Cay

Behavioral Flexibility: Attentional Shifting, Rule Switching and Response Reversal. Fig. 1. Rats are presented with a pair of bowls on either side of a divider. Both bowls contain a different digging medium filling the bowl and they smell differently (odors are represented by lines above the bowls), but only one of the bowls is baited with food. In an initial acquisition phase (ACQ), either the odor (as shown in the illustration) or the medium indicates which bowl is baited. At the intradimensional (ID) stage, the media and the odors are replaced with novel stimuli. The relevant dimension (in the illustration, the odor) remains relevant for finding the food. At the extradimensional (ED) stage, the media and odors are again replaced with novel stimuli. The previously relevant dimension no longer indicates the location of the food. The animal must change its attentional focus to the other dimension - the medium. Typically, animals require more trials to learn new discriminations when they must reorient their attention (ED stage) compared to when their attention is already appropriately focused (ID stage).

stages, but, at the ED stage, the characteristic of the bowl that is relevant to solve the discrimination is also changed. The additional trials required to learn the discrimination are indicative of the strength of attentional set. The fact that the rodent can discriminate between a very large number of odors and haptic stimuli overcomes the limitations of using visual stimuli.

In the case of rule-switching tasks, it is not stimuli, but responses that must be novel; however, it is not trivial to devise a task for a rodent in which a rule will be extrapolated to form a learning set, which will then benefit new learning, while not being "the same'' discrimination. With foraging animals, spatial discriminations are powerful tools as a variety of rules (e.g., egocentric ("turn right''), visual ("approach the light''), and allocentric ("head South'')) can be generated to solve them. However, it is problematic to prevent the partial reinforcement of the application of a previously correct rule because there are not a similar variety of responses to express the learning of those rules. If there is still the possibility of making a previously rewarded response by applying an old rule, then the previously learned discrimination will be unintentionally partially reinforced and this might retard learning of the new rule, rather than an attentional switch-cost per se.

Impact of Psychoactive Drugs

Impairments in behavioral flexibility have been reported in many different psychiatric and neurological conditions, including ► schizophrenia, ► attention deficit hyperactiv-ity disorder, ► Parkinson's disease, ► mild cognitive impairment, Alzheimer's disease, and ► bipolar disorder. Most of our current understanding of impairment in behavioral flexibility derives from studies of these conditions, or animal models of these conditions (► Primate models of cognition, ► Rodent models of cognition, ► Dementias: animal models, ► Depression: animal models, ► Animal models for psychiatric states, ► Schizophrenia: animal models), compared to control subject performance. Thus, (dorso)lateral prefrontal cortex of primates (medial prefrontal cortex of rodents) has been implicated in both attentional shifting and rule switching, while impairments in reversal learning are associated with orbital prefrontal cortex. Investigations of the effects of psychoactive drugs on behavioral flexibility have served either to model human pathological conditions by inducing neurochemical imbalance, or to ameliorate the effects of those models. In particular, dopamine (DA), serotonin (5-HT), norepinephrine (NE), and acetylcholine (ACh) have all been implicated in shifting/switching and/or reversal learning.

Dopamine (DA)

Most of the evidence, from patients and experimental animals, implicates prefrontal cortical, and not striatal,

► dopamine in shifting/switching performance while striatal dopamine has been implicated in reversal learning.

Impairments in attentional shifting are consistently reported in patients with schizophrenia, a disorder long associated with dopamine overactivity. However, while

► first-generation antipsychotic treatments, which block striatal dopamine D2 receptors, are effective treatments for positive symptoms of schizophrenia, they do not improve and may further impair cognitive (including shifting) impairments. ► Second-generation antipsycho-tics, such as clozapine, olanzapine, and risperidone, do offer some cognitive benefits, perhaps deriving from their actions on prefrontal cortical function and perhaps mediated by effects on receptors other than dopamine.

Parkinson's disease is associated with both frontal and striatal dopamine depletion, either of which could account for the shifting deficits reported in these patients. Nevertheless, converging data suggest that it is prefrontal, rather than striatal, dopamine that is responsible.

Shifting and/or switching impairments in rats have been reported in a variety of animal models of schizophrenia). Subchronic ► phencyclidine (PCP) impairs shifting and second-generation, but not the first, antipsychotics ameliorate the deficits. Similarly, ► amphetamine sensiti-zation (► Sensitization to drugs) impairs shifting and reversal learning. Infusion of the D1 receptor agonist 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF38393) into medial prefrontal cortex ameliorates the effect of amphetamine sensitization on shifting, without improving the impairment in reversal learning.

Antagonism of the D1 receptor by 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) impairs switching, with the D1 agonist 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine hydrobromide (SKF 81297) having no effect. Switching is also impaired by the D4 agonist, N-(Methyl-4-(2-cyanophenyl)piperazinyl-3-methylbenzamide maleate (PD168077), and improved by the D4 antagonist, 3-[{4-(4-chlorophenyl)piperazin-1-yl}methyl)-1H-pyrrolo[2,3-b]pyridine (L745870).

Serotonin (5-HT)

► Serotonin is implicated in various forms of behavioral flexibility, including shifting, switching, and reversal learning. There may be a direct effect in the orbital prefron-tal cortex on reversal learning. For example, serotonergic depletion of frontal cortex with 5,7-dihydroxytryptamine

(5,7-DHT) has been reported to impair reversal learning without impairing rule-switching.

A variety of serotonergic compounds improve shifting, but the serotonergic action might be indirect, via a modulation of levels of dopamine, norepinephrine, and/or acetylcholine. For example, the 5-HT6 receptor antagonist N-[3,5-dichloro-2-(methoxy)phenyl]-4-(meth-oxy)-3-(1-piperazinyl)benzenesulfonamide (SB399885T) improves shifting in normal rats and both the selective 5-HT6 antagonist 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide (SB271046A) and the antipsychotic, sertindole, ameliorate PCP-induced impairment in shifting. Asenapine (a second-generation antipsychotic, which has higher affinity for 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7, as well as a2-adrenergic receptors than it does for D2 receptors) ameliorates shifting impairments following a lesion of the prefrontal cortex.

Norepinephrine (NE)

Increasing prefrontal cortical ► norepinephrine in normal rats has been reported to improve shifting. However, increasing norepinephrine also increases prefrontal cortical dopamine and this co-modulation means that it is difficult to separate their effects on behavioral flexibility (for review see Arnsten and Li 2005). Nevertheless, there may be specific and selective effects: noradrenergic-specific lesions have been reported to result in impairments in shifting/switching in rats, which can be reversed by the selective NE reuptake inhibitor ► atomoxetine, at doses reported to have no effect on prefrontal cortical dopamine.

Acetylcholine (ACh)

Scopolamine (► Muscarinic agonists and antagonists) impairs shifting and switching in rats and there have been reports of beneficial effects of nicotine (► Nicotinic agonists and antagonists). However, selective lesions of prefrontal or basal forebrain cholinergic neurons impact reversal learning and not shifting (for review see Robbins and Roberts 2007).

Conclusion

Specifying the neurochemical profile of behavioral flexibility is made complex by the co-modulatory effects of the monoaminergic systems in frontal cortex. Nevertheless, there is little doubt that the prefrontal cortex and the innervating neurochemical projection systems are important for executive control, of which behavioral flexibility is a key component.

Cross-References

► Animal Models for Psychiatric States

► Atomoxetine

► Attention Deficit Hyperactivity Disorder

► Bipolar Disorder

► Classical (Pavlovian) Conditioning

► Dementias: Animal Models

► Depression: Animal Models

► First-Generation Antipsychotics

► Impulse Control Disorders

► Impulsivity

► Instrumental Conditioning

► Mild Cognitive Impairment

► Muscarinic Agonists and Antagonists

► Nicotinic Agonists and Antagonists

► Primate Models of Cognition

► Rodent Models of Cognition

► Schizophrenia

► Schizophrenia: Animal Models

► Second Generation Antipsychotics

► Sensitization to Drugs

References

Arnsten AF, Li BM (2005) Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry 57:1377-1384

Berg EA (1948) A simple objective technique for measuring flexibility in thinking. J Gen Psychol 39:15-22

Gibson JJ (1941) A critical review of the concept of set in contemporary experimental psychology. Psychol Bull 38:781-817

Lawrence DH (1949) The acquired distinctiveness of cues: I. Transfer between discriminations on the basis of familiarity with the stimulus. J Exp Psychol 39:770-784

Luchins AS (1942) Mechanization in problem solving. The effect of "Einstellung". Psychol Monogr 54:248

Robbins TW, Roberts AC (2007) Differential regulation of fronto-executive function by the monoamines and acetylcholine. Cereb Cortex 17:i151-i160

Was this article helpful?

0 0
Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

Get My Free Ebook


Post a comment