@article {2480, title = {Dopamine signaling regulates predator-driven changes in egg laying behavior.}, journal = {Elife}, volume = {12}, year = {2023}, month = {2023 Jul 11}, abstract = {

Prey respond to predators by altering their behavior to optimize their own fitness and survival. Specifically, prey are known to avoid predator-occupied territories to reduce their risk of harm or injury to themselves and their progeny. We probe the interactions between and its naturally cohabiting predator to reveal the pathways driving changes in prey behavior. While prefers to lay its eggs on a bacteria food lawn, the presence of a predator inside a lawn induces to lay more eggs away from that lawn. We confirm that this change in egg laying is in response to bites from predators, rather than to predatory secretions. Moreover, predator-exposed prey continue to lay their eggs away from the dense lawn even after the predator is removed, indicating a form of learning. Next, we find that mutants in dopamine synthesis significantly reduce egg laying behavior off the lawn in both predator-free and predator-inhabited lawns, which we can rescue by transgenic complementation or supplementation with exogenous dopamine. Moreover, we find that dopamine is likely released from multiple dopaminergic neurons and requires combinations of both D1- (DOP-1) and D2-like (DOP-2 and DOP-3) dopamine receptors to alter predator-induced egg laying behavior, whereas other combinations modify baseline levels of egg laying behavior. Together, we show that dopamine signaling can alter both predator-free and predator-induced foraging strategies, suggesting a role for this pathway in defensive behaviors.

}, keywords = {Animals, Caenorhabditis elegans, Dopamine, Eggs, Receptors, Dopamine, Signal Transduction}, issn = {2050-084X}, doi = {10.7554/eLife.83957}, author = {Pribadi, Amy and Rieger, Michael A and Rosales, Kaila and Reddy, Kirthi C and Chalasani, Sreekanth H} } @article {2268, title = {Adaptive integration of self-motion and goals in posterior parietal cortex.}, journal = {Cell Rep}, volume = {38}, year = {2022}, month = {2022 Mar 08}, pages = {110504}, abstract = {

Rats readily switch between foraging and more complex navigational behaviors such as pursuit of other rats or prey. These tasks require vastly different tracking of multiple behaviorally significant variables including self-motion state. To explore whether navigational context modulates self-motion tracking, we examined self-motion tuning in posterior parietal cortex neurons during foraging versus visual target pursuit. Animals performing the pursuit task demonstrate predictive processing of target trajectories by anticipating and intercepting them. Relative to foraging, pursuit yields multiplicative gain modulation of self-motion tuning and enhances self-motion state decoding. Self-motion sensitivity in parietal cortex neurons is, on average, history dependent regardless of behavioral context, but the temporal window of self-motion integration extends during target pursuit. Finally, many self-motion-sensitive neurons conjunctively track the visual target position relative to the animal. Thus, posterior parietal cortex functions to integrate the location of navigationally relevant target stimuli into an ongoing representation of past, present, and future locomotor trajectories.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2022.110504}, author = {Alexander, Andrew S and Tung, Janet C and Chapman, G William and Conner, Allison M and Shelley, Laura E and Hasselmo, Michael E and Nitz, Douglas A} } @article {2220, title = {Differential mechanisms underlie trace and delay conditioning in Drosophila.}, journal = {Nature}, year = {2022}, month = {2022 Feb 16}, abstract = {

Two forms of associative learning-delay conditioning and trace conditioning-have been widely investigated in humans and higher-order mammals. In delay conditioning, an unconditioned stimulus (for example, an electric shock) is introduced in the final moments of a conditioned stimulus (for example, a tone), with both ending at the same time. In trace conditioning, a {\textquoteright}trace{\textquoteright} interval separates the conditioned stimulus and the unconditioned stimulus. Trace conditioning therefore relies on maintaining a neural representation of the conditioned stimulus after its termination (hence making distraction possible), to learn the conditioned stimulus-unconditioned stimulus contingency; this makes it more cognitively demanding than delay conditioning. Here, by combining virtual-reality behaviour with neurogenetic manipulations and in vivo two-photon brain imaging, we show that visual trace conditioning and delay conditioning in Drosophila mobilize R2 and R4m ring neurons in the ellipsoid body. In trace conditioning, calcium transients during the trace interval show increased oscillations and slower declines over repeated training, and both of these effects are sensitive to distractions. Dopaminergic activity accompanies signal persistence in ring neurons, and this is decreased by distractions solely during trace conditioning. Finally, dopamine D1-like and D2-like receptor signalling in ring neurons have different roles in delay and trace conditioning; dopamine D1-like receptor 1 mediates both forms of conditioning, whereas the dopamine D2-like receptor is involved exclusively in sustaining ring neuron activity during the trace interval of trace conditioning. These observations are similar to those previously reported in mammals during arousal, prefrontal activation and high-level cognitive learning.

}, issn = {1476-4687}, doi = {10.1038/s41586-022-04433-6}, author = {Grover, Dhruv and Chen, Jen-Yung and Xie, Jiayun and Li, Jinfang and Changeux, Jean-Pierre and Greenspan, Ralph J} } @article {2188, title = {Discovery of genomic loci of the human cerebral cortex using genetically informed brain atlases.}, journal = {Science}, volume = {375}, year = {2022}, month = {2022 02 04}, pages = {522-528}, abstract = {

To determine the impact of genetic variants on the brain, we used genetically informed brain atlases in genome-wide association studies of regional cortical surface area and thickness in 39,898 adults and 9136 children. We uncovered 440 genome-wide significant loci in the discovery cohort and 800 from a post hoc combined meta-analysis. Loci in adulthood were largely captured in childhood, showing signatures of negative selection, and were linked to early neurodevelopment and pathways associated with neuropsychiatric risk. Opposing gradations of decreased surface area and increased thickness were associated with common inversion polymorphisms. Inferior frontal regions, encompassing Broca{\textquoteright}s area, which is important for speech, were enriched for human-specific genomic elements. Thus, a mixed genetic landscape of conserved and human-specific features is concordant with brain hierarchy and morphogenetic gradients.

}, keywords = {Adult, Aged, Aged, 80 and over, Cerebral Cortex, Child, Chromatin, Cohort Studies, Female, Gene Ontology, Genetic Association Studies, Genetic Loci, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Mental Disorders, Middle Aged, Molecular Sequence Annotation, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid}, issn = {1095-9203}, doi = {10.1126/science.abe8457}, author = {Makowski, Carolina and van der Meer, Dennis and Dong, Weixiu and Wang, Hao and Wu, Yan and Zou, Jingjing and Liu, Cin and Rosenthal, Sara B and Hagler, Donald J and Fan, Chun Chieh and Kremen, William S and Andreassen, Ole A and Jernigan, Terry L and Dale, Anders M and Zhang, Kun and Visscher, Peter M and Yang, Jian and Chen, Chi-Hua} } @article {2288, title = {Electro-optical mechanically flexible coaxial microprobes for minimally invasive interfacing with intrinsic neural circuits.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 Jun 07}, pages = {3286}, abstract = {

Central to advancing our understanding of neural circuits is developing minimally invasive, multi-modal interfaces capable of simultaneously recording and modulating neural activity. Recent devices have focused on matching the mechanical compliance of tissue to reduce inflammatory responses. However, reductions in the size of multi-modal interfaces are needed to further improve biocompatibility and long-term recording capabilities. Here a multi-modal coaxial microprobe design with a minimally invasive footprint (8-14 {\textmu}m diameter over millimeter lengths) that enables efficient electrical and optical interrogation of neural networks is presented. In the brain, the probes allowed robust electrical measurement and optogenetic stimulation. Scalable fabrication strategies can be used with various electrical and optical materials, making the probes highly customizable to experimental requirements, including length, diameter, and mechanical properties. Given their negligible inflammatory response, these probes promise to enable a new generation of readily tunable multi-modal devices for long-term, minimally invasive interfacing with neural circuits.

}, keywords = {Brain, Optogenetics}, issn = {2041-1723}, doi = {10.1038/s41467-022-30275-x}, author = {Ward, Spencer and Riley, Conor and Carey, Erin M and Nguyen, Jenny and Esener, Sadik and Nimmerjahn, Axel and Sirbuly, Donald J} } @article {2291, title = {knockout in excitatory neurons impairs postnatal synapse maturation and increases the repressive histone modification H3K27me3.}, journal = {Elife}, volume = {11}, year = {2022}, month = {2022 May 23}, abstract = {

Two epigenetic pathways of transcriptional repression, DNA methylation and polycomb repressive complex 2 (PRC2), are known to regulate neuronal development and function. However, their respective contributions to brain maturation are unknown. We found that conditional loss of the de novo DNA methyltransferase in mouse excitatory neurons altered expression of synapse-related genes, stunted synapse maturation, and impaired working memory and social interest. At the genomic level, loss of abolished postnatal accumulation of CG and non-CG DNA methylation, leaving adult neurons with an unmethylated, fetal-like epigenomic pattern at ~222,000 genomic regions. The PRC2-associated histone modification, H3K27me3, increased at many of these sites. Our data support a dynamic interaction between two fundamental modes of epigenetic repression during postnatal maturation of excitatory neurons, which together confer robustness on neuronal regulation.

}, keywords = {Animals, Brain, Disease Models, Animal, DNA Methyltransferase 3A, Histone Code, Histones, Mice, Mice, Knockout, Neurons, Polycomb Repressive Complex 2, Synapses}, issn = {2050-084X}, doi = {10.7554/eLife.66909}, author = {Li, Junhao and Pinto-Duarte, Ant{\'o}nio and Zander, Mark and Cuoco, Michael S and Lai, Chi-Yu and Osteen, Julia and Fang, Linjing and Luo, Chongyuan and Lucero, Jacinta D and Gomez-Castanon, Rosa and Nery, Joseph R and Silva-Garcia, Isai and Pang, Yan and Sejnowski, Terrence J and Powell, Susan B and Ecker, Joseph R and Mukamel, Eran A and Behrens, M Margarita} } @article {2289, title = {Lessons from the Stories of Women in Neuroscience.}, journal = {J Neurosci}, volume = {42}, year = {2022}, month = {2022 Jun 15}, pages = {4769-4773}, abstract = {

Women have been contributing to the field of neuroscience since its inception, but their accomplishments are often overlooked. Lack of recognition, among other issues, has led to progressively fewer women at each academic stage; although half of neuroscience graduate students are women, women comprise less than one-third of neuroscience faculty, and even fewer full professors. Those who reach this level continue to struggle to get their work recognized. Women from historically excluded backgrounds are even more starkly underrepresented and face added challenges related to racial, ethnic, and other biases. To increase the visibility of women in neuroscience, promote their voices, and learn about their career journeys, we created Stories of Women in Neuroscience (Stories of WiN). Stories of WiN shares the scientific and personal stories of women neuroscientists with diverse backgrounds, identities, research interests, and at various career stages. From \>70 women highlighted thus far, a major theme has emerged: there is not a single archetype of a woman neuroscientist, nor a single path to "success." Yet, through these diverse experiences run common threads, such as the importance of positive early research experiences, managing imposter syndrome, the necessity of work-life balance, and the challenges of fitting into-or resisting-the "scientist mold" within a patriarchal, racialized academic system. These commonalities reveal important considerations for supporting women neuroscientists. Through the lens of women highlighted by Stories of WiN, we explore the similarities among their journeys and detail specific actionable items to help encourage, support, and sustain women in neuroscience.

}, keywords = {Anxiety Disorders, Ethnicity, Female, Humans, Male, Neurosciences, Racial Groups, Self Concept}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.0536-22.2022}, author = {Sibener, Leslie J and Kirchgessner, Megan A and Steiner, Sheila and Santiago, Chiaki and Cassataro, Daniela and Rossa, Marley and Profaci, Caterina P and Padilla-Coreano, Nancy} } @article {2179, title = {Valence opponency in peripheral olfactory processing.}, journal = {Proc Natl Acad Sci U S A}, volume = {119}, year = {2022}, month = {2022 Feb 01}, abstract = {

A hallmark of complex sensory systems is the organization of neurons into functionally meaningful maps, which allow for comparison and contrast of parallel inputs via lateral inhibition. However, it is unclear whether such a map exists in olfaction. Here, we address this question by determining the organizing principle underlying the stereotyped pairing of olfactory receptor neurons (ORNs) in sensory hairs, wherein compartmentalized neurons inhibit each other via ephaptic coupling. Systematic behavioral assays reveal that most paired ORNs antagonistically regulate the same type of behavior. Such valence opponency is relevant in critical behavioral contexts including place preference, egg laying, and courtship. Odor-mixture experiments show that ephaptic inhibition provides a peripheral means for evaluating and shaping countervailing cues relayed to higher brain centers. Furthermore, computational modeling suggests that this organization likely contributes to processing ratio information in odor mixtures. This olfactory valence map may have evolved to swiftly process ethologically meaningful odor blends without involving costly synaptic computation.

}, issn = {1091-6490}, doi = {10.1073/pnas.2120134119}, author = {Wu, Shiuan-Tze and Chen, Jen-Yung and Martin, Vanessa and Ng, Renny and Zhang, Ye and Grover, Dhruv and Greenspan, Ralph J and Aljadeff, Johnatan and Su, Chih-Ying} } @article {1789, title = {Activation of MAP3K DLK and LZK in Purkinje cells causes rapid and slow degeneration depending on signaling strength.}, journal = {Elife}, volume = {10}, year = {2021}, month = {2021 Jan 21}, abstract = {

The conserved MAP3K Dual-Leucine-Zipper Kinase (DLK) and Leucine-Zipper-bearing Kinase (LZK) can activate JNK via MKK4 or MKK7. These two MAP3Ks share similar biochemical activities and undergo auto-activation upon increased expression. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing of , strongly attenuates Purkinje cell degeneration induced by LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

}, issn = {2050-084X}, doi = {10.7554/eLife.63509}, author = {Li, Yunbo and Ritchie, Erin M and Steinke, Christopher L and Qi, Cai and Chen, Lizhen and Zheng, Binhai and Jin, Yishi} } @article {1805, title = {Neurally driven synthesis of learned, complex vocalizations}, journal = {Current Biology}, year = {2021}, abstract = {

Summary Brain machine interfaces (BMIs) hold promise to restore impaired motor function and serve as powerful tools to study learned motor skill. While limb-based motor prosthetic systems have leveraged nonhuman primates as an important animal model,1, 2, 3, 4 speech prostheses lack a similar animal model and are more limited in terms of neural interface technology, brain coverage, and behavioral study design.5, 6, 7 Songbirds are an attractive model for learned complex vocal behavior. Birdsong shares a number of unique similarities with human speech,8, 9, 10 and its study has yielded general insight into multiple mechanisms and circuits behind learning, execution, and maintenance of vocal motor skill.11, 12, 13, 14, 15, 16, 17, 18 In addition, the biomechanics of song production bear similarity to those of humans and some nonhuman primates.19, 20, 21, 22, 23 Here, we demonstrate a vocal synthesizer for birdsong, realized by mapping neural population activity recorded from electrode arrays implanted in the premotor nucleus HVC onto low-dimensional compressed representations of song, using simple computational methods that are implementable in real time. Using a generative biomechanical model of the vocal organ (syrinx) as the low-dimensional target for these mappings allows for the synthesis of vocalizations that match the bird{\textquoteright}s own song. These results provide proof of concept that high-dimensional, complex natural behaviors can be directly synthesized from ongoing neural activity. This may inspire similar approaches to prosthetics in other species by exploiting knowledge of the peripheral systems and the temporal structure of their output.

}, keywords = {bioprosthetics, birdsong, brain machine interfaces, Electrophysiology, neural networks, nonlinear dynamics, Speech}, issn = {0960-9822}, doi = {https://doi.org/10.1016/j.cub.2021.05.035}, url = {https://www.sciencedirect.com/science/article/pii/S0960982221007338}, author = {Ezequiel M. Arneodo and Shukai Chen and Daril E. Brown and Vikash Gilja and Timothy Q. Gentner} } @article {1685, title = {Apical-Basal Polarity Signaling Components, Lgl1 and aPKCs, Control Glutamatergic Synapse Number and Function.}, journal = {iScience}, volume = {20}, year = {2019}, month = {2019 Oct 25}, pages = {25-41}, abstract = {

Normal synapse formation is fundamental to brain function. We show here that an apical-basal polarity (A-BP) protein, Lgl1, is present in the postsynaptic density and negatively regulates glutamatergic synapse numbers by antagonizing the atypical protein kinase Cs (aPKCs). A planar cell polarity protein, Vangl2, which inhibits synapse formation, was decreased in synaptosome fractions of cultured cortical neurons from Lgl1 knockout embryos. Conditional knockout of Lgl1 in pyramidal neurons led to reduction of AMPA/NMDA ratio and impaired plasticity. Lgl1 is frequently deleted in Smith-Magenis syndrome (SMS). Lgl1 conditional knockout led to increased locomotion, impaired novel object recognition and social interaction. Lgl1+/- animals also showed increased synapse numbers, defects in open field and social interaction, as well as stereotyped repetitive behavior. Social interaction in Lgl1+/- could be rescued by NMDA antagonists. Our findings reveal a role of apical-basal polarity proteins in glutamatergic synapse development and function and also suggest a potential treatment for SMS patients with Lgl1 deletion.

}, issn = {2589-0042}, doi = {10.1016/j.isci.2019.09.005}, author = {Scott, John and Thakar, Sonal and Mao, Ye and Qin, Huaping and Hejran, Helen and Lee, Su-Yee and Yu, Ting and Klezovitch, Olga and Cheng, Hongqiang and Mu, Yongxin and Ghosh, Sourav and Vasioukhin, Valeri and Zou, Yimin} } @article {1693, title = {Asymmetric ephaptic inhibition between compartmentalized olfactory receptor neurons.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 04 05}, pages = {1560}, abstract = {

In the Drosophila antenna, different subtypes of olfactory receptor neurons (ORNs) housed in the same sensory hair (sensillum) can inhibit each other non-synaptically. However, the mechanisms underlying this underexplored form of lateral inhibition remain unclear. Here we use recordings from pairs of sensilla impaled by the same tungsten electrode to demonstrate that direct electrical ("ephaptic") interactions mediate lateral inhibition between ORNs. Intriguingly, within individual sensilla, we find that ephaptic lateral inhibition is asymmetric such that one ORN exerts greater influence onto its neighbor. Serial block-face scanning electron microscopy of genetically identified ORNs and circuit modeling indicate that asymmetric lateral inhibition reflects a surprisingly simple mechanism: the physically larger ORN in a pair corresponds to the dominant neuron in ephaptic interactions. Thus, morphometric differences between compartmentalized ORNs account for highly specialized inhibitory interactions that govern information processing at the earliest stages of olfactory coding.

}, keywords = {Animals, Drosophila, Imaging, Three-Dimensional, Models, Biological, Olfactory Pathways, Olfactory Receptor Neurons, Sensilla, Smell}, issn = {2041-1723}, doi = {10.1038/s41467-019-09346-z}, author = {Zhang, Ye and Tsang, Tin Ki and Bushong, Eric A and Chu, Li-An and Chiang, Ann-Shyn and Ellisman, Mark H and Reingruber, J{\"u}rgen and Su, Chih-Ying} } @article {1469, title = {Biosynthesis of Orthogonal Molecules Using Ferredoxin and Ferredoxin-NADP+ Reductase Systems Enables Genetically Encoded PhyB Optogenetics.}, journal = {ACS Synth Biol}, year = {2018}, month = {2018 Jan 24}, abstract = {

Transplanting metabolic reactions from one species into another has many uses as a research tool with applications ranging from optogenetics to crop production. Ferredoxin (Fd), the enzyme that most often supplies electrons to these reactions, is often overlooked when transplanting enzymes from one species to another because most cells already contain endogenous Fd. However, we have shown that the production of chromophores used in Phytochrome B (PhyB) optogenetics is greatly enhanced in mammalian cells by expressing bacterial and plant Fds with ferredoxin-NADP+ reductases (FNR). We delineated the rate limiting factors and found that the main metabolic precursor, heme, was not the primary limiting factor for producing either the cyanobacterial or plant chromophores, phycocyanobilin or phytochromobilin, respectively. In fact, Fd is limiting, followed by Fd+FNR and finally heme. Using these findings, we optimized the PCB production system and combined it with a tissue penetrating red/far-red sensing PhyB optogenetic gene switch in animal cells. We further characterized this system in several mammalian cell lines using red and far-red light. Importantly, we found that the light-switchable gene system remains active for several hours upon illumination, even with a short light pulse, and requires very small amounts of light for maximal activation. Boosting chromophore production by matching metabolic pathways with specific ferredoxin systems will enable the unparalleled use of the many PhyB optogenetic tools and has broader implications for optimizing synthetic metabolic pathways.

}, issn = {2161-5063}, doi = {10.1021/acssynbio.7b00413}, author = {Kyriakakis, Phillip and Catanho, Marianne and Hoffner, Nicole and Thavarajah, Walter and Hu, Vincent J and Chao, Syh-Shiuan and Hsu, Athena and Pham, Vivian and Naghavian, Ladan and Dozier, Lara E and Patrick, Gentry N and Coleman, Todd P} } @article {1696, title = {Multiplexed oscillations and phase rate coding in the basal forebrain.}, journal = {Sci Adv}, volume = {4}, year = {2018}, month = {2018 08}, pages = {eaar3230}, abstract = {

Complex behaviors demand temporal coordination among functionally distinct brain regions. The basal forebrain{\textquoteright}s afferent and efferent structure suggests a capacity for mediating this coordination at a large scale. During performance of a spatial orientation task, synaptic activity in this region was dominated by four amplitude-independent oscillations temporally organized by the phase of the slowest, a theta-frequency rhythm. Oscillation amplitudes were also organized by task epoch and positively correlated to the task-related modulation of individual neuron firing rates. For many neurons, spiking was temporally organized through phase precession against theta band field potential oscillations. Theta phase precession advanced in parallel to task progression, rather than absolute spatial location or time. Together, the findings reveal a process by which associative brain regions can integrate independent oscillatory inputs and transform them into sequence-specific, rate-coded outputs that are adaptive to the pace with which organisms interact with their environment.

}, keywords = {Animals, Basal Forebrain, Male, Models, Neurological, Neurons, Rats, Rats, Long-Evans, Space Perception, Theta Rhythm}, issn = {2375-2548}, doi = {10.1126/sciadv.aar3230}, author = {Tingley, David and Alexander, Andrew S and Quinn, Laleh K and Chiba, Andrea A and Nitz, Douglas} } @article {1676, title = {Single-Trial EEG Analysis Predicts Memory Retrieval and Reveals Source-Dependent Differences.}, journal = {Front Hum Neurosci}, volume = {12}, year = {2018}, month = {2018}, pages = {258}, abstract = {

We used pattern classifiers to extract features related to recognition memory retrieval from the temporal information in single-trial electroencephalography (EEG) data during attempted memory retrieval. Two-class classification was conducted on correctly remembered trials with accurate context (or source) judgments vs. correctly rejected trials. The average accuracy for datasets recorded in a single session was 61\% while the average accuracy for datasets recorded in two separate sessions was 56\%. To further understand the basis of the classifier{\textquoteright}s performance, two other pattern classifiers were trained on different pairs of behavioral conditions. The first of these was designed to use information related to remembering the item and the second to use information related to remembering the contextual information (or source) about the item. Mollison and Curran (2012) had earlier shown that subjects{\textquoteright} familiarity judgments contributed to improved memory of spatial contextual information but not of extrinsic associated color information. These behavioral results were similarly reflected in the event-related potential (ERP) known as the FN400 (an early frontal effect relating to familiarity) which revealed differences between correct and incorrect context memories in the spatial but not color conditions. In our analyses we show that a classifier designed to distinguish between correct and incorrect context memories, more strongly involves early activity (400-500 ms) over the frontal channels for the location distinctions, than for the extrinsic color associations. In contrast, the classifier designed to classify memory for the item (without memory for the context), had more frontal channel involvement for the color associated experiments than for the spatial experiments. Taken together these results argue that location may be bound more tightly with the item than an extrinsic color association. The multivariate classification approach also showed that trial-by-trial variation in EEG corresponding to these ERP components were predictive of subjects{\textquoteright} behavioral responses. Additionally, the multivariate classification approach enabled analysis of error conditions that did not have sufficient trials for standard ERP analyses. These results suggested that false alarms were primarily attributable to item memory (as opposed to memory of associated context), as commonly predicted, but with little previous corroborating EEG evidence.

}, issn = {1662-5161}, doi = {10.3389/fnhum.2018.00258}, author = {Noh, Eunho and Liao, Kueida and Mollison, Matthew V and Curran, Tim and de Sa, Virginia R} } @article {123, title = {Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke.}, journal = {Brain}, volume = {139}, year = {2016}, month = {2016 Jan}, pages = {259-75}, abstract = {

There is an urgent need for a therapy that reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. We show here that intramuscular delivery of neurotrophin-3 (NT3, encoded by NTF3) can induce sensorimotor recovery when treatment is initiated 24 h after stroke. Specifically, in two randomized, blinded preclinical trials, we show improved sensory and locomotor function in adult (6 months) and elderly (18 months) rats treated 24 h following cortical ischaemic stroke with human NT3 delivered using a clinically approved serotype of adeno-associated viral vector (AAV1). Importantly, AAV1-hNT3 was given in a clinically-feasible timeframe using a straightforward, targeted route (injections into disabled forelimb muscles). Magnetic resonance imaging and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, treatment caused corticospinal axons from the less affected hemisphere to sprout in the spinal cord. This treatment is the first gene therapy that reverses disability after stroke when administered intramuscularly in an elderly body. Importantly, phase I and II clinical trials by others show that repeated, peripherally administered high doses of recombinant NT3 are safe and well tolerated in humans with other conditions. This paves the way for NT3 as a therapy for stroke.

}, keywords = {Adenoviridae, Age Factors, Animals, Endothelin-1, Female, Genetic Vectors, Humans, Injections, Intramuscular, Locomotion, Magnetic Resonance Imaging, Microinjections, Muscle, Skeletal, Neuroimaging, Neurotrophin 3, Pyramidal Tracts, Rats, Recovery of Function, Spinal Cord, Stroke, Time Factors}, issn = {1460-2156}, doi = {10.1093/brain/awv341}, author = {Duricki, Denise A and Hutson, Thomas H and Kathe, Claudia and Soleman, Sara and Gonzalez-Carter, Daniel and Petruska, Jeffrey C and Shine, H David and Chen, Qin and Wood, Tobias C and Bernanos, Michel and Cash, Diana and Williams, Steven C R and Gage, Fred H and Moon, Lawrence D F} } @article {1680, title = {Optogenetic manipulation of neural circuits in awake marmosets.}, journal = {J Neurophysiol}, volume = {116}, year = {2016}, month = {2016 09 01}, pages = {1286-94}, abstract = {

Optogenetics has revolutionized the study of functional neuronal circuitry (Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Nat Neurosci 8: 1263-1268, 2005; Deisseroth K. Nat Methods 8: 26-29, 2011). Although these techniques have been most successfully implemented in rodent models, they have the potential to be similarly impactful in studies of nonhuman primate brains. Common marmosets (Callithrix jacchus) have recently emerged as a candidate primate model for gene editing, providing a potentially powerful model for studies of neural circuitry and disease in primates. The application of viral transduction methods in marmosets for identifying and manipulating neuronal circuitry is a crucial step in developing this species for neuroscience research. In the present study we developed a novel, chronic method to successfully induce rapid photostimulation in individual cortical neurons transduced by adeno-associated virus to express channelrhodopsin (ChR2) in awake marmosets. We found that large proportions of neurons could be effectively photoactivated following viral transduction and that this procedure could be repeated for several months. These data suggest that techniques for viral transduction and optical manipulation of neuronal populations are suitable for marmosets and can be combined with existing behavioral preparations in the species to elucidate the functional neural circuitry underlying perceptual and cognitive processes.

}, keywords = {Action Potentials, Animals, Bacterial Proteins, Brain, Callithrix, Dependovirus, Female, Genetic Vectors, Luminescent Proteins, Microelectrodes, Models, Animal, Neural Pathways, Neurons, Optogenetics, Photic Stimulation, Rhodopsin, Serogroup, Wakefulness}, issn = {1522-1598}, doi = {10.1152/jn.00197.2016}, author = {MacDougall, Matthew and Nummela, Samuel U and Coop, Shanna and Disney, Anita and Mitchell, Jude F and Miller, Cory T} } @article {127, title = {Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.}, journal = {Nature}, volume = {527}, year = {2015}, month = {2015 Nov 5}, pages = {95-9}, abstract = {

Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15\% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

}, keywords = {Action Potentials, Antipsychotic Agents, Bipolar Disorder, Calcium Signaling, Dentate Gyrus, Endophenotypes, Humans, Induced Pluripotent Stem Cells, Lithium Compounds, Male, Mitochondria, Neurons, Patch-Clamp Techniques}, issn = {1476-4687}, doi = {10.1038/nature15526}, author = {Mertens, Jerome and Wang, Qiu-Wen and Kim, Yongsung and Yu, Diana X and Pham, Son and Yang, Bo and Zheng, Yi and Diffenderfer, Kenneth E and Zhang, Jian and Soltani, Sheila and Eames, Tameji and Schafer, Simon T and Boyer, Leah and Marchetto, Maria C and Nurnberger, John I and Calabrese, Joseph R and {\O}degaard, Ketil J and McCarthy, Michael J and Zandi, Peter P and Alda, Martin and Alba, Martin and Nievergelt, Caroline M and Mi, Shuangli and Brennand, Kristen J and Kelsoe, John R and Gage, Fred H and Yao, Jun} } @article {126, title = {REST Regulates Non-Cell-Autonomous Neuronal Differentiation and Maturation of Neural Progenitor Cells via Secretogranin II.}, journal = {J Neurosci}, volume = {35}, year = {2015}, month = {2015 Nov 4}, pages = {14872-84}, abstract = {

UNLABELLED: RE-1 silencing transcription factor (REST), a master negative regulator of neuronal differentiation, controls neurogenesis by preventing the differentiation of neural stem cells. Here we focused on the role of REST in the early steps of differentiation and maturation of adult hippocampal progenitors (AHPs). REST knockdown promoted differentiation and affected the maturation of rat AHPs. Surprisingly, REST knockdown cells enhanced the differentiation of neighboring wild-type AHPs, suggesting that REST may play a non-cell-autonomous role. Gene expression analysis identified Secretogranin II (Scg2) as the major secreted REST target responsible for the non-cell-autonomous phenotype. Loss-of-function of Scg2 inhibited differentiation in vitro, and exogenous SCG2 partially rescued this phenotype. Knockdown of REST in neural progenitors in mice led to precocious maturation into neurons at the expense of mushroom spines in vivo. In summary, we found that, in addition to its cell-autonomous function, REST regulates differentiation and maturation of AHPs non-cell-autonomously via SCG2.

SIGNIFICANCE STATEMENT: Our results reveal that REST regulates differentiation and maturation of neural progenitor cells in vitro by orchestrating both cell-intrinsic and non-cell-autonomous factors and that Scg2 is a major secretory target of REST with a differentiation-enhancing activity in a paracrine manner. In vivo, REST depletion causes accelerated differentiation of newborn neurons at the expense of spine defects, suggesting a potential role for REST in the timing of the maturation of granule neurons.

}, keywords = {Animals, Cell Differentiation, Cells, Cultured, Female, Hippocampus, Mice, Mice, Inbred C57BL, Neural Stem Cells, Neurogenesis, Neurons, Rats, Wistar, Repressor Proteins, Secretogranin II}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.4286-14.2015}, author = {Kim, Hyung Joon and Denli, Ahmet M and Wright, Rebecca and Baul, Tithi D and Clemenson, Gregory D and Morcos, Ari S and Zhao, Chunmei and Schafer, Simon T and Gage, Fred H and Kagalwala, Mohamedi N} } @article {205, title = {Age-related changes in tissue signal properties within cortical areas important for word understanding in 12- to 19-month-old infants.}, journal = {Cereb Cortex}, volume = {24}, year = {2014}, month = {2014 Jul}, pages = {1948-55}, abstract = {

Recently, our laboratory has shown that the neural mechanisms for encoding lexico-semantic information in adults operate functionally by 12-18 months of age within left frontotemporal cortices (Travis et al., 2011. Spatiotemporal neural dynamics of word understanding in 12- to 18-month-old-infants. Cereb Cortex. 8:1832-1839). However, there is minimal knowledge of the structural changes that occur within these and other cortical regions important for language development. To identify regional structural changes taking place during this important period in infant development, we examined age-related changes in tissue signal properties of gray matter (GM) and white matter (WM) intensity and contrast. T1-weighted surface-based measures were acquired from 12- to 19-month-old infants and analyzed using a general linear model. Significant age effects were observed for GM and WM intensity and contrast within bilateral inferior lateral and anterovental temporal regions, dorsomedial frontal, and superior parietal cortices. Region of interest (ROI) analyses revealed that GM and WM intensity and contrast significantly increased with age within the same left lateral temporal regions shown to generate lexico-semantic activity in infants and adults. These findings suggest that neurophysiological processes supporting linguistic and cognitive behaviors may develop before cellular and structural maturation is complete within associative cortices. These results have important implications for understanding the neurobiological mechanisms relating structural to functional brain development.

}, keywords = {Aging, Brain Mapping, Cerebral Cortex, Comprehension, Female, Humans, Image Processing, Computer-Assisted, Infant, Language Development, Magnetic Resonance Imaging, Male, Vocabulary}, issn = {1460-2199}, doi = {10.1093/cercor/bht052}, author = {Travis, Katherine E and Curran, Megan M and Torres, Christina and Leonard, Matthew K and Brown, Timothy T and Dale, Anders M and Elman, Jeffrey L and Halgren, Eric} } @article {176, title = {Nerve growth factor is primarily produced by GABAergic neurons of the adult rat cortex.}, journal = {Front Cell Neurosci}, volume = {8}, year = {2014}, month = {2014}, pages = {220}, abstract = {

Within the cortex, nerve growth factor (NGF) mediates the innervation of cholinergic neurons during development, maintains cholinergic corticopetal projections during adulthood and modulates cholinergic function through phenotypic control of the cholinergic gene locus. Recent studies suggest NGF may also play an important role in cortical plasticity in adulthood. Previously, NGF-producing cells have been shown to colocalize with GABAergic cell markers within the hippocampus, striatum, and basal forebrain. Classification of cells producing NGF in the cortex is lacking, however, and cholinergic corticopetal projections have been shown to innervate both pyramidal and GABAergic neurons in the cortex. In order to clarify potential trophic interactions between cortical neurons and cholinergic projections, we used double-fluorescent immunohistochemistry to classify NGF-expressing cells in several cortical regions, including the prefrontal cortex, primary motor cortex, parietal cortex and temporal cortex. Our results show that NGF colocalizes extensively with GABAergic cell markers in all cortical regions examined, with \>91\% of NGF-labeled cells coexpressing GAD65/67. Conversely, NGF-labeled cells exhibit very little co-localization with the excitatory cell marker CaMKIIα (\<5\% of cells expressing NGF). NGF expression was present in 56\% of GAD-labeled cells, suggesting that production is confined to a specific subset of GABAergic neurons. These findings demonstrate that GABAergic cells are the primary source of NGF production in the cortex, and likely support the maintenance and function of basal forebrain cholinergic projections in adulthood.

}, issn = {1662-5102}, doi = {10.3389/fncel.2014.00220}, author = {Biane, Jeremy and Conner, James M and Tuszynski, Mark H} } @article {180, title = {Speech-specific tuning of neurons in human superior temporal gyrus.}, journal = {Cereb Cortex}, volume = {24}, year = {2014}, month = {2014 Oct}, pages = {2679-93}, abstract = {

How the brain extracts words from auditory signals is an unanswered question. We recorded approximately 150 single and multi-units from the left anterior superior temporal gyrus of a patient during multiple auditory experiments. Against low background activity, 45\% of units robustly fired to particular spoken words with little or no response to pure tones, noise-vocoded speech, or environmental sounds. Many units were tuned to complex but specific sets of phonemes, which were influenced by local context but invariant to speaker, and suppressed during self-produced speech. The firing of several units to specific visual letters was correlated with their response to the corresponding auditory phonemes, providing the first direct neural evidence for phonological recoding during reading. Maximal decoding of individual phonemes and words identities was attained using firing rates from approximately 5 neurons within 200 ms after word onset. Thus, neurons in human superior temporal gyrus use sparse spatially organized population encoding of complex acoustic-phonetic features to help recognize auditory and visual words.

}, keywords = {Acoustic Stimulation, Adult, Humans, Male, Neurons, Phonetics, Speech Perception, Temporal Lobe}, issn = {1460-2199}, doi = {10.1093/cercor/bht127}, author = {Chan, Alexander M and Dykstra, Andrew R and Jayaram, Vinay and Leonard, Matthew K and Travis, Katherine E and Gygi, Brian and Baker, Janet M and Eskandar, Emad and Hochberg, Leigh R and Halgren, Eric and Cash, Sydney S} } @article {1675, title = {Using single-trial EEG to predict and analyze subsequent memory.}, journal = {Neuroimage}, volume = {84}, year = {2014}, month = {2014 Jan 01}, pages = {712-23}, abstract = {

We show that it is possible to successfully predict subsequent memory performance based on single-trial EEG activity before and during item presentation in the study phase. Two-class classification was conducted to predict subsequently remembered vs. forgotten trials based on subjects{\textquoteright} responses in the recognition phase. The overall accuracy across 18 subjects was 59.6\% by combining pre- and during-stimulus information. The single-trial classification analysis provides a dimensionality reduction method to project the high-dimensional EEG data onto a discriminative space. These projections revealed novel findings in the pre- and during-stimulus periods related to levels of encoding. It was observed that the pre-stimulus information (specifically oscillatory activity between 25 and 35Hz) -300 to 0ms before stimulus presentation and during-stimulus alpha (7-12Hz) information between 1000 and 1400ms after stimulus onset distinguished between recollection and familiarity while the during-stimulus alpha information and temporal information between 400 and 800ms after stimulus onset mapped these two states to similar values.

}, keywords = {Adolescent, Adult, Brain, Electroencephalography, Humans, Male, Memory, Young Adult}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2013.09.028}, author = {Noh, Eunho and Herzmann, Grit and Curran, Tim and de Sa, Virginia R} } @article {166, title = {A comprehensive wiring diagram of the protocerebral bridge for visual information processing in the Drosophila brain.}, journal = {Cell Rep}, volume = {3}, year = {2013}, month = {2013 May 30}, pages = {1739-53}, abstract = {

How the brain perceives sensory information and generates meaningful behavior depends critically on its underlying circuitry. The protocerebral bridge (PB) is a major part of the insect central complex (CX), a premotor center that may be analogous to the human basal ganglia. Here, by deconstructing hundreds of PB single neurons and reconstructing them into a common three-dimensional framework, we have constructed a comprehensive map of PB circuits with labeled polarity and predicted directions of information flow. Our analysis reveals a highly ordered information processing system that involves directed information flow among CX subunits through 194 distinct PB neuron types. Circuitry properties such as mirroring, convergence, divergence, tiling, reverberation, and parallel signal propagation were observed; their functional and evolutional significance is discussed. This layout of PB neuronal circuitry may provide guidelines for further investigations on transformation of sensory (e.g., visual) input into locomotor commands in fly brains.

}, keywords = {Animals, Brain, Drosophila, Models, Biological, Neurons}, issn = {2211-1247}, doi = {10.1016/j.celrep.2013.04.022}, author = {Lin, Chih-Yung and Chuang, Chao-Chun and Hua, Tzu-En and Chen, Chun-Chao and Dickson, Barry J and Greenspan, Ralph J and Chiang, Ann-Shyn} } @article {200, title = {Contrast dependence and differential contributions from somatostatin- and parvalbumin-expressing neurons to spatial integration in mouse V1.}, journal = {J Neurosci}, volume = {33}, year = {2013}, month = {2013 Jul 3}, pages = {11145-54}, abstract = {

A characteristic feature in the primary visual cortex is that visual responses are suppressed as a stimulus extends beyond the classical receptive field. Here, we examined the role of inhibitory neurons expressing somatostatin (SOM$^{+}$) or parvalbumin (PV$^{+}$) on surround suppression and preferred receptive field size. We recorded multichannel extracellular activity in V1 of transgenic mice expressing channelrhodopsin in SOM$^{+}$ neurons or PV$^{+}$ neurons. Preferred size and surround suppression were measured using drifting square-wave gratings of varying radii and at two contrasts. Consistent with findings in primates, we found that the preferred size was larger for lower contrasts across all cortical depths, whereas the suppression index (SI) showed a trend to decrease with contrast. We then examined the effect of these metrics on units that were suppressed by photoactivation of either SOM$^{+}$ or PV$^{+}$ neurons. When activating SOM$^{+}$ neurons, we found a significant increase in SI at cortical depths \>400 μm, whereas activating PV$^{+}$ neurons caused a trend toward lower SIs regardless of cortical depth. Conversely, activating PV$^{+}$ neurons significantly increased preferred size across all cortical depths, similar to lowering contrast, whereas activating SOM$^{+}$ neurons had no systematic effect on preferred size across all depths. These data suggest that SOM$^{+}$ and PV$^{+}$ neurons contribute differently to spatial integration. Our findings are compatible with the notion that SOM$^{+}$ neurons mediate surround suppression, particularly in deeper cortex, whereas PV$^{+}$ activation decreases the drive of the input to cortex and therefore resembles the effects on spatial integration of lowering contrast.

}, keywords = {Animals, Contrast Sensitivity, Female, Male, Mice, Mice, Transgenic, Neurons, Parvalbumins, Photic Stimulation, Somatostatin, Space Perception, Visual Cortex}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.5320-12.2013}, author = {Nienborg, Hendrikje and Hasenstaub, Andrea and Nauhaus, Ian and Taniguchi, Hiroki and Huang, Z Josh and Callaway, Edward M} } @article {201, title = {Evidence that primary visual cortex is required for image, orientation, and motion discrimination by rats.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e56543}, abstract = {

The pigmented Long-Evans rat has proven to be an excellent subject for studying visually guided behavior including quantitative visual psychophysics. This observation, together with its experimental accessibility and its close homology to the mouse, has made it an attractive model system in which to dissect the thalamic and cortical circuits underlying visual perception. Given that visually guided behavior in the absence of primary visual cortex has been described in the literature, however, it is an empirical question whether specific visual behaviors will depend on primary visual cortex in the rat. Here we tested the effects of cortical lesions on performance of two-alternative forced-choice visual discriminations by Long-Evans rats. We present data from one highly informative subject that learned several visual tasks and then received a bilateral lesion ablating \>90\% of primary visual cortex. After the lesion, this subject had a profound and persistent deficit in complex image discrimination, orientation discrimination, and full-field optic flow motion discrimination, compared with both pre-lesion performance and sham-lesion controls. Performance was intact, however, on another visual two-alternative forced-choice task that required approaching a salient visual target. A second highly informative subject learned several visual tasks prior to receiving a lesion ablating \>90\% of medial extrastriate cortex. This subject showed no impairment on any of the four task categories. Taken together, our data provide evidence that these image, orientation, and motion discrimination tasks require primary visual cortex in the Long-Evans rat, whereas approaching a salient visual target does not.

}, keywords = {Animals, Discrimination (Psychology), Discrimination Learning, Male, Motion, Orientation, Photic Stimulation, Psychomotor Performance, Rats, Visual Cortex}, issn = {1932-6203}, doi = {10.1371/journal.pone.0056543}, author = {Petruno, Sarah K and Clark, Robert E and Reinagel, Pamela} } @article {204, title = {Independence of early speech processing from word meaning.}, journal = {Cereb Cortex}, volume = {23}, year = {2013}, month = {2013 Oct}, pages = {2370-9}, abstract = {

We combined magnetoencephalography (MEG) with magnetic resonance imaging and electrocorticography to separate in anatomy and latency 2 fundamental stages underlying speech comprehension. The first acoustic-phonetic stage is selective for words relative to control stimuli individually matched on acoustic properties. It begins \~{}60 ms after stimulus onset and is localized to middle superior temporal cortex. It was replicated in another experiment, but is strongly dissociated from the response to tones in the same subjects. Within the same task, semantic priming of the same words by a related picture modulates cortical processing in a broader network, but this does not begin until \~{}217 ms. The earlier onset of acoustic-phonetic processing compared with lexico-semantic modulation was significant in each individual subject. The MEG source estimates were confirmed with intracranial local field potential and high gamma power responses acquired in 2 additional subjects performing the same task. These recordings further identified sites within superior temporal cortex that responded only to the acoustic-phonetic contrast at short latencies, or the lexico-semantic at long. The independence of the early acoustic-phonetic response from semantic context suggests a limited role for lexical feedback in early speech perception.

}, keywords = {Adult, Brain, Brain Mapping, Female, Humans, Magnetic Resonance Imaging, Magnetoencephalography, Male, Speech Perception, Young Adult}, issn = {1460-2199}, doi = {10.1093/cercor/bhs228}, author = {Travis, Katherine E and Leonard, Matthew K and Chan, Alexander M and Torres, Christina and Sizemore, Marisa L and Qu, Zhe and Eskandar, Emad and Dale, Anders M and Elman, Jeffrey L and Cash, Sydney S and Halgren, Eric} } @article {158, title = {Neuroscience. The brain activity map.}, journal = {Science}, volume = {339}, year = {2013}, month = {2013 Mar 15}, pages = {1284-5}, keywords = {Brain Diseases, Brain Mapping, Hippocampus, Humans, Neural Pathways, Neurons}, issn = {1095-9203}, doi = {10.1126/science.1236939}, author = {Alivisatos, A Paul and Chun, Miyoung and Church, George M and Deisseroth, Karl and Donoghue, John P and Greenspan, Ralph J and McEuen, Paul L and Roukes, Michael L and Sejnowski, Terrence J and Weiss, Paul S and Yuste, Rafael} } @article {164, title = {Vertebrate versus invertebrate neural circuits.}, journal = {Curr Biol}, volume = {23}, year = {2013}, month = {2013 Jun 17}, pages = {R504-6}, keywords = {Animals, Invertebrates, Nervous System, Nervous System Physiological Phenomena, Vertebrates}, issn = {1879-0445}, author = {Katz, Paul and Grillner, Sten and Wilson, Rachel and Borst, Alexander and Greenspan, Ralph and Buzs{\'a}ki, Gy{\"o}rgy and Martin, Kevan and Marder, Eve and Kristan, William and Friedrich, Rainer and Chklovskii, Dmitri Mitya} } @article {181, title = {Atypical social referencing in infant siblings of children with autism spectrum disorders.}, journal = {J Autism Dev Disord}, volume = {42}, year = {2012}, month = {2012 Dec}, pages = {2611-21}, abstract = {

Social referencing was investigated in 18-month-old siblings of children with autism spectrum disorders (ASD; "high-risk infants"). Infants were exposed to novel toys, which were emotionally tagged via adults{\textquoteright} facial and vocal signals. Infants{\textquoteright} information seeking (initiation of joint attention with an adult) and their approach/withdrawal behavior toward the toys before versus after the adults{\textquoteright} emotional signals was measured. Compared to both typically developing infants and high-risk infants without ASD, infants later diagnosed with ASD engaged in slower information seeking, suggesting that this aspect of referencing may be an early indicator of ASD. High-risk infants, both those who were and those who were not later diagnosed with ASD, exhibited impairments in regulating their behavior based on the adults{\textquoteright} emotional signals, suggesting that this aspect of social referencing may reflect an endophenotype for ASD.

}, keywords = {Attention, Child, Child Development, Child Development Disorders, Pervasive, Child, Preschool, Emotions, Endophenotypes, Female, Humans, Infant, Infant Behavior, Male, Risk Factors, Siblings, Social Behavior}, issn = {1573-3432}, doi = {10.1007/s10803-012-1518-8}, author = {Cornew, Lauren and Dobkins, Karen R and Akshoomoff, Natacha and McCleery, Joseph P and Carver, Leslie J} } @article {159, title = {The brain activity map project and the challenge of functional connectomics.}, journal = {Neuron}, volume = {74}, year = {2012}, month = {2012 Jun 21}, pages = {970-4}, abstract = {

The function of neural circuits is an emergent property that arises from the coordinated activity of large numbers of neurons. To capture this, we propose launching a large-scale, international public effort, the Brain Activity Map Project, aimed at reconstructing the full record of neural activity across complete neural circuits. This technological challenge could prove to be an invaluable step toward understanding fundamental and pathological brain processes.

}, keywords = {Action Potentials, Brain, Brain Mapping, Humans, Models, Neurological, Nerve Net, Neural Pathways, Neurons}, issn = {1097-4199}, doi = {10.1016/j.neuron.2012.06.006}, author = {Alivisatos, A Paul and Chun, Miyoung and Church, George M and Greenspan, Ralph J and Roukes, Michael L and Yuste, Rafael} } @article {206, title = {Spatiotemporal neural dynamics of word understanding in 12- to 18-month-old-infants.}, journal = {Cereb Cortex}, volume = {21}, year = {2011}, month = {2011 Aug}, pages = {1832-9}, abstract = {

Learning words is central in human development. However, lacking clear evidence for how or where language is processed in the developing brain, it is unknown whether these processes are similar in infants and adults. Here, we use magnetoencephalography in combination with high-resolution structural magnetic resonance imaging to noninvasively estimate the spatiotemporal distribution of word-selective brain activity in 12- to 18-month-old infants. Infants watched pictures of common objects and listened to words that they understood. A subset of these infants also listened to familiar words compared with sensory control sounds. In both experiments, words evoked a characteristic event-related brain response peaking \~{}400 ms after word onset, which localized to left frontotemporal cortices. In adults, this activity, termed the N400m, is associated with lexico-semantic encoding. Like adults, we find that the amplitude of the infant N400m is also modulated by semantic priming, being reduced to words preceded by a semantically related picture. These findings suggest that similar left frontotemporal areas are used for encoding lexico-semantic information throughout the life span, from the earliest stages of word learning. Furthermore, this ontogenetic consistency implies that the neurophysiological processes underlying the N400m may be important both for understanding already known words and for learning new words.

}, keywords = {Adult, Brain Mapping, Cerebral Cortex, Evoked Potentials, Auditory, Female, Humans, Infant, Language Tests, Learning, Magnetic Resonance Imaging, Magnetoencephalography, Male, Neurons, Speech Perception, Vocabulary}, issn = {1460-2199}, doi = {10.1093/cercor/bhq259}, author = {Travis, Katherine E and Leonard, Matthew K and Brown, Timothy T and Hagler, Donald J and Curran, Megan and Dale, Anders M and Elman, Jeffrey L and Halgren, Eric} } @article {177, title = {Sustained dorsal hippocampal activity is not obligatory for either the maintenance or retrieval of long-term spatial memory.}, journal = {Hippocampus}, volume = {20}, year = {2010}, month = {2010 Dec}, pages = {1366-75}, abstract = {

Memories are initially stored in a labile state and are subject to modification by a variety of treatments, including disruption of hippocampal function. We infused a sodium channel blocker (or CNQX) to inactivate the rat dorsal hippocampus reversibly for 1 week following training on a task of spatial memory (the water maze). Previous work with conventional lesions has established that the dorsal hippocampus is essential for both the acquisition and expression of memory in this task. The question in the present study was whether chronic disruption of neuronal activity in the dorsal hippocampus after training would abolish memory or whether memory would survive extended disruption of hippocampal activity. As expected from earlier work, we found that performance was impaired during the infusion period. The critical test occurred 1 week after the lesion was reversed. We found that retention of the water maze recovered to control levels. Accordingly, sustained hippocampal activity following training is not obligatory for either the maintenance of long-term spatial memory or its subsequent retrieval.

}, keywords = {6-Cyano-7-nitroquinoxaline-2,3-dione, Animals, Excitatory Amino Acid Antagonists, Hippocampus, Male, Maze Learning, Memory, Rats, Rats, Long-Evans, Space Perception, Spatial Behavior}, issn = {1098-1063}, doi = {10.1002/hipo.20722}, author = {Broadbent, Nicola J and Squire, Larry R and Clark, Robert E} } @article {193, title = {Targeting single neuronal networks for gene expression and cell labeling in vivo.}, journal = {Neuron}, volume = {67}, year = {2010}, month = {2010 Aug 26}, pages = {562-74}, abstract = {

To understand fine-scale structure and function of single mammalian neuronal networks, we developed and validated a strategy to genetically target and trace monosynaptic inputs to a single neuron in vitro and in vivo. The strategy independently targets a neuron and its presynaptic network for specific gene expression and fine-scale labeling, using single-cell electroporation of DNA to target infection and monosynaptic retrograde spread of a genetically modifiable rabies virus. The technique is highly reliable, with transsynaptic labeling occurring in every electroporated neuron infected by the virus. Targeting single neocortical neuronal networks in vivo, we found clusters of both spiny and aspiny neurons surrounding the electroporated neuron in each case, in addition to intricately labeled distal cortical and subcortical inputs. This technique, broadly applicable for probing and manipulating single neuronal networks with single-cell resolution in vivo, may help shed new light on fundamental mechanisms underlying circuit development and information processing by neuronal networks throughout the brain.

}, keywords = {Animals, Electroporation, Gene Expression, Genetic Vectors, Histological Techniques, In Vitro Techniques, Mice, Neocortex, Neural Pathways, Neuroanatomical Tract-Tracing Techniques, Neuronal Tract-Tracers, Neurons, Presynaptic Terminals, Pyramidal Cells, Rabies virus, Rats, Reproducibility of Results, Visual Cortex}, issn = {1097-4199}, doi = {10.1016/j.neuron.2010.08.001}, author = {Marshel, James H and Mori, Takuma and Nielsen, Kristina J and Callaway, Edward M} } @article {194, title = {Atypical face versus object processing and hemispheric asymmetries in 10-month-old infants at risk for autism.}, journal = {Biol Psychiatry}, volume = {66}, year = {2009}, month = {2009 Nov 15}, pages = {950-7}, abstract = {

BACKGROUND: Previous studies have documented atypicalities in face/object processing in children and adults with autism spectrum disorders (ASDs). To investigate whether such atypicalities may reflect a genetically mediated risk factor present early in development, we measured face/object processing in 10-month-old high-risk infants who carry some of the genes associated with ASD because they have an older sibling diagnosed with the disorder.

METHODS: We employed event-related potentials (ERPs) to measure cortical responses to pictures of faces and objects, the objects being toys. Latencies and amplitudes of four ERP components (P100, N290, P400, and Nc) were compared between 20 high-risk infants and 20 low-risk control subjects (infants with no family history of ASD).

RESULTS: Responses to faces versus objects differed between high- and low-risk infants for the latencies of the N290 and P400. Differences were driven by faster responses to faces than objects in low-risk, but not high-risk, infants (P400) and, conversely, faster responses to objects than faces in high-risk, but not low-risk, infants (N290). Object responses were also faster in high-risk than low-risk infants (both N290 and P400). Left versus right hemisphere responses also differed between high- and low-risk infants for the amplitudes of the P100, N290, and P400; collapsed across faces/objects, low-risk, but not high-risk, infants exhibited hemisphere asymmetries.

CONCLUSIONS: Genetic risk for ASD is associated with atypical face versus object processing and an atypical lack of hemispheric asymmetry early in life. These atypicalities might contribute to development of the disorder.

}, keywords = {Analysis of Variance, Autistic Disorder, Brain, Brain Mapping, Cerebral Cortex, Child, Child, Preschool, Electroencephalography, Evoked Potentials, Face, Female, Fourier Analysis, Functional Laterality, Humans, Infant, Male, Neuropsychological Tests, Pattern Recognition, Visual, Photic Stimulation, Reaction Time, Risk}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2009.07.031}, author = {McCleery, Joseph P and Akshoomoff, Natacha and Dobkins, Karen R and Carver, Leslie J} } @article {165, title = {The Drosophila foraging gene mediates adult plasticity and gene-environment interactions in behaviour, metabolites, and gene expression in response to food deprivation.}, journal = {PLoS Genet}, volume = {5}, year = {2009}, month = {2009 Aug}, pages = {e1000609}, abstract = {

Nutrition is known to interact with genotype in human metabolic syndromes, obesity, and diabetes, and also in Drosophila metabolism. Plasticity in metabolic responses, such as changes in body fat or blood sugar in response to changes in dietary alterations, may also be affected by genotype. Here we show that variants of the foraging (for) gene in Drosophila melanogaster affect the response to food deprivation in a large suite of adult phenotypes by measuring gene by environment interactions (GEI) in a suite of food-related traits. for affects body fat, carbohydrates, food-leaving behavior, metabolite, and gene expression levels in response to food deprivation. This results in broad patterns of metabolic, genomic, and behavioral gene by environment interactions (GEI), in part by interaction with the insulin signaling pathway. Our results show that a single gene that varies in nature can have far reaching effects on behavior and metabolism by acting through multiple other genes and pathways.

}, keywords = {Animals, Carbohydrate Metabolism, Cyclic GMP-Dependent Protein Kinases, Drosophila melanogaster, Drosophila Proteins, Ecosystem, Fats, Food Deprivation, Gene Expression, Signal Transduction}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1000609}, author = {Kent, Clement F and Daskalchuk, Tim and Cook, Lisa and Sokolowski, Marla B and Greenspan, Ralph J} } @article {160, title = {A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale.}, journal = {PLoS Comput Biol}, volume = {5}, year = {2009}, month = {2009 Mar}, pages = {e1000334}, abstract = {

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is critical, however, for both basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brainwide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brainwide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open-access data repository; compatibility with existing resources; and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.

}, keywords = {Animals, Brain, Databases, Factual, Humans, Macaca, Mice, Models, Neurological, Nerve Net, Neuroanatomy, Research Design}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1000334}, author = {Bohland, Jason W and Wu, Caizhi and Barbas, Helen and Bokil, Hemant and Bota, Mihail and Breiter, Hans C and Cline, Hollis T and Doyle, John C and Freed, Peter J and Greenspan, Ralph J and Haber, Suzanne N and Hawrylycz, Michael and Herrera, Daniel G and Hilgetag, Claus C and Huang, Z Josh and Jones, Allan and Jones, Edward G and Karten, Harvey J and Kleinfeld, David and K{\"o}tter, Rolf and Lester, Henry A and Lin, John M and Mensh, Brett D and Mikula, Shawn and Panksepp, Jaak and Price, Joseph L and Safdieh, Joseph and Saper, Clifford B and Schiff, Nicholas D and Schmahmann, Jeremy D and Stillman, Bruce W and Svoboda, Karel and Swanson, Larry W and Toga, Arthur W and Van Essen, David C and Watson, James D and Mitra, Partha P} } @article {130, title = {Activity-dependent homeostatic specification of transmitter expression in embryonic neurons.}, journal = {Nature}, volume = {429}, year = {2004}, month = {2004 Jun 3}, pages = {523-30}, abstract = {

Neurotransmitters are essential for interneuronal signalling, and the specification of appropriate transmitters in differentiating neurons has been related to intrinsic neuronal identity and to extrinsic signalling proteins. Here we show that altering the distinct patterns of Ca2+ spike activity spontaneously generated by different classes of embryonic spinal neurons in vivo changes the transmitter that neurons express without affecting the expression of markers of cell identity. Regulation seems to be homeostatic: suppression of activity leads to an increased number of neurons expressing excitatory transmitters and a decreased number of neurons expressing inhibitory transmitters; the reverse occurs when activity is enhanced. The imposition of specific spike frequencies in vitro does not affect labels of cell identity but again specifies the expression of transmitters that are inappropriate for the markers they express, during an early critical period. The results identify a new role of patterned activity in development of the central nervous system.

}, keywords = {Action Potentials, Animals, Calcium, Calcium Signaling, Cell Differentiation, Cells, Cultured, Gene Expression Regulation, Homeostasis, Humans, Neurons, Neurotransmitter Agents, Organ Specificity, Phenotype, Potassium Channels, Inwardly Rectifying, Rats, Sodium Channels, Spinal Cord, Xenopus laevis}, issn = {1476-4687}, doi = {10.1038/nature02518}, author = {Borodinsky, Laura N and Root, Cory M and Cronin, Julia A and Sann, Sharon B and Gu, Xiaonan and Spitzer, Nicholas C} } @article {152, title = {Correlates of sleep and waking in Drosophila melanogaster.}, journal = {Science}, volume = {287}, year = {2000}, month = {2000 Mar 10}, pages = {1834-7}, abstract = {

Drosophila exhibits a circadian rest-activity cycle, but it is not known whether fly rest constitutes sleep or is mere inactivity. It is shown here that, like mammalian sleep, rest in Drosophila is characterized by an increased arousal threshold and is homeostatically regulated independently of the circadian clock. As in mammals, rest is abundant in young flies, is reduced in older flies, and is modulated by stimulants and hypnotics. Several molecular markers modulated by sleep and waking in mammals are modulated by rest and activity in Drosophila, including cytochrome oxidase C, the endoplasmic reticulum chaperone protein BiP, and enzymes implicated in the catabolism of monoamines. Flies lacking one such enzyme, arylalkylamine N-acetyltransferase, show increased rest after rest deprivation. These results implicate the catabolism of monoamines in the regulation of sleep and waking in the fly and suggest that Drosophila may serve as a model system for the genetic dissection of sleep.

}, keywords = {Animals, Arylamine N-Acetyltransferase, Behavior, Animal, Biogenic Monoamines, Caffeine, Carrier Proteins, Circadian Rhythm, Cytochrome P-450 Enzyme System, Drosophila melanogaster, Drosophila Proteins, Fatty Acid Synthases, Female, Gene Dosage, Gene Expression Profiling, Genes, Insect, Homeostasis, HSC70 Heat-Shock Proteins, HSP70 Heat-Shock Proteins, Hydroxyzine, Mutation, Rest, Sleep, Transcription, Genetic, Wakefulness}, issn = {0036-8075}, author = {Shaw, P J and Cirelli, C and Greenspan, R J and Tononi, G} } @article {153, title = {Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila.}, journal = {Science}, volume = {277}, year = {1997}, month = {1997 Aug 8}, pages = {834-6}, abstract = {

Naturally occuring polymorphisms in behavior are difficult to map genetically and thus are refractory to molecular characterization. An exception is the foraging gene (for), a gene that has two naturally occurring variants in Drosophila melanogaster food-search behavior: rover and sitter. Molecular mapping placed for mutations in the dg2 gene, which encodes a cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG). Rovers had higher PKG activity than sitters, and transgenic sitters expressing a dg2 complementary DNA from rover showed transformation of behavior to rover. Thus, PKG levels affected food-search behavior, and natural variation in PKG activity accounted for a behavioral polymorphism.

}, keywords = {Animals, Animals, Genetically Modified, Cyclic GMP, Cyclic GMP-Dependent Protein Kinases, Drosophila melanogaster, Feeding Behavior, Genes, Insect, Larva, Phenotype, Polymorphism, Genetic, Signal Transduction}, issn = {0036-8075}, author = {Osborne, K A and Robichon, A and Burgess, E and Butland, S and Shaw, R A and Coulthard, A and Pereira, H S and Greenspan, R J and Sokolowski, M B} }