The Attentional Set Shifting Task: A Measure of Cognitive Flexibility in Mice

Abstract

Cognitive impairment, particularly involving dysfunction of circuitry within the prefrontal cortex (PFC), represents a core feature of many neuropsychiatric and neurodevelopmental disorders, including depression, post-traumatic stress disorder, schizophrenia and autism spectrum disorder. Deficits in cognitive function also represent the most difficult symptom domain to successfully treat, as serotonin reuptake inhibitors and tricyclic antidepressants have only modest effects. Functional neuroimaging studies and postmortem analysis of human brain tissue implicate the PFC as being a primary region of dysregulation in patients with these disorders. However, preclinical behavioral assays used to assess these deficits in mouse models which can be readily manipulated genetically and could provide the basis for studies of new treatment avenues have been underutilized. Here we describe the adaptation of a behavioral assay, the attentional set shifting task (AST), to be performed in mice to assess prefrontal cortex mediated cognitive deficits. The neural circuits underlying behavior during the AST are highly conserved across humans, nonhuman primates and rodents, providing excellent face, construct and predictive validity.

Investigating Individual Pre-trauma Susceptibility to a PTSD-Like Phenotype in Animals

“…For example, improving hippocampal and mPFC function of susceptible rats by engaging them in behavioral tasks that involve both regions should increase their resilience as measured by a post-trauma behavioral phenotype, similar to that of resilient rats. We have initiated experiments to test this hypothesis by subjecting SUS rats to a series of set shifting tasks (George et al, 2015;Heisler et al, 2015) before trauma and measuring their post-trauma PTSD-like phenotype, as well as learning-induced expression of plasticity-related immediate early genes.…”

Neuropathic Pain Creates an Enduring Prefrontal Cortex Dysfunction Corrected by the Type II Diabetic Drug Metformin But Not by Gabapentin

“…Cognitive flexibility, the ability to recognize and react to new stimuli in the environment, is an executive function that depends on areas in the frontal cortex in rodents and humans (Birrell and Brown, 2000;Heisler et al, 2015;Livingston-Thomas et al, 2015). Patients with chronic intractable pain (Eccleston, 1995;Dick et al, 2002;Karp et al, 2006;Schiltenwolf et al, 2014) and neuropathic pain (Ryan et al, 1993;Povedano et al, 2007;Attal et al, 2014) have poor performance in tasks that assess cognitive flexibility, suggesting that persistent pain disrupts normal cortical function.…”

“…Optogenetic activation or inhibition of parvalbumin (PV)-positive GABAergic interneurons in neuropathic mice causes an increase or decrease, respectively, in mechanical hypersensitivity, suggesting that these cells may be directly involved in sensory processing of chronic pain . In other disease models, a loss of PV expression in the mPFC has also been linked to deficits in cognitive flexibility (Murray et al, 2015;Zhou et al, 2015;Hashemi et al, 2017), increased GABA release, abnormal spike timing, disrupted inhibition, and asynchronous gamma wave oscillations (Vreugdenhil et al, 2003;Volman et al, 2011;Petitjean et al, 2015;Filice et al, 2016). Recent studies have also demonstrated that sensory experience can impact axon initial segments (AISs) in cortical regions (Grubb and Burrone, 2010;Kuba et al, 2010;Grubb et al, 2011;Leterrier, 2018), but this has not been studied in the context of neuropathic pain.…”

Donepezil down‐regulates propionylation, 2‐hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation in the brain of bilateral common carotid artery occlusion‐induced vascular dementia rats

“…Cognitive flexibility was assessed using the ASST 38 . In brief, rats that underwent sham (n = 8), BCCAO (n = 8) and BCCAO + donepezil (n = 9) treatment were singly housed and food deprived to maintain 85% of free‐feeding body weight.…”