the hardware-based artificial intelligence, based on Spiking-Neural- Network (SNN).

Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection

PubMed Central

2017-01-01

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is vital to the survival, growth, and maintenance of neurons in key brain circuits involved in emotional and cognitive function. Convergent evidence indicates that neuroplastic mechanisms involving BDNF are deleteriously altered in major depressive disorder (MDD) and animal models of stress. Herein, clinical and preclinical evidence provided that stress-induced depressive pathology contributes to altered BDNF level and function in persons with MDD and, thereby, disruptions in neuroplasticity at the regional and circuit level. Conversely, effective therapeutics that mitigate depressive-related symptoms (e.g., antidepressants and physical activity) optimize BDNF in key brain regions, promote neuronal health and recovery of function in MDD-related circuits, and enhance pharmacotherapeutic response. A greater knowledge of the interrelationship between BDNF, depression, therapeutic mechanisms of action, and neuroplasticity is important as it necessarily precedes the derivation and deployment of more efficacious treatments. PMID:28928987

Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection.

PubMed

Phillips, Cristy

2017-01-01

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is vital to the survival, growth, and maintenance of neurons in key brain circuits involved in emotional and cognitive function. Convergent evidence indicates that neuroplastic mechanisms involving BDNF are deleteriously altered in major depressive disorder (MDD) and animal models of stress. Herein, clinical and preclinical evidence provided that stress-induced depressive pathology contributes to altered BDNF level and function in persons with MDD and, thereby, disruptions in neuroplasticity at the regional and circuit level. Conversely, effective therapeutics that mitigate depressive-related symptoms (e.g., antidepressants and physical activity) optimize BDNF in key brain regions, promote neuronal health and recovery of function in MDD-related circuits, and enhance pharmacotherapeutic response. A greater knowledge of the interrelationship between BDNF, depression, therapeutic mechanisms of action, and neuroplasticity is important as it necessarily precedes the derivation and deployment of more efficacious treatments.

Reserve pool neuron transmitter respecification: Novel neuroplasticity.

PubMed

Dulcis, Davide; Spitzer, Nicholas C

2012-04-01

The identity of the neurotransmitters expressed by neurons has been thought to be fixed and immutable, but recent studies demonstrate that changes in electrical activity can rapidly and reversibly reconfigure the transmitters and corresponding transmitter receptors that neurons express. Induction of transmitter expression can be achieved by selective activation of afferents recruited by a physiological range of sensory input. Strikingly, neurons acquiring an additional transmitter project to appropriate targets prior to transmitter respecification in some cases, indicating the presence of reserve pools of neurons that can boost circuit function. We discuss the evidence for such reserve pools, their likely locations and ways to test for their existence, and the potential clinical value of such circuit-specific neurotransmitter respecification for treatments of neurological disorders. Copyright © 2011 Wiley Periodicals, Inc.

An optogenetics- and imaging-assisted simultaneous multiple patch-clamp recording system for decoding complex neural circuits

PubMed Central

Wang, Guangfu; Wyskiel, Daniel R; Yang, Weiguo; Wang, Yiqing; Milbern, Lana C; Lalanne, Txomin; Jiang, Xiaolong; Shen, Ying; Sun, Qian-Quan; Zhu, J Julius

2015-01-01

Deciphering neuronal circuitry is central to understanding brain function and dysfunction, yet it remains a daunting task. To facilitate the dissection of neuronal circuits, a process requiring functional analysis of synaptic connections and morphological identification of interconnected neurons, we present here a method for stable simultaneous octuple patch-clamp recordings. This method allows physiological analysis of synaptic interconnections among 4–8 simultaneously recorded neurons and/or 10–30 sequentially recorded neurons, and it allows anatomical identification of >85% of recorded interneurons and >99% of recorded principal neurons. We describe how to apply the method to rodent tissue slices; however, it can be used on other model organisms. We also describe the latest refinements and optimizations of mechanics, electronics, optics and software programs that are central to the realization of a combined single- and two-photon microscopy–based, optogenetics- and imaging-assisted, stable, simultaneous quadruple–viguple patch-clamp recording system. Setting up the system, from the beginning of instrument assembly and software installation to full operation, can be completed in 3–4 d. PMID:25654757

Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit.

PubMed

Mapelli, Lisa; Pagani, Martina; Garrido, Jesus A; D'Angelo, Egidio

2015-01-01

The way long-term potentiation (LTP) and depression (LTD) are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network, in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei) and correspondingly regulate the function of their three main neurons: granule cells (GrCs), Purkinje cells (PCs) and deep cerebellar nuclear (DCN) cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

Universality in the Evolution of Orientation Columns in the Visual Cortex

PubMed Central

Kaschube, Matthias; Schnabel, Michael; Löwel, Siegrid; Coppola, David M.; White, Leonard E.; Wolf, Fred

2011-01-01

The brain’s visual cortex processes information concerning form, pattern, and motion within functional maps that reflect the layout of neuronal circuits. We analyzed functional maps of orientation preference in the ferret, tree shrew, and galago—three species separated since the basal radiation of placental mammals more than 65 million years ago—and found a common organizing principle. A symmetry-based class of models for the self-organization of cortical networks predicts all essential features of the layout of these neuronal circuits, but only if suppressive long-range interactions dominate development. We show mathematically that orientation-selective long-range connectivity can mediate the required interactions. Our results suggest that self-organization has canalized the evolution of the neuronal circuitry underlying orientation preference maps into a single common design. PMID:21051599

Whole-brain activity maps reveal stereotyped, distributed networks for visuomotor behavior.

PubMed

Portugues, Ruben; Feierstein, Claudia E; Engert, Florian; Orger, Michael B

2014-03-19

Most behaviors, even simple innate reflexes, are mediated by circuits of neurons spanning areas throughout the brain. However, in most cases, the distribution and dynamics of firing patterns of these neurons during behavior are not known. We imaged activity, with cellular resolution, throughout the whole brains of zebrafish performing the optokinetic response. We found a sparse, broadly distributed network that has an elaborate but ordered pattern, with a bilaterally symmetrical organization. Activity patterns fell into distinct clusters reflecting sensory and motor processing. By correlating neuronal responses with an array of sensory and motor variables, we find that the network can be clearly divided into distinct functional modules. Comparing aligned data from multiple fish, we find that the spatiotemporal activity dynamics and functional organization are highly stereotyped across individuals. These experiments systematically reveal the functional architecture of neural circuits underlying a sensorimotor behavior in a vertebrate brain. Copyright © 2014 Elsevier Inc. All rights reserved.

Whole-brain activity maps reveal stereotyped, distributed networks for visuomotor behavior

PubMed Central

Portugues, Ruben; Feierstein, Claudia E.; Engert, Florian; Orger, Michael B.

2014-01-01

Summary Most behaviors, even simple innate reflexes, are mediated by circuits of neurons spanning areas throughout the brain. However, in most cases, the distribution and dynamics of firing patterns of these neurons during behavior are not known. We imaged activity, with cellular resolution, throughout the whole brains of zebrafish performing the optokinetic response. We found a sparse, broadly distributed network that has an elaborate, but ordered, pattern, with a bilaterally symmetrical organization. Activity patterns fell into distinct clusters reflecting sensory and motor processing. By correlating neuronal responses with an array of sensory and motor variables, we find that the network can be clearly divided into distinct functional modules. Comparing aligned data from multiple fish, we find that the spatiotemporal activity dynamics and functional organization are highly stereotyped across individuals. These experiments reveal, for the first time in a vertebrate, the comprehensive functional architecture of the neural circuits underlying a sensorimotor behavior. PMID:24656252

Morphological evidence for novel enteric neuronal circuitry in guinea pig distal colon.

PubMed

Smolilo, D J; Costa, M; Hibberd, T J; Wattchow, D A; Spencer, Nick J

2018-07-01

The gastrointestinal (GI) tract is unique compared to all other internal organs; it is the only organ with its own nervous system and its own population of intrinsic sensory neurons, known as intrinsic primary afferent neurons (IPANs). How these IPANs form neuronal circuits with other functional classes of neurons in the enteric nervous system (ENS) is incompletely understood. We used a combination of light microscopy, immunohistochemistry and confocal microscopy to examine the topographical distribution of specific classes of neurons in the myenteric plexus of guinea-pig colon, including putative IPANs, with other classes of enteric neurons. These findings were based on immunoreactivity to the neuronal markers, calbindin, calretinin and nitric oxide synthase. We then correlated the varicose outputs formed by putative IPANs with subclasses of excitatory interneurons and motor neurons. We revealed that calbindin-immunoreactive varicosities form specialized structures resembling 'baskets' within the majority of myenteric ganglia, which were arranged in clusters around calretinin-immunoreactive neurons. These calbindin baskets directly arose from projections of putative IPANs and represent morphological evidence of preferential input from sensory neurons directly to a select group of calretinin neurons. Our findings uncovered that these neurons are likely to be ascending excitatory interneurons and excitatory motor neurons. Our study reveals for the first time in the colon, a novel enteric neural circuit, whereby calbindin-immunoreactive putative sensory neurons form specialized varicose structures that likely direct synaptic outputs to excitatory interneurons and motor neurons. This circuit likely forms the basis of polarized neuronal pathways underlying motility. © 2018 Wiley Periodicals, Inc.

Morphological Analysis of the Axonal Projections of EGFP-Labeled Esr1-Expressing Neurons in Transgenic Female Medaka.

PubMed

Zempo, Buntaro; Karigo, Tomomi; Kanda, Shinji; Akazome, Yasuhisa; Oka, Yoshitaka

2018-02-01

Some hypothalamic neurons expressing estrogen receptor α (Esr1) are thought to transmit a gonadal estrogen feedback signal to gonadotropin-releasing hormone 1 (GnRH1) neurons, which is the final common pathway for feedback regulation of reproductive functions. Moreover, estrogen-sensitive neurons are suggested to control sexual behaviors in coordination with reproduction. In mammals, hypothalamic estrogen-sensitive neurons release the peptide kisspeptin and regulate GnRH1 neurons. However, a growing body of evidence in nonmammalian species casts doubt on the regulation of GnRH1 neurons by kisspeptin neurons. As a step toward understanding how estrogen regulates neuronal circuits for reproduction and sex behavior in vertebrates in general, we generated a transgenic (Tg) medaka that expresses enhanced green fluorescent protein (EGFP) specifically in esr1-expressing neurons (esr1 neurons) and analyzed their axonal projections. We found that esr1 neurons in the preoptic area (POA) project to the gnrh1 neurons. We also demonstrated by transcriptome and histological analyses that these esr1 neurons are glutamatergic or γ-aminobutyric acidergic (GABAergic) but not kisspeptinergic. We therefore suggest that glutamatergic and GABAergic esr1 neurons in the POA regulate gnrh1 neurons. This hypothesis is consistent with previous studies in mice that found that glutamatergic and GABAergic transmission is critical for estrogen-dependent changes in GnRH1 neuron firing. Thus, we propose that this neuronal circuit may provide an evolutionarily conserved mechanism for regulation of reproduction. In addition, we showed that telencephalic esr1 neurons project to medulla, which may control sexual behavior. Moreover, we found that some POA-esr1 neurons coexpress progesterone receptors. These neurons may form the neuronal circuits that regulate reproduction and sex behavior in response to the serum estrogen/progesterone. Copyright © 2018 Endocrine Society.

Robo2 determines subtype-specific axonal projections of trigeminal sensory neurons

PubMed Central

Pan, Y. Albert; Choy, Margaret; Prober, David A.; Schier, Alexander F.

2012-01-01

How neurons connect to form functional circuits is central to the understanding of the development and function of the nervous system. In the somatosensory system, perception of sensory stimuli to the head requires specific connections between trigeminal sensory neurons and their many target areas in the central nervous system. Different trigeminal subtypes have specialized functions and downstream circuits, but it has remained unclear how subtype-specific axonal projection patterns are formed. Using zebrafish as a model system, we followed the development of two trigeminal sensory neuron subtypes: one that expresses trpa1b, a nociceptive channel important for sensing environmental chemicals; and a distinct subtype labeled by an islet1 reporter (Isl1SS). We found that Trpa1b and Isl1SS neurons have overall similar axon trajectories but different branching morphologies and distributions of presynaptic sites. Compared with Trpa1b neurons, Isl1SS neurons display reduced branch growth and synaptogenesis at the hindbrain-spinal cord junction. The subtype-specific morphogenesis of Isl1SS neurons depends on the guidance receptor Robo2. robo2 is preferentially expressed in the Isl1SS subset and inhibits branch growth and synaptogenesis. In the absence of Robo2, Isl1SS afferents acquire many of the characteristics of Trpa1b afferents. These results reveal that subtype-specific activity of Robo2 regulates subcircuit morphogenesis in the trigeminal sensory system. PMID:22190641

Synaptic Activity in Serotonergic Neurons Is Required for Air-Puff Stimulated Flight in Drosophila melanogaster

PubMed Central

Sadaf, Sufia; Birman, Serge; Hasan, Gaiti

2012-01-01

Background Flight is an integral component of many complex behavioral patterns in insects. The giant fiber circuit has been well studied in several insects including Drosophila. However, components of the insect flight circuit that respond to an air-puff stimulus and comprise the flight central pattern generator are poorly defined. Aminergic neurons have been implicated in locust, moth and Drosophila flight. Here we have investigated the requirement of neuronal activity in serotonergic neurons, during development and in adults, on air-puff induced flight in Drosophila. Methodology/Principal Findings To target serotonergic neurons specifically, a Drosophila strain that contains regulatory regions from the TRH (Tryptophan Hydroxylase) gene linked to the yeast transcription factor GAL4 was used. By blocking synaptic transmission from serotonergic neurons with a tetanus toxin transgene or by hyperpolarisation with Kir2.1, close to 50% adults became flightless. Temporal expression of a temperature sensitive Dynamin mutant transgene (Shits) suggests that synaptic function in serotonergic neurons is required both during development and in adults. Depletion of IP3R in serotonergic neurons via RNAi did not affect flight. Interestingly, at all stages a partial requirement for synaptic activity in serotonergic neurons was observed. The status of serotonergic neurons was investigated in the central nervous system of larvae and adults expressing tetanus toxin. A small but significant reduction was observed in serotonergic cell number in adult second thoracic segments from flightless tetanus toxin expressing animals. Conclusions These studies show that loss of synaptic activity in serotonergic neurons causes a flight deficit. The temporal focus of the flight deficit is during pupal development and in adults. The cause of the flight deficit is likely to be loss of neurons and reduced synaptic function. Based on the partial phenotypes, serotonergic neurons appear to be modulatory, rather than an intrinsic part of the flight circuit. PMID:23029511

Neuronal replacement therapy: previous achievements and challenges ahead

NASA Astrophysics Data System (ADS)

Grade, Sofia; Götz, Magdalena

2017-10-01

Lifelong neurogenesis and incorporation of newborn neurons into mature neuronal circuits operates in specialized niches of the mammalian brain and serves as role model for neuronal replacement strategies. However, to which extent can the remaining brain parenchyma, which never incorporates new neurons during the adulthood, be as plastic and readily accommodate neurons in networks that suffered neuronal loss due to injury or neurological disease? Which microenvironment is permissive for neuronal replacement and synaptic integration and which cells perform best? Can lost function be restored and how adequate is the participation in the pre-existing circuitry? Could aberrant connections cause malfunction especially in networks dominated by excitatory neurons, such as the cerebral cortex? These questions show how important connectivity and circuitry aspects are for regenerative medicine, which is the focus of this review. We will discuss the impressive advances in neuronal replacement strategies and success from exogenous as well as endogenous cell sources. Both have seen key novel technologies, like the groundbreaking discovery of induced pluripotent stem cells and direct neuronal reprogramming, offering alternatives to the transplantation of fetal neurons, and both herald great expectations. For these to become reality, neuronal circuitry analysis is key now. As our understanding of neuronal circuits increases, neuronal replacement therapy should fulfill those prerequisites in network structure and function, in brain-wide input and output. Now is the time to incorporate neural circuitry research into regenerative medicine if we ever want to truly repair brain injury.

Spectral fingerprints of large-scale neuronal interactions.

PubMed

Siegel, Markus; Donner, Tobias H; Engel, Andreas K

2012-01-11

Cognition results from interactions among functionally specialized but widely distributed brain regions; however, neuroscience has so far largely focused on characterizing the function of individual brain regions and neurons therein. Here we discuss recent studies that have instead investigated the interactions between brain regions during cognitive processes by assessing correlations between neuronal oscillations in different regions of the primate cerebral cortex. These studies have opened a new window onto the large-scale circuit mechanisms underlying sensorimotor decision-making and top-down attention. We propose that frequency-specific neuronal correlations in large-scale cortical networks may be 'fingerprints' of canonical neuronal computations underlying cognitive processes.

A Class of Visual Neurons with Wide-Field Properties Is Required for Local Motion Detection.

PubMed

Fisher, Yvette E; Leong, Jonathan C S; Sporar, Katja; Ketkar, Madhura D; Gohl, Daryl M; Clandinin, Thomas R; Silies, Marion

2015-12-21

Visual motion cues are used by many animals to guide navigation across a wide range of environments. Long-standing theoretical models have made predictions about the computations that compare light signals across space and time to detect motion. Using connectomic and physiological approaches, candidate circuits that can implement various algorithmic steps have been proposed in the Drosophila visual system. These pathways connect photoreceptors, via interneurons in the lamina and the medulla, to direction-selective cells in the lobula and lobula plate. However, the functional architecture of these circuits remains incompletely understood. Here, we use a forward genetic approach to identify the medulla neuron Tm9 as critical for motion-evoked behavioral responses. Using in vivo calcium imaging combined with genetic silencing, we place Tm9 within motion-detecting circuitry. Tm9 receives functional inputs from the lamina neurons L3 and, unexpectedly, L1 and passes information onto the direction-selective T5 neuron. Whereas the morphology of Tm9 suggested that this cell would inform circuits about local points in space, we found that the Tm9 spatial receptive field is large. Thus, this circuit informs elementary motion detectors about a wide region of the visual scene. In addition, Tm9 exhibits sustained responses that provide a tonic signal about incoming light patterns. Silencing Tm9 dramatically reduces the response amplitude of T5 neurons under a broad range of different motion conditions. Thus, our data demonstrate that sustained and wide-field signals are essential for elementary motion processing. Copyright © 2015 Elsevier Ltd. All rights reserved.

Identifying behavioral circuits in Drosophila melanogaster: moving targets in a flying insect.

PubMed

Griffith, Leslie C

2012-08-01

Drosophila melanogaster has historically been the premier model system for understanding the molecular and genetic bases of complex behaviors. In the last decade technical advances, in the form of new genetic tools and electrophysiological and optical methods, have allowed investigators to begin to dissect the neuronal circuits that generate behavior in the adult. The blossoming of circuit analysis in this organism has also reinforced our appreciation of the inadequacy of wiring diagrams for specifying complex behavior. Neuromodulation and neuronal plasticity act to reconfigure circuits on both short and long time scales. These processes act on the connectome, providing context by integrating external and internal cues that are relevant for behavioral choices. New approaches in the fly are providing insight into these basic principles of circuit function. Copyright © 2012 Elsevier Ltd. All rights reserved.

Precise Spatiotemporal Control of Optogenetic Activation Using an Acousto-Optic Device

PubMed Central

Guo, Yanmeng; Song, Peipei; Zhang, Xiaohui; Zeng, Shaoqun; Wang, Zuoren

2011-01-01

Light activation and inactivation of neurons by optogenetic techniques has emerged as an important tool for studying neural circuit function. To achieve a high resolution, new methods are being developed to selectively manipulate the activity of individual neurons. Here, we report that the combination of an acousto-optic device (AOD) and single-photon laser was used to achieve rapid and precise spatiotemporal control of light stimulation at multiple points in a neural circuit with millisecond time resolution. The performance of this system in activating ChIEF expressed on HEK 293 cells as well as cultured neurons was first evaluated, and the laser stimulation patterns were optimized. Next, the spatiotemporally selective manipulation of multiple neurons was achieved in a precise manner. Finally, we demonstrated the versatility of this high-resolution method in dissecting neural circuits both in the mouse cortical slice and the Drosophila brain in vivo. Taken together, our results show that the combination of AOD-assisted laser stimulation and optogenetic tools provides a flexible solution for manipulating neuronal activity at high efficiency and with high temporal precision. PMID:22174813

A new approach to spike sorting for multi-neuronal activities recorded with a tetrode--how ICA can be practical.

PubMed

Takahashi, Susumu; Anzai, Yuichiro; Sakurai, Yoshio

2003-07-01

Multi-neuronal recording with a tetrode is a powerful technique to reveal neuronal interactions in local circuits. However, it is difficult to detect precise spike timings among closely neighboring neurons because the spike waveforms of individual neurons overlap on the electrode when more than two neurons fire simultaneously. In addition, the spike waveforms of single neurons, especially in the presence of complex spikes, are often non-stationary. These problems limit the ability of ordinary spike sorting to sort multi-neuronal activities recorded using tetrodes into their single-neuron components. Though sorting with independent component analysis (ICA) can solve these problems, it has one serious limitation that the number of separated neurons must be less than the number of electrodes. Using a combination of ICA and the efficiency of ordinary spike sorting technique (k-means clustering), we developed an automatic procedure to solve the spike-overlapping and the non-stationarity problems with no limitation on the number of separated neurons. The results for the procedure applied to real multi-neuronal data demonstrated that some outliers which may be assigned to distinct clusters if ordinary spike-sorting methods were used can be identified as overlapping spikes, and that there are functional connections between a putative pyramidal neuron and its putative dendrite. These findings suggest that the combination of ICA and k-means clustering can provide insights into the precise nature of functional circuits among neurons, i.e. cell assemblies.

A Putative Role for Neurogenesis in Neurocomputational Terms: Inferences from a Hippocampal Model

ERIC Educational Resources Information Center

Weisz, Victoria I.; Argibay, Pablo F.

2009-01-01

New neurons are generated daily in the hippocampus during adult life. They are integrated into the existing neuronal circuits according to several factors such as age, physical exercise and hormonal status. At present, the role of these new neurons is debated. Computational simulations of hippocampal function allow the effects of neurogenesis to…

A circuit mechanism for the propagation of waves of muscle contraction in Drosophila

PubMed Central

Fushiki, Akira; Zwart, Maarten F; Kohsaka, Hiroshi; Fetter, Richard D; Cardona, Albert; Nose, Akinao

2016-01-01

Animals move by adaptively coordinating the sequential activation of muscles. The circuit mechanisms underlying coordinated locomotion are poorly understood. Here, we report on a novel circuit for the propagation of waves of muscle contraction, using the peristaltic locomotion of Drosophila larvae as a model system. We found an intersegmental chain of synaptically connected neurons, alternating excitatory and inhibitory, necessary for wave propagation and active in phase with the wave. The excitatory neurons (A27h) are premotor and necessary only for forward locomotion, and are modulated by stretch receptors and descending inputs. The inhibitory neurons (GDL) are necessary for both forward and backward locomotion, suggestive of different yet coupled central pattern generators, and its inhibition is necessary for wave propagation. The circuit structure and functional imaging indicated that the commands to contract one segment promote the relaxation of the next segment, revealing a mechanism for wave propagation in peristaltic locomotion. DOI: http://dx.doi.org/10.7554/eLife.13253.001 PMID:26880545

Nicotine recruits a local glutamatergic circuit to excite septohippocampal GABAergic neurons.

PubMed

Wu, Min; Hajszan, Tibor; Leranth, Csaba; Alreja, Meenakshi

2003-09-01

Tonic impulse flow in the septohippocampal GABAergic pathway is essential for normal cognitive functioning and is sustained, in part, by acetylcholine (ACh) that is released locally via axon collaterals of septohippocampal cholinergic neurons. Septohippocampal cholinergic neurons degenerate in Alzheimer's disease and other neurodegenerative disorders. While the importance of the muscarinic effects of ACh on septohippocampal GABAergic neurons is well recognized, the nicotinic effects of ACh remain unstudied despite the reported benefits of nicotine on cognitive functioning. In the present study, using electrophysiological recordings in a rat brain slice preparation, rapid applications of nicotine excited 90% of retrogradely labelled septohippocampal GABA-type neurons with an EC50 of 17 microm and increased the frequency of spontaneously occurring, impulse-dependent fast GABAergic and glutamatergic synaptic currents via the alpha4beta2-nicotinic receptor. Interestingly, tetrodotoxin blocked all effects of nicotine on septohippocampal GABAergic type neurons, suggesting involvement of indirect mechanisms. We demonstrate that the effects of nicotine on septohippocampal GABA-type neurons involve recruitment of a novel, local glutamatergic circuitry as (i). Group I metabotropic glutamatergic receptor antagonists reduced the effects of nicotine; (ii). the number of nicotine responsive neurons was significantly reduced in recordings from slices that had been trimmed so as to reduce the number of glutamate-containing neurons within the slice preparation; (iii). in light and ultrastructural double immunocytochemical labelling studies vesicular glutamate 2 transporter immunoreactive terminals made synaptic contacts with parvalbumin-immunoreactive septohippocampal GABAergic neurons. The discovery of a local glutamatergic circuit within the septum may provide another avenue for restoring septohippocampal GABAergic functions in neurodegenerative disorders associated with a loss of septohippocampal cholinergic neurons.

Leaky Integrate-and-Fire Neuron Circuit Based on Floating-Gate Integrator

PubMed Central

Kornijcuk, Vladimir; Lim, Hyungkwang; Seok, Jun Yeong; Kim, Guhyun; Kim, Seong Keun; Kim, Inho; Choi, Byung Joon; Jeong, Doo Seok

2016-01-01

The artificial spiking neural network (SNN) is promising and has been brought to the notice of the theoretical neuroscience and neuromorphic engineering research communities. In this light, we propose a new type of artificial spiking neuron based on leaky integrate-and-fire (LIF) behavior. A distinctive feature of the proposed FG-LIF neuron is the use of a floating-gate (FG) integrator rather than a capacitor-based one. The relaxation time of the charge on the FG relies mainly on the tunnel barrier profile, e.g., barrier height and thickness (rather than the area). This opens up the possibility of large-scale integration of neurons. The circuit simulation results offered biologically plausible spiking activity (<100 Hz) with a capacitor of merely 6 fF, which is hosted in an FG metal-oxide-semiconductor field-effect transistor. The FG-LIF neuron also has the advantage of low operation power (<30 pW/spike). Finally, the proposed circuit was subject to possible types of noise, e.g., thermal noise and burst noise. The simulation results indicated remarkable distributional features of interspike intervals that are fitted to Gamma distribution functions, similar to biological neurons in the neocortex. PMID:27242416

Cognitive Consilience: Primate Non-Primary Neuroanatomical Circuits Underlying Cognition

PubMed Central

Solari, Soren Van Hout; Stoner, Rich

2011-01-01

Interactions between the cerebral cortex, thalamus, and basal ganglia form the basis of cognitive information processing in the mammalian brain. Understanding the principles of neuroanatomical organization in these structures is critical to understanding the functions they perform and ultimately how the human brain works. We have manually distilled and synthesized hundreds of primate neuroanatomy facts into a single interactive visualization. The resulting picture represents the fundamental neuroanatomical blueprint upon which cognitive functions must be implemented. Within this framework we hypothesize and detail 7 functional circuits corresponding to psychological perspectives on the brain: consolidated long-term declarative memory, short-term declarative memory, working memory/information processing, behavioral memory selection, behavioral memory output, cognitive control, and cortical information flow regulation. Each circuit is described in terms of distinguishable neuronal groups including the cerebral isocortex (9 pyramidal neuronal groups), parahippocampal gyrus and hippocampus, thalamus (4 neuronal groups), basal ganglia (7 neuronal groups), metencephalon, basal forebrain, and other subcortical nuclei. We focus on neuroanatomy related to primate non-primary cortical systems to elucidate the basis underlying the distinct homotypical cognitive architecture. To display the breadth of this review, we introduce a novel method of integrating and presenting data in multiple independent visualizations: an interactive website (http://www.frontiersin.org/files/cognitiveconsilience/index.html) and standalone iPhone and iPad applications. With these tools we present a unique, annotated view of neuroanatomical consilience (integration of knowledge). PMID:22194717

Spatial gradients and multidimensional dynamics in a neural integrator circuit

PubMed Central

Miri, Andrew; Daie, Kayvon; Arrenberg, Aristides B.; Baier, Herwig; Aksay, Emre; Tank, David W.

2011-01-01

In a neural integrator, the variability and topographical organization of neuronal firing rate persistence can provide information about the circuit’s functional architecture. Here we use optical recording to measure the time constant of decay of persistent firing (“persistence time”) across a population of neurons comprising the larval zebrafish oculomotor velocity-to-position neural integrator. We find extensive persistence time variation (10-fold; coefficients of variation 0.58–1.20) across cells within individual larvae. We also find that the similarity in firing between two neurons decreased as the distance between them increased and that a gradient in persistence time was mapped along the rostrocaudal and dorsoventral axes. This topography is consistent with the emergence of persistence time heterogeneity from a circuit architecture in which nearby neurons are more strongly interconnected than distant ones. Collectively, our results can be accounted for by integrator circuit models characterized by multiple dimensions of slow firing rate dynamics. PMID:21857656

Orientation-Selective Retinal Circuits in Vertebrates

PubMed Central

Antinucci, Paride; Hindges, Robert

2018-01-01

Visual information is already processed in the retina before it is transmitted to higher visual centers in the brain. This includes the extraction of salient features from visual scenes, such as motion directionality or contrast, through neurons belonging to distinct neural circuits. Some retinal neurons are tuned to the orientation of elongated visual stimuli. Such ‘orientation-selective’ neurons are present in the retinae of most, if not all, vertebrate species analyzed to date, with species-specific differences in frequency and degree of tuning. In some cases, orientation-selective neurons have very stereotyped functional and morphological properties suggesting that they represent distinct cell types. In this review, we describe the retinal cell types underlying orientation selectivity found in various vertebrate species, and highlight their commonalities and differences. In addition, we discuss recent studies that revealed the cellular, synaptic and circuit mechanisms at the basis of retinal orientation selectivity. Finally, we outline the significance of these findings in shaping our current understanding of how this fundamental neural computation is implemented in the visual systems of vertebrates. PMID:29467629

Orientation-Selective Retinal Circuits in Vertebrates.

PubMed

Antinucci, Paride; Hindges, Robert

2018-01-01

Visual information is already processed in the retina before it is transmitted to higher visual centers in the brain. This includes the extraction of salient features from visual scenes, such as motion directionality or contrast, through neurons belonging to distinct neural circuits. Some retinal neurons are tuned to the orientation of elongated visual stimuli. Such 'orientation-selective' neurons are present in the retinae of most, if not all, vertebrate species analyzed to date, with species-specific differences in frequency and degree of tuning. In some cases, orientation-selective neurons have very stereotyped functional and morphological properties suggesting that they represent distinct cell types. In this review, we describe the retinal cell types underlying orientation selectivity found in various vertebrate species, and highlight their commonalities and differences. In addition, we discuss recent studies that revealed the cellular, synaptic and circuit mechanisms at the basis of retinal orientation selectivity. Finally, we outline the significance of these findings in shaping our current understanding of how this fundamental neural computation is implemented in the visual systems of vertebrates.

Life and death of neurons in the aging brain

NASA Technical Reports Server (NTRS)

Morrison, J. H.; Hof, P. R.; Bloom, F. E. (Principal Investigator)

1997-01-01

Neurodegenerative disorders are characterized by extensive neuron death that leads to functional decline, but the neurobiological correlates of functional decline in normal aging are less well defined. For decades, it has been a commonly held notion that widespread neuron death in the neocortex and hippocampus is an inevitable concomitant of brain aging, but recent quantitative studies suggest that neuron death is restricted in normal aging and unlikely to account for age-related impairment of neocortical and hippocampal functions. In this article, the qualitative and quantitative differences between aging and Alzheimer's disease with respect to neuron loss are discussed, and age-related changes in functional and biochemical attributes of hippocampal circuits that might mediate functional decline in the absence of neuron death are explored. When these data are viewed comprehensively, it appears that the primary neurobiological substrates for functional impairment in aging differ in important ways from those in neurodegenerative disorders such as Alzheimer's disease.

Advancing multiscale structural mapping of the brain through fluorescence imaging and analysis across length scales

PubMed Central

Hogstrom, L. J.; Guo, S. M.; Murugadoss, K.; Bathe, M.

2016-01-01

Brain function emerges from hierarchical neuronal structure that spans orders of magnitude in length scale, from the nanometre-scale organization of synaptic proteins to the macroscopic wiring of neuronal circuits. Because the synaptic electrochemical signal transmission that drives brain function ultimately relies on the organization of neuronal circuits, understanding brain function requires an understanding of the principles that determine hierarchical neuronal structure in living or intact organisms. Recent advances in fluorescence imaging now enable quantitative characterization of neuronal structure across length scales, ranging from single-molecule localization using super-resolution imaging to whole-brain imaging using light-sheet microscopy on cleared samples. These tools, together with correlative electron microscopy and magnetic resonance imaging at the nanoscopic and macroscopic scales, respectively, now facilitate our ability to probe brain structure across its full range of length scales with cellular and molecular specificity. As these imaging datasets become increasingly accessible to researchers, novel statistical and computational frameworks will play an increasing role in efforts to relate hierarchical brain structure to its function. In this perspective, we discuss several prominent experimental advances that are ushering in a new era of quantitative fluorescence-based imaging in neuroscience along with novel computational and statistical strategies that are helping to distil our understanding of complex brain structure. PMID:26855758

Qualitative-Modeling-Based Silicon Neurons and Their Networks

PubMed Central

Kohno, Takashi; Sekikawa, Munehisa; Li, Jing; Nanami, Takuya; Aihara, Kazuyuki

2016-01-01

The ionic conductance models of neuronal cells can finely reproduce a wide variety of complex neuronal activities. However, the complexity of these models has prompted the development of qualitative neuron models. They are described by differential equations with a reduced number of variables and their low-dimensional polynomials, which retain the core mathematical structures. Such simple models form the foundation of a bottom-up approach in computational and theoretical neuroscience. We proposed a qualitative-modeling-based approach for designing silicon neuron circuits, in which the mathematical structures in the polynomial-based qualitative models are reproduced by differential equations with silicon-native expressions. This approach can realize low-power-consuming circuits that can be configured to realize various classes of neuronal cells. In this article, our qualitative-modeling-based silicon neuron circuits for analog and digital implementations are quickly reviewed. One of our CMOS analog silicon neuron circuits can realize a variety of neuronal activities with a power consumption less than 72 nW. The square-wave bursting mode of this circuit is explained. Another circuit can realize Class I and II neuronal activities with about 3 nW. Our digital silicon neuron circuit can also realize these classes. An auto-associative memory realized on an all-to-all connected network of these silicon neurons is also reviewed, in which the neuron class plays important roles in its performance. PMID:27378842

Synchrony dynamics underlying effective connectivity reconstruction of neuronal circuits

NASA Astrophysics Data System (ADS)

Yu, Haitao; Guo, Xinmeng; Qin, Qing; Deng, Yun; Wang, Jiang; Liu, Jing; Cao, Yibin

2017-04-01

Reconstruction of effective connectivity between neurons is essential for neural systems with function-related significance, characterizing directionally causal influences among neurons. In this work, causal interactions between neurons in spinal dorsal root ganglion, activated by manual acupuncture at Zusanli acupoint of experimental rats, are estimated using Granger causality (GC) method. Different patterns of effective connectivity are obtained for different frequencies and types of acupuncture. Combined with synchrony analysis between neurons, we show a dependence of effective connection on the synchronization dynamics. Based on the experimental findings, a neuronal circuit model with synaptic connections is constructed. The variation of neuronal effective connectivity with respect to its structural connectivity and synchronization dynamics is further explored. Simulation results show that reciprocally causal interactions with statistically significant are formed between well-synchronized neurons. The effective connectivity may be not necessarily equivalent to synaptic connections, but rather depend on the synchrony relationship. Furthermore, transitions of effective interaction between neurons are observed following the synchronization transitions induced by conduction delay and synaptic conductance. These findings are helpful to further investigate the dynamical mechanisms underlying the reconstruction of effective connectivity of neuronal population.

Static and dynamic views of visual cortical organization.

PubMed

Casagrande, Vivien A; Xu, Xiangmin; Sáry, Gyula

2002-01-01

Without the aid of modern techniques Cajal speculated that cells in the visual cortex were connected in circuits. From Cajal's time until fairly recently, the flow of information within the cells and circuits of visual cortex has been described as progressing from input to output, from sensation to action. In this chapter we argue that a paradigm shift in our concept of the visual cortical neuron is under way. The most important change in our view concerns the neuron's functional role. Visual cortical neurons do not have static functional signatures but instead function dynamically depending on the ongoing activity of the networks to which they belong. These networks are not merely top-down or bottom-up unidirectional transmission lines, but rather represent machinery that uses recurrent information and is dynamic and highly adaptable. With the advancement of technology for analyzing the conversations of multiple neurons at many levels in the visual system and higher resolution imaging, we predict that the paradigm shift will progress to the point where neurons are no longer viewed as independent processing units but as members of subsets of networks where their role is mapped in space-time coordinates in relationship to the other neuronal members. This view moves us far from Cajal's original views of the neuron. Nevertheless, we believe that understanding the basic morphology and wiring of networks will continue to contribute to our overall understanding of the visual cortex.

Simulated mossy fiber associated feedforward circuit functioning as a highpass filter.

PubMed

Zalay, Osbert C; Bardakjian, Berj L

2006-01-01

Learning and memory rely on the strict regulation of communication between neurons in the hippocampus. The mossy fiber (MF) pathway connects the dentate gyrus to the auto-associative CA3 network, and the information it carries is controlled by a feedforward circuit combining disynaptic inhibition with monosynaptic excitation. Analysis of the MF associated circuit using a mapped clock oscillator (MCO) model reveals the circuit to be a highpass filter.

The computational worm: spatial orientation and its neuronal basis in C. elegans.

PubMed

Lockery, Shawn R

2011-10-01

Spatial orientation behaviors in animals are fundamental for survival but poorly understood at the neuronal level. The nematode Caenorhabditis elegans orients to a wide range of stimuli and has a numerically small and well-described nervous system making it advantageous for investigating the mechanisms of spatial orientation. Recent work by the C. elegans research community has identified essential computational elements of the neural circuits underlying two orientation strategies that operate in five different sensory modalities. Analysis of these circuits reveals novel motifs including simple circuits for computing temporal derivatives of sensory input and for integrating sensory input with behavioral state to generate adaptive behavior. These motifs constitute hypotheses concerning the identity and functionality of circuits controlling spatial orientation in higher organisms. Copyright © 2011 Elsevier Ltd. All rights reserved.

Sensing of glucose in the brain.

PubMed

Thorens, Bernard

2012-01-01

The brain, and in particular the hypothalamus and brainstem, have been recognized for decades as important centers for the homeostatic control of feeding, energy expenditure, and glucose homeostasis. These structures contain neurons and neuronal circuits that may be directly or indirectly activated or inhibited by glucose, lipids, or amino acids. The detection by neurons of these nutrient cues may become deregulated, and possibly cause metabolic diseases such as obesity and diabetes. Thus, there is a major interest in identifying these neurons, how they respond to nutrients, the neuronal circuits they form, and the physiological function they control. Here I will review some aspects of glucose sensing by the brain. The brain is responsive to both hyperglycemia and hypoglycemia, and the glucose sensing cells involved are distributed in several anatomical sites that are connected to each other. These eventually control the activity of the sympathetic or parasympathetic nervous system, which regulates the function of peripheral organs such as liver, white and brown fat, muscle, and pancreatic islets alpha and beta cells. There is now evidence for an extreme diversity in the sensing mechanisms used, and these will be reviewed.

Functional Maps of Neocortical Local Circuitry

PubMed Central

Thomson, Alex M.; Lamy, Christophe

2007-01-01

This review aims to summarize data obtained with different techniques to provide a functional map of the local circuit connections made by neocortical neurones, a reference for those interested in cortical circuitry and the numerical information required by those wishing to model the circuit. A brief description of the main techniques used to study circuitry is followed by outline descriptions of the major classes of neocortical excitatory and inhibitory neurones and the connections that each layer makes with other cortical and subcortical regions. Maps summarizing the projection patterns of each class of neurone within the local circuit and tables of the properties of these local circuit connections are provided. This review relies primarily on anatomical studies that have identified the classes of neurones and their local and long distance connections and on paired intracellular and whole-cell recordings which have documented the properties of the connections between them. A large number of different types of synaptic connections have been described, but for some there are only a few published examples and for others the details that can only be obtained with paired recordings and dye-filling are lacking. A further complication is provided by the range of species, technical approaches and age groups used in these studies. Wherever possible the range of available data are summarised and compared. To fill some of the more obvious gaps for the less well-documented cases, data obtained with other methods are also summarized. PMID:18982117

Sonic Hedgehog Expression in Corticofugal Projection Neurons Directs Cortical Microcircuit Formation

PubMed Central

Harwell, Corey C.; Parker, Philip R.L.; Gee, Steven M.; Okada, Ami; McConnell, Susan K.; Kreitzer, Anatol C.; Kriegstein, Arnold R.

2012-01-01

SUMMARY The precise connectivity of inputs and outputs is critical for cerebral cortex function; however, the cellular mechanisms that establish these connections are poorly understood. Here, we show that the secreted molecule Sonic Hedgehog (Shh) is involved in synapse formation of a specific cortical circuit. Shh is expressed in layer V corticofugal projection neurons and the Shh receptor, Brother of CDO (Boc), is expressed in local and callosal projection neurons of layer II/III that synapse onto the subcortical projection neurons. Layer V neurons of mice lacking functional Shh exhibit decreased synapses. Conversely, the loss of functional Boc leads to a reduction in the strength of synaptic connections onto layer Vb, but not layer II/III, pyramidal neurons. These results demonstrate that Shh is expressed in postsynaptic target cells while Boc is expressed in a complementary population of presynaptic input neurons, and they function to guide the formation of cortical microcircuitry. PMID:22445340

Control of Excitation/Inhibition Balance in a Hippocampal Circuit by Calcium Sensor Protein Regulation of Presynaptic Calcium Channels.

PubMed

Nanou, Evanthia; Lee, Amy; Catterall, William A

2018-05-02

Activity-dependent regulation controls the balance of synaptic excitation to inhibition in neural circuits, and disruption of this regulation impairs learning and memory and causes many neurological disorders. The molecular mechanisms underlying short-term synaptic plasticity are incompletely understood, and their role in inhibitory synapses remains uncertain. Here we show that regulation of voltage-gated calcium (Ca 2+ ) channel type 2.1 (Ca V 2.1) by neuronal Ca 2+ sensor (CaS) proteins controls synaptic plasticity and excitation/inhibition balance in a hippocampal circuit. Prevention of CaS protein regulation by introducing the IM-AA mutation in Ca V 2.1 channels in male and female mice impairs short-term synaptic facilitation at excitatory synapses of CA3 pyramidal neurons onto parvalbumin (PV)-expressing basket cells. In sharp contrast, the IM-AA mutation abolishes rapid synaptic depression in the inhibitory synapses of PV basket cells onto CA1 pyramidal neurons. These results show that CaS protein regulation of facilitation and inactivation of Ca V 2.1 channels controls the direction of short-term plasticity at these two synapses. Deletion of the CaS protein CaBP1/caldendrin also blocks rapid depression at PV-CA1 synapses, implicating its upregulation of inactivation of Ca V 2.1 channels in control of short-term synaptic plasticity at this inhibitory synapse. Studies of local-circuit function revealed reduced inhibition of CA1 pyramidal neurons by the disynaptic pathway from CA3 pyramidal cells via PV basket cells and greatly increased excitation/inhibition ratio of the direct excitatory input versus indirect inhibitory input from CA3 pyramidal neurons to CA1 pyramidal neurons. This striking defect in local-circuit function may contribute to the dramatic impairment of spatial learning and memory in IM-AA mice. SIGNIFICANCE STATEMENT Many forms of short-term synaptic plasticity in neuronal circuits rely on regulation of presynaptic voltage-gated Ca 2+ (Ca V ) channels. Regulation of Ca V 2.1 channels by neuronal calcium sensor (CaS) proteins controls short-term synaptic plasticity. Here we demonstrate a direct link between regulation of Ca V 2.1 channels and short-term synaptic plasticity in native hippocampal excitatory and inhibitory synapses. We also identify CaBP1/caldendrin as the calcium sensor interacting with Ca V 2.1 channels to mediate rapid synaptic depression in the inhibitory hippocampal synapses of parvalbumin-expressing basket cells to CA1 pyramidal cells. Disruption of this regulation causes altered short-term plasticity and impaired balance of hippocampal excitatory to inhibitory circuits. Copyright © 2018 the authors 0270-6474/18/384430-11$15.00/0.

Fibroblast Growth Factor 8 Deficiency Compromises the Functional Response of the Serotonergic System to Stress

PubMed Central

Brooks, Leah R.; Pals, Heide L.; Enix, Courtney L.; Woolaver, Rachel A.; Paul, Evan D.; Lowry, Christopher A.; Tsai, Pei-San

2014-01-01

Functionally heterogeneous populations of serotonergic neurons, located within the dorsal raphe nucleus (DR), play a role in stress-related behaviors and neuropsychiatric illnesses such as anxiety and depression. Abnormal development of these neurons may permanently alter their structure and connections, making the organism more susceptible to anxiety-related disorders. A factor that critically regulates the development of serotonergic neurons is fibroblast growth factor 8 (Fgf8). In this study, we used acute restraint stress followed by behavioral testing to examine whether Fgf8 signaling during development is important for establishing functional stress- and anxiety-related DR neurocircuits in adulthood. Wild-type and heterozygous male mice globally hypomorphic for Fgf8 were exposed to acute restraint stress and then tested for anxiety-like behavior on the elevated plus-maze. Further, we measured c-Fos immunostaining as a marker of serotonergic neuronal activation and tissue 5-hydroxyindoleacetic acid concentrations as a marker of serotonin functional output. Results showed that Fgf8 hypomorphs exhibited 1) an exaggerated response of DR anxiety-promoting circuits and 2) a blunted response of a DR panic-inhibiting circuit to stress, effects that together were associated with increased baseline anxiety-like behavior. Overall, our results provide a neural substrate upon which Fgf8 deficiency could affect stress response and support the hypothesis that developmental disruptions of serotonergic neurons affect their postnatal functional integrity. PMID:24992493

Fibroblast growth factor 8 deficiency compromises the functional response of the serotonergic system to stress.

PubMed

Brooks, Leah R; Pals, Heide L; Enix, Courtney L; Woolaver, Rachel A; Paul, Evan D; Lowry, Christopher A; Tsai, Pei-San

2014-01-01

Functionally heterogeneous populations of serotonergic neurons, located within the dorsal raphe nucleus (DR), play a role in stress-related behaviors and neuropsychiatric illnesses such as anxiety and depression. Abnormal development of these neurons may permanently alter their structure and connections, making the organism more susceptible to anxiety-related disorders. A factor that critically regulates the development of serotonergic neurons is fibroblast growth factor 8 (Fgf8). In this study, we used acute restraint stress followed by behavioral testing to examine whether Fgf8 signaling during development is important for establishing functional stress- and anxiety-related DR neurocircuits in adulthood. Wild-type and heterozygous male mice globally hypomorphic for Fgf8 were exposed to acute restraint stress and then tested for anxiety-like behavior on the elevated plus-maze. Further, we measured c-Fos immunostaining as a marker of serotonergic neuronal activation and tissue 5-hydroxyindoleacetic acid concentrations as a marker of serotonin functional output. Results showed that Fgf8 hypomorphs exhibited 1) an exaggerated response of DR anxiety-promoting circuits and 2) a blunted response of a DR panic-inhibiting circuit to stress, effects that together were associated with increased baseline anxiety-like behavior. Overall, our results provide a neural substrate upon which Fgf8 deficiency could affect stress response and support the hypothesis that developmental disruptions of serotonergic neurons affect their postnatal functional integrity.

Inhibition of oxidative stress in cholinergic projection neurons fully rescues aging-associated olfactory circuit degeneration in Drosophila

PubMed Central

Loschek, Laura F; La Fortezza, Marco; Friedrich, Anja B; Blais, Catherine-Marie; Üçpunar, Habibe K; Yépez, Vicente A; Lehmann, Martin; Gompel, Nicolas; Gagneur, Julien; Sigrist, Stephan J

2018-01-01

Loss of the sense of smell is among the first signs of natural aging and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Cellular and molecular mechanisms promoting this smell loss are not understood. Here, we show that Drosophila melanogaster also loses olfaction before vision with age. Within the olfactory circuit, cholinergic projection neurons show a reduced odor response accompanied by a defect in axonal integrity and reduction in synaptic marker proteins. Using behavioral functional screening, we pinpoint that expression of the mitochondrial reactive oxygen scavenger SOD2 in cholinergic projection neurons is necessary and sufficient to prevent smell degeneration in aging flies. Together, our data suggest that oxidative stress induced axonal degeneration in a single class of neurons drives the functional decline of an entire neural network and the behavior it controls. Given the important role of the cholinergic system in neurodegeneration, the fly olfactory system could be a useful model for the identification of drug targets. PMID:29345616

Central neural pathways for thermoregulation.

PubMed

Morrison, Shaun F; Nakamura, Kazuhiro

2011-01-01

Central neural circuits orchestrate a homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the functional organization of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for heat loss, the brown adipose tissue, skeletal muscle and heart for thermogenesis and species-dependent mechanisms (sweating, panting and saliva spreading) for evaporative heat loss. These effectors are regulated by parallel but distinct, effector-specific neural pathways that share a common peripheral thermal sensory input. The thermal afferent circuits include cutaneous thermal receptors, spinal dorsal horn neurons and lateral parabrachial nucleus neurons projecting to the preoptic area to influence warm-sensitive, inhibitory output neurons which control thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus neurons controlling cutaneous vasoconstriction.

Tracing neuronal circuits in transgenic animals by transneuronal control of transcription (TRACT)

PubMed Central

Huang, Ting-hao; Niesman, Peter; Arasu, Deepshika; Lee, Donghyung; De La Cruz, Aubrie L; Callejas, Antuca; Hong, Elizabeth J

2017-01-01

Understanding the computations that take place in brain circuits requires identifying how neurons in those circuits are connected to one another. We describe a technique called TRACT (TRAnsneuronal Control of Transcription) based on ligand-induced intramembrane proteolysis to reveal monosynaptic connections arising from genetically labeled neurons of interest. In this strategy, neurons expressing an artificial ligand (‘donor’ neurons) bind to and activate a genetically-engineered artificial receptor on their synaptic partners (‘receiver’ neurons). Upon ligand-receptor binding at synapses the receptor is cleaved in its transmembrane domain and releases a protein fragment that activates transcription in the synaptic partners. Using TRACT in Drosophila we have confirmed the connectivity between olfactory receptor neurons and their postsynaptic targets, and have discovered potential new connections between neurons in the circadian circuit. Our results demonstrate that the TRACT method can be used to investigate the connectivity of neuronal circuits in the brain. PMID:29231171

The neuroendocrine genesis of polycystic ovary syndrome: A role for arcuate nucleus GABA neurons.

PubMed

Moore, Aleisha M; Campbell, Rebecca E

2016-06-01

Polycystic ovary syndrome (PCOS) is a prevalent and distressing endocrine disorder lacking a clearly identified aetiology. Despite its name, PCOS may result from impaired neuronal circuits in the brain that regulate steroid hormone feedback to the hypothalamo-pituitary-gonadal axis. Ovarian function in all mammals is controlled by the gonadotropin-releasing hormone (GnRH) neurons, a small group of neurons that reside in the pre-optic area of the hypothalamus. GnRH neurons drive the secretion of the gonadotropins from the pituitary gland that subsequently control ovarian function, including the production of gonadal steroid hormones. These hormones, in turn, provide important feedback signals to GnRH neurons via a hormone sensitive neuronal network in the brain. In many women with PCOS this feedback pathway is impaired, resulting in the downstream consequences of the syndrome. This review will explore what is currently known from clinical and animal studies about the identity, relative contribution and significance of the individual neuronal components within the GnRH neuronal network that contribute to the pathophysiology of PCOS. We review evidence for the specific neuronal pathways hypothesised to mediate progesterone negative feedback to GnRH neurons, and discuss the potential mechanisms by which androgens may evoke disruptions in these circuits at different developmental time points. Finally, this review discusses data providing compelling support for disordered progesterone-sensitive GABAergic input to GnRH neurons, originating specifically within the arcuate nucleus in prenatal androgen induced forms of PCOS. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cognitive-motor interactions of the basal ganglia in development

PubMed Central

Leisman, Gerry; Braun-Benjamin, Orit; Melillo, Robert

2014-01-01

Neural circuits linking activity in anatomically segregated populations of neurons in subcortical structures and the neocortex throughout the human brain regulate complex behaviors such as walking, talking, language comprehension, and other cognitive functions associated with frontal lobes. The basal ganglia, which regulate motor control, are also crucial elements in the circuits that confer human reasoning and adaptive function. The basal ganglia are key elements in the control of reward-based learning, sequencing, discrete elements that constitute a complete motor act, and cognitive function. Imaging studies of intact human subjects and electrophysiologic and tracer studies of the brains and behavior of other species confirm these findings. We know that the relation between the basal ganglia and the cerebral cortical region allows for connections organized into discrete circuits. Rather than serving as a means for widespread cortical areas to gain access to the motor system, these loops reciprocally interconnect a large and diverse set of cerebral cortical areas with the basal ganglia. Neuronal activity within the basal ganglia associated with motor areas of the cerebral cortex is highly correlated with parameters of movement. Neuronal activity within the basal ganglia and cerebellar loops associated with the prefrontal cortex is related to the aspects of cognitive function. Thus, individual loops appear to be involved in distinct behavioral functions. Damage to the basal ganglia of circuits with motor areas of the cortex leads to motor symptoms, whereas damage to the subcortical components of circuits with non-motor areas of the cortex causes higher-order deficits. In this report, we review some of the anatomic, physiologic, and behavioral findings that have contributed to a reappraisal of function concerning the basal ganglia and cerebellar loops with the cerebral cortex and apply it in clinical applications to attention deficit/hyperactivity disorder (ADHD) with biomechanics and a discussion of retention of primitive reflexes being highly associated with the condition. PMID:24592214

Optimizing the 3D-reconstruction technique for serial block-face scanning electron microscopy.

PubMed

Wernitznig, Stefan; Sele, Mariella; Urschler, Martin; Zankel, Armin; Pölt, Peter; Rind, F Claire; Leitinger, Gerd

2016-05-01

Elucidating the anatomy of neuronal circuits and localizing the synaptic connections between neurons, can give us important insights in how the neuronal circuits work. We are using serial block-face scanning electron microscopy (SBEM) to investigate the anatomy of a collision detection circuit including the Lobula Giant Movement Detector (LGMD) neuron in the locust, Locusta migratoria. For this, thousands of serial electron micrographs are produced that allow us to trace the neuronal branching pattern. The reconstruction of neurons was previously done manually by drawing cell outlines of each cell in each image separately. This approach was very time consuming and troublesome. To make the process more efficient a new interactive software was developed. It uses the contrast between the neuron under investigation and its surrounding for semi-automatic segmentation. For segmentation the user sets starting regions manually and the algorithm automatically selects a volume within the neuron until the edges corresponding to the neuronal outline are reached. Internally the algorithm optimizes a 3D active contour segmentation model formulated as a cost function taking the SEM image edges into account. This reduced the reconstruction time, while staying close to the manual reference segmentation result. Our algorithm is easy to use for a fast segmentation process, unlike previous methods it does not require image training nor an extended computing capacity. Our semi-automatic segmentation algorithm led to a dramatic reduction in processing time for the 3D-reconstruction of identified neurons. Copyright © 2016 Elsevier B.V. All rights reserved.

Probing the function of neuronal populations: combining micromirror-based optogenetic photostimulation with voltage-sensitive dye imaging

PubMed Central

Tsuda, Sachiko; Kee, Michelle Z.L.; Cunha, Catarina; Kim, Jinsook; Yan, Ping; Loew, Leslie M.; Augustine, George J.

2013-01-01

Recent advances in our understanding of brain function have come from using light to either control or image neuronal activity. Here we describe an approach that combines both techniques: a micromirror array is used to photostimulate populations of presynaptic neurons expressing channelrhodopsin-2, while a red-shifted voltage-sensitive dye allows optical detection of resulting postsynaptic activity. Such technology allowed us to control the activity of cerebellar interneurons while simultaneously recording inhibitory responses in multiple Purkinje neurons, their postsynaptic targets. This approach should substantially accelerate our understanding of information processing by populations of neurons within brain circuits. PMID:23254260

A theory of neural dimensionality, dynamics, and measurement

NASA Astrophysics Data System (ADS)

Ganguli, Surya

In many experiments, neuroscientists tightly control behavior, record many trials, and obtain trial-averaged firing rates from hundreds of neurons in circuits containing millions of behaviorally relevant neurons. Dimensionality reduction has often shown that such datasets are strikingly simple; they can be described using a much smaller number of dimensions than the number of recorded neurons, and the resulting projections onto these dimensions yield a remarkably insightful dynamical portrait of circuit computation. This ubiquitous simplicity raises several profound and timely conceptual questions. What is the origin of this simplicity and its implications for the complexity of brain dynamics? Would neuronal datasets become more complex if we recorded more neurons? How and when can we trust dynamical portraits obtained from only hundreds of neurons in circuits containing millions of neurons? We present a theory that answers these questions, and test it using neural data recorded from reaching monkeys. Overall, this theory yields a picture of the neural measurement process as a random projection of neural dynamics, conceptual insights into how we can reliably recover dynamical portraits in such under-sampled measurement regimes, and quantitative guidelines for the design of future experiments. Moreover, it reveals the existence of phase transition boundaries in our ability to successfully decode cognition and behavior as a function of the number of recorded neurons, the complexity of the task, and the smoothness of neural dynamics. membership pending.

POMC Neurons: From Birth to Death

PubMed Central

Toda, Chitoku; Santoro, Anna; Kim, Jung Dae

2017-01-01

The hypothalamus is an evolutionarily conserved brain structure that regulates an organism’s basic functions, such as homeostasis and reproduction. Several hypothalamic nuclei and neuronal circuits have been the focus of many studies to understand their role in regulating these basic functions. Within the hypothalamic neuronal populations, the arcuate melanocortin system plays a major role in controlling homeostatic functions. The arcuate pro-opiomelanocortin (POMC) neurons in particular have been shown to be critical regulators of metabolism and reproduction because of their projections to several brain areas both in and outside of the hypothalamus, such as autonomic regions of the brain stem and spinal cord. Here, we review and discuss the current understanding of POMC neurons from their development and intracellular regulators to their physiological functions and pathological dysregulation. PMID:28192062

Signals and circuits in the purkinje neuron.

PubMed

Abrams, Zéev R; Zhang, Xiang

2011-01-01

Purkinje neurons (PN) in the cerebellum have over 100,000 inputs organized in an orthogonal geometry, and a single output channel. As the sole output of the cerebellar cortex layer, their complex firing pattern has been associated with motor control and learning. As such they have been extensively modeled and measured using tools ranging from electrophysiology and neuroanatomy, to dynamic systems and artificial intelligence methods. However, there is an alternative approach to analyze and describe the neuronal output of these cells using concepts from electrical engineering, particularly signal processing and digital/analog circuits. By viewing the PN as an unknown circuit to be reverse-engineered, we can use the tools that provide the foundations of today's integrated circuits and communication systems to analyze the Purkinje system at the circuit level. We use Fourier transforms to analyze and isolate the inherent frequency modes in the PN and define three unique frequency ranges associated with the cells' output. Comparing the PN to a signal generator that can be externally modulated adds an entire level of complexity to the functional role of these neurons both in terms of data analysis and information processing, relying on Fourier analysis methods in place of statistical ones. We also re-describe some of the recent literature in the field, using the nomenclature of signal processing. Furthermore, by comparing the experimental data of the past decade with basic electronic circuitry, we can resolve the outstanding controversy in the field, by recognizing that the PN can act as a multivibrator circuit.

Layer-specific excitation/inhibition balances during neuronal synchronization in the visual cortex.

PubMed

Adesnik, Hillel

2018-05-01

Understanding the balance between synaptic excitation and inhibition in cortical circuits in the brain, and how this contributes to cortical rhythms, is fundamental to explaining information processing in the cortex. This study used cortical layer-specific optogenetic activation in mouse cortex to show that excitatory neurons in any cortical layer can drive powerful gamma rhythms, while inhibition balances excitation. The net impact of this is to keep activity within each layer in check, but simultaneously to promote the propagation of activity to downstream layers. The data show that rhythm-generating circuits exist in all principle layers of the cortex, and provide layer-specific balances of excitation and inhibition that affect the flow of information across the layers. Rhythmic activity can synchronize neural ensembles within and across cortical layers. While gamma band rhythmicity has been observed in all layers, the laminar sources and functional impacts of neuronal synchronization in the cortex remain incompletely understood. Here, layer-specific optogenetic stimulation demonstrates that populations of excitatory neurons in any cortical layer of the mouse's primary visual cortex are sufficient to powerfully entrain neuronal oscillations in the gamma band. Within each layer, inhibition balances excitation and keeps activity in check. Across layers, translaminar output overcomes inhibition and drives downstream firing. These data establish that rhythm-generating circuits exist in all principle layers of the cortex, but provide layer-specific balances of excitation and inhibition that may dynamically shape the flow of information through cortical circuits. These data might help explain how excitation/inhibition (E/I) balances across cortical layers shape information processing, and shed light on the diverse nature and functional impacts of cortical gamma rhythms. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

ENCODING OF TEMPORAL FEATURES OF AUDITORY STIMULI IN THE MEDIAL NUCLEUS OF THE TRAPEZOID BODY AND SUPERIOR PARAOLIVARY NUCLEUS OF THE RAT

PubMed Central

Kadner, Alexander; Berrebi, Albert S.

2008-01-01

Neurons in the superior paraolivary nucleus (SPON) respond to the offset of pure tones with a brief burst of spikes. Medial nucleus of the trapezoid body (MNTB) neurons, which inhibit the SPON, produce a sustained pure tone response followed by an offset response characterized by a period of suppressed spontaneous activity. This MNTB offset response is duration dependent and critical to the formation of SPON offset spikes (Kadner et al., 2006; Kulesza, Jr. et al., 2007). Here we examine the temporal resolution of the MNTB/SPON circuit by assessing its capability to i) detect gaps in tones, and ii) synchronize to sinusoidally amplitude modulated (SAM) tones. Gap detection was tested by presenting two identical pure tone markers interrupted by gaps ranging from 0–25 ms duration. SPON neurons responded to the offset of the leading marker even when the two markers were separated only by their ramps (i.e., a 0 ms gap); longer gap durations elicited progressively larger responses. MNTB neurons produced an offset response at gap durations of 2 ms or longer, with a subset of neurons responding to 0 ms gaps. SAM tone stimuli used the unit’s characteristic frequency as a carrier, and modulation rates ranged from 40–1160 Hz. MNTB neurons synchronized to modulation rates up to ~1 KHz, whereas spiking of SPON neurons decreased sharply at modulation rates ≥ 400 Hz. Modulation transfer functions based on spike count were all-pass for MNTB neurons and low-pass for SPON neurons; the modulation transfer functions based on vector strength were low-pass for both nuclei, with a steeper cut-off for SPON neurons. Thus, the MNTB/SPON circuit encodes episodes of low stimulus energy, such as gaps in pure tones and troughs in amplitude modulated tones. The output of this circuit consists of brief SPON spiking episodes; their potential effects on the auditory midbrain and forebrain are discussed. PMID:18155850

Activity of the C. elegans egg-laying behavior circuit is controlled by competing activation and feedback inhibition

PubMed Central

Collins, Kevin M; Bode, Addys; Fernandez, Robert W; Tanis, Jessica E; Brewer, Jacob C; Creamer, Matthew S; Koelle, Michael R

2016-01-01

Like many behaviors, Caenorhabditis elegans egg laying alternates between inactive and active states. To understand how the underlying neural circuit turns the behavior on and off, we optically recorded circuit activity in behaving animals while manipulating circuit function using mutations, optogenetics, and drugs. In the active state, the circuit shows rhythmic activity phased with the body bends of locomotion. The serotonergic HSN command neurons initiate the active state, but accumulation of unlaid eggs also promotes the active state independent of the HSNs. The cholinergic VC motor neurons slow locomotion during egg-laying muscle contraction and egg release. The uv1 neuroendocrine cells mechanically sense passage of eggs through the vulva and release tyramine to inhibit egg laying, in part via the LGC-55 tyramine-gated Cl- channel on the HSNs. Our results identify discrete signals that entrain or detach the circuit from the locomotion central pattern generator to produce active and inactive states. DOI: http://dx.doi.org/10.7554/eLife.21126.001 PMID:27849154

Graph Theoretic and Motif Analyses of the Hippocampal Neuron Type Potential Connectome.

PubMed

Rees, Christopher L; Wheeler, Diek W; Hamilton, David J; White, Charise M; Komendantov, Alexander O; Ascoli, Giorgio A

2016-01-01

We computed the potential connectivity map of all known neuron types in the rodent hippocampal formation by supplementing scantly available synaptic data with spatial distributions of axons and dendrites from the open-access knowledge base Hippocampome.org. The network that results from this endeavor, the broadest and most complete for a mammalian cortical region at the neuron-type level to date, contains more than 3200 connections among 122 neuron types across six subregions. Analyses of these data using graph theory metrics unveil the fundamental architectural principles of the hippocampal circuit. Globally, we identify a highly specialized topology minimizing communication cost; a modular structure underscoring the prominence of the trisynaptic loop; a core set of neuron types serving as information-processing hubs as well as a distinct group of particular antihub neurons; a nested, two-tier rich club managing much of the network traffic; and an innate resilience to random perturbations. At the local level, we uncover the basic building blocks, or connectivity patterns, that combine to produce complex global functionality, and we benchmark their utilization in the circuit relative to random networks. Taken together, these results provide a comprehensive connectivity profile of the hippocampus, yielding novel insights on its functional operations at the computationally crucial level of neuron types.

Network interactions within the canine intrinsic cardiac nervous system: implications for reflex control of regional cardiac function

PubMed Central

Beaumont, Eric; Salavatian, Siamak; Southerland, E Marie; Vinet, Alain; Jacquemet, Vincent; Armour, J Andrew; Ardell, Jeffrey L

2013-01-01

The aims of the study were to determine how aggregates of intrinsic cardiac (IC) neurons transduce the cardiovascular milieu versus responding to changes in central neuronal drive and to determine IC network interactions subsequent to induced neural imbalances in the genesis of atrial fibrillation (AF). Activity from multiple IC neurons in the right atrial ganglionated plexus was recorded in eight anaesthetized canines using a 16-channel linear microelectrode array. Induced changes in IC neuronal activity were evaluated in response to: (1) focal cardiac mechanical distortion; (2) electrical activation of cervical vagi or stellate ganglia; (3) occlusion of the inferior vena cava or thoracic aorta; (4) transient ventricular ischaemia, and (5) neurally induced AF. Low level activity (ranging from 0 to 2.7 Hz) generated by 92 neurons was identified in basal states, activities that displayed functional interconnectivity. The majority (56%) of IC neurons so identified received indirect central inputs (vagus alone: 25%; stellate ganglion alone: 27%; both: 48%). Fifty per cent transduced the cardiac milieu responding to multimodal stressors applied to the great vessels or heart. Fifty per cent of IC neurons exhibited cardiac cycle periodicity, with activity occurring primarily in late diastole into isovolumetric contraction. Cardiac-related activity in IC neurons was primarily related to direct cardiac mechano-sensory inputs and indirect autonomic efferent inputs. In response to mediastinal nerve stimulation, most IC neurons became excessively activated; such network behaviour preceded and persisted throughout AF. It was concluded that stochastic interactions occur among IC local circuit neuronal populations in the control of regional cardiac function. Modulation of IC local circuit neuronal recruitment may represent a novel approach for the treatment of cardiac disease, including atrial arrhythmias. PMID:23818689

Towards circuit optogenetics.

PubMed

Chen, I-Wen; Papagiakoumou, Eirini; Emiliani, Valentina

2018-06-01

Optogenetics neuronal targeting combined with single-photon wide-field illumination has already proved its enormous potential in neuroscience, enabling the optical control of entire neuronal networks and disentangling their role in the control of specific behaviors. However, establishing how a single or a sub-set of neurons controls a specific behavior, or how functionally identical neurons are connected in a particular task, or yet how behaviors can be modified in real-time by the complex wiring diagram of neuronal connections requires more sophisticated approaches enabling to drive neuronal circuits activity with single-cell precision and millisecond temporal resolution. This has motivated on one side the development of flexible optical methods for two-photon (2P) optogenetic activation using either, or a hybrid of two approaches: scanning and parallel illumination. On the other side, it has stimulated the engineering of new opsins with modified spectral characteristics, channel kinetics and spatial distribution of expression, offering the necessary flexibility of choosing the appropriate opsin for each application. The need for optical manipulation of multiple targets with millisecond temporal resolution has imposed three-dimension (3D) parallel holographic illumination as the technique of choice for optical control of neuronal circuits organized in 3D. Today 3D parallel illumination exists in several complementary variants, each with a different degree of simplicity, light uniformity, temporal precision and axial resolution. In parallel, the possibility to reach hundreds of targets in 3D volumes has prompted the development of low-repetition rate amplified laser sources enabling high peak power, while keeping low average power for stimulating each cell. All together those progresses open the way for a precise optical manipulation of neuronal circuits with unprecedented precision and flexibility. Copyright © 2018 Elsevier Ltd. All rights reserved.

Cell type-specific long-range connections of basal forebrain circuit.

PubMed

Do, Johnny Phong; Xu, Min; Lee, Seung-Hee; Chang, Wei-Cheng; Zhang, Siyu; Chung, Shinjae; Yung, Tyler J; Fan, Jiang Lan; Miyamichi, Kazunari; Luo, Liqun; Dan, Yang

2016-09-19

The basal forebrain (BF) plays key roles in multiple brain functions, including sleep-wake regulation, attention, and learning/memory, but the long-range connections mediating these functions remain poorly characterized. Here we performed whole-brain mapping of both inputs and outputs of four BF cell types - cholinergic, glutamatergic, and parvalbumin-positive (PV+) and somatostatin-positive (SOM+) GABAergic neurons - in the mouse brain. Using rabies virus -mediated monosynaptic retrograde tracing to label the inputs and adeno-associated virus to trace axonal projections, we identified numerous brain areas connected to the BF. The inputs to different cell types were qualitatively similar, but the output projections showed marked differences. The connections to glutamatergic and SOM+ neurons were strongly reciprocal, while those to cholinergic and PV+ neurons were more unidirectional. These results reveal the long-range wiring diagram of the BF circuit with highly convergent inputs and divergent outputs and point to both functional commonality and specialization of different BF cell types.

Cellular resolution circuit mapping with temporal-focused excitation of soma-targeted channelrhodopsin

PubMed Central

Baker, Christopher A; Elyada, Yishai M; Parra, Andres; Bolton, M McLean

2016-01-01

We describe refinements in optogenetic methods for circuit mapping that enable measurements of functional synaptic connectivity with single-neuron resolution. By expanding a two-photon beam in the imaging plane using the temporal focusing method and restricting channelrhodopsin to the soma and proximal dendrites, we are able to reliably evoke action potentials in individual neurons, verify spike generation with GCaMP6s, and determine the presence or absence of synaptic connections with patch-clamp electrophysiological recording. DOI: http://dx.doi.org/10.7554/eLife.14193.001 PMID:27525487

GaAs Optoelectronic Integrated-Circuit Neurons

NASA Technical Reports Server (NTRS)

Lin, Steven H.; Kim, Jae H.; Psaltis, Demetri

1992-01-01

Monolithic GaAs optoelectronic integrated circuits developed for use as artificial neurons. Neural-network computer contains planar arrays of optoelectronic neurons, and variable synaptic connections between neurons effected by diffraction of light from volume hologram in photorefractive material. Basic principles of neural-network computers explained more fully in "Optoelectronic Integrated Circuits For Neural Networks" (NPO-17652). In present circuits, devices replaced by metal/semiconductor field effect transistors (MESFET's), which consume less power.

Cell diversity and network dynamics in photosensitive human brain organoids

PubMed Central

Quadrato, Giorgia; Nguyen, Tuan; Macosko, Evan Z.; Sherwood, John L.; Yang, Sung Min; Berger, Daniel; Maria, Natalie; Scholvin, Jorg; Goldman, Melissa; Kinney, Justin; Boyden, Edward S.; Lichtman, Jeff; Williams, Ziv M.; McCarroll, Steven A.; Arlotta, Paola

2017-01-01

In vitro models of the developing brain such as 3D brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, it remains undefined what cells are generated within organoids and to what extent they recapitulate the regional complexity, cellular diversity, and circuit functionality of the brain. Here, we analyzed gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (over 9 months) enabling unprecedented levels of maturity including the formation of dendritic spines and of spontaneously-active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photoreceptor-like cells, which may offer ways to probe the functionality of human neuronal circuits using physiological sensory stimuli. PMID:28445462

Cell diversity and network dynamics in photosensitive human brain organoids.

PubMed

Quadrato, Giorgia; Nguyen, Tuan; Macosko, Evan Z; Sherwood, John L; Min Yang, Sung; Berger, Daniel R; Maria, Natalie; Scholvin, Jorg; Goldman, Melissa; Kinney, Justin P; Boyden, Edward S; Lichtman, Jeff W; Williams, Ziv M; McCarroll, Steven A; Arlotta, Paola

2017-05-04

In vitro models of the developing brain such as three-dimensional brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, the cells generated within organoids and the extent to which they recapitulate the regional complexity, cellular diversity and circuit functionality of the brain remain undefined. Here we analyse gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (more than 9 months), allowing for the establishment of relatively mature features, including the formation of dendritic spines and spontaneously active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photosensitive cells, which may offer a way to probe the functionality of human neuronal circuits using physiological sensory stimuli.

Dopamine prediction errors in reward learning and addiction: from theory to neural circuitry

PubMed Central

Keiflin, Ronald; Janak, Patricia H.

2015-01-01

Summary Midbrain dopamine (DA) neurons are proposed to signal reward prediction error (RPE), a fundamental parameter in associative learning models. This RPE hypothesis provides a compelling theoretical framework for understanding DA function in reward learning and addiction. New studies support a causal role for DA-mediated RPE activity in promoting learning about natural reward; however, this question has not been explicitly tested in the context of drug addiction. In this review, we integrate theoretical models with experimental findings on the activity of DA systems, and on the causal role of specific neuronal projections and cell types, to provide a circuit-based framework for probing DA-RPE function in addiction. By examining error-encoding DA neurons in the neural network in which they are embedded, hypotheses regarding circuit-level adaptations that possibly contribute to pathological error-signaling and addiction can be formulated and tested. PMID:26494275

Ion channels to inactivate neurons in Drosophila.

PubMed

Hodge, James J L

2009-01-01

Ion channels are the determinants of excitability; therefore, manipulation of their levels and properties provides an opportunity for the investigator to modulate neuronal and circuit function. There are a number of ways to suppress electrical activity in Drosophila neurons, for instance, over-expression of potassium channels (i.e. Shaker Kv1, Shaw Kv3, Kir2.1 and DORK) that are open at resting membrane potential. This will result in increased potassium efflux and membrane hyperpolarisation setting resting membrane potential below the threshold required to fire action potentials. Alternatively over-expression of other channels, pumps or co-transporters that result in a hyperpolarised membrane potential will also prevent firing. Lastly, neurons can be inactivated by, disrupting or reducing the level of functional voltage-gated sodium (Nav1 paralytic) or calcium (Cav2 cacophony) channels that mediate the depolarisation phase of action potentials. Similarly, strategies involving the opposite channel manipulation should allow net depolarisation and hyperexcitation in a given neuron. These changes in ion channel expression can be brought about by the versatile transgenic (i.e. Gal4/UAS based) systems available in Drosophila allowing fine temporal and spatial control of (channel) transgene expression. These systems are making it possible to electrically inactivate (or hyperexcite) any neuron or neural circuit in the fly brain, and much like an exquisite lesion experiment, potentially elucidate whatever interesting behaviour or phenotype each network mediates. These techniques are now being used in Drosophila to reprogram electrical activity of well-defined circuits and bring about robust and easily quantifiable changes in behaviour, allowing different models and hypotheses to be rapidly tested.

Plasticity of vagal brainstem circuits in the control of gastric function

PubMed Central

Browning, Kirsteen N.; Travagli, R. Alberto

2010-01-01

Background Sensory information from the viscera, including the gastrointestinal (GI) tract, is transmitted through the afferent vagus via a glutamatergic synapse to neurons of the nucleus tractus solitarius (NTS), which integrate this sensory information to regulate autonomic functions and homeostasis. The integrated response is conveyed to, amongst other nuclei, the preganglionic neurons of the dorsal motor nucleus of the vagus (DMV) using mainly GABA, glutamate and catecholamines as neurotransmitters. Despite being modulated by almost all the neurotransmitters tested so far, the glutamatergic synapse between NTS and DMV does not appear to be tonically active in the control of gastric motility and tone. Conversely, tonic inhibitory GABAergic neurotransmission from the NTS to the DMV appears critical in setting gastric tone and motility, yet, under basal conditions, this synapse appears resistant to modulation. Purpose Here, we review the available evidence suggesting that vagal efferent output to the GI tract is regulated, perhaps even controlled, in an “on-demand” and efficient manner in response to ever-changing homeostatic conditions. The focus of this review is on the plasticity induced by variations in the levels of second messengers in the brainstem neurons that form vago-vagal reflex circuits. Emphasis is placed upon the modulation of GABAergic transmission to DMV neurons and the modulation of afferent input from the GI tract by neurohormones/neurotransmitters and macronutrients. Derangement of this “on-demand” organization of brainstem vagal circuits may be one of the factors underlying the pathophysiological changes observed in functional dyspepsia or hyperglycemic gastroparesis. PMID:20804520

Assimilation of Biophysical Neuronal Dynamics in Neuromorphic VLSI.

PubMed

Wang, Jun; Breen, Daniel; Akinin, Abraham; Broccard, Frederic; Abarbanel, Henry D I; Cauwenberghs, Gert

2017-12-01

Representing the biophysics of neuronal dynamics and behavior offers a principled analysis-by-synthesis approach toward understanding mechanisms of nervous system functions. We report on a set of procedures assimilating and emulating neurobiological data on a neuromorphic very large scale integrated (VLSI) circuit. The analog VLSI chip, NeuroDyn, features 384 digitally programmable parameters specifying for 4 generalized Hodgkin-Huxley neurons coupled through 12 conductance-based chemical synapses. The parameters also describe reversal potentials, maximal conductances, and spline regressed kinetic functions for ion channel gating variables. In one set of experiments, we assimilated membrane potential recorded from one of the neurons on the chip to the model structure upon which NeuroDyn was designed using the known current input sequence. We arrived at the programmed parameters except for model errors due to analog imperfections in the chip fabrication. In a related set of experiments, we replicated songbird individual neuron dynamics on NeuroDyn by estimating and configuring parameters extracted using data assimilation from intracellular neural recordings. Faithful emulation of detailed biophysical neural dynamics will enable the use of NeuroDyn as a tool to probe electrical and molecular properties of functional neural circuits. Neuroscience applications include studying the relationship between molecular properties of neurons and the emergence of different spike patterns or different brain behaviors. Clinical applications include studying and predicting effects of neuromodulators or neurodegenerative diseases on ion channel kinetics.

Energy-efficient neuron, synapse and STDP integrated circuits.

PubMed

Cruz-Albrecht, Jose M; Yung, Michael W; Srinivasa, Narayan

2012-06-01

Ultra-low energy biologically-inspired neuron and synapse integrated circuits are presented. The synapse includes a spike timing dependent plasticity (STDP) learning rule circuit. These circuits have been designed, fabricated and tested using a 90 nm CMOS process. Experimental measurements demonstrate proper operation. The neuron and the synapse with STDP circuits have an energy consumption of around 0.4 pJ per spike and synaptic operation respectively.

The Drosophila TRPA1 Channel and Neuronal Circuits Controlling Rhythmic Behaviours and Sleep in Response to Environmental Temperature.

PubMed

Roessingh, Sanne; Stanewsky, Ralf

2017-10-03

trpA1 encodes a thermosensitive transient receptor potential channel (TRP channel) that functions in selection of preferred temperatures and noxious heat avoidance. In this review, we discuss the evidence for a role of TRPA1 in the control of rhythmic behaviours in Drosophila melanogaster . Activity levels during the afternoon and rhythmic temperature preference are both regulated by TRPA1. In contrast, TRPA1 is dispensable for temperature synchronisation of circadian clocks. We discuss the neuronal basis of TRPA1-mediated temperature effects on rhythmic behaviours, and conclude that they are mediated by partly overlapping but distinct neuronal circuits. We have previously shown that TRPA1 is required to maintain siesta sleep under warm temperature cycles. Here, we present new data investigating the neuronal circuit responsible for this regulation. First, we discuss the difficulties that remain in identifying the responsible neurons. Second, we discuss the role of clock neurons (s-LNv/DN1 network) in temperature-driven regulation of siesta sleep, and highlight the role of TRPA1 therein. Finally, we discuss the sexual dimorphic nature of siesta sleep and propose that the s-LNv/DN1 clock network could play a role in the integration of environmental information, mating status and other internal drives, to appropriately drive adaptive sleep/wake behaviour.

Command and Compensation in a Neuromodulatory Decision Network

PubMed Central

Luan, Haojiang; Diao, Fengqiu; Peabody, Nathan C.; White, Benjamin H.

2012-01-01

The neural circuits that mediate behavioral choices must not only weigh internal demands and environmental circumstances, but also select and implement specific actions, including associated visceral or neuroendocrine functions. Coordinating these multiple processes suggests considerable complexity. As a consequence, even circuits that support simple behavioral decisions remain poorly understood. Here we show that the environmentally-sensitive wing expansion decision of adult fruit flies is coordinated by a single pair of neuromodulatory neurons with command-like function. Targeted suppression of these neurons using the Split Gal4 system abrogates the fly's ability to expand its wings in the face of environmental challenges, while stimulating them forces expansion by coordinately activating both motor and neuroendocrine outputs. The arbitration and implementation of the wing expansion decision by this neuronal pair may illustrate a general strategy by which neuromodulatory neurons orchestrate behavior. Interestingly, the decision network shows a behavioral plasticity that is unmasked under conducive environmental conditions in flies lacking the function of the command-like neuromodulatory neurons. Such flies can often expand their wings using a motor program distinct from that of wildtype animals and controls. This compensatory program may be the vestige of an ancestral, environmentally-insensitive program used for wing expansion that existed prior to the evolution of the environmentally-adaptive program currently used by Drosophila and other cyclorrhaphan flies. PMID:22262886

Fluorescence lifetime images of different green fluorescent proteins in fly brain

NASA Astrophysics Data System (ADS)

Lai, Sih-Yu; Lin, Y. Y.; Chiang, A. S.; Huang, Y. C.

2009-02-01

The mechanisms of learning and memory are the most important functions in an animal brain. Investigating neuron circuits and network maps in a brain is the first step toward understanding memory and learning behavior. Since Drosophila brain is the major model for understanding brain functions, we measure the florescence lifetimes of different GFP-based reporters expressed in a fly brain. In this work, two Gal4 drivers, OK 107 and MZ 19 were used. Intracellular calcium ([Ca2+]) concentration is an importation indicator of neuronal activity. Therefore, several groups have developed GFP-based calcium sensors, among which G-CaMP is the most popular and reliable. The fluorescence intensity of G-CaMP will increase when it binds to calcium ion; however, individual variation from different animals prevents quantitative research. In this work, we found that the florescence lifetime of G-CaMP will shrink from 1.8 ns to 1.0 ns when binding to Ca2+. This finding can potentially help us to understand the neuron circuits by fluorescence lifetime imaging microscopy (FLIM). Channelrhodopsin-2 (ChR2) is a light-activated ion-channel protein on a neuron cell membrane. In this work, we express ChR2 and G-CaMP in a fly brain. Using a pulsed 470-nm laser to activate the neurons, we can also record the fluorescence lifetime changes in the structure. Hence, we can trace and manipulate a specific circuit in this animal. This method provides more flexibility in brain research.

Engineering-Aligned 3D Neural Circuit in Microfluidic Device.

PubMed

Bang, Seokyoung; Na, Sangcheol; Jang, Jae Myung; Kim, Jinhyun; Jeon, Noo Li

2016-01-07

The brain is one of the most important and complex organs in the human body. Although various neural network models have been proposed for in vitro 3D neuronal networks, it has been difficult to mimic functional and structural complexity of the in vitro neural circuit. Here, a microfluidic model of a simplified 3D neural circuit is reported. First, the microfluidic device is filled with Matrigel and continuous flow is delivered across the device during gelation. The fluidic flow aligns the extracellular matrix (ECM) components along the flow direction. Following the alignment of ECM fibers, neurites of primary rat cortical neurons are grown into the Matrigel at the average speed of 250 μm d(-1) and form axon bundles approximately 1500 μm in length at 6 days in vitro (DIV). Additionally, neural networks are developed from presynaptic to postsynaptic neurons at 14 DIV. The establishment of aligned 3D neural circuits is confirmed with the immunostaining of PSD-95 and synaptophysin and the observation of calcium signal transmission. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Neurexin dysfunction in adult neurons results in autistic-like behavior in mice.

PubMed

Rabaneda, Luis G; Robles-Lanuza, Estefanía; Nieto-González, José Luis; Scholl, Francisco G

2014-07-24

Autism spectrum disorders (ASDs) comprise a group of clinical phenotypes characterized by repetitive behavior and social and communication deficits. Autism is generally viewed as a neurodevelopmental disorder where insults during embryonic or early postnatal periods result in aberrant wiring and function of neuronal circuits. Neurexins are synaptic proteins associated with autism. Here, we generated transgenic βNrx1ΔC mice in which neurexin function is selectively impaired during late postnatal stages. Whole-cell recordings in cortical neurons show an impairment of glutamatergic synaptic transmission in the βNrx1ΔC mice. Importantly, mutant mice exhibit autism-related symptoms, such as increased self-grooming, deficits in social interactions, and altered interaction for nonsocial olfactory cues. The autistic-like phenotype of βNrx1ΔC mice can be reversed after removing the mutant protein in aged animals. The defects resulting from disruption of neurexin function after the completion of embryonic and early postnatal development suggest that functional impairment of mature circuits can trigger autism-related phenotypes. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Developmental Connectivity and Molecular Phenotypes of Unique Cortical Projection Neurons that Express a Synapse-Associated Receptor Tyrosine Kinase.

PubMed

Kast, Ryan J; Wu, Hsiao-Huei; Levitt, Pat

2017-11-28

The complex circuitry and cell-type diversity of the cerebral cortex are required for its high-level functions. The mechanisms underlying the diversification of cortical neurons during prenatal development have received substantial attention, but understanding of neuronal heterogeneity is more limited during later periods of cortical circuit maturation. To address this knowledge gap, connectivity analysis and molecular phenotyping of cortical neuron subtypes that express the developing synapse-enriched MET receptor tyrosine kinase were performed. Experiments used a MetGFP transgenic mouse line, combined with coexpression analysis of class-specific molecular markers and retrograde connectivity mapping. The results reveal that MET is expressed by a minor subset of subcerebral and a larger number of intratelencephalic projection neurons. Remarkably, MET is excluded from most layer 6 corticothalamic neurons. These findings are particularly relevant for understanding the maturation of discrete cortical circuits, given converging evidence that MET influences dendritic elaboration and glutamatergic synapse maturation. The data suggest that classically defined cortical projection classes can be further subdivided based on molecular characteristics that likely influence synaptic maturation and circuit wiring. Additionally, given that MET is classified as a high confidence autism risk gene, the data suggest that projection neuron subpopulations may be differentially vulnerable to disorder-associated genetic variation. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons.

PubMed

Prouty, Eric W; Chandler, Daniel J; Waterhouse, Barry D

2017-11-15

Serotonin (5-HT)-containing neurons in the dorsal raphe (DR) nucleus project throughout the forebrain and are implicated in many physiological processes and neuropsychiatric disorders. Diversity among these neurons has been characterized in terms of their neurochemistry and anatomical organization, but a clear sense of whether these attributes align with specific brain functions or terminal fields is lacking. DR 5-HT neurons can co-express additional neuroactive substances, increasing the potential for individualized regulation of target circuits. The goal of this study was to link DR neurons to a specific functional role by characterizing cells according to both their neurotransmitter expression and efferent connectivity; specifically, cells projecting to the medial prefrontal cortex (mPFC), a region implicated in cognition, emotion, and responses to stress. Following retrograde tracer injection, brainstem sections from Sprague-Dawley rats were immunohistochemically stained for markers of serotonin, glutamate, GABA, and nitric oxide (NO). 98% of the mPFC-projecting serotonergic neurons co-expressed the marker for glutamate, while the markers for NO and GABA were observed in 60% and less than 1% of those neurons, respectively. To identify potential target-specific differences in co-transmitter expression, we also characterized DR neurons projecting to a visual sensory structure, the lateral geniculate nucleus (LGN). The proportion of serotonergic neurons co-expressing NO was greater amongst cells targeting the mPFC vs LGN (60% vs 22%). The established role of 5-HT in affective disorders and the emerging role of NO in stress signaling suggest that the impact of 5-HT/NO co-localization in DR neurons that regulate mPFC circuit function may be clinically relevant. Copyright © 2017 Elsevier B.V. All rights reserved.

Connexin-Mediated Functional and Metabolic Coupling Between Astrocytes and Neurons.

PubMed

Mayorquin, Lady C; Rodriguez, Andrea V; Sutachan, Jhon-Jairo; Albarracín, Sonia L

2018-01-01

The central nervous system (CNS) requires sophisticated regulation of neuronal activity. This modulation is partly accomplished by non-neuronal cells, characterized by the presence of transmembrane gap junctions (GJs) and hemichannels (HCs). This allows small molecule diffusion to guarantee neuronal synaptic activity and plasticity. Astrocytes are metabolically and functionally coupled to neurons by the uptake, binding and recycling of neurotransmitters. In addition, astrocytes release metabolites, such as glutamate, glutamine, D-serine, adenosine triphosphate (ATP) and lactate, regulating synaptic activity and plasticity by pre- and postsynaptic mechanisms. Uncoupling neuroglial communication leads to alterations in synaptic transmission that can be detrimental to neuronal circuit function and behavior. Therefore, understanding the pathways and mechanisms involved in this intercellular communication is fundamental for the search of new targets that can be used for several neurological disease treatments. This review will focus on molecular mechanisms mediating physiological and pathological coupling between astrocytes and neurons through GJs and HCs.

Functional identification of spike-processing neural circuits.

PubMed

Lazar, Aurel A; Slutskiy, Yevgeniy B

2014-02-01

We introduce a novel approach for a complete functional identification of biophysical spike-processing neural circuits. The circuits considered accept multidimensional spike trains as their input and comprise a multitude of temporal receptive fields and conductance-based models of action potential generation. Each temporal receptive field describes the spatiotemporal contribution of all synapses between any two neurons and incorporates the (passive) processing carried out by the dendritic tree. The aggregate dendritic current produced by a multitude of temporal receptive fields is encoded into a sequence of action potentials by a spike generator modeled as a nonlinear dynamical system. Our approach builds on the observation that during any experiment, an entire neural circuit, including its receptive fields and biophysical spike generators, is projected onto the space of stimuli used to identify the circuit. Employing the reproducing kernel Hilbert space (RKHS) of trigonometric polynomials to describe input stimuli, we quantitatively describe the relationship between underlying circuit parameters and their projections. We also derive experimental conditions under which these projections converge to the true parameters. In doing so, we achieve the mathematical tractability needed to characterize the biophysical spike generator and identify the multitude of receptive fields. The algorithms obviate the need to repeat experiments in order to compute the neurons' rate of response, rendering our methodology of interest to both experimental and theoretical neuroscientists.

An analog silicon retina with multichip configuration.

PubMed

Kameda, Seiji; Yagi, Tetsuya

2006-01-01

The neuromorphic silicon retina is a novel analog very large scale integrated circuit that emulates the structure and the function of the retinal neuronal circuit. We fabricated a neuromorphic silicon retina, in which sample/hold circuits were embedded to generate fluctuation-suppressed outputs in the previous study [1]. The applications of this silicon retina, however, are limited because of a low spatial resolution and computational variability. In this paper, we have fabricated a multichip silicon retina in which the functional network circuits are divided into two chips: the photoreceptor network chip (P chip) and the horizontal cell network chip (H chip). The output images of the P chip are transferred to the H chip with analog voltages through the line-parallel transfer bus. The sample/hold circuits embedded in the P and H chips compensate for the pattern noise generated on the circuits, including the analog communication pathway. Using the multichip silicon retina together with an off-chip differential amplifier, spatial filtering of the image with an odd- and an even-symmetric orientation selective receptive fields was carried out in real time. The analog data transfer method in the present multichip silicon retina is useful to design analog neuromorphic multichip systems that mimic the hierarchical structure of neuronal networks in the visual system.

Intrinsic modulation of pulse-coupled integrate-and-fire neurons

NASA Astrophysics Data System (ADS)

Coombes, S.; Lord, G. J.

1997-11-01

Intrinsic neuromodulation is observed in sensory and neuromuscular circuits and in biological central pattern generators. We model a simple neuronal circuit with a system of two pulse-coupled integrate-and-fire neurons and explore the parameter regimes for periodic firing behavior. The inclusion of biologically realistic features shows that the speed and onset of neuronal response plays a crucial role in determining the firing phase for periodic rhythms. We explore the neurophysiological function of distributed delays arising from both the synaptic transmission process and dendritic structure as well as discrete delays associated with axonal communication delays. Bifurcation and stability diagrams are constructed with a mixture of simple analysis, numerical continuation and the Kuramoto phase-reduction technique. Moreover, we show that, for asynchronous behavior, the strength of electrical synapses can control the firing rate of the system.

Simultaneous two-photon imaging and two-photon optogenetics of cortical circuits in three dimensions

PubMed Central

Carrillo-Reid, Luis; Bando, Yuki; Peterka, Darcy S

2018-01-01

The simultaneous imaging and manipulating of neural activity could enable the functional dissection of neural circuits. Here we have combined two-photon optogenetics with simultaneous volumetric two-photon calcium imaging to measure and manipulate neural activity in mouse neocortex in vivo in three-dimensions (3D) with cellular resolution. Using a hybrid holographic approach, we simultaneously photostimulate more than 80 neurons over 150 μm in depth in layer 2/3 of the mouse visual cortex, while simultaneously imaging the activity of the surrounding neurons. We validate the usefulness of the method by photoactivating in 3D selected groups of interneurons, suppressing the response of nearby pyramidal neurons to visual stimuli in awake animals. Our all-optical approach could be used as a general platform to read and write neuronal activity. PMID:29412138

Probing the function of neuronal populations: combining micromirror-based optogenetic photostimulation with voltage-sensitive dye imaging.

PubMed

Tsuda, Sachiko; Kee, Michelle Z L; Cunha, Catarina; Kim, Jinsook; Yan, Ping; Loew, Leslie M; Augustine, George J

2013-01-01

Recent advances in our understanding of brain function have come from using light to either control or image neuronal activity. Here we describe an approach that combines both techniques: a micromirror array is used to photostimulate populations of presynaptic neurons expressing channelrhodopsin-2, while a red-shifted voltage-sensitive dye allows optical detection of resulting postsynaptic activity. Such technology allowed us to control the activity of cerebellar interneurons while simultaneously recording inhibitory responses in multiple Purkinje neurons, their postsynaptic targets. This approach should substantially accelerate our understanding of information processing by populations of neurons within brain circuits. Copyright © 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Activation of Pedunculopontine Glutamate Neurons Is Reinforcing

PubMed Central

Yoo, Ji Hoon; Zell, Vivien; Wu, Johnathan; Punta, Cindy; Ramajayam, Nivedita; Shen, Xinyi; Faget, Lauren; Lilascharoen, Varoth; Lim, Byung Kook

2017-01-01

Dopamine transmission from midbrain ventral tegmental area (VTA) neurons underlies behavioral processes related to motivation and drug addiction. The pedunculopontine tegmental nucleus (PPTg) is a brainstem nucleus containing glutamate-, acetylcholine-, and GABA-releasing neurons with connections to basal ganglia and limbic brain regions. Here we investigated the role of PPTg glutamate neurons in reinforcement, with an emphasis on their projections to VTA dopamine neurons. We used cell-type-specific anterograde tracing and optogenetic methods to selectively label and manipulate glutamate projections from PPTg neurons in mice. We used anatomical, electrophysiological, and behavioral assays to determine their patterns of connectivity and ascribe functional roles in reinforcement. We found that photoactivation of PPTg glutamate cell bodies could serve as a direct positive reinforcer on intracranial self-photostimulation assays. Further, PPTg glutamate neurons directly innervate VTA; photostimulation of this pathway preferentially excites VTA dopamine neurons and is sufficient to induce behavioral reinforcement. These results demonstrate that ascending PPTg glutamate projections can drive motivated behavior, and PPTg to VTA synapses may represent an important target relevant to drug addiction and other mental health disorders. SIGNIFICANCE STATEMENT Uncovering brain circuits underlying reward-seeking is an important step toward understanding the circuit bases of drug addiction and other psychiatric disorders. The dopaminergic system emanating from the ventral tegmental area (VTA) plays a key role in regulating reward-seeking behaviors. We used optogenetics to demonstrate that the pedunculopontine tegmental nucleus sends glutamatergic projections to VTA dopamine neurons, and that stimulation of this circuit promotes behavioral reinforcement. The findings support a critical role for pedunculopontine tegmental nucleus glutamate neurotransmission in modulating VTA dopamine neuron activity and behavioral reinforcement. PMID:28053028

Mapping sensory circuits by anterograde trans-synaptic transfer of recombinant rabies virus

PubMed Central

Zampieri, Niccolò; Jessell, Thomas M.; Murray, Andrew J.

2014-01-01

Summary Primary sensory neurons convey information from the external world to relay circuits within the central nervous system (CNS), but the identity and organization of the neurons that process incoming sensory information remains sketchy. Within the CNS viral tracing techniques that rely on retrograde trans-synaptic transfer provide a powerful tool for delineating circuit organization. Viral tracing of the circuits engaged by primary sensory neurons has, however, been hampered by the absence of a genetically tractable anterograde transfer system. In this study we demonstrate that rabies virus can infect sensory neurons in the somatosensory system, is subject to anterograde trans-synaptic transfer from primary sensory to spinal target neurons, and can delineate output connectivity with third-order neurons. Anterograde trans-synaptic transfer is a feature shared by other classes of primary sensory neurons, permitting the identification and potentially the manipulation of neural circuits processing sensory feedback within the mammalian CNS. PMID:24486087

Large scale in vivo recordings to study neuronal biophysics.

PubMed

Giocomo, Lisa M

2015-06-01

Over the last several years, technological advances have enabled researchers to more readily observe single-cell membrane biophysics in awake, behaving animals. Studies utilizing these technologies have provided important insights into the mechanisms generating functional neural codes in both sensory and non-sensory cortical circuits. Crucial for a deeper understanding of how membrane biophysics control circuit dynamics however, is a continued effort to move toward large scale studies of membrane biophysics, in terms of the numbers of neurons and ion channels examined. Future work faces a number of theoretical and technical challenges on this front but recent technological developments hold great promise for a larger scale understanding of how membrane biophysics contribute to circuit coding and computation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Structural basis for serotonergic regulation of neural circuits in the mouse olfactory bulb.

PubMed

Suzuki, Yoshinori; Kiyokage, Emi; Sohn, Jaerin; Hioki, Hiroyuki; Toida, Kazunori

2015-02-01

Olfactory processing is well known to be regulated by centrifugal afferents from other brain regions, such as noradrenergic, acetylcholinergic, and serotonergic neurons. Serotonergic neurons widely innervate and regulate the functions of various brain regions. In the present study, we focused on serotonergic regulation of the olfactory bulb (OB), one of the most structurally and functionally well-defined brain regions. Visualization of a single neuron among abundant and dense fibers is essential to characterize and understand neuronal circuits. We accomplished this visualization by successfully labeling and reconstructing serotonin (5-hydroxytryptamine: 5-HT) neurons by infection with sindbis and adeno-associated virus into dorsal raphe nuclei (DRN) of mice. 5-HT synapses were analyzed by correlative confocal laser microscopy and serial-electron microscopy (EM) study. To further characterize 5-HT neuronal and network function, we analyzed whether glutamate was released from 5-HT synaptic terminals using immuno-EM. Our results are the first visualizations of complete 5-HT neurons and fibers projecting from DRN to the OB with bifurcations. We found that a single 5-HT axon can form synaptic contacts to both type 1 and 2 periglomerular cells within a single glomerulus. Through immunolabeling, we also identified vesicular glutamate transporter 3 in 5-HT neurons terminals, indicating possible glutamatergic transmission. Our present study strongly implicates the involvement of brain regions such as the DRN in regulation of the elaborate mechanisms of olfactory processing. We further provide a structure basis of the network for coordinating or linking olfactory encoding with other neural systems, with special attention to serotonergic regulation. © 2014 Wiley Periodicals, Inc.

Axon and dendrite geography predict the specificity of synaptic connections in a functioning spinal cord network.

PubMed

Li, Wen-Chang; Cooke, Tom; Sautois, Bart; Soffe, Stephen R; Borisyuk, Roman; Roberts, Alan

2007-09-10

How specific are the synaptic connections formed as neuronal networks develop and can simple rules account for the formation of functioning circuits? These questions are assessed in the spinal circuits controlling swimming in hatchling frog tadpoles. This is possible because detailed information is now available on the identity and synaptic connections of the main types of neuron. The probabilities of synapses between 7 types of identified spinal neuron were measured directly by making electrical recordings from 500 pairs of neurons. For the same neuron types, the dorso-ventral distributions of axons and dendrites were measured and then used to calculate the probabilities that axons would encounter particular dendrites and so potentially form synaptic connections. Surprisingly, synapses were found between all types of neuron but contact probabilities could be predicted simply by the anatomical overlap of their axons and dendrites. These results suggested that synapse formation may not require axons to recognise specific, correct dendrites. To test the plausibility of simpler hypotheses, we first made computational models that were able to generate longitudinal axon growth paths and reproduce the axon distribution patterns and synaptic contact probabilities found in the spinal cord. To test if probabilistic rules could produce functioning spinal networks, we then made realistic computational models of spinal cord neurons, giving them established cell-specific properties and connecting them into networks using the contact probabilities we had determined. A majority of these networks produced robust swimming activity. Simple factors such as morphogen gradients controlling dorso-ventral soma, dendrite and axon positions may sufficiently constrain the synaptic connections made between different types of neuron as the spinal cord first develops and allow functional networks to form. Our analysis implies that detailed cellular recognition between spinal neuron types may not be necessary for the reliable formation of functional networks to generate early behaviour like swimming.

Extracting functionally feedforward networks from a population of spiking neurons

PubMed Central

Vincent, Kathleen; Tauskela, Joseph S.; Thivierge, Jean-Philippe

2012-01-01

Neuronal avalanches are a ubiquitous form of activity characterized by spontaneous bursts whose size distribution follows a power-law. Recent theoretical models have replicated power-law avalanches by assuming the presence of functionally feedforward connections (FFCs) in the underlying dynamics of the system. Accordingly, avalanches are generated by a feedforward chain of activation that persists despite being embedded in a larger, massively recurrent circuit. However, it is unclear to what extent networks of living neurons that exhibit power-law avalanches rely on FFCs. Here, we employed a computational approach to reconstruct the functional connectivity of cultured cortical neurons plated on multielectrode arrays (MEAs) and investigated whether pharmacologically induced alterations in avalanche dynamics are accompanied by changes in FFCs. This approach begins by extracting a functional network of directed links between pairs of neurons, and then evaluates the strength of FFCs using Schur decomposition. In a first step, we examined the ability of this approach to extract FFCs from simulated spiking neurons. The strength of FFCs obtained in strictly feedforward networks diminished monotonically as links were gradually rewired at random. Next, we estimated the FFCs of spontaneously active cortical neuron cultures in the presence of either a control medium, a GABAA receptor antagonist (PTX), or an AMPA receptor antagonist combined with an NMDA receptor antagonist (APV/DNQX). The distribution of avalanche sizes in these cultures was modulated by this pharmacology, with a shallower power-law under PTX (due to the prominence of larger avalanches) and a steeper power-law under APV/DNQX (due to avalanches recruiting fewer neurons) relative to control cultures. The strength of FFCs increased in networks after application of PTX, consistent with an amplification of feedforward activity during avalanches. Conversely, FFCs decreased after application of APV/DNQX, consistent with fading feedforward activation. The observed alterations in FFCs provide experimental support for recent theoretical work linking power-law avalanches to the feedforward organization of functional connections in local neuronal circuits. PMID:23091458

Extracting functionally feedforward networks from a population of spiking neurons.

PubMed

Vincent, Kathleen; Tauskela, Joseph S; Thivierge, Jean-Philippe

2012-01-01

Neuronal avalanches are a ubiquitous form of activity characterized by spontaneous bursts whose size distribution follows a power-law. Recent theoretical models have replicated power-law avalanches by assuming the presence of functionally feedforward connections (FFCs) in the underlying dynamics of the system. Accordingly, avalanches are generated by a feedforward chain of activation that persists despite being embedded in a larger, massively recurrent circuit. However, it is unclear to what extent networks of living neurons that exhibit power-law avalanches rely on FFCs. Here, we employed a computational approach to reconstruct the functional connectivity of cultured cortical neurons plated on multielectrode arrays (MEAs) and investigated whether pharmacologically induced alterations in avalanche dynamics are accompanied by changes in FFCs. This approach begins by extracting a functional network of directed links between pairs of neurons, and then evaluates the strength of FFCs using Schur decomposition. In a first step, we examined the ability of this approach to extract FFCs from simulated spiking neurons. The strength of FFCs obtained in strictly feedforward networks diminished monotonically as links were gradually rewired at random. Next, we estimated the FFCs of spontaneously active cortical neuron cultures in the presence of either a control medium, a GABA(A) receptor antagonist (PTX), or an AMPA receptor antagonist combined with an NMDA receptor antagonist (APV/DNQX). The distribution of avalanche sizes in these cultures was modulated by this pharmacology, with a shallower power-law under PTX (due to the prominence of larger avalanches) and a steeper power-law under APV/DNQX (due to avalanches recruiting fewer neurons) relative to control cultures. The strength of FFCs increased in networks after application of PTX, consistent with an amplification of feedforward activity during avalanches. Conversely, FFCs decreased after application of APV/DNQX, consistent with fading feedforward activation. The observed alterations in FFCs provide experimental support for recent theoretical work linking power-law avalanches to the feedforward organization of functional connections in local neuronal circuits.

Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.

PubMed

Fletcher, Emily V; Simon, Christian M; Pagiazitis, John G; Chalif, Joshua I; Vukojicic, Aleksandra; Drobac, Estelle; Wang, Xiaojian; Mentis, George Z

2017-07-01

Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.

Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy

PubMed Central

Fletcher, Emily V.; Simon, Christian M.; Pagiazitis, John G.; Chalif, Joshua I.; Vukojicic, Aleksandra; Drobac, Estelle; Wang, Xiaojian; Mentis, George Z.

2017-01-01

Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contribution of their synaptic partners to the disease process is largely unknown. Here, we show that in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission we observed a decrease in the motor neuron firing which could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Increasing neuronal activity pharmacologically by chronic exposure in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease. PMID:28504671

In vivo imaging of neural activity

PubMed Central

Yang, Weijian; Yuste, Rafael

2017-01-01

Since the introduction of calcium imaging to monitor neuronal activity with single-cell resolution, optical imaging methods have revolutionized neuroscience by enabling systematic recordings of neuronal circuits in living animals. The plethora of methods for functional neural imaging can be daunting to the nonexpert to navigate. Here we review advanced microscopy techniques for in vivo functional imaging and offer guidelines for which technologies are best suited for particular applications. PMID:28362436

Graphene foam as a biocompatible scaffold for culturing human neurons

PubMed Central

Mattei, Cristiana; Nasr, Babak; Hudson, Emma J.; Alshawaf, Abdullah J.; Chana, Gursharan; Everall, Ian P.; Dottori, Mirella; Skafidas, Efstratios

2018-01-01

In this study, we explore the use of electrically active graphene foam as a scaffold for the culture of human-derived neurons. Human embryonic stem cell (hESC)-derived cortical neurons fated as either glutamatergic or GABAergic neuronal phenotypes were cultured on graphene foam. We show that graphene foam is biocompatible for the culture of human neurons, capable of supporting cell viability and differentiation of hESC-derived cortical neurons. Based on the findings, we propose that graphene foam represents a suitable scaffold for engineering neuronal tissue and warrants further investigation as a model for understanding neuronal maturation, function and circuit formation. PMID:29657752

Oligodendrocyte-Neuron Interactions: Impact on Myelination and Brain Function.

PubMed

Shimizu, Takeshi; Osanai, Yasuyuki; Ikenaka, Kazuhiro

2018-01-01

In the past, glial cells were considered to be 'glue' cells whose primary role was thought to be merely filling gaps in neural circuits. However, a growing number of reports have indicated the role of glial cells in higher brain function through their interaction with neurons. Myelin was originally thought to be just a sheath structure surrounding neuronal axons, but recently it has been shown that myelin exerts effects on the conduction velocity of neuronal axons even after myelin formation. Therefore, the investigation of glial cell properties and the neuron-glial interactions is important for understanding higher brain function. Moreover, since there are many neurological disorders caused by glial abnormalities, further understanding of glial cell-related diseases and the development of effective therapeutic strategies are warranted. In this review, we focused on oligodendrocyte-neuron interactions, with particular attention on (1) axonal signals underlying oligodendrocyte differentiation and myelination, (2) neuronal activity-dependent myelination and (3) the effects of myelination on higher brain function.

Sonic hedgehog expression in corticofugal projection neurons directs cortical microcircuit formation.

PubMed

Harwell, Corey C; Parker, Philip R L; Gee, Steven M; Okada, Ami; McConnell, Susan K; Kreitzer, Anatol C; Kriegstein, Arnold R

2012-03-22

The precise connectivity of inputs and outputs is critical for cerebral cortex function; however, the cellular mechanisms that establish these connections are poorly understood. Here, we show that the secreted molecule Sonic Hedgehog (Shh) is involved in synapse formation of a specific cortical circuit. Shh is expressed in layer V corticofugal projection neurons and the Shh receptor, Brother of CDO (Boc), is expressed in local and callosal projection neurons of layer II/III that synapse onto the subcortical projection neurons. Layer V neurons of mice lacking functional Shh exhibit decreased synapses. Conversely, the loss of functional Boc leads to a reduction in the strength of synaptic connections onto layer Vb, but not layer II/III, pyramidal neurons. These results demonstrate that Shh is expressed in postsynaptic target cells while Boc is expressed in a complementary population of presynaptic input neurons, and they function to guide the formation of cortical microcircuitry. Copyright © 2012 Elsevier Inc. All rights reserved.

Early Correlated Network Activity in the Hippocampus: Its Putative Role in Shaping Neuronal Circuits.

PubMed

Griguoli, Marilena; Cherubini, Enrico

2017-01-01

Synchronized neuronal activity occurring at different developmental stages in various brain structures represents a hallmark of developmental circuits. This activity, which differs in its specific patterns among animal species may play a crucial role in de novo formation and in shaping neuronal networks. In the rodent hippocampus in vitro , the so-called giant depolarizing potentials (GDPs) constitute a primordial form of neuronal synchrony preceding more organized forms of activity such as oscillations in the theta and gamma frequency range. GDPs are generated at the network level by the interaction of the neurotransmitters glutamate and GABA which, immediately after birth, exert both a depolarizing and excitatory action on their targets. GDPs are triggered by GABAergic interneurons, which in virtue of their extensive axonal branching operate as functional hubs to synchronize large ensembles of cells. Intrinsic bursting activity, driven by a persistent sodium conductance and facilitated by the low expression of Kv7.2 and Kv7.3 channel subunits, responsible for I M , exerts a permissive role in GDP generation. Here, we discuss how GDPs are generated in a probabilistic way when neuronal excitability within a local circuit reaches a certain threshold and how GDP-associated calcium transients act as coincident detectors for enhancing synaptic strength at emerging GABAergic and glutamatergic synapses. We discuss the possible in vivo correlate of this activity. Finally, we debate recent data showing how, in several animal models of neuropsychiatric disorders including autism, a GDPs dysfunction is associated to morphological alterations of neuronal circuits and behavioral deficits reminiscent of those observed in patients.

Local domains of motor cortical activity revealed by fiber-optic calcium recordings in behaving nonhuman primates.

PubMed

Adelsberger, Helmuth; Zainos, Antonio; Alvarez, Manuel; Romo, Ranulfo; Konnerth, Arthur

2014-01-07

Brain mapping experiments involving electrical microstimulation indicate that the primary motor cortex (M1) directly regulates muscle contraction and thereby controls specific movements. Possibly, M1 contains a small circuit "map" of the body that is formed by discrete local networks that code for specific movements. Alternatively, movements may be controlled by distributed, larger-scale overlapping circuits. Because of technical limitations, it remained unclear how movement-determining circuits are organized in M1. Here we introduce a method that allows the functional mapping of small local neuronal circuits in awake behaving nonhuman primates. For this purpose, we combined optic-fiber-based calcium recordings of neuronal activity and cortical microstimulation. The method requires targeted bulk loading of synthetic calcium indicators (e.g., OGB-1 AM) for the staining of neuronal microdomains. The tip of a thin (200 µm) optical fiber can detect the coherent activity of a small cluster of neurons, but is insensitive to the asynchronous activity of individual cells. By combining such optical recordings with microstimulation at two well-separated sites of M1, we demonstrate that local cortical activity was tightly associated with distinct and stereotypical simple movements. Increasing stimulation intensity increased both the amplitude of the movements and the level of neuronal activity. Importantly, the activity remained local, without invading the recording domain of the second optical fiber. Furthermore, there was clear response specificity at the two recording sites in a trained behavioral task. Thus, the results provide support for movement control in M1 by local neuronal clusters that are organized in discrete cortical domains.

Central neural pathways for thermoregulation

PubMed Central

Morrison, Shaun F.; Nakamura, Kazuhiro

2010-01-01

Central neural circuits orchestrate a homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the functional organization of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for heat loss, the brown adipose tissue, skeletal muscle and heart for thermogenesis and species-dependent mechanisms (sweating, panting and saliva spreading) for evaporative heat loss. These effectors are regulated by parallel but distinct, effector-specific neural pathways that share a common peripheral thermal sensory input. The thermal afferent circuits include cutaneous thermal receptors, spinal dorsal horn neurons and lateral parabrachial nucleus neurons projecting to the preoptic area to influence warm-sensitive, inhibitory output neurons which control thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus neurons controlling cutaneous vasoconstriction. PMID:21196160

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow N. D.; Wang G.; Volkow, N.D.

The ability to resist the urge to eat requires the proper functioning of neuronal circuits involved in top-down control to oppose the conditioned responses that predict reward from eating the food and the desire to eat the food. Imaging studies show that obese subjects might have impairments in dopaminergic pathways that regulate neuronal systems associated with reward sensitivity, conditioning and control. It is known that the neuropeptides that regulate energy balance (homeostatic processes) through the hypothalamus also modulate the activity of dopamine cells and their projections into regions involved in the rewarding processes underlying food intake. It is postulated thatmore » this could also be a mechanism by which overeating and the resultant resistance to homoeostatic signals impairs the function of circuits involved in reward sensitivity, conditioning and cognitive control.« less

Negative Correlations in Visual Cortical Networks

PubMed Central

Chelaru, Mircea I.; Dragoi, Valentin

2016-01-01

The amount of information encoded by cortical circuits depends critically on the capacity of nearby neurons to exhibit trial-to-trial (noise) correlations in their responses. Depending on their sign and relationship to signal correlations, noise correlations can either increase or decrease the population code accuracy relative to uncorrelated neuronal firing. Whereas positive noise correlations have been extensively studied using experimental and theoretical tools, the functional role of negative correlations in cortical circuits has remained elusive. We addressed this issue by performing multiple-electrode recording in the superficial layers of the primary visual cortex (V1) of alert monkey. Despite the fact that positive noise correlations decayed exponentially with the difference in the orientation preference between cells, negative correlations were uniformly distributed across the population. Using a statistical model for Fisher Information estimation, we found that a mild increase in negative correlations causes a sharp increase in network accuracy even when mean correlations were held constant. To examine the variables controlling the strength of negative correlations, we implemented a recurrent spiking network model of V1. We found that increasing local inhibition and reducing excitation causes a decrease in the firing rates of neurons while increasing the negative noise correlations, which in turn increase the population signal-to-noise ratio and network accuracy. Altogether, these results contribute to our understanding of the neuronal mechanism involved in the generation of negative correlations and their beneficial impact on cortical circuit function. PMID:25217468

Persistent activity in a recurrent circuit underlies courtship memory in Drosophila.

PubMed

Zhao, Xiaoliang; Lenek, Daniela; Dag, Ugur; Dickson, Barry J; Keleman, Krystyna

2018-01-11

Recurrent connections are thought to be a common feature of the neural circuits that encode memories, but how memories are laid down in such circuits is not fully understood. Here we present evidence that courtship memory in Drosophila relies on the recurrent circuit between mushroom body gamma (MBγ), M6 output, and aSP13 dopaminergic neurons. We demonstrate persistent neuronal activity of aSP13 neurons and show that it transiently potentiates synaptic transmission from MBγ>M6 neurons. M6 neurons in turn provide input to aSP13 neurons, prolonging potentiation of MB γ >M6 synapses over time periods that match short-term memory. These data support a model in which persistent aSP13 activity within a recurrent circuit lays the foundation for a short-term memory. © 2018, Zhao et al.

Persistent activity in a recurrent circuit underlies courtship memory in Drosophila

PubMed Central

Zhao, Xiaoliang; Lenek, Daniela; Dag, Ugur; Dickson, Barry J

2018-01-01

Recurrent connections are thought to be a common feature of the neural circuits that encode memories, but how memories are laid down in such circuits is not fully understood. Here we present evidence that courtship memory in Drosophila relies on the recurrent circuit between mushroom body gamma (MBγ), M6 output, and aSP13 dopaminergic neurons. We demonstrate persistent neuronal activity of aSP13 neurons and show that it transiently potentiates synaptic transmission from MBγ>M6 neurons. M6 neurons in turn provide input to aSP13 neurons, prolonging potentiation of MBγ>M6 synapses over time periods that match short-term memory. These data support a model in which persistent aSP13 activity within a recurrent circuit lays the foundation for a short-term memory. PMID:29322941

Transition to Chaos in Random Neuronal Networks

NASA Astrophysics Data System (ADS)

Kadmon, Jonathan; Sompolinsky, Haim

2015-10-01

Firing patterns in the central nervous system often exhibit strong temporal irregularity and considerable heterogeneity in time-averaged response properties. Previous studies suggested that these properties are the outcome of the intrinsic chaotic dynamics of the neural circuits. Indeed, simplified rate-based neuronal networks with synaptic connections drawn from Gaussian distribution and sigmoidal nonlinearity are known to exhibit chaotic dynamics when the synaptic gain (i.e., connection variance) is sufficiently large. In the limit of an infinitely large network, there is a sharp transition from a fixed point to chaos, as the synaptic gain reaches a critical value. Near the onset, chaotic fluctuations are slow, analogous to the ubiquitous, slow irregular fluctuations observed in the firing rates of many cortical circuits. However, the existence of a transition from a fixed point to chaos in neuronal circuit models with more realistic architectures and firing dynamics has not been established. In this work, we investigate rate-based dynamics of neuronal circuits composed of several subpopulations with randomly diluted connections. Nonzero connections are either positive for excitatory neurons or negative for inhibitory ones, while single neuron output is strictly positive with output rates rising as a power law above threshold, in line with known constraints in many biological systems. Using dynamic mean field theory, we find the phase diagram depicting the regimes of stable fixed-point, unstable-dynamic, and chaotic-rate fluctuations. We focus on the latter and characterize the properties of systems near this transition. We show that dilute excitatory-inhibitory architectures exhibit the same onset to chaos as the single population with Gaussian connectivity. In these architectures, the large mean excitatory and inhibitory inputs dynamically balance each other, amplifying the effect of the residual fluctuations. Importantly, the existence of a transition to chaos and its critical properties depend on the shape of the single-neuron nonlinear input-output transfer function, near firing threshold. In particular, for nonlinear transfer functions with a sharp rise near threshold, the transition to chaos disappears in the limit of a large network; instead, the system exhibits chaotic fluctuations even for small synaptic gain. Finally, we investigate transition to chaos in network models with spiking dynamics. We show that when synaptic time constants are slow relative to the mean inverse firing rates, the network undergoes a transition from fast spiking fluctuations with constant rates to a state where the firing rates exhibit chaotic fluctuations, similar to the transition predicted by rate-based dynamics. Systems with finite synaptic time constants and firing rates exhibit a smooth transition from a regime dominated by stationary firing rates to a regime of slow rate fluctuations. This smooth crossover obeys scaling properties, similar to crossover phenomena in statistical mechanics. The theoretical results are supported by computer simulations of several neuronal architectures and dynamics. Consequences for cortical circuit dynamics are discussed. These results advance our understanding of the properties of intrinsic dynamics in realistic neuronal networks and their functional consequences.

Alzheimer's disease Braak Stage progressions: reexamined and redefined as Borrelia infection transmission through neural circuits.

PubMed

MacDonald, Alan B

2007-01-01

Brain structure in health is a dynamic energized equation incorporating chemistry, neuronal structure, and circuitry components. The chemistry "piece" is represented by multiple neurotransmitters such as Acetylcholine, Serotonin, and Dopamine. The neuronal structure "piece" incorporates synapses and their connections. And finally circuits of neurons establish "architectural blueprints" of anatomic wiring diagrams of the higher order of brain neuron organizations. In Alzheimer's disease, there are progressive losses in all of these components. Brain structure crumbles. The deterioration in Alzheimer's is ordered, reproducible, and stepwise. Drs. Braak and Braak have described stages in the Alzheimer disease continuum. "Progressions" through Braak Stages benchmark "Regressions" in Cognitive function. Under the microscope, the Stages of Braak commence in brain regions near to the hippocampus, and over time, like a tsunami wave of destruction, overturn healthy brain regions, with neurofibrillary tangle damaged neurons "marching" through the temporal lobe, neocortex and occipital cortex. In effect the destruction ascends from the limbic regions to progressively destroy the higher brain centers. Rabies infection also "begins low and finishes high" in its wave of destruction of brain tissue. Herpes Zoster infections offer the paradigm of clinical latency of infection inside of nerves before the "marching commences". Varicella Zoster virus enters neurons in the pediatric years. Dormant virus remains inside the neurons for 50-80 years, tissue damage late in life (shingles) demonstrates the "march of the infection" down neural pathways (dermatomes) as linear areas of painful blisters loaded with virus from a childhood infection. Amalgamation of Zoster with Rabies models produces a hybrid model to explain all of the Braak Stages of Alzheimer's disease under a new paradigm, namely "Alzheimer's neuroborreliosis" in which latent Borrelia infections ascend neural circuits through the hippocampus to the higher brain centers, creating a trail of neurofibrillary tangle injured neurons in neural circuits of cholinergic neurons by transsynaptic transmission of infection from nerve to nerve.

Genetic address book for retinal cell types.

PubMed

Siegert, Sandra; Scherf, Brigitte Gross; Del Punta, Karina; Didkovsky, Nick; Heintz, Nathaniel; Roska, Botond

2009-09-01

The mammalian brain is assembled from thousands of neuronal cell types that are organized in distinct circuits to perform behaviorally relevant computations. Transgenic mouse lines with selectively marked cell types would facilitate our ability to dissect functional components of complex circuits. We carried out a screen for cell type-specific green fluorescent protein expression in the retina using BAC transgenic mice from the GENSAT project. Among others, we identified mouse lines in which the inhibitory cell types of the night vision and directional selective circuit were selectively labeled. We quantified the stratification patterns to predict potential synaptic connectivity between marked cells of different lines and found that some of the lines enabled targeted recordings and imaging of cell types from developing or mature retinal circuits. Our results suggest the potential use of a stratification-based screening approach for characterizing neuronal circuitry in other layered brain structures, such as the neocortex.

Retrieving fear memories, as time goes by…

PubMed Central

Do Monte, Fabricio H.; Quirk, Gregory J.; Li, Bo; Penzo, Mario A.

2016-01-01

Fear conditioning researches have led to a comprehensive picture of the neuronal circuit underlying the formation of fear memories. In contrast, knowledge about the retrieval of fear memories is much more limited. This disparity may stem from the fact that fear memories are not rigid, but reorganize over time. To bring clarity and raise awareness on the time-dependent dynamics of retrieval circuits, we review current evidence on the neuronal circuitry participating in fear memory retrieval at both early and late time points after conditioning. We focus on the temporal recruitment of the paraventricular nucleus of the thalamus, and its BDNFergic efferents to the central nucleus of the amygdala, for the retrieval and maintenance of fear memories. Finally, we speculate as to why retrieval circuits change across time, and the functional benefits of recruiting structures such as the paraventricular nucleus into the retrieval circuit. PMID:27217148

BK channels are required for multisensory plasticity in the oculomotor system

PubMed Central

Nelson, Alexandra; Faulstich, Michael; Moghadam, Setareh; Onori, Kimberly; Meredith, Andrea; du Lac, Sascha

2017-01-01

SUMMARY Neural circuits are endowed with several forms of intrinsic and synaptic plasticity that could contribute to adaptive changes in behavior, but circuit complexities have hindered linking specific cellular mechanisms with their behavioral consequences. Eye movements generated by simple brainstem circuits provide a means for relating cellular plasticity to behavioral gain control. Here we show that firing rate potentiation, a form of intrinsic plasticity mediated by reductions in BK-type calcium activated potassium currents in spontaneously firing neurons, is engaged during optokinetic reflex compensation for inner ear dysfunction. Vestibular loss triggers transient increases in postsynaptic excitability, occlusion of firing rate potentiation, and reductions in BK currents in vestibular nucleus neurons. Concurrently, adaptive increases in visually-evoked eye movements rapidly restore oculomotor function in wildtype mice but are profoundly impaired in BK channel null mice. Activity-dependent regulation of intrinsic excitability may be a general mechanism for adaptive control of behavioral output in multisensory circuits. PMID:27989457

Delineating the Diversity of Spinal Interneurons in Locomotor Circuits.

PubMed

Gosgnach, Simon; Bikoff, Jay B; Dougherty, Kimberly J; El Manira, Abdeljabbar; Lanuza, Guillermo M; Zhang, Ying

2017-11-08

Locomotion is common to all animals and is essential for survival. Neural circuits located in the spinal cord have been shown to be necessary and sufficient for the generation and control of the basic locomotor rhythm by activating muscles on either side of the body in a specific sequence. Activity in these neural circuits determines the speed, gait pattern, and direction of movement, so the specific locomotor pattern generated relies on the diversity of the neurons within spinal locomotor circuits. Here, we review findings demonstrating that developmental genetics can be used to identify populations of neurons that comprise these circuits and focus on recent work indicating that many of these populations can be further subdivided into distinct subtypes, with each likely to play complementary functions during locomotion. Finally, we discuss data describing the manner in which these populations interact with each other to produce efficient, task-dependent locomotion. Copyright © 2017 the authors 0270-6474/17/3710835-07$15.00/0.

Corticostriatal connectivity and its role in disease

PubMed Central

Shepherd, Gordon M. G.

2014-01-01

Corticostriatal projections are essential components of forebrain circuits widely involved in motivated behavior. These axonal projections are formed by two distinct classes of cortical neurons, intratelencephalic (IT) and pyramidal tract (PT) type neurons. Convergent evidence points to IT/PT differentiation of the corticostriatal system at all levels of functional organization, from cellular signaling mechanisms to circuit topology. There is also growing evidence for IT/PT imbalance as an etiological factor in neurodevelopmental, neuropsychiatric, and movement disorders – autism, amyotrophic lateral sclerosis, obsessive-compulsive disorder, schizophrenia, Huntington’s and Parkinson’s diseases, and major depression are highlighted here. PMID:23511908

Connectomic constraints on computation in feedforward networks of spiking neurons.

PubMed

Ramaswamy, Venkatakrishnan; Banerjee, Arunava

2014-10-01

Several efforts are currently underway to decipher the connectome or parts thereof in a variety of organisms. Ascertaining the detailed physiological properties of all the neurons in these connectomes, however, is out of the scope of such projects. It is therefore unclear to what extent knowledge of the connectome alone will advance a mechanistic understanding of computation occurring in these neural circuits, especially when the high-level function of the said circuit is unknown. We consider, here, the question of how the wiring diagram of neurons imposes constraints on what neural circuits can compute, when we cannot assume detailed information on the physiological response properties of the neurons. We call such constraints-that arise by virtue of the connectome-connectomic constraints on computation. For feedforward networks equipped with neurons that obey a deterministic spiking neuron model which satisfies a small number of properties, we ask if just by knowing the architecture of a network, we can rule out computations that it could be doing, no matter what response properties each of its neurons may have. We show results of this form, for certain classes of network architectures. On the other hand, we also prove that with the limited set of properties assumed for our model neurons, there are fundamental limits to the constraints imposed by network structure. Thus, our theory suggests that while connectomic constraints might restrict the computational ability of certain classes of network architectures, we may require more elaborate information on the properties of neurons in the network, before we can discern such results for other classes of networks.

Laminar circuit organization and response modulation in mouse visual cortex

PubMed Central

Olivas, Nicholas D.; Quintanar-Zilinskas, Victor; Nenadic, Zoran; Xu, Xiangmin

2012-01-01

The mouse has become an increasingly important animal model for visual system studies, but few studies have investigated local functional circuit organization of mouse visual cortex. Here we used our newly developed mapping technique combining laser scanning photostimulation (LSPS) with fast voltage-sensitive dye (VSD) imaging to examine the spatial organization and temporal dynamics of laminar circuit responses in living slice preparations of mouse primary visual cortex (V1). During experiments, LSPS using caged glutamate provided spatially restricted neuronal activation in a specific cortical layer, and evoked responses from the stimulated layer to its functionally connected regions were detected by VSD imaging. In this study, we first provided a detailed analysis of spatiotemporal activation patterns at specific V1 laminar locations and measured local circuit connectivity. Then we examined the role of cortical inhibition in the propagation of evoked cortical responses by comparing circuit activity patterns in control and in the presence of GABAa receptor antagonists. We found that GABAergic inhibition was critical in restricting layer-specific excitatory activity spread and maintaining topographical projections. In addition, we investigated how AMPA and NMDA receptors influenced cortical responses and found that blocking AMPA receptors abolished interlaminar functional projections, and the NMDA receptor activity was important in controlling visual cortical circuit excitability and modulating activity propagation. The NMDA receptor antagonist reduced neuronal population activity in time-dependent and laminar-specific manners. Finally, we used the quantitative information derived from the mapping experiments and presented computational modeling analysis of V1 circuit organization. Taken together, the present study has provided important new information about mouse V1 circuit organization and response modulation. PMID:23060751

Impaired recruitment of seizure-generated neurons into functional memory networks of the adult dentate gyrus following long-term amygdala kindling.

PubMed

Fournier, Neil M; Botterill, Justin J; Marks, Wendie N; Guskjolen, Axel J; Kalynchuk, Lisa E

2013-06-01

Epileptic seizures increase the birth of new neurons in the adult hippocampus. Although the consequences of aberrant neurogenesis on behavior are not fully understood, one hypothesis is that seizure-generated neurons might form faulty circuits that disrupt hippocampal functions, such as learning and memory. In the present study, we employed long-term amygdala kindling (i.e., rats receive 99-electrical stimulations) to examine the effect of repeated seizures on hippocampal neurogenesis and behavior. We labeled seizure-generated cells with the proliferation marker BrdU after 30-stimulations and continued kindling for an additional 4weeks to allow newborn neurons to mature under conditions of repeated seizures. After kindling was complete, rats were tested in a trace fear conditioning task and sacrificed 2h later to examine if 4-week old newborn cells were recruited into circuits involved in the retrieval of emotional memory. Compared to non-kindled controls, long-term kindled rats showed significant impairments in fear memory reflected in a decrease in conditioned freezing to both tone and contextual cues during testing. Moreover, long-term kindling also prevented the activation of 4-week old newborn cells in response to fear memory retrieval. These results indicate that the presence of seizure activity during cell maturation impedes the ability of new neurons to integrate properly into circuits important in memory formation. Together, our findings suggest that aberrant seizure-induced neurogenesis might contribute to the development of learning impairments in chronic epilepsy and raise the possibility that targeting the reduced activation of adult born neurons could represent a beneficial strategy to reverse cognitive deficits in some epileptic patients. Copyright © 2012 Elsevier Inc. All rights reserved.

Nanotools for Neuroscience and Brain Activity Mapping

PubMed Central

Alivisatos, A. Paul; Andrews, Anne M.; Boyden, Edward S.; Chun, Miyoung; Church, George M.; Deisseroth, Karl; Donoghue, John P.; Fraser, Scott E.; Lippincott-Schwartz, Jennifer; Looger, Loren L.; Masmanidis, Sotiris; McEuen, Paul L.; Nurmikko, Arto V.; Park, Hongkun; Peterka, Darcy S.; Reid, Clay; Roukes, Michael L.; Scherer, Axel; Schnitzer, Mark; Sejnowski, Terrence J.; Shepard, Kenneth L.; Tsao, Doris; Turrigiano, Gina; Weiss, Paul S.; Xu, Chris; Yuste, Rafael; Zhuang, Xiaowei

2013-01-01

Neuroscience is at a crossroads. Great effort is being invested into deciphering specific neural interactions and circuits. At the same time, there exist few general theories or principles that explain brain function. We attribute this disparity, in part, to limitations in current methodologies. Traditional neurophysiological approaches record the activities of one neuron or a few neurons at a time. Neurochemical approaches focus on single neurotransmitters. Yet, there is an increasing realization that neural circuits operate at emergent levels, where the interactions between hundreds or thousands of neurons, utilizing multiple chemical transmitters, generate functional states. Brains function at the nanoscale, so tools to study brains must ultimately operate at this scale, as well. Nanoscience and nanotechnology are poised to provide a rich toolkit of novel methods to explore brain function by enabling simultaneous measurement and manipulation of activity of thousands or even millions of neurons. We and others refer to this goal as the Brain Activity Mapping Project. In this Nano Focus, we discuss how recent developments in nanoscale analysis tools and in the design and synthesis of nanomaterials have generated optical, electrical, and chemical methods that can readily be adapted for use in neuroscience. These approaches represent exciting areas of technical development and research. Moreover, unique opportunities exist for nanoscientists, nanotechnologists, and other physical scientists and engineers to contribute to tackling the challenging problems involved in understanding the fundamentals of brain function. PMID:23514423

Reorganization of neuronal circuits of the central olfactory system during postprandial sleep

PubMed Central

Yamaguchi, Masahiro; Manabe, Hiroyuki; Murata, Koshi; Mori, Kensaku

2013-01-01

Plastic changes in neuronal circuits often occur in association with specific behavioral states. In this review, we focus on an emerging view that neuronal circuits in the olfactory system are reorganized along the wake-sleep cycle. Olfaction is crucial to sustaining the animals' life, and odor-guided behaviors have to be newly acquired or updated to successfully cope with a changing odor world. It is therefore likely that neuronal circuits in the olfactory system are highly plastic and undergo repeated reorganization in daily life. A remarkably plastic feature of the olfactory system is that newly generated neurons are continually integrated into neuronal circuits of the olfactory bulb (OB) throughout life. New neurons in the OB undergo an extensive selection process, during which many are eliminated by apoptosis for the fine tuning of neuronal circuits. The life and death decision of new neurons occurs extensively during a short time window of sleep after food consumption (postprandial sleep), a typical daily olfactory behavior. We review recent studies that explain how olfactory information is transferred between the OB and the olfactory cortex (OC) along the course of the wake-sleep cycle. Olfactory sensory input is effectively transferred from the OB to the OC during waking, while synchronized top-down inputs from the OC to the OB are promoted during the slow-wave sleep. We discuss possible neuronal circuit mechanisms for the selection of new neurons in the OB, which involves the encoding of olfactory sensory inputs and memory trace formation during waking and internally generated activities in the OC and OB during subsequent sleep. The plastic changes in the OB and OC are well coordinated along the course of olfactory behavior during wakefulness and postbehavioral rest and sleep. We therefore propose that the olfactory system provides an excellent model in which to understand behavioral state-dependent plastic mechanisms of the neuronal circuits in the brain. PMID:23966911

The Intrinsic Electrophysiological Properties of Mammalian Neurons: Insights into Central Nervous System Function

NASA Astrophysics Data System (ADS)

Llinas, Rodolfo R.

1988-12-01

This article reviews the electroresponsive properties of single neurons in the mammalian central nervous system (CNS). In some of these cells the ionic conductances responsible for their excitability also endow them with autorhythmic electrical oscillatory properties. Chemical or electrical synaptic contacts between these neurons often result in network oscillations. In such networks, autorhytmic neurons may act as true oscillators (as pacemakers) or as resonators (responding preferentially to certain firing frequencies). Oscillations and resonance in the CNS are proposed to have diverse functional roles, such as (i) determining global functional states (for example, sleep-wakefulness or attention), (ii) timing in motor coordination, and (iii) specifying connectivity during development. Also, oscillation, especially in the thalamo-cortical circuits, may be related to certain neurological and psychiatric disorders. This review proposes that the autorhythmic electrical properties of central neurons and their connectivity form the basis for an intrinsic functional coordinate system that provides internal context to sensory input.

Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.

PubMed

Castilla-Ortega, Estela; Blanco, Eduardo; Serrano, Antonia; Ladrón de Guevara-Miranda, David; Pedraz, María; Estivill-Torrús, Guillermo; Pavón, Francisco Javier; Rodríguez de Fonseca, Fernando; Santín, Luis J

2016-05-01

We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model. © 2015 Society for the Study of Addiction.

GABAergic neurons in ferret visual cortex participate in functionally specific networks

PubMed Central

Wilson, Daniel E.; Smith, Gordon B.; Jacob, Amanda; Walker, Theo; Dimidschstein, Jordane; Fishell, Gord J.; Fitzpatrick, David

2017-01-01

Summary Functional circuits in the visual cortex require the coordinated activity of excitatory and inhibitory neurons. Molecular genetic approaches in the mouse have led to the ‘local nonspecific pooling principle’ of inhibitory connectivity, in which inhibitory neurons are untuned for stimulus features due to the random pooling of local inputs. However, it remains unclear whether this principle generalizes to species with a columnar organization of feature selectivity such as carnivores, primates, and humans. Here we use virally-mediated GABAergic-specific GCaMP6f expression to demonstrate that inhibitory neurons in ferret visual cortex respond robustly and selectively to oriented stimuli. We find that the tuning of inhibitory neurons is inconsistent with the local non-specific pooling of excitatory inputs, and that inhibitory neurons exhibit orientation-specific noise correlations with local and distant excitatory neurons. These findings challenge the generality of the non-specific pooling principle for inhibitory neurons, suggesting different rules for functional excitatory-inhibitory interactions in non-murine species. PMID:28279352

Functional optical probing of the hippocampal trisynaptic circuit in vitro: network dynamics, filter properties, and polysynaptic induction of CA1 LTP.

PubMed

Stepan, Jens; Dine, Julien; Eder, Matthias

2015-01-01

Decades of brain research have identified various parallel loops linking the hippocampus with neocortical areas, enabling the acquisition of spatial and episodic memories. Especially the hippocampal trisynaptic circuit [entorhinal cortex layer II → dentate gyrus (DG) → cornu ammonis (CA)-3 → CA1] was studied in great detail because of its seemingly simple connectivity and characteristic structures that are experimentally well accessible. While numerous researchers focused on functional aspects, obtained from a limited number of cells in distinct hippocampal subregions, little is known about the neuronal network dynamics which drive information across multiple synapses for subsequent long-term storage. Fast voltage-sensitive dye imaging in vitro allows real-time recording of activity patterns in large/meso-scale neuronal networks with high spatial resolution. In this way, we recently found that entorhinal theta-frequency input to the DG most effectively passes filter mechanisms of the trisynaptic circuit network, generating activity waves which propagate across the entire DG-CA axis. These "trisynaptic circuit waves" involve high-frequency firing of CA3 pyramidal neurons, leading to a rapid induction of classical NMDA receptor-dependent long-term potentiation (LTP) at CA3-CA1 synapses (CA1 LTP). CA1 LTP has been substantially evidenced to be essential for some forms of explicit learning in mammals. Here, we review data with particular reference to whole network-level approaches, illustrating how activity propagation can take place within the trisynaptic circuit to drive formation of CA1 LTP.

Neuronal Calcium Signaling in Metabolic Regulation and Adaptation to Nutrient Stress.

PubMed

Jayakumar, Siddharth; Hasan, Gaiti

2018-01-01

All organisms can respond physiologically and behaviorally to environmental fluxes in nutrient levels. Different nutrient sensing pathways exist for specific metabolites, and their inputs ultimately define appropriate nutrient uptake and metabolic homeostasis. Nutrient sensing mechanisms at the cellular level require pathways such as insulin and target of rapamycin (TOR) signaling that integrates information from different organ systems like the fat body and the gut. Such integration is essential for coordinating growth with development. Here we review the role of a newly identified set of integrative interneurons and the role of intracellular calcium signaling within these neurons, in regulating nutrient sensing under conditions of nutrient stress. A comparison of the identified Drosophila circuit and cellular mechanisms employed in this circuit, with vertebrate systems, suggests that the identified cell signaling mechanisms may be conserved for neural circuit function related to nutrient sensing by central neurons. The ideas proposed are potentially relevant for understanding the molecular basis of metabolic disorders, because these are frequently linked to nutritional stress.

Mechanisms of input and output synaptic specificity: finding partners, building synapses, and fine-tuning communication.

PubMed

Rawson, Randi L; Martin, E Anne; Williams, Megan E

2017-08-01

For most neurons to function properly, they need to develop synaptic specificity. This requires finding specific partner neurons, building the correct types of synapses, and fine-tuning these synapses in response to neural activity. Synaptic specificity is common at both a neuron's input and output synapses, whereby unique synapses are built depending on the partnering neuron. Neuroscientists have long appreciated the remarkable specificity of neural circuits but identifying molecular mechanisms mediating synaptic specificity has only recently accelerated. Here, we focus on recent progress in understanding input and output synaptic specificity in the mammalian brain. We review newly identified circuit examples for both and the latest research identifying molecular mediators including Kirrel3, FGFs, and DGLα. Lastly, we expect the pace of research on input and output specificity to continue to accelerate with the advent of new technologies in genomics, microscopy, and proteomics. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synaptic Regulation of a Thalamocortical Circuit Controls Depression-Related Behavior.

PubMed

Miller, Oliver H; Bruns, Andreas; Ben Ammar, Imen; Mueggler, Thomas; Hall, Benjamin J

2017-08-22

The NMDA receptor (NMDAR) antagonist ketamine elicits a long-lasting antidepressant response in patients with treatment-resistant depression. Understanding how antagonism of NMDARs alters synapse and circuit function is pivotal to developing circuit-based therapies for depression. Using virally induced gene deletion, ex vivo optogenetic-assisted circuit analysis, and in vivo chemogenetics and fMRI, we assessed the role of NMDARs in the medial prefrontal cortex (mPFC) in controlling depression-related behavior in mice. We demonstrate that post-developmental genetic deletion of the NMDAR subunit GluN2B from pyramidal neurons in the mPFC enhances connectivity between the mPFC and limbic thalamus, but not the ventral hippocampus, and reduces depression-like behavior. Using intersectional chemogenetics, we show that activation of this thalamocortical circuit is sufficient to elicit a decrease in despair-like behavior. Our findings reveal that GluN2B exerts input-specific control of pyramidal neuron innervation and identify a medial dorsal thalamus (MDT)→mPFC circuit that controls depression-like behavior. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Real-time cerebellar neuroprosthetic system based on a spiking neural network model of motor learning.

PubMed

Xu, Tao; Xiao, Na; Zhai, Xiaolong; Kwan Chan, Pak; Tin, Chung

2018-02-01

Damage to the brain, as a result of various medical conditions, impacts the everyday life of patients and there is still no complete cure to neurological disorders. Neuroprostheses that can functionally replace the damaged neural circuit have recently emerged as a possible solution to these problems. Here we describe the development of a real-time cerebellar neuroprosthetic system to substitute neural function in cerebellar circuitry for learning delay eyeblink conditioning (DEC). The system was empowered by a biologically realistic spiking neural network (SNN) model of the cerebellar neural circuit, which considers the neuronal population and anatomical connectivity of the network. The model simulated synaptic plasticity critical for learning DEC. This SNN model was carefully implemented on a field programmable gate array (FPGA) platform for real-time simulation. This hardware system was interfaced in in vivo experiments with anesthetized rats and it used neural spikes recorded online from the animal to learn and trigger conditioned eyeblink in the animal during training. This rat-FPGA hybrid system was able to process neuronal spikes in real-time with an embedded cerebellum model of ~10 000 neurons and reproduce learning of DEC with different inter-stimulus intervals. Our results validated that the system performance is physiologically relevant at both the neural (firing pattern) and behavioral (eyeblink pattern) levels. This integrated system provides the sufficient computation power for mimicking the cerebellar circuit in real-time. The system interacts with the biological system naturally at the spike level and can be generalized for including other neural components (neuron types and plasticity) and neural functions for potential neuroprosthetic applications.

Organization of dopamine and serotonin system: Anatomical and functional mapping of monosynaptic inputs using rabies virus.

PubMed

Ogawa, Sachie K; Watabe-Uchida, Mitsuko

2017-05-02

Dopamine and serotonin play critical roles in flexible behaviors and are related to various psychiatric and motor disorders. This paper reviews the global organization of dopamine and serotonin systems through recent findings using a modified rabies virus. We first introduce methods for comprehensive mapping of monosynaptic inputs. We then describe quantitative comparisons across the data regarding monosynaptic inputs to dopamine neurons versus serotonin neurons. There is surprising similarity between the input to dopamine neurons in the ventral tegmental area (VTA) and the input to serotonin neurons in the dorsal raphe (DR), suggesting functional interactions between these systems. We next introduce studies of mapping monosynaptic inputs to subpopulations of dopamine neurons specified by their projection targets. It was found that the population of dopamine neurons that project to the tail of the striatum (TS) forms an anatomically distinct outlier, suggesting a unique function. From these series of anatomical studies, we propose that there are three information flows that regulate these neuromodulatory systems: the midline stream to serotonin neurons in median raphe (MR) and B6, the central stream to value-coding dopamine neurons and serotonin neurons in rostral DR, and the lateral stream to TS-projecting dopamine neurons. Finally we introduce a new approach to investigate firing patterns of monosynaptic inputs to dopamine neurons in behaving animals. Combining anatomical and physiological findings, we propose that within the central stream, dopamine neurons broadcast a central teaching signal rather than personal teaching signals to multiple brain areas, which are computed in a redundant way in multi-layered neural circuits. Examination of global organization of the dopamine and serotonin circuits not only revealed the complexity of the systems but also revealed some principles of their organization. We will also discuss limitations, practical issues and the possibility of future improvements of the rabies virus-mediated tracing system. Copyright © 2017 Elsevier Inc. All rights reserved.

Choice-specific sequences in parietal cortex during a virtual-navigation decision task

PubMed Central

Harvey, Christopher D.; Coen, Philip; Tank, David W.

2012-01-01

The posterior parietal cortex (PPC) plays an important role in many cognitive behaviors; however, the neural circuit dynamics underlying PPC function are not well understood. Here we optically imaged the spatial and temporal activity patterns of neuronal populations in mice performing a PPC-dependent task that combined a perceptual decision and memory-guided navigation in a virtual environment. Individual neurons had transient activation staggered relative to one another in time, forming a sequence of neuronal activation spanning the entire length of a task trial. Distinct sequences of neurons were triggered on trials with opposite behavioral choices and defined divergent, choice-specific trajectories through a state space of neuronal population activity. Cells participating in the different sequences and at distinct time points in the task were anatomically intermixed over microcircuit length scales (< 100 micrometers). During working memory decision tasks the PPC may therefore perform computations through sequence-based circuit dynamics, rather than long-lived stable states, implemented using anatomically intermingled microcircuits. PMID:22419153

The Drosophila TRPA1 Channel and Neuronal Circuits Controlling Rhythmic Behaviours and Sleep in Response to Environmental Temperature

PubMed Central

2017-01-01

trpA1 encodes a thermosensitive transient receptor potential channel (TRP channel) that functions in selection of preferred temperatures and noxious heat avoidance. In this review, we discuss the evidence for a role of TRPA1 in the control of rhythmic behaviours in Drosophila melanogaster. Activity levels during the afternoon and rhythmic temperature preference are both regulated by TRPA1. In contrast, TRPA1 is dispensable for temperature synchronisation of circadian clocks. We discuss the neuronal basis of TRPA1-mediated temperature effects on rhythmic behaviours, and conclude that they are mediated by partly overlapping but distinct neuronal circuits. We have previously shown that TRPA1 is required to maintain siesta sleep under warm temperature cycles. Here, we present new data investigating the neuronal circuit responsible for this regulation. First, we discuss the difficulties that remain in identifying the responsible neurons. Second, we discuss the role of clock neurons (s-LNv/DN1 network) in temperature-driven regulation of siesta sleep, and highlight the role of TRPA1 therein. Finally, we discuss the sexual dimorphic nature of siesta sleep and propose that the s-LNv/DN1 clock network could play a role in the integration of environmental information, mating status and other internal drives, to appropriately drive adaptive sleep/wake behaviour. PMID:28972543

Vulnerability-Based Critical Neurons, Synapses, and Pathways in the Caenorhabditis elegans Connectome

PubMed Central

Kim, Seongkyun; Kim, Hyoungkyu; Kralik, Jerald D.; Jeong, Jaeseung

2016-01-01

Determining the fundamental architectural design of complex nervous systems will lead to significant medical and technological advances. Yet it remains unclear how nervous systems evolved highly efficient networks with near optimal sharing of pathways that yet produce multiple distinct behaviors to reach the organism’s goals. To determine this, the nematode roundworm Caenorhabditis elegans is an attractive model system. Progress has been made in delineating the behavioral circuits of the C. elegans, however, many details are unclear, including the specific functions of every neuron and synapse, as well as the extent the behavioral circuits are separate and parallel versus integrative and serial. Network analysis provides a normative approach to help specify the network design. We investigated the vulnerability of the Caenorhabditis elegans connectome by performing computational experiments that (a) “attacked” 279 individual neurons and 2,990 weighted synaptic connections (composed of 6,393 chemical synapses and 890 electrical junctions) and (b) quantified the effects of each removal on global network properties that influence information processing. The analysis identified 12 critical neurons and 29 critical synapses for establishing fundamental network properties. These critical constituents were found to be control elements—i.e., those with the most influence over multiple underlying pathways. Additionally, the critical synapses formed into circuit-level pathways. These emergent pathways provide evidence for (a) the importance of backward locomotion, avoidance behavior, and social feeding behavior to the organism; (b) the potential roles of specific neurons whose functions have been unclear; and (c) both parallel and serial design elements in the connectome—i.e., specific evidence for a mixed architectural design. PMID:27540747

Cell Type–Specific Three-Dimensional Structure of Thalamocortical Circuits in a Column of Rat Vibrissal Cortex

PubMed Central

de Kock, Christiaan P. J.; Bruno, Randy M.; Ramirez, Alejandro; Meyer, Hanno S.; Dercksen, Vincent J.; Helmstaedter, Moritz; Sakmann, Bert

2012-01-01

Soma location, dendrite morphology, and synaptic innervation may represent key determinants of functional responses of individual neurons, such as sensory-evoked spiking. Here, we reconstruct the 3D circuits formed by thalamocortical afferents from the lemniscal pathway and excitatory neurons of an anatomically defined cortical column in rat vibrissal cortex. We objectively classify 9 cortical cell types and estimate the number and distribution of their somata, dendrites, and thalamocortical synapses. Somata and dendrites of most cell types intermingle, while thalamocortical connectivity depends strongly upon the cell type and the 3D soma location of the postsynaptic neuron. Correlating dendrite morphology and thalamocortical connectivity to functional responses revealed that the lemniscal afferents can account for some of the cell type- and location-specific subthreshold and spiking responses after passive whisker touch (e.g., in layer 4, but not for other cell types, e.g., in layer 5). Our data provides a quantitative 3D prediction of the cell type–specific lemniscal synaptic wiring diagram and elucidates structure–function relationships of this physiologically relevant pathway at single-cell resolution. PMID:22089425

Transgenic Mouse Lines Subdivide External Segment of the Globus Pallidus (GPe) Neurons and Reveal Distinct GPe Output Pathways

PubMed Central

Mastro, Kevin J.; Bouchard, Rachel S.; Holt, Hiromi A. K.

2014-01-01

Cell-type diversity in the brain enables the assembly of complex neural circuits, whose organization and patterns of activity give rise to brain function. However, the identification of distinct neuronal populations within a given brain region is often complicated by a lack of objective criteria to distinguish one neuronal population from another. In the external segment of the globus pallidus (GPe), neuronal populations have been defined using molecular, anatomical, and electrophysiological criteria, but these classification schemes are often not generalizable across preparations and lack consistency even within the same preparation. Here, we present a novel use of existing transgenic mouse lines, Lim homeobox 6 (Lhx6)–Cre and parvalbumin (PV)–Cre, to define genetically distinct cell populations in the GPe that differ molecularly, anatomically, and electrophysiologically. Lhx6–GPe neurons, which do not express PV, are concentrated in the medial portion of the GPe. They have lower spontaneous firing rates, narrower dynamic ranges, and make stronger projections to the striatum and substantia nigra pars compacta compared with PV–GPe neurons. In contrast, PV–GPe neurons are more concentrated in the lateral portions of the GPe. They have narrower action potentials, deeper afterhyperpolarizations, and make stronger projections to the subthalamic nucleus and parafascicular nucleus of the thalamus. These electrophysiological and anatomical differences suggest that Lhx6–GPe and PV–GPe neurons participate in different circuits with the potential to contribute to different aspects of motor function and dysfunction in disease. PMID:24501350

Visual Input to the Drosophila Central Complex by Developmentally and Functionally Distinct Neuronal Populations.

PubMed

Omoto, Jaison Jiro; Keleş, Mehmet Fatih; Nguyen, Bao-Chau Minh; Bolanos, Cheyenne; Lovick, Jennifer Kelly; Frye, Mark Arthur; Hartenstein, Volker

2017-04-24

The Drosophila central brain consists of stereotyped neural lineages, developmental-structural units of macrocircuitry formed by the sibling neurons of single progenitors called neuroblasts. We demonstrate that the lineage principle guides the connectivity and function of neurons, providing input to the central complex, a collection of neuropil compartments important for visually guided behaviors. One of these compartments is the ellipsoid body (EB), a structure formed largely by the axons of ring (R) neurons, all of which are generated by a single lineage, DALv2. Two further lineages, DALcl1 and DALcl2, produce neurons that connect the anterior optic tubercle, a central brain visual center, with R neurons. Finally, DALcl1/2 receive input from visual projection neurons of the optic lobe medulla, completing a three-legged circuit that we call the anterior visual pathway (AVP). The AVP bears a fundamental resemblance to the sky-compass pathway, a visual navigation circuit described in other insects. Neuroanatomical analysis and two-photon calcium imaging demonstrate that DALcl1 and DALcl2 form two parallel channels, establishing connections with R neurons located in the peripheral and central domains of the EB, respectively. Although neurons of both lineages preferentially respond to bright objects, DALcl1 neurons have small ipsilateral, retinotopically ordered receptive fields, whereas DALcl2 neurons share a large excitatory receptive field in the contralateral hemifield. DALcl2 neurons become inhibited when the object enters the ipsilateral hemifield and display an additional excitation after the object leaves the field of view. Thus, the spatial position of a bright feature, such as a celestial body, may be encoded within this pathway. Copyright © 2017 Elsevier Ltd. All rights reserved.

2010 Carl Ludwig Distinguished Lectureship of the APS Neural Control and Autonomic Regulation Section: Central neural pathways for thermoregulatory cold defense

PubMed Central

2011-01-01

Central neural circuits orchestrate the homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the research leading to a model representing our current understanding of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for control of heat loss, and brown adipose tissue, skeletal muscle, and the heart for thermogenesis. The activation of these effectors is regulated by parallel but distinct, effector-specific core efferent pathways within the central nervous system (CNS) that share a common peripheral thermal sensory input. The thermal afferent circuit from cutaneous thermal receptors includes neurons in the spinal dorsal horn projecting to lateral parabrachial nucleus neurons that project to the medial aspect of the preoptic area. Within the preoptic area, warm-sensitive, inhibitory output neurons control heat production by reducing the discharge of thermogenesis-promoting neurons in the dorsomedial hypothalamus. The rostral ventromedial medulla, including the raphe pallidus, receives projections form the dorsomedial hypothalamus and contains spinally projecting premotor neurons that provide the excitatory drive to spinal circuits controlling the activity of thermogenic effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus sympathetic premotor neurons controlling cutaneous vasoconstriction. The model proposed for central thermoregulatory control provides a platform for further understanding of the functional organization of central thermoregulation. PMID:21270352

Thalamocortical and corticothalamic pathways differentially contribute to goal-directed behaviors in the rat

PubMed Central

Alcaraz, Fabien; Fresno, Virginie; Marchand, Alain R; Kremer, Eric J; Coutureau, Etienne

2018-01-01

Highly distributed neural circuits are thought to support adaptive decision-making in volatile and complex environments. Notably, the functional interactions between prefrontal and reciprocally connected thalamic nuclei areas may be important when choices are guided by current goal value or action-outcome contingency. We examined the functional involvement of selected thalamocortical and corticothalamic pathways connecting the dorsomedial prefrontal cortex (dmPFC) and the mediodorsal thalamus (MD) in the behaving rat. Using a chemogenetic approach to inhibit projection-defined dmPFC and MD neurons during an instrumental learning task, we show that thalamocortical and corticothalamic pathways differentially support goal attributes. Both pathways participate in adaptation to the current goal value, but only thalamocortical neurons are required to integrate current causal relationships. These data indicate that antiparallel flow of information within thalamocortical circuits may convey qualitatively distinct aspects of adaptive decision-making and highlight the importance of the direction of information flow within neural circuits. PMID:29405119

Implementation of olfactory bulb glomerular-layer computations in a digital neurosynaptic core.

PubMed

Imam, Nabil; Cleland, Thomas A; Manohar, Rajit; Merolla, Paul A; Arthur, John V; Akopyan, Filipp; Modha, Dharmendra S

2012-01-01

We present a biomimetic system that captures essential functional properties of the glomerular layer of the mammalian olfactory bulb, specifically including its capacity to decorrelate similar odor representations without foreknowledge of the statistical distributions of analyte features. Our system is based on a digital neuromorphic chip consisting of 256 leaky-integrate-and-fire neurons, 1024 × 256 crossbar synapses, and address-event representation communication circuits. The neural circuits configured in the chip reflect established connections among mitral cells, periglomerular cells, external tufted cells, and superficial short-axon cells within the olfactory bulb, and accept input from convergent sets of sensors configured as olfactory sensory neurons. This configuration generates functional transformations comparable to those observed in the glomerular layer of the mammalian olfactory bulb. Our circuits, consuming only 45 pJ of active power per spike with a power supply of 0.85 V, can be used as the first stage of processing in low-power artificial chemical sensing devices inspired by natural olfactory systems.

Functional Peptidomics: Combining Discovery-Based Mass Spectrometry and Neurophysiology to Explore Communication of Phase-Resetting Cues in the Rat Suprachiasmatic Nucleus

ERIC Educational Resources Information Center

Atkins, Norman, Jr.

2009-01-01

Intercellular signaling is vital to communication within neuronal circuits. The suprachiasmatic nucleus (SCN), the master circadian clock of mammals, contains a dense collection of neurons that align their intrinsic rhythmicity with environmental stimulus and physiological state. While peptide physiology has been demonstrated as a contributor to…

[Review of the regeneration mechanism of complete spinal cord injury].

PubMed

Li, Jiayin; Li, Xing; Xiao, Zhifeng; Dai, Jianwu

2018-06-01

Spinal cord injury (SCI), especially the complete SCI, usually results in complete paralysis below the level of the injury and seriously affects the patient's quality of life. SCI repair is still a worldwide medical problem. In the last twenty years, Professor DAI Jianwu and his team pioneered complete SCI model by removing spinal tissue with varied lengths in rodents, canine, and non-human primates to verify therapeutic effect of different repair strategies. Moreover, they also started the first clinical study of functional collagen scaffold on patients with acute complete SCI on January 16th, 2015. This review mainly focusses on the possible mechanisms responsible for complete SCI. In common, recovery of some sensory and motor functions post complete SCI include the following three contributing reasons. ① Regeneration of long ascending and descending axons throughout the lesion site to re-connect the original targets; ② New neural circuits formed in the lesion site by newly generated neurons post injury, which effectively re-connect the transected stumps; ③ The combined effect of ① and ②. The numerous studies have confirmed that neural circuits rebuilt across the injury site by newborn neurons might be the main mechanisms for functional recovery of animals from rodents to dogs. In many SCI model, especially the complete spinal cord transection model, many studies have convincingly demonstrated that the quantity and length of regenerated long descending axons, particularly like CST fibers, are too few to across the lesion site that is millimeters in length to realize motor functional recovery. Hence, it is more feasible in guiding neuronal relays formation by bio-scaffolds implantation than directing long motor axons regeneration in improving motor function of animals with complete spinal cord transection. However, some other issues such as promoting more neuronal relays formation, debugging wrong connections, and maintaining adequate neural circuits for functional recovery are urgent problems to be addressed.

Maturation of a central brain flight circuit in Drosophila requires Fz2/Ca2+ signaling

PubMed Central

Agrawal, Tarjani; Hasan, Gaiti

2015-01-01

The final identity of a differentiated neuron is determined by multiple signaling events, including activity dependent calcium transients. Non-canonical Frizzled2 (Fz2) signaling generates calcium transients that determine neuronal polarity, neuronal migration, and synapse assembly in the developing vertebrate brain. Here, we demonstrate a requirement for Fz2/Ca2+ signaling in determining the final differentiated state of a set of central brain dopaminergic neurons in Drosophila, referred to as the protocerebral anterior medial (PAM) cluster. Knockdown or inhibition of Fz2/Ca2+ signaling during maturation of the flight circuit in pupae reduces Tyrosine Hydroxylase (TH) expression in the PAM neurons and affects maintenance of flight. Thus, we demonstrate that Fz2/Ca2+ transients during development serve as a pre-requisite for normal adult behavior. Our results support a neural mechanism where PAM neuron send projections to the α' and β' lobes of a higher brain centre, the mushroom body, and function in dopaminergic re-inforcement of flight. DOI: http://dx.doi.org/10.7554/eLife.07046.001 PMID:25955970

Homeodomain protein Otp affects developmental neuropeptide switching in oxytocin neurons associated with a long-term effect on social behavior

PubMed Central

Wircer, Einav; Blechman, Janna; Borodovsky, Nataliya; Tsoory, Michael; Nunes, Ana Rita; Oliveira, Rui F; Levkowitz, Gil

2017-01-01

Proper response to stress and social stimuli depends on orchestrated development of hypothalamic neuronal circuits. Here we address the effects of the developmental transcription factor orthopedia (Otp) on hypothalamic development and function. We show that developmental mutations in the zebrafish paralogous gene otpa but not otpb affect both stress response and social preference. These behavioral phenotypes were associated with developmental alterations in oxytocinergic (OXT) neurons. Thus, otpa and otpb differentially regulate neuropeptide switching in a newly identified subset of OXT neurons that co-express the corticotropin-releasing hormone (CRH). Single-cell analysis revealed that these neurons project mostly to the hindbrain and spinal cord. Ablation of this neuronal subset specifically reduced adult social preference without affecting stress behavior, thereby uncoupling the contribution of a specific OXT cluster to social behavior from the general otpa−/− deficits. Our findings reveal a new role for Otp in controlling developmental neuropeptide balance in a discrete OXT circuit whose disrupted development affects social behavior. DOI: http://dx.doi.org/10.7554/eLife.22170.001 PMID:28094761

In Vitro Studies of Neuronal Networks and Synaptic Plasticity in Invertebrates and in Mammals Using Multielectrode Arrays

PubMed Central

Tessadori, Jacopo; Ghirardi, Mirella

2015-01-01

Brain functions are strictly dependent on neural connections formed during development and modified during life. The cellular and molecular mechanisms underlying synaptogenesis and plastic changes involved in learning and memory have been analyzed in detail in simple animals such as invertebrates and in circuits of mammalian brains mainly by intracellular recordings of neuronal activity. In the last decades, the evolution of techniques such as microelectrode arrays (MEAs) that allow simultaneous, long-lasting, noninvasive, extracellular recordings from a large number of neurons has proven very useful to study long-term processes in neuronal networks in vivo and in vitro. In this work, we start off by briefly reviewing the microelectrode array technology and the optimization of the coupling between neurons and microtransducers to detect subthreshold synaptic signals. Then, we report MEA studies of circuit formation and activity in invertebrate models such as Lymnaea, Aplysia, and Helix. In the following sections, we analyze plasticity and connectivity in cultures of mammalian dissociated neurons, focusing on spontaneous activity and electrical stimulation. We conclude by discussing plasticity in closed-loop experiments. PMID:25866681

Functional architecture of an optic flow-responsive area that drives horizontal eye movements in zebrafish.

PubMed

Kubo, Fumi; Hablitzel, Bastian; Dal Maschio, Marco; Driever, Wolfgang; Baier, Herwig; Arrenberg, Aristides B

2014-03-19

Animals respond to whole-field visual motion with compensatory eye and body movements in order to stabilize both their gaze and position with respect to their surroundings. In zebrafish, rotational stimuli need to be distinguished from translational stimuli to drive the optokinetic and the optomotor responses, respectively. Here, we systematically characterize the neural circuits responsible for these operations using a combination of optogenetic manipulation and in vivo calcium imaging during optic flow stimulation. By recording the activity of thousands of neurons within the area pretectalis (APT), we find four bilateral pairs of clusters that process horizontal whole-field motion and functionally classify eleven prominent neuron types with highly selective response profiles. APT neurons are prevalently direction selective, either monocularly or binocularly driven, and hierarchically organized to distinguish between rotational and translational optic flow. Our data predict a wiring diagram of a neural circuit tailored to drive behavior that compensates for self-motion. Copyright © 2014 Elsevier Inc. All rights reserved.

A neural circuit transforming temporal periodicity information into a rate-based representation in the mammalian auditory system.

PubMed

Dicke, Ulrike; Ewert, Stephan D; Dau, Torsten; Kollmeier, Birger

2007-01-01

Periodic amplitude modulations (AMs) of an acoustic stimulus are presumed to be encoded in temporal activity patterns of neurons in the cochlear nucleus. Physiological recordings indicate that this temporal AM code is transformed into a rate-based periodicity code along the ascending auditory pathway. The present study suggests a neural circuit for the transformation from the temporal to the rate-based code. Due to the neural connectivity of the circuit, bandpass shaped rate modulation transfer functions are obtained that correspond to recorded functions of inferior colliculus (IC) neurons. In contrast to previous modeling studies, the present circuit does not employ a continuously changing temporal parameter to obtain different best modulation frequencies (BMFs) of the IC bandpass units. Instead, different BMFs are yielded from varying the number of input units projecting onto different bandpass units. In order to investigate the compatibility of the neural circuit with a linear modulation filterbank analysis as proposed in psychophysical studies, complex stimuli such as tones modulated by the sum of two sinusoids, narrowband noise, and iterated rippled noise were processed by the model. The model accounts for the encoding of AM depth over a large dynamic range and for modulation frequency selective processing of complex sounds.

Neuroestrogen signaling in the songbird auditory cortex propagates into a sensorimotor network via an `interface' nucleus

PubMed Central

Pawlisch, Benjamin A.; Remage-Healey, Luke

2014-01-01

Neuromodulators rapidly alter activity of neural circuits and can therefore shape higher-order functions, such as sensorimotor integration. Increasing evidence suggests that brain-derived estrogens, such as 17-β-estradiol, can act rapidly to modulate sensory processing. However, less is known about how rapid estrogen signaling can impact downstream circuits. Past studies have demonstrated that estradiol levels increase within the songbird auditory cortex (the caudomedial nidopallium, NCM) during social interactions. Local estradiol signaling enhances the auditory-evoked firing rate of neurons in NCM to a variety of stimuli, while also enhancing the selectivity of auditory-evoked responses of neurons in a downstream sensorimotor brain region, HVC (proper name). Since these two brain regions are not directly connected, we employed dual extracellular recordings in HVC and the upstream nucleus interfacialis of the nidopallium (NIf) during manipulations of estradiol within NCM to better understand the pathway by which estradiol signaling propagates to downstream circuits. NIf has direct input into HVC, passing auditory information into the vocal motor output pathway, and is a possible source of the neural selectivity within HVC. Here, during acute estradiol administration in NCM, NIf neurons showed increases in baseline firing rates and auditory-evoked firing rates to all stimuli. Furthermore, when estradiol synthesis was blocked in NCM, we observed simultaneous decreases in the selectivity of NIf and HVC neurons. These effects were not due to direct estradiol actions because NIf has little to no capability for local estrogen synthesis or estrogen receptors, and these effects were specific to NIf because other neurons immediately surrounding NIf did not show these changes. Our results demonstrate that transsynaptic, rapid fluctuations in neuroestrogens are transmitted into NIf and subsequently HVC, both regions important for sensorimotor integration. Overall, these findings support the hypothesis that acute neurosteroid actions can propagate within and between neural circuits to modulate their functional connectivity. PMID:25453773

Neuroestrogen signaling in the songbird auditory cortex propagates into a sensorimotor network via an 'interface' nucleus.

PubMed

Pawlisch, B A; Remage-Healey, L

2015-01-22

Neuromodulators rapidly alter activity of neural circuits and can therefore shape higher order functions, such as sensorimotor integration. Increasing evidence suggests that brain-derived estrogens, such as 17-β-estradiol, can act rapidly to modulate sensory processing. However, less is known about how rapid estrogen signaling can impact downstream circuits. Past studies have demonstrated that estradiol levels increase within the songbird auditory cortex (the caudomedial nidopallium, NCM) during social interactions. Local estradiol signaling enhances the auditory-evoked firing rate of neurons in NCM to a variety of stimuli, while also enhancing the selectivity of auditory-evoked responses of neurons in a downstream sensorimotor brain region, HVC (proper name). Since these two brain regions are not directly connected, we employed dual extracellular recordings in HVC and the upstream nucleus interfacialis of the nidopallium (NIf) during manipulations of estradiol within NCM to better understand the pathway by which estradiol signaling propagates to downstream circuits. NIf has direct input into HVC, passing auditory information into the vocal motor output pathway, and is a possible source of the neural selectivity within HVC. Here, during acute estradiol administration in NCM, NIf neurons showed increases in baseline firing rates and auditory-evoked firing rates to all stimuli. Furthermore, when estradiol synthesis was blocked in NCM, we observed simultaneous decreases in the selectivity of NIf and HVC neurons. These effects were not due to direct estradiol actions because NIf has little to no capability for local estrogen synthesis or estrogen receptors, and these effects were specific to NIf because other neurons immediately surrounding NIf did not show these changes. Our results demonstrate that transsynaptic, rapid fluctuations in neuroestrogens are transmitted into NIf and subsequently HVC, both regions important for sensorimotor integration. Overall, these findings support the hypothesis that acute neurosteroid actions can propagate within and between neural circuits to modulate their functional connectivity. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

A PDF/NPF neuropeptide signaling circuitry of male Drosophila melanogaster controls rival-induced prolonged mating.

PubMed

Kim, Woo Jae; Jan, Lily Yeh; Jan, Yuh Nung

2013-12-04

A primary function of males for many species involves mating with females for reproduction. Drosophila melanogaster males respond to the presence of other males by prolonging mating duration to increase the chance of passing on their genes. To understand the basis of such complex behaviors, we examine the genetic network and neural circuits that regulate rival-induced Longer-Mating-Duration (LMD). Here, we identify a small subset of clock neurons in the male brain that regulate LMD via neuropeptide signaling. LMD requires the function of pigment-dispersing factor (PDF) in four s-LNv neurons and its receptor PDFR in two LNd neurons per hemisphere, as well as the function of neuropeptide F (NPF) in two neurons within the sexually dimorphic LNd region and its receptor NPFR1 in four s-LNv neurons per hemisphere. Moreover, rival exposure modifies the neuronal activities of a subset of clock neurons involved in neuropeptide signaling for LMD. Copyright © 2013 Elsevier Inc. All rights reserved.

A PDF/NPF neuropeptide signaling circuitry of male Drosophila melanogaster controls rival-induced prolonged mating

PubMed Central

Kim, Woo Jae; Jan, Lily Yeh; Jan, Yuh Nung

2013-01-01

SUMMARY A primary function of males for many species involves mating with females for reproduction. Drosophila melanogaster males respond to the presence of other males by prolonging mating duration to increase the chance of passing on their genes. To understand the basis of such complex behaviors, we examine the genetic network and neural circuits that regulate rival-induced longer mating duration (LMD). Here we identify a small subset of clock neurons in the male brain that regulate LMD via neuropeptide signaling. LMD requires the function of pigment-dispersing factor (PDF) in four s-LNv neurons and its receptor PDFR in two LNd neurons per hemisphere, as well as the function of neuropeptide F (NPF) in two neurons within the sexually dimorphic LNd region and its receptor NPFR1 in four s-LNv neurons per hemisphere. Moreover, rival exposure modifies the neuronal activities of a subset of clock neurons involved in neuropeptide signaling for LMD. PMID:24314729

Differential Receptive Field Properties of Parvalbumin and Somatostatin Inhibitory Neurons in Mouse Auditory Cortex.

PubMed

Li, Ling-Yun; Xiong, Xiaorui R; Ibrahim, Leena A; Yuan, Wei; Tao, Huizhong W; Zhang, Li I

2015-07-01

Cortical inhibitory circuits play important roles in shaping sensory processing. In auditory cortex, however, functional properties of genetically identified inhibitory neurons are poorly characterized. By two-photon imaging-guided recordings, we specifically targeted 2 major types of cortical inhibitory neuron, parvalbumin (PV) and somatostatin (SOM) expressing neurons, in superficial layers of mouse auditory cortex. We found that PV cells exhibited broader tonal receptive fields with lower intensity thresholds and stronger tone-evoked spike responses compared with SOM neurons. The latter exhibited similar frequency selectivity as excitatory neurons. The broader/weaker frequency tuning of PV neurons was attributed to a broader range of synaptic inputs and stronger subthreshold responses elicited, which resulted in a higher efficiency in the conversion of input to output. In addition, onsets of both the input and spike responses of SOM neurons were significantly delayed compared with PV and excitatory cells. Our results suggest that PV and SOM neurons engage in auditory cortical circuits in different manners: while PV neurons may provide broadly tuned feedforward inhibition for a rapid control of ascending inputs to excitatory neurons, the delayed and more selective inhibition from SOM neurons may provide a specific modulation of feedback inputs on their distal dendrites. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Non-overlapping Neural Networks in Hydra vulgaris.

PubMed

Dupre, Christophe; Yuste, Rafael

2017-04-24

To understand the emergent properties of neural circuits, it would be ideal to record the activity of every neuron in a behaving animal and decode how it relates to behavior. We have achieved this with the cnidarian Hydra vulgaris, using calcium imaging of genetically engineered animals to measure the activity of essentially all of its neurons. Although the nervous system of Hydra is traditionally described as a simple nerve net, we surprisingly find instead a series of functional networks that are anatomically non-overlapping and are associated with specific behaviors. Three major functional networks extend through the entire animal and are activated selectively during longitudinal contractions, elongations in response to light, and radial contractions, whereas an additional network is located near the hypostome and is active during nodding. These results demonstrate the functional sophistication of apparently simple nerve nets, and the potential of Hydra and other basal metazoans as a model system for neural circuit studies. Published by Elsevier Ltd.

Tryptophan circuit in fatigue: From blood to brain and cognition.

PubMed

Yamashita, Masatoshi; Yamamoto, Takanobu

2017-11-15

Brain tryptophan and its neuroactive metabolites play key roles in central fatigue. However, previous brain function analysis targets may have included both glia and neurons together. Here, we clarified the fatigue-cognitive circuit of the central-peripheral linkage, including the role of glial-neuronal interaction in cognition. Using a rat model of central fatigue induced by chronic sleep disorder (CFSD), we isolated presynaptic terminals and oligodendrocytes. Results showed that compared to control group, presynaptic levels of tryptophan, kynurenine, and kynurenic acid, but not serotonin, in the CFSD group were higher in the hypothalamus and hippocampus. Moreover, CFSD group had higher oligodendrocytic levels of tryptophan, and impaired spatial cognitive memory accuracy and increased hyperactivity and impulsivity. These findings suggest that dynamic change in glial-neuronal interactions within the hypothalamus-hippocampal circuit causes central fatigue, and increased tryptophan-kynurenic acid pathway activity in this circuit causes reduced cognitive function. Additionally, CFSD group had 1.5 times higher plasma levels of tryptophan and kynurenine. Furthermore, in rats undergoing intraperitoneal administration of kynurenine (100mg/kg) versus vehicle, kynurenine-treated rats showed enhanced production of kynurenic acid in the hippocampus, with suppressed recall of retained spatial cognitive memory. The study revealed that uptake of periphery-derived kynurenine and tryptophan into the brain enhances kynurenic acid production in the brain, and the three factors produce amplification effect involved in the role of central-peripheral linkage in central fatigue, triggering cognitive dysfunction. Copyright © 2017 Elsevier B.V. All rights reserved.

Long-lasting dysregulation of gene expression in corticostriatal circuits after repeated cocaine treatment in adult rats: Effects on zif 268 and homer 1a

PubMed Central

Unal, Cagri T.; Beverley, Joel A.; Willuhn, Ingo; Steiner, Heinz

2009-01-01

Human imaging studies show that psychostimulants such as cocaine produce functional changes in several areas of cortex and striatum. These may reflect neuronal changes related to addiction. We employed gene markers (zif 268, homer 1a) that offer a high anatomical resolution to map cocaine-induced changes in 22 cortical areas and 23 functionally related striatal sectors, in order to determine the corticostriatal circuits altered by repeated cocaine exposure (25 mg/kg, 5 days). Effects were investigated 1 day and 21 days after repeated treatment to assess their longevity. Repeated cocaine treatment increased basal expression of zif 268 predominantly in sensorimotor areas of the cortex. This effect endured for 3 weeks in some areas. These changes were accompanied by attenuated gene induction by a cocaine challenge. In the insular cortex, the cocaine challenge produced a decrease in zif 268 expression after the 21-day, but not 1-day, withdrawal period. In the striatum, cocaine also affected mostly sensorimotor sectors. Repeated cocaine resulted in blunted inducibility of both zif 268 and homer 1a, changes that were still very robust 3 weeks later. Thus, our findings demonstrate that cocaine produces robust and long-lasting changes in gene regulation predominantly in sensorimotor corticostriatal circuits. These neuronal changes were associated with behavioral stereotypies, which are thought to reflect dysfunction in sensorimotor corticostriatal circuits. Future studies will have to elucidate the role of such neuronal changes in psychostimulant addiction. PMID:19419424

In vivo Labeling of Constellations of Functionally Identified Neurons for Targeted in vitro Recordings

PubMed Central

Lien, Anthony D.; Scanziani, Massimo

2011-01-01

Relating the functional properties of neurons in an intact organism with their cellular and synaptic characteristics is necessary for a mechanistic understanding of brain function. However, while the functional properties of cortical neurons (e.g., tuning to sensory stimuli) are necessarily determined in vivo, detailed cellular and synaptic analysis relies on in vitro techniques. Here we describe an approach that combines in vivo calcium imaging (for functional characterization) with photo-activation of fluorescent proteins (for neuron labeling), thereby allowing targeted in vitro recording of multiple neurons with known functional properties. We expressed photo-activatable GFP rendered non-diffusible through fusion with a histone protein (H2B–PAGFP) in the mouse visual cortex to rapidly photo-label constellations of neurons in vivo at cellular and sub-cellular resolution using two-photon excitation. This photo-labeling method was compatible with two-photon calcium imaging of neuronal responses to visual stimuli, allowing us to label constellations of neurons with specific functional properties. Photo-labeled neurons were easily identified in vitro in acute brain slices and could be targeted for whole-cell recording. We also demonstrate that in vitro and in vivo image stacks of the same photo-labeled neurons could be registered to one another, allowing the exact in vivo response properties of individual neurons recorded in vitro to be known. The ability to perform in vitro recordings from neurons with known functional properties opens up exciting new possibilities for dissecting the cellular, synaptic, and circuit mechanisms that underlie neuronal function in vivo. PMID:22144948

Gene Expression Profiling with Cre-Conditional Pseudorabies Virus Reveals a Subset of Midbrain Neurons That Participate in Reward Circuitry

PubMed Central

Pomeranz, Lisa E.; Ekstrand, Mats I.; Latcha, Kaamashri N.; Smith, Gregory A.; Enquist, Lynn W.

2017-01-01

The mesolimbic dopamine pathway receives inputs from numerous regions of the brain as part of a neural system that detects rewarding stimuli and coordinates a behavioral response. The capacity to simultaneously map and molecularly define the components of this complex multisynaptic circuit would thus advance our understanding of the determinants of motivated behavior. To accomplish this, we have constructed pseudorabies virus (PRV) strains in which viral propagation and fluorophore expression are activated only after exposure to Cre recombinase. Once activated in Cre-expressing neurons, the virus serially labels chains of presynaptic neurons. Dual injection of GFP and mCherry tracing viruses simultaneously illuminates nigrostriatal and mesolimbic circuitry and shows no overlap, demonstrating that PRV transmission is confined to synaptically connected neurons. To molecularly profile mesolimbic dopamine neurons and their presynaptic inputs, we injected Cre-conditional GFP virus into the NAc of (anti-GFP) nanobody-L10 transgenic mice and immunoprecipitated translating ribosomes from neurons infected after retrograde tracing. Analysis of purified RNA revealed an enrichment of transcripts expressed in neurons of the dorsal raphe nuclei and lateral hypothalamus that project to the mesolimbic dopamine circuit. These studies identify important inputs to the mesolimbic dopamine pathway and further show that PRV circuit-directed translating ribosome affinity purification can be broadly applied to identify molecularly defined neurons comprising complex, multisynaptic circuits. SIGNIFICANCE STATEMENT The mesolimbic dopamine circuit integrates signals from key brain regions to detect and respond to rewarding stimuli. To further define this complex multisynaptic circuit, we constructed a panel of Cre recombinase-activated pseudorabies viruses (PRVs) that enabled retrograde tracing of neural inputs that terminate on Cre-expressing neurons. Using these viruses and Retro-TRAP (translating ribosome affinity purification), a previously reported molecular profiling method, we developed a novel technique that provides anatomic as well as molecular information about the neural components of polysynaptic circuits. We refer to this new method as PRV-Circuit-TRAP (PRV circuit-directed TRAP). Using it, we have identified major projections to the mesolimbic dopamine circuit from the lateral hypothalamus and dorsal raphe nucleus and defined a discrete subset of transcripts expressed in these projecting neurons, which will allow further characterization of this important pathway. Moreover, the method we report is general and can be applied to the study of other neural circuits. PMID:28283558

Intrinsic neuromodulation: altering neuronal circuits from within.

PubMed

Katz, P S; Frost, W N

1996-02-01

There are two sources of neuromodulation for neuronal circuits: extrinsic inputs and intrinsic components of the circuits themselves. Extrinsic neuromodulation is known to be pervasive in nervous systems, but intrinsic neuromodulation is less recognized, despite the fact that it has now been demonstrated in sensory and neuromuscular circuits and in central pattern generators. By its nature, intrinsic neuromodulation produces local changes in neuronal computation, whereas extrinsic neuromodulation can cause global changes, often affecting many circuits simultaneously. Studies in a number of systems are defining the different properties of these two forms of neuromodulation.

Role of motoneuron-derived neurotrophin 3 in survival and axonal projection of sensory neurons during neural circuit formation.

PubMed

Usui, Noriyoshi; Watanabe, Keisuke; Ono, Katsuhiko; Tomita, Koichi; Tamamaki, Nobuaki; Ikenaka, Kazuhiro; Takebayashi, Hirohide

2012-03-01

Sensory neurons possess the central and peripheral branches and they form unique spinal neural circuits with motoneurons during development. Peripheral branches of sensory axons fasciculate with the motor axons that extend toward the peripheral muscles from the central nervous system (CNS), whereas the central branches of proprioceptive sensory neurons directly innervate motoneurons. Although anatomically well documented, the molecular mechanism underlying sensory-motor interaction during neural circuit formation is not fully understood. To investigate the role of motoneuron on sensory neuron development, we analyzed sensory neuron phenotypes in the dorsal root ganglia (DRG) of Olig2 knockout (KO) mouse embryos, which lack motoneurons. We found an increased number of apoptotic cells in the DRG of Olig2 KO embryos at embryonic day (E) 10.5. Furthermore, abnormal axonal projections of sensory neurons were observed in both the peripheral branches at E10.5 and central branches at E15.5. To understand the motoneuron-derived factor that regulates sensory neuron development, we focused on neurotrophin 3 (Ntf3; NT-3), because Ntf3 and its receptors (Trk) are strongly expressed in motoneurons and sensory neurons, respectively. The significance of motoneuron-derived Ntf3 was analyzed using Ntf3 conditional knockout (cKO) embryos, in which we observed increased apoptosis and abnormal projection of the central branch innervating motoneuron, the phenotypes being apparently comparable with that of Olig2 KO embryos. Taken together, we show that the motoneuron is a functional source of Ntf3 and motoneuron-derived Ntf3 is an essential pre-target neurotrophin for survival and axonal projection of sensory neurons.

From Whole-Brain Data to Functional Circuit Models: The Zebrafish Optomotor Response.

PubMed

Naumann, Eva A; Fitzgerald, James E; Dunn, Timothy W; Rihel, Jason; Sompolinsky, Haim; Engert, Florian

2016-11-03

Detailed descriptions of brain-scale sensorimotor circuits underlying vertebrate behavior remain elusive. Recent advances in zebrafish neuroscience offer new opportunities to dissect such circuits via whole-brain imaging, behavioral analysis, functional perturbations, and network modeling. Here, we harness these tools to generate a brain-scale circuit model of the optomotor response, an orienting behavior evoked by visual motion. We show that such motion is processed by diverse neural response types distributed across multiple brain regions. To transform sensory input into action, these regions sequentially integrate eye- and direction-specific sensory streams, refine representations via interhemispheric inhibition, and demix locomotor instructions to independently drive turning and forward swimming. While experiments revealed many neural response types throughout the brain, modeling identified the dimensions of functional connectivity most critical for the behavior. We thus reveal how distributed neurons collaborate to generate behavior and illustrate a paradigm for distilling functional circuit models from whole-brain data. Copyright © 2016 Elsevier Inc. All rights reserved.

Two neuropeptides colocalized in a command-like neuron use distinct mechanisms to enhance its fast synaptic connection.

PubMed

Koh, H Y; Vilim, F S; Jing, J; Weiss, K R

2003-09-01

In many neurons more than one peptide is colocalized with a classical neurotransmitter. The functional consequence of such an arrangement has been rarely investigated. Here, within the feeding circuit of Aplysia, we investigate at a single synapse the actions of two modulatory neuropeptides that are present in a cholinergic interneuron. In combination with previous work, our study shows that the command-like neuron for feeding, CBI-2, contains two neuropeptides, feeding circuit activating peptide (FCAP) and cerebral peptide 2 (CP2). Previous studies showed that high-frequency prestimulation or repeated stimulation of CBI-2 increases the size of CBI-2 to B61/62 excitatory postsynaptic potentials (EPSPs) and shortens the latency of firing of neuron B61/62 in response to CBI-2 stimulation. We find that both FCAP and CP2 mimic these two effects. The variance method of quantal analysis indicates that FCAP increases the calculated quantal size (q) and CP2 increases the calculated quantal content (m) of EPSPs. Since the PSP amplitude represents the product of q and m, the joint action of the two peptides is expected to be cooperative. This observation suggests a possible functional implication for multiple neuropeptides colocalized with a classical neurotransmitter in one neuron.

Cracking the barcode of fullerene-like cortical microcolumns.

PubMed

Tozzi, Arturo; Peters, James F; Ori, Ottorino

2017-03-22

Artificial neural systems and nervous graph theoretical analysis rely upon the stance that the neural code is embodied in logic circuits, e.g., spatio-temporal sequences of ON/OFF spiking neurons. Nevertheless, this assumption does not fully explain complex brain functions. Here we show how nervous activity, other than logic circuits, could instead depend on topological transformations and symmetry constraints occurring at the micro-level of the cortical microcolumn, i.e., the embryological, anatomical and functional basic unit of the brain. Tubular microcolumns can be flattened in fullerene-like two-dimensional lattices, equipped with about 80 nodes standing for pyramidal neurons where neural computations take place. We show how the countless possible combinations of activated neurons embedded in the lattice resemble a barcode. Despite the fact that further experimental verification is required in order to validate our claim, different assemblies of firing neurons might have the appearance of diverse codes, each one responsible for a single mental activity. A two-dimensional fullerene-like lattice, grounded on simple topological changes standing for pyramidal neurons' activation, not just displays analogies with the real microcolumn's microcircuitry and the neural connectome, but also the potential for the manufacture of plastic, robust and fast artificial networks in robotic forms of full-fledged neural systems. Copyright © 2017 Elsevier B.V. All rights reserved.

An Anatomically Constrained Model for Path Integration in the Bee Brain.

PubMed

Stone, Thomas; Webb, Barbara; Adden, Andrea; Weddig, Nicolai Ben; Honkanen, Anna; Templin, Rachel; Wcislo, William; Scimeca, Luca; Warrant, Eric; Heinze, Stanley

2017-10-23

Path integration is a widespread navigational strategy in which directional changes and distance covered are continuously integrated on an outward journey, enabling a straight-line return to home. Bees use vision for this task-a celestial-cue-based visual compass and an optic-flow-based visual odometer-but the underlying neural integration mechanisms are unknown. Using intracellular electrophysiology, we show that polarized-light-based compass neurons and optic-flow-based speed-encoding neurons converge in the central complex of the bee brain, and through block-face electron microscopy, we identify potential integrator cells. Based on plausible output targets for these cells, we propose a complete circuit for path integration and steering in the central complex, with anatomically identified neurons suggested for each processing step. The resulting model circuit is thus fully constrained biologically and provides a functional interpretation for many previously unexplained architectural features of the central complex. Moreover, we show that the receptive fields of the newly discovered speed neurons can support path integration for the holonomic motion (i.e., a ground velocity that is not precisely aligned with body orientation) typical of bee flight, a feature not captured in any previously proposed model of path integration. In a broader context, the model circuit presented provides a general mechanism for producing steering signals by comparing current and desired headings-suggesting a more basic function for central complex connectivity, from which path integration may have evolved. Copyright © 2017 Elsevier Ltd. All rights reserved.

Voltage imaging to understand connections and functions of neuronal circuits.

PubMed

Antic, Srdjan D; Empson, Ruth M; Knöpfel, Thomas

2016-07-01

Understanding of the cellular mechanisms underlying brain functions such as cognition and emotions requires monitoring of membrane voltage at the cellular, circuit, and system levels. Seminal voltage-sensitive dye and calcium-sensitive dye imaging studies have demonstrated parallel detection of electrical activity across populations of interconnected neurons in a variety of preparations. A game-changing advance made in recent years has been the conceptualization and development of optogenetic tools, including genetically encoded indicators of voltage (GEVIs) or calcium (GECIs) and genetically encoded light-gated ion channels (actuators, e.g., channelrhodopsin2). Compared with low-molecular-weight calcium and voltage indicators (dyes), the optogenetic imaging approaches are 1) cell type specific, 2) less invasive, 3) able to relate activity and anatomy, and 4) facilitate long-term recordings of individual cells' activities over weeks, thereby allowing direct monitoring of the emergence of learned behaviors and underlying circuit mechanisms. We highlight the potential of novel approaches based on GEVIs and compare those to calcium imaging approaches. We also discuss how novel approaches based on GEVIs (and GECIs) coupled with genetically encoded actuators will promote progress in our knowledge of brain circuits and systems. Copyright © 2016 the American Physiological Society.

Voltage imaging to understand connections and functions of neuronal circuits

PubMed Central

Antic, Srdjan D.; Empson, Ruth M.

2016-01-01

Understanding of the cellular mechanisms underlying brain functions such as cognition and emotions requires monitoring of membrane voltage at the cellular, circuit, and system levels. Seminal voltage-sensitive dye and calcium-sensitive dye imaging studies have demonstrated parallel detection of electrical activity across populations of interconnected neurons in a variety of preparations. A game-changing advance made in recent years has been the conceptualization and development of optogenetic tools, including genetically encoded indicators of voltage (GEVIs) or calcium (GECIs) and genetically encoded light-gated ion channels (actuators, e.g., channelrhodopsin2). Compared with low-molecular-weight calcium and voltage indicators (dyes), the optogenetic imaging approaches are 1) cell type specific, 2) less invasive, 3) able to relate activity and anatomy, and 4) facilitate long-term recordings of individual cells' activities over weeks, thereby allowing direct monitoring of the emergence of learned behaviors and underlying circuit mechanisms. We highlight the potential of novel approaches based on GEVIs and compare those to calcium imaging approaches. We also discuss how novel approaches based on GEVIs (and GECIs) coupled with genetically encoded actuators will promote progress in our knowledge of brain circuits and systems. PMID:27075539

Genetic dissection of neural circuits underlying sexually dimorphic social behaviours

PubMed Central

Bayless, Daniel W.; Shah, Nirao M.

2016-01-01

The unique hormonal, genetic and epigenetic environments of males and females during development and adulthood shape the neural circuitry of the brain. These differences in neural circuitry result in sex-typical displays of social behaviours such as mating and aggression. Like other neural circuits, those underlying sex-typical social behaviours weave through complex brain regions that control a variety of diverse behaviours. For this reason, the functional dissection of neural circuits underlying sex-typical social behaviours has proved to be difficult. However, molecularly discrete neuronal subpopulations can be identified in the heterogeneous brain regions that control sex-typical social behaviours. In addition, the actions of oestrogens and androgens produce sex differences in gene expression within these brain regions, thereby highlighting the neuronal subpopulations most likely to control sexually dimorphic social behaviours. These conditions permit the implementation of innovative genetic approaches that, in mammals, are most highly advanced in the laboratory mouse. Such approaches have greatly advanced our understanding of the functional significance of sexually dimorphic neural circuits in the brain. In this review, we discuss the neural circuitry of sex-typical social behaviours in mice while highlighting the genetic technical innovations that have advanced the field. PMID:26833830

From synapses to behavior: development of a sensory-motor circuit in the leech.

PubMed

Marin-Burgin, Antonia; Kristan, William B; French, Kathleen A

2008-05-01

The development of neuronal circuits has been advanced greatly by the use of imaging techniques that reveal the activity of neurons during the period when they are constructing synapses and forming circuits. This review focuses on experiments performed in leech embryos to characterize the development of a neuronal circuit that produces a simple segmental behavior called "local bending." The experiments combined electrophysiology, anatomy, and FRET-based voltage-sensitive dyes (VSDs). The VSDs offered two major advantages in these experiments: they allowed us to record simultaneously the activity of many neurons, and unlike other imaging techniques, they revealed inhibition as well as excitation. The results indicated that connections within the circuit are formed in a predictable sequence: initially neurons in the circuit are connected by electrical synapses, forming a network that itself generates an embryonic behavior and prefigures the adult circuit; later chemical synapses, including inhibitory connections, appear, "sculpting" the circuit to generate a different, mature behavior. In this developmental process, some of the electrical connections are completely replaced by chemical synapses, others are maintained into adulthood, and still others persist and share their targets with chemical synaptic connections.

Motor cognition-motor semantics: action perception theory of cognition and communication.

PubMed

Pulvermüller, Friedemann; Moseley, Rachel L; Egorova, Natalia; Shebani, Zubaida; Boulenger, Véronique

2014-03-01

A new perspective on cognition views cortical cell assemblies linking together knowledge about actions and perceptions not only as the vehicles of integrated action and perception processing but, furthermore, as a brain basis for a wide range of higher cortical functions, including attention, meaning and concepts, sequences, goals and intentions, and even communicative social interaction. This article explains mechanisms relevant to mechanistic action perception theory, points to concrete neuronal circuits in brains along with artificial neuronal network simulations, and summarizes recent brain imaging and other experimental data documenting the role of action perception circuits in cognition, language and communication. © 2013 Published by Elsevier Ltd.

Evaluating the functional state of adult-born neurons in the adult dentate gyrus of the hippocampus: from birth to functional integration.

PubMed

Aguilar-Arredondo, Andrea; Arias, Clorinda; Zepeda, Angélica

2015-01-01

Hippocampal neurogenesis occurs in the adult brain in various species, including humans. A compelling question that arose when neurogenesis was accepted to occur in the adult dentate gyrus (DG) is whether new neurons become functionally relevant over time, which is key for interpreting their potential contributions to synaptic circuitry. The functional state of adult-born neurons has been evaluated using various methodological approaches, which have, in turn, yielded seemingly conflicting results regarding the timing of maturation and functional integration. Here, we review the contributions of different methodological approaches to addressing the maturation process of adult-born neurons and their functional state, discussing the contributions and limitations of each method. We aim to provide a framework for interpreting results based on the approaches currently used in neuroscience for evaluating functional integration. As shown by the experimental evidence, adult-born neurons are prone to respond from early stages, even when they are not yet fully integrated into circuits. The ongoing integration process for the newborn neurons is characterised by different features. However, they may contribute differently to the network depending on their maturation stage. When combined, the strategies used to date convey a comprehensive view of the functional development of newly born neurons while providing a framework for approaching the critical time at which new neurons become functionally integrated and influence brain function.

Myostatin-like proteins regulate synaptic function and neuronal morphology.

PubMed

Augustin, Hrvoje; McGourty, Kieran; Steinert, Joern R; Cochemé, Helena M; Adcott, Jennifer; Cabecinha, Melissa; Vincent, Alec; Halff, Els F; Kittler, Josef T; Boucrot, Emmanuel; Partridge, Linda

2017-07-01

Growth factors of the TGFβ superfamily play key roles in regulating neuronal and muscle function. Myostatin (or GDF8) and GDF11 are potent negative regulators of skeletal muscle mass. However, expression of myostatin and its cognate receptors in other tissues, including brain and peripheral nerves, suggests a potential wider biological role. Here, we show that Myoglianin (MYO), the Drosophila homolog of myostatin and GDF11, regulates not only body weight and muscle size, but also inhibits neuromuscular synapse strength and composition in a Smad2-dependent manner. Both myostatin and GDF11 affected synapse formation in isolated rat cortical neuron cultures, suggesting an effect on synaptogenesis beyond neuromuscular junctions. We also show that MYO acts in vivo to inhibit synaptic transmission between neurons in the escape response neural circuit of adult flies. Thus, these anti-myogenic proteins act as important inhibitors of synapse function and neuronal growth. © 2017. Published by The Company of Biologists Ltd.

Planar cell polarity genes control the connectivity of enteric neurons

PubMed Central

Sasselli, Valentina; Boesmans, Werend; Vanden Berghe, Pieter; Tissir, Fadel; Goffinet, André M.; Pachnis, Vassilis

2013-01-01

A highly complex network of intrinsic enteric neurons is required for the digestive and homeostatic functions of the gut. Nevertheless, the genetic and molecular mechanisms that regulate their assembly into functional neuronal circuits are currently unknown. Here we report that the planar cell polarity (PCP) genes Celsr3 and Fzd3 are required during murine embryogenesis to specifically control the guidance and growth of enteric neuronal projections relative to the longitudinal and radial gut axes. Ablation of these genes disrupts the normal organization of nascent neuronal projections, leading to subtle changes of axonal tract configuration in the mature enteric nervous system (ENS), but profound abnormalities in gastrointestinal motility. Our data argue that PCP-dependent modules of connectivity established at early stages of enteric neurogenesis control gastrointestinal function in adult animals and provide the first evidence that developmental deficits in ENS wiring may contribute to the pathogenesis of idiopathic bowel disorders. PMID:23478408

Computer model of a reverberant and parallel circuit coupling

NASA Astrophysics Data System (ADS)

Kalil, Camila de Andrade; de Castro, Maria Clícia Stelling; Cortez, Célia Martins

2017-11-01

The objective of the present study was to deepen the knowledge about the functioning of the neural circuits by implementing a signal transmission model using the Graph Theory in a small network of neurons composed of an interconnected reverberant and parallel circuit, in order to investigate the processing of the signals in each of them and the effects on the output of the network. For this, a program was developed in C language and simulations were done using neurophysiological data obtained in the literature.

Single-cell axotomy of cultured hippocampal neurons integrated in neuronal circuits.

PubMed

Gomis-Rüth, Susana; Stiess, Michael; Wierenga, Corette J; Meyn, Liane; Bradke, Frank

2014-05-01

An understanding of the molecular mechanisms of axon regeneration after injury is key for the development of potential therapies. Single-cell axotomy of dissociated neurons enables the study of the intrinsic regenerative capacities of injured axons. This protocol describes how to perform single-cell axotomy on dissociated hippocampal neurons containing synapses. Furthermore, to axotomize hippocampal neurons integrated in neuronal circuits, we describe how to set up coculture with a few fluorescently labeled neurons. This approach allows axotomy of single cells in a complex neuronal network and the observation of morphological and molecular changes during axon regeneration. Thus, single-cell axotomy of mature neurons is a valuable tool for gaining insights into cell intrinsic axon regeneration and the plasticity of neuronal polarity of mature neurons. Dissociation of the hippocampus and plating of hippocampal neurons takes ∼2 h. Neurons are then left to grow for 2 weeks, during which time they integrate into neuronal circuits. Subsequent axotomy takes 10 min per neuron and further imaging takes 10 min per neuron.

Phospholipase A2 - nexus of aging, oxidative stress, neuronal excitability, and functional decline of the aging nervous system? Insights from a snail model system of neuronal aging and age-associated memory impairment.

PubMed

Hermann, Petra M; Watson, Shawn N; Wildering, Willem C

2014-01-01

The aging brain undergoes a range of changes varying from subtle structural and physiological changes causing only minor functional decline under healthy normal aging conditions, to severe cognitive or neurological impairment associated with extensive loss of neurons and circuits due to age-associated neurodegenerative disease conditions. Understanding how biological aging processes affect the brain and how they contribute to the onset and progress of age-associated neurodegenerative diseases is a core research goal in contemporary neuroscience. This review focuses on the idea that changes in intrinsic neuronal electrical excitability associated with (per)oxidation of membrane lipids and activation of phospholipase A2 (PLA2) enzymes are an important mechanism of learning and memory failure under normal aging conditions. Specifically, in the context of this special issue on the biology of cognitive aging we portray the opportunities offered by the identifiable neurons and behaviorally characterized neural circuits of the freshwater snail Lymnaea stagnalis in neuronal aging research and recapitulate recent insights indicating a key role of lipid peroxidation-induced PLA2 as instruments of aging, oxidative stress and inflammation in age-associated neuronal and memory impairment in this model system. The findings are discussed in view of accumulating evidence suggesting involvement of analogous mechanisms in the etiology of age-associated dysfunction and disease of the human and mammalian brain.

Architecture of enteric neural circuits involved in intestinal motility.

PubMed

Costa, M; Brookes, S H

2008-08-01

This short review describes the conceptual development in the search for the enteric neural circuits with the initial identifications of the classes of enteric neurons on the bases of their morphology, neurochemistry, biophysical properties, projections and connectivity. The discovery of the presence of multiple neurochemicals in the same nerve cells in specific combinations led to the concept of "chemical coding" and of "plurichemical transmission". The proposal that enteric reflexes are largely responsible for the propulsion of contents led to investigations of polarised reflex pathways and how these may be activated to generate the coordinated propulsive behaviour of the intestine. The research over the past decades attempted to integrate information of chemical neuroanatomy with functional studies, with the development of methods combining anatomical, functional and pharmacological techniques. This multidisciplinary strategy led to a full accounting of all functional classes of enteric neurons in the guinea-pig, and advanced wiring diagrams of the enteric neural circuits have been proposed. In parallel, investigations of the actual behaviour of the intestine during physiological motor activity have advanced with the development of spatio-temporal analysis from video recordings. The relation between neural pathways, their activities and the generation of patterns of motor activity remain largely unexplained. The enteric neural circuits appear not set in rigid programs but respond to different physico-chemical contents in an adaptable way (neuromechanical hypothesis). The generation of the complex repertoire of motor patterns results from the interplay of myogenic and neuromechanical mechanisms with spontaneous generation of migratory motor activity by enteric circuits.

A new era for functional labeling of neurons: activity-dependent promoters have come of age

PubMed Central

Kawashima, Takashi; Okuno, Hiroyuki; Bito, Haruhiko

2014-01-01

Genetic labeling of neurons with a specific response feature is an emerging technology for precise dissection of brain circuits that are functionally heterogeneous at the single-cell level. While immediate early gene mapping has been widely used for decades to identify brain regions which are activated by external stimuli, recent characterization of the promoter and enhancer elements responsible for neuronal activity-dependent transcription have opened new avenues for live imaging of active neurons. Indeed, these advancements provided the basis for a growing repertoire of novel experiments to address the role of active neuronal networks in cognitive behaviors. In this review, we summarize the current literature on the usage and development of activity-dependent promoters and discuss the future directions of this expanding new field. PMID:24795570

Signaling in large-scale neural networks.

PubMed

Berg, Rune W; Hounsgaard, Jørn

2009-02-01

We examine the recent finding that neurons in spinal motor circuits enter a high conductance state during functional network activity. The underlying concomitant increase in random inhibitory and excitatory synaptic activity leads to stochastic signal processing. The possible advantages of this metabolically costly organization are analyzed by comparing with synaptically less intense networks driven by the intrinsic response properties of the network neurons.

Spatial distribution of intermingling pools of projection neurons with distinct targets: A 3D analysis of the commissural ganglia in Cancer borealis.

PubMed

Follmann, Rosangela; Goldsmith, Christopher John; Stein, Wolfgang

2017-06-01

Projection neurons play a key role in carrying long-distance information between spatially distant areas of the nervous system and in controlling motor circuits. Little is known about how projection neurons with distinct anatomical targets are organized, and few studies have addressed their spatial organization at the level of individual cells. In the paired commissural ganglia (CoGs) of the stomatogastric nervous system of the crab Cancer borealis, projection neurons convey sensory, motor, and modulatory information to several distinct anatomical regions. While the functions of descending projection neurons (dPNs) which control downstream motor circuits in the stomatogastric ganglion are well characterized, their anatomical distribution as well as that of neurons projecting to the labrum, brain, and thoracic ganglion have received less attention. Using cell membrane staining, we investigated the spatial distribution of CoG projection neurons in relation to all CoG neurons. Retrograde tracing revealed that somata associated with different axonal projection pathways were not completely spatially segregated, but had distinct preferences within the ganglion. Identified dPNs had diameters larger than 70% of CoG somata and were restricted to the most medial and anterior 25% of the ganglion. They were contained within a cluster of motor neurons projecting through the same nerve to innervate the labrum, indicating that soma position was independent of function and target area. Rather, our findings suggest that CoG neurons projecting to a variety of locations follow a generalized rule: for all nerve pathway origins, the soma cluster centroids in closest proximity are those whose axons project down that pathway. © 2017 Wiley Periodicals, Inc.

Functional connectivity in the resting brain as biological correlate of the Affective Neuroscience Personality Scales.

PubMed

Deris, Nadja; Montag, Christian; Reuter, Martin; Weber, Bernd; Markett, Sebastian

2017-02-15

According to Jaak Panksepp's Affective Neuroscience Theory and the derived self-report measure, the Affective Neuroscience Personality Scales (ANPS), differences in the responsiveness of primary emotional systems form the basis of human personality. In order to investigate neuronal correlates of personality, the underlying neuronal circuits of the primary emotional systems were analyzed in the present fMRI-study by associating the ANPS to functional connectivity in the resting brain. N=120 healthy participants were invited for the present study. The results were reinvestigated in an independent, smaller sample of N=52 participants. A seed-based whole brain approach was conducted with seed-regions bilaterally in the basolateral and superficial amygdalae. The selection of seed-regions was based on meta-analytic data on affective processing and the Juelich histological atlas. Multiple regression analyses on the functional connectivity maps revealed associations with the SADNESS-scale in both samples. Functional resting-state connectivity between the left basolateral amygdala and a cluster in the postcentral gyrus, and between the right basolateral amygdala and clusters in the superior parietal lobe and subgyral in the parietal lobe was associated with SADNESS. No other ANPS-scale revealed replicable results. The present findings give first insights into the neuronal basis of the SADNESS-scale of the ANPS and support the idea of underlying neuronal circuits. In combination with previous research on genetic associations of the ANPS functional resting-state connectivity is discussed as a possible endophenotype of personality. Copyright © 2016 Elsevier Inc. All rights reserved.

A ‘tool box’ for deciphering neuronal circuits in the developing chick spinal cord

PubMed Central

Hadas, Yoav; Etlin, Alex; Falk, Haya; Avraham, Oshri; Kobiler, Oren; Panet, Amos; Lev-Tov, Aharon; Klar, Avihu

2014-01-01

The genetic dissection of spinal circuits is an essential new means for understanding the neural basis of mammalian behavior. Molecular targeting of specific neuronal populations, a key instrument in the genetic dissection of neuronal circuits in the mouse model, is a complex and time-demanding process. Here we present a circuit-deciphering ‘tool box’ for fast, reliable and cheap genetic targeting of neuronal circuits in the developing spinal cord of the chick. We demonstrate targeting of motoneurons and spinal interneurons, mapping of axonal trajectories and synaptic targeting in both single and populations of spinal interneurons, and viral vector-mediated labeling of pre-motoneurons. We also demonstrate fluorescent imaging of the activity pattern of defined spinal neurons during rhythmic motor behavior, and assess the role of channel rhodopsin-targeted population of interneurons in rhythmic behavior using specific photoactivation. PMID:25147209

Synaptic Circuit Organization of Motor Corticothalamic Neurons

PubMed Central

Yamawaki, Naoki

2015-01-01

Corticothalamic (CT) neurons in layer 6 constitute a large but enigmatic class of cortical projection neurons. How they are integrated into intracortical and thalamo-cortico-thalamic circuits is incompletely understood, especially outside of sensory cortex. Here, we investigated CT circuits in mouse forelimb motor cortex (M1) using multiple circuit-analysis methods. Stimulating and recording from CT, intratelencephalic (IT), and pyramidal tract (PT) projection neurons, we found strong CT↔ CT and CT↔ IT connections; however, CT→IT connections were limited to IT neurons in layer 6, not 5B. There was strikingly little CT↔ PT excitatory connectivity. Disynaptic inhibition systematically accompanied excitation in these pathways, scaling with the amplitude of excitation according to both presynaptic (class-specific) and postsynaptic (cell-by-cell) factors. In particular, CT neurons evoked proportionally more inhibition relative to excitation (I/E ratio) than IT neurons. Furthermore, the amplitude of inhibition was tuned to match the amount of excitation at the level of individual neurons; in the extreme, neurons receiving no excitation received no inhibition either. Extending these studies to dissect the connectivity between cortex and thalamus, we found that M1-CT neurons and thalamocortical neurons in the ventrolateral (VL) nucleus were remarkably unconnected in either direction. Instead, VL axons in the cortex excited both IT and PT neurons, and CT axons in the thalamus excited other thalamic neurons, including those in the posterior nucleus, which additionally received PT excitation. These findings, which contrast in several ways with previous observations in sensory areas, illuminate the basic circuit organization of CT neurons within M1 and between M1 and thalamus. PMID:25653383

Real-time cerebellar neuroprosthetic system based on a spiking neural network model of motor learning

NASA Astrophysics Data System (ADS)

Xu, Tao; Xiao, Na; Zhai, Xiaolong; Chan, Pak Kwan; Tin, Chung

2018-02-01

Objective. Damage to the brain, as a result of various medical conditions, impacts the everyday life of patients and there is still no complete cure to neurological disorders. Neuroprostheses that can functionally replace the damaged neural circuit have recently emerged as a possible solution to these problems. Here we describe the development of a real-time cerebellar neuroprosthetic system to substitute neural function in cerebellar circuitry for learning delay eyeblink conditioning (DEC). Approach. The system was empowered by a biologically realistic spiking neural network (SNN) model of the cerebellar neural circuit, which considers the neuronal population and anatomical connectivity of the network. The model simulated synaptic plasticity critical for learning DEC. This SNN model was carefully implemented on a field programmable gate array (FPGA) platform for real-time simulation. This hardware system was interfaced in in vivo experiments with anesthetized rats and it used neural spikes recorded online from the animal to learn and trigger conditioned eyeblink in the animal during training. Main results. This rat-FPGA hybrid system was able to process neuronal spikes in real-time with an embedded cerebellum model of ~10 000 neurons and reproduce learning of DEC with different inter-stimulus intervals. Our results validated that the system performance is physiologically relevant at both the neural (firing pattern) and behavioral (eyeblink pattern) levels. Significance. This integrated system provides the sufficient computation power for mimicking the cerebellar circuit in real-time. The system interacts with the biological system naturally at the spike level and can be generalized for including other neural components (neuron types and plasticity) and neural functions for potential neuroprosthetic applications.

Mu opioid receptors in GABAergic forebrain neurons moderate motivation for heroin and palatable food

PubMed Central

Charbogne, Pauline; Gardon, Olivier; Martín-García, Elena; Keyworth, Helen L.; Matsui, Aya; Mechling, Anna E.; Bienert, Thomas; Nasseef, Taufiq; Robé, Anne; Moquin, Luc; Darcq, Emmanuel; Ben Hamida, Sami; Robledo, Patricia; Matifas, Audrey; Befort, Katia; Gavériaux-Ruff, Claire; Harsan, Laura-Adela; Von Everfeldt, Dominik; Hennig, Jurgen; Gratton, Alain; Kitchen, Ian; Bailey, Alexis; Alvarez, Veronica A.; Maldonado, Rafael; Kieffer, Brigitte L.

2016-01-01

BACKGROUND Mu opioid receptors (MORs) are central to pain control, drug reward and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in GABAergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward. METHODS We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in GABAergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology and microdialysis, probed neuronal activation by c-Fos immunohistochemistry and resting state-functional magnetic resonance imaging, and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food. RESULTS Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area (VTA), local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures. CONCLUSIONS Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus beyond a well-established role in reward processing, operating at the level of local VTA neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors. PMID:28185645

All‐optical functional synaptic connectivity mapping in acute brain slices using the calcium integrator CaMPARI

PubMed Central

Sha, Fern; Johenning, Friedrich W.; Schreiter, Eric R.; Looger, Loren L.; Larkum, Matthew E.

2016-01-01

Key points The genetically encoded fluorescent calcium integrator calcium‐modulated photoactivatable ratiobetric integrator (CaMPARI) reports calcium influx induced by synaptic and neural activity. Its fluorescence is converted from green to red in the presence of violet light and calcium.The rate of conversion – the sensitivity to activity – is tunable and depends on the intensity of violet light.Synaptic activity and action potentials can independently initiate significant CaMPARI conversion.The level of conversion by subthreshold synaptic inputs is correlated to the strength of input, enabling optical readout of relative synaptic strength.When combined with optogenetic activation of defined presynaptic neurons, CaMPARI provides an all‐optical method to map synaptic connectivity. Abstract The calcium‐modulated photoactivatable ratiometric integrator (CaMPARI) is a genetically encoded calcium integrator that facilitates the study of neural circuits by permanently marking cells active during user‐specified temporal windows. Permanent marking enables measurement of signals from large swathes of tissue and easy correlation of activity with other structural or functional labels. One potential application of CaMPARI is labelling neurons postsynaptic to specific populations targeted for optogenetic stimulation, giving rise to all‐optical functional connectivity mapping. Here, we characterized the response of CaMPARI to several common types of neuronal calcium signals in mouse acute cortical brain slices. Our experiments show that CaMPARI is effectively converted by both action potentials and subthreshold synaptic inputs, and that conversion level is correlated to synaptic strength. Importantly, we found that conversion rate can be tuned: it is linearly related to light intensity. At low photoconversion light levels CaMPARI offers a wide dynamic range due to slower conversion rate; at high light levels conversion is more rapid and more sensitive to activity. Finally, we employed CaMPARI and optogenetics for functional circuit mapping in ex vivo acute brain slices, which preserve in vivo‐like connectivity of axon terminals. With a single light source, we stimulated channelrhodopsin‐2‐expressing long‐range posteromedial (POm) thalamic axon terminals in cortex and induced CaMPARI conversion in recipient cortical neurons. We found that POm stimulation triggers robust photoconversion of layer 5 cortical neurons and weaker conversion of layer 2/3 neurons. Thus, CaMPARI enables network‐wide, tunable, all‐optical functional circuit mapping that captures supra‐ and subthreshold depolarization. PMID:27861906

Communication and wiring in the cortical connectome

PubMed Central

Budd, Julian M. L.; Kisvárday, Zoltán F.

2012-01-01

In cerebral cortex, the huge mass of axonal wiring that carries information between near and distant neurons is thought to provide the neural substrate for cognitive and perceptual function. The goal of mapping the connectivity of cortical axons at different spatial scales, the cortical connectome, is to trace the paths of information flow in cerebral cortex. To appreciate the relationship between the connectome and cortical function, we need to discover the nature and purpose of the wiring principles underlying cortical connectivity. A popular explanation has been that axonal length is strictly minimized both within and between cortical regions. In contrast, we have hypothesized the existence of a multi-scale principle of cortical wiring where to optimize communication there is a trade-off between spatial (construction) and temporal (routing) costs. Here, using recent evidence concerning cortical spatial networks we critically evaluate this hypothesis at neuron, local circuit, and pathway scales. We report three main conclusions. First, the axonal and dendritic arbor morphology of single neocortical neurons may be governed by a similar wiring principle, one that balances the conservation of cellular material and conduction delay. Second, the same principle may be observed for fiber tracts connecting cortical regions. Third, the absence of sufficient local circuit data currently prohibits any meaningful assessment of the hypothesis at this scale of cortical organization. To avoid neglecting neuron and microcircuit levels of cortical organization, the connectome framework should incorporate more morphological description. In addition, structural analyses of temporal cost for cortical circuits should take account of both axonal conduction and neuronal integration delays, which appear mostly of the same order of magnitude. We conclude the hypothesized trade-off between spatial and temporal costs may potentially offer a powerful explanation for cortical wiring patterns. PMID:23087619

Location matters: distinct DNA methylation patterns in GABAergic interneuronal populations from separate microcircuits within the human hippocampus.

PubMed

Ruzicka, W Brad; Subburaju, Sivan; Coyle, Joseph T; Benes, Francine M

2018-01-15

Recent studies describe distinct DNA methylomes among phenotypic subclasses of neurons in the human brain, but variation in DNA methylation between common neuronal phenotypes distinguished by their function within distinct neural circuits remains an unexplored concept. Studies able to resolve epigenetic profiles at the level of microcircuits are needed to illuminate chromatin dynamics in the regulation of specific neuronal populations and circuits mediating normal and abnormal behaviors. The Illumina HumanMethylation450 BeadChip was used to assess genome-wide DNA methylation in stratum oriens GABAergic interneurons sampled by laser-microdissection from two discrete microcircuits along the trisynaptic pathway in postmortem human hippocampus from eight control, eight schizophrenia, and eight bipolar disorder subjects. Data were analysed using the minfi Bioconductor package in R software version 3.3.2. We identified 11 highly significant differentially methylated regions associated with a group of genes with high construct-validity, including multiple zinc finger of the cerebellum gene family members and WNT signaling factors. Genomic locations of differentially methylated regions were highly similar between diagnostic categories, with a greater number of differentially methylated individual cytosine residues between circuit locations in bipolar disorder cases than in schizophrenia or control (42, 7, and 7 differentially methylated positions, respectively). These findings identify distinct DNA methylomes among phenotypically similar populations of GABAergic interneurons functioning within separate hippocampal subfields. These data compliment recent studies describing diverse epigenotypes among separate neuronal subclasses, extending this concept to distinct epigenotypes within similar neuronal phenotypes from separate microcircuits within the human brain. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Song Selectivity in the Pallial-Basal Ganglia Song Circuit of Zebra Finches Raised Without Tutor Song Exposure

PubMed Central

Kojima, Satoshi; Doupe, Allison J.

2008-01-01

Acoustic experience critically influences auditory cortical development as well as emergence of highly selective auditory neurons in the songbird sensorimotor circuit. In adult zebra finches, these “song-selective” neurons respond better to the bird's own song (BOS) than to songs of other conspecifics. Birds learn their songs by memorizing a tutor's song and then matching auditory feedback of their voice to the tutor song memory. Song-selective neurons in the pallial-basal ganglia circuit called the anterior forebrain pathway (AFP) reflect the development of BOS. However, during learning, they also respond strongly to tutor song and are compromised in their adult selectivity when birds are prevented from matching BOS to tutor, suggesting that selectivity depends on tutor song learning as well as sensorimotor matching of BOS feedback to the tutor song memory. We examined the contribution of sensory learning of tutor song to song selectivity by recording from AFP neurons in birds reared without exposure to adult conspecifics. We found that AFP neurons in these “isolate” birds had highly tuned responses to isolate BOS. The selectivity was as high, and in the striato-pallidal nucleus Area X, even higher than that in normal birds, due to abnormally weak responsiveness to conspecific song. These results demonstrate that sensory learning of tutor song is not necessary for BOS tuning of AFP neurons. Because isolate birds develop their song via sensorimotor learning, our data further illustrate the importance of individual sensorimotor learning for song selectivity and provide insight into possible functions of song-selective neurons. PMID:17625059

Genetic visualization with an improved GCaMP calcium indicator reveals spatiotemporal activation of the spinal motor neurons in zebrafish

PubMed Central

Muto, Akira; Ohkura, Masamichi; Kotani, Tomoya; Higashijima, Shin-ichi; Nakai, Junichi; Kawakami, Koichi

2011-01-01

Animal behaviors are generated by well-coordinated activation of neural circuits. In zebrafish, embryos start to show spontaneous muscle contractions at 17 to 19 h postfertilization. To visualize how motor circuits in the spinal cord are activated during this behavior, we developed GCaMP-HS (GCaMP-hyper sensitive), an improved version of the genetically encoded calcium indicator GCaMP, and created transgenic zebrafish carrying the GCaMP-HS gene downstream of the Gal4-recognition sequence, UAS (upstream activation sequence). Then we performed a gene-trap screen and identified the SAIGFF213A transgenic fish that expressed Gal4FF, a modified version of Gal4, in a subset of spinal neurons including the caudal primary (CaP) motor neurons. We conducted calcium imaging using the SAIGFF213A; UAS:GCaMP-HS double transgenic embryos during the spontaneous contractions. We demonstrated periodic and synchronized activation of a set of ipsilateral motor neurons located on the right and left trunk in accordance with actual muscle movements. The synchronized activation of contralateral motor neurons occurred alternately with a regular interval. Furthermore, a detailed analysis revealed rostral-to-caudal propagation of activation of the ipsilateral motor neuron, which is similar to but much slower than the rostrocaudal delay observed during swimming in later stages. Our study thus demonstrated coordinated activities of the motor neurons during the first behavior in a vertebrate. We propose the GCaMP technology combined with the Gal4FF-UAS system is a powerful tool to study functional neural circuits in zebrafish. PMID:21383146

Cellular complexity in subcortical white matter: a distributed control circuit?

PubMed

Colombo, Jorge A

2018-03-01

The subcortical white matter (SWM) has been traditionally considered as a site for passive-neutral-information transfer through cerebral cortex association and projection fibers. Yet, the presence of subcortical neuronal and glial "interstitial" cells expressing immunolabelled neurotransmitters/neuromodulators and synaptic vesicular proteins, and recent immunohistochemical and electrophysiological observations on the rat visual cortex as well as interactive regulation of myelinating processes support the possibility that SWM nests subcortical, regionally variable, distributed neuronal-glial circuits, that could influence information transfer. Their hypothetical involvement in regulating the timing and signal transfer probability at the SWM axonal components ought to be considered and experimentally analysed. Thus, the "interstitial" neuronal cells-associated with local glial cells-traditionally considered to be vestigial and functionally inert under normal conditions, they may well turn to be critical in regulating information transfer at the SWM.

Theoretical Limitations on Functional Imaging Resolution in Auditory Cortex

PubMed Central

Chen, Thomas L.; Watkins, Paul V.; Barbour, Dennis L.

2010-01-01

Functional imaging can reveal detailed organizational structure in cerebral cortical areas, but neuronal response features and local neural interconnectivity can influence the resulting images, possibly limiting the inferences that can be drawn about neural function. Discerning the fundamental principles of organizational structure in the auditory cortex of multiple species has been somewhat challenging historically both with functional imaging and with electrophysiology. A possible limitation affecting any methodology using pooled neuronal measures may be the relative distribution of response selectivity throughout the population of auditory cortex neurons. One neuronal response type inherited from the cochlea, for example, exhibits a receptive field that increases in size (i.e., decreases in selectivity) at higher stimulus intensities. Even though these neurons appear to represent a minority of auditory cortex neurons, they are likely to contribute disproportionately to the activity detected in functional images, especially if intense sounds are used for stimulation. To evaluate the potential influence of neuronal subpopulations upon functional images of primary auditory cortex, a model array representing cortical neurons was probed with virtual imaging experiments under various assumptions about the local circuit organization. As expected, different neuronal subpopulations were activated preferentially under different stimulus conditions. In fact, stimulus protocols that can preferentially excite selective neurons, resulting in a relatively sparse activation map, have the potential to improve the effective resolution of functional auditory cortical images. These experimental results also make predictions about auditory cortex organization that can be tested with refined functional imaging experiments. PMID:20079343

Illuminating the multifaceted roles of neurotransmission in shaping neuronal circuitry.

PubMed

Okawa, Haruhisa; Hoon, Mrinalini; Yoshimatsu, Takeshi; Della Santina, Luca; Wong, Rachel O L

2014-09-17

Across the nervous system, neurons form highly stereotypic patterns of synaptic connections that are designed to serve specific functions. Mature wiring patterns are often attained upon the refinement of early, less precise connectivity. Much work has led to the prevailing view that many developing circuits are sculpted by activity-dependent competition among converging afferents, which results in the elimination of unwanted synapses and the maintenance and strengthening of desired connections. Studies of the vertebrate retina, however, have recently revealed that activity can play a role in shaping developing circuits without engaging competition among converging inputs that differ in their activity levels. Such neurotransmission-mediated processes can produce stereotypic wiring patterns by promoting selective synapse formation rather than elimination. We discuss how the influence of transmission may also be limited by circuit design and further highlight the importance of transmission beyond development in maintaining wiring specificity and synaptic organization of neural circuits. Copyright © 2014 Elsevier Inc. All rights reserved.

BK Channels Are Required for Multisensory Plasticity in the Oculomotor System.

PubMed

Nelson, Alexandra B; Faulstich, Michael; Moghadam, Setareh; Onori, Kimberly; Meredith, Andrea; du Lac, Sascha

2017-01-04

Neural circuits are endowed with several forms of intrinsic and synaptic plasticity that could contribute to adaptive changes in behavior, but circuit complexities have hindered linking specific cellular mechanisms with their behavioral consequences. Eye movements generated by simple brainstem circuits provide a means for relating cellular plasticity to behavioral gain control. Here we show that firing rate potentiation, a form of intrinsic plasticity mediated by reductions in BK-type calcium-activated potassium currents in spontaneously firing neurons, is engaged during optokinetic reflex compensation for inner ear dysfunction. Vestibular loss triggers transient increases in postsynaptic excitability, occlusion of firing rate potentiation, and reductions in BK currents in vestibular nucleus neurons. Concurrently, adaptive increases in visually evoked eye movements rapidly restore oculomotor function in wild-type mice but are profoundly impaired in BK channel-null mice. Activity-dependent regulation of intrinsic excitability may be a general mechanism for adaptive control of behavioral output in multisensory circuits. Copyright © 2017 Elsevier Inc. All rights reserved.

Regulation of cerebral cortex development by Rho GTPases: insights from in vivo studies

PubMed Central

Azzarelli, Roberta; Kerloch, Thomas; Pacary, Emilie

2015-01-01

The cerebral cortex is the site of higher human cognitive and motor functions. Histologically, it is organized into six horizontal layers, each containing unique populations of molecularly and functionally distinct excitatory projection neurons and inhibitory interneurons. The stereotyped cellular distribution of cortical neurons is crucial for the formation of functional neural circuits and it is predominantly established during embryonic development. Cortical neuron development is a multiphasic process characterized by sequential steps of neural progenitor proliferation, cell cycle exit, neuroblast migration and neuronal differentiation. This series of events requires an extensive and dynamic remodeling of the cell cytoskeleton at each step of the process. As major regulators of the cytoskeleton, the family of small Rho GTPases has been shown to play essential functions in cerebral cortex development. Here we review in vivo findings that support the contribution of Rho GTPases to cortical projection neuron development and we address their involvement in the etiology of cerebral cortex malformations. PMID:25610373

Synapse Formation in Monosynaptic Sensory–Motor Connections Is Regulated by Presynaptic Rho GTPase Cdc42

PubMed Central

Imai, Fumiyasu; Ladle, David R.; Leslie, Jennifer R.; Duan, Xin; Rizvi, Tilat A.; Ciraolo, Georgianne M.; Zheng, Yi

2016-01-01

Spinal reflex circuit development requires the precise regulation of axon trajectories, synaptic specificity, and synapse formation. Of these three crucial steps, the molecular mechanisms underlying synapse formation between group Ia proprioceptive sensory neurons and motor neurons is the least understood. Here, we show that the Rho GTPase Cdc42 controls synapse formation in monosynaptic sensory–motor connections in presynaptic, but not postsynaptic, neurons. In mice lacking Cdc42 in presynaptic sensory neurons, proprioceptive sensory axons appropriately reach the ventral spinal cord, but significantly fewer synapses are formed with motor neurons compared with wild-type mice. Concordantly, electrophysiological analyses show diminished EPSP amplitudes in monosynaptic sensory–motor circuits in these mutants. Temporally targeted deletion of Cdc42 in sensory neurons after sensory–motor circuit establishment reveals that Cdc42 does not affect synaptic transmission. Furthermore, addition of the synaptic organizers, neuroligins, induces presynaptic differentiation of wild-type, but not Cdc42-deficient, proprioceptive sensory neurons in vitro. Together, our findings demonstrate that Cdc42 in presynaptic neurons is required for synapse formation in monosynaptic sensory–motor circuits. SIGNIFICANCE STATEMENT Group Ia proprioceptive sensory neurons form direct synapses with motor neurons, but the molecular mechanisms underlying synapse formation in these monosynaptic sensory–motor connections are unknown. We show that deleting Cdc42 in sensory neurons does not affect proprioceptive sensory axon targeting because axons reach the ventral spinal cord appropriately, but these neurons form significantly fewer presynaptic terminals on motor neurons. Electrophysiological analysis further shows that EPSPs are decreased in these mice. Finally, we demonstrate that Cdc42 is involved in neuroligin-dependent presynaptic differentiation of proprioceptive sensory neurons in vitro. These data suggest that Cdc42 in presynaptic sensory neurons is essential for proper synapse formation in the development of monosynaptic sensory–motor circuits. PMID:27225763

From structure to function, via dynamics

NASA Astrophysics Data System (ADS)

Stetter, O.; Soriano, J.; Geisel, T.; Battaglia, D.

2013-01-01

Neurons in the brain are wired into a synaptic network that spans multiple scales, from local circuits within cortical columns to fiber tracts interconnecting distant areas. However, brain function require the dynamic control of inter-circuit interactions on time-scales faster than synaptic changes. In particular, strength and direction of causal influences between neural populations (described by the so-called directed functional connectivity) must be reconfigurable even when the underlying structural connectivity is fixed. Such directed functional influences can be quantified resorting to causal analysis of time-series based on tools like Granger Causality or Transfer Entropy. The ability to quickly reorganize inter-areal interactions is a chief requirement for performance in a changing natural environment. But how can manifold functional networks stem "on demand" from an essentially fixed structure? We explore the hypothesis that the self-organization of neuronal synchronous activity underlies the control of brain functional connectivity. Based on simulated and real recordings of critical neuronal cultures in vitro, as well as on mean-field and spiking network models of interacting brain areas, we have found that "function follows dynamics", rather than structure. Different dynamic states of a same structural network, characterized by different synchronization properties, are indeed associated to different functional digraphs (functional multiplicity). We also highlight the crucial role of dynamics in establishing a structure-to-function link, by showing that whenever different structural topologies lead to similar dynamical states, than the associated functional connectivities are also very similar (structural degeneracy).

Effects of Anesthetics on Brain Circuit Formation

PubMed Central

Wagner, Meredith; Ryu, Yun Kyoung; Smith, Sarah C.; Mintz, C. David

2014-01-01

The results of several retrospective clinical studies suggest that exposure to anesthetic agents early in life is correlated with subsequent learning and behavioral disorders. While ongoing prospective clinical trials may help to clarify this association, they remain confounded by numerous factors. Thus, some of the most compelling data supporting the hypothesis that a relatively short anesthetic exposure can lead to a long-lasting change in brain function are derived from animal models. The mechanism by which such changes could occur remains incompletely understood. Early studies identified anesthetic-induced neuronal apoptosis as a possible mechanism of injury, and more recent work suggests that anesthetics may interfere with several critical processes in brain development. The function of the mature brain requires the presence of circuits, established during development, that perform the computations underlying learning and cognition. In this review we examine the mechanisms by which anesthetics could disrupt brain circuit formation, including effects on neuronal survival and neurogenesis, neurite growth and guidance, formation of synapses, and function of supporting cells. There is evidence that anesthetics can disrupt aspects of all of these processes, and further research is required to elucidate which are most relevant to pediatric anesthetic neurotoxicity. PMID:25144504

Activity of cardiorespiratory networks revealed by transsynaptic virus expressing GFP.

PubMed

Irnaten, M; Neff, R A; Wang, J; Loewy, A D; Mettenleiter, T C; Mendelowitz, D

2001-01-01

A fluorescent transneuronal marker capable of labeling individual neurons in a central network while maintaining their normal physiology would permit functional studies of neurons within entire networks responsible for complex behaviors such as cardiorespiratory reflexes. The Bartha strain of pseudorabies virus (PRV), an attenuated swine alpha herpesvirus, can be used as a transsynaptic marker of neural circuits. Bartha PRV invades neuronal networks in the CNS through peripherally projecting axons, replicates in these parent neurons, and then travels transsynaptically to continue labeling the second- and higher-order neurons in a time-dependent manner. A Bartha PRV mutant that expresses green fluorescent protein (GFP) was used to visualize and record from neurons that determine the vagal motor outflow to the heart. Here we show that Bartha PRV-GFP-labeled neurons retain their normal electrophysiological properties and that the labeled baroreflex pathways that control heart rate are unaltered by the virus. This novel transynaptic virus permits in vitro studies of identified neurons within functionally defined neuronal systems including networks that mediate cardiovascular and respiratory function and interactions. We also demonstrate superior laryngeal motorneurons fire spontaneously and synapse on cardiac vagal neurons in the nucleus ambiguus. This cardiorespiratory pathway provides a neural basis of respiratory sinus arrhythmias.

Equivalent Circuit of the Neuro-Electronic Junction for Signal Recordings From Planar and Engulfed Micro-Nano-Electrodes.

PubMed

Massobrio, Giuseppe; Martinoia, Sergio; Massobrio, Paolo

2018-02-01

In the latest years, several attempts to develop extracellular microtransducers to record electrophysiological activity of excitable cells have been done. In particular, many efforts have been oriented to increase the coupling conditions, and, thus, improving the quality of the recorded signal. Gold mushroom-shaped microelectrodes (GMμE) are an example of nano-devices to achieve those requirements. In this study, we developed an equivalent electrical circuit of the neuron-microelectrode system interface to simulate signal recordings from both planar and engulfed micro-nano-electrodes. To this purpose, models of the neuron, planar, gold planar microelectrode, and GMμE, neuro-electronic junction (microelectrode-electrolyte interface, cleft effect, and protein-glycocalyx electric double layer) are presented. Then, neuronal electrical activity is simulated by Hspice software, and analyzed as a function of the most sensitive biophysical models parameters, such as the neuron-microelectrode cleft width, spreading and seal resistances, ion-channel densities, double-layer properties, and microelectrode geometries. Results are referenced to the experimentally recorded electrophysiological neuronal signals reported in the literature.

Response sensitivity of barrel neuron subpopulations to simulated thalamic input.

PubMed

Pesavento, Michael J; Rittenhouse, Cynthia D; Pinto, David J

2010-06-01

Our goal is to examine the relationship between neuron- and network-level processing in the context of a well-studied cortical function, the processing of thalamic input by whisker-barrel circuits in rodent neocortex. Here we focus on neuron-level processing and investigate the responses of excitatory and inhibitory barrel neurons to simulated thalamic inputs applied using the dynamic clamp method in brain slices. Simulated inputs are modeled after real thalamic inputs recorded in vivo in response to brief whisker deflections. Our results suggest that inhibitory neurons require more input to reach firing threshold, but then fire earlier, with less variability, and respond to a broader range of inputs than do excitatory neurons. Differences in the responses of barrel neuron subtypes depend on their intrinsic membrane properties. Neurons with a low input resistance require more input to reach threshold but then fire earlier than neurons with a higher input resistance, regardless of the neuron's classification. Our results also suggest that the response properties of excitatory versus inhibitory barrel neurons are consistent with the response sensitivities of the ensemble barrel network. The short response latency of inhibitory neurons may serve to suppress ensemble barrel responses to asynchronous thalamic input. Correspondingly, whereas neurons acting as part of the barrel circuit in vivo are highly selective for temporally correlated thalamic input, excitatory barrel neurons acting alone in vitro are less so. These data suggest that network-level processing of thalamic input in barrel cortex depends on neuron-level processing of the same input by excitatory and inhibitory barrel neurons.

Emergence of context-dependent variability across a basal ganglia network.

PubMed

Woolley, Sarah C; Rajan, Raghav; Joshua, Mati; Doupe, Allison J

2014-04-02

Context dependence is a key feature of cortical-basal ganglia circuit activity, and in songbirds the cortical outflow of a basal ganglia circuit specialized for song, LMAN, shows striking increases in trial-by-trial variability and bursting when birds sing alone rather than to females. To reveal where this variability and its social regulation emerge, we recorded stepwise from corticostriatal (HVC) neurons and their target spiny and pallidal neurons in Area X. We find that corticostriatal and spiny neurons both show precise singing-related firing across both social settings. Pallidal neurons, in contrast, exhibit markedly increased trial-by-trial variation when birds sing alone, created by highly variable pauses in firing. This variability persists even when recurrent inputs from LMAN are ablated. These data indicate that variability and its context sensitivity emerge within the basal ganglia network, suggest a network mechanism for this emergence, and highlight variability generation and regulation as basal ganglia functions. Copyright © 2014 Elsevier Inc. All rights reserved.

Emergence of context-dependent variability across a basal ganglia network

PubMed Central

Woolley, Sarah C.; Rajan, Raghav; Joshua, Mati; Doupe, Allison J.

2014-01-01

Summary Context-dependence is a key feature of cortical-basal ganglia circuit activity, and in songbirds, the cortical outflow of a basal ganglia circuit specialized for song, LMAN, shows striking increases in trial-by-trial variability and bursting when birds sing alone rather than to females. To reveal where this variability and its social regulation emerge, we recorded stepwise from cortico-striatal (HVC) neurons and their target spiny and pallidal neurons in Area X. We find that cortico-striatal and spiny neurons both show precise singing-related firing across both social settings. Pallidal neurons, in contrast, exhibit markedly increased trial-by-trial variation when birds sing alone, created by highly variable pauses in firing. This variability persists even when recurrent inputs from LMAN are ablated. These data indicate that variability and its context-sensitivity emerge within the basal ganglia network, suggest a network mechanism for this emergence, and highlight variability generation and regulation as basal ganglia functions. PMID:24698276

Theory of population coupling and applications to describe high order correlations in large populations of interacting neurons

NASA Astrophysics Data System (ADS)

Huang, Haiping

2017-03-01

To understand the collective spiking activity in neuronal populations, it is essential to reveal basic circuit variables responsible for these emergent functional states. Here, I develop a mean field theory for the population coupling recently proposed in the studies of the visual cortex of mouse and monkey, relating the individual neuron activity to the population activity, and extend the original form to the second order, relating neuron-pair’s activity to the population activity, to explain the high order correlations observed in the neural data. I test the computational framework on the salamander retinal data and the cortical spiking data of behaving rats. For the retinal data, the original form of population coupling and its advanced form can explain a significant fraction of two-cell correlations and three-cell correlations, respectively. For the cortical data, the performance becomes much better, and the second order population coupling reveals non-local effects in local cortical circuits.

The interplay between neurons and glia in synapse development and plasticity.

PubMed

Stogsdill, Jeff A; Eroglu, Cagla

2017-02-01

In the brain, the formation of complex neuronal networks amenable to experience-dependent remodeling is complicated by the diversity of neurons and synapse types. The establishment of a functional brain depends not only on neurons, but also non-neuronal glial cells. Glia are in continuous bi-directional communication with neurons to direct the formation and refinement of synaptic connectivity. This article reviews important findings, which uncovered cellular and molecular aspects of the neuron-glia cross-talk that govern the formation and remodeling of synapses and circuits. In vivo evidence demonstrating the critical interplay between neurons and glia will be the major focus. Additional attention will be given to how aberrant communication between neurons and glia may contribute to neural pathologies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Circuit to Construct Mapping: A Mathematical Tool for Assisting the Diagnosis and Treatment in Major Depressive Disorder

PubMed Central

Bielczyk, Natalia Z.; Buitelaar, Jan K.; Glennon, Jeffrey C.; Tiesinga, Paul H. E.

2015-01-01

Major depressive disorder (MDD) is a serious condition with a lifetime prevalence exceeding 16% worldwide. MDD is a heterogeneous disorder that involves multiple behavioral symptoms on the one hand and multiple neuronal circuits on the other hand. In this review, we integrate the literature on cognitive and physiological biomarkers of MDD with the insights derived from mathematical models of brain networks, especially models that can be used for fMRI datasets. We refer to the recent NIH research domain criteria initiative, in which a concept of “constructs” as functional units of mental disorders is introduced. Constructs are biomarkers present at multiple levels of brain functioning – cognition, genetics, brain anatomy, and neurophysiology. In this review, we propose a new approach which we called circuit to construct mapping (CCM), which aims to characterize causal relations between the underlying network dynamics (as the cause) and the constructs referring to the clinical symptoms of MDD (as the effect). CCM involves extracting diagnostic categories from behavioral data, linking circuits that are causal to these categories with use of clinical neuroimaging data, and modeling the dynamics of the emerging circuits with attractor dynamics in order to provide new, neuroimaging-related biomarkers for MDD. The CCM approach optimizes the clinical diagnosis and patient stratification. It also addresses the recent demand for linking circuits to behavior, and provides a new insight into clinical treatment by investigating the dynamics of neuronal circuits underneath cognitive dimensions of MDD. CCM can serve as a new regime toward personalized medicine, assisting the diagnosis and treatment of MDD. PMID:25767450

Dynamic microtubules drive circuit rewiring in the absence of neurite remodeling

PubMed Central

Kurup, Naina; Yan, Dong; Goncharov, Alexandr; Jin, Yishi

2015-01-01

A striking neuronal connectivity change in C. elegans involves the coordinated elimination of existing synapses and formation of synapses at new locations, without altering neuronal morphology. Here, we investigate the tripartite interaction between dynamic microtubules (MTs), kinesin-1, and vesicular cargo during this synapse remodeling. We find that a reduction in the dynamic MT population in motor neuron axons, resulting from genetic interaction between loss of function in the conserved MAPKKK dlk-1 and an α-tubulin mutation, specifically blocks synapse remodeling. Using live imaging and pharmacological modulation of the MT cytoskeleton, we show that dynamic MTs are increased at the onset of remodeling and are critical for new synapse formation. DLK-1 acts during synapse remodeling, and its function involves MT catastrophe factors including kinesin-13/KLP-7 and spastin/SPAS-1. Through a forward genetic screen, we identify gain-of-function mutations in kinesin-1 that can compensate for reduced dynamic MTs to promote synaptic vesicle transport during remodeling. Our data provide in vivo evidence supporting the requirement of dynamic MTs for kinesin-1 dependent axonal transport and shed insight on the role of the MT cytoskeleton in facilitating neural circuit plasticity. PMID:26051896

Imaging Voltage in Genetically Defined Neuronal Subpopulations with a Cre Recombinase-Targeted Hybrid Voltage Sensor.

PubMed

Bayguinov, Peter O; Ma, Yihe; Gao, Yu; Zhao, Xinyu; Jackson, Meyer B

2017-09-20

Genetically encoded voltage indicators create an opportunity to monitor electrical activity in defined sets of neurons as they participate in the complex patterns of coordinated electrical activity that underlie nervous system function. Taking full advantage of genetically encoded voltage indicators requires a generalized strategy for targeting the probe to genetically defined populations of cells. To this end, we have generated a mouse line with an optimized hybrid voltage sensor (hVOS) probe within a locus designed for efficient Cre recombinase-dependent expression. Crossing this mouse with Cre drivers generated double transgenics expressing hVOS probe in GABAergic, parvalbumin, and calretinin interneurons, as well as hilar mossy cells, new adult-born neurons, and recently active neurons. In each case, imaging in brain slices from male or female animals revealed electrically evoked optical signals from multiple individual neurons in single trials. These imaging experiments revealed action potentials, dynamic aspects of dendritic integration, and trial-to-trial fluctuations in response latency. The rapid time response of hVOS imaging revealed action potentials with high temporal fidelity, and enabled accurate measurements of spike half-widths characteristic of each cell type. Simultaneous recording of rapid voltage changes in multiple neurons with a common genetic signature offers a powerful approach to the study of neural circuit function and the investigation of how neural networks encode, process, and store information. SIGNIFICANCE STATEMENT Genetically encoded voltage indicators hold great promise in the study of neural circuitry, but realizing their full potential depends on targeting the sensor to distinct cell types. Here we present a new mouse line that expresses a hybrid optical voltage sensor under the control of Cre recombinase. Crossing this line with Cre drivers generated double-transgenic mice, which express this sensor in targeted cell types. In brain slices from these animals, single-trial hybrid optical voltage sensor recordings revealed voltage changes with submillisecond resolution in multiple neurons simultaneously. This imaging tool will allow for the study of the emergent properties of neural circuits and permit experimental tests of the roles of specific types of neurons in complex circuit activity. Copyright © 2017 the authors 0270-6474/17/379305-15$15.00/0.

The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and Evoked Release

PubMed Central

2017-01-01

Hypothalamic agouti-related peptide (AgRP) neurons potently stimulate food intake, whereas proopiomelanocortin (POMC) neurons inhibit feeding. Whether AgRP neurons exert their orexigenic actions, at least in part, by inhibiting anorexigenic POMC neurons remains unclear. Here, the connectivity between GABA-releasing AgRP neurons and POMC neurons was examined in brain slices from male and female mice. GABA-mediated spontaneous IPSCs (sIPSCs) in POMC neurons were unaffected by disturbing GABA release from AgRP neurons either by cell type-specific deletion of the vesicular GABA transporter or by expression of botulinum toxin in AgRP neurons to prevent vesicle-associated membrane protein 2-dependent vesicle fusion. Additionally, there was no difference in the ability of μ-opioid receptor (MOR) agonists to inhibit sIPSCs in POMC neurons when MORs were deleted from AgRP neurons, and activation of the inhibitory designer receptor hM4Di on AgRP neurons did not affect sIPSCs recorded from POMC neurons. These approaches collectively indicate that AgRP neurons do not significantly contribute to the strong spontaneous GABA input to POMC neurons. Despite these observations, optogenetic stimulation of AgRP neurons reliably produced evoked IPSCs in POMC neurons, leading to the inhibition of POMC neuron firing. Thus, AgRP neurons can potently affect POMC neuron function without contributing a significant source of spontaneous GABA input to POMC neurons. Together, these results indicate that the relevance of GABAergic inputs from AgRP to POMC neurons is state dependent and highlight the need to consider different types of transmitter release in circuit mapping and physiologic regulation. SIGNIFICANCE STATEMENT Agouti-related peptide (AgRP) neurons play an important role in driving food intake, while proopiomelanocortin (POMC) neurons inhibit feeding. Despite the importance of these two well characterized neuron types in maintaining metabolic homeostasis, communication between these cells remains poorly understood. To provide clarity to this circuit, we made electrophysiological recordings from mouse brain slices and found that AgRP neurons do not contribute spontaneously released GABA onto POMC neurons, although when activated with channelrhodopsin AgRP neurons inhibit POMC neurons through GABA-mediated transmission. These findings indicate that the relevance of AgRP to POMC neuron GABA connectivity depends on the state of AgRP neuron activity and suggest that different types of transmitter release should be considered when circuit mapping. PMID:28667175

The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and Evoked Release.

PubMed

Rau, Andrew R; Hentges, Shane T

2017-08-02

Hypothalamic agouti-related peptide (AgRP) neurons potently stimulate food intake, whereas proopiomelanocortin (POMC) neurons inhibit feeding. Whether AgRP neurons exert their orexigenic actions, at least in part, by inhibiting anorexigenic POMC neurons remains unclear. Here, the connectivity between GABA-releasing AgRP neurons and POMC neurons was examined in brain slices from male and female mice. GABA-mediated spontaneous IPSCs (sIPSCs) in POMC neurons were unaffected by disturbing GABA release from AgRP neurons either by cell type-specific deletion of the vesicular GABA transporter or by expression of botulinum toxin in AgRP neurons to prevent vesicle-associated membrane protein 2-dependent vesicle fusion. Additionally, there was no difference in the ability of μ-opioid receptor (MOR) agonists to inhibit sIPSCs in POMC neurons when MORs were deleted from AgRP neurons, and activation of the inhibitory designer receptor hM4Di on AgRP neurons did not affect sIPSCs recorded from POMC neurons. These approaches collectively indicate that AgRP neurons do not significantly contribute to the strong spontaneous GABA input to POMC neurons. Despite these observations, optogenetic stimulation of AgRP neurons reliably produced evoked IPSCs in POMC neurons, leading to the inhibition of POMC neuron firing. Thus, AgRP neurons can potently affect POMC neuron function without contributing a significant source of spontaneous GABA input to POMC neurons. Together, these results indicate that the relevance of GABAergic inputs from AgRP to POMC neurons is state dependent and highlight the need to consider different types of transmitter release in circuit mapping and physiologic regulation. SIGNIFICANCE STATEMENT Agouti-related peptide (AgRP) neurons play an important role in driving food intake, while proopiomelanocortin (POMC) neurons inhibit feeding. Despite the importance of these two well characterized neuron types in maintaining metabolic homeostasis, communication between these cells remains poorly understood. To provide clarity to this circuit, we made electrophysiological recordings from mouse brain slices and found that AgRP neurons do not contribute spontaneously released GABA onto POMC neurons, although when activated with channelrhodopsin AgRP neurons inhibit POMC neurons through GABA-mediated transmission. These findings indicate that the relevance of AgRP to POMC neuron GABA connectivity depends on the state of AgRP neuron activity and suggest that different types of transmitter release should be considered when circuit mapping. Copyright © 2017 the authors 0270-6474/17/377362-11$15.00/0.

Spike synchrony reveals emergence of proto-objects in visual cortex.

PubMed

Martin, Anne B; von der Heydt, Rüdiger

2015-04-29

Neurons at early stages of the visual cortex signal elemental features, such as pieces of contour, but how these signals are organized into perceptual objects is unclear. Theories have proposed that spiking synchrony between these neurons encodes how features are grouped (binding-by-synchrony), but recent studies did not find the predicted increase in synchrony with binding. Here we propose that features are grouped to "proto-objects" by intrinsic feedback circuits that enhance the responses of the participating feature neurons. This hypothesis predicts synchrony exclusively between feature neurons that receive feedback from the same grouping circuit. We recorded from neurons in macaque visual cortex and used border-ownership selectivity, an intrinsic property of the neurons, to infer whether or not two neurons are part of the same grouping circuit. We found that binding produced synchrony between same-circuit neurons, but not between other pairs of neurons, as predicted by the grouping hypothesis. In a selective attention task, synchrony emerged with ignored as well as attended objects, and higher synchrony was associated with faster behavioral responses, as would be expected from early grouping mechanisms that provide the structure for object-based processing. Thus, synchrony could be produced by automatic activation of intrinsic grouping circuits. However, the binding-related elevation of synchrony was weak compared with its random fluctuations, arguing against synchrony as a code for binding. In contrast, feedback grouping circuits encode binding by modulating the response strength of related feature neurons. Thus, our results suggest a novel coding mechanism that might underlie the proto-objects of perception. Copyright © 2015 the authors 0270-6474/15/356860-11$15.00/0.

Mini Review: Biomaterials for Enhancing Neuronal Repair

NASA Astrophysics Data System (ADS)

Cangellaris, Olivia V.; Gillette, Martha U.

2018-04-01

As they differentiate from neuroblasts, nascent neurons become highly polarized and elongate. Neurons extend and elaborate fine and fragile cellular extensions that form circuits enabling long-distance communication and signal integration within the body. While other organ systems are developing, projections of differentiating neurons find paths to distant targets. Subsequent post-developmental neuronal damage is catastrophic because the cues for reinnervation are no longer active. Advances in biomaterials are enabling fabrication of micro-environments that encourage neuronal regrowth and restoration of function by recreating these developmental cues. This mini-review considers new materials that employ topographical, chemical, electrical, and/or mechanical cues for use in neuronal repair. Manipulating and integrating these elements in different combinations will generate new technologies to enhance neural repair.

Cornu Ammonis Regions–Antecedents of Cortical Layers?

PubMed Central

Mercer, Audrey; Thomson, Alex M.

2017-01-01

Studying neocortex and hippocampus in parallel, we are struck by the similarities. All three to four layered allocortices and the six layered mammalian neocortex arise in the pallium. All receive and integrate multiple cortical and subcortical inputs, provide multiple outputs and include an array of neuronal classes. During development, each cell positions itself to sample appropriate local and distant inputs and to innervate appropriate targets. Simpler cortices had already solved the need to transform multiple coincident inputs into serviceable outputs before neocortex appeared in mammals. Why then do phylogenetically more recent cortices need multiple pyramidal cell layers? A simple answer is that more neurones can compute more complex functions. The dentate gyrus and hippocampal CA regions—which might be seen as hippocampal antecedents of neocortical layers—lie side by side, albeit around a tight bend. Were the millions of cells of rat neocortex arranged in like fashion, the surface area of the CA pyramidal cell layers would be some 40 times larger. Even if evolution had managed to fold this immense sheet into the space available, the distances between neurones that needed to be synaptically connected would be huge and to maintain the speed of information transfer, massive, myelinated fiber tracts would be needed. How much more practical to stack the “cells that fire and wire together” into narrow columns, while retaining the mechanisms underlying the extraordinary precision with which circuits form. This demonstrably efficient arrangement presents us with challenges, however, not the least being to categorize the baffling array of neuronal subtypes in each of five “pyramidal layers.” If we imagine the puzzle posed by this bewildering jumble of apical dendrites, basal dendrites and axons, from many different pyramidal and interneuronal classes, that is encountered by a late-arriving interneurone insinuating itself into a functional circuit, we can perhaps begin to understand why definitive classification, covering every aspect of each neurone's structure and function, is such a challenge. Here, we summarize and compare the development of these two cortices, the properties of their neurones, the circuits they form and the ordered, unidirectional flow of information from one hippocampal region, or one neocortical layer, to another. PMID:29018334

Transient Receptor Potential Channels TRPM4 and TRPC3 Critically Contribute to Respiratory Motor Pattern Formation but not Rhythmogenesis in Rodent Brainstem Circuits

PubMed Central

Tariq, Mohammad F.; Phillips, Ryan S.; Mosher, Bryan; Thompson, Ryan; Zhang, Ruli

2018-01-01

Abstract Transient receptor potential channel, TRPM4, the putative molecular substrate for Ca2+-activated nonselective cation current (ICAN), is hypothesized to generate bursting activity of pre-Bötzinger complex (pre-BötC) inspiratory neurons and critically contribute to respiratory rhythmogenesis. Another TRP channel, TRPC3, which mediates Na+/Ca2+ fluxes, may be involved in regulating Ca2+-related signaling, including affecting TRPM4/ICAN in respiratory pre-BötC neurons. However, TRPM4 and TRPC3 expression in pre-BötC inspiratory neurons and functional roles of these channels remain to be determined. By single-cell multiplex RT-PCR, we show mRNA expression for these channels in pre-BötC inspiratory neurons in rhythmically active medullary in vitro slices from neonatal rats and mice. Functional contributions were analyzed with pharmacological inhibitors of TRPM4 or TRPC3 in vitro as well as in mature rodent arterially perfused in situ brainstem–spinal cord preparations. Perturbations of respiratory circuit activity were also compared with those by a blocker of ICAN. Pharmacologically attenuating endogenous activation of TRPM4, TRPC3, or ICAN in vitro similarly reduced the amplitude of inspiratory motoneuronal activity without significant perturbations of inspiratory frequency or variability of the rhythm. Amplitude perturbations were correlated with reduced inspiratory glutamatergic pre-BötC neuronal activity, monitored by multicellular dynamic calcium imaging in vitro. In more intact circuits in situ, the reduction of pre-BötC and motoneuronal inspiratory activity amplitude was accompanied by reduced post-inspiratory motoneuronal activity, without disruption of rhythm generation. We conclude that endogenously activated TRPM4, which likely mediates ICAN, and TRPC3 channels in pre-BötC inspiratory neurons play fundamental roles in respiratory pattern formation but are not critically involved in respiratory rhythm generation. PMID:29435486

Optimization Methods for Spiking Neurons and Networks

PubMed Central

Russell, Alexander; Orchard, Garrick; Dong, Yi; Mihalaş, Ştefan; Niebur, Ernst; Tapson, Jonathan; Etienne-Cummings, Ralph

2011-01-01

Spiking neurons and spiking neural circuits are finding uses in a multitude of tasks such as robotic locomotion control, neuroprosthetics, visual sensory processing, and audition. The desired neural output is achieved through the use of complex neuron models, or by combining multiple simple neurons into a network. In either case, a means for configuring the neuron or neural circuit is required. Manual manipulation of parameters is both time consuming and non-intuitive due to the nonlinear relationship between parameters and the neuron’s output. The complexity rises even further as the neurons are networked and the systems often become mathematically intractable. In large circuits, the desired behavior and timing of action potential trains may be known but the timing of the individual action potentials is unknown and unimportant, whereas in single neuron systems the timing of individual action potentials is critical. In this paper, we automate the process of finding parameters. To configure a single neuron we derive a maximum likelihood method for configuring a neuron model, specifically the Mihalas–Niebur Neuron. Similarly, to configure neural circuits, we show how we use genetic algorithms (GAs) to configure parameters for a network of simple integrate and fire with adaptation neurons. The GA approach is demonstrated both in software simulation and hardware implementation on a reconfigurable custom very large scale integration chip. PMID:20959265

Dendrite architecture organized by transcriptional control of the F-actin nucleator Spire.

PubMed

Ferreira, Tiago; Ou, Yimiao; Li, Sally; Giniger, Edward; van Meyel, Donald J

2014-02-01

The architectures of dendritic trees are crucial for the wiring and function of neuronal circuits because they determine coverage of receptive territories, as well as the nature and strength of sensory or synaptic inputs. Here, we describe a cell-intrinsic pathway sculpting dendritic arborization (da) neurons in Drosophila that requires Longitudinals Lacking (Lola), a BTB/POZ transcription factor, and its control of the F-actin cytoskeleton through Spire (Spir), an actin nucleation protein. Loss of Lola from da neurons reduced the overall length of dendritic arbors, increased the expression of Spir, and produced inappropriate F-actin-rich dendrites at positions too near the cell soma. Selective removal of Lola from only class IV da neurons decreased the evasive responses of larvae to nociception. The increased Spir expression contributed to the abnormal F-actin-rich dendrites and the decreased nocifensive responses because both were suppressed by reduced dose of Spir. Thus, an important role of Lola is to limit expression of Spir to appropriate levels within da neurons. We found Spir to be expressed in dendritic arbors and to be important for their development. Removal of Spir from class IV da neurons reduced F-actin levels and total branch number, shifted the position of greatest branch density away from the cell soma, and compromised nocifensive behavior. We conclude that the Lola-Spir pathway is crucial for the spatial arrangement of branches within dendritic trees and for neural circuit function because it provides balanced control of the F-actin cytoskeleton.

Neural circuit activity in freely behaving zebrafish (Danio rerio).

PubMed

Issa, Fadi A; O'Brien, Georgeann; Kettunen, Petronella; Sagasti, Alvaro; Glanzman, David L; Papazian, Diane M

2011-03-15

Examining neuronal network activity in freely behaving animals is advantageous for probing the function of the vertebrate central nervous system. Here, we describe a simple, robust technique for monitoring the activity of neural circuits in unfettered, freely behaving zebrafish (Danio rerio). Zebrafish respond to unexpected tactile stimuli with short- or long-latency escape behaviors, which are mediated by distinct neural circuits. Using dipole electrodes immersed in the aquarium, we measured electric field potentials generated in muscle during short- and long-latency escapes. We found that activation of the underlying neural circuits produced unique field potential signatures that are easily recognized and can be repeatedly monitored. In conjunction with behavioral analysis, we used this technique to track changes in the pattern of circuit activation during the first week of development in animals whose trigeminal sensory neurons were unilaterally ablated. One day post-ablation, the frequency of short- and long-latency responses was significantly lower on the ablated side than on the intact side. Three days post-ablation, a significant fraction of escapes evoked by stimuli on the ablated side was improperly executed, with the animal turning towards rather than away from the stimulus. However, the overall response rate remained low. Seven days post-ablation, the frequency of escapes increased dramatically and the percentage of improperly executed escapes declined. Our results demonstrate that trigeminal ablation results in rapid reconfiguration of the escape circuitry, with reinnervation by new sensory neurons and adaptive changes in behavior. This technique is valuable for probing the activity, development, plasticity and regeneration of neural circuits under natural conditions.

Neural circuit activity in freely behaving zebrafish (Danio rerio)

PubMed Central

Issa, Fadi A.; O'Brien, Georgeann; Kettunen, Petronella; Sagasti, Alvaro; Glanzman, David L.; Papazian, Diane M.

2011-01-01

Examining neuronal network activity in freely behaving animals is advantageous for probing the function of the vertebrate central nervous system. Here, we describe a simple, robust technique for monitoring the activity of neural circuits in unfettered, freely behaving zebrafish (Danio rerio). Zebrafish respond to unexpected tactile stimuli with short- or long-latency escape behaviors, which are mediated by distinct neural circuits. Using dipole electrodes immersed in the aquarium, we measured electric field potentials generated in muscle during short- and long-latency escapes. We found that activation of the underlying neural circuits produced unique field potential signatures that are easily recognized and can be repeatedly monitored. In conjunction with behavioral analysis, we used this technique to track changes in the pattern of circuit activation during the first week of development in animals whose trigeminal sensory neurons were unilaterally ablated. One day post-ablation, the frequency of short- and long-latency responses was significantly lower on the ablated side than on the intact side. Three days post-ablation, a significant fraction of escapes evoked by stimuli on the ablated side was improperly executed, with the animal turning towards rather than away from the stimulus. However, the overall response rate remained low. Seven days post-ablation, the frequency of escapes increased dramatically and the percentage of improperly executed escapes declined. Our results demonstrate that trigeminal ablation results in rapid reconfiguration of the escape circuitry, with reinnervation by new sensory neurons and adaptive changes in behavior. This technique is valuable for probing the activity, development, plasticity and regeneration of neural circuits under natural conditions. PMID:21346131

Spinal interneurons differentiate sequentially from those driving the fastest swimming movements in larval zebrafish to those driving the slowest ones.

PubMed

McLean, David L; Fetcho, Joseph R

2009-10-28

Studies of neuronal networks have revealed few general principles that link patterns of development with later functional roles. While investigating the neural control of movements, we recently discovered a topographic map in the spinal cord of larval zebrafish that relates the position of motoneurons and interneurons to their order of recruitment during swimming. Here, we show that the map reflects an orderly pattern of differentiation of neurons driving different movements. First, we use high-speed filming to show that large-amplitude swimming movements with bending along much of the body appear first, with smaller, regional swimming movements emerging later. Next, using whole-cell patch recordings, we demonstrate that the excitatory circuits that drive large-amplitude, fast swimming movements at larval stages are present and functional early on in embryos. Finally, we systematically assess the orderly emergence of spinal circuits according to swimming speed using transgenic fish expressing the photoconvertible protein Kaede to track neuronal differentiation in vivo. We conclude that a simple principle governs the development of spinal networks in which the neurons driving the fastest, most powerful swimming in larvae develop first with ones that drive increasingly weaker and slower larval movements layered on over time. Because the neurons are arranged by time of differentiation in the spinal cord, the result is a topographic map that represents the speed/strength of movements at which neurons are recruited and the temporal emergence of networks. This pattern may represent a general feature of neuronal network development throughout the brain and spinal cord.

Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex

PubMed Central

McGarry, Laura M.

2016-01-01

Interactions between the prefrontal cortex (PFC) and basolateral amygdala (BLA) regulate emotional behaviors. However, a circuit-level understanding of functional connections between these brain regions remains incomplete. The BLA sends prominent glutamatergic projections to the PFC, but the overall influence of these inputs is predominantly inhibitory. Here we combine targeted recordings and optogenetics to examine the synaptic underpinnings of this inhibition in the mouse infralimbic PFC. We find that BLA inputs preferentially target layer 2 corticoamygdala over neighboring corticostriatal neurons. However, these inputs make even stronger connections onto neighboring parvalbumin and somatostatin expressing interneurons. Inhibitory connections from these two populations of interneurons are also much stronger onto corticoamygdala neurons. Consequently, BLA inputs are able to drive robust feedforward inhibition via two parallel interneuron pathways. Moreover, the contributions of these interneurons shift during repetitive activity, due to differences in short-term synaptic dynamics. Thus, parvalbumin interneurons are activated at the start of stimulus trains, whereas somatostatin interneuron activation builds during these trains. Together, these results reveal how the BLA impacts the PFC through a complex interplay of direct excitation and feedforward inhibition. They also highlight the roles of targeted connections onto multiple projection neurons and interneurons in this cortical circuit. Our findings provide a mechanistic understanding for how the BLA can influence the PFC circuit, with important implications for how this circuit participates in the regulation of emotion. SIGNIFICANCE STATEMENT The prefrontal cortex (PFC) and basolateral amygdala (BLA) interact to control emotional behaviors. Here we show that BLA inputs elicit direct excitation and feedforward inhibition of layer 2 projection neurons in infralimbic PFC. BLA inputs are much stronger at corticoamygdala neurons compared with nearby corticostriatal neurons. However, these inputs are even more powerful at parvalbumin and somatostatin expressing interneurons. BLA inputs thus activate two parallel inhibitory networks, whose contributions change during repetitive activity. Finally, connections from these interneurons are also more powerful at corticoamygdala neurons compared with corticostriatal neurons. Together, our results demonstrate how the BLA predominantly inhibits the PFC via a complex sequence involving multiple cell-type and input-specific connections. PMID:27605614

Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex.

PubMed

McGarry, Laura M; Carter, Adam G

2016-09-07

Interactions between the prefrontal cortex (PFC) and basolateral amygdala (BLA) regulate emotional behaviors. However, a circuit-level understanding of functional connections between these brain regions remains incomplete. The BLA sends prominent glutamatergic projections to the PFC, but the overall influence of these inputs is predominantly inhibitory. Here we combine targeted recordings and optogenetics to examine the synaptic underpinnings of this inhibition in the mouse infralimbic PFC. We find that BLA inputs preferentially target layer 2 corticoamygdala over neighboring corticostriatal neurons. However, these inputs make even stronger connections onto neighboring parvalbumin and somatostatin expressing interneurons. Inhibitory connections from these two populations of interneurons are also much stronger onto corticoamygdala neurons. Consequently, BLA inputs are able to drive robust feedforward inhibition via two parallel interneuron pathways. Moreover, the contributions of these interneurons shift during repetitive activity, due to differences in short-term synaptic dynamics. Thus, parvalbumin interneurons are activated at the start of stimulus trains, whereas somatostatin interneuron activation builds during these trains. Together, these results reveal how the BLA impacts the PFC through a complex interplay of direct excitation and feedforward inhibition. They also highlight the roles of targeted connections onto multiple projection neurons and interneurons in this cortical circuit. Our findings provide a mechanistic understanding for how the BLA can influence the PFC circuit, with important implications for how this circuit participates in the regulation of emotion. The prefrontal cortex (PFC) and basolateral amygdala (BLA) interact to control emotional behaviors. Here we show that BLA inputs elicit direct excitation and feedforward inhibition of layer 2 projection neurons in infralimbic PFC. BLA inputs are much stronger at corticoamygdala neurons compared with nearby corticostriatal neurons. However, these inputs are even more powerful at parvalbumin and somatostatin expressing interneurons. BLA inputs thus activate two parallel inhibitory networks, whose contributions change during repetitive activity. Finally, connections from these interneurons are also more powerful at corticoamygdala neurons compared with corticostriatal neurons. Together, our results demonstrate how the BLA predominantly inhibits the PFC via a complex sequence involving multiple cell-type and input-specific connections. Copyright © 2016 the authors 0270-6474/16/369391-16$15.00/0.

Functional identification of an aggression locus in the mouse hypothalamus

PubMed Central

Lin, Dayu; Boyle, Maureen P.; Dollar, Piotr; Lee, Hyosang; Perona, Pietro; Lein, Ed S.; Anderson, David J.

2010-01-01

Electrical stimulation of certain hypothalamic regions in cats and rodents can elicit attack behavior, but the exact location of relevant cells within these regions, their requirement for naturally occurring aggression and their relationship to mating circuits have not been clear. Genetic methods for neural circuit manipulation in mice provide a potentially powerful approach to this problem, but brain stimulation-evoked aggression has never been demonstrated in this species. Here we show that optogenetic, but not electrical, stimulation of neurons in the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) causes male mice to attack both females and inanimate objects, as well as males. Pharmacogenetic silencing of VMHvl reversibly inhibits inter-male aggression. Immediate early gene analysis and single unit recordings from VMHvl during social interactions reveal overlapping but distinct neuronal subpopulations involved in fighting and mating. Neurons activated during attack are inhibited during mating, suggesting a potential neural substrate for competition between these behaviors. PMID:21307935

Functional identification of an aggression locus in the mouse hypothalamus.

PubMed

Lin, Dayu; Boyle, Maureen P; Dollar, Piotr; Lee, Hyosang; Lein, E S; Perona, Pietro; Anderson, David J

2011-02-10

Electrical stimulation of certain hypothalamic regions in cats and rodents can elicit attack behaviour, but the exact location of relevant cells within these regions, their requirement for naturally occurring aggression and their relationship to mating circuits have not been clear. Genetic methods for neural circuit manipulation in mice provide a potentially powerful approach to this problem, but brain-stimulation-evoked aggression has never been demonstrated in this species. Here we show that optogenetic, but not electrical, stimulation of neurons in the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) causes male mice to attack both females and inanimate objects, as well as males. Pharmacogenetic silencing of VMHvl reversibly inhibits inter-male aggression. Immediate early gene analysis and single unit recordings from VMHvl during social interactions reveal overlapping but distinct neuronal subpopulations involved in fighting and mating. Neurons activated during attack are inhibited during mating, suggesting a potential neural substrate for competition between these opponent social behaviours.

Optogenetic mapping of brain circuitry

NASA Astrophysics Data System (ADS)

Augustine, George J.; Berglund, Ken; Gill, Harin; Hoffmann, Carolin; Katarya, Malvika; Kim, Jinsook; Kudolo, John; Lee, Li M.; Lee, Molly; Lo, Daniel; Nakajima, Ryuichi; Park, Min Yoon; Tan, Gregory; Tang, Yanxia; Teo, Peggy; Tsuda, Sachiko; Wen, Lei; Yoon, Su-In

2012-10-01

Studies of the brain promise to be revolutionized by new experimental strategies that harness the combined power of optical techniques and genetics. We have mapped the circuitry of the mouse brain by using both optogenetic actuators that control neuronal activity and optogenetic sensors that detect neuronal activity. Using the light-activated cation channel, channelrhodopsin-2, to locally photostimulate neurons allows high-speed mapping of local and long-range circuitry. For example, with this approach we have mapped local circuits in the cerebral cortex, cerebellum and many other brain regions. Using the fluorescent sensor for chloride ions, Clomeleon, allows imaging of the spatial and temporal dimensions of inhibitory circuits in the brain. This approach allows imaging of both conventional "phasic" synaptic inhibition as well as unconventional "tonic" inhibition. The combined use of light to both control and monitor neural activity creates unprecedented opportunities to explore brain function, screen pharmaceutical agents, and potentially to use light to ameliorate psychiatric and neurological disorders.

Oscillatory integration windows in neurons

PubMed Central

Gupta, Nitin; Singh, Swikriti Saran; Stopfer, Mark

2016-01-01

Oscillatory synchrony among neurons occurs in many species and brain areas, and has been proposed to help neural circuits process information. One hypothesis states that oscillatory input creates cyclic integration windows: specific times in each oscillatory cycle when postsynaptic neurons become especially responsive to inputs. With paired local field potential (LFP) and intracellular recordings and controlled stimulus manipulations we directly test this idea in the locust olfactory system. We find that inputs arriving in Kenyon cells (KCs) sum most effectively in a preferred window of the oscillation cycle. With a computational model, we show that the non-uniform structure of noise in the membrane potential helps mediate this process. Further experiments performed in vivo demonstrate that integration windows can form in the absence of inhibition and at a broad range of oscillation frequencies. Our results reveal how a fundamental coincidence-detection mechanism in a neural circuit functions to decode temporally organized spiking. PMID:27976720

The many worlds hypothesis of dopamine prediction error: implications of a parallel circuit architecture in the basal ganglia.

PubMed

Lau, Brian; Monteiro, Tiago; Paton, Joseph J

2017-10-01

Computational models of reinforcement learning (RL) strive to produce behavior that maximises reward, and thus allow software or robots to behave adaptively [1]. At the core of RL models is a learned mapping between 'states'-situations or contexts that an agent might encounter in the world-and actions. A wealth of physiological and anatomical data suggests that the basal ganglia (BG) is important for learning these mappings [2,3]. However, the computations performed by specific circuits are unclear. In this brief review, we highlight recent work concerning the anatomy and physiology of BG circuits that suggest refinements in our understanding of computations performed by the basal ganglia. We focus on one important component of basal ganglia circuitry, midbrain dopamine neurons, drawing attention to data that has been cast as supporting or departing from the RL framework that has inspired experiments in basal ganglia research over the past two decades. We suggest that the parallel circuit architecture of the BG might be expected to produce variability in the response properties of different dopamine neurons, and that variability in response profile may not reflect variable functions, but rather different arguments that serve as inputs to a common function: the computation of prediction error. Copyright © 2017 Elsevier Ltd. All rights reserved.

Circuit Analysis of a Drosophila Dopamine Type 2 Receptor That Supports Anesthesia-Resistant Memory.

PubMed

Scholz-Kornehl, Sabrina; Schwärzel, Martin

2016-07-27

Dopamine is central to reinforcement processing and exerts this function in species ranging from humans to fruit flies. It can do so via two different types of receptors (i.e., D1 or D2) that mediate either augmentation or abatement of cellular cAMP levels. Whereas D1 receptors are known to contribute to Drosophila aversive odor learning per se, we here show that D2 receptors are specific for support of a consolidated form of odor memory known as anesthesia-resistant memory. By means of genetic mosaicism, we localize this function to Kenyon cells, the mushroom body intrinsic neurons, as well as GABAergic APL neurons and local interneurons of the antennal lobes, suggesting that consolidated anesthesia-resistant memory requires widespread dopaminergic modulation within the olfactory circuit. Additionally, dopaminergic neurons themselves require D2R, suggesting a critical role in dopamine release via its recognized autoreceptor function. Considering the dual role of dopamine in balancing memory acquisition (proactive function of dopamine) and its "forgetting" (retroactive function of dopamine), our analysis suggests D2R as central player of either process. Dopamine provides different information; while it mediates reinforcement during the learning act (proactive function), it balances memory performance between two antithetic processes thereafter (retroactive function) (i.e., forgetting and augmentation). Such bidirectional design can also be found at level of dopamine receptors, where augmenting D1 and abating D2 receptors are engaged to balance cellular cAMP levels. Here, we report that consolidated anesthesia-resistant memory (ARM), but not other concomitant memory phases, are sensitive to bidirectional dopaminergic signals. By means of genetic mosaicism, we identified widespread dopaminergic modulation within the olfactory circuit that suggests nonredundant and reiterating functions of D2R in support of ARM. Our results oppose ARM to its concomitant memory phases that localize to mushroom bodies and propose a decentralized organization of consolidated ARM. Copyright © 2016 the authors 0270-6474/16/367936-10$15.00/0.

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.

PubMed

Charbogne, Pauline; Gardon, Olivier; Martín-García, Elena; Keyworth, Helen L; Matsui, Aya; Mechling, Anna E; Bienert, Thomas; Nasseef, Taufiq; Robé, Anne; Moquin, Luc; Darcq, Emmanuel; Ben Hamida, Sami; Robledo, Patricia; Matifas, Audrey; Befort, Katia; Gavériaux-Ruff, Claire; Harsan, Laura-Adela; von Elverfeldt, Dominik; Hennig, Jurgen; Gratton, Alain; Kitchen, Ian; Bailey, Alexis; Alvarez, Veronica A; Maldonado, Rafael; Kieffer, Brigitte L

2017-05-01

Mu opioid receptors (MORs) are central to pain control, drug reward, and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in gamma-aminobutyric acidergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward. We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in gamma-aminobutyric acidergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology, and microdialysis; probed neuronal activation by c-Fos immunohistochemistry and resting-state functional magnetic resonance imaging; and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food. Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area, local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, and neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures. Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus, beyond a well-established role in reward processing, operating at the level of local ventral tegmental area neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Homeostatic scaling of vesicular glutamate and GABA transporter expression in rat neocortical circuits.

PubMed

De Gois, Stéphanie; Schäfer, Martin K-H; Defamie, Norah; Chen, Chu; Ricci, Anthony; Weihe, Eberhard; Varoqui, Hélène; Erickson, Jeffrey D

2005-08-03

Homeostatic control of pyramidal neuron firing rate involves a functional balance of feedforward excitation and feedback inhibition in neocortical circuits. Here, we reveal a dynamic scaling in vesicular excitatory (vesicular glutamate transporters VGLUT1 and VGLUT2) and inhibitory (vesicular inhibitory amino acid transporter VIAAT) transporter mRNA and synaptic protein expression in rat neocortical neuronal cultures, using a well established in vitro protocol to induce homeostatic plasticity. During the second and third week of synaptic differentiation, the predominant vesicular transporters expressed in neocortical neurons, VGLUT1 and VIAAT, are both dramatically upregulated. In mature cultures, VGLUT1 and VIAAT exhibit bidirectional and opposite regulation by prolonged activity changes. Endogenous coregulation during development and homeostatic scaling of the expression of the transporters in functionally differentiated cultures may serve to control vesicular glutamate and GABA filling and adjust functional presynaptic excitatory/inhibitory balance. Unexpectedly, hyperexcitation in differentiated cultures triggers a striking increase in VGLUT2 mRNA and synaptic protein, whereas decreased excitation reduces levels. VGLUT2 mRNA and protein are expressed in subsets of VGLUT1-encoded neocortical neurons that we identify in primary cultures and in neocortex in situ and in vivo. After prolonged hyperexcitation, downregulation of VGLUT1/synaptophysin intensity ratios at most synapses is observed, whereas a subset of VGLUT1-containing boutons selectively increase the expression of VGLUT2. Bidirectional and opposite regulation of VGLUT1 and VGLUT2 by activity may serve as positive or negative feedback regulators for cortical synaptic transmission. Intracortical VGLUT1/VGLUT2 coexpressing neurons have the capacity to independently modulate the level of expression of either transporter at discrete synapses and therefore may serve as a plastic interface between subcortical thalamic input (VGLUT2) and cortical output (VGLUT1) neurons.

A plausible neural circuit for decision making and its formation based on reinforcement learning.

PubMed

Wei, Hui; Dai, Dawei; Bu, Yijie

2017-06-01

A human's, or lower insects', behavior is dominated by its nervous system. Each stable behavior has its own inner steps and control rules, and is regulated by a neural circuit. Understanding how the brain influences perception, thought, and behavior is a central mandate of neuroscience. The phototactic flight of insects is a widely observed deterministic behavior. Since its movement is not stochastic, the behavior should be dominated by a neural circuit. Based on the basic firing characteristics of biological neurons and the neural circuit's constitution, we designed a plausible neural circuit for this phototactic behavior from logic perspective. The circuit's output layer, which generates a stable spike firing rate to encode flight commands, controls the insect's angular velocity when flying. The firing pattern and connection type of excitatory and inhibitory neurons are considered in this computational model. We simulated the circuit's information processing using a distributed PC array, and used the real-time average firing rate of output neuron clusters to drive a flying behavior simulation. In this paper, we also explored how a correct neural decision circuit is generated from network flow view through a bee's behavior experiment based on the reward and punishment feedback mechanism. The significance of this study: firstly, we designed a neural circuit to achieve the behavioral logic rules by strictly following the electrophysiological characteristics of biological neurons and anatomical facts. Secondly, our circuit's generality permits the design and implementation of behavioral logic rules based on the most general information processing and activity mode of biological neurons. Thirdly, through computer simulation, we achieved new understanding about the cooperative condition upon which multi-neurons achieve some behavioral control. Fourthly, this study aims in understanding the information encoding mechanism and how neural circuits achieve behavior control. Finally, this study also helps establish a transitional bridge between the microscopic activity of the nervous system and macroscopic animal behavior.

Connecting the ear to the brain: molecular mechanisms of auditory circuit assembly

PubMed Central

Appler, Jessica M.; Goodrich, Lisa V.

2011-01-01

Our sense of hearing depends on precisely organized circuits that allow us to sense, perceive, and respond to complex sounds in our environment, from music and language to simple warning signals. Auditory processing begins in the cochlea of the inner ear, where sounds are detected by sensory hair cells and then transmitted to the central nervous system by spiral ganglion neurons, which faithfully preserve the frequency, intensity, and timing of each stimulus. During the assembly of auditory circuits, spiral ganglion neurons establish precise connections that link hair cells in the cochlea to target neurons in the auditory brainstem, develop specific firing properties, and elaborate unusual synapses both in the periphery and in the CNS. Understanding how spiral ganglion neurons acquire these unique properties is a key goal in auditory neuroscience, as these neurons represent the sole input of auditory information to the brain. In addition, the best currently available treatment for many forms of deafness is the cochlear implant, which compensates for lost hair cell function by directly stimulating the auditory nerve. Historically, studies of the auditory system have lagged behind other sensory systems due to the small size and inaccessibility of the inner ear. With the advent of new molecular genetic tools, this gap is narrowing. Here, we summarize recent insights into the cellular and molecular cues that guide the development of spiral ganglion neurons, from their origin in the proneurosensory domain of the otic vesicle to the formation of specialized synapses that ensure rapid and reliable transmission of sound information from the ear to the brain. PMID:21232575

Temporal Requirements of the Fragile X Mental Retardation Protein in Modulating Circadian Clock Circuit Synaptic Architecture

PubMed Central

Gatto, Cheryl L.; Broadie, Kendal

2009-01-01

Loss of fragile X mental retardation 1 (FMR1) gene function is the most common cause of inherited mental retardation and autism spectrum disorders, characterized by attention disorder, hyperactivity and disruption of circadian activity cycles. Pursuit of effective intervention strategies requires determining when the FMR1 product (FMRP) is required in the regulation of neuronal circuitry controlling these behaviors. In the well-characterized Drosophila disease model, loss of the highly conserved dFMRP causes circadian arrhythmicity and conspicuous abnormalities in the circadian clock circuitry. Here, a novel Sholl Analysis was used to quantify over-elaborated synaptic architecture in dfmr1-null small ventrolateral neurons (sLNvs), a key subset of clock neurons. The transgenic Gene-Switch system was employed to drive conditional neuronal dFMRP expression in the dfmr1-null mutant background in order to dissect temporal requirements within the clock circuit. Introduction of dFMRP during early brain development, including the stages of neurogenesis, neuronal fate specification and early pathfinding, provided no rescue of dfmr1 mutant phenotypes. Similarly, restoring normal dFMRP expression in the adult failed to restore circadian circuit architecture. In sharp contrast, supplying dFMRP during a transient window of very late brain development, wherein synaptogenesis and substantial subsequent synaptic reorganization (e.g. use-dependent pruning) occur, provided strong morphological rescue to reestablish normal sLNvs synaptic arbors. We conclude that dFMRP plays a developmentally restricted role in sculpting synaptic architecture in these neurons that cannot be compensated for by later reintroduction of the protein at maturity. PMID:19738924

Lessons from sleeping flies: insights from Drosophila melanogaster on the neuronal circuitry and importance of sleep.

PubMed

Potdar, Sheetal; Sheeba, Vasu

2013-06-01

Sleep is a highly conserved behavior whose role is as yet unknown, although it is widely acknowledged as being important. Here we provide an overview of many vital questions regarding this behavior, that have been addressed in recent years using the genetically tractable model organism Drosophila melanogaster in several laboratories around the world. Rest in D. melanogaster has been compared to mammalian sleep and its homeostatic and circadian regulation have been shown to be controlled by intricate neuronal circuitry involving circadian clock neurons, mushroom bodies, and pars intercerebralis, although their exact roles are not entirely clear. We draw attention to the yet unanswered questions and contradictions regarding the nature of the interactions between the brain regions implicated in the control of sleep. Dopamine, octopamine, γ-aminobutyric acid (GABA), and serotonin are the chief neurotransmitters identified as functioning in different limbs of this circuit, either promoting arousal or sleep by modulating membrane excitability of underlying neurons. Some studies have suggested that certain brain areas may contribute towards both sleep and arousal depending on activation of specific subsets of neurons. Signaling pathways implicated in the sleep circuit include cyclic adenosine monophosphate (cAMP) and epidermal growth factor receptor-extracellular signal-regulated kinase (EGFR-ERK) signaling pathways that operate on different neural substrates. Thus, this field of research appears to be on the cusp of many new and exciting findings that may eventually help in understanding how this complex physiological phenomenon is modulated by various neuronal circuits in the brain. Finally, some efforts to approach the "Holy Grail" of why we sleep have been summarized.

Meigo governs dendrite targeting specificity by modulating Ephrin level and N-glycosylation

PubMed Central

Sekine, Sayaka U; Haraguchi, Shuka; Chao, Kinhong; Kato, Tomoko; Luo, Liqun; Miura, Masayuki; Chihara, Takahiro

2016-01-01

Neural circuit assembly requires precise dendrite and axon targeting. We identified an evolutionarily conserved endoplasmic reticulum (ER) protein, Meigo, from a mosaic genetic screen in Drosophila melanogaster. Meigo was cell-autonomously required in olfactory receptor neurons and projection neurons to target their axons and dendrites to the lateral antennal lobe and to refine projection neuron dendrites into individual glomeruli. Loss of Meigo induced an unfolded protein response and reduced the amount of neuronal cell surface proteins, including Ephrin. Ephrin overexpression specifically suppressed the projection neuron dendrite refinement defect present in meigo mutant flies, and ephrin knockdown caused a similar projection neuron dendrite refinement defect. Meigo positively regulated the level of Ephrin N-glycosylation, which was required for its optimal function in vivo. Thus, Meigo, an ER-resident protein, governs neuronal targeting specificity by regulating ER folding capacity and protein N-glycosylation. Furthermore, Ephrin appears to be an important substrate that mediates Meigo’s function in refinement of glomerular targeting. PMID:23624514

Precision of Discrete and Rhythmic Forelimb Movements Requires a Distinct Neuronal Subpopulation in the Interposed Anterior Nucleus.

PubMed

Low, Aloysius Y T; Thanawalla, Ayesha R; Yip, Alaric K K; Kim, Jinsook; Wong, Kelly L L; Tantra, Martesa; Augustine, George J; Chen, Albert I

2018-02-27

The deep cerebellar nuclei (DCN) represent output channels of the cerebellum, and they transmit integrated sensorimotor signals to modulate limb movements. But the functional relevance of identifiable neuronal subpopulations within the DCN remains unclear. Here, we examine a genetically tractable population of neurons in the mouse interposed anterior nucleus (IntA). We show that these neurons represent a subset of glutamatergic neurons in the IntA and constitute a specific element of an internal feedback circuit within the cerebellar cortex and cerebello-thalamo-cortical pathway associated with limb control. Ablation and optogenetic stimulation of these neurons disrupt efficacy of skilled reach and locomotor movement and reveal that they control positioning and timing of the forelimb and hindlimb. Together, our findings uncover the function of a distinct neuronal subpopulation in the deep cerebellum and delineate the anatomical substrates and kinematic parameters through which it modulates precision of discrete and rhythmic limb movements. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Plasticity in single neuron and circuit computations

NASA Astrophysics Data System (ADS)

Destexhe, Alain; Marder, Eve

2004-10-01

Plasticity in neural circuits can result from alterations in synaptic strength or connectivity, as well as from changes in the excitability of the neurons themselves. To better understand the role of plasticity in the brain, we need to establish how brain circuits work and the kinds of computations that different circuit structures achieve. By linking theoretical and experimental studies, we are beginning to reveal the consequences of plasticity mechanisms for network dynamics, in both simple invertebrate circuits and the complex circuits of mammalian cerebral cortex.

NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury

PubMed Central

Yang, Zhaoyang; Zhang, Aifeng; Duan, Hongmei; Zhang, Sa; Hao, Peng; Ye, Keqiang; Sun, Yi E.; Li, Xiaoguang

2015-01-01

Neural stem cells (NSCs) in the adult mammalian central nervous system (CNS) hold the key to neural regeneration through proper activation, differentiation, and maturation, to establish nascent neural networks, which can be integrated into damaged neural circuits to repair function. However, the CNS injury microenvironment is often inhibitory and inflammatory, limiting the ability of activated NSCs to differentiate into neurons and form nascent circuits. Here we report that neurotrophin-3 (NT3)-coupled chitosan biomaterial, when inserted into a 5-mm gap of completely transected and excised rat thoracic spinal cord, elicited robust activation of endogenous NSCs in the injured spinal cord. Through slow release of NT3, the biomaterial attracted NSCs to migrate into the lesion area, differentiate into neurons, and form functional neural networks, which interconnected severed ascending and descending axons, resulting in sensory and motor behavioral recovery. Our study suggests that enhancing endogenous neurogenesis could be a novel strategy for treatment of spinal cord injury. PMID:26460015

Complete Disruption of the Kainate Receptor Gene Family Results in Corticostriatal Dysfunction in Mice.

PubMed

Xu, Jian; Marshall, John J; Fernandes, Herman B; Nomura, Toshihiro; Copits, Bryan A; Procissi, Daniele; Mori, Susumu; Wang, Lei; Zhu, Yongling; Swanson, Geoffrey T; Contractor, Anis

2017-02-21

Kainate receptors are members of the glutamate receptor family that regulate synaptic function in the brain. They modulate synaptic transmission and the excitability of neurons; however, their contributions to neural circuits that underlie behavior are unclear. To understand the net impact of kainate receptor signaling, we generated knockout mice in which all five kainate receptor subunits were ablated (5ko). These mice displayed compulsive and perseverative behaviors, including over-grooming, as well as motor problems, indicative of alterations in striatal circuits. There were deficits in corticostriatal input to spiny projection neurons (SPNs) in the dorsal striatum and correlated reductions in spine density. The behavioral alterations were not present in mice only lacking the primary receptor subunit expressed in adult striatum (GluK2 KO), suggesting that signaling through multiple receptor types is required for proper striatal function. This demonstrates that alterations in striatal function dominate the behavioral phenotype in mice without kainate receptors. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

A Complete Developmental Sequence of a Drosophila Neuronal Lineage as Revealed by Twin-Spot MARCM

PubMed Central

He, Yisheng; Ding, Peng; Kao, Jui-Chun; Lee, Tzumin

2010-01-01

Drosophila brains contain numerous neurons that form complex circuits. These neurons are derived in stereotyped patterns from a fixed number of progenitors, called neuroblasts, and identifying individual neurons made by a neuroblast facilitates the reconstruction of neural circuits. An improved MARCM (mosaic analysis with a repressible cell marker) technique, called twin-spot MARCM, allows one to label the sister clones derived from a common progenitor simultaneously in different colors. It enables identification of every single neuron in an extended neuronal lineage based on the order of neuron birth. Here we report the first example, to our knowledge, of complete lineage analysis among neurons derived from a common neuroblast that relay olfactory information from the antennal lobe (AL) to higher brain centers. By identifying the sequentially derived neurons, we found that the neuroblast serially makes 40 types of AL projection neurons (PNs). During embryogenesis, one PN with multi-glomerular innervation and 18 uniglomerular PNs targeting 17 glomeruli of the adult AL are born. Many more PNs of 22 additional types, including four types of polyglomerular PNs, derive after the neuroblast resumes dividing in early larvae. Although different offspring are generated in a rather arbitrary sequence, the birth order strictly dictates the fate of each post-mitotic neuron, including the fate of programmed cell death. Notably, the embryonic progenitor has an altered temporal identity following each self-renewing asymmetric cell division. After larval hatching, the same progenitor produces multiple neurons for each cell type, but the number of neurons for each type is tightly regulated. These observations substantiate the origin-dependent specification of neuron types. Sequencing neuronal lineages will not only unravel how a complex brain develops but also permit systematic identification of neuron types for detailed structure and function analysis of the brain. PMID:20808769

Mirror neurons: functions, mechanisms and models.

PubMed

Oztop, Erhan; Kawato, Mitsuo; Arbib, Michael A

2013-04-12

Mirror neurons for manipulation fire both when the animal manipulates an object in a specific way and when it sees another animal (or the experimenter) perform an action that is more or less similar. Such neurons were originally found in macaque monkeys, in the ventral premotor cortex, area F5 and later also in the inferior parietal lobule. Recent neuroimaging data indicate that the adult human brain is endowed with a "mirror neuron system," putatively containing mirror neurons and other neurons, for matching the observation and execution of actions. Mirror neurons may serve action recognition in monkeys as well as humans, whereas their putative role in imitation and language may be realized in human but not in monkey. This article shows the important role of computational models in providing sufficient and causal explanations for the observed phenomena involving mirror systems and the learning processes which form them, and underlines the need for additional circuitry to lift up the monkey mirror neuron circuit to sustain the posited cognitive functions attributed to the human mirror neuron system. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Manipulating neural activity in physiologically classified neurons: triumphs and challenges

PubMed Central

Gore, Felicity; Schwartz, Edmund C.; Salzman, C. Daniel

2015-01-01

Understanding brain function requires knowing both how neural activity encodes information and how this activity generates appropriate responses. Electrophysiological, imaging and immediate early gene immunostaining studies have been instrumental in identifying and characterizing neurons that respond to different sensory stimuli, events and motor actions. Here we highlight approaches that have manipulated the activity of physiologically classified neurons to determine their role in the generation of behavioural responses. Previous experiments have often exploited the functional architecture observed in many cortical areas, where clusters of neurons share response properties. However, many brain structures do not exhibit such functional architecture. Instead, neurons with different response properties are anatomically intermingled. Emerging genetic approaches have enabled the identification and manipulation of neurons that respond to specific stimuli despite the lack of discernable anatomical organization. These approaches have advanced understanding of the circuits mediating sensory perception, learning and memory, and the generation of behavioural responses by providing causal evidence linking neural response properties to appropriate behavioural output. However, significant challenges remain for understanding cognitive processes that are probably mediated by neurons with more complex physiological response properties. Currently available strategies may prove inadequate for determining how activity in these neurons is causally related to cognitive behaviour. PMID:26240431

Large-scale imaging in small brains

PubMed Central

Ahrens, Misha B.; Engert, Florian

2016-01-01

The dense connectivity in the brain and arrangements of cells into circuits means that one neuron’s activity can influence many others. To observe this interconnected system comprehensively, an aspiration within neuroscience is to record from as many neurons as possible at the same time. There are two useful routes toward this goal: one is to expand the spatial extent of functional imaging techniques, and the second is to use animals with small brains. Here we review recent progress toward imaging many neurons and complete populations of identified neurons in small vertebrates and invertebrates. PMID:25636154

Neural circuits and motivational processes for hunger

PubMed Central

Sternson, Scott M; Betley, J Nicholas; Huang Cao, Zhen Fang

2014-01-01

How does an organism’s internal state direct its actions? At one moment an animal forages for food with acrobatic feats such as tree climbing and jumping between branches. At another time, it travels along the ground to find water or a mate, exposing itself to predators along the way. These behaviors are costly in terms of energy or physical risk, and the likelihood of performing one set of actions relative to another is strongly modulated by internal state. For example, an animal in energy deficit searches for food and a dehydrated animal looks for water. The crosstalk between physiological state and motivational processes influences behavioral intensity and intent, but the underlying neural circuits are poorly understood. Molecular genetics along with optogenetic and pharmacogenetic tools for perturbing neuron function have enabled cell type-selective dissection of circuits that mediate behavioral responses to physiological state changes. Here, we review recent progress into neural circuit analysis of hunger in the mouse by focusing on a starvation-sensitive neuron population in the hypothalamus that is sufficient to promote voracious eating. We also consider research into the motivational processes that are thought to underlie hunger in order to outline considerations for bridging the gap between homeostatic and motivational neural circuits. PMID:23648085

Orexin modulates behavioral fear expression through the locus coeruleus.

PubMed

Soya, Shingo; Takahashi, Tohru M; McHugh, Thomas J; Maejima, Takashi; Herlitze, Stefan; Abe, Manabu; Sakimura, Kenji; Sakurai, Takeshi

2017-11-20

Emotionally salient information activates orexin neurons in the lateral hypothalamus, leading to increase in sympathetic outflow and vigilance level. How this circuit alters animals' behavior remains unknown. Here we report that noradrenergic neurons in the locus coeruleus (NA LC neurons) projecting to the lateral amygdala (LA) receive synaptic input from orexin neurons. Pharmacogenetic/optogenetic silencing of this circuit as well as acute blockade of the orexin receptor-1 (OX1R) decreases conditioned fear responses. In contrast, optogenetic stimulation of this circuit potentiates freezing behavior against a similar but distinct context or cue. Increase of orexinergic tone by fasting also potentiates freezing behavior and LA activity, which are blocked by pharmacological blockade of OX1R in the LC. These findings demonstrate the circuit involving orexin, NA LC and LA neurons mediates fear-related behavior and suggests inappropriate excitation of this pathway may cause fear generalization sometimes seen in psychiatric disorders, such as PTSD.

Schaffer Collateral Inputs to CA1 Excitatory and Inhibitory Neurons Follow Different Connectivity Rules.

PubMed

Kwon, Osung; Feng, Linqing; Druckmann, Shaul; Kim, Jinhyun

2018-05-30

Neural circuits, governed by a complex interplay between excitatory and inhibitory neurons, are the substrate for information processing, and the organization of synaptic connectivity in neural network is an important determinant of circuit function. Here, we analyzed the fine structure of connectivity in hippocampal CA1 excitatory and inhibitory neurons innervated by Schaffer collaterals (SCs) using mGRASP in male mice. Our previous study revealed spatially structured synaptic connectivity between CA3 and CA1 pyramidal cells (PCs). Surprisingly, parvalbumin-positive interneurons (PVs) showed a significantly more random pattern spatial structure. Notably, application of Peters' rule for synapse prediction by random overlap between axons and dendrites enhanced structured connectivity in PCs, but, by contrast, made the connectivity pattern in PVs more random. In addition, PCs in a deep sublayer of striatum pyramidale appeared more highly structured than PCs in superficial layers, and little or no sublayer specificity was found in PVs. Our results show that CA1 excitatory PCs and inhibitory PVs innervated by the same SC inputs follow different connectivity rules. The different organizations of fine scale structured connectivity in hippocampal excitatory and inhibitory neurons provide important insights into the development and functions of neural networks. SIGNIFICANCE STATEMENT Understanding how neural circuits generate behavior is one of the central goals of neuroscience. An important component of this endeavor is the mapping of fine-scale connection patterns that underlie, and help us infer, signal processing in the brain. Here, using our recently developed synapse detection technology (mGRASP and neuTube), we provide detailed profiles of synaptic connectivity in excitatory (CA1 pyramidal) and inhibitory (CA1 parvalbumin-positive) neurons innervated by the same presynaptic inputs (CA3 Schaffer collaterals). Our results reveal that these two types of CA1 neurons follow different connectivity patterns. Our new evidence for differently structured connectivity at a fine scale in hippocampal excitatory and inhibitory neurons provides a better understanding of hippocampal networks and will guide theoretical and experimental studies. Copyright © 2018 the authors 0270-6474/18/385140-13$15.00/0.

Neuropeptide transmission in brain circuits

PubMed Central

van den Pol, Anthony N.

2014-01-01

Neuropeptides are found in many mammalian CNS neurons where they play key roles in modulating neuronal activity. In contrast to amino acid transmitter release at the synapse, neuropeptide release is not restricted to the synaptic specialization, and after release, a neuropeptide may diffuse some distance to exert its action through a G-protein coupled receptor. Some neuropeptides such as hypocretin/orexin are synthesized only in single regions of the brain, and the neurons releasing these peptides probably have similar functional roles. Other peptides such as neuropeptide Y (NPY) are synthesized throughout the brain, and neurons that synthesize the peptide in one region have no anatomical or functional connection with NPY neurons in other brain regions. Here, I review converging data revealing a complex interaction between slow-acting neuromodulator peptides and fast-acting amino acid transmitters in the control of energy homeostasis, drug addiction, mood and motivation, sleep-wake states, and neuroendocrine regulation. PMID:23040809

Pharmacological characterization of ionic currents that regulate high-frequency spontaneous activity of electromotor neurons in the weakly electric fish, Apteronotus leptorhynchus.

PubMed

Smith, G Troy

2006-01-01

The neural circuit that controls the electric organ discharge (EOD) of the brown ghost knifefish (Apteronotus leptorhynchus) contains two spontaneous oscillators. Both pacemaker neurons in the medulla and electromotor neurons (EMNs) in the spinal cord fire spontaneously at frequencies of 500-1,000 Hz to control the EOD. These neurons continue to fire in vitro at frequencies that are highly correlated with in vivo EOD frequency. Previous studies used channel blocking drugs to pharmacologically characterize ionic currents that control high-frequency firing in pacemaker neurons. The goal of the present study was to use similar techniques to investigate ionic currents in EMNs, the other type of spontaneously active neuron in the electromotor circuit. As in pacemaker neurons, high-frequency firing of EMNs was regulated primarily by tetrodotoxin-sensitive sodium currents and by potassium currents that were sensitive to 4-aminopyridine and kappaA-conotoxin SIVA, but resistant to tetraethylammonium. EMNs, however, differed from pacemaker neurons in their sensitivity to some channel blocking drugs. Alpha-dendrotoxin, which blocks a subset of Kv1 potassium channels, increased firing rates in EMNs, but not pacemaker neurons; and the sodium channel blocker muO-conotoxin MrVIA, which reduced firing rates of pacemaker neurons, had no effect on EMNs. These results suggest that similar, but not identical, ionic currents regulate high-frequency firing in EMNs and pacemaker neurons. The differences in the ionic currents expressed in pacemaker neurons and EMNs might be related to differences in the morphology, connectivity, or function of these two cell types.

Energy-efficient neural information processing in individual neurons and neuronal networks.

PubMed

Yu, Lianchun; Yu, Yuguo

2017-11-01

Brains are composed of networks of an enormous number of neurons interconnected with synapses. Neural information is carried by the electrical signals within neurons and the chemical signals among neurons. Generating these electrical and chemical signals is metabolically expensive. The fundamental issue raised here is whether brains have evolved efficient ways of developing an energy-efficient neural code from the molecular level to the circuit level. Here, we summarize the factors and biophysical mechanisms that could contribute to the energy-efficient neural code for processing input signals. The factors range from ion channel kinetics, body temperature, axonal propagation of action potentials, low-probability release of synaptic neurotransmitters, optimal input and noise, the size of neurons and neuronal clusters, excitation/inhibition balance, coding strategy, cortical wiring, and the organization of functional connectivity. Both experimental and computational evidence suggests that neural systems may use these factors to maximize the efficiency of energy consumption in processing neural signals. Studies indicate that efficient energy utilization may be universal in neuronal systems as an evolutionary consequence of the pressure of limited energy. As a result, neuronal connections may be wired in a highly economical manner to lower energy costs and space. Individual neurons within a network may encode independent stimulus components to allow a minimal number of neurons to represent whole stimulus characteristics efficiently. This basic principle may fundamentally change our view of how billions of neurons organize themselves into complex circuits to operate and generate the most powerful intelligent cognition in nature. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons.

PubMed

Tepper, James M; Wilson, Charles J; Koós, Tibor

2008-08-01

There are two distinct inhibitory GABAergic circuits in the neostriatum. The feedforward circuit consists of a relatively small population of GABAergic interneurons that receives excitatory input from the neocortex and exerts monosynaptic inhibition onto striatal spiny projection neurons. The feedback circuit comprises the numerous spiny projection neurons and their interconnections via local axon collaterals. This network has long been assumed to provide the majority of striatal GABAergic inhibition and to sharpen and shape striatal output through lateral inhibition, producing increased activity in the most strongly excited spiny cells at the expense of their less strongly excited neighbors. Recent results, mostly from recording experiments of synaptically connected pairs of neurons, have revealed that the two GABAergic circuits differ markedly in terms of the total number of synapses made by each, the strength of the postsynaptic response detected at the soma, the extent of presynaptic convergence and divergence and the net effect of the activation of each circuit on the postsynaptic activity of the spiny neuron. These data have revealed that the feedforward inhibition is powerful and widespread, with spiking in a single interneuron being capable of significantly delaying or even blocking the generation of spikes in a large number of postsynaptic spiny neurons. In contrast, the postsynaptic effects of spiking in a single presynaptic spiny neuron on postsynaptic spiny neurons are weak when measured at the soma, and unable to significantly affect spike timing or generation. Further, reciprocity of synaptic connections between spiny neurons is only rarely observed. These results suggest that the bulk of the fast inhibition that has the strongest effects on spiny neuron spike timing comes from the feedforward interneuronal system whereas the axon collateral feedback system acts principally at the dendrites to control local excitability as well as the overall level of activity of the spiny neuron.

Curtailing effect of awakening on visual responses of cortical neurons by cholinergic activation of inhibitory circuits.

PubMed

Kimura, Rui; Safari, Mir-Shahram; Mirnajafi-Zadeh, Javad; Kimura, Rie; Ebina, Teppei; Yanagawa, Yuchio; Sohya, Kazuhiro; Tsumoto, Tadaharu

2014-07-23

Visual responsiveness of cortical neurons changes depending on the brain state. Neural circuit mechanism underlying this change is unclear. By applying the method of in vivo two-photon functional calcium imaging to transgenic rats in which GABAergic neurons express fluorescent protein, we analyzed changes in visual response properties of cortical neurons when animals became awakened from anesthesia. In the awake state, the magnitude and reliability of visual responses of GABAergic neurons increased whereas the decay of responses of excitatory neurons became faster. To test whether the basal forebrain (BF) cholinergic projection is involved in these changes, we analyzed effects of electrical and optogenetic activation of BF on visual responses of mouse cortical neurons with in vivo imaging and whole-cell recordings. Electrical BF stimulation in anesthetized animals induced the same direction of changes in visual responses of both groups of neurons as awakening. Optogenetic activation increased the frequency of visually evoked action potentials in GABAergic neurons but induced the delayed hyperpolarization that ceased the late generation of action potentials in excitatory neurons. Pharmacological analysis in slice preparations revealed that photoactivation-induced depolarization of layer 1 GABAergic neurons was blocked by a nicotinic receptor antagonist, whereas non-fast-spiking layer 2/3 GABAergic neurons was blocked only by the application of both nicotinic and muscarinic receptor antagonists. These results suggest that the effect of awakening is mediated mainly through nicotinic activation of layer 1 GABAergic neurons and mixed nicotinic/muscarinic activation of layer 2/3 non-fast-spiking GABAergic neurons, which together curtails the visual responses of excitatory neurons. Copyright © 2014 the authors 0270-6474/14/3410122-12$15.00/0.

From migration to settlement: the pathways, migration modes and dynamics of neurons in the developing brain

PubMed Central

HATANAKA, Yumiko; ZHU, Yan; TORIGOE, Makio; KITA, Yoshiaki; MURAKAMI, Fujio

2016-01-01

Neuronal migration is crucial for the construction of the nervous system. To reach their correct destination, migrating neurons choose pathways using physical substrates and chemical cues of either diffusible or non-diffusible nature. Migrating neurons extend a leading and a trailing process. The leading process, which extends in the direction of migration, determines navigation, in particular when a neuron changes its direction of migration. While most neurons simply migrate radially, certain neurons switch their mode of migration between radial and tangential, with the latter allowing migration to destinations far from the neurons’ site of generation. Consequently, neurons with distinct origins are intermingled, which results in intricate neuronal architectures and connectivities and provides an important basis for higher brain function. The trailing process, in contrast, contributes to the late stage of development by turning into the axon, thus contributing to the formation of neuronal circuits. PMID:26755396

A generalized analog implementation of piecewise linear neuron models using CCII building blocks.

PubMed

Soleimani, Hamid; Ahmadi, Arash; Bavandpour, Mohammad; Sharifipoor, Ozra

2014-03-01

This paper presents a set of reconfigurable analog implementations of piecewise linear spiking neuron models using second generation current conveyor (CCII) building blocks. With the same topology and circuit elements, without W/L modification which is impossible after circuit fabrication, these circuits can produce different behaviors, similar to the biological neurons, both for a single neuron as well as a network of neurons just by tuning reference current and voltage sources. The models are investigated, in terms of analog implementation feasibility and costs, targeting large scale hardware implementations. Results show that, in order to gain the best performance, area and accuracy; these models can be compromised. Simulation results are presented for different neuron behaviors with CMOS 350 nm technology. Copyright © 2013 Elsevier Ltd. All rights reserved.

Noise in Neuronal and Electronic Circuits: A General Modeling Framework and Non-Monte Carlo Simulation Techniques.

PubMed

Kilinc, Deniz; Demir, Alper

2017-08-01

The brain is extremely energy efficient and remarkably robust in what it does despite the considerable variability and noise caused by the stochastic mechanisms in neurons and synapses. Computational modeling is a powerful tool that can help us gain insight into this important aspect of brain mechanism. A deep understanding and computational design tools can help develop robust neuromorphic electronic circuits and hybrid neuroelectronic systems. In this paper, we present a general modeling framework for biological neuronal circuits that systematically captures the nonstationary stochastic behavior of ion channels and synaptic processes. In this framework, fine-grained, discrete-state, continuous-time Markov chain models of both ion channels and synaptic processes are treated in a unified manner. Our modeling framework features a mechanism for the automatic generation of the corresponding coarse-grained, continuous-state, continuous-time stochastic differential equation models for neuronal variability and noise. Furthermore, we repurpose non-Monte Carlo noise analysis techniques, which were previously developed for analog electronic circuits, for the stochastic characterization of neuronal circuits both in time and frequency domain. We verify that the fast non-Monte Carlo analysis methods produce results with the same accuracy as computationally expensive Monte Carlo simulations. We have implemented the proposed techniques in a prototype simulator, where both biological neuronal and analog electronic circuits can be simulated together in a coupled manner.

Chronic Stress Alters Striosome-Circuit Dynamics, Leading to Aberrant Decision-Making.

PubMed

Friedman, Alexander; Homma, Daigo; Bloem, Bernard; Gibb, Leif G; Amemori, Ken-Ichi; Hu, Dan; Delcasso, Sebastien; Truong, Timothy F; Yang, Joyce; Hood, Adam S; Mikofalvy, Katrina A; Beck, Dirk W; Nguyen, Norah; Nelson, Erik D; Toro Arana, Sebastian E; Vorder Bruegge, Ruth H; Goosens, Ki A; Graybiel, Ann M

2017-11-16

Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, "rational" decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Concomitantly, alterations in the task-related spike activity of medial prefrontal neurons correspond with increased activity of their striosome-predominant striatal projection neuron targets and with decreased and delayed striatal fast-firing interneuron activity. These effects of chronic stress on prefronto-striatal circuit dynamics could be blocked or be mimicked by selective optogenetic manipulation of these circuits. We suggest that altered excitation-inhibition dynamics of striosome-based circuit function could be an underlying mechanism by which chronic stress contributes to disorders characterized by aberrant decision-making under conflict. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.

Early Disruption of Extracellular Pleiotrophin Distribution Alters Cerebellar Neuronal Circuit Development and Function.

PubMed

Hamza, M M; Rey, S A; Hilber, P; Arabo, A; Collin, T; Vaudry, D; Burel, D

2016-10-01

The cerebellum is a structure of the central nervous system involved in balance, motor coordination, and voluntary movements. The elementary circuit implicated in the control of locomotion involves Purkinje cells, which receive excitatory inputs from parallel and climbing fibers, and are regulated by cerebellar interneurons. In mice as in human, the cerebellar cortex completes its development mainly after birth with the migration, differentiation, and synaptogenesis of granule cells. These cellular events are under the control of numerous extracellular matrix molecules including pleiotrophin (PTN). This cytokine has been shown to regulate the morphogenesis of Purkinje cells ex vivo and in vivo via its receptor PTPζ. Since Purkinje cells are the unique output of the cerebellar cortex, we explored the consequences of their PTN-induced atrophy on the function of the cerebellar neuronal circuit in mice. Behavioral experiments revealed that, despite a normal overall development, PTN-treated mice present a delay in the maturation of their flexion reflex. Moreover, patch clamp recording of Purkinje cells revealed a significant increase in the frequency of spontaneous excitatory postsynaptic currents in PTN-treated mice, associated with a decrease of climbing fiber innervations and an abnormal perisomatic localization of the parallel fiber contacts. At adulthood, PTN-treated mice exhibit coordination impairment on the rotarod test associated with an alteration of the synchronization gait. Altogether these histological, electrophysiological, and behavior data reveal that an early ECM disruption of PTN composition induces short- and long-term defaults in the establishment of proper functional cerebellar circuit.

Alternative Post-Processing on a CMOS Chip to Fabricate a Planar Microelectrode Array

PubMed Central

López-Huerta, Francisco; Herrera-May, Agustín L.; Estrada-López, Johan J.; Zuñiga-Islas, Carlos; Cervantes-Sanchez, Blanca; Soto, Enrique; Soto-Cruz, Blanca S.

2011-01-01

We present an alternative post-processing on a CMOS chip to release a planar microelectrode array (pMEA) integrated with its signal readout circuit, which can be used for monitoring the neuronal activity of vestibular ganglion neurons in newborn Wistar strain rats. This chip is fabricated through a 0.6 μm CMOS standard process and it has 12 pMEA through a 4 × 3 electrodes matrix. The alternative CMOS post-process includes the development of masks to protect the readout circuit and the power supply pads. A wet etching process eliminates the aluminum located on the surface of the p+-type silicon. This silicon is used as transducer for recording the neuronal activity and as interface between the readout circuit and neurons. The readout circuit is composed of an amplifier and tunable bandpass filter, which is placed on a 0.015 mm2 silicon area. The tunable bandpass filter has a bandwidth of 98 kHz and a common mode rejection ratio (CMRR) of 87 dB. These characteristics of the readout circuit are appropriate for neuronal recording applications. PMID:22346681

Alternative post-processing on a CMOS chip to fabricate a planar microelectrode array.

PubMed

López-Huerta, Francisco; Herrera-May, Agustín L; Estrada-López, Johan J; Zuñiga-Islas, Carlos; Cervantes-Sanchez, Blanca; Soto, Enrique; Soto-Cruz, Blanca S

2011-01-01

We present an alternative post-processing on a CMOS chip to release a planar microelectrode array (pMEA) integrated with its signal readout circuit, which can be used for monitoring the neuronal activity of vestibular ganglion neurons in newborn Wistar strain rats. This chip is fabricated through a 0.6 μm CMOS standard process and it has 12 pMEA through a 4 × 3 electrodes matrix. The alternative CMOS post-process includes the development of masks to protect the readout circuit and the power supply pads. A wet etching process eliminates the aluminum located on the surface of the p+ -type silicon. This silicon is used as transducer for recording the neuronal activity and as interface between the readout circuit and neurons. The readout circuit is composed of an amplifier and tunable bandpass filter, which is placed on a 0.015 mm2 silicon area. The tunable bandpass filter has a bandwidth of 98 kHz and a common mode rejection ratio (CMRR) of 87 dB. These characteristics of the readout circuit are appropriate for neuronal recording applications.

Relaxation oscillator-realized artificial electronic neurons, their responses, and noise

NASA Astrophysics Data System (ADS)

Lim, Hyungkwang; Ahn, Hyung-Woo; Kornijcuk, Vladimir; Kim, Guhyun; Seok, Jun Yeong; Kim, Inho; Hwang, Cheol Seong; Jeong, Doo Seok

2016-05-01

A proof-of-concept relaxation oscillator-based leaky integrate-and-fire (ROLIF) neuron circuit is realized by using an amorphous chalcogenide-based threshold switch and non-ideal operational amplifier (op-amp). The proposed ROLIF neuron offers biologically plausible features such as analog-type encoding, signal amplification, unidirectional synaptic transmission, and Poisson noise. The synaptic transmission between pre- and postsynaptic neurons is achieved through a passive synapse (simple resistor). The synaptic resistor coupled to the non-ideal op-amp realizes excitatory postsynaptic potential (EPSP) evolution that evokes postsynaptic neuron spiking. In an attempt to generalize our proposed model, we theoretically examine ROLIF neuron circuits adopting different non-ideal op-amps having different gains and slew rates. The simulation results indicate the importance of gain in postsynaptic neuron spiking, irrespective of the slew rate (as long as the rate exceeds a particular value), providing the basis for the ROLIF neuron circuit design. Eventually, the behavior of a postsynaptic neuron in connection to multiple presynaptic neurons via synapses is highlighted in terms of EPSP evolution amid simultaneously incident asynchronous presynaptic spikes, which in fact reveals an important role of the random noise in spatial integration.A proof-of-concept relaxation oscillator-based leaky integrate-and-fire (ROLIF) neuron circuit is realized by using an amorphous chalcogenide-based threshold switch and non-ideal operational amplifier (op-amp). The proposed ROLIF neuron offers biologically plausible features such as analog-type encoding, signal amplification, unidirectional synaptic transmission, and Poisson noise. The synaptic transmission between pre- and postsynaptic neurons is achieved through a passive synapse (simple resistor). The synaptic resistor coupled to the non-ideal op-amp realizes excitatory postsynaptic potential (EPSP) evolution that evokes postsynaptic neuron spiking. In an attempt to generalize our proposed model, we theoretically examine ROLIF neuron circuits adopting different non-ideal op-amps having different gains and slew rates. The simulation results indicate the importance of gain in postsynaptic neuron spiking, irrespective of the slew rate (as long as the rate exceeds a particular value), providing the basis for the ROLIF neuron circuit design. Eventually, the behavior of a postsynaptic neuron in connection to multiple presynaptic neurons via synapses is highlighted in terms of EPSP evolution amid simultaneously incident asynchronous presynaptic spikes, which in fact reveals an important role of the random noise in spatial integration. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr01278g

Medial Habenula Output Circuit Mediated by α5 Nicotinic Receptor-Expressing GABAergic Neurons in the Interpeduncular Nucleus

PubMed Central

Hsu, Yun-Wei A.; Tempest, Lynne; Quina, Lely A.; Wei, Aguan D.; Zeng, Hongkui

2013-01-01

The Chrna5 gene encodes the α5 nicotinic acetylcholine receptor subunit, an “accessory” subunit of pentameric nicotinic receptors, that has been shown to play a role in nicotine-related behaviors in rodents and is genetically linked to smoking behavior in humans. Here we have used a BAC transgenic mouse line, α5GFP, to examine the cellular phenotype, connectivity, and function of α5-expressing neurons. Although the medial habenula (MHb) has been proposed as a site of α5 function, α5GFP is not detectable in the MHb, and α5 mRNA is expressed there only at very low levels. However, α5GFP is strongly expressed in a subset of neurons in the interpeduncular nucleus (IP), median raphe/paramedian raphe (MnR/PMnR), and dorsal tegmental area (DTg). Double-label fluorescence in situ hybridization reveals that these neurons are exclusively GABAergic. Transgenic and conventional tract tracing show that α5GFP neurons in the IP project principally to the MnR/PMnR and DTg/interfascicular dorsal raphe, both areas rich in serotonergic neurons. The α5GFP neurons in the IP are located in a region that receives cholinergic fiber inputs from the ventral MHb, and optogenetically assisted circuit mapping demonstrates a monosynaptic connection between these cholinergic neurons and α5GFP IP neurons. Selective inhibitors of both α4β2- and α3β4-containing nicotinic receptors were able to reduce nicotine-evoked inward currents in α5GFP neurons in the IP, suggesting a mixed nicotinic receptor profile in these cells. Together, these findings show that the α5-GABAergic interneurons form a link from the MHb to serotonergic brain centers, which is likely to mediate some of the behavioral effects of nicotine. PMID:24227714

Neuromodulation targets intrinsic cardiac neurons to attenuate neuronally mediated atrial arrhythmias.

PubMed

Gibbons, David D; Southerland, E Marie; Hoover, Donald B; Beaumont, Eric; Armour, J Andrew; Ardell, Jeffrey L

2012-02-01

Our objective was to determine whether atrial fibrillation (AF) results from excessive activation of intrinsic cardiac neurons (ICNs) and, if so, whether select subpopulations of neurons therein represent therapeutic targets for suppression of this arrhythmogenic potential. Trains of five electrical stimuli (0.3-1.2 mA, 1 ms) were delivered during the atrial refractory period to mediastinal nerves (MSN) on the superior vena cava to evoke AF. Neuroanatomical studies were performed by injecting the neuronal tracer DiI into MSN sites that induced AF. Functional studies involved recording of neuronal activity in situ from the right atrial ganglionated plexus (RAGP) in response to MSN stimulation (MSNS) prior to and following neuromodulation involving either preemptive spinal cord stimulation (SCS; T(1)-T(3), 50 Hz, 200-ms duration) or ganglionic blockade (hexamethonium, 5 mg/kg). The tetramethylindocarbocyanine perchlorate (DiI) neuronal tracer labeled a subset (13.2%) of RAGP neurons, which also colocalized with cholinergic or adrenergic markers. A subset of DiI-labeled RAGP neurons were noncholinergic/nonadrenergic. MSNS evoked an ∼4-fold increase in RAGP neuronal activity from baseline, which SCS reduced by 43%. Hexamethonium blocked MSNS-evoked increases in neuronal activity. MSNS evoked AF in 78% of right-sided MSN sites, which SCS reduced to 33% and hexamethonium reduced to 7%. MSNS-induced bradycardia was maintained with SCS but was mitigated by hexamethonium. We conclude that MSNS activates subpopulations of intrinsic cardiac neurons, thereby resulting in the formation of atrial arrhythmias leading to atrial fibrillation. Stabilization of ICN local circuit neurons by SCS or the local circuit and autonomic efferent neurons with hexamethonium reduces the arrhythmogenic potential.

Synaptic Effects of Electric Fields

NASA Astrophysics Data System (ADS)

Rahman, Asif

Learning and sensory processing in the brain relies on the effective transmission of information across synapses. The strength and efficacy of synaptic transmission is modifiable through training and can be modulated with noninvasive electrical brain stimulation. Transcranial electrical stimulation (TES), specifically, induces weak intensity and spatially diffuse electric fields in the brain. Despite being weak, electric fields modulate spiking probability and the efficacy of synaptic transmission. These effects critically depend on the direction of the electric field relative to the orientation of the neuron and on the level of endogenous synaptic activity. TES has been used to modulate a wide range of neuropsychiatric indications, for various rehabilitation applications, and cognitive performance in diverse tasks. How can a weak and diffuse electric field, which simultaneously polarizes neurons across the brain, have precise changes in brain function? Designing therapies to maximize desired outcomes and minimize undesired effects presents a challenging problem. A series of experiments and computational models are used to define the anatomical and functional factors leading to specificity of TES. Anatomical specificity derives from guiding current to targeted brain structures and taking advantage of the direction-sensitivity of neurons with respect to the electric field. Functional specificity originates from preferential modulation of neuronal networks that are already active. Diffuse electric fields may recruit connected brain networks involved in a training task and promote plasticity along active synaptic pathways. In vitro, electric fields boost endogenous synaptic plasticity and raise the ceiling for synaptic learning with repeated stimulation sessions. Synapses undergoing strong plasticity are preferentially modulated over weak synapses. Therefore, active circuits that are involved in a task could be more susceptible to stimulation than inactive circuits. Moreover, stimulation polarity has asymmetric effects on synaptic strength making it easier to enhance ongoing plasticity. These results suggest that the susceptibility of brain networks to an electric field depends on the state of synaptic activity. Combining a training task, which activates specific circuits, with TES may lead to functionally-specific effects. Given the simplicity of TES and the complexity of brain function, understanding the mechanisms leading to specificity is fundamental to the rational advancement of TES.

Differentially Timed Extracellular Signals Synchronize Pacemaker Neuron Clocks

PubMed Central

Collins, Ben; Kaplan, Harris S.; Cavey, Matthieu; Lelito, Katherine R.; Bahle, Andrew H.; Zhu, Zhonghua; Macara, Ann Marie; Roman, Gregg; Shafer, Orie T.; Blau, Justin

2014-01-01

Synchronized neuronal activity is vital for complex processes like behavior. Circadian pacemaker neurons offer an unusual opportunity to study synchrony as their molecular clocks oscillate in phase over an extended timeframe (24 h). To identify where, when, and how synchronizing signals are perceived, we first studied the minimal clock neural circuit in Drosophila larvae, manipulating either the four master pacemaker neurons (LNvs) or two dorsal clock neurons (DN1s). Unexpectedly, we found that the PDF Receptor (PdfR) is required in both LNvs and DN1s to maintain synchronized LNv clocks. We also found that glutamate is a second synchronizing signal that is released from DN1s and perceived in LNvs via the metabotropic glutamate receptor (mGluRA). Because simultaneously reducing Pdfr and mGluRA expression in LNvs severely dampened Timeless clock protein oscillations, we conclude that the master pacemaker LNvs require extracellular signals to function normally. These two synchronizing signals are released at opposite times of day and drive cAMP oscillations in LNvs. Finally we found that PdfR and mGluRA also help synchronize Timeless oscillations in adult s-LNvs. We propose that differentially timed signals that drive cAMP oscillations and synchronize pacemaker neurons in circadian neural circuits will be conserved across species. PMID:25268747

Morphometric analysis of astrocytes in brainstem respiratory regions.

PubMed

Sheikhbahaei, Shahriar; Morris, Brian; Collina, Jared; Anjum, Sommer; Znati, Sami; Gamarra, Julio; Zhang, Ruli; Gourine, Alexander V; Smith, Jeffrey C

2018-06-11

Astrocytes, the most abundant and structurally complex glial cells of the central nervous system, are proposed to play an important role in modulating the activities of neuronal networks, including respiratory rhythm-generating circuits of the preBötzinger complex (preBötC) located in the ventrolateral medulla of the brainstem. However, structural properties of astrocytes residing within different brainstem regions are unknown. In this study astrocytes in the preBötC, an intermediate reticular formation (IRF) region with respiratory-related function, and a region of the nucleus tractus solitarius (NTS) in adult rats were reconstructed and their morphological features were compared. Detailed morphological analysis revealed that preBötC astrocytes are structurally more complex than those residing within the functionally distinct neighboring IRF region, or the NTS, located at the dorsal aspect of the medulla oblongata. Structural analyses of the brainstem microvasculature indicated no significant regional differences in vascular properties. We hypothesize that high morphological complexity of preBötC astrocytes reflects their functional role in providing structural/metabolic support and modulation of the key neuronal circuits essential for breathing, as well as constraints imposed by arrangements of associated neurons and/or other local structural features of the brainstem parenchyma. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Autonomic control network active in Aplysia during locomotion includes neurons that express splice variants of R15-neuropeptides.

PubMed

Romanova, Elena V; McKay, Natasha; Weiss, Klaudiusz R; Sweedler, Jonathan V; Koester, John

2007-01-01

Splice-variant products of the R15 neuropeptide gene are differentially expressed within the CNS of Aplysia. The goal of this study was to test whether the neurons in the abdominal ganglion that express the peptides encoded by this gene are part of a common circuit. Expression of R15 peptides had been demonstrated previously in neuron R15. Using a combination of immunocytochemical and analytical methods, this study demonstrated that R15 peptides are also expressed in heart exciter neuron RB(HE), the two L9(G) gill motoneurons, and L40--a newly identified interneuron. Mass spectrometric profiling of individual neurons that exhibit R15 peptide-like immunoreactivity confirmed the mutually exclusive expression of two splice-variant forms of R15 peptides in different neurons. The L9(G) cells were found to co-express pedal peptide in addition to the R15 peptides. The R15 peptide-expressing neurons examined here were shown to be part of an autonomic control circuit that is active during fictive locomotion. Activity in this circuit contributes to implementing a central command that may help to coordinate autonomic activity with escape locomotion. Chronic extracellular nerve recording was used to determine the activity patterns of a subset of neurons of this circuit in vivo. These results demonstrate the potential utility of using shared patterns of neuropeptide expression as a guide for neural circuit identification.

Ultrasonic modulation of neural circuit activity.

PubMed

Tyler, William J; Lani, Shane W; Hwang, Grace M

2018-06-01

Ultrasound (US) is recognized for its use in medical imaging as a diagnostic tool. As an acoustic energy source, US has become increasingly appreciated over the past decade for its ability to non-invasively modulate cellular activity including neuronal activity. Data obtained from a host of experimental models has shown that low-intensity US can reversibly modulate the physiological activity of neurons in peripheral nerves, spinal cord, and intact brain circuits. Experimental evidence indicates that acoustic pressures exerted by US act, in part, on mechanosensitive ion channels to modulate activity. While the precise mechanisms of action enabling US to both stimulate and suppress neuronal activity remain to be clarified, there are several advantages conferred by the physics of US that make it an appealing option for neuromodulation. For example, it can be focused with millimeter spatial resolutions through skull bone to deep-brain regions. By increasing our engineering capability to leverage such physical advantages while growing our understanding of how US affects neuronal function, the development of a new generation of non-invasive neurotechnology can be developed using ultrasonic methods. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Common key-signals in learning and neurodegeneration: focus on excito-amino acids, beta-amyloid peptides and alpha-synuclein.

PubMed

Agnati, L F; Leo, G; Genedani, S; Piron, L; Rivera, A; Guidolin, D; Fuxe, K

2009-08-01

In this paper a hypothesis that some special signals ("key-signals" excito-amino acids, beta-amyloid peptides and alpha-synuclein) are not only involved in information handling by the neuronal circuits, but also trigger out substantial structural and/or functional changes in the Central Nervous System (CNS) is introduced. This forces the neuronal circuits to move from one stable state towards a new state, but in doing so these signals became potentially dangerous. Several mechanisms are put in action to protect neurons and glial cells from these potentially harmful signals. However, in agreement with the Red Queen Theory of Ageing (Agnati et al. in Acta Physiol Scand 145:301-309, 1992), it is proposed that during ageing these neuroprotective processes become less effective while, in the meantime, a shortage of brain plasticity occurs together with an increased need of plasticity for repairing the wear and tear of the CNS. The paper presents findings supporting the concept that such key-signals in instances such as ageing may favour neurodegenerative processes in an attempt of maximizing neuronal plasticity.

Delayed Maturation of Fast-Spiking Interneurons Is Rectified by Activation of the TrkB Receptor in the Mouse Model of Fragile X Syndrome

PubMed Central

Nomura, Toshihiro; Zhu, Yiwen; Remmers, Christine L.; Xu, Jian; Nicholson, Daniel A.

2017-01-01

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is a leading cause of inherited intellectual disability, and the most common known cause of autism spectrum disorder. FXS is broadly characterized by sensory hypersensitivity and several developmental alterations in synaptic and circuit function have been uncovered in the sensory cortex of the mouse model of FXS (Fmr1 KO). GABA-mediated neurotransmission and fast-spiking (FS) GABAergic interneurons are central to cortical circuit development in the neonate. Here we demonstrate that there is a delay in the maturation of the intrinsic properties of FS interneurons in the sensory cortex, and a deficit in the formation of excitatory synaptic inputs on to these neurons in neonatal Fmr1 KO mice. Both these delays in neuronal and synaptic maturation were rectified by chronic administration of a TrkB receptor agonist. These results demonstrate that the maturation of the GABAergic circuit in the sensory cortex is altered during a critical developmental period due in part to a perturbation in BDNF-TrkB signaling, and could contribute to the alterations in cortical development underlying the sensory pathophysiology of FXS. SIGNIFICANCE STATEMENT Fragile X (FXS) individuals have a range of sensory related phenotypes, and there is growing evidence of alterations in neuronal circuits in the sensory cortex of the mouse model of FXS (Fmr1 KO). GABAergic interneurons are central to the correct formation of circuits during cortical critical periods. Here we demonstrate a delay in the maturation of the properties and synaptic connectivity of interneurons in Fmr1 KO mice during a critical period of cortical development. The delays both in cellular and synaptic maturation were rectified by administration of a TrkB receptor agonist, suggesting reduced BDNF-TrkB signaling as a contributing factor. These results provide evidence that the function of fast-spiking interneurons is disrupted due to a deficiency in neurotrophin signaling during early development in FXS. PMID:29038238

Sensory Optimization by Stochastic Tuning

PubMed Central

Jurica, Peter; Gepshtein, Sergei; Tyukin, Ivan; van Leeuwen, Cees

2013-01-01

Individually, visual neurons are each selective for several aspects of stimulation, such as stimulus location, frequency content, and speed. Collectively, the neurons implement the visual system’s preferential sensitivity to some stimuli over others, manifested in behavioral sensitivity functions. We ask how the individual neurons are coordinated to optimize visual sensitivity. We model synaptic plasticity in a generic neural circuit, and find that stochastic changes in strengths of synaptic connections entail fluctuations in parameters of neural receptive fields. The fluctuations correlate with uncertainty of sensory measurement in individual neurons: the higher the uncertainty the larger the amplitude of fluctuation. We show that this simple relationship is sufficient for the stochastic fluctuations to steer sensitivities of neurons toward a characteristic distribution, from which follows a sensitivity function observed in human psychophysics, and which is predicted by a theory of optimal allocation of receptive fields. The optimal allocation arises in our simulations without supervision or feedback about system performance and independently of coupling between neurons, making the system highly adaptive and sensitive to prevailing stimulation. PMID:24219849

Drebrin-mediated microtubule–actomyosin coupling steers cerebellar granule neuron nucleokinesis and migration pathway selection

PubMed Central

Trivedi, Niraj; Stabley, Daniel R.; Cain, Blake; Howell, Danielle; Laumonnerie, Christophe; Ramahi, Joseph S.; Temirov, Jamshid; Kerekes, Ryan A.; Gordon-Weeks, Phillip R.; Solecki, David J.

2017-01-01

Neuronal migration from a germinal zone to a final laminar position is essential for the morphogenesis of neuronal circuits. While it is hypothesized that microtubule–actomyosin crosstalk is required for a neuron's ‘two-stroke' nucleokinesis cycle, the molecular mechanisms controlling such crosstalk are not defined. By using the drebrin microtubule–actin crosslinking protein as an entry point into the cerebellar granule neuron system in combination with super-resolution microscopy, we investigate how these cytoskeletal systems interface during migration. Lattice light-sheet and structured illumination microscopy reveal a proximal leading process nanoscale architecture wherein f-actin and drebrin intervene between microtubules and the plasma membrane. Functional perturbations of drebrin demonstrate that proximal leading process microtubule–actomyosin coupling steers the direction of centrosome and somal migration, as well as the switch from tangential to radial migration. Finally, the Siah2 E3 ubiquitin ligase antagonizes drebrin function, suggesting a model for control of the microtubule–actomyosin interfaces during neuronal differentiation. PMID:28230156

Comparison of extrinsic and intrinsic neuromodulation in two central pattern generator circuits in invertebrates.

PubMed

Katz, P S

1998-05-01

There are many sources of modulatory input to CPGs and other types of neuronal circuits. These inputs can change the properties of cells and synapses and dramatically alter the production of motor patterns. Sometimes this enables the production of motor patterns by the circuit. At other times, the modulation allows alternate motor patterns to be produced by a single circuit. Modulatory neurones have fast as well as slow actions. In some cases, such as with GPR, the two types of effects are due to the release of co-transmitters. In other cases, such as with the DSIs, a single substance can act at different receptors to cause fast and slow postsynaptic actions. The effect of a neuromodulatory neurone is determined by the type of receptor on the target neurone. Thus a single modulatory neurone evokes a suite of actions in a circuit and thereby produces a co-ordinated output. Extrinsic and intrinsic sources of neuromodulation have different sets of constraints acting upon them. For example, extrinsic neuromodulation can easily be used for motor pattern selection; a different pattern is produced depending upon which modulatory inputs are active. However, intrinsic neuromodulation is not well suited to that task. Instead, it is useful for self-organizing properties and experience-dependent effects. One clear conclusion from this work and other work in the field is that neuromodulation by neurones intrinsic and extrinsic to CPGs is not uncommon (Katz, 1995; Katz & Frost, 1996). It is part of the normal process of motor pattern generation. As such, it needs to be considered when discussing mechanisms for neuronal circuit actions.

A Screening of UNF Targets Identifies Rnb, a Novel Regulator of Drosophila Circadian Rhythms.

PubMed

Kozlov, Anatoly; Jaumouillé, Edouard; Machado Almeida, Pedro; Koch, Rafael; Rodriguez, Joseph; Abruzzi, Katharine C; Nagoshi, Emi

2017-07-12

Behavioral circadian rhythms are controlled by multioscillator networks comprising functionally different subgroups of clock neurons. Studies have demonstrated that molecular clocks in the fruit fly Drosophila melanogaster are regulated differently in clock neuron subclasses to support their specific functions (Lee et al., 2016; Top et al., 2016). The nuclear receptor unfulfilled ( unf ) represents a regulatory node that provides the small ventral lateral neurons (s-LNvs) unique characteristics as the master pacemaker (Beuchle et al., 2012). We previously showed that UNF interacts with the s-LNv molecular clocks by regulating transcription of the core clock gene period ( per ) (Jaumouillé et al., 2015). To gain more insight into the mechanisms by which UNF contributes to the functioning of the circadian master pacemaker, we identified UNF target genes using chromatin immunoprecipitation. Our data demonstrate that a previously uncharacterized gene CG7837 , which we termed R and B ( Rnb ), acts downstream of UNF to regulate the function of the s-LNvs as the master circadian pacemaker. Mutations and LNv-targeted adult-restricted knockdown of Rnb impair locomotor rhythms. RNB localizes to the nucleus, and its loss-of-function blunts the molecular rhythms and output rhythms of the s-LNvs, particularly the circadian rhythms in PDF accumulation and axonal arbor remodeling. These results establish a second pathway by which UNF interacts with the molecular clocks in the s-LNvs and highlight the mechanistic differences in the molecular clockwork within the pacemaker circuit. SIGNIFICANCE STATEMENT Circadian behavior is generated by a pacemaker circuit comprising diverse classes of pacemaker neurons, each of which contains a molecular clock. In addition to the anatomical and functional diversity, recent studies have shown the mechanistic differences in the molecular clockwork among the pacemaker neurons in Drosophila Here, we identified the molecular characteristics distinguishing the s-LNvs, the master pacemaker of the locomotor rhythms, from other clock neuron subtypes. We demonstrated that a newly identified gene Rnb is an s-LNv-specific regulator of the molecular clock and essential for the generation of circadian locomotor behavior. Our results provide additional evidence to the emerging view that the differential regulation of the molecular clocks underlies the functional differences among the pacemaker neuron subgroups. Copyright © 2017 the authors 0270-6474/17/376673-13$15.00/0.

A neuromorphic circuit mimicking biological short-term memory.

PubMed

Barzegarjalali, Saeid; Parker, Alice C

2016-08-01

Research shows that the way we remember things for a few seconds is a different mechanism from the way we remember things for a longer time. Short-term memory is based on persistently firing neurons, whereas storing information for a longer time is based on strengthening the synapses or even forming new neural connections. Information about location and appearance of an object is segregated and processed by separate neurons. Furthermore neurons can continue firing using different mechanisms. Here, we have designed a biomimetic neuromorphic circuit that mimics short-term memory by firing neurons, using biological mechanisms to remember location and shape of an object. Our neuromorphic circuit has a hybrid architecture. Neurons are designed with CMOS 45nm technology and synapses are designed with carbon nanotubes (CNT).

Reward from bugs to bipeds: a comparative approach to understanding how reward circuits function

PubMed Central

Scaplen, Kristin M.; Kaun, Karla R.

2016-01-01

Abstract In a complex environment, animals learn from their responses to stimuli and events. Appropriate response to reward and punishment can promote survival, reproduction and increase evolutionary fitness. Interestingly, the neural processes underlying these responses are remarkably similar across phyla. In all species, dopamine is central to encoding reward and directing motivated behaviors, however, a comprehensive understanding of how circuits encode reward and direct motivated behaviors is still lacking. In part, this is a result of the sheer diversity of neurons, the heterogeneity of their responses and the complexity of neural circuits within which they are found. We argue that general features of reward circuitry are common across model organisms, and thus principles learned from invertebrate model organisms can inform research across species. In particular, we discuss circuit motifs that appear to be functionally equivalent from flies to primates. We argue that a comparative approach to studying and understanding reward circuit function provides a more comprehensive understanding of reward circuitry, and informs disorders that affect the brain’s reward circuitry. PMID:27328845

Brain selective transgene expression in zebrafish using an NRSE derived motif

PubMed Central

Bergeron, Sadie A.; Hannan, Markus C.; Codore, Hiba; Fero, Kandice; Li, Grace H.; Moak, Zachary; Yokogawa, Tohei; Burgess, Harold A.

2012-01-01

Transgenic technologies enable the manipulation and observation of circuits controlling behavior by permitting expression of genetically encoded reporter genes in neurons. Frequently though, neuronal expression is accompanied by transgene expression in non-neuronal tissues, which may preclude key experimental manipulations, including assessment of the contribution of neurons to behavior by ablation. To better restrict transgene expression to the nervous system in zebrafish larvae, we have used DNA sequences derived from the neuron-restrictive silencing element (NRSE). We find that one such sequence, REx2, when used in conjunction with several basal promoters, robustly suppresses transgene expression in non-neuronal tissues. Both in transient transgenic experiments and in stable enhancer trap lines, suppression is achieved without compromising expression within the nervous system. Furthermore, in REx2 enhancer trap lines non-neuronal expression can be de-repressed by knocking down expression of the NRSE binding protein RE1-silencing transcription factor (Rest). In one line, we show that the resulting pattern of reporter gene expression coincides with that of the adjacent endogenous gene, hapln3. We demonstrate that three common basal promoters are susceptible to the effects of the REx2 element, suggesting that this method may be useful for confining expression from many other promoters to the nervous system. This technique enables neural specific targeting of reporter genes and thus will facilitate the use of transgenic methods to manipulate circuit function in freely behaving larvae. PMID:23293587

Characteristic and intermingled neocortical circuits encode different visual object discriminations.

PubMed

Zhang, Guo-Rong; Zhao, Hua; Cook, Nathan; Svestka, Michael; Choi, Eui M; Jan, Mary; Cook, Robert G; Geller, Alfred I

2017-07-28

Synaptic plasticity and neural network theories hypothesize that the essential information for advanced cognitive tasks is encoded in specific circuits and neurons within distributed neocortical networks. However, these circuits are incompletely characterized, and we do not know if a specific discrimination is encoded in characteristic circuits among multiple animals. Here, we determined the spatial distribution of active neurons for a circuit that encodes some of the essential information for a cognitive task. We genetically activated protein kinase C pathways in several hundred spatially-grouped glutamatergic and GABAergic neurons in rat postrhinal cortex, a multimodal associative area that is part of a distributed circuit that encodes visual object discriminations. We previously established that this intervention enhances accuracy for specific discriminations. Moreover, the genetically-modified, local circuit in POR cortex encodes some of the essential information, and this local circuit is preferentially activated during performance, as shown by activity-dependent gene imaging. Here, we mapped the positions of the active neurons, which revealed that two image sets are encoded in characteristic and different circuits. While characteristic circuits are known to process sensory information, in sensory areas, this is the first demonstration that characteristic circuits encode specific discriminations, in a multimodal associative area. Further, the circuits encoding the two image sets are intermingled, and likely overlapping, enabling efficient encoding. Consistent with reconsolidation theories, intermingled and overlapping encoding could facilitate formation of associations between related discriminations, including visually similar discriminations or discriminations learned at the same time or place. Copyright © 2017 Elsevier B.V. All rights reserved.

Dopamine-dependent non-linear correlation between subthalamic rhythms in Parkinson's disease.

PubMed

Marceglia, S; Foffani, G; Bianchi, A M; Baselli, G; Tamma, F; Egidi, M; Priori, A

2006-03-15

The basic information architecture in the basal ganglia circuit is under debate. Whereas anatomical studies quantify extensive convergence/divergence patterns in the circuit, suggesting an information sharing scheme, neurophysiological studies report an absence of linear correlation between single neurones in normal animals, suggesting a segregated parallel processing scheme. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and in parkinsonian patients single neurones become linearly correlated, thus leading to a loss of segregation between neurones. Here we propose a possible integrative solution to this debate, by extending the concept of functional segregation from the cellular level to the network level. To this end, we recorded local field potentials (LFPs) from electrodes implanted for deep brain stimulation (DBS) in the subthalamic nucleus (STN) of parkinsonian patients. By applying bispectral analysis, we found that in the absence of dopamine stimulation STN LFP rhythms became non-linearly correlated, thus leading to a loss of segregation between rhythms. Non-linear correlation was particularly consistent between the low-beta rhythm (13-20 Hz) and the high-beta rhythm (20-35 Hz). Levodopa administration significantly decreased these non-linear correlations, therefore increasing segregation between rhythms. These results suggest that the extensive convergence/divergence in the basal ganglia circuit is physiologically necessary to sustain LFP rhythms distributed in large ensembles of neurones, but is not sufficient to induce correlated firing between neurone pairs. Conversely, loss of dopamine generates pathological linear correlation between neurone pairs, alters the patterns within LFP rhythms, and induces non-linear correlation between LFP rhythms operating at different frequencies. The pathophysiology of information processing in the human basal ganglia therefore involves not only activities of individual rhythms, but also interactions between rhythms.

Dopamine-dependent non-linear correlation between subthalamic rhythms in Parkinson's disease

PubMed Central

Marceglia, S; Foffani, G; Bianchi, A M; Baselli, G; Tamma, F; Egidi, M; Priori, A

2006-01-01

The basic information architecture in the basal ganglia circuit is under debate. Whereas anatomical studies quantify extensive convergence/divergence patterns in the circuit, suggesting an information sharing scheme, neurophysiological studies report an absence of linear correlation between single neurones in normal animals, suggesting a segregated parallel processing scheme. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and in parkinsonian patients single neurones become linearly correlated, thus leading to a loss of segregation between neurones. Here we propose a possible integrative solution to this debate, by extending the concept of functional segregation from the cellular level to the network level. To this end, we recorded local field potentials (LFPs) from electrodes implanted for deep brain stimulation (DBS) in the subthalamic nucleus (STN) of parkinsonian patients. By applying bispectral analysis, we found that in the absence of dopamine stimulation STN LFP rhythms became non-linearly correlated, thus leading to a loss of segregation between rhythms. Non-linear correlation was particularly consistent between the low-beta rhythm (13–20 Hz) and the high-beta rhythm (20–35 Hz). Levodopa administration significantly decreased these non-linear correlations, therefore increasing segregation between rhythms. These results suggest that the extensive convergence/divergence in the basal ganglia circuit is physiologically necessary to sustain LFP rhythms distributed in large ensembles of neurones, but is not sufficient to induce correlated firing between neurone pairs. Conversely, loss of dopamine generates pathological linear correlation between neurone pairs, alters the patterns within LFP rhythms, and induces non-linear correlation between LFP rhythms operating at different frequencies. The pathophysiology of information processing in the human basal ganglia therefore involves not only activities of individual rhythms, but also interactions between rhythms. PMID:16410285

The role of prefrontal catecholamines in attention and working memory

PubMed Central

Clark, Kelsey L.; Noudoost, Behrad

2014-01-01

While much progress has been made in identifying the brain regions and neurochemical systems involved in the cognitive processes disrupted in mental illnesses, to date, the level of detail at which neurobiologists can describe the chain of events giving rise to cognitive functions is very rudimentary. Much of the intense interest in understanding cognitive functions is motivated by the hope that it might be possible to understand these complex functions at the level of neurons and neural circuits. Here, we review the current state of the literature regarding how modulations in catecholamine levels within the prefrontal cortex (PFC) alter the neuronal and behavioral correlates of cognitive functions, particularly attention and working memory. PMID:24782714

Brain Embodiment of Syntax and Grammar: Discrete Combinatorial Mechanisms Spelt Out in Neuronal Circuits

ERIC Educational Resources Information Center

Pulvermuller, Friedemann

2010-01-01

Neuroscience has greatly improved our understanding of the brain basis of abstract lexical and semantic processes. The neuronal devices underlying words and concepts are distributed neuronal assemblies reaching into sensory and motor systems of the cortex and, at the cognitive level, information binding in such widely dispersed circuits is…

An Integrated Circuit for Simultaneous Extracellular Electrophysiology Recording and Optogenetic Neural Manipulation

PubMed Central

Chen, Chang Hao; McCullagh, Elizabeth A.; Pun, Sio Hang; Mak, Peng Un; Vai, Mang I; Mak, Pui In; Klug, Achim; Lei, Tim C.

2017-01-01

The ability to record and to control action potential firing in neuronal circuits of the brain is critical to understand how the brain functions on the cellular and network levels. Recent development of optogenetic proteins allows direct stimulation or inhibition of action potential firing of neurons upon optical illumination. In this paper, we combined a low-noise and high input impedance (or low input capacitance) neural recording amplifier, and a high current laser/LED driver in a monolithic integrated circuit (IC) for simultaneous neural recording and optogenetic neural control. The low input capacitance of the amplifier (9.7 pF) was achieved through adding a dedicated unity gain input stage optimized for high impedance metal electrodes. The input referred noise of the amplifier was measured to be 4.57 µVrms, which is lower than the estimated thermal noise of the metal electrode. Thus, action potentials originating from a single neuron can be recorded with a signal-to-noise ratio of ~6.6. The LED/laser current driver delivers a maximum current of 330 mA to generate adequate light for optogenetic control. We experimentally tested the functionality of the IC with an anesthetized Mongolian gerbil and recorded auditory stimulated action potentials from the inferior colliculus. Furthermore, we showed that spontaneous firing of 5th (trigeminal) nerve fibers was inhibited using the optogenetic protein Halorhodopsin. A noise model was also derived including the equivalent electronic components of the metal electrode and the high current driver to guide the design. PMID:28221990

Muscle spindle feedback directs locomotor recovery and circuit reorganization after spinal cord injury.

PubMed

Takeoka, Aya; Vollenweider, Isabel; Courtine, Grégoire; Arber, Silvia

2014-12-18

Spinal cord injuries alter motor function by disconnecting neural circuits above and below the lesion, rendering sensory inputs a primary source of direct external drive to neuronal networks caudal to the injury. Here, we studied mice lacking functional muscle spindle feedback to determine the role of this sensory channel in gait control and locomotor recovery after spinal cord injury. High-resolution kinematic analysis of intact mutant mice revealed proficient execution in basic locomotor tasks but poor performance in a precision task. After injury, wild-type mice spontaneously recovered basic locomotor function, whereas mice with deficient muscle spindle feedback failed to regain control over the hindlimb on the lesioned side. Virus-mediated tracing demonstrated that mutant mice exhibit defective rearrangements of descending circuits projecting to deprived spinal segments during recovery. Our findings reveal an essential role for muscle spindle feedback in directing basic locomotor recovery and facilitating circuit reorganization after spinal cord injury. Copyright © 2014 Elsevier Inc. All rights reserved.

Dissection of neuronal gap junction circuits that regulate social behavior in Caenorhabditis elegans.

PubMed

Jang, Heeun; Levy, Sagi; Flavell, Steven W; Mende, Fanny; Latham, Richard; Zimmer, Manuel; Bargmann, Cornelia I

2017-02-14

A hub-and-spoke circuit of neurons connected by gap junctions controls aggregation behavior and related behavioral responses to oxygen, pheromones, and food in Caenorhabditis elegans The molecular composition of the gap junctions connecting RMG hub neurons with sensory spoke neurons is unknown. We show here that the innexin gene unc-9 is required in RMG hub neurons to drive aggregation and related behaviors, indicating that UNC-9-containing gap junctions mediate RMG signaling. To dissect the circuit in detail, we developed methods to inhibit unc-9 -based gap junctions with dominant-negative unc-1 transgenes. unc-1(dn) alters a stomatin-like protein that regulates unc-9 electrical signaling; its disruptive effects can be rescued by a constitutively active UNC-9::GFP protein, demonstrating specificity. Expression of unc-1(dn) in RMG hub neurons, ADL or ASK pheromone-sensing neurons, or URX oxygen-sensing neurons disrupts specific elements of aggregation-related behaviors. In ADL, unc-1(dn) has effects opposite to those of tetanus toxin light chain, separating the roles of ADL electrical and chemical synapses. These results reveal roles of gap junctions in a complex behavior at cellular resolution and provide a tool for similar exploration of other gap junction circuits.

Dissection of neuronal gap junction circuits that regulate social behavior in Caenorhabditis elegans

PubMed Central

Jang, Heeun; Levy, Sagi; Flavell, Steven W.; Mende, Fanny; Latham, Richard; Zimmer, Manuel; Bargmann, Cornelia I.

2017-01-01

A hub-and-spoke circuit of neurons connected by gap junctions controls aggregation behavior and related behavioral responses to oxygen, pheromones, and food in Caenorhabditis elegans. The molecular composition of the gap junctions connecting RMG hub neurons with sensory spoke neurons is unknown. We show here that the innexin gene unc-9 is required in RMG hub neurons to drive aggregation and related behaviors, indicating that UNC-9–containing gap junctions mediate RMG signaling. To dissect the circuit in detail, we developed methods to inhibit unc-9–based gap junctions with dominant-negative unc-1 transgenes. unc-1(dn) alters a stomatin-like protein that regulates unc-9 electrical signaling; its disruptive effects can be rescued by a constitutively active UNC-9::GFP protein, demonstrating specificity. Expression of unc-1(dn) in RMG hub neurons, ADL or ASK pheromone-sensing neurons, or URX oxygen-sensing neurons disrupts specific elements of aggregation-related behaviors. In ADL, unc-1(dn) has effects opposite to those of tetanus toxin light chain, separating the roles of ADL electrical and chemical synapses. These results reveal roles of gap junctions in a complex behavior at cellular resolution and provide a tool for similar exploration of other gap junction circuits. PMID:28143932

Loss of MeCP2 From Forebrain Excitatory Neurons Leads to Cortical Hyperexcitation and Seizures

PubMed Central

Zhang, Wen; Peterson, Matthew; Beyer, Barbara; Frankel, Wayne N.

2014-01-01

Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of motor and cognitive functions, impaired social interactions, and seizure at young ages. Defects of neuronal circuit development and function are thought to be responsible for the symptoms of RTT. The majority of RTT patients show recurrent seizures, indicating that neuronal hyperexcitation is a common feature of RTT. However, mechanisms underlying hyperexcitation in RTT are poorly understood. Here we show that deletion of Mecp2 from cortical excitatory neurons but not forebrain inhibitory neurons in the mouse leads to spontaneous seizures. Selective deletion of Mecp2 from excitatory but not inhibitory neurons in the forebrain reduces GABAergic transmission in layer 5 pyramidal neurons in the prefrontal and somatosensory cortices. Loss of MeCP2 from cortical excitatory neurons reduces the number of GABAergic synapses in the cortex, and enhances the excitability of layer 5 pyramidal neurons. Using single-cell deletion of Mecp2 in layer 2/3 pyramidal neurons, we show that GABAergic transmission is reduced in neurons without MeCP2, but is normal in neighboring neurons with MeCP2. Together, these results suggest that MeCP2 in cortical excitatory neurons plays a critical role in the regulation of GABAergic transmission and cortical excitability. PMID:24523563

Medial prefrontal cortex neuronal circuits in fear behavior.

PubMed

Courtin, J; Bienvenu, T C M; Einarsson, E Ö; Herry, C

2013-06-14

The medial prefrontal cortex (mPFC) has emerged as a key structure involved in the modulation of fear behavior over the past few decades. Anatomical, functional and electrophysiological studies have begun to shed light on the precise mechanisms by which different prefrontal regions regulate the expression and inhibition of fear behavior. These studies have established a canonical view of mPFC functions during fear behavior with dorsal regions selectively involved in the expression of fear behavior and ventral regions linked to the inhibition of fear behavior. Although numerous reports support this view, recent data have refined this model and suggested that dorsal prefrontal regions might also play an important role in the encoding of fear behavior itself. The recent development of sophisticated approaches such as large scale neuronal recordings, simultaneous multisite recordings of spiking activity and local field potentials (LFPs) along with optogenetic approaches will facilitate the testing of these new hypotheses in the near future. Here we provide an extensive review of the literature on the role of mPFC in fear behavior and propose further directions to dissect the contribution of specific prefrontal neuronal elements and circuits in the regulation of fear behavior. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Optogenetic approaches to evaluate striatal function in animal models of Parkinson disease.

PubMed

Parker, Krystal L; Kim, Youngcho; Alberico, Stephanie L; Emmons, Eric B; Narayanan, Nandakumar S

2016-03-01

Optogenetics refers to the ability to control cells that have been genetically modified to express light-sensitive ion channels. The introduction of optogenetic approaches has facilitated the dissection of neural circuits. Optogenetics allows for the precise stimulation and inhibition of specific sets of neurons and their projections with fine temporal specificity. These techniques are ideally suited to investigating neural circuitry underlying motor and cognitive dysfunction in animal models of human disease. Here, we focus on how optogenetics has been used over the last decade to probe striatal circuits that are involved in Parkinson disease, a neurodegenerative condition involving motor and cognitive abnormalities resulting from degeneration of midbrain dopaminergic neurons. The precise mechanisms underlying the striatal contribution to both cognitive and motor dysfunction in Parkinson disease are unknown. Although optogenetic approaches are somewhat removed from clinical use, insight from these studies can help identify novel therapeutic targets and may inspire new treatments for Parkinson disease. Elucidating how neuronal and behavioral functions are influenced and potentially rescued by optogenetic manipulation in animal models could prove to be translatable to humans. These insights can be used to guide future brain-stimulation approaches for motor and cognitive abnormalities in Parkinson disease and other neuropsychiatric diseases.

Parallel circuits control temperature preference in Drosophila during ageing.

PubMed

Shih, Hsiang-Wen; Wu, Chia-Lin; Chang, Sue-Wei; Liu, Tsung-Ho; Lai, Jason Sih-Yu; Fu, Tsai-Feng; Fu, Chien-Chung; Chiang, Ann-Shyn

2015-07-16

The detection of environmental temperature and regulation of body temperature are integral determinants of behaviour for all animals. These functions become less efficient in aged animals, particularly during exposure to cold environments, yet the cellular and molecular mechanisms are not well understood. Here, we identify an age-related change in the temperature preference of adult fruit flies that results from a shift in the relative contributions of two parallel mushroom body (MB) circuits—the β'- and β-systems. The β'-circuit primarily controls cold avoidance through dopamine signalling in young flies, whereas the β-circuit increasingly contributes to cold avoidance as adult flies age. Elevating dopamine levels in β'-afferent neurons of aged flies restores cold sensitivity, suggesting that the alteration of cold avoidance behaviour with ageing is functionally reversible. These results provide a framework for investigating how molecules and individual neural circuits modulate homeostatic alterations during the course of senescence.

Parallel circuits control temperature preference in Drosophila during ageing

PubMed Central

Shih, Hsiang-Wen; Wu, Chia-Lin; Chang, Sue-Wei; Liu, Tsung-Ho; Sih-Yu Lai, Jason; Fu, Tsai-Feng; Fu, Chien-Chung; Chiang, Ann-Shyn

2015-01-01

The detection of environmental temperature and regulation of body temperature are integral determinants of behaviour for all animals. These functions become less efficient in aged animals, particularly during exposure to cold environments, yet the cellular and molecular mechanisms are not well understood. Here, we identify an age-related change in the temperature preference of adult fruit flies that results from a shift in the relative contributions of two parallel mushroom body (MB) circuits—the β′- and β-systems. The β′-circuit primarily controls cold avoidance through dopamine signalling in young flies, whereas the β-circuit increasingly contributes to cold avoidance as adult flies age. Elevating dopamine levels in β′-afferent neurons of aged flies restores cold sensitivity, suggesting that the alteration of cold avoidance behaviour with ageing is functionally reversible. These results provide a framework for investigating how molecules and individual neural circuits modulate homeostatic alterations during the course of senescence. PMID:26178754

Developmental Profiling of Spiral Ganglion Neurons Reveals Insights into Auditory Circuit Assembly

PubMed Central

Lu, Cindy C.; Appler, Jessica M.; Houseman, E. Andres; Goodrich, Lisa V.

2011-01-01

The sense of hearing depends on the faithful transmission of sound information from the ear to the brain by spiral ganglion (SG) neurons. However, how SG neurons develop the connections and properties that underlie auditory processing is largely unknown. We catalogued gene expression in mouse SG neurons from embryonic day 12 (E12), when SG neurons first extend projections, up until postnatal day 15 (P15), after the onset of hearing. For comparison, we also analyzed the closely-related vestibular ganglion (VG). Gene ontology analysis confirmed enriched expression of genes associated with gene regulation and neurite outgrowth at early stages, with the SG and VG often expressing different members of the same gene family. At later stages, the neurons transcribe more genes related to mature function, and exhibit a dramatic increase in immune gene expression. Comparisons of the two populations revealed enhanced expression of TGFβ pathway components in SG neurons and established new markers that consistently distinguish auditory and vestibular neurons. Unexpectedly, we found that Gata3, a transcription factor commonly associated with auditory development, is also expressed in VG neurons at early stages. We therefore defined new cohorts of transcription factors and axon guidance molecules that are uniquely expressed in SG neurons and may drive auditory-specific aspects of their differentiation and wiring. We show that one of these molecules, the receptor guanylyl cyclase Npr2, is required for bifurcation of the SG central axon. Hence, our data set provides a useful resource for uncovering the molecular basis of specific auditory circuit assembly events. PMID:21795542

Computer simulations of stimulus dependent state switching in basic circuits of bursting neurons

NASA Astrophysics Data System (ADS)

Rabinovich, Mikhail; Huerta, Ramón; Bazhenov, Maxim; Kozlov, Alexander K.; Abarbanel, Henry D. I.

1998-11-01

We investigate the ability of oscillating neural circuits to switch between different states of oscillation in two basic neural circuits. We model two quite distinct small neural circuits. The first circuit is based on invertebrate central pattern generator (CPG) studies [A. I. Selverston and M. Moulins, The Crustacean Stomatogastric System (Springer-Verlag, Berlin, 1987)] and is composed of two neurons coupled via both gap junction and inhibitory synapses. The second consists of coupled pairs of interconnected thalamocortical relay and thalamic reticular neurons with both inhibitory and excitatory synaptic coupling. The latter is an elementary unit of the thalamic networks passing sensory information to the cerebral cortex [M. Steriade, D. A. McCormick, and T. J. Sejnowski, Science 262, 679 (1993)]. Both circuits have contradictory coupling between symmetric parts. The thalamocortical model has excitatory and inhibitory connections and the CPG has reciprocal inhibitory and electrical coupling. We describe the dynamics of the individual neurons in these circuits by conductance based ordinary differential equations of Hodgkin-Huxley type [J. Physiol. (London) 117, 500 (1952)]. Both model circuits exhibit bistability and hysteresis in a wide region of coupling strengths. The two main modes of behavior are in-phase and out-of-phase oscillations of the symmetric parts of the network. We investigate the response of these circuits, while they are operating in bistable regimes, to externally imposed excitatory spike trains with varying interspike timing and small amplitude pulses. These are meant to represent spike trains received by the basic circuits from sensory neurons. Circuits operating in a bistable region are sensitive to the frequency of these excitatory inputs. Frequency variations lead to changes from in-phase to out-of-phase coordination or vice versa. The signaling information contained in a spike train driving the network can place the circuit into one or another state depending on the interspike interval and this happens within a few spikes. These states are maintained by the basic circuit after the input signal is ended. When a new signal of the correct frequency enters the circuit, it can be switched to another state with the same ease.

Response-dependent dynamics of cell-specific inhibition in cortical networks in vivo

PubMed Central

El-Boustani, Sami; Sur, Mriganka

2014-01-01

In the visual cortex, inhibitory neurons alter the computations performed by target cells via combination of two fundamental operations, division and subtraction. The origins of these operations have been variously ascribed to differences in neuron classes, synapse location or receptor conductances. Here, by utilizing specific visual stimuli and single optogenetic probe pulses, we show that the function of parvalbumin-expressing and somatostatin-expressing neurons in mice in vivo is governed by the overlap of response timing between these neurons and their targets. In particular, somatostatin-expressing neurons respond at longer latencies to small visual stimuli compared with their target neurons and provide subtractive inhibition. With large visual stimuli, however, they respond at short latencies coincident with their target cells and switch to provide divisive inhibition. These results indicate that inhibition mediated by these neurons is a dynamic property of cortical circuits rather than an immutable property of neuronal classes. PMID:25504329

Structural-Functional Properties of Identified Excitatory and Inhibitory Interneurons within Pre-Bötzinger Complex Respiratory Microcircuits

PubMed Central

Koizumi, Hidehiko; Koshiya, Naohiro; Chia, Justine X.; Cao, Fang; Nugent, Joseph; Zhang, Ruli

2013-01-01

We comparatively analyzed cellular and circuit properties of identified rhythmic excitatory and inhibitory interneurons within respiratory microcircuits of the neonatal rodent pre-Bötzinger complex (pre-BötC), the structure generating inspiratory rhythm in the brainstem. We combined high-resolution structural–functional imaging, molecular assays for neurotransmitter phenotype identification in conjunction with electrophysiological property phenotyping, and morphological reconstruction of interneurons in neonatal rat and mouse slices in vitro. This approach revealed previously undifferentiated structural–functional features that distinguish excitatory and inhibitory interneuronal populations. We identified distinct subpopulations of pre-BötC glutamatergic, glycinergic, GABAergic, and glycine-GABA coexpressing interneurons. Most commissural pre-BötC inspiratory interneurons were glutamatergic, with a substantial subset exhibiting intrinsic oscillatory bursting properties. Commissural excitatory interneurons projected with nearly planar trajectories to the contralateral pre-BötC, many also with axon collaterals to areas containing inspiratory hypoglossal (XII) premotoneurons and motoneurons. Inhibitory neurons as characterized in the present study did not exhibit intrinsic oscillatory bursting properties, but were electrophysiologically distinguished by more pronounced spike frequency adaptation properties. Axons of many inhibitory neurons projected ipsilaterally also to regions containing inspiratory XII premotoneurons and motoneurons, whereas a minority of inhibitory neurons had commissural axonal projections. Dendrites of both excitatory and inhibitory interneurons were arborized asymmetrically, primarily in the coronal plane. The dendritic fields of inhibitory neurons were more spatially compact than those of excitatory interneurons. Our results are consistent with the concepts of a compartmental circuit organization, a bilaterally coupled excitatory rhythmogenic kernel, and a role of pre-BötC inhibitory neurons in shaping inspiratory pattern as well as coordinating inspiratory and expiratory activity. PMID:23407957

From neurons to circuits: linear estimation of local field potentials.

PubMed

Rasch, Malte; Logothetis, Nikos K; Kreiman, Gabriel

2009-11-04

Extracellular physiological recordings are typically separated into two frequency bands: local field potentials (LFPs) (a circuit property) and spiking multiunit activity (MUA). Recently, there has been increased interest in LFPs because of their correlation with functional magnetic resonance imaging blood oxygenation level-dependent measurements and the possibility of studying local processing and neuronal synchrony. To further understand the biophysical origin of LFPs, we asked whether it is possible to estimate their time course based on the spiking activity from the same electrode or nearby electrodes. We used "signal estimation theory" to show that a linear filter operation on the activity of one or a few neurons can explain a significant fraction of the LFP time course in the macaque monkey primary visual cortex. The linear filter used to estimate the LFPs had a stereotypical shape characterized by a sharp downstroke at negative time lags and a slower positive upstroke for positive time lags. The filter was similar across different neocortical regions and behavioral conditions, including spontaneous activity and visual stimulation. The estimations had a spatial resolution of approximately 1 mm and a temporal resolution of approximately 200 ms. By considering a causal filter, we observed a temporal asymmetry such that the positive time lags in the filter contributed more to the LFP estimation than the negative time lags. Additionally, we showed that spikes occurring within approximately 10 ms of spikes from nearby neurons yielded better estimation accuracies than nonsynchronous spikes. In summary, our results suggest that at least some circuit-level local properties of the field potentials can be predicted from the activity of one or a few neurons.

Global dysrhythmia of cerebro-basal ganglia-cerebellar networks underlies motor tics following striatal disinhibition.

PubMed

McCairn, Kevin W; Iriki, Atsushi; Isoda, Masaki

2013-01-09

Motor tics, a cardinal symptom of Tourette syndrome (TS), are hypothesized to arise from abnormalities within cerebro-basal ganglia circuits. Yet noninvasive neuroimaging of TS has previously identified robust activation in the cerebellum. To date, electrophysiological properties of cerebellar activation and its role in basal ganglia-mediated tic expression remain unknown. We performed multisite, multielectrode recordings of single-unit activity and local field potentials from the cerebellum, basal ganglia, and primary motor cortex using a pharmacologic monkey model of motor tics/TS. Following microinjections of bicuculline into the sensorimotor putamen, periodic tics occurred predominantly in the orofacial region, and a sizable number of cerebellar neurons showed phasic changes in activity associated with tic episodes. Specifically, 64% of the recorded cerebellar cortex neurons exhibited increases in activity, and 85% of the dentate nucleus neurons displayed excitatory, inhibitory, or multiphasic responses. Critically, abnormal discharges of cerebellar cortex neurons and excitatory-type dentate neurons mostly preceded behavioral tic onset, indicating their central origins. Latencies of pathological activity in the cerebellum and primary motor cortex substantially overlapped, suggesting that aberrant signals may be traveling along divergent pathways to these structures from the basal ganglia. Furthermore, the occurrence of tic movement was most closely associated with local field potential spikes in the cerebellum and primary motor cortex, implying that these structures may function as a gate to release overt tic movements. These findings indicate that tic-generating networks in basal ganglia mediated tic disorders extend beyond classical cerebro-basal ganglia circuits, leading to global network dysrhythmia including cerebellar circuits.

Two-photon holographic optogenetics of neural circuits (Conference Presentation)

NASA Astrophysics Data System (ADS)

Yang, Weijian; Carrillo-Reid, Luis; Peterka, Darcy S.; Yuste, Rafael

2016-03-01

Optical manipulation of in vivo neural circuits with cellular resolution could be important for understanding cortical function. Despite recent progress, simultaneous optogenetic activation with cellular precision has either been limited to 2D planes, or a very small numbers of neurons over a limited volume. Here we demonstrate a novel paradigm for simultaneous 3D activation using a low repetition rate pulse-amplified fiber laser system and a spatial light modulator (SLM) to project 3D holographic excitation patterns on the cortex of mice in vivo for targeted volumetric 3D photoactivation. This method is compatible with two-photon imaging, and enables the simultaneous activation of multiple cells in 3D, using red-shifted opsins, such as C1V1 or ReaChR, while simultaneously imaging GFP-based sensors such as GCaMP6. This all-optical imaging and 3D manipulation approach achieves simultaneous reading and writing of cortical activity, and should be a powerful tool for the study of neuronal circuits.

Nuclear Organization in the Spinal Cord Depends on Motor Neuron Lamination Orchestrated by Catenin and Afadin Function.

PubMed

Dewitz, Carola; Pimpinella, Sofia; Hackel, Patrick; Akalin, Altuna; Jessell, Thomas M; Zampieri, Niccolò

2018-02-13

Motor neurons in the spinal cord are found grouped in nuclear structures termed pools, whose position is precisely orchestrated during development. Despite the emerging role of pool organization in the assembly of spinal circuits, little is known about the morphogenetic programs underlying the patterning of motor neuron subtypes. We applied three-dimensional analysis of motor neuron position to reveal the roles and contributions of cell adhesive function by inactivating N-cadherin, catenin, and afadin signaling. Our findings reveal that nuclear organization of motor neurons is dependent on inside-out positioning, orchestrated by N-cadherin, catenin, and afadin activities, controlling cell body layering on the medio-lateral axis. In addition to this lamination-like program, motor neurons undergo a secondary, independent phase of organization. This process results in segregation of motor neurons along the dorso-ventral axis of the spinal cord, does not require N-cadherin or afadin activity, and can proceed even when medio-lateral positioning is perturbed. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Gap Junction-Mediated Signaling from Motor Neurons Regulates Motor Generation in the Central Circuits of Larval Drosophila.

PubMed

Matsunaga, Teruyuki; Kohsaka, Hiroshi; Nose, Akinao

2017-02-22

In this study, we used the peristaltic crawling of Drosophila larvae as a model to study how motor patterns are regulated by central circuits. We built an experimental system that allows simultaneous application of optogenetics and calcium imaging to the isolated ventral nerve cord (VNC). We then investigated the effects of manipulating local activity of motor neurons (MNs) on fictive locomotion observed as waves of MN activity propagating along neuromeres. Optical inhibition of MNs with halorhodopsin3 in a middle segment (A4, A5, or A6), but not other segments, dramatically decreased the frequency of the motor waves. Conversely, local activation of MNs with channelrhodopsin2 in a posterior segment (A6 or A7) increased the frequency of the motor waves. Since peripheral nerves mediating sensory feedback were severed in the VNC preparation, these results indicate that MNs send signals to the central circuits to regulate motor pattern generation. Our results also indicate segmental specificity in the roles of MNs in motor control. The effects of the local MN activity manipulation were lost in shaking-B 2 ( shakB 2 ) or ogre 2 , gap-junction mutations in Drosophila , or upon acute application of the gap junction blocker carbenoxolone, implicating electrical synapses in the signaling from MNs. Cell-type-specific RNAi suggested shakB and ogre function in MNs and interneurons, respectively, during the signaling. Our results not only reveal an unexpected role for MNs in motor pattern regulation, but also introduce a powerful experimental system that enables examination of the input-output relationship among the component neurons in this system. SIGNIFICANCE STATEMENT Motor neurons are generally considered passive players in motor pattern generation, simply relaying information from upstream interneuronal circuits to the target muscles. This study shows instead that MNs play active roles in the control of motor generation by conveying information via gap junctions to the central pattern-generating circuits in larval Drosophila , providing novel insights into motor circuit control. The experimental system introduced in this study also presents a new approach for studying intersegmentally coordinated locomotion. Unlike traditional electrophysiology methods, this system enables the simultaneous recording and manipulation of populations of neurons that are genetically specified and span multiple segments. Copyright © 2017 the authors 0270-6474/17/372045-16$15.00/0.

Genetically increased cell-intrinsic excitability enhances neuronal integration into adult brain circuits

PubMed Central

Lin, Chia-Wei; Sim, Shuyin; Ainsworth, Alice; Okada, Masayoshi; Kelsch, Wolfgang; Lois, Carlos

2009-01-01

New neurons are added to the adult brain throughout life, but only half ultimately integrate into existing circuits. Sensory experience is an important regulator of the selection of new neurons but it remains unknown whether experience provides specific patterns of synaptic input, or simply a minimum level of overall membrane depolarization critical for integration. To investigate this issue, we genetically modified intrinsic electrical properties of adult-generated neurons in the mammalian olfactory bulb. First, we observed that suppressing levels of cell-intrinsic neuronal activity via expression of ESKir2.1 potassium channels decreases, whereas enhancing activity via expression of NaChBac sodium channels increases survival of new neurons. Neither of these modulations affects synaptic formation. Furthermore, even when neurons are induced to fire dramatically altered patterns of action potentials, increased levels of cell-intrinsic activity completely blocks cell death triggered by NMDA receptor deletion. These findings demonstrate that overall levels of cell-intrinsic activity govern survival of new neurons and precise firing patterns are not essential for neuronal integration into existing brain circuits. PMID:20152111

Anatomic and Physiologic Heterogeneity of Subgroup-A Auditory Sensory Neurons in Fruit Flies.

PubMed

Ishikawa, Yuki; Okamoto, Natsuki; Nakamura, Mizuki; Kim, Hyunsoo; Kamikouchi, Azusa

2017-01-01

The antennal ear of the fruit fly detects acoustic signals in intraspecific communication, such as the courtship song and agonistic sounds. Among the five subgroups of mechanosensory neurons in the fly ear, subgroup-A neurons respond maximally to vibrations over a wide frequency range between 100 and 1,200 Hz. The functional organization of the neural circuit comprised of subgroup-A neurons, however, remains largely unknown. In the present study, we used 11 GAL4 strains that selectively label subgroup-A neurons and explored the diversity of subgroup-A neurons by combining single-cell anatomic analysis and Ca 2+ imaging. Our findings indicate that the subgroup-A neurons that project into various combinations of subareas in the brain are more anatomically diverse than previously described. Subgroup-A neurons were also physiologically diverse, and some types were tuned to a narrow frequency range, suggesting that the response of subgroup-A neurons to sounds of a wide frequency range is due to the existence of several types of subgroup-A neurons. Further, we found that an auditory behavioral response to the courtship song of flies was attenuated when most subgroup-A neurons were silenced. Together, these findings characterize the heterogeneous functional organization of subgroup-A neurons, which might facilitate species-specific acoustic signal detection.

Anatomic and Physiologic Heterogeneity of Subgroup-A Auditory Sensory Neurons in Fruit Flies

PubMed Central

Ishikawa, Yuki; Okamoto, Natsuki; Nakamura, Mizuki; Kim, Hyunsoo; Kamikouchi, Azusa

2017-01-01

The antennal ear of the fruit fly detects acoustic signals in intraspecific communication, such as the courtship song and agonistic sounds. Among the five subgroups of mechanosensory neurons in the fly ear, subgroup-A neurons respond maximally to vibrations over a wide frequency range between 100 and 1,200 Hz. The functional organization of the neural circuit comprised of subgroup-A neurons, however, remains largely unknown. In the present study, we used 11 GAL4 strains that selectively label subgroup-A neurons and explored the diversity of subgroup-A neurons by combining single-cell anatomic analysis and Ca2+ imaging. Our findings indicate that the subgroup-A neurons that project into various combinations of subareas in the brain are more anatomically diverse than previously described. Subgroup-A neurons were also physiologically diverse, and some types were tuned to a narrow frequency range, suggesting that the response of subgroup-A neurons to sounds of a wide frequency range is due to the existence of several types of subgroup-A neurons. Further, we found that an auditory behavioral response to the courtship song of flies was attenuated when most subgroup-A neurons were silenced. Together, these findings characterize the heterogeneous functional organization of subgroup-A neurons, which might facilitate species-specific acoustic signal detection. PMID:28701929

Neuromorphic Silicon Neuron Circuits

PubMed Central

Indiveri, Giacomo; Linares-Barranco, Bernabé; Hamilton, Tara Julia; van Schaik, André; Etienne-Cummings, Ralph; Delbruck, Tobi; Liu, Shih-Chii; Dudek, Piotr; Häfliger, Philipp; Renaud, Sylvie; Schemmel, Johannes; Cauwenberghs, Gert; Arthur, John; Hynna, Kai; Folowosele, Fopefolu; Saighi, Sylvain; Serrano-Gotarredona, Teresa; Wijekoon, Jayawan; Wang, Yingxue; Boahen, Kwabena

2011-01-01

Hardware implementations of spiking neurons can be extremely useful for a large variety of applications, ranging from high-speed modeling of large-scale neural systems to real-time behaving systems, to bidirectional brain–machine interfaces. The specific circuit solutions used to implement silicon neurons depend on the application requirements. In this paper we describe the most common building blocks and techniques used to implement these circuits, and present an overview of a wide range of neuromorphic silicon neurons, which implement different computational models, ranging from biophysically realistic and conductance-based Hodgkin–Huxley models to bi-dimensional generalized adaptive integrate and fire models. We compare the different design methodologies used for each silicon neuron design described, and demonstrate their features with experimental results, measured from a wide range of fabricated VLSI chips. PMID:21747754

CB1 Cannabinoid Receptor Expression in the Striatum: Association with Corticostriatal Circuits and Developmental Regulation

PubMed Central

Van Waes, Vincent; Beverley, Joel A.; Siman, Homayoun; Tseng, Kuei Y.; Steiner, Heinz

2012-01-01

Corticostriatal circuits mediate various aspects of goal-directed behavior and are critically important for basal ganglia-related disorders. Activity in these circuits is regulated by the endocannabinoid system via stimulation of CB1 cannabinoid receptors. CB1 receptors are highly expressed in projection neurons and select interneurons of the striatum, but expression levels vary considerably between different striatal regions (functional domains). We investigated CB1 receptor expression within specific corticostriatal circuits by mapping CB1 mRNA levels in striatal sectors defined by their cortical inputs in rats. We also assessed changes in CB1 expression in the striatum during development. Our results show that CB1 expression is highest in juveniles (P25) and then progressively decreases toward adolescent (P40) and adult (P70) levels. At every age, CB1 receptors are predominantly expressed in sensorimotor striatal sectors, with considerably lower expression in associative and limbic sectors. Moreover, for most corticostriatal circuits there is an inverse relationship between cortical and striatal expression levels. Thus, striatal sectors with high CB1 expression (sensorimotor sectors) tend to receive inputs from cortical areas with low expression, while striatal sectors with low expression (associative/limbic sectors) receive inputs from cortical regions with higher expression (medial prefrontal cortex). In so far as CB1 mRNA levels reflect receptor function, our findings suggest differential CB1 signaling between different developmental stages and between sensorimotor and associative/limbic circuits. The regional distribution of CB1 receptor expression in the striatum further suggests that, in sensorimotor sectors, CB1 receptors mostly regulate GABA inputs from local axon collaterals of projection neurons, whereas in associative/limbic sectors, CB1 regulation of GABA inputs from interneurons and glutamate inputs may be more important. PMID:22416230

Tissue engineering the mechanosensory circuit of the stretch reflex arc: sensory neuron innervation of intrafusal muscle fibers.

PubMed

Rumsey, John W; Das, Mainak; Bhalkikar, Abhijeet; Stancescu, Maria; Hickman, James J

2010-11-01

The sensory circuit of the stretch reflex arc, composed of specialized intrafusal muscle fibers and type Ia proprioceptive sensory neurons, converts mechanical information regarding muscle length and stretch to electrical action potentials and relays them to the central nervous system. Utilizing a non-biological substrate, surface patterning photolithography and a serum-free medium formulation a co-culture system was developed that facilitated functional interactions between intrafusal muscle fibers and sensory neurons. The presence of annulospiral wrappings (ASWs) and flower-spray endings (FSEs), both physiologically relevant morphologies in sensory neuron-intrafusal fiber interactions, were demonstrated and quantified using immunocytochemistry. Furthermore, two proposed components of the mammalian mechanosensory transduction system, BNaC1 and PICK1, were both identified at the ASWs and FSEs. To verify functionality of the mechanoreceptor elements the system was integrated with a MEMS cantilever device, and Ca(2+) currents were imaged along the length of an axon innervating an intrafusal fiber when stretched by cantilever deflection. This system provides a platform for examining the role of this mechanosensory complex in the pathology of myotonic and muscular dystrophies, peripheral neuropathy, and spasticity inducing diseases like Parkinson's. These studies will also assist in engineering fine motor control for prosthetic devices by improving our understanding of mechanosensitive feedback. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Whole-brain serial-section electron microscopy in larval zebrafish.

PubMed

Hildebrand, David Grant Colburn; Cicconet, Marcelo; Torres, Russel Miguel; Choi, Woohyuk; Quan, Tran Minh; Moon, Jungmin; Wetzel, Arthur Willis; Scott Champion, Andrew; Graham, Brett Jesse; Randlett, Owen; Plummer, George Scott; Portugues, Ruben; Bianco, Isaac Henry; Saalfeld, Stephan; Baden, Alexander David; Lillaney, Kunal; Burns, Randal; Vogelstein, Joshua Tzvi; Schier, Alexander Franz; Lee, Wei-Chung Allen; Jeong, Won-Ki; Lichtman, Jeff William; Engert, Florian

2017-05-18

High-resolution serial-section electron microscopy (ssEM) makes it possible to investigate the dense meshwork of axons, dendrites, and synapses that form neuronal circuits. However, the imaging scale required to comprehensively reconstruct these structures is more than ten orders of magnitude smaller than the spatial extents occupied by networks of interconnected neurons, some of which span nearly the entire brain. Difficulties in generating and handling data for large volumes at nanoscale resolution have thus restricted vertebrate studies to fragments of circuits. These efforts were recently transformed by advances in computing, sample handling, and imaging techniques, but high-resolution examination of entire brains remains a challenge. Here, we present ssEM data for the complete brain of a larval zebrafish (Danio rerio) at 5.5 days post-fertilization. Our approach utilizes multiple rounds of targeted imaging at different scales to reduce acquisition time and data management requirements. The resulting dataset can be analysed to reconstruct neuronal processes, permitting us to survey all myelinated axons (the projectome). These reconstructions enable precise investigations of neuronal morphology, which reveal remarkable bilateral symmetry in myelinated reticulospinal and lateral line afferent axons. We further set the stage for whole-brain structure-function comparisons by co-registering functional reference atlases and in vivo two-photon fluorescence microscopy data from the same specimen. All obtained images and reconstructions are provided as an open-access resource.

Whole-brain serial-section electron microscopy in larval zebrafish

NASA Astrophysics Data System (ADS)

Hildebrand, David Grant Colburn; Cicconet, Marcelo; Torres, Russel Miguel; Choi, Woohyuk; Quan, Tran Minh; Moon, Jungmin; Wetzel, Arthur Willis; Scott Champion, Andrew; Graham, Brett Jesse; Randlett, Owen; Plummer, George Scott; Portugues, Ruben; Bianco, Isaac Henry; Saalfeld, Stephan; Baden, Alexander David; Lillaney, Kunal; Burns, Randal; Vogelstein, Joshua Tzvi; Schier, Alexander Franz; Lee, Wei-Chung Allen; Jeong, Won-Ki; Lichtman, Jeff William; Engert, Florian

2017-05-01

High-resolution serial-section electron microscopy (ssEM) makes it possible to investigate the dense meshwork of axons, dendrites, and synapses that form neuronal circuits. However, the imaging scale required to comprehensively reconstruct these structures is more than ten orders of magnitude smaller than the spatial extents occupied by networks of interconnected neurons, some of which span nearly the entire brain. Difficulties in generating and handling data for large volumes at nanoscale resolution have thus restricted vertebrate studies to fragments of circuits. These efforts were recently transformed by advances in computing, sample handling, and imaging techniques, but high-resolution examination of entire brains remains a challenge. Here, we present ssEM data for the complete brain of a larval zebrafish (Danio rerio) at 5.5 days post-fertilization. Our approach utilizes multiple rounds of targeted imaging at different scales to reduce acquisition time and data management requirements. The resulting dataset can be analysed to reconstruct neuronal processes, permitting us to survey all myelinated axons (the projectome). These reconstructions enable precise investigations of neuronal morphology, which reveal remarkable bilateral symmetry in myelinated reticulospinal and lateral line afferent axons. We further set the stage for whole-brain structure-function comparisons by co-registering functional reference atlases and in vivo two-photon fluorescence microscopy data from the same specimen. All obtained images and reconstructions are provided as an open-access resource.

Scaling of Topologically Similar Functional Modules Defines Mouse Primary Auditory and Somatosensory Microcircuitry

PubMed Central

Sadovsky, Alexander J.

2013-01-01

Mapping the flow of activity through neocortical microcircuits provides key insights into the underlying circuit architecture. Using a comparative analysis we determined the extent to which the dynamics of microcircuits in mouse primary somatosensory barrel field (S1BF) and auditory (A1) neocortex generalize. We imaged the simultaneous dynamics of up to 1126 neurons spanning multiple columns and layers using high-speed multiphoton imaging. The temporal progression and reliability of reactivation of circuit events in both regions suggested common underlying cortical design features. We used circuit activity flow to generate functional connectivity maps, or graphs, to test the microcircuit hypothesis within a functional framework. S1BF and A1 present a useful test of the postulate as both regions map sensory input anatomically, but each area appears organized according to different design principles. We projected the functional topologies into anatomical space and found benchmarks of organization that had been previously described using physiology and anatomical methods, consistent with a close mapping between anatomy and functional dynamics. By comparing graphs representing activity flow we found that each region is similarly organized as highlighted by hallmarks of small world, scale free, and hierarchical modular topologies. Models of prototypical functional circuits from each area of cortex were sufficient to recapitulate experimentally observed circuit activity. Convergence to common behavior by these models was accomplished using preferential attachment to scale from an auditory up to a somatosensory circuit. These functional data imply that the microcircuit hypothesis be framed as scalable principles of neocortical circuit design. PMID:23986241

Large-scale automated histology in the pursuit of connectomes.

PubMed

Kleinfeld, David; Bharioke, Arjun; Blinder, Pablo; Bock, Davi D; Briggman, Kevin L; Chklovskii, Dmitri B; Denk, Winfried; Helmstaedter, Moritz; Kaufhold, John P; Lee, Wei-Chung Allen; Meyer, Hanno S; Micheva, Kristina D; Oberlaender, Marcel; Prohaska, Steffen; Reid, R Clay; Smith, Stephen J; Takemura, Shinya; Tsai, Philbert S; Sakmann, Bert

2011-11-09

How does the brain compute? Answering this question necessitates neuronal connectomes, annotated graphs of all synaptic connections within defined brain areas. Further, understanding the energetics of the brain's computations requires vascular graphs. The assembly of a connectome requires sensitive hardware tools to measure neuronal and neurovascular features in all three dimensions, as well as software and machine learning for data analysis and visualization. We present the state of the art on the reconstruction of circuits and vasculature that link brain anatomy and function. Analysis at the scale of tens of nanometers yields connections between identified neurons, while analysis at the micrometer scale yields probabilistic rules of connection between neurons and exact vascular connectivity.

Large-Scale Automated Histology in the Pursuit of Connectomes

PubMed Central

Bharioke, Arjun; Blinder, Pablo; Bock, Davi D.; Briggman, Kevin L.; Chklovskii, Dmitri B.; Denk, Winfried; Helmstaedter, Moritz; Kaufhold, John P.; Lee, Wei-Chung Allen; Meyer, Hanno S.; Micheva, Kristina D.; Oberlaender, Marcel; Prohaska, Steffen; Reid, R. Clay; Smith, Stephen J.; Takemura, Shinya; Tsai, Philbert S.; Sakmann, Bert

2011-01-01

How does the brain compute? Answering this question necessitates neuronal connectomes, annotated graphs of all synaptic connections within defined brain areas. Further, understanding the energetics of the brain's computations requires vascular graphs. The assembly of a connectome requires sensitive hardware tools to measure neuronal and neurovascular features in all three dimensions, as well as software and machine learning for data analysis and visualization. We present the state of the art on the reconstruction of circuits and vasculature that link brain anatomy and function. Analysis at the scale of tens of nanometers yields connections between identified neurons, while analysis at the micrometer scale yields probabilistic rules of connection between neurons and exact vascular connectivity. PMID:22072665

Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies

PubMed Central

McGourty, Kieran; Allen, Marcus J.; Madem, Sirisha Kudumala; Adcott, Jennifer; Kerr, Fiona; Wong, Chi Tung; Vincent, Alec; Godenschwege, Tanja; Boucrot, Emmanuel; Partridge, Linda

2017-01-01

Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the “insulin paradox”). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders. PMID:28902870

Multiple conserved cell adhesion protein interactions mediate neural wiring of a sensory circuit in C. elegans.

PubMed

Kim, Byunghyuk; Emmons, Scott W

2017-09-13

Nervous system function relies on precise synaptic connections. A number of widely-conserved cell adhesion proteins are implicated in cell recognition between synaptic partners, but how these proteins act as a group to specify a complex neural network is poorly understood. Taking advantage of known connectivity in C. elegans , we identified and studied cell adhesion genes expressed in three interacting neurons in the mating circuits of the adult male. Two interacting pairs of cell surface proteins independently promote fasciculation between sensory neuron HOA and its postsynaptic target interneuron AVG: BAM-2/neurexin-related in HOA binds to CASY-1/calsyntenin in AVG; SAX-7/L1CAM in sensory neuron PHC binds to RIG-6/contactin in AVG. A third, basal pathway results in considerable HOA-AVG fasciculation and synapse formation in the absence of the other two. The features of this multiplexed mechanism help to explain how complex connectivity is encoded and robustly established during nervous system development.

SHANK3 controls maturation of social reward circuits in the VTA

PubMed Central

Glangetas, Christelle; Prévost-Solié, Clément; Pucci, Luca; Viguié, Joanna; Bezzi, Paola; O’Connor, Eoin C.; Georges, François; Lüscher, Christian; Bellone, Camilla

2016-01-01

Summary Haploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of Autism Spectrum Disorder (ASD). How SHANK3 insufficiency affects specific neural circuits and this is related to specific ASD symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the Ventral Tegmental Area (VTA) of mice. We identified dopamine (DA) and GABA cell-type specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors (mGluR1) during the first postnatal week restored DA neuron excitatory synapse transmission and rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired VTA function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy. PMID:27273769

Properties of Neurons in External Globus Pallidus Can Support Optimal Action Selection

PubMed Central

Bogacz, Rafal; Martin Moraud, Eduardo; Abdi, Azzedine; Magill, Peter J.; Baufreton, Jérôme

2016-01-01

The external globus pallidus (GPe) is a key nucleus within basal ganglia circuits that are thought to be involved in action selection. A class of computational models assumes that, during action selection, the basal ganglia compute for all actions available in a given context the probabilities that they should be selected. These models suggest that a network of GPe and subthalamic nucleus (STN) neurons computes the normalization term in Bayes’ equation. In order to perform such computation, the GPe needs to send feedback to the STN equal to a particular function of the activity of STN neurons. However, the complex form of this function makes it unlikely that individual GPe neurons, or even a single GPe cell type, could compute it. Here, we demonstrate how this function could be computed within a network containing two types of GABAergic GPe projection neuron, so-called ‘prototypic’ and ‘arkypallidal’ neurons, that have different response properties in vivo and distinct connections. We compare our model predictions with the experimentally-reported connectivity and input-output functions (f-I curves) of the two populations of GPe neurons. We show that, together, these dichotomous cell types fulfil the requirements necessary to compute the function needed for optimal action selection. We conclude that, by virtue of their distinct response properties and connectivities, a network of arkypallidal and prototypic GPe neurons comprises a neural substrate capable of supporting the computation of the posterior probabilities of actions. PMID:27389780

The laminar organization of the Drosophila ellipsoid body is semaphorin-dependent and prevents the formation of ectopic synaptic connections

PubMed Central

Xie, Xiaojun; Tabuchi, Masashi; Brown, Matthew P; Mitchell, Sarah P; Wu, Mark N; Kolodkin, Alex L

2017-01-01

The ellipsoid body (EB) in the Drosophila brain is a central complex (CX) substructure that harbors circumferentially laminated ring (R) neuron axons and mediates multifaceted sensory integration and motor coordination functions. However, what regulates R axon lamination and how lamination affects R neuron function remain unknown. We show here that the EB is sequentially innervated by small-field and large-field neurons and that early developing EB neurons play an important regulatory role in EB laminae formation. The transmembrane proteins semaphorin-1a (Sema-1a) and plexin A function together to regulate R axon lamination. R neurons recruit both GABA and GABA-A receptors to their axon terminals in the EB, and optogenetic stimulation coupled with electrophysiological recordings show that Sema-1a-dependent R axon lamination is required for preventing the spread of synaptic inhibition between adjacent EB lamina. These results provide direct evidence that EB lamination is critical for local pre-synaptic inhibitory circuit organization. DOI: http://dx.doi.org/10.7554/eLife.25328.001 PMID:28632130

A Simple Picaxe Microcontroller Pulse Source for Juxtacellular Neuronal Labelling.

PubMed

Verberne, Anthony J M

2016-10-19

Juxtacellular neuronal labelling is a method which allows neurophysiologists to fill physiologically-identified neurons with small positively-charged marker molecules. Labelled neurons are identified by histochemical processing of brain sections along with immunohistochemical identification of neuropeptides, neurotransmitters, neurotransmitter transporters or biosynthetic enzymes. A microcontroller-based pulser circuit and associated BASIC software script is described for incorporation into the design of a commercially-available intracellular electrometer for use in juxtacellular neuronal labelling. Printed circuit board construction has been used for reliability and reproducibility. The current design obviates the need for a separate digital pulse source and simplifies the juxtacellular neuronal labelling procedure.

Lag Synchronization of Switched Neural Networks via Neural Activation Function and Applications in Image Encryption.

PubMed

Wen, Shiping; Zeng, Zhigang; Huang, Tingwen; Meng, Qinggang; Yao, Wei

2015-07-01

This paper investigates the problem of global exponential lag synchronization of a class of switched neural networks with time-varying delays via neural activation function and applications in image encryption. The controller is dependent on the output of the system in the case of packed circuits, since it is hard to measure the inner state of the circuits. Thus, it is critical to design the controller based on the neuron activation function. Comparing the results, in this paper, with the existing ones shows that we improve and generalize the results derived in the previous literature. Several examples are also given to illustrate the effectiveness and potential applications in image encryption.

Single-Neuron NMDA Receptor Phenotype Influences Neuronal Rewiring and Reintegration following Traumatic Injury

PubMed Central

Patel, Tapan P.; Ventre, Scott C.; Geddes-Klein, Donna; Singh, Pallab K.

2014-01-01

Alterations in the activity of neural circuits are a common consequence of traumatic brain injury (TBI), but the relationship between single-neuron properties and the aggregate network behavior is not well understood. We recently reported that the GluN2B-containing NMDA receptors (NMDARs) are key in mediating mechanical forces during TBI, and that TBI produces a complex change in the functional connectivity of neuronal networks. Here, we evaluated whether cell-to-cell heterogeneity in the connectivity and aggregate contribution of GluN2B receptors to [Ca2+]i before injury influenced the functional rewiring, spontaneous activity, and network plasticity following injury using primary rat cortical dissociated neurons. We found that the functional connectivity of a neuron to its neighbors, combined with the relative influx of calcium through distinct NMDAR subtypes, together contributed to the individual neuronal response to trauma. Specifically, individual neurons whose [Ca2+]i oscillations were largely due to GluN2B NMDAR activation lost many of their functional targets 1 h following injury. In comparison, neurons with large GluN2A contribution or neurons with high functional connectivity both independently protected against injury-induced loss in connectivity. Mechanistically, we found that traumatic injury resulted in increased uncorrelated network activity, an effect linked to reduction of the voltage-sensitive Mg2+ block of GluN2B-containing NMDARs. This uncorrelated activation of GluN2B subtypes after injury significantly limited the potential for network remodeling in response to a plasticity stimulus. Together, our data suggest that two single-cell characteristics, the aggregate contribution of NMDAR subtypes and the number of functional connections, influence network structure following traumatic injury. PMID:24647941

MET receptor tyrosine kinase controls dendritic complexity, spine morphogenesis, and glutamatergic synapse maturation in the hippocampus.

PubMed

Qiu, Shenfeng; Lu, Zhongming; Levitt, Pat

2014-12-03

The MET receptor tyrosine kinase (RTK), implicated in risk for autism spectrum disorder (ASD) and in functional and structural circuit integrity in humans, is a temporally and spatially regulated receptor enriched in dorsal pallial-derived structures during mouse forebrain development. Here we report that loss or gain of function of MET in vitro or in vivo leads to changes, opposite in nature, in dendritic complexity, spine morphogenesis, and the timing of glutamatergic synapse maturation onto hippocampus CA1 neurons. Consistent with the morphological and biochemical changes, deletion of Met in mutant mice results in precocious maturation of excitatory synapse, as indicated by a reduction of the proportion of silent synapses, a faster GluN2A subunit switch, and an enhanced acquisition of AMPA receptors at synaptic sites. Thus, MET-mediated signaling appears to serve as a mechanism for controlling the timing of neuronal growth and functional maturation. These studies suggest that mistimed maturation of glutamatergic synapses leads to the aberrant neural circuits that may be associated with ASD risk. Copyright © 2014 the authors 0270-6474/14/3416166-14$15.00/0.

MET Receptor Tyrosine Kinase Controls Dendritic Complexity, Spine Morphogenesis, and Glutamatergic Synapse Maturation in the Hippocampus

PubMed Central

Lu, Zhongming; Levitt, Pat

2014-01-01

The MET receptor tyrosine kinase (RTK), implicated in risk for autism spectrum disorder (ASD) and in functional and structural circuit integrity in humans, is a temporally and spatially regulated receptor enriched in dorsal pallial-derived structures during mouse forebrain development. Here we report that loss or gain of function of MET in vitro or in vivo leads to changes, opposite in nature, in dendritic complexity, spine morphogenesis, and the timing of glutamatergic synapse maturation onto hippocampus CA1 neurons. Consistent with the morphological and biochemical changes, deletion of Met in mutant mice results in precocious maturation of excitatory synapse, as indicated by a reduction of the proportion of silent synapses, a faster GluN2A subunit switch, and an enhanced acquisition of AMPA receptors at synaptic sites. Thus, MET-mediated signaling appears to serve as a mechanism for controlling the timing of neuronal growth and functional maturation. These studies suggest that mistimed maturation of glutamatergic synapses leads to the aberrant neural circuits that may be associated with ASD risk. PMID:25471559

Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity

PubMed Central

Yonehara, Keisuke; Fiscella, Michele; Drinnenberg, Antonia; Esposti, Federico; Trenholm, Stuart; Krol, Jacek; Franke, Felix; Scherf, Brigitte Gross; Kusnyerik, Akos; Müller, Jan; Szabo, Arnold; Jüttner, Josephine; Cordoba, Francisco; Reddy, Ashrithpal Police; Németh, János; Nagy, Zoltán Zsolt; Munier, Francis; Hierlemann, Andreas; Roska, Botond

2016-01-01

Summary Neuronal circuit asymmetries are important components of brain circuits, but the molecular pathways leading to their establishment remain unknown. Here we found that the mutation of FRMD7, a gene that is defective in human congenital nystagmus, leads to the selective loss of the horizontal optokinetic reflex in mice, as it does in humans. This is accompanied by the selective loss of horizontal direction selectivity in retinal ganglion cells and the transition from asymmetric to symmetric inhibitory input to horizontal direction-selective ganglion cells. In wild-type retinas, we found FRMD7 specifically expressed in starburst amacrine cells, the interneuron type that provides asymmetric inhibition to direction-selective retinal ganglion cells. This work identifies FRMD7 as a key regulator in establishing a neuronal circuit asymmetry, and it suggests the involvement of a specific inhibitory neuron type in the pathophysiology of a neurological disease. Video Abstract PMID:26711119

Massively parallel neural circuits for stereoscopic color vision: encoding, decoding and identification.

PubMed

Lazar, Aurel A; Slutskiy, Yevgeniy B; Zhou, Yiyin

2015-03-01

Past work demonstrated how monochromatic visual stimuli could be faithfully encoded and decoded under Nyquist-type rate conditions. Color visual stimuli were then traditionally encoded and decoded in multiple separate monochromatic channels. The brain, however, appears to mix information about color channels at the earliest stages of the visual system, including the retina itself. If information about color is mixed and encoded by a common pool of neurons, how can colors be demixed and perceived? We present Color Video Time Encoding Machines (Color Video TEMs) for encoding color visual stimuli that take into account a variety of color representations within a single neural circuit. We then derive a Color Video Time Decoding Machine (Color Video TDM) algorithm for color demixing and reconstruction of color visual scenes from spikes produced by a population of visual neurons. In addition, we formulate Color Video Channel Identification Machines (Color Video CIMs) for functionally identifying color visual processing performed by a spiking neural circuit. Furthermore, we derive a duality between TDMs and CIMs that unifies the two and leads to a general theory of neural information representation for stereoscopic color vision. We provide examples demonstrating that a massively parallel color visual neural circuit can be first identified with arbitrary precision and its spike trains can be subsequently used to reconstruct the encoded stimuli. We argue that evaluation of the functional identification methodology can be effectively and intuitively performed in the stimulus space. In this space, a signal reconstructed from spike trains generated by the identified neural circuit can be compared to the original stimulus. Copyright © 2014 Elsevier Ltd. All rights reserved.

Stochastic inference with spiking neurons in the high-conductance state

NASA Astrophysics Data System (ADS)

Petrovici, Mihai A.; Bill, Johannes; Bytschok, Ilja; Schemmel, Johannes; Meier, Karlheinz

2016-10-01

The highly variable dynamics of neocortical circuits observed in vivo have been hypothesized to represent a signature of ongoing stochastic inference but stand in apparent contrast to the deterministic response of neurons measured in vitro. Based on a propagation of the membrane autocorrelation across spike bursts, we provide an analytical derivation of the neural activation function that holds for a large parameter space, including the high-conductance state. On this basis, we show how an ensemble of leaky integrate-and-fire neurons with conductance-based synapses embedded in a spiking environment can attain the correct firing statistics for sampling from a well-defined target distribution. For recurrent networks, we examine convergence toward stationarity in computer simulations and demonstrate sample-based Bayesian inference in a mixed graphical model. This points to a new computational role of high-conductance states and establishes a rigorous link between deterministic neuron models and functional stochastic dynamics on the network level.

Transsynaptic trophic effects of steroid hormones in an avian model of adult brain plasticity

PubMed Central

Brenowitz, Eliot A.

2014-01-01

The avian song control system provides an excellent model for studying transsynaptic trophic effects of steroid sex hormones. Seasonal changes in systemic testosterone (T) and its metabolites regulate plasticity of this system. Steroids interact with the neurotrophin brain-derived neurotrophic factor (BDNF) to influence cellular processes of plasticity in nucleus HVC of adult birds, including the addition of newborn neurons. This interaction may also occur transsynpatically; T increases the synthesis of BDNF in HVC, and BDNF protein is then released by HVC neurons on to postsynaptic cells in nucleus RA where it has trophic effects on activity and morphology. Androgen action on RA neurons increases their activity and this has a retrograde trophic effect on the addition of new neurons to HVC. The functional linkage of sex steroids to BDNF may be of adaptive value in regulating the trophic effects of the neurotrophin and coordinating circuit function in reproductively relevant contexts. PMID:25285401

Layer 5 Callosal Parvalbumin-Expressing Neurons: A Distinct Functional Group of GABAergic Neurons

PubMed Central

Zurita, Hector; Feyen, Paul L. C.; Apicella, Alfonso Junior

2018-01-01

Previous studies have shown that parvalbumin-expressing neurons (CC-Parv neurons) connect the two hemispheres of motor and sensory areas via the corpus callosum, and are a functional part of the cortical circuit. Here we test the hypothesis that layer 5 CC-Parv neurons possess anatomical and molecular mechanisms which dampen excitability and modulate the gating of interhemispheric inhibition. In order to investigate this hypothesis we use viral tracing to determine the anatomical and electrophysiological properties of layer 5 CC-Parv and parvalbumin-expressing (Parv) neurons of the mouse auditory cortex (AC). Here we show that layer 5 CC-Parv neurons had larger dendritic fields characterized by longer dendrites that branched farther from the soma, whereas layer 5 Parv neurons had smaller dendritic fields characterized by shorter dendrites that branched nearer to the soma. The layer 5 CC-Parv neurons are characterized by delayed action potential (AP) responses to threshold currents, lower firing rates, and lower instantaneous frequencies compared to the layer 5 Parv neurons. Kv1.1 containing K+ channels are the main source of the AP repolarization of the layer 5 CC-Parv and have a major role in determining both the spike delayed response, firing rate and instantaneous frequency of these neurons. PMID:29559891

Layer 5 Callosal Parvalbumin-Expressing Neurons: A Distinct Functional Group of GABAergic Neurons.

PubMed

Zurita, Hector; Feyen, Paul L C; Apicella, Alfonso Junior

2018-01-01

Previous studies have shown that parvalbumin-expressing neurons (CC-Parv neurons) connect the two hemispheres of motor and sensory areas via the corpus callosum, and are a functional part of the cortical circuit. Here we test the hypothesis that layer 5 CC-Parv neurons possess anatomical and molecular mechanisms which dampen excitability and modulate the gating of interhemispheric inhibition. In order to investigate this hypothesis we use viral tracing to determine the anatomical and electrophysiological properties of layer 5 CC-Parv and parvalbumin-expressing (Parv) neurons of the mouse auditory cortex (AC). Here we show that layer 5 CC-Parv neurons had larger dendritic fields characterized by longer dendrites that branched farther from the soma, whereas layer 5 Parv neurons had smaller dendritic fields characterized by shorter dendrites that branched nearer to the soma. The layer 5 CC-Parv neurons are characterized by delayed action potential (AP) responses to threshold currents, lower firing rates, and lower instantaneous frequencies compared to the layer 5 Parv neurons. Kv1.1 containing K + channels are the main source of the AP repolarization of the layer 5 CC-Parv and have a major role in determining both the spike delayed response, firing rate and instantaneous frequency of these neurons.

Bacterial Signaling to the Nervous System through Toxins and Metabolites.

PubMed

Yang, Nicole J; Chiu, Isaac M

2017-03-10

Mammalian hosts interface intimately with commensal and pathogenic bacteria. It is increasingly clear that molecular interactions between the nervous system and microbes contribute to health and disease. Both commensal and pathogenic bacteria are capable of producing molecules that act on neurons and affect essential aspects of host physiology. Here we highlight several classes of physiologically important molecular interactions that occur between bacteria and the nervous system. First, clostridial neurotoxins block neurotransmission to or from neurons by targeting the SNARE complex, causing the characteristic paralyses of botulism and tetanus during bacterial infection. Second, peripheral sensory neurons-olfactory chemosensory neurons and nociceptor sensory neurons-detect bacterial toxins, formyl peptides, and lipopolysaccharides through distinct molecular mechanisms to elicit smell and pain. Bacteria also damage the central nervous system through toxins that target the brain during infection. Finally, the gut microbiota produces molecules that act on enteric neurons to influence gastrointestinal motility, and metabolites that stimulate the "gut-brain axis" to alter neural circuits, autonomic function, and higher-order brain function and behavior. Furthering the mechanistic and molecular understanding of how bacteria affect the nervous system may uncover potential strategies for modulating neural function and treating neurological diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Brain/MINDS: brain-mapping project in Japan

PubMed Central

Okano, Hideyuki; Miyawaki, Atsushi; Kasai, Kiyoto

2015-01-01

There is an emerging interest in brain-mapping projects in countries across the world, including the USA, Europe, Australia and China. In 2014, Japan started a brain-mapping project called Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS). Brain/MINDS aims to map the structure and function of neuronal circuits to ultimately understand the vast complexity of the human brain, and takes advantage of a unique non-human primate animal model, the common marmoset (Callithrix jacchus). In Brain/MINDS, the RIKEN Brain Science Institute acts as a central institute. The objectives of Brain/MINDS can be categorized into the following three major subject areas: (i) structure and functional mapping of a non-human primate brain (the marmoset brain); (ii) development of innovative neurotechnologies for brain mapping; and (iii) human brain mapping; and clinical research. Brain/MINDS researchers are highly motivated to identify the neuronal circuits responsible for the phenotype of neurological and psychiatric disorders, and to understand the development of these devastating disorders through the integration of these three subject areas. PMID:25823872

The serotonin receptor 7 and the structural plasticity of brain circuits

PubMed Central

Volpicelli, Floriana; Speranza, Luisa; di Porzio, Umberto; Crispino, Marianna; Perrone-Capano, Carla

2014-01-01

Serotonin (5-hydroxytryptamine, 5-HT) modulates numerous physiological processes in the nervous system. Together with its function as neurotransmitter, 5-HT regulates neurite outgrowth, dendritic spine shape and density, growth cone motility and synapse formation during development. In the mammalian brain 5-HT innervation is virtually ubiquitous and the diversity and specificity of its signaling and function arise from at least 20 different receptors, grouped in 7 classes. Here we will focus on the role 5-HT7 receptor (5-HT7R) in the correct establishment of neuronal cytoarchitecture during development, as also suggested by its involvement in several neurodevelopmental disorders. The emerging picture shows that this receptor is a key player contributing not only to shape brain networks during development but also to remodel neuronal wiring in the mature brain, thus controlling cognitive and emotional responses. The activation of 5-HT7R might be one of the mechanisms underlying the ability of the CNS to respond to different stimuli by modulation of its circuit configuration. PMID:25309369

Pbx3 is required for normal locomotion and dorsal horn development.

PubMed

Rottkamp, Catherine A; Lobur, Katherine J; Wladyka, Cynthia L; Lucky, Amy K; O'Gorman, Stephen

2008-02-01

The transcription cofactor Pbx3 is critical for the function of hindbrain circuits controlling respiration in mammals, but the perinatal lethality caused by constitutively null mutations has hampered investigation of other roles it may play in neural development and function. Here we report that the conditional loss of Pbx3 function in most tissues caudal to the hindbrain resulted in progressive deficits of posture, locomotion, and sensation that became apparent during adolescence. In adult mutants, the size of the dorsal horn of the spinal cord and the numbers of calbindin-, PKC-gamma, and calretinin-expressing neurons in laminae I-III were markedly reduced, but the ventral cord and peripheral nervous system appeared normal. In the embryonic dorsal horn, Pbx3 expression was restricted to a subset of glutamatergic neurons, but its absence did not affect the initial balance of excitatory and inhibitory interneuron phenotypes. By embryonic day 15 a subset of Meis(+) glutamatergic neurons assumed abnormally superficial positions and the number of calbindin(+) neurons was increased three-fold in the mutants. Loss of Pbx3 function thus leads to the incorrect specification of some glutamatergic neurons in the dorsal horn and alters the integration of peripheral sensation into the spinal circuitry regulating locomotion.

Mathematical neuroscience: from neurons to circuits to systems.

PubMed

Gutkin, Boris; Pinto, David; Ermentrout, Bard

2003-01-01

Applications of mathematics and computational techniques to our understanding of neuronal systems are provided. Reduction of membrane models to simplified canonical models demonstrates how neuronal spike-time statistics follow from simple properties of neurons. Averaging over space allows one to derive a simple model for the whisker barrel circuit and use this to explain and suggest several experiments. Spatio-temporal pattern formation methods are applied to explain the patterns seen in the early stages of drug-induced visual hallucinations.

A Viral Receptor Complementation Strategy to Overcome CAV-2 Tropism for Efficient Retrograde Targeting of Neurons.

PubMed

Li, Shu-Jing; Vaughan, Alexander; Sturgill, James Fitzhugh; Kepecs, Adam

2018-06-06

Retrogradely transported neurotropic viruses enable genetic access to neurons based on their long-range projections and have become indispensable tools for linking neural connectivity with function. A major limitation of viral techniques is that they rely on cell-type-specific molecules for uptake and transport. Consequently, viruses fail to infect variable subsets of neurons depending on the complement of surface receptors expressed (viral tropism). We report a receptor complementation strategy to overcome this by potentiating neurons for the infection of the virus of interest-in this case, canine adenovirus type-2 (CAV-2). We designed AAV vectors for expressing the coxsackievirus and adenovirus receptor (CAR) throughout candidate projection neurons. CAR expression greatly increased retrograde-labeling rates, which we demonstrate for several long-range projections, including some resistant to other retrograde-labeling techniques. Our results demonstrate a receptor complementation strategy to abrogate endogenous viral tropism and thereby facilitate efficient retrograde targeting for functional analysis of neural circuits. Copyright © 2018 Elsevier Inc. All rights reserved.

Drebrin-mediated microtubule–actomyosin coupling steers cerebellar granule neuron nucleokinesis and migration pathway selection

DOE PAGES

Trivedi, Niraj; Stabley, Daniel R.; Cain, Blake; ...

2017-02-23

Neuronal migration from a germinal zone to a final laminar position is essential for the morphogenesis of neuronal circuits. While it is hypothesized that microtubule–actomyosin crosstalk is required for a neuron’s ‘two-stroke’ nucleokinesis cycle, the molecular mechanisms controlling such crosstalk are not defined. By using the drebrin microtubule–actin crosslinking protein as an entry point into the cerebellar granule neuron system in combination with super-resolution microscopy, we investigate how these cytoskeletal systems interface during migration. Lattice light-sheet and structured illumination microscopy reveal a proximal leading process nanoscale architecture wherein f-actin and drebrin intervene between microtubules and the plasma membrane. Functional perturbationsmore » of drebrin demonstrate that proximal leading process microtubule–actomyosin coupling steers the direction of centrosome and somal migration, as well as the switch from tangential to radial migration. Finally, the Siah2 E3 ubiquitin ligase antagonizes drebrin function, suggesting a model for control of the microtubule–actomyosin interfaces during neuronal differentiation.« less

Fast targeted gene transfection and optogenetic modification of single neurons using femtosecond laser irradiation

PubMed Central

Antkowiak, Maciej; Torres-Mapa, Maria Leilani; Witts, Emily C.; Miles, Gareth B.; Dholakia, Kishan; Gunn-Moore, Frank J.

2013-01-01

A prevailing problem in neuroscience is the fast and targeted delivery of DNA into selected neurons. The development of an appropriate methodology would enable the transfection of multiple genes into the same cell or different genes into different neighboring cells as well as rapid cell selective functionalization of neurons. Here, we show that optimized femtosecond optical transfection fulfills these requirements. We also demonstrate successful optical transfection of channelrhodopsin-2 in single selected neurons. We extend the functionality of this technique for wider uptake by neuroscientists by using fast three-dimensional laser beam steering enabling an image-guided “point-and-transfect” user-friendly transfection of selected cells. A sub-second transfection timescale per cell makes this method more rapid by at least two orders of magnitude when compared to alternative single-cell transfection techniques. This novel technology provides the ability to carry out large-scale cell selective genetic studies on neuronal ensembles and perform rapid genetic programming of neural circuits. PMID:24257461

Different requirements of functional telomeres in neural stem cells and terminally differentiated neurons.

PubMed

Lobanova, Anastasia; She, Robert; Pieraut, Simon; Clapp, Charlie; Maximov, Anton; Denchi, Eros Lazzerini

2017-04-01

Telomeres have been studied extensively in peripheral tissues, but their relevance in the nervous system remains poorly understood. Here, we examine the roles of telomeres at distinct stages of murine brain development by using lineage-specific genetic ablation of TRF2, an essential component of the shelterin complex that protects chromosome ends from the DNA damage response machinery. We found that functional telomeres are required for embryonic and adult neurogenesis, but their uncapping has surprisingly no detectable consequences on terminally differentiated neurons. Conditional knockout of TRF2 in post-mitotic immature neurons had virtually no detectable effect on circuit assembly, neuronal gene expression, and the behavior of adult animals despite triggering massive end-to-end chromosome fusions across the brain. These results suggest that telomeres are dispensable in terminally differentiated neurons and provide mechanistic insight into cognitive abnormalities associated with aberrant telomere length in humans. © 2017 Lobanova et al.; Published by Cold Spring Harbor Laboratory Press.

Fast targeted gene transfection and optogenetic modification of single neurons using femtosecond laser irradiation.

PubMed

Antkowiak, Maciej; Torres-Mapa, Maria Leilani; Witts, Emily C; Miles, Gareth B; Dholakia, Kishan; Gunn-Moore, Frank J

2013-11-21

A prevailing problem in neuroscience is the fast and targeted delivery of DNA into selected neurons. The development of an appropriate methodology would enable the transfection of multiple genes into the same cell or different genes into different neighboring cells as well as rapid cell selective functionalization of neurons. Here, we show that optimized femtosecond optical transfection fulfills these requirements. We also demonstrate successful optical transfection of channelrhodopsin-2 in single selected neurons. We extend the functionality of this technique for wider uptake by neuroscientists by using fast three-dimensional laser beam steering enabling an image-guided "point-and-transfect" user-friendly transfection of selected cells. A sub-second transfection timescale per cell makes this method more rapid by at least two orders of magnitude when compared to alternative single-cell transfection techniques. This novel technology provides the ability to carry out large-scale cell selective genetic studies on neuronal ensembles and perform rapid genetic programming of neural circuits.

The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus.

PubMed

Martin, E Anne; Muralidhar, Shruti; Wang, Zhirong; Cervantes, Diégo Cordero; Basu, Raunak; Taylor, Matthew R; Hunter, Jennifer; Cutforth, Tyler; Wilke, Scott A; Ghosh, Anirvan; Williams, Megan E

2015-11-17

Synaptic target specificity, whereby neurons make distinct types of synapses with different target cells, is critical for brain function, yet the mechanisms driving it are poorly understood. In this study, we demonstrate Kirrel3 regulates target-specific synapse formation at hippocampal mossy fiber (MF) synapses, which connect dentate granule (DG) neurons to both CA3 and GABAergic neurons. Here, we show Kirrel3 is required for formation of MF filopodia; the structures that give rise to DG-GABA synapses and that regulate feed-forward inhibition of CA3 neurons. Consequently, loss of Kirrel3 robustly increases CA3 neuron activity in developing mice. Alterations in the Kirrel3 gene are repeatedly associated with intellectual disabilities, but the role of Kirrel3 at synapses remained largely unknown. Our findings demonstrate that subtle synaptic changes during development impact circuit function and provide the first insight toward understanding the cellular basis of Kirrel3-dependent neurodevelopmental disorders.

Two-photon imaging in mice shows striosomes and matrix have overlapping but differential reinforcement-related responses

PubMed Central

Sur, Mriganka

2017-01-01

Striosomes were discovered several decades ago as neurochemically identified zones in the striatum, yet technical hurdles have hampered the study of the functions of these striatal compartments. Here we used 2-photon calcium imaging in neuronal birthdate-labeled Mash1-CreER;Ai14 mice to image simultaneously the activity of striosomal and matrix neurons as mice performed an auditory conditioning task. With this method, we identified circumscribed zones of tdTomato-labeled neuropil that correspond to striosomes as verified immunohistochemically. Neurons in both striosomes and matrix responded to reward-predicting cues and were active during or after consummatory licking. However, we found quantitative differences in response strength: striosomal neurons fired more to reward-predicting cues and encoded more information about expected outcome as mice learned the task, whereas matrix neurons were more strongly modulated by recent reward history. These findings open the possibility of harnessing in vivo imaging to determine the contributions of striosomes and matrix to striatal circuit function. PMID:29251596

Presynaptic Partners of Dorsal Raphe Serotonergic and GABAergic Neurons

PubMed Central

Weissbourd, Brandon; Ren, Jing; DeLoach, Katherine E.; Guenthner, Casey J.; Miyamichi, Kazunari; Luo, Liqun

2016-01-01

SUMMARY The serotonin system powerfully modulates physiology and behavior in health and disease, yet the circuit mechanisms underlying serotonin neuron activity are poorly understood. The major source of forebrain serotonergic innervation is from the dorsal raphe nucleus (DR), which contains both serotonin and GABA neurons. Using viral tracing combined with electrophysiology, we found that GABA and serotonin neurons in the DR receive excitatory, inhibitory, and peptidergic inputs from the same specific brain regions. Embedded in this overall similarity are important differences. Serotonin neurons are more likely to receive synaptic inputs from anterior neocortex while GABA neurons receive disproportionally higher input from the central amygdala. Local input mapping revealed extensive serotonin-serotonin as well as GABA-serotonin connectivity with a distinct spatial organization. Covariance analysis suggests heterogeneity of both serotonin and GABA neurons with respect to the inputs they receive. These analyses provide a foundation for further functional dissection of the serotonin system. PMID:25102560

Netrin-G1 regulates fear-like and anxiety-like behaviors in dissociable neural circuits.

PubMed

Zhang, Qi; Sano, Chie; Masuda, Akira; Ando, Reiko; Tanaka, Mika; Itohara, Shigeyoshi

2016-06-27

In vertebrate mammals, distributed neural circuits in the brain are involved in emotion-related behavior. Netrin-G1 is a glycosyl-phosphatidylinositol-anchored synaptic adhesion molecule whose deficiency results in impaired fear-like and anxiety-like behaviors under specific circumstances. To understand the cell type and circuit specificity of these responses, we generated netrin-G1 conditional knockout mice with loss of expression in cortical excitatory neurons, inhibitory neurons, or thalamic neurons. Genetic deletion of netrin-G1 in cortical excitatory neurons resulted in altered anxiety-like behavior, but intact fear-like behavior, whereas loss of netrin-G1 in inhibitory neurons resulted in attenuated fear-like behavior, but intact anxiety-like behavior. These data indicate a remarkable double dissociation of fear-like and anxiety-like behaviors involving netrin-G1 in excitatory and inhibitory neurons, respectively. Our findings support a crucial role for netrin-G1 in dissociable neural circuits for the modulation of emotion-related behaviors, and provide genetic models for investigating the mechanisms underlying the dissociation. The results also suggest the involvement of glycosyl-phosphatidylinositol-anchored synaptic adhesion molecules in the development and pathogenesis of emotion-related behavior.

The sox gene Dichaete is expressed in local interneurons and functions in development of the Drosophila adult olfactory circuit.

PubMed

Melnattur, Krishna V; Berdnik, Daniela; Rusan, Zeid; Ferreira, Christopher J; Nambu, John R

2013-02-01

In insects, the primary sites of integration for olfactory sensory input are the glomeruli in the antennal lobes. Here, axons of olfactory receptor neurons synapse with dendrites of the projection neurons that relay olfactory input to higher brain centers, such as the mushroom bodies and lateral horn. Interactions between olfactory receptor neurons and projection neurons are modulated by excitatory and inhibitory input from a group of local interneurons. While significant insight has been gleaned into the differentiation of olfactory receptor and projection neurons, much less is known about the development and function of the local interneurons. We have found that Dichaete, a conserved Sox HMG box gene, is strongly expressed in a cluster of LAAL cells located adjacent to each antennal lobe in the adult brain. Within these clusters, Dichaete protein expression is detected in both cholinergic and GABAergic local interneurons. In contrast, Dichaete expression is not detected in mature or developing projection neurons, or developing olfactory receptor neurons. Analysis of novel viable Dichaete mutant alleles revealed misrouting of specific projection neuron dendrites and axons, and alterations in glomeruli organization. These results suggest noncell autonomous functions of Dichaete in projection neuron differentiation as well as a potential role for Dichaete-expressing local interneurons in development of the adult olfactory circuitry. Copyright © 2012 Wiley Periodicals, Inc.

Dual Anterograde and Retrograde Viral Tracing of Reciprocal Connectivity.

PubMed

Haberl, Matthias G; Ginger, Melanie; Frick, Andreas

2017-01-01

Current large-scale approaches in neuroscience aim to unravel the complete connectivity map of specific neuronal circuits, or even the entire brain. This emerging research discipline has been termed connectomics. Recombinant glycoprotein-deleted rabies virus (RABV ∆G) has become an important tool for the investigation of neuronal connectivity in the brains of a variety of species. Neuronal infection with even a single RABV ∆G particle results in high-level transgene expression, revealing the fine-detailed morphology of all neuronal features-including dendritic spines, axonal processes, and boutons-on a brain-wide scale. This labeling is eminently suitable for subsequent post-hoc morphological analysis, such as semiautomated reconstruction in 3D. Here we describe the use of a recently developed anterograde RABV ∆G variant together with a retrograde RABV ∆G for the investigation of projections both to, and from, a particular brain region. In addition to the automated reconstruction of a dendritic tree, we also give as an example the volume measurements of axonal boutons following RABV ∆G-mediated fluorescent marker expression. In conclusion RABV ∆G variants expressing a combination of markers and/or tools for stimulating/monitoring neuronal activity, used together with genetic or behavioral animal models, promise important insights in the structure-function relationship of neural circuits.

Central neural control of thermoregulation and brown adipose tissue

PubMed Central

Morrison, Shaun F.

2016-01-01

Central neural circuits orchestrate the homeostatic repertoire that maintains body temperature during environmental temperature challenges and alters body temperature during the inflammatory response. This review summarizes the experimental underpinnings of our current model of the CNS pathways controlling the principal thermoeffectors for body temperature regulation: cutaneous vasoconstriction controlling heat loss, and shivering and brown adipose tissue for thermogenesis. The activation of these effectors is regulated by parallel but distinct, effector-specific, core efferent pathways within the CNS that share a common peripheral thermal sensory input. Via the lateral parabrachial nucleus, skin thermal afferent input reaches the hypothalamic preoptic area to inhibit warm-sensitive, inhibitory output neurons which control heat production by inhibiting thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to thermogenesis-controlling premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation of spinal circuits necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus sympathetic premotor neurons controlling cutaneous vasoconstriction. The model proposed for central thermoregulatory control provides a useful platform for further understanding of the functional organization of central thermoregulation and elucidating the hypothalamic circuitry and neurotransmitters involved in body temperature regulation. PMID:26924538

Central neural control of thermoregulation and brown adipose tissue.

PubMed

Morrison, Shaun F

2016-04-01

Central neural circuits orchestrate the homeostatic repertoire that maintains body temperature during environmental temperature challenges and alters body temperature during the inflammatory response. This review summarizes the experimental underpinnings of our current model of the CNS pathways controlling the principal thermoeffectors for body temperature regulation: cutaneous vasoconstriction controlling heat loss, and shivering and brown adipose tissue for thermogenesis. The activation of these effectors is regulated by parallel but distinct, effector-specific, core efferent pathways within the CNS that share a common peripheral thermal sensory input. Via the lateral parabrachial nucleus, skin thermal afferent input reaches the hypothalamic preoptic area to inhibit warm-sensitive, inhibitory output neurons which control heat production by inhibiting thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to thermogenesis-controlling premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation of spinal circuits necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus sympathetic premotor neurons controlling cutaneous vasoconstriction. The model proposed for central thermoregulatory control provides a useful platform for further understanding of the functional organization of central thermoregulation and elucidating the hypothalamic circuitry and neurotransmitters involved in body temperature regulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Multivariable harmonic balance analysis of the neuronal oscillator for leech swimming.

PubMed

Chen, Zhiyong; Zheng, Min; Friesen, W Otto; Iwasaki, Tetsuya

2008-12-01

Biological systems, and particularly neuronal circuits, embody a very high level of complexity. Mathematical modeling is therefore essential for understanding how large sets of neurons with complex multiple interconnections work as a functional system. With the increase in computing power, it is now possible to numerically integrate a model with many variables to simulate behavior. However, such analysis can be time-consuming and may not reveal the mechanisms underlying the observed phenomena. An alternative, complementary approach is mathematical analysis, which can demonstrate direct and explicit relationships between a property of interest and system parameters. This paper introduces a mathematical tool for analyzing neuronal oscillator circuits based on multivariable harmonic balance (MHB). The tool is applied to a model of the central pattern generator (CPG) for leech swimming, which comprises a chain of weakly coupled segmental oscillators. The results demonstrate the effectiveness of the MHB method and provide analytical explanations for some CPG properties. In particular, the intersegmental phase lag is estimated to be the sum of a nominal value and a perturbation, where the former depends on the structure and span of the neuronal connections and the latter is roughly proportional to the period gradient, communication delay, and the reciprocal of the intersegmental coupling strength.

Bidirectional electromagnetic control of the hypothalamus regulates feeding and metabolism

PubMed Central

Stanley, Sarah A.; Kelly, Leah; Latcha, Kaamashri N.; Schmidt, Sarah F.; Yu, Xiaofei; Nectow, Alexander R.; Sauer, Jeremy; Dyke, Jonathan P.; Dordick, Jonathan S.; Friedman, Jeffrey M.

2016-01-01

Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP–TRPV1)1. Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase–Cre mice, which express Cre in glucose-sensing neurons2. Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types. PMID:27007848

The functional architectures of addition and subtraction: Network discovery using fMRI and DCM.

PubMed

Yang, Yang; Zhong, Ning; Friston, Karl; Imamura, Kazuyuki; Lu, Shengfu; Li, Mi; Zhou, Haiyan; Wang, Haiyuan; Li, Kuncheng; Hu, Bin

2017-06-01

The neuronal mechanisms underlying arithmetic calculations are not well understood but the differences between mental addition and subtraction could be particularly revealing. Using fMRI and dynamic causal modeling (DCM), this study aimed to identify the distinct neuronal architectures engaged by the cognitive processes of simple addition and subtraction. Our results revealed significantly greater activation during subtraction in regions along the dorsal pathway, including the left inferior frontal gyrus (IFG), middle portion of dorsolateral prefrontal cortex (mDLPFC), and supplementary motor area (SMA), compared with addition. Subsequent analysis of the underlying changes in connectivity - with DCM - revealed a common circuit processing basic (numeric) attributes and the retrieval of arithmetic facts. However, DCM showed that addition was more likely to engage (numeric) retrieval-based circuits in the left hemisphere, while subtraction tended to draw on (magnitude) processing in bilateral parietal cortex, especially the right intraparietal sulcus (IPS). Our findings endorse previous hypotheses about the differences in strategic implementation, dominant hemisphere, and the neuronal circuits underlying addition and subtraction. Moreover, for simple arithmetic, our connectivity results suggest that subtraction calls on more complex processing than addition: auxiliary phonological, visual, and motor processes, for representing numbers, were engaged by subtraction, relative to addition. Hum Brain Mapp 38:3210-3225, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Visuomotor Transformations Underlying Hunting Behavior in Zebrafish

PubMed Central

Bianco, Isaac H.; Engert, Florian

2015-01-01

Summary Visuomotor circuits filter visual information and determine whether or not to engage downstream motor modules to produce behavioral outputs. However, the circuit mechanisms that mediate and link perception of salient stimuli to execution of an adaptive response are poorly understood. We combined a virtual hunting assay for tethered larval zebrafish with two-photon functional calcium imaging to simultaneously monitor neuronal activity in the optic tectum during naturalistic behavior. Hunting responses showed mixed selectivity for combinations of visual features, specifically stimulus size, speed, and contrast polarity. We identified a subset of tectal neurons with similar highly selective tuning, which show non-linear mixed selectivity for visual features and are likely to mediate the perceptual recognition of prey. By comparing neural dynamics in the optic tectum during response versus non-response trials, we discovered premotor population activity that specifically preceded initiation of hunting behavior and exhibited anatomical localization that correlated with motor variables. In summary, the optic tectum contains non-linear mixed selectivity neurons that are likely to mediate reliable detection of ethologically relevant sensory stimuli. Recruitment of small tectal assemblies appears to link perception to action by providing the premotor commands that release hunting responses. These findings allow us to propose a model circuit for the visuomotor transformations underlying a natural behavior. PMID:25754638

Visuomotor transformations underlying hunting behavior in zebrafish.

PubMed

Bianco, Isaac H; Engert, Florian

2015-03-30

Visuomotor circuits filter visual information and determine whether or not to engage downstream motor modules to produce behavioral outputs. However, the circuit mechanisms that mediate and link perception of salient stimuli to execution of an adaptive response are poorly understood. We combined a virtual hunting assay for tethered larval zebrafish with two-photon functional calcium imaging to simultaneously monitor neuronal activity in the optic tectum during naturalistic behavior. Hunting responses showed mixed selectivity for combinations of visual features, specifically stimulus size, speed, and contrast polarity. We identified a subset of tectal neurons with similar highly selective tuning, which show non-linear mixed selectivity for visual features and are likely to mediate the perceptual recognition of prey. By comparing neural dynamics in the optic tectum during response versus non-response trials, we discovered premotor population activity that specifically preceded initiation of hunting behavior and exhibited anatomical localization that correlated with motor variables. In summary, the optic tectum contains non-linear mixed selectivity neurons that are likely to mediate reliable detection of ethologically relevant sensory stimuli. Recruitment of small tectal assemblies appears to link perception to action by providing the premotor commands that release hunting responses. These findings allow us to propose a model circuit for the visuomotor transformations underlying a natural behavior. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Toward a multiscale modeling framework for understanding serotonergic function

PubMed Central

Wong-Lin, KongFatt; Wang, Da-Hui; Moustafa, Ahmed A; Cohen, Jeremiah Y; Nakamura, Kae

2017-01-01

Despite its importance in regulating emotion and mental wellbeing, the complex structure and function of the serotonergic system present formidable challenges toward understanding its mechanisms. In this paper, we review studies investigating the interactions between serotonergic and related brain systems and their behavior at multiple scales, with a focus on biologically-based computational modeling. We first discuss serotonergic intracellular signaling and neuronal excitability, followed by neuronal circuit and systems levels. At each level of organization, we will discuss the experimental work accompanied by related computational modeling work. We then suggest that a multiscale modeling approach that integrates the various levels of neurobiological organization could potentially transform the way we understand the complex functions associated with serotonin. PMID:28417684

Increased Cell-Intrinsic Excitability Induces Synaptic Changes in New Neurons in the Adult Dentate Gyrus That Require Npas4

PubMed Central

Sim, Shuyin; Antolin, Salome; Lin, Chia-Wei; Lin, Ying-Xi

2013-01-01

Electrical activity regulates the manner in which neurons mature and form connections to each other. However, it remains unclear whether increased single-cell activity is sufficient to alter the development of synaptic connectivity of that neuron or whether a global increase in circuit activity is necessary. To address this question, we genetically increased neuronal excitability of in vivo individual adult-born neurons in the mouse dentate gyrus via expression of a voltage-gated bacterial sodium channel. We observed that increasing the excitability of new neurons in an otherwise unperturbed circuit leads to changes in both their input and axonal synapses. Furthermore, the activity-dependent transcription factor Npas4 is necessary for the changes in the input synapses of these neurons, but it is not involved in changes to their axonal synapses. Our results reveal that an increase in cell-intrinsic activity during maturation is sufficient to alter the synaptic connectivity of a neuron with the hippocampal circuit and that Npas4 is required for activity-dependent changes in input synapses. PMID:23637184

Lhx2 Expression in Postmitotic Cortical Neurons Initiates Assembly of the Thalamocortical Somatosensory Circuit.

PubMed

Wang, Chia-Fang; Hsing, Hsiang-Wei; Zhuang, Zi-Hui; Wen, Meng-Hsuan; Chang, Wei-Jen; Briz, Carlos G; Nieto, Marta; Shyu, Bai Chuang; Chou, Shen-Ju

2017-01-24

Cortical neurons must be specified and make the correct connections during development. Here, we examine a mechanism initiating neuronal circuit formation in the barrel cortex, a circuit comprising thalamocortical axons (TCAs) and layer 4 (L4) neurons. When Lhx2 is selectively deleted in postmitotic cortical neurons using conditional knockout (cKO) mice, L4 neurons in the barrel cortex are initially specified but fail to form cellular barrels or develop polarized dendrites. In Lhx2 cKO mice, TCAs from the thalamic ventral posterior nucleus reach the barrel cortex but fail to further arborize to form barrels. Several activity-regulated genes and genes involved in regulating barrel formation are downregulated in the Lhx2 cKO somatosensory cortex. Among them, Btbd3, an activity-regulated gene controlling dendritic development, is a direct downstream target of Lhx2. We find that Lhx2 confers neuronal competency for activity-dependent dendritic development in L4 neurons by inducing the expression of Btbd3. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Hypothalamic Tuberomammillary Nucleus Neurons: Electrophysiological Diversity and Essential Role in Arousal Stability.

PubMed

Fujita, Akie; Bonnavion, Patricia; Wilson, Miryam H; Mickelsen, Laura E; Bloit, Julien; de Lecea, Luis; Jackson, Alexander C

2017-09-27

Histaminergic (HA) neurons, found in the posterior hypothalamic tuberomammillary nucleus (TMN), extend fibers throughout the brain and exert modulatory influence over numerous physiological systems. Multiple lines of evidence suggest that the activity of HA neurons is important in the regulation of vigilance despite the lack of direct, causal evidence demonstrating its requirement for the maintenance of arousal during wakefulness. Given the strong correlation between HA neuron excitability and behavioral arousal, we investigated both the electrophysiological diversity of HA neurons in brain slices and the effect of their acute silencing in vivo in male mice. For this purpose, we first validated a transgenic mouse line expressing cre recombinase in histidine decarboxylase-expressing neurons ( Hdc -Cre) followed by a systematic census of the membrane properties of both HA and non-HA neurons in the ventral TMN (TMNv) region. Through unsupervised hierarchical cluster analysis, we found electrophysiological diversity both between TMNv HA and non-HA neurons, and among HA neurons. To directly determine the impact of acute cessation of HA neuron activity on sleep-wake states in awake and behaving mice, we examined the effects of optogenetic silencing of TMNv HA neurons in vivo We found that acute silencing of HA neurons during wakefulness promotes slow-wave sleep, but not rapid eye movement sleep, during a period of low sleep pressure. Together, these data suggest that the tonic firing of HA neurons is necessary for the maintenance of wakefulness, and their silencing not only impairs arousal but is sufficient to rapidly and selectively induce slow-wave sleep. SIGNIFICANCE STATEMENT The function of monoaminergic systems and circuits that regulate sleep and wakefulness is often disrupted as part of the pathophysiology of many neuropsychiatric disorders. One such circuit is the posterior hypothalamic histamine (HA) system, implicated in supporting wakefulness and higher brain function, but has been difficult to selectively manipulate owing to cellular heterogeneity in this region. Here we use a transgenic mouse to interrogate both the characteristic firing properties of HA neurons and their specific role in maintaining wakefulness. Our results demonstrate that the acute, cell type-specific silencing of HA neurons during wakefulness is sufficient to not only impair arousal but to rapidly and selectively induce slow-wave sleep. This work furthers our understanding of HA-mediated mechanisms that regulate behavioral arousal. Copyright © 2017 the authors 0270-6474/17/379575-19$15.00/0.

Hypothalamic Tuberomammillary Nucleus Neurons: Electrophysiological Diversity and Essential Role in Arousal Stability

PubMed Central

Fujita, Akie; Mickelsen, Laura E.; Bloit, Julien

2017-01-01

Histaminergic (HA) neurons, found in the posterior hypothalamic tuberomammillary nucleus (TMN), extend fibers throughout the brain and exert modulatory influence over numerous physiological systems. Multiple lines of evidence suggest that the activity of HA neurons is important in the regulation of vigilance despite the lack of direct, causal evidence demonstrating its requirement for the maintenance of arousal during wakefulness. Given the strong correlation between HA neuron excitability and behavioral arousal, we investigated both the electrophysiological diversity of HA neurons in brain slices and the effect of their acute silencing in vivo in male mice. For this purpose, we first validated a transgenic mouse line expressing cre recombinase in histidine decarboxylase-expressing neurons (Hdc-Cre) followed by a systematic census of the membrane properties of both HA and non-HA neurons in the ventral TMN (TMNv) region. Through unsupervised hierarchical cluster analysis, we found electrophysiological diversity both between TMNv HA and non-HA neurons, and among HA neurons. To directly determine the impact of acute cessation of HA neuron activity on sleep–wake states in awake and behaving mice, we examined the effects of optogenetic silencing of TMNv HA neurons in vivo. We found that acute silencing of HA neurons during wakefulness promotes slow-wave sleep, but not rapid eye movement sleep, during a period of low sleep pressure. Together, these data suggest that the tonic firing of HA neurons is necessary for the maintenance of wakefulness, and their silencing not only impairs arousal but is sufficient to rapidly and selectively induce slow-wave sleep. SIGNIFICANCE STATEMENT The function of monoaminergic systems and circuits that regulate sleep and wakefulness is often disrupted as part of the pathophysiology of many neuropsychiatric disorders. One such circuit is the posterior hypothalamic histamine (HA) system, implicated in supporting wakefulness and higher brain function, but has been difficult to selectively manipulate owing to cellular heterogeneity in this region. Here we use a transgenic mouse to interrogate both the characteristic firing properties of HA neurons and their specific role in maintaining wakefulness. Our results demonstrate that the acute, cell type-specific silencing of HA neurons during wakefulness is sufficient to not only impair arousal but to rapidly and selectively induce slow-wave sleep. This work furthers our understanding of HA-mediated mechanisms that regulate behavioral arousal. PMID:28874450

Circadian pacemaking in cells and circuits of the suprachiasmatic nucleus.

PubMed

Hastings, M H; Brancaccio, M; Maywood, E S

2014-01-01

The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian pacemaker of the brain. It co-ordinates the daily rhythms of sleep and wakefulness, as well as physiology and behaviour, that set the tempo to our lives. Disturbance of this daily pattern, most acutely with jet-lag but more insidiously with rotational shift-work, can have severely deleterious effects for mental function and long-term health. The present review considers recent developments in our understanding of the properties of the SCN that make it a robust circadian time-keeper. It first focuses on the intracellular transcriptional/ translational feedback loops (TTFL) that constitute the cellular clockwork of the SCN neurone. Daily timing by these loops pivots around the negative regulation of the Period (Per) and Cryptochrome (Cry) genes by their protein products. The period of the circadian cycle is set by the relative stability of Per and Cry proteins, and this can be controlled by both genetic and pharmacological interventions. It then considers the function of these feedback loops in the context of cytosolic signalling by cAMP and intracellular calcium ([Ca(2+) ]i ), which are both outputs from, and inputs to, the TTFL, as well as the critical role of vasoactive intestinal peptide (VIP) signalling in synchronising cellular clocks across the SCN. Synchronisation by VIP in the SCN is paracrine, operating over an unconventionally long time frame (i.e. 24 h) and wide spatial domain, mediated via the cytosolic pathways upstream of the TTFL. Finally, we show how intersectional pharmacogenetics can be used to control G-protein-coupled signalling in individual SCN neurones, and how manipulation of Gq/[Ca(2+) ]i -signalling in VIP neurones can re-programme the circuit-level encoding of circadian time. Circadian pacemaking in the SCN therefore provides an unrivalled context in which to understand how a complex, adaptive behaviour can be organised by the dynamic activity of a relatively few gene products, operating in a clearly defined neuronal circuit, with both cell-autonomous and emergent, circuit-level properties. © 2014 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of The British Society for Neuroendocrinology.

Intrinsic and extrinsic neuromodulation of motor circuits.

PubMed

Katz, P S

1995-12-01

Neuromodulation of motor circuits by extrinsic inputs provides enormous flexibility in the production of behavior. Recent work has shown that neurons intrinsic to central pattern-generating circuits can evoke neuromodulatory effects in addition to their neurotransmitting actions. Modulatory neurons often elicit a multitude of different effects attributable to actions at different receptors and/or through the release of co-transmitters. Differences in neuromodulation between species can account for differences in behavior. Modulation of neuromodulation may provide an additional level of flexibility to motor circuits.

Left-right asymmetry is required for the habenulae to respond to both visual and olfactory stimuli.

PubMed

Dreosti, Elena; Vendrell Llopis, Nuria; Carl, Matthias; Yaksi, Emre; Wilson, Stephen W

2014-02-17

Left-right asymmetries are most likely a universal feature of bilaterian nervous systems and may serve to increase neural capacity by specializing equivalent structures on left and right sides for distinct roles. However, little is known about how asymmetries are encoded within vertebrate neural circuits and how lateralization influences processing of information in the brain. Consequently, it remains unclear the extent to which lateralization of the nervous system is important for normal cognitive and other brain functions and whether defects in lateralization contribute to neurological deficits. Here we show that sensory responses to light and odor are lateralized in larval zebrafish habenulae and that loss of brain asymmetry leads to concomitant loss of responsiveness to either visual or olfactory stimuli. We find that in wild-type zebrafish, most habenular neurons responding to light are present on the left, whereas neurons responding to odor are more frequent on the right. Manipulations that reverse the direction of brain asymmetry reverse the functional properties of habenular neurons, whereas manipulations that generate either double-left- or double-right-sided brains lead to loss of habenular responsiveness to either odor or light, respectively. Our results indicate that loss of brain lateralization has significant consequences upon sensory processing and circuit function. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Multiple functions of GABA A and GABA B receptors during pattern processing in the zebrafish olfactory bulb.

PubMed

Tabor, Rico; Yaksi, Emre; Friedrich, Rainer W

2008-07-01

gamma-Aminobutyric acid (GABA)ergic synapses are thought to play pivotal roles in the processing of activity patterns in the olfactory bulb (OB), but their functions have been difficult to study during odor responses in the intact system. We pharmacologically manipulated GABA(A) and GABA(B) receptors in the OB of zebrafish and analysed the effects on odor responses of the output neurons, the mitral cells (MCs), by electrophysiological recordings and temporally deconvolved two-photon Ca2+ imaging. The blockade of GABA(B) receptors enhanced presynaptic Ca2+ influx into afferent axon terminals, and changed the amplitude and time course of a subset of MC responses, indicating that GABA(B) receptors have a modulatory influence on OB output activity. The blockade of GABA(A) receptors induced epileptiform firing, enhanced excitatory responses and abolished fast oscillations in the local field potential. Moreover, the topological reorganization and decorrelation of MC activity patterns during the initial phase of the response was perturbed. These results indicate that GABA(A) receptor-containing circuits participate in the balance of excitation and inhibition, the regulation of total OB output activity, the synchronization of odor-dependent neuronal ensembles, and the reorganization of odor-encoding activity patterns. GABA(A) and GABA(B) receptors are therefore differentially involved in multiple functions of neuronal circuits in the OB.

How does calcium interact with the cytoskeleton to regulate growth cone motility during axon pathfinding?

PubMed

Gasperini, Robert J; Pavez, Macarena; Thompson, Adrian C; Mitchell, Camilla B; Hardy, Holly; Young, Kaylene M; Chilton, John K; Foa, Lisa

2017-10-01

The precision with which neurons form connections is crucial for the normal development and function of the nervous system. The development of neuronal circuitry in the nervous system is accomplished by axon pathfinding: a process where growth cones guide axons through the embryonic environment to connect with their appropriate synaptic partners to form functional circuits. Despite intense efforts over many years to understand how this process is regulated, the complete repertoire of molecular mechanisms that govern the growth cone cytoskeleton and hence motility, remain unresolved. A central tenet in the axon guidance field is that calcium signals regulate growth cone behaviours such as extension, turning and pausing by regulating rearrangements of the growth cone cytoskeleton. Here, we provide evidence that not only the amplitude of a calcium signal is critical for growth cone motility but also the source of calcium mobilisation. We provide an example of this idea by demonstrating that manipulation of calcium signalling via L-type voltage gated calcium channels can perturb sensory neuron motility towards a source of netrin-1. Understanding how calcium signals can be transduced to initiate cytoskeletal changes represents a significant gap in our current knowledge of the mechanisms that govern axon guidance, and consequently the formation of functional neural circuits in the developing nervous system. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Developmental origins of brain disorders: roles for dopamine

PubMed Central

Money, Kelli M.; Stanwood, Gregg D.

2013-01-01

Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse. Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific. For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders. PMID:24391541

Midbrain dopamine neurons reflect affiliation phenotypes in finches and are tightly coupled to courtship.

PubMed

Goodson, James L; Kabelik, David; Kelly, Aubrey M; Rinaldi, Jacob; Klatt, James D

2009-05-26

Mesolimbic dopamine (DA) circuits mediate a wide range of goal-oriented behavioral processes, and DA strongly influences appetitive and consummatory aspects of male sexual behavior. In both birds and mammals, mesolimbic projections arise primarily from the ventral tegmental area (VTA), with a smaller contribution from the midbrain central gray (CG). Despite the well known importance of the VTA cell group for incentive motivation functions, relationships of VTA subpopulations to specific aspects of social phenotype remain wholly undescribed. We now show that in male zebra finches (Estrildidae: Taeniopygia guttata), Fos activity within a subpopulation of tyrosine hydroxylase-immunoreactive (TH-ir; presumably dopaminergic) neurons in the caudal VTA is significantly correlated with courtship singing and coupled to gonadal state. In addition, the number of TH-ir neurons in this caudal subpopulation dichotomously differentiates courting from non-courting male phenotypes, and evolves in relation to sociality (flocking vs. territorial) across several related finch species. Combined, these findings for the VTA suggest that divergent social phenotypes may arise due to the differential assignment of "incentive value" to conspecific stimuli. TH-ir neurons of the CG (a population of unknown function in mammals) exhibit properties that are even more selectively and tightly coupled to the expression of courtship phenotypes (and appetitive courtship singing), both in terms of TH-ir cell number, which correlates significantly with constitutive levels of courtship motivation, and with TH-Fos colocalization, which increases in direct proportion to the phasic expression of song. We propose that these neurons may be core components of social communication circuits across diverse vertebrate taxa.

Sensorimotor function is modulated by the serotonin receptor 1d, a novel marker for gamma motor neurons

PubMed Central

Enjin, Anders; Leão, Katarina E.; Mikulovic, Sanja; Le Merre, Pierre; Tourtellotte, Warren G.; Kullander, Klas

2012-01-01

Gamma motor neurons (MNs), the efferent component of the fusimotor system, regulate muscle spindle sensitivity. Muscle spindle sensory feedback is required for proprioception that includes sensing the relative position of neighboring body parts and appropriately adjust the employed strength in a movement. The lack of a single and specific genetic marker has long hampered functional and developmental studies of gamma MNs. Here we show that the serotonin receptor 1d (5-ht1d) is specifically expressed by gamma MNs and proprioceptive sensory neurons. Using mice expressing GFP driven by the 5-ht1d promotor, we performed whole-cell patch-clamp recordings of 5-ht1d∷GFP+ and 5-ht1d∷GFP− motor neurons from young mice. Hierarchal clustering analysis revealed that gamma MNs have distinct electrophysiological properties intermediate to fast-like and slow-like alpha MNs. Moreover, mice lacking 5-ht1d displayed lower monosynaptic reflex amplitudes suggesting a reduced response to sensory stimulation in motor neurons. Interestingly, adult 5-ht1d knockout mice also displayed improved coordination skills on a beam-walking task, implying that reduced activation of MNs by Ia afferents during provoked movement tasks could reduce undesired exaggerated muscle output. In summary, we show that 5-ht1d is a novel marker for gamma MNs and that the 5-ht1d receptor is important for the ability of proprioceptive circuits to receive and relay accurate sensory information in developing and mature spinal cord motor circuits. PMID:22273508

Activity propagation in an avian basal ganglia-thalamo-cortical circuit essential for vocal learning

PubMed Central

Kojima, Satoshi; Doupe, Allison J.

2009-01-01

In mammalian basal ganglia-thalamo-cortical circuits, GABAergic pallidal neurons are thought to ‘gate’ or modulate excitation in thalamus with their strong inhibitory inputs, and thus signal to cortex by pausing and permitting thalamic neurons to fire in response to excitatory drive. In contrast, in a homologous circuit specialized for vocal learning in songbirds, evidence suggests that pallidal neurons signal by eliciting postinhibitory rebound spikes in thalamus, which could occur even without any excitatory drive to thalamic neurons. To test whether songbird pallidal neurons can also communicate with thalamus by gating excitatory drive, as well as by postinhibitory rebound, we examined the activity of thalamic relay neurons in response to acute inactivation of the basal ganglia structure Area X; Area X contains the pallidal neurons that project to thalamus. Although inactivation of Area X should eliminate rebound-mediated spiking in thalamus, this manipulation tonically increases the firing rate of thalamic relay neurons, providing evidence that songbird pallidal neurons can gate tonic thalamic excitatory drive. We also found that the increased thalamic activity was fed forward to its target in the avian equivalent of cortex, which includes neurons that project to the vocal premotor area. These data raise the possibility that basal ganglia circuits can signal to cortex through thalamus both by generating postinhibitory rebound and by gating excitatory drive, and may switch between these modes depending on the statistics of pallidal firing. Moreover, these findings provide insight into the strikingly different disruptive effects of basal ganglia and ‘cortical’ lesions on songbird vocal learning. PMID:19369547

Network architectures and circuit function: testing alternative hypotheses in multifunctional networks.

PubMed

Leonard, J L

2000-05-01

Understanding how species-typical movement patterns are organized in the nervous system is a central question in neurobiology. The current explanations involve 'alphabet' models in which an individual neuron may participate in the circuit for several behaviors but each behavior is specified by a specific neural circuit. However, not all of the well-studied model systems fit the 'alphabet' model. The 'equation' model provides an alternative possibility, whereby a system of parallel motor neurons, each with a unique (but overlapping) field of innervation, can account for the production of stereotyped behavior patterns by variable circuits. That is, it is possible for such patterns to arise as emergent properties of a generalized neural network in the absence of feedback, a simple version of a 'self-organizing' behavioral system. Comparison of systems of identified neurons suggest that the 'alphabet' model may account for most observations where CPGs act to organize motor patterns. Other well-known model systems, involving architectures corresponding to feed-forward neural networks with a hidden layer, may organize patterned behavior in a manner consistent with the 'equation' model. Such architectures are found in the Mauthner and reticulospinal circuits, 'escape' locomotion in cockroaches, CNS control of Aplysia gill, and may also be important in the coordination of sensory information and motor systems in insect mushroom bodies and the vertebrate hippocampus. The hidden layer of such networks may serve as an 'internal representation' of the behavioral state and/or body position of the animal, allowing the animal to fine-tune oriented, or particularly context-sensitive, movements to the prevalent conditions. Experiments designed to distinguish between the two models in cases where they make mutually exclusive predictions provide an opportunity to elucidate the neural mechanisms by which behavior is organized in vivo and in vitro. Copyright 2000 S. Karger AG, Basel

Cell-Specific Cholinergic Modulation of Excitability of Layer 5B Principal Neurons in Mouse Auditory Cortex

PubMed Central

Joshi, Ankur; Kalappa, Bopanna I.; Anderson, Charles T.

2016-01-01

The neuromodulator acetylcholine (ACh) is crucial for several cognitive functions, such as perception, attention, and learning and memory. Whereas, in most cases, the cellular circuits or the specific neurons via which ACh exerts its cognitive effects remain unknown, it is known that auditory cortex (AC) neurons projecting from layer 5B (L5B) to the inferior colliculus, corticocollicular neurons, are required for cholinergic-mediated relearning of sound localization after occlusion of one ear. Therefore, elucidation of the effects of ACh on the excitability of corticocollicular neurons will bridge the cell-specific and cognitive properties of ACh. Because AC L5B contains another class of neurons that project to the contralateral cortex, corticocallosal neurons, to identify the cell-specific mechanisms that enable corticocollicular neurons to participate in sound localization relearning, we investigated the effects of ACh release on both L5B corticocallosal and corticocollicular neurons. Using in vitro electrophysiology and optogenetics in mouse brain slices, we found that ACh generated nicotinic ACh receptor (nAChR)-mediated depolarizing potentials and muscarinic ACh receptor (mAChR)-mediated hyperpolarizing potentials in AC L5B corticocallosal neurons. In corticocollicular neurons, ACh release also generated nAChR-mediated depolarizing potentials. However, in contrast to the mAChR-mediated hyperpolarizing potentials in corticocallosal neurons, ACh generated prolonged mAChR-mediated depolarizing potentials in corticocollicular neurons. These prolonged depolarizing potentials generated persistent firing in corticocollicular neurons, whereas corticocallosal neurons lacking mAChR-mediated depolarizing potentials did not show persistent firing. We propose that ACh-mediated persistent firing in corticocollicular neurons may represent a critical mechanism required for learning-induced plasticity in AC. SIGNIFICANCE STATEMENT Acetylcholine (ACh) is crucial for cognitive functions. Whereas in most cases the cellular circuits or the specific neurons via which ACh exerts its cognitive effects remain unknown, it is known that auditory cortex (AC) corticocollicular neurons projecting from layer 5B to the inferior colliculus are required for cholinergic-mediated relearning of sound localization after occlusion of one ear. Therefore, elucidation of the effects of ACh on the excitability of corticocollicular neurons will bridge the cell-specific and cognitive properties of ACh. Our results suggest that cell-specific ACh-mediated persistent firing in corticocollicular neurons may represent a critical mechanism required for learning-induced plasticity in AC. Moreover, our results provide synaptic mechanisms via which ACh may mediate its effects on AC receptive fields. PMID:27511019

Design and Application of a Circuit for Measuring Frequency and Duty Cycle of Stimulated Bioelectrical Signal

NASA Astrophysics Data System (ADS)

Tang, Li-Ming; Chang, Ben-Kang; Liu, Tie-Bing; Wu, Min; Ling, Gang

2002-12-01

To design a new type of circuit for measuring frequency & duty cycle of stimulated bioelectrical signal for the project of 'the map of neuron-threshold in human brain and its clinical application'. This circuit was designed according to the character of stimulated bioelectrical signals. It was tested and improved and then used in the neuron -threshold stimulator. The circuit was found to be very accurate for measuring frequency and the error for measuring duty cycle was below 0.2%. This circuit is well-designed, simple, easy to use, and can be applied in many systems.

Electrophysiological Recordings from Lobula Plate Tangential Cells in Drosophila.

PubMed

Mauss, Alex S; Borst, Alexander

2016-01-01

Drosophila has emerged as an important model organism for the study of the neural basis of behavior. Its main asset is the experimental accessibility of identified neurons by genetic manipulation and physiological recordings. Drosophila therefore offers the opportunity to reach an integrative understanding of the development and neural underpinnings of behavior at all processing stages, from sensing to motor control, in a single species. Here, we will provide an account of the procedures involved in recording the electrical potential of individual neurons in the visual system of adult Drosophila using the whole-cell patch-clamp method. To this end, animals are fixed to a holder and mounted below a recording chamber. The head capsule is cut open and the glial sheath covering the brain is ruptured by a combination of shearing and enzymatic digest. Neuronal somata are thus exposed and targeted by low-resistance patch electrodes. After formation of a high resistance seal, electrical access to the cell is gained by small current pulses and suction. Stable recordings of large neurons are feasible for >1 h and can be combined with controlled visual stimulation as well as genetic and pharmacological manipulation of upstream circuit elements to infer circuit function in great detail.

Caveolin1 Identifies a Specific Subpopulation of Cerebral Cortex Callosal Projection Neurons (CPN) Including Dual Projecting Cortical Callosal/Frontal Projection Neurons (CPN/FPN)

PubMed Central

2018-01-01

Abstract The neocortex is composed of many distinct subtypes of neurons that must form precise subtype-specific connections to enable the cortex to perform complex functions. Callosal projection neurons (CPN) are the broad population of commissural neurons that connect the cerebral hemispheres via the corpus callosum (CC). Currently, how the remarkable diversity of CPN subtypes and connectivity is specified, and how they differentiate to form highly precise and specific circuits, are largely unknown. We identify in mouse that the lipid-bound scaffolding domain protein Caveolin 1 (CAV1) is specifically expressed by a unique subpopulation of Layer V CPN that maintain dual ipsilateral frontal projections to premotor cortex. CAV1 is expressed by over 80% of these dual projecting callosal/frontal projection neurons (CPN/FPN), with expression peaking early postnatally as axonal and dendritic targets are being reached and refined. CAV1 is localized to the soma and dendrites of CPN/FPN, a unique population of neurons that shares information both between hemispheres and with premotor cortex, suggesting function during postmitotic development and refinement of these neurons, rather than in their specification. Consistent with this, we find that Cav1 function is not necessary for the early specification of CPN/FPN, or for projecting to their dual axonal targets. CPN subtype-specific expression of Cav1 identifies and characterizes a first molecular component that distinguishes this functionally unique projection neuron population, a population that expands in primates, and is prototypical of additional dual and higher-order projection neuron subtypes. PMID:29379878

Sensory optimization by stochastic tuning.

PubMed

Jurica, Peter; Gepshtein, Sergei; Tyukin, Ivan; van Leeuwen, Cees

2013-10-01

Individually, visual neurons are each selective for several aspects of stimulation, such as stimulus location, frequency content, and speed. Collectively, the neurons implement the visual system's preferential sensitivity to some stimuli over others, manifested in behavioral sensitivity functions. We ask how the individual neurons are coordinated to optimize visual sensitivity. We model synaptic plasticity in a generic neural circuit and find that stochastic changes in strengths of synaptic connections entail fluctuations in parameters of neural receptive fields. The fluctuations correlate with uncertainty of sensory measurement in individual neurons: The higher the uncertainty the larger the amplitude of fluctuation. We show that this simple relationship is sufficient for the stochastic fluctuations to steer sensitivities of neurons toward a characteristic distribution, from which follows a sensitivity function observed in human psychophysics and which is predicted by a theory of optimal allocation of receptive fields. The optimal allocation arises in our simulations without supervision or feedback about system performance and independently of coupling between neurons, making the system highly adaptive and sensitive to prevailing stimulation. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Imprinting and recalling cortical ensembles.

PubMed

Carrillo-Reid, Luis; Yang, Weijian; Bando, Yuki; Peterka, Darcy S; Yuste, Rafael

2016-08-12

Neuronal ensembles are coactive groups of neurons that may represent building blocks of cortical circuits. These ensembles could be formed by Hebbian plasticity, whereby synapses between coactive neurons are strengthened. Here we report that repetitive activation with two-photon optogenetics of neuronal populations from ensembles in the visual cortex of awake mice builds neuronal ensembles that recur spontaneously after being imprinted and do not disrupt preexisting ones. Moreover, imprinted ensembles can be recalled by single- cell stimulation and remain coactive on consecutive days. Our results demonstrate the persistent reconfiguration of cortical circuits by two-photon optogenetics into neuronal ensembles that can perform pattern completion. Copyright © 2016, American Association for the Advancement of Science.

A Simple Picaxe Microcontroller Pulse Source for Juxtacellular Neuronal Labelling †

PubMed Central

Verberne, Anthony J. M.

2016-01-01

Juxtacellular neuronal labelling is a method which allows neurophysiologists to fill physiologically-identified neurons with small positively-charged marker molecules. Labelled neurons are identified by histochemical processing of brain sections along with immunohistochemical identification of neuropeptides, neurotransmitters, neurotransmitter transporters or biosynthetic enzymes. A microcontroller-based pulser circuit and associated BASIC software script is described for incorporation into the design of a commercially-available intracellular electrometer for use in juxtacellular neuronal labelling. Printed circuit board construction has been used for reliability and reproducibility. The current design obviates the need for a separate digital pulse source and simplifies the juxtacellular neuronal labelling procedure. PMID:28952589

Circadian Integration of Glutamatergic Signals by Little SAAS in Novel Suprachiasmatic Circuits

PubMed Central

Atkins, Norman; Mitchell, Jennifer W.; Romanova, Elena V.; Morgan, Daniel J.; Cominski, Tara P.; Ecker, Jennifer L.; Pintar, John E.; Sweedler, Jonathan V.; Gillette, Martha U.

2010-01-01

Background Neuropeptides are critical integrative elements within the central circadian clock in the suprachiasmatic nucleus (SCN), where they mediate both cell-to-cell synchronization and phase adjustments that cause light entrainment. Forward peptidomics identified little SAAS, derived from the proSAAS prohormone, among novel SCN peptides, but its role in the SCN is poorly understood. Methodology/Principal Findings Little SAAS localization and co-expression with established SCN neuropeptides were evaluated by immunohistochemistry using highly specific antisera and stereological analysis. Functional context was assessed relative to c-FOS induction in light-stimulated animals and on neuronal circadian rhythms in glutamate-stimulated brain slices. We found that little SAAS-expressing neurons comprise the third most abundant neuropeptidergic class (16.4%) with unusual functional circuit contexts. Little SAAS is localized within the densely retinorecipient central SCN of both rat and mouse, but not the retinohypothalamic tract (RHT). Some little SAAS colocalizes with vasoactive intestinal polypeptide (VIP) or gastrin-releasing peptide (GRP), known mediators of light signals, but not arginine vasopressin (AVP). Nearly 50% of little SAAS neurons express c-FOS in response to light exposure in early night. Blockade of signals that relay light information, via NMDA receptors or VIP- and GRP-cognate receptors, has no effect on phase delays of circadian rhythms induced by little SAAS. Conclusions/Significance Little SAAS relays signals downstream of light/glutamatergic signaling from eye to SCN, and independent of VIP and GRP action. These findings suggest that little SAAS forms a third SCN neuropeptidergic system, processing light information and activating phase-shifts within novel circuits of the central circadian clock. PMID:20830308

Circadian integration of glutamatergic signals by little SAAS in novel suprachiasmatic circuits.

PubMed

Atkins, Norman; Mitchell, Jennifer W; Romanova, Elena V; Morgan, Daniel J; Cominski, Tara P; Ecker, Jennifer L; Pintar, John E; Sweedler, Jonathan V; Gillette, Martha U

2010-09-07

Neuropeptides are critical integrative elements within the central circadian clock in the suprachiasmatic nucleus (SCN), where they mediate both cell-to-cell synchronization and phase adjustments that cause light entrainment. Forward peptidomics identified little SAAS, derived from the proSAAS prohormone, among novel SCN peptides, but its role in the SCN is poorly understood. Little SAAS localization and co-expression with established SCN neuropeptides were evaluated by immunohistochemistry using highly specific antisera and stereological analysis. Functional context was assessed relative to c-FOS induction in light-stimulated animals and on neuronal circadian rhythms in glutamate-stimulated brain slices. We found that little SAAS-expressing neurons comprise the third most abundant neuropeptidergic class (16.4%) with unusual functional circuit contexts. Little SAAS is localized within the densely retinorecipient central SCN of both rat and mouse, but not the retinohypothalamic tract (RHT). Some little SAAS colocalizes with vasoactive intestinal polypeptide (VIP) or gastrin-releasing peptide (GRP), known mediators of light signals, but not arginine vasopressin (AVP). Nearly 50% of little SAAS neurons express c-FOS in response to light exposure in early night. Blockade of signals that relay light information, via NMDA receptors or VIP- and GRP-cognate receptors, has no effect on phase delays of circadian rhythms induced by little SAAS. Little SAAS relays signals downstream of light/glutamatergic signaling from eye to SCN, and independent of VIP and GRP action. These findings suggest that little SAAS forms a third SCN neuropeptidergic system, processing light information and activating phase-shifts within novel circuits of the central circadian clock.

A Circuit for Motor Cortical Modulation of Auditory Cortical Activity

PubMed Central

Nelson, Anders; Schneider, David M.; Takatoh, Jun; Sakurai, Katsuyasu; Wang, Fan

2013-01-01

Normal hearing depends on the ability to distinguish self-generated sounds from other sounds, and this ability is thought to involve neural circuits that convey copies of motor command signals to various levels of the auditory system. Although such interactions at the cortical level are believed to facilitate auditory comprehension during movements and drive auditory hallucinations in pathological states, the synaptic organization and function of circuitry linking the motor and auditory cortices remain unclear. Here we describe experiments in the mouse that characterize circuitry well suited to transmit motor-related signals to the auditory cortex. Using retrograde viral tracing, we established that neurons in superficial and deep layers of the medial agranular motor cortex (M2) project directly to the auditory cortex and that the axons of some of these deep-layer cells also target brainstem motor regions. Using in vitro whole-cell physiology, optogenetics, and pharmacology, we determined that M2 axons make excitatory synapses in the auditory cortex but exert a primarily suppressive effect on auditory cortical neuron activity mediated in part by feedforward inhibition involving parvalbumin-positive interneurons. Using in vivo intracellular physiology, optogenetics, and sound playback, we also found that directly activating M2 axon terminals in the auditory cortex suppresses spontaneous and stimulus-evoked synaptic activity in auditory cortical neurons and that this effect depends on the relative timing of motor cortical activity and auditory stimulation. These experiments delineate the structural and functional properties of a corticocortical circuit that could enable movement-related suppression of auditory cortical activity. PMID:24005287

Descending projections from the basal forebrain to the orexin neurons in mice.

PubMed

Agostinelli, Lindsay J; Ferrari, Loris L; Mahoney, Carrie E; Mochizuki, Takatoshi; Lowell, Bradford B; Arrigoni, Elda; Scammell, Thomas E

2017-05-01

The orexin (hypocretin) neurons play an essential role in promoting arousal, and loss of the orexin neurons results in narcolepsy, a condition characterized by chronic sleepiness and cataplexy. The orexin neurons excite wake-promoting neurons in the basal forebrain (BF), and a reciprocal projection from the BF back to the orexin neurons may help promote arousal and motivation. The BF contains at least three different cell types (cholinergic, glutamatergic, and γ-aminobutyric acid (GABA)ergic neurons) across its different regions (medial septum, diagonal band, magnocellular preoptic area, and substantia innominata). Given the neurochemical and anatomical heterogeneity of the BF, we mapped the pattern of BF projections to the orexin neurons across multiple BF regions and neuronal types. We performed conditional anterograde tracing using mice that express Cre recombinase only in neurons producing acetylcholine, glutamate, or GABA. We found that the orexin neurons are heavily apposed by axon terminals of glutamatergic and GABAergic neurons of the substantia innominata (SI) and magnocellular preoptic area, but there was no innervation by the cholinergic neurons. Channelrhodopsin-assisted circuit mapping (CRACM) demonstrated that glutamatergic SI neurons frequently form functional synapses with the orexin neurons, but, surprisingly, functional synapses from SI GABAergic neurons were rare. Considering their strong reciprocal connections, BF and orexin neurons likely work in concert to promote arousal, motivation, and other behaviors. J. Comp. Neurol. 525:1668-1684, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Functional Reintegration of Sensory Neurons and Transitional Dendritic Reduction of Mitral/Tufted Cells during Injury-Induced Recovery of the Larval Xenopus Olfactory Circuit.

PubMed

Hawkins, Sara J; Weiss, Lukas; Offner, Thomas; Dittrich, Katarina; Hassenklöver, Thomas; Manzini, Ivan

2017-01-01

Understanding the mechanisms involved in maintaining lifelong neurogenesis has a clear biological and clinical interest. In the present study, we performed olfactory nerve transection on larval Xenopus to induce severe damage to the olfactory circuitry. We surveyed the timing of the degeneration, subsequent rewiring and functional regeneration of the olfactory system following injury. A range of structural labeling techniques and functional calcium imaging were performed on both tissue slices and whole brain preparations. Cell death of olfactory receptor neurons and proliferation of stem cells in the olfactory epithelium were immediately increased following lesion. New olfactory receptor neurons repopulated the olfactory epithelium and once again showed functional responses to natural odorants within 1 week after transection. Reinnervation of the olfactory bulb (OB) by newly formed olfactory receptor neuron axons also began at this time. Additionally, we observed a temporary increase in cell death in the OB and a subsequent loss in OB volume. Mitral/tufted cells, the second order neurons of the olfactory system, largely survived, but transiently lost dendritic tuft complexity. The first odorant-induced responses in the OB were observed 3 weeks after nerve transection and the olfactory network showed signs of major recovery, both structurally and functionally, after 7 weeks.

Functional Reintegration of Sensory Neurons and Transitional Dendritic Reduction of Mitral/Tufted Cells during Injury-Induced Recovery of the Larval Xenopus Olfactory Circuit

PubMed Central

Hawkins, Sara J.; Weiss, Lukas; Offner, Thomas; Dittrich, Katarina; Hassenklöver, Thomas; Manzini, Ivan

2017-01-01

Understanding the mechanisms involved in maintaining lifelong neurogenesis has a clear biological and clinical interest. In the present study, we performed olfactory nerve transection on larval Xenopus to induce severe damage to the olfactory circuitry. We surveyed the timing of the degeneration, subsequent rewiring and functional regeneration of the olfactory system following injury. A range of structural labeling techniques and functional calcium imaging were performed on both tissue slices and whole brain preparations. Cell death of olfactory receptor neurons and proliferation of stem cells in the olfactory epithelium were immediately increased following lesion. New olfactory receptor neurons repopulated the olfactory epithelium and once again showed functional responses to natural odorants within 1 week after transection. Reinnervation of the olfactory bulb (OB) by newly formed olfactory receptor neuron axons also began at this time. Additionally, we observed a temporary increase in cell death in the OB and a subsequent loss in OB volume. Mitral/tufted cells, the second order neurons of the olfactory system, largely survived, but transiently lost dendritic tuft complexity. The first odorant-induced responses in the OB were observed 3 weeks after nerve transection and the olfactory network showed signs of major recovery, both structurally and functionally, after 7 weeks. PMID:29234276

Convergence of circuit dysfunction in ASD: a common bridge between diverse genetic and environmental risk factors and common clinical electrophysiology.

PubMed

Port, Russell G; Gandal, Michael J; Roberts, Timothy P L; Siegel, Steven J; Carlson, Gregory C

2014-01-01

Most recent estimates indicate that 1 in 68 children are affected by an autism spectrum disorder (ASD). Though decades of research have uncovered much about these disorders, the pathological mechanism remains unknown. Hampering efforts is the seeming inability to integrate findings over the micro to macro scales of study, from changes in molecular, synaptic and cellular function to large-scale brain dysfunction impacting sensory, communicative, motor and cognitive activity. In this review, we describe how studies focusing on neuronal circuit function provide unique context for identifying common neurobiological disease mechanisms of ASD. We discuss how recent EEG and MEG studies in subjects with ASD have repeatedly shown alterations in ensemble population recordings (both in simple evoked related potential latencies and specific frequency subcomponents). Because these disease-associated electrophysiological abnormalities have been recapitulated in rodent models, studying circuit differences in these models may provide access to abnormal circuit function found in ASD. We then identify emerging in vivo and ex vivo techniques, focusing on how these assays can characterize circuit level dysfunction and determine if these abnormalities underlie abnormal clinical electrophysiology. Such circuit level study in animal models may help us understand how diverse genetic and environmental risks can produce a common set of EEG, MEG and anatomical abnormalities found in ASD.

FMRFamide produces biphasic modulation of the LFS motor neurons in the neural circuit of the siphon withdrawal reflex of Aplysia by activating Na+ and K+ currents.

PubMed

Belkin, K J; Abrams, T W

1993-12-01

The molluscan neuropeptide FMRFamide has an inhibitory effect on transmitter release from the presynaptic sensory neurons in the neural circuit for the siphon withdrawal reflex. We have explored whether FMRFamide also acts postsynaptically in motor neurons in this circuit, focusing on the LFS motor neurons. FMRFamide typically produces a biphasic response in LFS neurons: a fast excitatory response followed by a prolonged inhibitory response. We have analyzed these postsynaptic actions and compared them with the mechanism of FMRFamide's inhibition of the presynaptic sensory neurons. The transient excitatory effect of FMRFamide, which desensitizes rapidly, is due to activation of a TTX-insensitive, Na(+)-dependent inward current. The late hyperpolarizing phase of the FMRFamide response results from activation of at least two K+ currents. One component of the hyperpolarizing response is active at rest and at more hyperpolarized membrane potentials, and is blocked by 5 mM 4-aminopyridine, suggesting that it differs from the previously described FMRFamide-modulated K+ currents in the presynaptic sensory neurons. In addition, FMRFamide increases a 4-aminopyridine-insensitive K+ current. Presynaptically, FMRFamide increases K+ conductance, acting via release of arachidonic acid. In the LFS motor neurons, application of arachidonic acid mimicked the prolonged, hyperpolarizing phase of the FMRFamide response; 4-bromophenacyl bromide, an inhibitor of phospholipase A2, selectively blocked this component of the FMRFamide response. Thus, FMRFamide may act in parallel pre- and post-synaptically to inhibit the output of the siphon withdrawal reflex circuit, producing this inhibitory effect via the same second messenger in the sensory neurons and motor neurons, though a number of the K+ currents modulated in these two types of neurons are different.

Temporal integration and 1/f power scaling in a circuit model of cerebellar interneurons.

PubMed

Maex, Reinoud; Gutkin, Boris

2017-07-01

Inhibitory interneurons interconnected via electrical and chemical (GABA A receptor) synapses form extensive circuits in several brain regions. They are thought to be involved in timing and synchronization through fast feedforward control of principal neurons. Theoretical studies have shown, however, that whereas self-inhibition does indeed reduce response duration, lateral inhibition, in contrast, may generate slow response components through a process of gradual disinhibition. Here we simulated a circuit of interneurons (stellate and basket cells) of the molecular layer of the cerebellar cortex and observed circuit time constants that could rise, depending on parameter values, to >1 s. The integration time scaled both with the strength of inhibition, vanishing completely when inhibition was blocked, and with the average connection distance, which determined the balance between lateral and self-inhibition. Electrical synapses could further enhance the integration time by limiting heterogeneity among the interneurons and by introducing a slow capacitive current. The model can explain several observations, such as the slow time course of OFF-beam inhibition, the phase lag of interneurons during vestibular rotation, or the phase lead of Purkinje cells. Interestingly, the interneuron spike trains displayed power that scaled approximately as 1/ f at low frequencies. In conclusion, stellate and basket cells in cerebellar cortex, and interneuron circuits in general, may not only provide fast inhibition to principal cells but also act as temporal integrators that build a very short-term memory. NEW & NOTEWORTHY The most common function attributed to inhibitory interneurons is feedforward control of principal neurons. In many brain regions, however, the interneurons are densely interconnected via both chemical and electrical synapses but the function of this coupling is largely unknown. Based on large-scale simulations of an interneuron circuit of cerebellar cortex, we propose that this coupling enhances the integration time constant, and hence the memory trace, of the circuit. Copyright © 2017 the American Physiological Society.

Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate

PubMed Central

Fudge, Julie L; Kelly, Emily A; Pal, Ria; Bedont, Joseph L; Park, Lydia; Ho, Brian

2017-01-01

The central extended amygdala (CEA) has been conceptualized as a ‘macrosystem’ that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the ‘limbic-associative’ striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning. PMID:28220796

Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate.

PubMed

Fudge, Julie L; Kelly, Emily A; Pal, Ria; Bedont, Joseph L; Park, Lydia; Ho, Brian

2017-07-01

The central extended amygdala (CEA) has been conceptualized as a 'macrosystem' that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the 'limbic-associative' striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning.

Caenorhabditis elegans Male Copulation Circuitry Incorporates Sex-Shared Defecation Components To Promote Intromission and Sperm Transfer

PubMed Central

LeBoeuf, Brigitte; Garcia, L. Rene

2016-01-01

Sexual dimorphism can be achieved using a variety of mechanisms, including sex-specific circuits and sex-specific function of shared circuits, though how these work together to produce sexually dimorphic behaviors requires further investigation. Here, we explore how components of the sex-shared defecation circuitry are incorporated into the sex-specific male mating circuitry in Caenorhabditis elegans to produce successful copulation. Using behavioral studies, calcium imaging, and genetic manipulation, we show that aspects of the defecation system are coopted by the male copulatory circuitry to facilitate intromission and ejaculation. Similar to hermaphrodites, male defecation is initiated by an intestinal calcium wave, but circuit activity is coordinated differently during mating. In hermaphrodites, the tail neuron DVB promotes expulsion of gut contents through the release of the neurotransmitter GABA onto the anal depressor muscle. However, in the male, both neuron and muscle take on modified functions to promote successful copulation. Males require calcium-dependent activator protein for secretion (CAPS)/unc-31, a dense core vesicle exocytosis activator protein, in the DVB to regulate copulatory spicule insertion, while the anal depressor is remodeled to promote release of sperm into the hermaphrodite. This work shows how sex-shared circuitry is modified in multiple ways to contribute to sex-specific mating. PMID:28031243

A two-layered diffusion model traces the dynamics of information processing in the valuation-and-choice circuit of decision making.

PubMed

Piu, Pietro; Fargnoli, Francesco; Innocenti, Alessandro; Rufa, Alessandra

2014-01-01

A circuit of evaluation and selection of the alternatives is considered a reliable model in neurobiology. The prominent contributions of the literature to this topic are reported. In this study, valuation and choice of a decisional process during Two-Alternative Forced-Choice (TAFC) task are represented as a two-layered network of computational cells, where information accrual and processing progress in nonlinear diffusion dynamics. The evolution of the response-to-stimulus map is thus modeled by two linked diffusive modules (2LDM) representing the neuronal populations involved in the valuation-and-decision circuit of decision making. Diffusion models are naturally appropriate for describing accumulation of evidence over the time. This allows the computation of the response times (RTs) in valuation and choice, under the hypothesis of ex-Wald distribution. A nonlinear transfer function integrates the activities of the two layers. The input-output map based on the infomax principle makes the 2LDM consistent with the reinforcement learning approach. Results from simulated likelihood time series indicate that 2LDM may account for the activity-dependent modulatory component of effective connectivity between the neuronal populations. Rhythmic fluctuations of the estimate gain functions in the delta-beta bands also support the compatibility of 2LDM with the neurobiology of DM.

A Genetic RNAi Screen for IP3/Ca2+ Coupled GPCRs in Drosophila Identifies the PdfR as a Regulator of Insect Flight

PubMed Central

Agrawal, Tarjani; Sadaf, Sufia; Hasan, Gaiti

2013-01-01

Insect flight is regulated by various sensory inputs and neuromodulatory circuits which function in synchrony to control and fine-tune the final behavioral outcome. The cellular and molecular bases of flight neuromodulatory circuits are not well defined. In Drosophila melanogaster, it is known that neuronal IP3 receptor mediated Ca2+ signaling and store-operated Ca2+ entry (SOCE) are required for air-puff stimulated adult flight. However, G-protein coupled receptors (GPCRs) that activate intracellular Ca2+ signaling in the context of flight are unknown in Drosophila. We performed a genetic RNAi screen to identify GPCRs that regulate flight by activating the IP3 receptor. Among the 108 GPCRs screened, we discovered 5 IP3/Ca2+ linked GPCRs that are necessary for maintenance of air-puff stimulated flight. Analysis of their temporal requirement established that while some GPCRs are required only during flight circuit development, others are required both in pupal development as well as during adult flight. Interestingly, our study identified the Pigment Dispersing Factor Receptor (PdfR) as a regulator of flight circuit development and as a modulator of acute flight. From the analysis of PdfR expressing neurons relevant for flight and its well-defined roles in other behavioral paradigms, we propose that PdfR signaling functions systemically to integrate multiple sensory inputs and modulate downstream motor behavior. PMID:24098151

Deep Brain Stimulation

PubMed Central

Lyketsos, Constantine G.; Pendergrass, Jo Cara; Lozano, Andres M.

2012-01-01

Recent studies have identified an association between memory deficits and defects of the integrated neuronal cortical areas known collectively as the default mode network. It is conceivable that the amyloid deposition or other molecular abnormalities seen in patients with Alzheimer’s disease may interfere with this network and disrupt neuronal circuits beyond the localized brain areas. Therefore, Alzheimer’s disease may be both a degenerative disease and a broader system-level disorder affecting integrated neuronal pathways involved in memory. In this paper, we describe the rationale and provide some evidence to support the study of deep brain stimulation of the hippocampal fornix as a novel treatment to improve neuronal circuitry within these integrated networks and thereby sustain memory function in early Alzheimer’s disease. PMID:23346514

Optoelectronic Integrated Circuits For Neural Networks

NASA Technical Reports Server (NTRS)

Psaltis, D.; Katz, J.; Kim, Jae-Hoon; Lin, S. H.; Nouhi, A.

1990-01-01

Many threshold devices placed on single substrate. Integrated circuits containing optoelectronic threshold elements developed for use as planar arrays of artificial neurons in research on neural-network computers. Mounted with volume holograms recorded in photorefractive crystals serving as dense arrays of variable interconnections between neurons.

Imprinting and Recalling Cortical Ensembles

PubMed Central

Carrillo-Reid, Luis; Yang, Weijian; Bando, Yuki; Peterka, Darcy S.; Yuste, Rafael

2017-01-01

Neuronal ensembles are coactive groups of neurons that may represent emergent building blocks of neural circuits. They could be formed by Hebbian plasticity, whereby synapses between coactive neurons are strengthened. Here we report that repetitive activation with two-photon optogenetics of neuronal populations in visual cortex of awake mice generates artificially induced ensembles which recur spontaneously after being imprinted and do not disrupt preexistent ones. Moreover, imprinted ensembles can be recalled by single cell stimulation and remain coactive on consecutive days. Our results demonstrate the persistent reconfiguration of cortical circuits by two-photon optogenetics into neuronal ensembles that can perform pattern completion. PMID:27516599

The central amygdala circuits in fear regulation

NASA Astrophysics Data System (ADS)

Li, Bo

The amygdala is essential for fear learning and expression. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear conditioning. However, how the CeA contributes to the learning and expression of fear remains unclear. Our recent studies in mice indicate that fear conditioning induces robust plasticity of excitatory synapses onto inhibitory neurons in the lateral subdivision of CeA (CeL). In particular, this plasticity is cell-type specific and is required for the formation of fear memory. In addition, sensory cues that predict threat can cause activation of the somatostatin-positive CeL neurons, which is sufficient to drive freezing behavior. Here I will report our recent findings regarding the circuit and cellular mechanisms underlying CeL function in fear processing.

A receptor and neuron that activate a circuit limiting sucrose consumption.

PubMed

Joseph, Ryan M; Sun, Jennifer S; Tam, Edric; Carlson, John R

2017-03-23

The neural control of sugar consumption is critical for normal metabolism. In contrast to sugar-sensing taste neurons that promote consumption, we identify a taste neuron that limits sucrose consumption in Drosophila . Silencing of the neuron increases sucrose feeding; optogenetic activation decreases it. The feeding inhibition depends on the IR60b receptor, as shown by behavioral analysis and Ca 2+ imaging of an IR60b mutant. The IR60b phenotype shows a high degree of chemical specificity when tested with a broad panel of tastants. An automated analysis of feeding behavior in freely moving flies shows that IR60b limits the duration of individual feeding bouts. This receptor and neuron provide the molecular and cellular underpinnings of a new element in the circuit logic of feeding regulation. We propose a dynamic model in which sucrose acts via IR60b to activate a circuit that inhibits feeding and prevents overconsumption.

Loss of Action via Neurotensin-Leptin Receptor Neurons Disrupts Leptin and Ghrelin-Mediated Control of Energy Balance.

PubMed

Brown, Juliette A; Bugescu, Raluca; Mayer, Thomas A; Gata-Garcia, Adriana; Kurt, Gizem; Woodworth, Hillary L; Leinninger, Gina M

2017-05-01

The hormones ghrelin and leptin act via the lateral hypothalamic area (LHA) to modify energy balance, but the underlying neural mechanisms remain unclear. We investigated how leptin and ghrelin engage LHA neurons to modify energy balance behaviors and whether there is any crosstalk between leptin and ghrelin-responsive circuits. We demonstrate that ghrelin activates LHA neurons expressing hypocretin/orexin (OX) to increase food intake. Leptin mediates anorectic actions via separate neurons expressing the long form of the leptin receptor (LepRb), many of which coexpress the neuropeptide neurotensin (Nts); we refer to these as NtsLepRb neurons. Because NtsLepRb neurons inhibit OX neurons, we hypothesized that disruption of the NtsLepRb neuronal circuit would impair both NtsLepRb and OX neurons from responding to their respective hormonal cues, thus compromising adaptive energy balance. Indeed, mice with developmental deletion of LepRb specifically from NtsLepRb neurons exhibit blunted adaptive responses to leptin and ghrelin that discoordinate the mesolimbic dopamine system and ingestive and locomotor behaviors, leading to weight gain. Collectively, these data reveal a crucial role for LepRb in the proper formation of LHA circuits, and that NtsLepRb neurons are important neuronal hubs within the LHA for hormone-mediated control of ingestive and locomotor behaviors. Copyright © 2017 Endocrine Society.

Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping.

PubMed

Beier, Kevin T; Steinberg, Elizabeth E; DeLoach, Katherine E; Xie, Stanley; Miyamichi, Kazunari; Schwarz, Lindsay; Gao, Xiaojing J; Kremer, Eric J; Malenka, Robert C; Luo, Liqun

2015-07-30

Dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) integrate complex inputs to encode multiple signals that influence motivated behaviors via diverse projections. Here, we combine axon-initiated viral transduction with rabies-mediated trans-synaptic tracing and Cre-based cell-type-specific targeting to systematically map input-output relationships of VTA-DA neurons. We found that VTA-DA (and VTA-GABA) neurons receive excitatory, inhibitory, and modulatory input from diverse sources. VTA-DA neurons projecting to different forebrain regions exhibit specific biases in their input selection. VTA-DA neurons projecting to lateral and medial nucleus accumbens innervate largely non-overlapping striatal targets, with the latter also sending extensive extra-striatal axon collaterals. Using electrophysiology and behavior, we validated new circuits identified in our tracing studies, including a previously unappreciated top-down reinforcing circuit from anterior cortex to lateral nucleus accumbens via VTA-DA neurons. This study highlights the utility of our viral-genetic tracing strategies to elucidate the complex neural substrates that underlie motivated behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

Role of neurotrophins in the development and function of neural circuits that regulate energy homeostasis.

PubMed

Fargali, Samira; Sadahiro, Masato; Jiang, Cheng; Frick, Amy L; Indall, Tricia; Cogliani, Valeria; Welagen, Jelle; Lin, Wei-Jye; Salton, Stephen R

2012-11-01

Members of the neurotrophin family, including nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5, and other neurotrophic growth factors such as ciliary neurotrophic factor and artemin, regulate peripheral and central nervous system development and function. A subset of the neurotrophin-dependent pathways in the hypothalamus, brainstem, and spinal cord, and those that project via the sympathetic nervous system to peripheral metabolic tissues including brown and white adipose tissue, muscle and liver, regulate feeding, energy storage, and energy expenditure. We briefly review the role that neurotrophic growth factors play in energy balance, as regulators of neuronal survival and differentiation, neurogenesis, and circuit formation and function, and as inducers of critical gene products that control energy homeostasis.