Neuromodulation of Thought: Flexibilities and Vulnerabilities in Prefrontal Cortical Network Synapses

Arnsten, Amy F.T.; Wang, Min J.; Paspalas, Constantinos D.

doi:10.1016/j.neuron.2012.08.038

Cited by 485 publications

(493 citation statements)

References 167 publications

(254 reference statements)

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“…This dissociation of cognitive effects is consistent with an emerging neurobiological framework that suggests that transient plasticity that underlies working memory is modulated in a fundamentally different way than lasting plasticity changes that support learning and memory consolidation (23,48). Thus, whereas experience-dependent learning is thought to be mediated by lasting structural changes at dendritic spines following NMDAR-induced signaling cascades, short-term representation of stimuli for spatial working memory is thought to be mediated by transient, persistent firing of dorsolateral prefrontal cortex (dlPFC) microcircuits over brief delays.…”

Section: Discussionsupporting

confidence: 82%

“…The n-back is a spatial working memory task. Working memory relies on reverberating activity in cortical microcircuits over short delays to maintain information in the absence of stimuli and, thus, does not rely on LTP (23). To facilitate dissociation of the effects of DCS on experiencedependent plasticity versus working memory, the n-back task was designed to be identical to the IIT in stimuli and trial structure.…”

mentioning

confidence: 99%

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Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain

Forsyth

Bachman

Mathalon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Experience-dependent plasticity is a fundamental property of the brain. It is critical for everyday function, is impaired in a range of neurological and psychiatric disorders, and frequently depends on long-term potentiation (LTP). Preclinical studies suggest that augmenting N-methyl-D-aspartate receptor (NMDAR) signaling may promote experience-dependent plasticity; however, a lack of noninvasive methods has limited our ability to test this idea in humans until recently. We examined the effects of enhancing NMDAR signaling using D-cycloserine (DCS) on a recently developed LTP EEG paradigm that uses high-frequency visual stimulation (HFvS) to induce neural potentiation in visual cortex neurons, as well as on three cognitive tasks: a weather prediction task (WPT), an information integration task (IIT), and a n-back task. The WPT and IIT are learning tasks that require practice with feedback to reach optimal performance. The n-back assesses working memory. Healthy adults were randomized to receive DCS (100 mg; n = 32) or placebo (n = 33); groups were similar in IQ and demographic characteristics. Participants who received DCS showed enhanced potentiation of neural responses following repetitive HFvS, as well as enhanced performance on the WPT and IIT. Groups did not differ on the n-back. Augmenting NMDAR signaling using DCS therefore enhanced activitydependent plasticity in human adults, as demonstrated by lasting enhancement of neural potentiation following repetitive HFvS and accelerated acquisition of two learning tasks. Results highlight the utility of considering cellular mechanisms underlying distinct cognitive functions when investigating potential cognitive enhancers.D-cycloserine | NMDA receptor | neuroplasticity | long-term potentiation | learning E xperience-dependent neuroplasticity is the capacity of the brain to change in response to environmental input, learning, and use. It is a fundamental property of the brain and is critical for everyday functioning. It allows us to learn and remember patterns, predict and obtain reward, and refine and accelerate response selection for adaptive behavior (1). During development, experience-dependent plasticity interacts with genetic programming to organize neurons into the structurally and functionally connected circuits that characterize a mature brain. Although this basic circuitry is established by early adulthood, experience-dependent plasticity continues to shape connectivity within these circuits such that important inputs and action outputs are represented by larger and more coordinated populations of neurons. Given that these changes are the primary means through which the adult brain enables new behavior and that such plasticity is impaired in a range of neurological and psychiatric disorders (2), identifying manipulations that can harness experiencedependent plasticity offers exciting possibilities. Here, we tested whether augmenting N-methyl-D-aspartate receptor (NMDAR) activity could enhance experience-dependent plasticity in the adult human brain.The ...

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain

Forsyth

Bachman

Mathalon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Although the postsynaptic processes involved in this interaction are not known, the D1 receptor is an attractive candidate. D1 stimulation enhances LTP between PFC layer III and layer V neurons (Goldwater et al, 2009;Huang et al, 2004), and tightly modulates neuronal activity during PFC-mediated tasks (Arnsten et al, 2012;Vijayraghavan et al, 2007). IL D1 receptors are reported to be critical to successful extinction in males (Hikind and Maroun, 2008), but their role in females is not known.…”

Section: Introductionmentioning

confidence: 99%

Dopamine D1 Receptor Activation Rescues Extinction Impairments in Low-Estrogen Female Rats and Induces Cortical Layer-Specific Activation Changes in Prefrontal–Amygdala Circuits

Rey

Lipps

Shansky

2013

Neuropsychopharmacol

103

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Post-traumatic stress disorder (PTSD) is twice as common in women as in men; it is a major public health problem whose neurobiological basis is unknown. In preclinical studies using fear conditioning and extinction paradigms, women and female animals with low estrogen levels exhibit impaired extinction retrieval, but the mechanisms that underlie these hormone-based discrepancies have not been identified. There is much evidence that estrogen can modulate dopaminergic transmission, and here we tested the hypothesis that dopamine-estrogen interactions drive extinction processes in females. Intact male and female rats were trained on cued fear conditioning, and received an intraperitoneal injection of a D1 agonist or vehicle before extinction learning. As reported previously, females that underwent extinction during low estrogen estrous phases (estrus/metaestrus/diestrus (EMD)) froze more during extinction retrieval than those that had been in the high-estrogen phase (proestrus; PRO). However, D1 stimulation reversed this relationship, impairing extinction retrieval in PRO and enhancing it in EMD. We also combined retrograde tracing and fluorescent immunohistochemistry to measure c-fos expression in infralimbic (IL) projections to the basolateral area of the amygdala (BLA), a neural pathway known to be critical to extinction retrieval. Again we observed diverging, estrous-dependent effects; SKF treatment induced a positive correlation between freezing and IL-BLA circuit activation in EMD animals, and a negative correlation in PRO animals. These results show for the first time that hormone-dependent extinction deficits can be overcome with non-hormone-based interventions, and suggest a circuit-specific mechanism by which these behavioral effects occur.

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“…Within and across these cognitive circuits, pyramidal cells excite each other through NMDA receptor (NMDAR) glutamate synapses on long thin spines (12). dlPFC synapses are modulated differently from those in V1, with permissive nicotinic-α7 receptor activation of NMDAR (13) and feedforward cAMP-Ca 2+ -K + channel signaling to gate network inputs (14). In dendritic spines, internal Ca 2+ is buffered by the spine apparatus (SA), the extension and elaboration of the smooth endoplasmic reticulum (SER) into the spine head.…”

mentioning

confidence: 99%

“…cAMP production (18), fueling feedforward signaling (14). Ca 2+ -cAMP-PKA signaling increases the open state of nearby K + channels (SK, HCN, KCNQ) on the spine membrane, which temporarily weakens synaptic efficacy, thus providing dynamic gating of network inputs to enhance mental flexibility and coordinate cognitive and arousal states (14) (see Fig.…”

mentioning

confidence: 99%

cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex

Carlyle¹,

Nairn²,

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

120

156

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The pattern of neurodegeneration in Alzheimer's disease (AD) is very distinctive: neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau selectively affect pyramidal neurons of the aging association cortex that interconnect extensively through glutamate synapses on dendritic spines. In contrast, primary sensory cortices have few NFTs, even in late-stage disease. Understanding this selective vulnerability, and why advancing age is such a high risk factor for the degenerative process, may help to reveal disease etiology and provide targets for intervention. Our study has revealed age-related increase in cAMP-dependent protein kinase (PKA) phosphorylation of tau at serine 214 (pS214-tau) in monkey dorsolateral prefrontal association cortex (dlPFC), which specifically targets spine synapses and the Ca 2+ -storing spine apparatus. This increase is mirrored by loss of phosphodiesterase 4A from the spine apparatus, consistent with increase in cAMP-Ca 2+ signaling in aging spines. Phosphorylated tau was not detected in primary visual cortex, similar to the pattern observed in AD. We also report electron microscopic evidence of previously unidentified vesicular trafficking of phosphorylated tau in normal association cortex-in axons in young dlPFC vs. in spines in aged dlPFC-consistent with the transneuronal lesion spread reported in genetic rodent models. pS214-Tau was not observed in normal aged mice, suggesting that it arises with the evolutionary expansion of corticocortical connections in primates, crossing the threshold into NFTs and degeneration in humans. Thus, the cAMP-Ca 2+ signaling mechanisms, needed for flexibly modulating network strength in young association cortex, confer vulnerability to degeneration when dysregulated with advancing age.

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Neuromodulation of Thought: Flexibilities and Vulnerabilities in Prefrontal Cortical Network Synapses

Cited by 485 publications

References 167 publications

Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain

Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain

Dopamine D1 Receptor Activation Rescues Extinction Impairments in Low-Estrogen Female Rats and Induces Cortical Layer-Specific Activation Changes in Prefrontal–Amygdala Circuits

cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex

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