Spatial discrimination reversal learning in weanling rats is impaired by striatal administration of an NMDA-receptor antagonist

Watson, Deborah; Stanton, Mark E.

doi:10.1101/lm.1448009

Cited by 24 publications

(18 citation statements)

References 41 publications

(73 reference statements)

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“…Successful reversal learning requires inhibition of the initially learned behavioral strategy and, subsequently, relearning of the opposing behavioral strategy (24,25). After acquiring robust discrimination of the FM modulation direction, untreated Mongolian gerbils failed or required a long period of training to behaviorally discriminate the two FM signals on the basis of the reversed contingency (group II; Fig.…”

Section: Discussionmentioning

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.

144

118

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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: Discussionmentioning

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.

144

118

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“…Antagonizing NMDARs (with MK-801 or AP-5) in the DMS of adult or weanling rats impairs spatial reversal learning (Palencia and Ragozzino, 2004, Watson and Stanton, 2009). Ragozzino and colleagues found that these deficits were accompanied by decreases in acetylcholine efflux (Palencia and Ragozzino, 2006) and could be mimicked by blocking muscarinic M1 (via pirenzepine) or stimulating M2 (via oxotremorine sesquifumurate), but not by antagonizing nicotinic (via mecamylamine), acetylcholine receptors in the DMS (Tzavos et al, 2004, McCool et al, 2008, Ragozzino et al, 2009).…”

Section: Neurochemical Modulation Of Reversalmentioning

confidence: 99%

The neural basis of reversal learning: An updated perspective

et al. 2017

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Reversal learning paradigms are among the most widely used tests of cognitive flexibility and have been used as assays, across species, for altered cognitive processes in a host of neuropsychiatric conditions. Based on recent studies in humans, non-human primates, and rodents, the notion that reversal learning tasks primarily measure response inhibition, has been revised. In this review, we describe how cognitive flexibility is measured by reversal learning and discuss new definitions of the construct validity of the task that are serving as an heuristic to guide future research in this field. We also provide an update on the available evidence implicating certain cortical and subcortical brain regions in the mediation of reversal learning, and an overview of the principle neurotransmitter systems involved.

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“…Using immunoelectron microscopy, we have recently shown that WLS and MOR are co-localized in somata and in dendritic processes in the murine striatum (Jin et al, 2010a; Reyes et al, 2010), a brain region which is also involved in goal oriented behaviors and extrapyramidal motor control (Watson and Stanton, 2009; Kehagia et al, 2010). We demonstrated that 32% of WLS-labeled dendrites contained MOR immunoreactivity while 37% of MOR-labeled profiles contained WLS immunoreactivity (Reyes et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Opiate agonist-induced re-distribution of Wntless, a mu-opioid receptor interacting protein, in rat striatal neurons

Reyes

Vakharia

Ferraro

et al. 2012

Experimental Neurology

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Wntless (WLS), a mu-opioid receptor (MOR) interacting protein, mediates Wnt protein secretion that is critical for neuronal development. We investigated whether MOR agonists induce re-distribution of WLS within rat striatal neurons. Adult male rats received either saline, morphine or [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO) directly into the lateral ventricles. Following thirty minutes, brains were extracted and tissue sections were processed for immunogold silver detection of WLS. In saline-treated rats, WLS was distributed along the plasma membrane and within the cytoplasmic compartment of striatal dendrites as previously described. The ratio of cytoplasmic to total dendritic WLS labeling was 0.70±0.03 in saline-treated striatal tissue. Morphine treatment decreased this ratio to 0.48±0.03 indicating a shift of WLS from the intracellular compartment to the plasma membrane. However, following DAMGO treatment, the ratio was 0.85±0.05 indicating a greater distribution of WLS intracellularly. The difference in the re-distribution of the WLS following different agonist exposure may be related to DAMGO’s well known ability to induce internalization of MOR in contrast to morphine, which is less effective in producing receptor internalization. Furthermore, these data are consistent with our hypothesis that MOR agonists promote dimerization of WLS and MOR, thereby preventing WLS from mediating Wnt secretion. In summary, our findings indicate differential agonist-induced trafficking of WLS in striatal neurons following distinct agonist exposure. Adaptations in WLS trafficking may represent a novel pharmacological target in the treatment of opiate addiction and/or pain.

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Spatial discrimination reversal learning in weanling rats is impaired by striatal administration of an NMDA-receptor antagonist

Cited by 24 publications

References 41 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

The neural basis of reversal learning: An updated perspective

Opiate agonist-induced re-distribution of Wntless, a mu-opioid receptor interacting protein, in rat striatal neurons

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