Chronic intermittent cold stress and serotonin depletion induce deficits of reversal learning in an attentional set-shifting test in rats

Abstract

Rationale-Chronic stress perturbs modulatory brain neurotransmitter systems, including serotonin (5-HT), and is a risk factor for psychiatric disorders such as depression. Deficits in cognitive flexibility, reflecting prefrontal cortical dysfunction, are prominent in such disorders. Orbitofrontal cortex (OFC) has been implicated specifically in reversal learning, a form of cognitive flexibility modulated by 5-HT.Objectives-Assess the effects of chronic intermittent cold (CIC) stress, a potent metabolic stressor, on performance of rats in an attentional set shifting test (AST). Assess a possible role for serotonin in CIC-induced deficits, and test the effects of acute serotonin reuptake blockade. Methods-MaleSprague-Dawley rats were exposed to CIC stress (14 days × 6 hr/day at 4 °C) before testing on the AST. In subsequent experiments, brain 5-HT was depleted in naïve rats with para-chlorophenylalanine, or 5-HT release was increased acutely in CIC-stressed rats with citalopram (5 mg/kg, s.c.) given 30 min prior to the first reversal task. Microdialysis was used to assess CICinduced changes in 5-HT release in OFC during testing.Results-CIC-stressed rats exhibited a selective impairment on the first reversal task in the AST. 5-HT depletion induced a similarly selective deficit in reversal learning. The CIC-induced impairment in reversal learning was attenuated by acute 5-HT reuptake blockade. 5-HT release was reduced in OFC of CIC-stressed rats during behavioral testing.Conclusions-The CIC stress-induced impairment of cognitive flexibility may involve dysregulation of 5-HT modulatory function in OFC. Such deficits may thus model relevant symptoms of neuropsychiatric disorders that respond positively to SSRI treatment.

Effects of acute restraint stress on set-shifting and reversal learning in male rats

“…However, previously stressed mice committed fewer errors than did unstressed mice later in reversal learning, when perseveration had ceased (i.e., accuracy ≥ 50 %), an effect prevented by brain-derived neurotrophic factor infusions into the ventral medial prefrontal cortex (Graybeal et al, 2011). The effects of other, longer chronic-stress protocols on reversal learning have been inconsistent (Bondi et al, 2008;Liston et al, 2006), although impaired reversal learning is consistently observed following some chronic stress protocols (Danet et al, 2010;Lapiz-Bluhm et al, 2009). The time frame of the acute stress-induced facilitation of reversal learning was much shorter in the present experimental design: Rats were subjected to acute stress for 30 min Stress refers only to stress on the reversal test day (see Fig.…”

“…For example, a recent report has shown that infusions of corticotropin-releasing factor (CRF) into the locus coeruleus produce a complex modulation of setshifting and reversal learning in rats (Snyder, Wang, Han, McFadden, & Valentino, 2012): Rats infused with higher doses of CRF displayed enhanced reversal learning, whereas a low dose enhanced the set-shifting component of the same task (Snyder et al, 2012). Serotonergic, dopaminergic, and glutamatergic systems are also involved in reversal learning (Balschun et al, 2010;Bannerman, Deacon, Seeburg, & Rawlins, 2003;Boulougouris & Robbins, 2010;Floresco et al, 2009;Lapiz-Bluhm et al, 2009;Robbins & Roberts, 2007). Therefore, a direction for further research could be to manipulate these neurotransmitter systems in order to assess the roles Fig.…”

“…Chronic stress with a variety of paradigms impairs attentional set-shifting in rats (Bondi, Jett, & Morilak, 2010;Bondi, Rodriguez, Gould, Frazer, & Morilak, 2008;Liston et al, 2006;Nikiforuk, 2012;Nikiforuk & Popik, 2011), an effect that is correlated with morphological alterations in the pyramidal cells of mPFC Radley et al, 2006). Either no effect , an inconsistent impairment (Bondi et al, 2008), or an impairment (Danet, Lapiz-Bluhm, & Morilak, 2010;Lapiz-Bluhm, Soto-Pina, Hensler, & Morilak, 2009) of reversal learning has been reported following various chronic-stress protocols. One recent study using a touch-screen assay in mice demonstrated that three days of swim stress enhanced reversal learning during late acquisition after severe perseveration had ceased (Graybeal et al, 2011).…”

Probing Compulsive and Impulsive Behaviors, from Animal Models to Endophenotypes: A Narrative Review

“…There is now considerable evidence linking reversal learning with 5-HT mechanisms, including in rodents (Masaki et al, 2006;Boulougouris et al, 2008;Lapiz-Bluhm et al, 2009), non-human primates (Clarke et al, 2004(Clarke et al, , 2005Walker et al, 2009), and human beings (Park et al, 1994;Rogers et al, 1999a;Evers et al, 2005) based on pharmacological, neurochemical and dietary manipulations, and evidence of genetic polymorphisms in rhesus monkeys (Izquierdo et al, 2007). Generally, reducing brain serotonin, especially in specific regions such as the OFC (eg Clarke et al, 2004), impairs reversal learning.…”

Physiologically Relevant Changes in Serotonin Resolved by Fast Microdialysis

“…76 Additionally, online microdialysis can be performed in experimental animals during behavioral tasks. 38,39 High temporal resolution and multiplexed measurements will be vital to understanding how behaviorally relevant information is encoded in chemical neurotransmission. 77,78 ■ METHODS Animals.…”