Dopaminergic Modulation of Auditory Cortex-Dependent Memory Consolidation through mTOR

Schicknick, Horst; Schott, Björn H.; Budinger, Eike; Smalla, Karl‐Heinz; Riedel, Anett; Seidenbecher, Constanze I.; Scheich, Henning; Gundelfinger, Eckart D.; Tischmeyer, Wolfgang

doi:10.1093/cercor/bhn026

Cited by 83 publications

(112 citation statements)

References 93 publications

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“…(Scale bar, 1,500 μm. ) discriminate the direction of linear FM modulations (250 ms tone with 5 ms linear onset and offset ramps, 250 ms pause, 4 s duration; rising, 2-4 kHz; falling, 4-2 kHz) as conditioned go/no go stimuli (CS+/CS-) in an active avoidance paradigm (18,47). As unconditioned stimulus, foot shocks were administered through a metal floor grid individually adjusted for each animal (150-600 mA) to elicit comparable response strengths for the escape behavior (18,20) (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…injection of 0.4 mL/100 g body weight of 45% ketamine (50 mg/mL), 5% xylazine (2 mg/mL), and 50% isotonic 0.9% saline solution (154 mM) were performed at three locations covering the primary, anterior, and posterior fields of primary and secondary ACx (47). Per injection site, 500 nL of HYase solution (500 units) (groups I, III, and IV) or 0.9% saline (group II) were injected in 22 steps (22.8 nL each; 3 s pause; Nanoliter injector 2000, World Precision Instruments).…”

Section: Methodsmentioning

confidence: 99%

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Enhanced cognitive flexibility in reversal learning induced by removal of the extracellular matrix in auditory cortex

Happel

Niekisch²,

Rivera³

et al. 2014

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

141

117

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During brain maturation, the occurrence of the extracellular matrix (ECM) terminates juvenile plasticity by mediating structural stability. Interestingly, enzymatic removal of the ECM restores juvenile forms of plasticity, as for instance demonstrated by topographical reconnectivity in sensory pathways. However, to which degree the mature ECM is a compromise between stability and flexibility in the adult brain impacting synaptic plasticity as a fundamental basis for learning, lifelong memory formation, and higher cognitive functions is largely unknown. In this study, we removed the ECM in the auditory cortex of adult Mongolian gerbils during specific phases of cortex-dependent auditory relearning, which was induced by the contingency reversal of a frequency-modulated tone discrimination, a task requiring high behavioral flexibility. We found that ECM removal promoted a significant increase in relearning performance, without erasing already establishedthat is, learned-capacities when continuing discrimination training. The cognitive flexibility required for reversal learning of previously acquired behavioral habits, commonly understood to mainly rely on frontostriatal circuits, was enhanced by promoting synaptic plasticity via ECM removal within the sensory cortex. Our findings further suggest experimental modulation of the cortical ECM as a tool to open short-term windows of enhanced activitydependent reorganization allowing for guided neuroplasticity.chondroitin sulfate proteoglycan | hyaluronidase | perineuronal net | intracortical microinjection | strategy change S tructural remodeling and stabilization of synaptic networks are key mechanisms underlying learning in the adult brain. During early life, high structural and functional plasticity is required for the experience-shaped development of basic neuronal circuits (1). With brain maturation, juvenile plasticity of so-called critical or sensitive periods is decreased and is accompanied by the appearance of the brain's extracellular matrix (ECM) and its specialized compact form named "perineuronal net" (PNN) enwrappping cell bodies and synaptic contacts (2, 3). Enzymatic degradation of the ECM in adult animals has been demonstrated to restore such forms of developmental (juvenile) plasticity with respect to topographical map plasticity in the visual cortex (4), fearresponse-mediating circuits in the amygdala (5), spinal cord injuries (6, 7), and song learning circuits of zebra finches (8). In addition, enzymatic ECM removal altered several forms of synaptic plasticity in vitro and in vivo (9-12). However, even though structural stability of networks acquired during developmental phases is essential for neuronal efficiency, mechanisms allowing synaptic remodeling are key events during learning and memory formation throughout life (13). We recently demonstrated that endogenous proteases moderately digesting specific components of the ECM are regulated in an activity-dependent manner (2, 14) and ECM removal modulates synaptic short-term plasticity by synaptic e...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Enhanced cognitive flexibility in reversal learning induced by removal of the extracellular matrix in auditory cortex

Happel

Niekisch²,

Rivera³

et al. 2014

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

141

117

View full text Add to dashboard Cite

show abstract

“…Previous reports have shown that injections of the dopamine D1 receptor agonist SKF38393 locally to the auditory cortex of gerbils after conditioning of linear frequency-modulated tones (FMs) discrimination paradigm induces memory consolidation, and this effect is sensitive to mTORC1 inhibitors (Schicknick et al 2008). Stimulation by dopamine of primary cortical mouse neurons causes a small increase in the phosphorylation of S6K.…”

Section: Translation Control By Neurotransmittersmentioning

confidence: 99%

Consolidation and translation regulation: Figure 1.

et al. 2012

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mRNA translation, or protein synthesis, is a major component of the transformation of the genetic code into any cellular activity. This complicated, multistep process is divided into three phases: initiation, elongation, and termination. Initiation is the step at which the ribosome is recruited to the mRNA, and is regarded as the major rate-limiting step in translation, while elongation consists of the elongation of the polypeptide chain; both steps are frequent targets for regulation, which is defined as a change in the rate of translation of an mRNA per unit time. In the normal brain, control of translation is a key mechanism for regulation of memory and synaptic plasticity consolidation, i.e., the off-line processing of acquired information. These regulation processes may differ between different brain structures or neuronal populations. Moreover, dysregulation of translation leads to pathological brain function such as memory impairment. Both normal and abnormal function of the translation machinery is believed to lead to translational up-regulation or down-regulation of a subset of mRNAs. However, the identification of these newly synthesized proteins and determination of the rates of protein synthesis or degradation taking place in different neuronal types and compartments at different time points in the brain demand new proteomic methods and system biology approaches. Here, we discuss in detail the relationship between translation regulation and memory or synaptic plasticity consolidation while focusing on a model of cortical-dependent taste learning task and hippocampal-dependent plasticity. In addition, we describe a novel systems biology perspective to better describe consolidation.

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“…These findings also suggest that FMRP might control shared signaling molecules that are key players to regulate neurotransmitter-mediated signaling and protein synthesis. The two major pathways regulating neurotransmitter-induced protein synthesis in neurons are the ERK1/2 and the PI3K/mTOR (mammalian target of rapamycin) pathways (Banko et al, 2006;Nagai et al, 2007;Schicknick et al, 2008;Santos et al, 2010;Zhou et al, 2010). Both pathways also play crucial roles for intracellular signaling, and many of the above discussed dysregulated neurotransmitter-dependent signaling mechanisms in FXS are regulated or mediated via ERK1/2 and/or PI3K signaling (Figure 1).…”

Section: Targeting Downstream Signaling Molecules In Fxsmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

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Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

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Dopaminergic Modulation of Auditory Cortex-Dependent Memory Consolidation through mTOR

Cited by 83 publications

References 93 publications

Enhanced cognitive flexibility in reversal learning induced by removal of the extracellular matrix in auditory cortex

Enhanced cognitive flexibility in reversal learning induced by removal of the extracellular matrix in auditory cortex

Consolidation and translation regulation: Figure 1.

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

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