Behavioral flexibility in rats and mice: contributions of distinct frontocortical regions

Hamilton, Derek A.; Brigman, Jonathan L.

doi:10.1111/gbb.12191

Cited by 152 publications

(118 citation statements)

References 139 publications

(203 reference statements)

Supporting

Mentioning

110

Contrasting

Order By: Relevance

“…The OFC is known to underlie flexible stimulus-reinforcement learning in humans (Cools et al 2002;Hornak et al 2004;Tsuchida et al 2010) and, similar to other animal studies (Hamilton and Brigman 2015), we observed that the OFC plays a fundamental role in reversal learning. However, the effect of our lesions on perseverative errors was only limited which asks for further investigation of the role of the OFC in response inhibition.…”

Section: Discussionsupporting

confidence: 90%

Measuring discrimination- and reversal learning in mouse models within 4 days and without prior food deprivation

et al. 2016

View full text Add to dashboard Cite

Many neurological and psychiatric disorders are characterized by deficits in cognitive flexibility. Modeling cognitive flexibility in mice enables the investigation of mechanisms underlying these deficits. The majority of currently available behavioral tests targeting this cognitive domain are reversal learning tasks that require scheduled food restriction, extended training periods and labor-intensive, and stress-inducing animal handling. Here, we describe a novel 4-day (4-d) continuously running task measuring discrimination-and reversal learning in an automated home cage (CognitionWall DL/RL task) that largely eliminates these limitations. In this task, mice can earn unlimited number of food rewards by passing through the correct hole of the three-holed CognitionWall. To assess the validity and sensitivity of this novel task, the performance of C57BL/6J mice, amyloid precursor protein/presenilin1 transgenic (APP/PS1) mice, a-calmodulin kinase-II (aCaMKII) T305D knock-in mice, and mice with an orbitofrontal cortex lesion were examined. We found that C57BL/6J mice reach stable performance levels within the 4 d of the task, while experiencing only slight reductions in weight and no major effects on circadian rhythm. The task detected learning deficits in APP/PS1 transgenic and aCaMKII T305D mutant mice. Additionally, we established that the orbitofrontal cortex underlies reversal learning performance in our task. Because of its short duration and the absence of food deprivation and concurrent weight loss, this novel automated home-cage task substantially improves comprehensive preclinical assessment of cognitive functions in mouse models of psychiatric and neurological disorders and also enables analysis during specific developmental stages.

show abstract

Section: Discussionsupporting

confidence: 90%

Measuring discrimination- and reversal learning in mouse models within 4 days and without prior food deprivation

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The ability to initiate, select, and shift action involves the ventromedial and orbitofrontal regions of the prefrontal cortex, and the dorsal striatum Hamilton and Brigman 2015). Reversal learning is thought to depend on medial prefrontal cortex, orbitofrontal cortex, and interconnected subcortical areas, most notably dorsal striatum (Ragozzino 2007;Bissonette et al 2008Bissonette et al , 2015Brigman and Rothblat 2008).…”

Section: Discussionmentioning

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

“…This ensured that tasks proceeded in order of increasing difficulty, but also resulted in an incorrect lever choice that was 1) naturally preferred and 2) illuminated 50% of trials (a previously reinforced cue). Second, strategy set-shifting and reversal learning are dependent on two distinct prefrontal regions, the mPFC and orbitofrontal cortex, respectively (Floresco, Zhang, & Enomoto, 2009; Ghods-Sharifi, Haluk, & Floresco, 2008; Hamilton & Brigman, 2015). Nevertheless, the finding that CTA only affected set-shifting and not reversal learning suggests that impairments in memory retrieval induced by these manipulations may be more apparent when distinct discrimination strategies are required, rather than situations requiring the use of the same basic strategy (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Efficient completion of these tasks is critically-dependent on the integrity of the prefrontal cortex (Hamilton & Brigman, 2015). Moreover, disrupting communication between the medial prefrontal cortex (mPFC) and nucleus accumbens core (NAc) impairs shifting between strategies by increasing perseverative responding (Block et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Persistent cognitive and morphological alterations induced by repeated exposure of adolescent rats to the abused inhalant toluene

Braunscheidel

Gass

Mulholland

et al. 2017

Neurobiology of Learning and Memory

View full text Add to dashboard Cite

While the psychoactive inhalant toluene causes behavioral effects similar to those produced by other drugs of abuse, the persistent behavioral and anatomical abnormalities induced by toluene exposure are not well known. To mimic human “binge-like” inhalant intoxication, adolescent, male Sprague-Dawley rats were exposed to toluene vapor (5700 ppm) twice daily for five consecutive days. These rats remained in their home cages until adulthood (P60), when they were trained in operant boxes to respond to a palatable food reward and then challenged with several different cognitive tasks. Rats that experienced chronic exposure to toluene plus abstinence (“CTA”) showed enhanced performance in a strategy set-shifting task using a between-session, but not a within-session test design. CTA also blunted operant and classical conditioning without affecting responding during a progressive ratio task. While CTA rats displayed normal latent inhibition, previous exposure to a non-reinforced cue enhanced extinction of classically conditioned approach behavior of these animals compared to air controls. To determine whether CTA alters the structural plasticity of brain areas involved in set-shifting and appetitive behaviors, we quantified basal dendritic spine morphology in DiI-labeled pyramidal neurons in layer 5 of the medial prefrontal cortex (mPFC) and medium spiny neurons in the nucleus accumbens (NAc). There were no changes in dendritic spine density or subtype in the mPFC of CTA rats while NAc spine density was significantly increased due to an enhanced prevalence of long-thin spines. Together, these findings suggest that the persistent effects of CTA on cognition are related to learning and memory consolidation/recall, but not mPFC-dependent behavioral flexibility.

show abstract

Behavioral flexibility in rats and mice: contributions of distinct frontocortical regions

Cited by 152 publications

References 139 publications

Measuring discrimination- and reversal learning in mouse models within 4 days and without prior food deprivation

Measuring discrimination- and reversal learning in mouse models within 4 days and without prior food deprivation

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

Persistent cognitive and morphological alterations induced by repeated exposure of adolescent rats to the abused inhalant toluene

Contact Info

Product

Resources

About