Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia

Zick, Jennifer L.; Blackman, Rachael K.; Crowe, David A.; Amirikian, Bagrat; DeNicola, Adele L.; Netoff, Theoden I.; Chafee, Matthew V.

doi:10.1016/j.neuron.2018.05.010

Cited by 43 publications

(90 citation statements)

References 68 publications

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“…For instance, in a working memory task, ketamine was found to increase spiking activity of response-selective cells, but decrease activity of the task-relevant delay-tuned cells in primate prefrontal cortex 26 . Such specificity might explain why several studies reported less conclusive effects of NMDA-R antagonists on overall prefrontal firing rates in monkeys 26,43 . In vitro work has also revealed the excitatory post-synaptic potentials (EPSPs) of prefrontal pyramidal neurons are much more reliant on NMDA-R conductance than parvalbumin interneurons 44 .…”

Section: Discussionmentioning

confidence: 99%

A circuit mechanism for irrationalities in decision-making and NMDA receptor hypofunction: behaviour, computational modelling, and pharmacology

Cavanagh

Lam

Murray

et al. 2019

Preprint

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24Decision-making biases can be systematic features of normal behaviour, or deficits underlying 25 neuropsychiatric symptoms. We used behavioural psychophysics, spiking-circuit modelling and 26 pharmacological manipulations to explore decision-making biases in health and disease. Monkeys 27 performed an evidence integration task in which they showed a pro-variance bias (PVB): a preference 28to choose options with more variable evidence. The PVB was also present in a spiking circuit model, 29revealing a neural mechanism for this behaviour. Because NMDA receptor (NMDA-R) hypofunction is 30 a leading hypothesis for neuropathology in schizophrenia, we simulated behavioural effects of NMDA-31 R hypofunction onto either excitatory or inhibitory neurons in the model. These were tested 32 experimentally using the NMDA-R antagonist ketamine, yielding changes in decision-making 33 consistent with lowered cortical excitation/inhibition balance from NMDA-R hypofunction onto 34 excitatory neurons. These results provide a circuit-level mechanism that bridges across explanatory 35 scales, from the synaptic to the behavioural, in neuropsychiatric disorders where decision-making 36 biases are prominent. 37Significance 38 39People can make apparently irrational decisions because of underlying features in their decision 40 circuitry. Deficits in the same neural circuits may also underlie debilitating cognitive symptoms of 41 neuropsychiatric patients. Here, we reveal a neural circuit mechanism explaining an irrationality 42 frequently observed in healthy humans making binary choices -the pro-variance bias. Our circuit 43 model could be perturbed by introducing deficits in either excitatory or inhibitory neuron function. 44These two perturbations made specific, dissociable predictions for the types of irrational decision-45 making behaviour produced. We used the NMDA-R antagonist ketamine, an experimental model for 46 schizophrenia, to test if these predictions were relevant to neuropsychiatric pathophysiology. The 47 results were consistent with impaired excitatory neuron function, providing important new insights into 48 the pathophysiology of schizophrenia. 49 50 51 52 53 54 55 56 57 58 59 60

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Section: Discussionmentioning

confidence: 99%

A circuit mechanism for irrationalities in decision-making and NMDA receptor hypofunction: behaviour, computational modelling, and pharmacology

Cavanagh

Lam

Murray

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Changes in synaptic plasticity expression may explain the hubs loss seen in schizophrenia. It has been suggested that spike timing-dependent plasticity alterations may be responsible of progressive disconnection of prefrontal circuits [175]. Altered NMDA-mediated synaptic plasticity reduces temporal correlation between converging inputs to connected neurons and could lead to additional activity-dependent disconnection of prefrontal networks [175].…”

Section: Synaptic Plasticity Dysfunction May Drive Brain Network Disrmentioning

confidence: 99%

“…It has been suggested that spike timing-dependent plasticity alterations may be responsible of progressive disconnection of prefrontal circuits [175]. Altered NMDA-mediated synaptic plasticity reduces temporal correlation between converging inputs to connected neurons and could lead to additional activity-dependent disconnection of prefrontal networks [175]. In fact, subverted spike timing-dependent plasticity could induce LTD instead of LTP in prefrontal networks, ultimately producing progressive disruption of anterior hubs and generating a persistent disconnection within the rich club.…”

Section: Synaptic Plasticity Dysfunction May Drive Brain Network Disrmentioning

confidence: 99%

Synaptic Plasticity Shapes Brain Connectivity: Implications for Network Topology

Bassi

Iezzi

Gilio

et al. 2019

IJMS

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Studies of brain network connectivity improved understanding on brain changes and adaptation in response to different pathologies. Synaptic plasticity, the ability of neurons to modify their connections, is involved in brain network remodeling following different types of brain damage (e.g., vascular, neurodegenerative, inflammatory). Although synaptic plasticity mechanisms have been extensively elucidated, how neural plasticity can shape network organization is far from being completely understood. Similarities existing between synaptic plasticity and principles governing brain network organization could be helpful to define brain network properties and reorganization profiles after damage. In this review, we discuss how different forms of synaptic plasticity, including homeostatic and anti-homeostatic mechanisms, could be directly involved in generating specific brain network characteristics. We propose that long-term potentiation could represent the neurophysiological basis for the formation of highly connected nodes (hubs). Conversely, homeostatic plasticity may contribute to stabilize network activity preventing poor and excessive connectivity in the peripheral nodes. In addition, synaptic plasticity dysfunction may drive brain network disruption in neuropsychiatric conditions such as Alzheimer’s disease and schizophrenia. Optimal network architecture, characterized by efficient information processing and resilience, and reorganization after damage strictly depend on the balance between these forms of plasticity.

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“…To relate the computations required for forms of cognitive control that are disrupted in schizophrenia to the activity of individual neurons in prefrontal networks, our lab recently translated a variant of the AX continuous performance task (AX-CPT) known as the dot-pattern expectancy (DPX) task that measures deficits in patients to nonhuman primates (Blackman et al, 2013(Blackman et al, , 2016Zick et al, 2018). In the current study we use linear electrode arrays to record MD and PFC neural activity simultaneously during DPX task performance.…”

Section: Introductionmentioning

confidence: 99%

Differential Roles of Mediodorsal Nucleus of the Thalamus and Prefrontal Cortex in Decision-Making and State Representation in a Cognitive Control Task Measuring Deficits in Schizophrenia

DeNicola¹,

Park²,

Crowe

et al. 2020

J. Neurosci.

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The mediodorsal nucleus of the thalamus (MD) is reciprocally connected with the prefrontal cortex (PFC), and although the MD has been implicated in a range of PFC-dependent cognitive functions (Watanabe and Funahashi, 2012; Mitchell and Chakraborty, 2013; Parnaudeau et al., 2018), little is known about how MD neurons in the primate participate specifically in cognitive control, a capability that reflects the ability to use contextual information (such as a rule) to modify responses to environmental stimuli. To learn how the MD-PFC thalamocortical network is engaged to mediate forms of cognitive control that are selectively disrupted in schizophrenia, we trained male monkeys to perform a variant of the AX continuous performance task, which reliably measures cognitive control deficits in patients (Henderson et al., 2012) and used linear multielectrode arrays to record neural activity in the MD and PFC simultaneously. We found that the two structures made clearly different contributions to distributed processing for cognitive control: MD neurons were specialized for decision-making and response selection, whereas prefrontal neurons were specialized to preferentially encode the environmental state on which the decision was based. In addition, we observed that functional coupling between MD and PFC was strongest when the decision as to which of the two responses in the task to execute was being made. These findings delineate unique contributions of MD and PFC to distributed processing for cognitive control and characterized neural dynamics in this network associated with normative cognitive control performance.

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Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia

Cited by 43 publications

References 68 publications

A circuit mechanism for irrationalities in decision-making and NMDA receptor hypofunction: behaviour, computational modelling, and pharmacology

A circuit mechanism for irrationalities in decision-making and NMDA receptor hypofunction: behaviour, computational modelling, and pharmacology

Synaptic Plasticity Shapes Brain Connectivity: Implications for Network Topology

Differential Roles of Mediodorsal Nucleus of the Thalamus and Prefrontal Cortex in Decision-Making and State Representation in a Cognitive Control Task Measuring Deficits in Schizophrenia

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