GluN2B in corticostriatal circuits governs choice learning and choice shifting

Brigman, Jonathan L.; Daut, Rachel A.; Wright, Tara; Gunduz-Cinar, Ozge; Graybeal, Carolyn; Davis, Margaret I.; Jiang, Zhihong; Saksida, Lisa M.; Jinde, Seiichiro; Pease, Matthew; Bussey, Timothy J.; Lovinger, David M.; Nakazawa, Kazu; Holmes, Andrew

doi:10.1038/nn.3457

Cited by 138 publications

(185 citation statements)

References 58 publications

(83 reference statements)

Supporting

Mentioning

171

Contrasting

Unclassified

Order By: Relevance

“…Previous studies have found that chronic EtOH up-regulates NMDAR function and plasticity in the DS (albeit medially), in a manner that underlies dependence drinking (20,21,36). Moreover, various forms of learning, including some of the tasks used in the current study, are critically dependent upon DS NMDARs (37,38). Thus, chronic alcohol may disrupt LTD-mediated plasticity in response to cortical input while at the same time unmasking NMDARdependent LTP and strengthening the associability of a subset of DS synapses.…”

Section: Significancementioning

confidence: 61%

See 1 more Smart Citation

Chronic alcohol produces neuroadaptations to prime dorsal striatal learning

DePoy

Daut

Brigman

et al. 2013

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

Self Cite

171

193

View full text Add to dashboard Cite

Drug addictions including alcoholism are characterized by degradation of executive control over behavior and increased compulsive drug seeking. These profound behavioral changes are hypothesized to involve a shift in the regulation of behavior from prefrontal cortex to dorsal striatum (DLS). Studies in rodents have shown that ethanol disrupts cognitive processes mediated by the prefrontal cortex, but the potential effects of chronic ethanol on DLS-mediated cognition and learning are much less well understood. Here, we first examined the effects of chronic EtOH on DLS neuronal morphology, synaptic plasticity, and endocannabinoid-CB1R signaling. We next tested for ethanol-induced changes in striatal-related learning and DLS in vivo single-unit activity during learning. Mice exposed to chronic intermittent ethanol (CIE) vapor exhibited expansion of dendritic material in DLS neurons. Following CIE, DLS endocannabinoid CB1 receptor signaling was down-regulated, and CB1 receptordependent long-term depression at DLS synapses was absent. CIE mice showed facilitation of DLS-dependent pairwise visual discrimination and reversal learning, relative to air-exposed controls. CIE mice were also quicker to extinguish a stimulus-reward instrumental response and faster to reduce Pavlovian approach behavior under an omission schedule. In vivo single-unit recording during learning revealed that CIE mice had augmented DLS neuronal activity during correct responses. Collectively, these findings support a model in which chronic ethanol causes neuroadaptations in the DLS that prime for greater DLS control over learning. The shift to striatal dominance over behavior may be a critical step in the progression of alcoholism.lcoholism is a highly prevalent disorder with a massive and growing impact on public health (1). The course of alcoholism and other chronic drug addictions has been conceptualized as involving the progressive deterioration of executive control of behavior and the corresponding emergence of compulsive drug seeking (2, 3). At the neural systems level, this shift is associated with a "devolution" away from prefrontal cortical (PFC) regulation of behavior in favor of greater control by subcortical regions including the dorsal striatum (DS) (2, 4).Consistent with this scheme, alcohol-dependent individuals show impairments on PFC-mediated cognitive measures, such as impulse control and reversal learning (5, 6), but exaggerated neural responses in the DS when, for example, presented with alcohol-associated cues (7-9). Along similar lines, rodents chronically exposed to ethanol (EtOH) exhibit deficits in PFC-and hippocampal-mediated tasks, including spatial and reversal learning, set-shifting, and fear extinction, that in some cases are linked to cortical cell death (10-17).These observations are consistent with an EtOH-induced impairment in various PFC-related cognitive behaviors but do not address the possibility of concomitant changes in processes mediated by the DS. In this context, recent studies in rats have found that ch...

show abstract

Section: Significancementioning

confidence: 61%

“…We next examined whether the structural and functional effects of CIE in the DLS affected learning processes previously shown to be mediated by this brain region (37,47). We first assessed the effects of CIE on pairwise visual discrimination learning (Fig.…”

Section: Significancementioning

confidence: 99%

Chronic alcohol produces neuroadaptations to prime dorsal striatal learning

DePoy

Daut

Brigman

et al. 2013

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

Self Cite

171

193

View full text Add to dashboard Cite

show abstract

“…Although anxiety is a common feature of FXS, Fmr1 KO mice display low anxiety-like behaviors [69]. Low scores on learning and memory tasks such as water maze spatial navigation, fear-conditioned freezing, novel object recognition, and touchscreen visual discrimination were seen in mice with mutations in genes including Nf1, En2, 16p11.2 deletion, and Plaur with decreased gamma-aminobutryic acid-ergic cortical interneurons [20,28,[70][71][72]. Further investigations of phenotypes in mice that have face validity and neuroanatomical construct validity to both diagnostic and associated symptoms of autism may prove particularly revealing.…”

Section: Discoveries Of Autism-relevant Behaviors In Mouse Modelsmentioning

confidence: 99%

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

2015

View full text Add to dashboard Cite

In order to understand the consequences of the mutation on behavioral and biological phenotypes relevant to autism, mutations in many of the risk genes for autism spectrum disorder have been experimentally generated in mice. Here, we summarize behavioral outcomes and neuroanatomical abnormalities, with a focus on highresolution magnetic resonance imaging of postmortem mouse brains. Results are described from multiple mouse models of autism spectrum disorder and comorbid syndromes, including the 15q11-13, 16p11.2, 22q11.2, Cntnap2, Engrailed2, Fragile X, Integrinβ3, MET, Neurexin1a, Neuroligin3, Reelin, Rett, Shank3, Slc6a4, tuberous sclerosis, and Williams syndrome models, and inbred strains with strong autism-relevant behavioral phenotypes, including BTBR and BALB. Concomitant behavioral and neuroanatomical abnormalities can strengthen the interpretation of results from a mouse model, and may elevate the usefulness of the model system for therapeutic discovery.

show abstract

“…Pairwise visual discrimination and reversal were tested in the automated Bussey-Saksida touchscreen equipment for mice (Campden Instruments Ltd/Lafayette Instruments), using a procedure based on methods described previously (Brigman and Rothblat 2008;Bussey et al 2008Bussey et al , 2012Brigman et al 2013;DePoy et al 2013;Horner et al 2013;Oomen et al 2013;Silverman et al 2015). Since we had discovered that the Dolmetsch line of 16p11.2 +/2 is deaf, using the acoustic startle response and the auditory brainstem response tests (Yang et al 2015b), operant methods were modified to accommodate +/2 mice.…”

Section: Touchscreen Pairwise Discrimination and Reversalmentioning

confidence: 99%

16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks

et al. 2015

View full text Add to dashboard Cite

Chromosomal 16p11.2 deletion syndrome frequently presents with intellectual disabilities, speech delays, and autism. Here we investigated the Dolmetsch line of 16p11.2 heterozygous (+/2) mice on a range of cognitive tasks with different neuroanatomical substrates. Robust novel object recognition deficits were replicated in two cohorts of 16p11.2+/2 mice, confirming previous findings. A similarly robust deficit in object location memory was discovered in +/2, indicating impaired spatial novelty recognition. Generalizability of novelty recognition deficits in +/2 mice extended to preference for social novelty. Robust learning deficits and cognitive inflexibility were detected using Bussey-Saksida touchscreen operant chambers. During acquisition of pairwise visual discrimination, +/2 mice required significantly more training trials to reach criterion than wild-type littermates (+/+), and made more errors and correction errors than +/+. In the reversal phase, all +/+ reached criterion, whereas most +/2 failed to reach criterion by the 30-d cutoff. Contextual and cued fear conditioning were normal in +/2. These cognitive phenotypes may be relevant to some aspects of cognitive impairments in humans with 16p11.2 deletion, and support the use of 16p11.2+/2 mice as a model system for discovering treatments for cognitive impairments in 16p11.2 deletion syndrome.Recurrent heterozygous deletions of a 600-kb segment on human chromosome 16 is found in 0.4% of individuals with intellectual disability (Bijlsma et al. 2009;Hanson et al. 2015) and 0.6% of individuals with autism (Marshall et al. 2008;Weiss et al. 2008;Walsh and Bracken 2011). 16p11.2 deletion syndrome presents with a range of mild-to-severe cognitive impairments, with IQ scores averaging 2 SDs lower than controls, and a confirmed diagnosis of autism in 15% of affected individuals (Hanson et al.

show abstract

GluN2B in corticostriatal circuits governs choice learning and choice shifting

Cited by 138 publications

References 58 publications

Chronic alcohol produces neuroadaptations to prime dorsal striatal learning

Chronic alcohol produces neuroadaptations to prime dorsal striatal learning

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks

Contact Info

Product

Resources

About