Research reportNeural circuits subserving behavioral flexibility and their relevance to schizophrenia
Introduction
Cognitive deficits observed in patients with schizophrenia have been recognized as a fundamental component to the disorder since its initial description (i.e., as “dementia praecox”). There has been a growing focus on the disruptions in cognitive functioning observed in schizophrenia, since it appears to be a core feature of the disorder, as opposed to being merely a result of the symptoms. Indeed, cognitive functioning in these patients is the single best predictor of long-term outcome [56]. Multiple domains of cognitive function are disrupted in schizophrenia (e.g., attention, working memory, reasoning and problem solving, etc.), and an emergent property of these executive functions is to facilitate alterations in well-established behaviors in response to changes in one's environment. As a consequence, impairment in different forms of behavioral flexibility is one of the most reliable deficits observed in these patients. Schizophrenics display great difficulty in shifting between different rules or strategies on tests such as the Wisconsin Card Sorting task [15], [50], [83], [90]. These impairments appear to be due in part to an inability to shift attentional set from one stimulus dimension to another, as similar impairments have been observed in patients tested on an intradimensional/extradimensional shifting (IDS/EDS) task [62], [88]. Furthermore, a subset of these patients also display impairments in reversal learning, a simpler form of behavioral flexibility entailing shifts between different stimulus–reward associations within a particular dimension [85], [117].
Impairments in behavioral flexibility observed in schizophrenia have long been attributed to perturbation in frontal lobe functioning. Post-mortem and functional imaging studies of schizophrenic brains have revealed cellular and neurophysiological abnormalities in the lateral, medial and orbital regions of the prefrontal cortex (PFC), which likely contribute to impairments in executive functioning [18], [71], [100], [106]. However, recent findings from both human and animal studies indicate that complex forms of behavioral flexibility mediated by the frontal lobes are also dependent on a number of subcortical systems that interact with the PFC. These include midline thalamic nuclei, dorsal and ventral regions of the striatum, and the meoscorticolimbic dopamine (DA) system. It is of note that abnormalities in each of these systems have also been proposed to contribute to pathophysiology of schizophrenia [5], [18], [31], [53], [107]. Thus, a more complete understanding of the mechanisms underlying impaired flexibility in schizophrenia may be obtained from the elucidation of dysfunction that occurs in these cortical–subcortical circuits, rather than focusing on disruptions in functioning of the PFC or subcortical systems alone.
A recent thrust of drug discovery research has focused on developing novel pro-cognitive compounds to treat the cognitive deficits in schizophrenia, and preclinical animal models are an essential first step in this process. Given that impairments in behavioral flexibility seems to be a core deficit in this disorder, modeling these impairments would be extremely beneficial in testing the potential efficacy of novel cognitive enhancers [43]. These models typically entail neurodevelopmental or pharmacological manipulations that lead to disruptions in neural circuits interconnected to the PFC in adulthood. However, a comprehensive understanding of how these models may impede cognitive functioning related to behavioral flexibility requires a basic understanding of the specific contributions and interactions between these cortical and subcortical systems in the normal brain that facilitate these cognitive operations. Thus, the purpose of this review is to summarize recent work elucidating the contributions of cortico-thalamic-striatal circuits make to different forms of behavioral flexibility, and how these findings relate to impairments in these processes which are observed both in schizophrenia and certain animal models of this disorder.
Section snippets
Assessing behavioral flexibility in rodents
It is important to note that behavioral flexibility is not a unitary phenomenon, but rather, may be viewed as a hierarchical process, with these different processes being subserved by anatomically distinct cortical and subcocortical regions. For example, extinction entails the suppression of a conditioned response elicited by a stimulus that no longer predicts reinforcement. Reversal learning is another form of flexibility that can occur when an organism discriminates between two or more
Prefrontal cortex
Across species, it is well established that anatomically distinct regions of the prefrontal cortex play a critical role in facilitating different forms of behavioral flexibility. For instance, inactivations or lesions of the medial PFC in rodents or the dorsolateral PFC in primates disrupt the shifting between novel strategies, rules or attentional sets [16], [32], [91]. Studies employing a strategy set-shifting task conducted on a maze or in an operant chamber have revealed that manipulations
Neurodevelopmental models
Initial attempts at developing rodent models of schizophrenia focused on certain neural manipulations that are related to some of the brain abnormalities observed in schizophrenia, and how these treatments affected simpler forms of behavior. These included enhanced sensitivity to the effects of amphetamine, disruptions in sensory motor gating and certain aspects of associative learning (e.g., latent inhibition), all of which have been observed in schizophrenic patients. More recently, these
Subjects
Male, Long Evans rats (Charles River Laboratories, Montreal, Canada), weighing between 250 and 300 g at the start of the experiment were used. Rats were group housed for the first week upon arrival from the supplier (food and water ad libitum). One week prior to the start of behavioral training, rats were individually housed and food restricted to 85% of their free feeding weight. Food restriction was maintained for the entire duration of the experiment. During the 1-week period prior to
Drug administration and locomotor activity
Following initial maze familiarization or initial lever pressing training (see below) animals were subjected to 10 injections of saline or 30 mg/kg ketamine i.p. (Bimeda-MTC, Cambridge, Ontario, Canada) at a volume of 1 ml/kg of body weight. This dose was chosen based on previous studies with this drug [8]. Injections were given twice daily (09:00 h/18:00 h), for 5 consecutive days. After the injection, rats were placed directly put back into their home cages. Ten minutes after the first and last
Maze familiarization
The familiarization procedure has also been described in detail previously [44], [45]. On the first day, a rat was allowed to freely navigate and consume 20 pellets placed throughout the 4 arms of the maze for 15 min. On the second day, arms were baited with three pellets each. To familiarize the rat to repeated handling, it was picked up and placed at the entrance of a different arm when it consumed all of the pellets in each of the other arms. Subsequent sessions were similar, except that only
Initial lever pressing training
These procedures have also been described previously [46] (see Fig. 1B). On the day before initial exposure to the operant chamber, rats were given ∼20 reward pellets in their home cage. Before the animal was placed in the chamber on the first day of training, two to three crushed pellets were placed in the food cup and on the active lever. Rats were trained under a fixed-ratio 1 schedule to a criterion of 50 presses in 30 min, first for one lever, then the other (counterbalanced left/right
Response to visual-cue set-shift using a maze-based procedure
Rats that received repeated ketamine treatments (n = 9) acquired the response discrimination in a comparable number of trials (126 ± 27) compared to control rats (118 ± 18; n = 8) (F(1, 15) = 0.063, n.s.). Similarly, there were no differences between groups in the number of errors made on this task (F(1, 15) = 0.313, n.s.; Fig. 3A), on the number of probe trials administered or the number of trials completed per minute (all p's >0.50). Thus, repeated ketamine treatments did not disrupt initial learning of
Discussion
Subchronic treatment with the non-competitive NMDA antagonist ketamine actually led to a reduction in perseverative errors during strategy set-shifting. These findings would seem at odds with other studies reporting increased number of errors during attentional set-shifting in rats treated with repeated PCP, a similar compound, assessed with an IDS/EDS task [36], [49], [76], [98], [99]. One potential reason for the differences between the present study and these previous findings may be due to
Summary and conclusions
From the findings reviewed here, it is clear that different forms of behavior flexibility governed by the frontal lobes are subserved by a complex interplay with subcortical systems, including different regions of the striatum, midline thalamus and the mesocorticolimbic DA system. Each of these circuits make distinct contributions to component processes of behavioral flexibility. This information provides valuable insight into how the multiple brain abnormalities present in schizophrenia may
Acknowledgments
This work was supported by a Discovery Grant from the Natural Science and Engineering Research Council of Canada, a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression and funding from Dainippon Sumitomo Pharma Co., Ltd. (Osaka, Japan) to SBF. SBF is a Michael Smith Foundation for Health Research Senior Scholar.
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