We monitored behavioral actions and electrical activity in the prelimbic PFC while rats performed a choice task with asymmetric reward outcomes that varied in time. Although NVHL rats were able to track changes in reward outcomes by selecting the wells delivering larger rewards, their performance was less flexible than that of control rats. During recording sessions in which the location of the large reward varied across trial blocks, NVHL rats did not learn to choose the well giving large rewards as rapidly as control rats on free-choice trials and made more response errors on forced-choice trials. These behavioral deficits were (i) associated with increased firing of medial PFC putative pyramidal neurons and a reduction in the power of PFC field potentials during odor sampling, and (ii) ameliorated by pharmacological reduction of glutamate release. These data reveal alterations in both behavior and PFC physiology in adult rats with a NVHL that are tightly timed to epochs in which response decisions are made, and support the idea that cortical hyperactivity impairs function.
The degraded performance of NVHL rats on the choice task is consistent with known cognitive deficits in this model. For example, the reduced selection of larger rewards on free choice trials may reflect problems in forming or utilizing information about the location of the well that gives large rewards. These problems could arise either from deficits in learning from past cue-response-reward outcomes or from deficits in using such information in working memory processes (Chambers et al., 1996
; Lipska et al., 2002
) to guide actions. However, learning or working memory deficits would not account for the pattern of errors on forced-choice trials or the overall reduction in reaction times. These behavioral features may be more related to the inability to use sensory information to overcome a prepotent response and may reflect impulsivity in NVHL rats, although a proper test of impulsivity remains to be conducted in this model. The reduced flexibility observed here in NVHL rats could also be interpreted as an equivalent of perseveration, a PFC-dependent phenomenon commonly observed in schizophrenia and PFC lesions (Milner, 1963
). Indeed, NVHL rats have been shown to exhibit perseverative behaviors in a set-shifting task (Brady, 2009
). The medial PFC is in fact important for inhibiting actions based on sensory cues, as medial PFC lesions or inactivation in otherwise normal rats lead to premature responses (Narayanan and Laubach, 2006
) and reduce the ability to resolve conflicts in sensory cues (Haddon and Killcross, 2006
). Interestingly, NVHL rats were not deficient in their ability to learn cue-response associations during shaping of the behavior in which only forced choice trials were given for equal reward size in both wells. Rather, the deficits emerged clearly only when free-choice trials and unequal reward outcomes were introduced, suggesting that neurophysiological changes in NVHL rats impact more strongly the cognitively demanding aspects of the task.
These behavioral deficits were closely associated with physiological anomalies in the medial PFC. Putative pyramidal neurons increased their firing to a greater extent during the odor sampling in NVHL rats than in controls. At the same time increased firing was observed, NVHL rats exhibited a dramatic failure to increase the strength of field potential oscillations presumed to reflect the activity of local inhibitory interneurons. Although we cannot rule out changes in the activity of VTA DA neurons in NVHL rats being involved in the present results, our previous data suggest altered PFC responses to burst firing of DA neurons. For example, medial PFC pyramidal neurons show abnormal increases in firing following VTA stimulation in NVHL rats (O’Donnell et al., 2002
), consistent with the proposed DA-mediated disinhibition in this rodent model. Furthermore, whole cell recordings in prelimbic PFC slices revealed that pyramidal neurons are more excitable (Tseng et al., 2007
) while fast-spiking interneurons are less excitable
in adult rats with a NVHL (Tseng et al., 2008
DA agonists increase excitability of fast-spiking interneurons in slices from adult naïve or sham rats (Tseng and O’Donnell, 2007
), but not from NVHL rats (Tseng et al., 2008
). Therefore, burst firing in VTA DA neurons should recruit interneurons in sham rats, but do so weakly in NVHL rats, thereby exacerbating disinhibition. As the period in the task in which increased firing and loss of beta activation were observed corresponds to the time of activation of DA neurons in the VTA (Roesch et al., 2007
), we suggest that the abnormal response to DA and loss of modulation of interneuron firing contribute to the excessive firing and recruitment of more units in NVHL rats. Our observations of increased task-related firing and reduced high-frequency field potential oscillations are complementary and expected outcomes of inhibitory dysfunction in PFC because of the important roles of GABAergic interneurons for regulating and synchronizing firing in neocortex (Traub et al., 1996
; Szabadics et al., 2001
; Cardin et al., 2009
). The most parsimonious mechanism to account for our observations is the deficient activation of PFC fast-spiking interneurons under conditions of high DA that has been revealed in our previous experiments with the NVHL model. Inappropriate activation of output from medial PFC is expected to interfere with normal performance on cognitively demanding tasks, such as the one used here. According to this model, the abnormal response of medial PFC to dopamine release in NVHL rats may prevent cortical circuits from filtering out irrelevant information, leading to poor decision-making. The ability to improve task performance by pharmacologically reducing glutamate release in NVHL rats may be due to a reduced pyramidal cell excitability that compensates for impaired inhibition such that filtering of PFC output is improved.
Cortical disinhibition is increasingly recognized as a critical element in schizophrenia pathophysiology. Indeed, postmortem studies and neurophysiological assessments reveal loss of interneuron function and impaired PFC information processing in schizophrenia (Benes and Berretta, 2001
). Our data suggest that such a loss may lead to an acute imbalance of excitation-inhibition when mesocortical DA pathways are activated, resulting in spurious information flow in cortical circuits and thus impairing decision-making processes. Such a state of exaggerated and inefficient activity has in fact been proposed for schizophrenia (Callicott et al., 2000
; Winterer et al., 2006
). Given the well-documented loss of specific interneuron populations in schizophrenia and the deficits in beta and gamma EEG oscillations, in particular when evoked by sensory stimuli (Spencer et al., 2008
), we propose that excessive “noisy” information flow may occur in patients during critical decision-making instances due to disinhibition. Indeed, a recent study revealed that despite intact reward-based learning, schizophrenia patients show a poor performance in using contextual information to guide decision-making when outcome values are considered (Heerey et al., 2008
). Although our study focused on the PFC, it is possible that interneuron deficits and cortical disinhibition constitute a global phenomenon in animal models of schizophrenia and perhaps in the human condition as well. A combination of current therapeutic approaches targeting DA receptors with novel approaches addressing disinhibition in cortical circuits would therefore be likely to provide a more efficacious treatment of schizophrenia.