A novel dopamine D1 receptor agonist excites delay-dependent working memory-related neuronal firing in primate dorsolateral prefrontal cortex

Wang, Min; Datta, Dibyadeep; Enwright, John F.; Galvin, Veronica C.; Yang, Shengtao; Paspalas, Constantinos D.; Kozak, Rouba; Gray, David; Lewis, David A.; Arnsten, Amy F.T.

doi:10.1016/j.neuropharm.2019.03.001

Cited by 46 publications

(67 citation statements)

References 70 publications

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“…A similar pattern of delay period activity was observed following somatosensory input ( Fig S2). A comparable inverted-U relationship has been observed in prefrontal cortex following local application of D1 receptor agonists during working memory tasks (Vijayraghavan et al 2007;Wang et al 2019). A mid-range level of dopamine release engaged a distributed pattern of persistent activity throughout these areas (Fig 2E, F), but to low or too high release led to only a transient response ( Fig 2F).…”

Section: A) B)supporting

confidence: 72%

“…An inverted-U relationship between dopamine and distributed working memory activity Previous experimental and modelling studies have shown an inverted-U relationship between D1 receptor stimulation and persistent activity in the prefrontal cortex in monkeys performing working memory tasks (Brunel and Wang 2001;Vijayraghavan et al 2007;Wang et al 2019). Stimulation of VTA (presumably leading to cortical dopamine release) in resting monkeys also has an inverted-U effect on cortical activity in distributed areas across cortex (Murris et al 2020).…”

Section: A Gradient Of D1 Receptors Along the Cortical Hierarchymentioning

confidence: 98%

“…After dopamine neurons fire, dopamine is released, and dopamine levels remain elevated in the cortex for hundreds of milliseconds to tens of seconds, before being slowly cleared away (Cass and Gerhardt 1995;Garris and Wightman 1994;Muller et al 2014;Mundorf et al 2001). Prefrontal neuron activity during working memory depends on precise levels of activation of the dopamine D1 receptors, with both too little and too much D1 receptor stimulation disrupting delay period activity (Vijayraghavan et al 2007;Wang et al 2019;Williams and Goldman-Rakic 1995).…”

Section: Introductionmentioning

confidence: 99%

“…Experimental and modelling studies of dopamine on persistent activity in working memory have focused on isolated local brain regions, generally in the lateral prefrontal cortex (Brunel and Wang 2001;Durstewitz et al 2000;Jacob et al 2016;Vijayraghavan et al 2016Vijayraghavan et al , 2007Wang et al 2019;Williams and Goldman-Rakic 1995), where it has been shown that dopamine can enhance persistent activity through its effects on the NMDA and GABA receptors (Seamans et al 2001a,b;Seamans and Yang 2004;Wang et al 2013). If the effects of dopamine are truly restricted to small areas of cortex, then dopamine seems unlikely to be able to engage the widespread distributed activity seen during active working memory.…”

Section: Introductionmentioning

confidence: 99%

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A dopamine gradient controls access to distributed working memory in monkey cortex

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Ding

Jankovic-Rapan

et al. 2020

Preprint

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SummaryDopamine is critical for working memory. However, its effects throughout the large-scale primate cortex are poorly understood. Here we report that dopamine receptor density per neuron, measured by receptor autoradiography in the macaque monkey cortex, displays a macroscopic gradient along the cortical hierarchy. We developed a connectome- and biophysically-based model for distributed working memory that incorporates multiple neuron types and a dopamine gradient. The model captures an inverted U-shaped dependence of working memory on dopamine. The spatial distribution of mnemonic persistent activity matches that observed in over 90 experimental studies. We show that dopamine filters out irrelevant stimuli by enhancing inhibition of pyramidal cell dendrites. The level of cortical dopamine can also determine whether memory encoding is through persistent activity or an internal synaptic state. Taken together, our work represents a cross-level understanding that links molecules, cell types, recurrent circuit dynamics and a core cognitive function distributed across the cortex.

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Section: A) B)supporting

confidence: 72%

Section: A Gradient Of D1 Receptors Along the Cortical Hierarchymentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A dopamine gradient controls access to distributed working memory in monkey cortex

Bliss

Ding

Jankovic-Rapan

et al. 2020

Preprint

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“…How do age-related changes in synaptic plasticity, discussed below, affect DRT performance? Might neuromodulation (Arnsten et al, 2012;Davis et al, 2017;Wang et al, 2019) during working memory task performance reduce the pyramidal neuron hyperexcitability observed in vitro? Computational models provide an essential means for testing and refining hypotheses as future data become available.…”

Section: Discussionmentioning

confidence: 99%

Network Models Predict That Pyramidal Neuron Hyperexcitability and Synapse Loss in the dlPFC Lead to Age-Related Spatial Working Memory Impairment in Rhesus Monkeys

Ibañez

Luebke

Chang

et al. 2020

Front. Comput. Neurosci.

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Behavioral studies have shown spatial working memory impairment with aging in several animal species, including humans. Persistent activity of layer 3 pyramidal dorsolateral prefrontal cortex (dlPFC) neurons during delay periods of working memory tasks is important for encoding memory of the stimulus. In vitro studies have shown that these neurons undergo significant age-related structural and functional changes, but the extent to which these changes affect neural mechanisms underlying spatial working memory is not understood fully. Here, we confirm previous studies showing impairment on the Delayed Recognition Span Task in the spatial condition (DRSTsp), and increased in vitro action potential firing rates (hyperexcitability), across the adult life span of the rhesus monkey. We use a bump attractor model to predict how empirically observed changes in the aging dlPFC affect performance on the Delayed Response Task (DRT), and introduce a model of memory retention in the DRSTsp. Persistent activity-and, in turn, cognitive performance-in both models was affected much more by hyperexcitability of pyramidal neurons than by a loss of synapses. Our DRT simulations predict that additional changes to the network, such as increased firing of inhibitory interneurons, are needed to account for lower firing rates during the DRT with aging reported in vivo. Synaptic facilitation was an essential feature of the DRSTsp model, but it did not compensate fully for the effects of the other age-related changes on DRT performance. Modeling pyramidal neuron hyperexcitability and synapse loss simultaneously led to a partial recovery of function in both tasks, with the simulated level of DRSTsp impairment similar to that observed in aging monkeys. This modeling work integrates empirical data across multiple scales, from synapse counts to cognitive testing, to further our understanding of aging in non-human primates.

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Prefrontal cortex and cognitive aging in macaque monkeys

Upright

Baxter

2021

American J Primatol

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Cognitive impairments that accompany aging, even in the absence of neurodegenerative diseases, include deficits in executive function and memory mediated by the prefrontal cortex. Because of the unique differentiation and expansion of the prefrontal cortex in primates, investigations of the neurobiological basis of cognitive aging in nonhuman primates have been particularly informative about the potential basis for age-related cognitive decline in humans. We review the cognitive functions mediated by specific subregions of prefrontal cortex, and their corresponding connections, as well as the evidence for age-related alterations in specific regions of prefrontal cortex. We also discuss evidence for similarities and differences in the effects of aging on prefrontal cortex across species.

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A novel dopamine D1 receptor agonist excites delay-dependent working memory-related neuronal firing in primate dorsolateral prefrontal cortex

Cited by 46 publications

References 70 publications

A dopamine gradient controls access to distributed working memory in monkey cortex

A dopamine gradient controls access to distributed working memory in monkey cortex

Network Models Predict That Pyramidal Neuron Hyperexcitability and Synapse Loss in the dlPFC Lead to Age-Related Spatial Working Memory Impairment in Rhesus Monkeys

Prefrontal cortex and cognitive aging in macaque monkeys

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