Circuit mechanisms for the chemical modulation of cortex-wide network interactions and behavioral variability

Influential theories postulate distinct roles of catecholamines and acetylcholine in cognition and behavior. However, previous physiological work reported similar effects of these neuromodulators on the response properties (specifically, the gain) of individual cortical neurons. Here, we show a double dissociation between the effects of catecholamines and acetylcholine at the level of large-scale interactions between cortical areas in humans. A pharmacological boost of catecholamine levels increased cortex-wide interactions during a visual task, but not rest. An acetylcholine boost decreased interactions during rest, but not task. Cortical circuit modeling explained this dissociation by differential changes in two circuit properties: the local excitation-inhibition balance (more strongly increased by catecholamines) and intracortical transmission (more strongly reduced by acetylcholine). The inferred catecholaminergic mechanism also predicted noisier decision-making, which we confirmed for both perceptual and value-based choice behavior. Our work highlights specific circuit mechanisms for shaping cortical network interactions and behavioral variability by key neuromodulatory systems.

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Circuit mechanisms for chemical modulation of cortex-wide network interactions and exploration behavior

10.1101/2020.06.25.171199 ◽

2020 ◽

Author(s):

T. Pfeffer ◽

A. Ponce-Alvarez ◽

T. Meindertsma ◽

C. Gahnström ◽

R. L. van den Brink ◽

...

Keyword(s):

Cortical Neurons ◽

Choice Task ◽

Circuit Modeling ◽

Local Excitation ◽

Double Dissociation ◽

Exploration Behavior ◽

Cortical Circuit ◽

Chemical Modulation ◽

And Behavior ◽

Catecholamine Levels

AbstractInfluential accounts postulate distinct roles of the catecholamine and acetylcholine neuromodulatory systems in cognition and behavior. But previous work found similar effects of these modulators on the response properties of individual cortical neurons. Here, we report a double dissociation between catecholamine and acetylcholine effects at the level of cortex-wide network interactions in humans. A pharmacological boost of catecholamine levels increased cortex-wide interactions during a visual task, but not rest. Conversely, an acetylcholine-boost decreased correlations during rest, but not task. Cortical circuit modeling explained this dissociation by differential changes in two circuit properties: the local excitation-inhibition balance (more strongly altered by catecholamines) and intracortical transmission (more strongly reduced by acetylcholine). The inferred catecholaminergic mechanism also predicted increased behavioral exploration, which we confirmed in human behavior during both a perceptual and value-based choice task. In sum, we identified specific circuit mechanisms for shaping cortex-wide network interactions and behavior by key neuromodulatory systems.

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Inferring cortical function in the mouse visual system through large-scale systems neuroscience

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1512901113 ◽

2016 ◽

Vol 113 (27) ◽

pp. 7337-7344 ◽

Cited By ~ 48

Author(s):

Michael Hawrylycz ◽

Costas Anastassiou ◽

Anton Arkhipov ◽

Jim Berg ◽

Michael Buice ◽

...

Keyword(s):

Cortical Neurons ◽

Large Scale ◽

Model Organism ◽

Building Blocks ◽

Mammalian Brain ◽

Cortical Function ◽

Scientific Mission ◽

Large Populations ◽

Cell Type Specific ◽

And Behavior

The scientific mission of the Project MindScope is to understand neocortex, the part of the mammalian brain that gives rise to perception, memory, intelligence, and consciousness. We seek to quantitatively evaluate the hypothesis that neocortex is a relatively homogeneous tissue, with smaller functional modules that perform a common computational function replicated across regions. We here focus on the mouse as a mammalian model organism with genetics, physiology, and behavior that can be readily studied and manipulated in the laboratory. We seek to describe the operation of cortical circuitry at the computational level by comprehensively cataloging and characterizing its cellular building blocks along with their dynamics and their cell type-specific connectivities. The project is also building large-scale experimental platforms (i.e., brain observatories) to record the activity of large populations of cortical neurons in behaving mice subject to visual stimuli. A primary goal is to understand the series of operations from visual input in the retina to behavior by observing and modeling the physical transformations of signals in the corticothalamic system. We here focus on the contribution that computer modeling and theory make to this long-term effort.

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Dehydroepiandrosterone (DHEA) and its Sulphate (DHEAS) in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205017666200317092310 ◽

2020 ◽

Vol 17 (2) ◽

pp. 141-157 ◽

Cited By ~ 2

Author(s):

Dubravka S. Strac ◽

Marcela Konjevod ◽

Matea N. Perkovic ◽

Lucija Tudor ◽

Gordana N. Erjavec ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

Therapeutic Potential ◽

Relevant Literature ◽

Comprehensive Overview ◽

Brain Functions ◽

Specific Effects ◽

And Behavior

Background: Neurosteroids Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulphate (DHEAS) are involved in many important brain functions, including neuronal plasticity and survival, cognition and behavior, demonstrating preventive and therapeutic potential in different neuropsychiatric and neurodegenerative disorders, including Alzheimer’s disease. Objective: The aim of the article was to provide a comprehensive overview of the literature on the involvement of DHEA and DHEAS in Alzheimer’s disease. Method: PubMed and MEDLINE databases were searched for relevant literature. The articles were selected considering their titles and abstracts. In the selected full texts, lists of references were searched manually for additional articles. Results: We performed a systematic review of the studies investigating the role of DHEA and DHEAS in various in vitro and animal models, as well as in patients with Alzheimer’s disease, and provided a comprehensive discussion on their potential preventive and therapeutic applications. Conclusion: Despite mixed results, the findings of various preclinical studies are generally supportive of the involvement of DHEA and DHEAS in the pathophysiology of Alzheimer’s disease, showing some promise for potential benefits of these neurosteroids in the prevention and treatment. However, so far small clinical trials brought little evidence to support their therapy in AD. Therefore, large-scale human studies are needed to elucidate the specific effects of DHEA and DHEAS and their mechanisms of action, prior to their applications in clinical practice.

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Subcortical circuits mediate communication between primary sensory cortical areas in mice

Nature Communications ◽

10.1038/s41467-021-24200-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Michael Lohse ◽

Johannes C. Dahmen ◽

Victoria M. Bajo ◽

Andrew J. King

Keyword(s):

Cortical Neurons ◽

Common Property ◽

Primary Auditory Cortex ◽

Facilitatory Effect ◽

Thalamic Nuclei ◽

Auditory Midbrain ◽

Cortical Areas ◽

Auditory Responses ◽

Evoked Activity

AbstractIntegration of information across the senses is critical for perception and is a common property of neurons in the cerebral cortex, where it is thought to arise primarily from corticocortical connections. Much less is known about the role of subcortical circuits in shaping the multisensory properties of cortical neurons. We show that stimulation of the whiskers causes widespread suppression of sound-evoked activity in mouse primary auditory cortex (A1). This suppression depends on the primary somatosensory cortex (S1), and is implemented through a descending circuit that links S1, via the auditory midbrain, with thalamic neurons that project to A1. Furthermore, a direct pathway from S1 has a facilitatory effect on auditory responses in higher-order thalamic nuclei that project to other brain areas. Crossmodal corticofugal projections to the auditory midbrain and thalamus therefore play a pivotal role in integrating multisensory signals and in enabling communication between different sensory cortical areas.

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Cortical neurons exhibit diverse myelination patterns that scale between mouse brain regions and regenerate after demyelination

Nature Communications ◽

10.1038/s41467-021-25035-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Cody L. Call ◽

Dwight E. Bergles

Keyword(s):

Cortical Neurons ◽

Regional Differences ◽

Brain Regions ◽

Axon Diameter ◽

Neuronal Identity ◽

Cortical Areas ◽

Myelin Sheaths ◽

Parvalbumin Interneurons ◽

Selection Of

ABSTRACTAxons in the cerebral cortex show a broad range of myelin coverage. Oligodendrocytes establish this pattern by selecting a cohort of axons for myelination; however, the distribution of myelin on distinct neurons and extent of internode replacement after demyelination remain to be defined. Here we show that myelination patterns of seven distinct neuron subtypes in somatosensory cortex are influenced by both axon diameter and neuronal identity. Preference for myelination of parvalbumin interneurons was preserved between cortical areas with varying myelin density, suggesting that regional differences in myelin abundance arises through local control of oligodendrogenesis. By imaging loss and regeneration of myelin sheaths in vivo we show that myelin distribution on individual axons was altered but overall myelin content on distinct neuron subtypes was restored. Our findings suggest that local changes in myelination are tolerated, allowing regenerated oligodendrocytes to restore myelin content on distinct neurons through opportunistic selection of axons.

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Multiple Alu exonization in 3’UTR of a primate specific isoform of CYP20A1 creates a potential miRNA sponge

Genome Biology and Evolution ◽

10.1093/gbe/evaa233 ◽

2020 ◽

Author(s):

Aniket Bhattacharya ◽

Vineet Jha ◽

Khushboo Singhal ◽

Mahar Fatima ◽

Dayanidhi Singh ◽

...

Keyword(s):

Heat Shock ◽

Cortical Neurons ◽

Regulatory Networks ◽

Large Scale ◽

Neuronal Development ◽

Random Sets ◽

Rna Seq ◽

Orphan Gene ◽

Mirna Sponge ◽

Human Neurons

Abstract Alu repeats contribute to phylogenetic novelties in conserved regulatory networks in primates. Our study highlights how exonized Alus could nucleate large-scale mRNA-miRNA interactions. Using a functional genomics approach, we characterize a transcript isoform of an orphan gene, CYP20A1 (CYP20A1_Alu-LT) that has exonization of 23 Alus in its 3’UTR. CYP20A1_Alu-LT, confirmed by 3’RACE, is an outlier in length (9 kb 3’UTR) and widely expressed. Using publically available datasets, we demonstrate its expression in higher primates and presence in single nucleus RNA-seq of 15928 human cortical neurons. miRanda predicts ∼4700 miRNA recognition elements (MREs) for ∼1000 miRNAs, primarily originated within these 3’UTR-Alus. CYP20A1_Alu-LT could be a potential multi-miRNA sponge as it harbors ≥10 MREs for 140 miRNAs and has cytosolic localization. We further tested whether expression of CYP20A1_Alu-LT correlates with mRNAs harboring similar MRE targets. RNA-seq with conjoint miRNA-seq analysis was done in primary human neurons where we observed CYP20A1_Alu-LT to be downregulated during heat shock response and upregulated in HIV1-Tat treatment. 380 genes were positively correlated with its expression (significantly downregulated in heat shock and upregulated in Tat) and they harbored MREs for nine expressed miRNAs which were also enriched in CYP20A1_Alu-LT. MREs were significantly enriched in these 380 genes compared to random sets of differentially expressed genes (p = 8.134e-12). Gene ontology suggested involvement of these genes in neuronal development and hemostasis pathways thus proposing a novel component of Alu-miRNA mediated transcriptional modulation that could govern specific physiological outcomes in higher primates.

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Pilot Clinical Trial of Time-Restricted Eating in Patients with Metabolic Syndrome

Nutrients ◽

10.3390/nu13020346 ◽

2021 ◽

Vol 13 (2) ◽

pp. 346

Author(s):

Iwona Świątkiewicz ◽

Celestyna Mila-Kierzenkowska ◽

Alina Woźniak ◽

Karolina Szewczyk-Golec ◽

Jarosław Nuszkiewicz ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Clinical Trial ◽

Dietary Intake ◽

Large Scale ◽

Controlled Trial ◽

European Population ◽

Cardiac Biomarkers ◽

Cardiometabolic Health ◽

And Behavior

Metabolic syndrome (MetS) and erratic eating patterns are associated with circadian rhythm disruption which contributes to an increased cardiometabolic risks. Restricting eating period (time-restricted eating, TRE) can restore robust circadian rhythms and improve cardiometabolic health. We describe a protocol of the Time-Restricted Eating on Metabolic and Neuroendocrine homeostasis, Inflammation, and Oxidative Stress (TREMNIOS) pilot clinical trial in Polish adult patients with MetS and eating period of ≥14 h/day. The study aims to test the feasibility of TRE intervention and methodology for evaluating its efficacy for improving metabolic, neuroendocrine, inflammatory, oxidative stress and cardiac biomarkers, and daily rhythms of behavior for such population. Participants will apply 10-h TRE over a 12-week monitored intervention followed by a 12-week self-directed intervention. Changes in eating window, body weight and composition, biomarkers, and rhythms of behavior will be evaluated. Dietary intake, sleep, activity and wellbeing will be monitored with the myCircadianClock application and questionnaires. Adherence to TRE defined as the proportion of days recorded with app during the monitored intervention in which participants satisfied 10-h TRE is the primary outcome. TREMNIOS will also provide an exploratory framework to depict post-TRE changes in cardiometabolic outcomes and behavior rhythms. This protocol extends previous TRE-related protocols by targeting European population with diagnosed MetS and including long-term intervention, validated tools for monitoring dietary intake and adherence, and comprehensive range of biomarkers. TREMNIOS trial will lay the groundwork for a large-scale randomized controlled trial to determine TRE efficacy for improving cardiometabolic health in MetS population.

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Gang Research in the Twenty-First Century

Annual Review of Criminology ◽

10.1146/annurev-criminol-030920-094656 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Caylin Louis Moore ◽

Forrest Stuart

Keyword(s):

Large Scale ◽

Criminological Theory ◽

First Century ◽

Annual Review ◽

Publication Date ◽

Theoretical Frameworks ◽

Twenty First Century ◽

State Interventions ◽

And Behavior ◽

Analytical Approaches

For nearly a century, gang scholarship has remained foundational to criminological theory and method. Twenty-first-century scholarship continues to refine and, in some cases, supplant long-held axioms about gang formation, organization, and behavior. Recent advances can be traced to shifts in the empirical social reality and conditions within which gangs exist and act. We draw out this relationship—between the ontological and epistemological—by identifying key macrostructural shifts that have transformed gang composition and behavior and, in turn, forced scholars to revise dominant theoretical frameworks and analytical approaches. These shifts include large-scale economic transformations, the expansion of punitive state interventions, the proliferation of the Internet and social media, intensified globalization, and the increasing presence of women and LGBTQ individuals in gangs and gang research. By introducing historically unprecedented conditions and actors, these developments provide novel opportunities to reconsider previous analyses of gang structure, violence, and other related objects of inquiry. Expected final online publication date for the Annual Review of Criminology, Volume 5 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Neural mechanisms of context-dependent segmentation tested on large-scale recording data

10.1101/2021.04.25.441363 ◽

2021 ◽

Author(s):

Toshitake Asabuki ◽

Tomoki Fukai

Keyword(s):

Cortical Neurons ◽

Large Scale ◽

Neural Mechanism ◽

Imaging Data ◽

Unsupervised Segmentation ◽

Spike Sequences ◽

Multiple Cell ◽

Context Dependent ◽

Current Flows ◽

The Given

The brain performs various cognitive functions by learning the spatiotemporal salient features of the environment. This learning likely requires unsupervised segmentation of hierarchically organized spike sequences, but the underlying neural mechanism is only poorly understood. Here, we show that a recurrent gated network of neurons with dendrites can context-dependently solve difficult segmentation tasks. Dendrites in this model learn to predict somatic responses in a self-supervising manner while recurrent connections learn a context-dependent gating of dendro-somatic current flows to minimize a prediction error. These connections select particular information suitable for the given context from input features redundantly learned by the dendrites. The model selectively learned salient segments in complex synthetic sequences. Furthermore, the model was also effective for detecting multiple cell assemblies repeating in large-scale calcium imaging data of more than 6,500 cortical neurons. Our results suggest that recurrent gating and dendrites are crucial for cortical learning of context-dependent segmentation tasks.

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Perinatal fentanyl exposure leads to long-lasting impairments in somatosensory circuit function and behavior

10.1101/2020.09.19.304352 ◽

2020 ◽

Author(s):

Jason Alipio ◽

Catherine Haga ◽

Megan E Fox ◽

Keiko Arakawa ◽

Rakshita Balaji ◽

...

Keyword(s):

Cortical Neurons ◽

Morphological Changes ◽

Anterior Cingulate ◽

Preclinical Model ◽

Sensory Stimuli ◽

Synaptic Excitation ◽

Molecular Abnormalities ◽

Postsynaptic Currents ◽

And Behavior

One consequence of the opioid epidemic are lasting neurodevelopmental sequelae afflicting adolescents exposed to opioids in the womb. A translationally relevant and developmentally accurate preclinical model is needed to understand the behavioral, circuit, network, and molecular abnormalities resulting from this exposure. By employing a novel preclinical model of perinatal fentanyl exposure, our data reveal that fentanyl has several dose-dependent, developmental consequences to somatosensory function and behavior. Newborn male and female mice exhibit signs of withdrawal and sensory-related deficits that extend at least to adolescence. As fentanyl exposure does not affect dams' health or maternal behavior, these effects result from the direct actions of perinatal fentanyl on the pups' developing brain. At adolescence, exposed mice exhibit reduced adaptation to sensory stimuli, and a corresponding impairment in primary somatosensory (S1) function. In vitro electrophysiology demonstrates a long-lasting reduction in S1 synaptic excitation, evidenced by decreases in release probability, NMDA receptor-mediated postsynaptic currents, and frequency of miniature excitatory postsynaptic currents, as well as increased frequency of miniature inhibitory postsynaptic currents. In contrast, anterior cingulate cortical neurons exhibit an opposite phenotype, with increased synaptic excitation. Consistent with these changes, electrocorticograms reveal suppressed ketamine-evoked γ oscillations. Morphological analysis of S1 pyramidal neurons indicate reduced dendritic complexity, dendritic length, and soma size. Further, exposed mice exhibited abnormal cortical mRNA expression of key receptors and neuronal growth and development, changes that were consistent with the electrophysiological and morphological changes. These findings demonstrate the lasting sequelae of perinatal fentanyl exposure on sensory processing and function.

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