Brain network dynamics during working memory are modulated by dopamine and diminished in schizophrenia

AbstractDynamical brain state transitions are critical for flexible working memory but the network mechanisms are incompletely understood. Here, we show that working memory performance entails brain-wide switching between activity states using a combination of functional magnetic resonance imaging in healthy controls and individuals with schizophrenia, pharmacological fMRI, genetic analyses and network control theory. The stability of states relates to dopamine D1 receptor gene expression while state transitions are influenced by D2 receptor expression and pharmacological modulation. Individuals with schizophrenia show altered network control properties, including a more diverse energy landscape and decreased stability of working memory representations. Our results demonstrate the relevance of dopamine signaling for the steering of whole-brain network dynamics during working memory and link these processes to schizophrenia pathophysiology.

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Brain state stability during working memory is explained by network control theory, modulated by dopamine D1/D2 receptor function, and diminished in schizophrenia

10.1101/679670 ◽

2019 ◽

Cited By ~ 6

Author(s):

Urs Braun ◽

Anais Harneit ◽

Giulio Pergola ◽

Tommaso Menara ◽

Axel Schaefer ◽

...

Keyword(s):

Working Memory ◽

Receptor Gene ◽

D2 Receptor ◽

Network Control ◽

D1 Receptor ◽

Receptor Expression ◽

State Transitions ◽

Brain State ◽

Memory Representations ◽

The Stability

Dynamical brain state transitions are critical for flexible working memory but the network mechanisms are incompletely understood. Here, we show that working memory entails brain-wide switching between activity states. The stability of states relates to dopamine D1 receptor gene expression while state transitions are influenced by D2 receptor expression and pharmacological modulation. Schizophrenia patients show altered network control properties, including a more diverse energy landscape and decreased stability of working memory representations.

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Abstract 432: Up-regulation of Calcyon Increases Arterial Pressure via Enhancement of Adrenergic Transmission

Hypertension ◽

10.1161/hyp.62.suppl_1.a432 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Ahmed A Elmarakby ◽

Almira Vazdarjanova ◽

Clare Bergson

Keyword(s):

Working Memory ◽

Arterial Pressure ◽

Executive Functions ◽

Spontaneously Hypertensive Rat ◽

D1 Receptor ◽

Receptor Expression ◽

Common Mechanism ◽

Normal Physiological Condition ◽

Adrenergic Transmission ◽

The Brain

Recent studies suggest a link between blood pressure (BP) and executive functions including working memory, response inhibition, and attention. Older adults and children with hypertension exhibit deficits in working memory and attention; however, it is not clear whether a common mechanism could link the elevation in BP and the cognitive abnormalities. The expression of the Calcyon (Caly), a protein which regulates receptor endocytosis, is increased in the brain of the spontaneously hypertensive rat (SHR), a widely accepted animal model of essential hypertension and attention deficit hyperactivity disorder. We hypothesize that Caly up-regulation in forebrain elevates BP under normal physiological response by altering adrenergic transmission. Radio-telemetry transmitters were implanted in CalOE transgenic mice in which Caly is up-regulated, and in tTA littermate controls. Mean arterial pressure was significantly higher in CalOE mice compared to tTA control (121± 1 vs. 108±1 mmHg, P<0.05). Consistent with deficits in executive functions, CalOE mice were also more active and less able to extinguish a learned behavior than tTA controls. Silencing the transgene with doxycycline treatment improved learning deficits and prevented the elevation in BP in CalOE mice. Plasma nor-epinephrine levels were higher in CalOE vs. tTA control mice (20±2 vs. 13±4 ng/ml). In the brain, dopamine levels were significantly lower in CalOE mice vs. control (0.2 ± 0.02 vs. 0.5±0.08 ng/mg) together with decreased dopamine D1 receptor expression whereas urinary dopamine excretion levels were higher in CalOE vs. control (0.5± 0.1 vs. 0.1± .04 μg/day, P<0.05). These data suggest that up-regulation of Caly in brain could increase BP and compromise inhibitory control mechanisms under normal physiological condition via the differential regulation of adrenergic transmission.

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Brain network dynamics in an event-related fMRI working memory paradigm

NeuroImage ◽

10.1016/s1053-8119(09)71497-1 ◽

2009 ◽

Vol 47 ◽

pp. S147

Author(s):

Q. Chen ◽

D.R. Weinberger ◽

J.H. Callicott ◽

H.Y. Tan

Keyword(s):

Working Memory ◽

Network Dynamics ◽

Brain Network

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Context-dependent architecture of brain state dynamics is explained by white matter connectivity and theories of network control

10.1101/412429 ◽

2018 ◽

Cited By ~ 2

Author(s):

Eli J. Cornblath ◽

Arian Ashourvan ◽

Jason Z. Kim ◽

Richard F. Betzel ◽

Rastko Ciric ◽

...

Keyword(s):

Working Memory ◽

White Matter ◽

Activity Patterns ◽

Network Control ◽

Membrane Properties ◽

Neuronal Membrane ◽

Brain State ◽

Cognitive States ◽

Brain States ◽

Context Dependent

A diverse white matter network and finely tuned neuronal membrane properties allow the brain to transition seamlessly between cognitive states. However, it remains unclear how static structural connections guide the temporal progression of large-scale brain activity patterns in different cognitive states. Here, we deploy an unsupervised machine learning algorithm to define brain states as time point level activity patterns from functional magnetic resonance imaging data acquired during passive visual fixation (rest) and an n-back working memory task. We find that brain states are composed of interdigitated functional networks and exhibit context-dependent dynamics. Using diffusion-weighted imaging acquired from the same subjects, we show that structural connectivity constrains the temporal progression of brain states. We also combine tools from network control theory with geometrically conservative null models to demonstrate that brains are wired to support states of high activity in default mode areas, while requiring relatively low energy. Finally, we show that brain state dynamics change throughout development and explain working memory performance. Overall, these results elucidate the structural underpinnings of cognitively and developmentally relevant spatiotemporal brain dynamics.

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LSD flattens the brain′s energy landscape: evidence from receptor-informed network control theory

10.1101/2021.05.14.444193 ◽

2021 ◽

Author(s):

S. Parker Singleton ◽

Andrea I Luppi ◽

Robin L. Carhart-Harris ◽

Josephine Cruzat ◽

Leor Roseman ◽

...

Keyword(s):

Control Theory ◽

Subjective Experience ◽

Brain Activity ◽

Energy Landscape ◽

Network Control ◽

State Transitions ◽

Brain State ◽

Control Analysis ◽

Brain States ◽

The Brain

Psychedelics like lysergic acid diethylamide (LSD) offer a powerful window into the function of the human brain and mind, by temporarily altering subjective experience through their neurochemical effects. The RElaxed Beliefs Under Psychedelics (REBUS) model postulates that 5-HT2a receptor agonism allows the brain to explore its dynamic landscape more readily, as suggested by more diverse (entropic) brain activity. Formally, this effect is theorized to correspond to a reduction in the energy required to transition between different brain-states, i.e. a ″flattening of the energy landscape.″ However, this hypothesis remains thus far untested. Here, we leverage network control theory to map the brain′s energy landscape, by quantifying the energy required to transition between recurrent brain states. In accordance with the REBUS model, we show that LSD reduces the energy required for brain-state transitions, and, furthermore, that this reduction in energy correlates with more frequent state transitions and increased entropy of brain-state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors, we demonstrate the specific role of this receptor in flattening the brain′s energy landscape. Also, in accordance with REBUS, we show that the occupancy of bottom-up states is increased by LSD. In addition to validating fundamental predictions of the REBUS model of psychedelic action, this work highlights the potential of receptor-informed network control theory to provide mechanistic insights into pharmacological modulation of brain dynamics.

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Neuromodulation of Persistent Activity and Working Memory Circuitry in Primate Prefrontal Cortex by Muscarinic Receptors

Frontiers in Neural Circuits ◽

10.3389/fncir.2021.648624 ◽

2021 ◽

Vol 15 ◽

Author(s):

Susheel Vijayraghavan ◽

Stefan Everling

Keyword(s):

Working Memory ◽

Prefrontal Cortex ◽

Cognitive Control ◽

Muscarinic Receptors ◽

Vital Role ◽

State Transitions ◽

Brain State ◽

Persistent Activity ◽

Memory Representations ◽

Underlying Mechanisms

Neuromodulation by acetylcholine plays a vital role in shaping the physiology and functions of cerebral cortex. Cholinergic neuromodulation influences brain-state transitions, controls the gating of cortical sensory stimulus responses, and has been shown to influence the generation and maintenance of persistent activity in prefrontal cortex. Here we review our current understanding of the role of muscarinic cholinergic receptors in primate prefrontal cortex during its engagement in the performance of working memory tasks. We summarize the localization of muscarinic receptors in prefrontal cortex, review the effects of muscarinic neuromodulation on arousal, working memory and cognitive control tasks, and describe the effects of muscarinic M1 receptor stimulation and blockade on the generation and maintenance of persistent activity of prefrontal neurons encoding working memory representations. Recent studies describing the pharmacological effects of M1 receptors on prefrontal persistent activity demonstrate the heterogeneity of muscarinic actions and delineate unexpected modulatory effects discovered in primate prefrontal cortex when compared with studies in rodents. Understanding the underlying mechanisms by which muscarinic receptors regulate prefrontal cognitive control circuitry will inform the search of muscarinic-based therapeutic targets in the treatment of neuropsychiatric disorders.

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Structural support for brain state transitions that contribute to working memory

10.32470/ccn.2018.1038-0 ◽

2018 ◽

Author(s):

Eli Cornblath ◽

Rastko Ciric ◽

Graham Baum ◽

Kosha Ruparel ◽

Tyler Moore ◽

...

Keyword(s):

Working Memory ◽

State Transitions ◽

Brain State ◽

Structural Support

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Functional MHCI deficiency induces ADHD-like symptoms with increased dopamine D1 receptor expression

Brain Behavior and Immunity ◽

10.1016/j.bbi.2021.05.015 ◽

2021 ◽

Author(s):

Hong-Rui Meng ◽

Toshiko Suenaga ◽

Mitsuhiro Edamura ◽

Atsuo Fukuda ◽

Yasushi Ishida ◽

...

Keyword(s):

Dopamine D1 Receptor ◽

D1 Receptor ◽

Receptor Expression

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Cholecystokinin receptors

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1995.269.5.g628 ◽

1995 ◽

Vol 269 (5) ◽

pp. G628-G646 ◽

Cited By ~ 48

Author(s):

S. A. Wank

Keyword(s):

Function Analysis ◽

Receptor Gene ◽

Wide Distribution ◽

Receptor Expression ◽

Receptor Subtypes ◽

Cck Receptors ◽

High Affinity ◽

Recombinant Receptor ◽

Receptor Pharmacology ◽

Specific Variation

The cholecystokinin (CCK) and gastrin families of peptides act as hormones and neuropeptides on central and peripheral CCK receptors to mediate secretion and motility in the gastrointestinal (GI) tract in the physiological response to a normal meal. CCK and its receptors are also widely distributed in the central nervous system (CNS) and contribute to the regulation of satiety, anxiety, analgesia, and dopamine-mediated behavior. Although the wide distribution, myriad number of functions, and reported pharmacological heterogeneity of CCK receptors would suggest a large number of receptor subtypes, the application of modern molecular biological techniques has identified two CCK receptors, CCK-A receptor (CCK-AR) and CCK-B receptor (CCK-BR), that mediate the actions of CCK and gastrin; gastrin receptors have been found to be identical to CCK-BR. CCK-AR, found predominantly in the GI system and select areas of the CNS, have high affinity for CCK and the nonpeptide antagonist L-364,718, whereas CCK-BR, found predominantly in the CNS and select areas of the GI system, have high affinity for CCK and gastrin and the nonpeptide antagonist L-365,260. Both CCK-AR and CCK-BR are highly conserved between species, although there is some tissue-specific variation in expression. Recombinant receptor expression faithfully reproduces the native receptor pharmacology and signal transduction pathways, allowing direct comparisons of receptor function between species as well as serving as a convenient source of receptor. Our present knowledge of the chromosomal localization, receptor gene structure, and primary sequence will allow further studies in disease association, receptor regulation, and structure-function analysis.

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