@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 {1788, title = {Imaging brain activity during complex social behaviors in Drosophila with Flyception2.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 01 30}, pages = {623}, abstract = {

Optical in vivo recordings from freely walking Drosophila are currently possible only for limited behaviors. Here, we expand the range of accessible behaviors with a retroreflective marker-based tracking and ratiometric brain imaging system, permitting brain activity imaging even in copulating male flies. We discover that P1 neurons, active during courtship, are inactive during copulation, whereas GABAergic mAL neurons remain active during copulation, suggesting a countervailing role of mAL in opposing P1 activity during mating.

}, keywords = {Animals, Brain, Copulation, Courtship, Drosophila, Drosophila Proteins, Female, GABAergic Neurons, Male, Neuroimaging, Neurons, Olfactory Cortex, Sexual Behavior, Animal, Social Behavior}, issn = {2041-1723}, doi = {10.1038/s41467-020-14487-7}, author = {Grover, Dhruv and Katsuki, Takeo and Li, Jinfang and Dawkins, Thomas J and Greenspan, Ralph J} } @article {1669, title = {Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.}, journal = {Transl Psychiatry}, volume = {9}, year = {2019}, month = {2019 01 17}, pages = {24}, abstract = {

SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multielectrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5 cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5 cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5 animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5 adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.

}, keywords = {Animals, Autism Spectrum Disorder, Behavior, Animal, Brain, Female, Genetic Predisposition to Disease, Haploinsufficiency, Heterozygote, Magnetic Resonance Imaging, Male, Methyltransferases, Mice, Mice, Knockout, Mutation, Neurons}, issn = {2158-3188}, doi = {10.1038/s41398-018-0344-y}, author = {Moore, Spencer M and Seidman, Jason S and Ellegood, Jacob and Gao, Richard and Savchenko, Alex and Troutman, Ty D and Abe, Yohei and Stender, Josh and Lee, Daehoon and Wang, Sicong and Voytek, Bradley and Lerch, Jason P and Suh, Hoonkyo and Glass, Christopher K and Muotri, Alysson R} } @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 {1468, title = {Neurotransmitter Switching Regulated by miRNAs Controls Changes in Social Preference.}, journal = {Neuron}, volume = {95}, year = {2017}, month = {2017 Sep 13}, pages = {1319-1333.e5}, abstract = {

Changes in social preference of amphibian larvae result from sustained exposure to kinship odorants. To understand the molecular and cellular mechanisms of this neuroplasticity, we investigated the effects of olfactory system activation on neurotransmitter (NT) expression in accessory olfactory bulb (AOB) interneurons during development. We show that protracted exposure to kin or non-kin odorants\ changes the number of dopamine (DA)- or gamma aminobutyric acid (GABA)-expressing neurons, with\ corresponding changes in attraction/aversion behavior. Changing the relative number of dopaminergic and GABAergic AOB interneurons or locally introducing DA or GABA receptor antagonists alters kinship preference. We then isolate AOB microRNAs (miRs) differentially regulated across these conditions. Inhibition of miR-375 and miR-200b reveals that they target Pax6 and Bcl11b to regulate the dopaminergic and GABAergic phenotypes. The results illuminate the role of NT switching governing experience-dependent social preference. VIDEO ABSTRACT.

}, keywords = {Animals, Choice Behavior, Dopamine, Dopamine Antagonists, GABA Antagonists, gamma-Aminobutyric Acid, Interneurons, MicroRNAs, Neurons, Neurotransmitter Agents, Olfactory Bulb, PAX6 Transcription Factor, Pheromones, Siblings, Social Behavior, Transcription Factors, Xenopus laevis, Xenopus Proteins}, issn = {1097-4199}, doi = {10.1016/j.neuron.2017.08.023}, author = {Dulcis, Davide and Lippi, Giordano and Stark, Christiana J and Do, Long H and Berg, Darwin K and Spitzer, Nicholas C} } @article {1688, title = {Subiculum neurons map the current axis of travel.}, journal = {Nat Neurosci}, volume = {20}, year = {2017}, month = {2017 02}, pages = {170-172}, abstract = {

Flexible navigation demands knowledge of boundaries, routes and their relationships. Within a multi-path environment, a subpopulation of subiculum neurons robustly encoded the axis of travel. The firing of axis-tuned neurons peaked bimodally, at head orientations 180{\textdegree} apart. Environmental manipulations showed these neurons to be anchored to environmental boundaries but to lack axis tuning in an open arena. Axis-tuned neurons thus provide a powerful mechanism for mapping relationships between routes and the larger environmental context.

}, keywords = {Action Potentials, Animals, Brain Mapping, Hippocampus, Male, Neurons, Orientation, Rats, Sprague-Dawley, Space Perception}, issn = {1546-1726}, doi = {10.1038/nn.4464}, author = {Olson, Jacob M and Tongprasearth, Kanyanat and Nitz, Douglas A} } @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 {1672, title = {Temporal and spatial tuning of dorsal lateral geniculate nucleus neurons in unanesthetized rats.}, journal = {J Neurophysiol}, volume = {115}, year = {2016}, month = {2016 06 01}, pages = {2658-71}, abstract = {

Visual response properties of neurons in the dorsolateral geniculate nucleus (dLGN) have been well described in several species, but not in rats. Analysis of responses from the unanesthetized rat dLGN will be needed to develop quantitative models that account for visual behavior of rats. We recorded visual responses from 130 single units in the dLGN of 7 unanesthetized rats. We report the response amplitudes, temporal frequency, and spatial frequency sensitivities in this population of cells. In response to 2-Hz visual stimulation, dLGN cells fired 15.9 {\textpm} 11.4 spikes/s (mean {\textpm} SD) modulated by 10.7 {\textpm} 8.4 spikes/s about the mean. The optimal temporal frequency for full-field stimulation ranged from 5.8 to 19.6 Hz across cells. The temporal high-frequency cutoff ranged from 11.7 to 33.6 Hz. Some cells responded best to low temporal frequency stimulation (low pass), and others were strictly bandpass; most cells fell between these extremes. At 2- to 4-Hz temporal modulation, the spatial frequency of drifting grating that drove cells best ranged from 0.008 to 0.18 cycles per degree (cpd) across cells. The high-frequency cutoff ranged from 0.01 to 1.07 cpd across cells. The majority of cells were driven best by the lowest spatial frequency tested, but many were partially or strictly bandpass. We conclude that single units in the rat dLGN can respond vigorously to temporal modulation up to at least 30 Hz and spatial detail up to 1 cpd. Tuning properties were heterogeneous, but each fell along a continuum; we found no obvious clustering into discrete cell types along these dimensions.

}, keywords = {Animals, Evoked Potentials, Visual, Geniculate Bodies, Male, Neurons, Rats, Rats, Long-Evans, Wakefulness}, issn = {1522-1598}, doi = {10.1152/jn.00812.2014}, author = {Sriram, Balaji and Meier, Philip M and Reinagel, Pamela} } @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 {140, title = {Non-cell-autonomous mechanism of activity-dependent neurotransmitter switching.}, journal = {Neuron}, volume = {82}, year = {2014}, month = {2014 Jun 4}, pages = {1004-16}, abstract = {

Activity-dependent neurotransmitter switching engages genetic programs regulating transmitter synthesis, but the mechanism by which activity is transduced is unknown. We suppressed activity in single neurons in the embryonic spinal cord to determine whether glutamate-gamma-aminobutyric acid (GABA) switching is cell autonomous. Transmitter respecification did not occur, suggesting that it is homeostatically regulated by the level of activity in surrounding neurons. Graded increase in the number of silenced neurons in cultures led to graded decrease in the number of neurons expressing GABA, supporting non-cell-autonomous transmitter switching. We found that brain-derived neurotrophic factor (BDNF) is expressed in the spinal cord during the period of transmitter respecification and that spike activity causes release of BDNF. Activation of TrkB receptors triggers a signaling cascade involving JNK-mediated activation of cJun that regulates tlx3, a glutamate/GABA selector gene, accounting for calcium-spike BDNF-dependent transmitter switching. Our findings identify a molecular mechanism for activity-dependent respecification of neurotransmitter phenotype in developing spinal neurons.

}, keywords = {Animals, Brain-Derived Neurotrophic Factor, Calcium, Cells, Cultured, Female, gamma-Aminobutyric Acid, Glutamic Acid, JNK Mitogen-Activated Protein Kinases, Neurons, Phosphorylation, Proto-Oncogene Proteins c-jun, Signal Transduction, Spinal Cord, Xenopus laevis}, issn = {1097-4199}, doi = {10.1016/j.neuron.2014.04.029}, author = {Guemez-Gamboa, Alicia and Xu, Lin and Meng, Da and Spitzer, Nicholas C} } @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 {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 {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 {183, title = {Selection of distinct populations of dentate granule cells in response to inputs as a mechanism for pattern separation in mice.}, journal = {Elife}, volume = {2}, year = {2013}, month = {2013}, pages = {e00312}, abstract = {

The hippocampus is critical for episodic memory and computational studies have predicted specific functions for each hippocampal subregion. Particularly, the dentate gyrus (DG) is hypothesized to perform pattern separation by forming distinct representations of similar inputs. How pattern separation is achieved by the DG remains largely unclear. By examining neuronal activities at a population level, we revealed that, unlike CA1 neuron populations, dentate granule cell (DGC) ensembles activated by learning were not preferentially reactivated by memory recall. Moreover, when mice encountered an environment to which they had not been previously exposed, a novel DGC population-rather than the previously activated DGC ensembles that responded to past events-was selected to represent the new environmental inputs. This selection of a novel responsive DGC population could be triggered by small changes in environmental inputs. Therefore, selecting distinct DGC populations to represent similar but not identical inputs is a mechanism for pattern separation. DOI:http://dx.doi.org/10.7554/eLife.00312.001.

}, keywords = {Animals, Behavior, Animal, Brain Mapping, CA1 Region, Hippocampal, Conditioning (Psychology), Cues, Dentate Gyrus, Environment, Fear, Gene Expression Regulation, Genes, Reporter, Memory, Memory, Episodic, Mental Recall, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Neural Pathways, Neurons, Pattern Recognition, Physiological, Time Factors}, issn = {2050-084X}, doi = {10.7554/eLife.00312}, author = {Deng, Wei and Mayford, Mark and Gage, Fred H} } @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 {137, title = {Spatial and temporal second messenger codes for growth cone turning.}, journal = {Proc Natl Acad Sci U S A}, volume = {108}, year = {2011}, month = {2011 Aug 16}, pages = {13776-81}, abstract = {

Cyclic AMP (cAMP) and calcium are ubiquitous, interdependent second messengers that regulate a wide range of cellular processes. During development of neuronal networks they are critical for the first step of circuit formation, transducing signals required for axon pathfinding. Surprisingly, the spatial and temporal cAMP and calcium codes used by axon guidance molecules are unknown. Here, we identify characteristics of cAMP and calcium transients generated in growth cones during Netrin-1-dependent axon guidance. In filopodia, Netrin-1-dependent Deleted in Colorectal Cancer (DCC) receptor activation induces a transient increase in cAMP that causes a brief increase in calcium transient frequency. In contrast, activation of DCC in growth cone centers leads to a transient calcium-dependent cAMP increase and a sustained increase in frequency of calcium transients. We show that filopodial cAMP transients regulate spinal axon guidance in vitro and commissural axon pathfinding in vivo. These growth cone codes provide a basis for selective activation of specific downstream effectors.

}, keywords = {Animals, Axons, Calcium, Cells, Cultured, Cyclic AMP, Growth Cones, Nerve Growth Factors, Neurons, Pseudopodia, Receptors, Cell Surface, Second Messenger Systems, Tumor Suppressor Proteins, Xenopus}, issn = {1091-6490}, doi = {10.1073/pnas.1100247108}, author = {Nicol, Xavier and Hong, Kwan Pyo and Spitzer, Nicholas C} } @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 {136, title = {Activity-dependent expression of Lmx1b regulates specification of serotonergic neurons modulating swimming behavior.}, journal = {Neuron}, volume = {67}, year = {2010}, month = {2010 Jul 29}, pages = {321-34}, abstract = {

Genetic programs, environmental factors, and electrical activity interact to drive the maturation of the brain. Although the cascade of transcription factors that leads to specification of the serotonergic phenotype has been well characterized, its interactions with electrical activity are not known. Here we show that spontaneous calcium spike activity in the hindbrain of developing Xenopus laevis larvae modulates the specification of serotonergic neurons via regulation of expression of the Lmx1b transcription factor. Activity acts downstream of Nkx2.2 but upstream of Lmx1b, leading to regulation of the serotonergic phenotype. Using global manipulation of activity and targeted alteration of Lmx1b expression, we also demonstrate that changes in the number of serotonergic neurons change larval swimming behavior. The results link activity-dependent regulation of a transcription factor to transmitter specification and altered behavior.

}, keywords = {Action Potentials, Animals, Behavior, Animal, Bromodeoxyuridine, Calcium, Electroporation, Embryo, Nonmammalian, gamma-Aminobutyric Acid, Gene Expression Regulation, Developmental, Green Fluorescent Proteins, Homeodomain Proteins, Membrane Potentials, Neurons, Otx Transcription Factors, Potassium Channels, Inwardly Rectifying, Raphe Nuclei, RNA, Messenger, Serotonin, Sodium Channels, Statistics, Nonparametric, Swimming, Transcription Factors, Tryptophan Hydroxylase, Xenopus laevis, Xenopus Proteins}, issn = {1097-4199}, doi = {10.1016/j.neuron.2010.06.006}, author = {Demarque, Micha{\"e}l and Spitzer, Nicholas C} } @article {174, title = {Adult neurogenesis: integrating theories and separating functions.}, journal = {Trends Cogn Sci}, volume = {14}, year = {2010}, month = {2010 Jul}, pages = {325-37}, abstract = {

The continuous incorporation of new neurons in the dentate gyrus of the adult hippocampus raises exciting questions about memory and learning, and has inspired new computational models to understand the function of adult neurogenesis. These theoretical approaches suggest distinct roles for new neurons as they slowly integrate into the existing dentate gyrus network: immature adult-born neurons seem to function as pattern integrators of temporally adjacent events, thereby enhancing pattern separation for events separated in time; whereas maturing adult-born neurons possibly contribute to pattern separation by being more amenable to learning new information, leading to dedicated groups of granule cells that respond to experienced environments. We review these hypothesized functions and supporting empirical research and point to new directions for future theoretical efforts.

}, keywords = {Adult, Adult Stem Cells, Animals, Cell Proliferation, Hippocampus, Humans, Models, Biological, Neurogenesis, Neurons}, issn = {1879-307X}, doi = {10.1016/j.tics.2010.04.003}, author = {Aimone, James B and Deng, Wei and Gage, Fred H} } @article {135, title = {cJun integrates calcium activity and tlx3 expression to regulate neurotransmitter specification.}, journal = {Nat Neurosci}, volume = {13}, year = {2010}, month = {2010 Aug}, pages = {944-50}, abstract = {

Neuronal differentiation is accomplished through cascades of intrinsic genetic factors initiated in neuronal progenitors by external gradients of morphogens. Activity has been thought to be important only late in development, but recent evidence suggests that activity also regulates early neuronal differentiation. Activity in post-mitotic neurons before synapse formation can regulate phenotypic specification, including neurotransmitter choice, but the mechanisms are not clear. We identified a mechanism that links endogenous calcium spike activity with an intrinsic genetic pathway to specify neurotransmitter choice in neurons in the dorsal embryonic spinal cord of Xenopus tropicalis. Early activity modulated transcription of the GABAergic/glutamatergic selection gene tlx3 through a variant cAMP response element (CRE) in its promoter. The cJun transcription factor bound to this CRE site, modulated transcription and regulated neurotransmitter phenotype via its transactivation domain. Calcium signaled through cJun N-terminal phosphorylation, which integrated activity-dependent and intrinsic neurotransmitter specification. This mechanism provides a basis for early activity to regulate genetic pathways at critical decision points, switching the phenotype of developing neurons.

}, keywords = {Animals, Base Sequence, Calcium, Calcium Signaling, Electrophoretic Mobility Shift Assay, Gene Expression, Gene Expression Regulation, Developmental, Homeodomain Proteins, Immunohistochemistry, In Situ Hybridization, Molecular Sequence Data, Neurogenesis, Neurons, Neurotransmitter Agents, Promoter Regions, Genetic, Proto-Oncogene Proteins c-jun, Response Elements, Reverse Transcriptase Polymerase Chain Reaction, Xenopus, Xenopus Proteins}, issn = {1546-1726}, doi = {10.1038/nn.2582}, author = {Marek, Kurt W and Kurtz, Lisa M and Spitzer, Nicholas C} } @article {182, title = {New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?}, journal = {Nat Rev Neurosci}, volume = {11}, year = {2010}, month = {2010 May}, pages = {339-50}, abstract = {

The integration of adult-born neurons into the circuitry of the adult hippocampus suggests an important role for adult hippocampal neurogenesis in learning and memory, but its specific function in these processes has remained elusive. In this article, we summarize recent progress in this area, including advances based on behavioural studies and insights provided by computational modelling. Increasingly, evidence suggests that newborn neurons might be involved in hippocampal functions that are particularly dependent on the dentate gyrus, such as pattern separation. Furthermore, newborn neurons at different maturation stages may make distinct contributions to learning and memory. In particular, computational studies suggest that, before newborn neurons are fully mature, they might function as a pattern integrator by introducing a degree of similarity to the encoding of events that occur closely in time.

}, keywords = {Adult Stem Cells, Animals, Hippocampus, Humans, Learning, Memory, Models, Neurological, Neurogenesis, Neurons}, issn = {1471-0048}, doi = {10.1038/nrn2822}, author = {Deng, Wei and Aimone, James B and Gage, Fred H} } @article {134, title = {Target-dependent regulation of neurotransmitter specification and embryonic neuronal calcium spike activity.}, journal = {J Neurosci}, volume = {30}, year = {2010}, month = {2010 Apr 21}, pages = {5792-801}, abstract = {

Neurotransmitter specification has been shown to depend on genetic programs and electrical activity; however, target-dependent regulation also plays important roles in neuronal development. We have investigated the impact of muscle targets on transmitter specification in Xenopus spinal neurons using a neuron-muscle coculture system. We find that neuron-muscle contact reduces the number of neurons expressing the noncholinergic transmitters GABA, glycine, and glutamate, while having no effect on the incidence of ChAT expression. We show that muscle activity is necessary for target-dependent reduction of noncholinergic transmitter expression. In addition, we demonstrate that coculture with muscle cells suppresses early spontaneous calcium spike activity in neurons and the presence of muscle cells abolishes activity-dependent transmitter specification. The results indicate that target-dependent regulation can be crucial in establishing neurotransmitter phenotypes and altering early neuronal excitability.

}, keywords = {Animals, Calcium Signaling, Cells, Cultured, Coculture Techniques, Myoblasts, Neurons, Neurotransmitter Agents, Xenopus laevis}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.5659-09.2010}, author = {Xiao, Qian and Xu, Lin and Spitzer, Nicholas C} } @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 {175, title = {Computational influence of adult neurogenesis on memory encoding.}, journal = {Neuron}, volume = {61}, year = {2009}, month = {2009 Jan 29}, pages = {187-202}, abstract = {

Adult neurogenesis in the hippocampus leads to the incorporation of thousands of new granule cells into the dentate gyrus every month, but its function remains unclear. Here, we present computational evidence that indicates that adult neurogenesis may make three separate but related contributions to memory formation. First, immature neurons introduce a degree of similarity to memories learned at the same time, a process we refer to as pattern integration. Second, the extended maturation and change in excitability of these neurons make this added similarity a time-dependent effect, supporting the possibility that temporal information is included in new hippocampal memories. Finally, our model suggests that the experience-dependent addition of neurons results in a dentate gyrus network well suited for encoding new memories in familiar contexts while treating novel contexts differently. Taken together, these results indicate that new granule cells may affect hippocampal function in several unique and previously unpredicted ways.

}, keywords = {Age Factors, Algorithms, Animals, Cell Proliferation, Computer Simulation, Dentate Gyrus, Humans, Memory, Nerve Net, Neural Pathways, Neurogenesis, Neuronal Plasticity, Neurons, Stem Cells, Synapses, Time Perception}, issn = {1097-4199}, doi = {10.1016/j.neuron.2008.11.026}, author = {Aimone, James B and Wiles, Janet and Gage, Fred H} } @article {132, title = {Embryonically expressed GABA and glutamate drive electrical activity regulating neurotransmitter specification.}, journal = {J Neurosci}, volume = {28}, year = {2008}, month = {2008 Apr 30}, pages = {4777-84}, abstract = {

Neurotransmitter signaling in the mature nervous system is well understood, but the functions of transmitters in the immature nervous system are less clear. Although transmitters released during embryogenesis regulate neuronal proliferation and migration, little is known about their role in regulating early neuronal differentiation. Here, we show that GABA and glutamate drive calcium-dependent embryonic electrical activity that regulates transmitter specification. The number of neurons expressing different transmitters changes when GABA or glutamate signaling is blocked chronically, either using morpholinos to knock down transmitter-synthetic enzymes or applying pharmacological receptor antagonists during a sensitive period of development. We find that calcium spikes are triggered by metabotropic GABA and glutamate receptors, which engage protein kinases A and C. The results reveal a novel role for embryonically expressed neurotransmitters.

}, keywords = {Animals, Antigens, CD57, Calcium, Choline O-Acetyltransferase, Embryo, Nonmammalian, Enzyme Inhibitors, Excitatory Amino Acid Antagonists, GABA Antagonists, gamma-Aminobutyric Acid, Gene Expression Regulation, Developmental, Glutamate Decarboxylase, Glutamic Acid, Health Services Research, Larva, Morpholines, Neurons, Phosphoserine, Receptors, GABA, Receptors, Glutamate, Synapses, Vesicular Glutamate Transport Proteins, Xenopus}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.4873-07.2008}, author = {Root, Cory M and Vel{\'a}zquez-Ulloa, Norma A and Monsalve, Gabriela C and Minakova, Elena and Spitzer, Nicholas C} } @article {133, title = {Illumination controls differentiation of dopamine neurons regulating behaviour.}, journal = {Nature}, volume = {456}, year = {2008}, month = {2008 Nov 13}, pages = {195-201}, abstract = {

Specification of the appropriate neurotransmitter is a crucial step in neuronal differentiation because it enables signalling among populations of neurons. Experimental manipulations demonstrate that both autonomous and activity-dependent genetic programs contribute to this process during development, but whether natural environmental stimuli specify transmitter expression in a neuronal population is unknown. We investigated neurons of the ventral suprachiasmatic nucleus that regulate neuroendocrine pituitary function in response to light in teleosts, amphibia and primates. Here we show that altering light exposure, which changes the sensory input to the circuit controlling adaptation of skin pigmentation to background, changes the number of neurons expressing dopamine in larvae of the amphibian Xenopus laevis in a circuit-specific and activity-dependent manner. Neurons newly expressing dopamine then regulate changes in camouflage colouration in response to illumination. Thus, physiological activity alters the numbers of behaviourally relevant amine-transmitter-expressing neurons in the brain at postembryonic stages of development. The results may be pertinent to changes in cognitive states that are regulated by biogenic amines.

}, keywords = {Animals, Behavior, Animal, Cell Count, Cell Differentiation, Chelating Agents, Dopamine, Egtazic Acid, Gene Expression Regulation, Developmental, Larva, Light, Lighting, Melanotrophs, Neurons, Neuropeptide Y, Photic Stimulation, Skin Pigmentation, Sodium Channel Blockers, Suprachiasmatic Nucleus, Tetrodotoxin, Xenopus laevis}, issn = {1476-4687}, doi = {10.1038/nature07569}, author = {Dulcis, Davide and Spitzer, Nicholas C} } @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 {149, title = {Salience modulates 20-30 Hz brain activity in Drosophila.}, journal = {Nat Neurosci}, volume = {6}, year = {2003}, month = {2003 Jun}, pages = {579-86}, abstract = {

Fruit flies selectively orient toward the visual stimuli that are most salient in their environment. We recorded local field potentials (LFPs) from the brains of Drosophila melanogaster as they responded to the presentation of visual stimuli. Coupling of salience effects (odor, heat or novelty) to these stimuli modulated LFPs in the 20-30 Hz range by evoking a transient, selective increase. We demonstrated the association of these responses with behavioral tracking and initiated a genetic approach to investigating neural correlates of perception.

}, keywords = {Action Potentials, Animals, Attention, Behavior, Animal, Brain, Cues, Drosophila, Drosophila Proteins, Exploratory Behavior, Mutation, Neurons, Orientation, Retina, Smell, Synaptic Transmission, Thermosensing, Visual Pathways, Visual Perception}, issn = {1097-6256}, doi = {10.1038/nn1054}, author = {van Swinderen, Bruno and Greenspan, Ralph J} }