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Bottom-up inputs are required for establishment of top-down connectivity onto cortical layer 1 neurogliaform cells

Ibrahim, Leena Ali; Huang, Shuhan; Fernandez-Otero, Marian; Sherer, Mia; Qiu, Yanjie; Vemuri, Spurti; Xu, Qing; Machold, Robert; Pouchelon, Gabrielle; Rudy, Bernardo; Fishell, Gord
Higher-order projections to sensory cortical areas converge on layer 1 (L1), the primary site for integration of top-down information via the apical dendrites of pyramidal neurons and L1 GABAergic interneurons. Here we investigated the contribution of early thalamic inputs onto L1 interneurons for establishment of top-down connectivity in the primary visual cortex. We find that bottom-up thalamic inputs predominate during L1 development and preferentially target neurogliaform cells. We show that these projections are critical for the subsequent strengthening of top-down inputs from the anterior cingulate cortex onto L1 neurogliaform cells. Sensory deprivation or selective removal of thalamic afferents blocked this phenomenon. Although early activation of the anterior cingulate cortex resulted in premature strengthening of these top-down afferents, this was dependent on thalamic inputs. Our results demonstrate that proper establishment of top-down connectivity in the visual cortex depends critically on bottom-up inputs from the thalamus during postnatal development.
PMID: 34478630
ISSN: 1097-4199
CID: 5079122

Neocortical Layer 1: An Elegant Solution to Top-Down and Bottom-Up Integration

Schuman, Benjamin; Dellal, Shlomo; Prönneke, Alvar; Machold, Robert; Rudy, Bernardo
Many of our daily activities, such as riding a bike to work or reading a book in a noisy cafe, and highly skilled activities, such as a professional playing a tennis match or a violin concerto, depend upon the ability of the brain to quickly make moment-to-moment adjustments to our behavior in response to the results of our actions. Particularly, they depend upon the ability of the neocortex to integrate the information provided by the sensory organs (bottom-up information) with internally generated signals such as expectations or attentional signals (top-down information). This integration occurs in pyramidal cells (PCs) and their long apical dendrite, which branches extensively into a dendritic tuft in layer 1 (L1). The outermost layer of the neocortex, L1 is highly conserved across cortical areas and species. Importantly, L1 is the predominant input layer for top-down information, relayed by a rich, dense mesh of long-range projections that provide signals to the tuft branches of the PCs. Here, we discuss recent progress in our understanding of the composition of L1 and review evidence that L1 processing contributes to functions such as sensory perception, cross-modal integration, controlling states of consciousness, attention, and learning. Expected final online publication date for the Annual Review of Neuroscience, Volume 44 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
PMID: 33730511
ISSN: 1545-4126
CID: 4851042

Sleep down state-active ID2/Nkx2.1 interneurons in the neocortex

Valero, Manuel; Viney, Tim J; Machold, Robert; Mederos, Sara; Zutshi, Ipshita; Schuman, Benjamin; Senzai, Yuta; Rudy, Bernardo; Buzsáki, György
Pyramidal cells and GABAergic interneurons fire together in balanced cortical networks. In contrast to this general rule, we describe a distinct neuron type in mice and rats whose spiking activity is anti-correlated with all principal cells and interneurons in all brain states but, most prevalently, during the down state of non-REM (NREM) sleep. We identify these down state-active (DSA) neurons as deep-layer neocortical neurogliaform cells that express ID2 and Nkx2.1 and are weakly immunoreactive to neuronal nitric oxide synthase. DSA neurons are weakly excited by deep-layer pyramidal cells and strongly inhibited by several other GABAergic cell types. Spiking of DSA neurons modified the sequential firing order of other neurons at down-up transitions. Optogenetic activation of ID2+Nkx2.1+ interneurons in the posterior parietal cortex during NREM sleep, but not during waking, interfered with consolidation of cue discrimination memory. Despite their sparsity, DSA neurons perform critical physiological functions.
PMID: 33619404
ISSN: 1546-1726
CID: 4794392

Cellular birthdate predicts laminar and regional cholinergic projection topography in the forebrain

Allaway, Kathryn C; Muñoz, William; Tremblay, Robin; Sherer, Mia; Herron, Jacob; Rudy, Bernardo; Machold, Robert; Fishell, Gordon
The basal forebrain cholinergic system projects broadly throughout the cortex and constitutes a critical source of neuromodulation for arousal and attention. Traditionally, this system was thought to function diffusely. However, recent studies have revealed a high degree of spatiotemporal specificity in cholinergic signaling. How the organization of cholinergic afferents confers this level of precision remains unknown. Here, using intersectional genetic fate mapping, we demonstrate that cholinergic fibers within the mouse cortex exhibit remarkable laminar and regional specificity and that this is organized in accordance with cellular birthdate. Strikingly, birthdated cholinergic projections within the cortex follow an inside-out pattern of innervation. While early born cholinergic populations target deep layers, late born ones innervate superficial laminae. We also find that birthdate predicts cholinergic innervation patterns within the amygdala, hippocampus, and prefrontal cortex. Our work reveals previously unappreciated specificity within the cholinergic system and the developmental logic by which these circuits are assembled.
PMCID:7758062
PMID: 33355093
ISSN: 2050-084x
CID: 4731082

Author Correction: Innovations present in the primate interneuron repertoire

Krienen, Fenna M; Goldman, Melissa; Zhang, Qiangge; Del Rosario, Ricardo C H; Florio, Marta; Machold, Robert; Saunders, Arpiar; Levandowski, Kirsten; Zaniewski, Heather; Schuman, Benjamin; Wu, Carolyn; Lutservitz, Alyssa; Mullally, Christopher D; Reed, Nora; Bien, Elizabeth; Bortolin, Laura; Fernandez-Otero, Marian; Lin, Jessica D; Wysoker, Alec; Nemesh, James; Kulp, David; Burns, Monika; Tkachev, Victor; Smith, Richard; Walsh, Christopher A; Dimidschstein, Jordane; Rudy, Bernardo; Kean, Leslie S; Berretta, Sabina; Fishell, Gord; Feng, Guoping; McCarroll, Steven A
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
PMID: 33230336
ISSN: 1476-4687
CID: 4684702

Innovations present in the primate interneuron repertoire

Krienen, Fenna M; Goldman, Melissa; Zhang, Qiangge; C H Del Rosario, Ricardo; Florio, Marta; Machold, Robert; Saunders, Arpiar; Levandowski, Kirsten; Zaniewski, Heather; Schuman, Benjamin; Wu, Carolyn; Lutservitz, Alyssa; Mullally, Christopher D; Reed, Nora; Bien, Elizabeth; Bortolin, Laura; Fernandez-Otero, Marian; Lin, Jessica D; Wysoker, Alec; Nemesh, James; Kulp, David; Burns, Monika; Tkachev, Victor; Smith, Richard; Walsh, Christopher A; Dimidschstein, Jordane; Rudy, Bernardo; S Kean, Leslie; Berretta, Sabina; Fishell, Gord; Feng, Guoping; McCarroll, Steven A
Primates and rodents, which descended from a common ancestor around 90 million years ago1, exhibit profound differences in behaviour and cognitive capacity; the cellular basis for these differences is unknown. Here we use single-nucleus RNA sequencing to profile RNA expression in 188,776 individual interneurons across homologous brain regions from three primates (human, macaque and marmoset), a rodent (mouse) and a weasel (ferret). Homologous interneuron types-which were readily identified by their RNA-expression patterns-varied in abundance and RNA expression among ferrets, mice and primates, but varied less among primates. Only a modest fraction of the genes identified as 'markers' of specific interneuron subtypes in any one species had this property in another species. In the primate neocortex, dozens of genes showed spatial expression gradients among interneurons of the same type, which suggests that regional variation in cortical contexts shapes the RNA expression patterns of adult neocortical interneurons. We found that an interneuron type that was previously associated with the mouse hippocampus-the 'ivy cell', which has neurogliaform characteristics-has become abundant across the neocortex of humans, macaques and marmosets but not mice or ferrets. We also found a notable subcortical innovation: an abundant striatal interneuron type in primates that had no molecularly homologous counterpart in mice or ferrets. These interneurons expressed a unique combination of genes that encode transcription factors, receptors and neuropeptides and constituted around 30% of striatal interneurons in marmosets and humans.
PMID: 32999462
ISSN: 1476-4687
CID: 4636632

Heterosynaptic Plasticity Determines the Set Point for Cortical Excitatory-Inhibitory Balance

Field, Rachel E; D'amour, James A; Tremblay, Robin; Miehl, Christoph; Rudy, Bernardo; Gjorgjieva, Julijana; Froemke, Robert C
Excitation in neural circuits must be carefully controlled by inhibition to regulate information processing and network excitability. During development, cortical inhibitory and excitatory inputs are initially mismatched but become co-tuned or balanced with experience. However, little is known about how excitatory-inhibitory balance is defined at most synapses or about the mechanisms for establishing or maintaining this balance at specific set points. Here we show how coordinated long-term plasticity calibrates populations of excitatory-inhibitory inputs onto mouse auditory cortical pyramidal neurons. Pairing pre- and postsynaptic activity induced plasticity at paired inputs and different forms of heterosynaptic plasticity at the strongest unpaired synapses, which required minutes of activity and dendritic Ca2+ signaling to be computed. Theoretical analyses demonstrated how the relative rate of heterosynaptic plasticity could normalize and stabilize synaptic strengths to achieve any possible excitatory-inhibitory correlation. Thus, excitatory-inhibitory balance is dynamic and cell specific, determined by distinct plasticity rules across multiple excitatory and inhibitory synapses.
PMID: 32213321
ISSN: 1097-4199
CID: 4358042

Mining the jewels of the cortex's crowning mystery

Ibrahim, Leena A; Schuman, Ben; Bandler, Rachel; Rudy, Bernardo; Fishell, Gord
Neocortical Layer 1 consists of a dense mesh of excitatory and inhibitory axons, dendrites of pyramidal neurons, as well as neuromodulatory inputs from diverse brain regions. Layer 1 also consists of a sparse population of inhibitory interneurons, which are appropriately positioned to receive and integrate the information from these regions of the brain and modulate cortical processing. Despite being among the sparsest neuronal population in the cortex, Layer 1 interneurons perform powerful computations and have elaborate morphologies. Here we review recent studies characterizing their origin, morphology, physiology, and molecular profiles, as well as their connectivity and in vivo response properties.
PMID: 32480351
ISSN: 1873-6882
CID: 4465962

Mapping Cortical Integration of Sensory and Affective Pain Pathways

Singh, Amrita; Patel, Divya; Li, Anna; Hu, Lizbeth; Zhang, Qiaosheng; Liu, Yaling; Guo, Xinling; Robinson, Eric; Martinez, Erik; Doan, Lisa; Rudy, Bernardo; Chen, Zhe S; Wang, Jing
Pain is an integrated sensory and affective experience. Cortical mechanisms of sensory and affective integration, however, remain poorly defined. Here, we investigate the projection from the primary somatosensory cortex (S1), which encodes the sensory pain information, to the anterior cingulate cortex (ACC), a key area for processing pain affect, in freely behaving rats. By using a combination of optogenetics, in vivo electrophysiology, and machine learning analysis, we find that a subset of neurons in the ACC receives S1 inputs, and activation of the S1 axon terminals increases the response to noxious stimuli in ACC neurons. Chronic pain enhances this cortico-cortical connection, as manifested by an increased number of ACC neurons that respond to S1 inputs and the magnified contribution of these neurons to the nociceptive response in the ACC. Furthermore, modulation of this S1→ACC projection regulates aversive responses to pain. Our results thus define a cortical circuit that plays a potentially important role in integrating sensory and affective pain signals.
PMID: 32220320
ISSN: 1879-0445
CID: 4368562

Densities and Laminar Distributions of Kv3.1b-, PV-, GABA-, and SMI-32-Immunoreactive Neurons in Macaque Area V1

Kelly, Jenna G; García-Marín, Virginia; Rudy, Bernardo; Hawken, Michael J
The Kv3.1b potassium channel subunit is associated with narrow spike widths and fast-spiking properties. In macaque primary visual cortex (V1), subsets of neurons have previously been found to be Kv3.1b-immunoreactive (ir) but not parvalbumin (PV)-ir or not GABA-ir, suggesting that they may be both fast-spiking and excitatory. This population includes Meynert cells, the large layer 5/6 pyramidal neurons that are also labeled by the neurofilament antibody SMI-32. In the present study, triple immunofluorescence labeling and confocal microscopy were used to measure the distribution of Kv3.1b-ir, non-PV-ir, non-GABA-ir neurons across cortical depth in V1, and to determine whether, like the Meynert cells, other Kv3.1b-ir excitatory neurons were also SMI-32-ir pyramidal neurons. We found that Kv3.1b-ir, non-PV-ir, non-GABA-ir neurons were most prevalent in the M pathway-associated layers 4 Cα and 4B. GABAergic neurons accounted for a smaller fraction (11%) of the total neuronal population across layers 1-6 than has previously been reported. Of Kv3.1b-ir neurons, PV expression reliably indicated GABA expression. Kv3.1b-ir, non-PV-ir neurons varied in SMI-32 coimmunoreactivity. The results suggest the existence of a heterogeneous population of excitatory neurons in macaque V1 with the potential for sustained high firing rates, and these neurons were particularly abundant in layers 4B and 4 Cα.
PMID: 29668858
ISSN: 1460-2199
CID: 3043112