Background-Alterations in cellular survival and plasticity are implicated in the neurobiology of depression, based primarily on the characterization of antidepressant efficacy in naïve rodents, rather than on models that capture the debilitating and protracted feelings of anhedonia and loss of motivation that are core features of depression.

Evaluation of the behavioral "costs," such as effort expenditure relative to the benefits of obtaining reward, is a major determinant of goal-directed action. Neuroimaging evidence suggests that the human medial orbitofrontal cortex (mOFC) is involved in this calculation and thereby guides goal-directed and choice behavior, but this region's functional significance in rodents is unknown despite extensive work characterizing the role of the lateral OFC in cuerelated response inhibition processes. We first tested mice with mOFC lesions in an instrumental reversal task lacking discrete cues signaling reinforcement; here, animals were required to shift responding based on the location of the reinforced aperture within the chamber. Mice with mOFC lesions acquired the reversal but failed to inhibit responding on the previously reinforced aperture, while mice with prelimbic prefrontal cortex lesions were unaffected. When tested on a progressive ratio schedule of reinforcement, mice with prelimbic cortical lesions were unable to maintain responding, resulting in declining response levels. Mice with mOFC lesions, by contrast, escalated responding. Neither lesion affected sensitivity to satiety-specific outcome devaluation or nonreinforcement (i.e., extinction), and neither had effects when placed after animals were trained on a progressive ratio response schedule. Lesions of the ventral hippocampus, which projects to the mOFC, resulted in similar response patterns, while lateral OFC and dorsal hippocampus lesions resulted in response acquisition, though not inhibition, deficits in an instrumental reversal. Our findings thus selectively implicate the rodent mOFC in braking reinforced goal-directed action when reinforcement requires the acquisition of novel response contingencies.

Stressor exposure biases decision-making strategies from those based on the relationship between actions and their consequences to others restricted by stimulus-response associations. Chronic stressor exposure also desensitizes glucocorticoid receptors (GR) and diminishes motivation to acquire food reinforcement, although causal relationships are largely not established. We show that a history of chronic exposure to the GR ligand corticosterone or acute posttraining GR blockade with RU38486 makes rodents less able to perform actions based on their consequences. Thus, optimal GR binding is necessary for the consolidation of new response-outcome learning. In contrast, medial prefrontal (but not striatal) BDNF can account for stress-related amotivation, in that selective medial prefrontal cortical Bdnf knockdown decreases break-point ratios in a progressive-ratio task. Knockdown also increases vulnerability to RU38486. Despite the role of BDNF in dendritic spine reorganization, deep-layer spine remodeling does not obviously parallel progressive-ratio response patterns, but treatment with the Na + -channel inhibitor riluzole reverses corticosteroid-induced motivational deficits and restores prefrontal BDNF expression after corticosterone. We argue that when prefrontal neurotrophin systems are compromised, and GR-mediated hypothalamic-pituitary-adrenal axis feedback is desensitized (as in the case of chronic stress hormone exposure), amotivation and inflexible maladaptive response strategies that contribute to stressrelated mood disorders result.hronic stressor exposure results in behavioral rigidity and poor decision-making that can accompany depressed mood, amotivation, and neurovegetative symptoms in clinical depression, and even acute stressor exposure in humans can impede one's ability to select appropriate actions based on their outcomes (1). Recent evidence suggests that chronic stressor exposure impairs action-outcome-also termed response-outcome-decision-making by structurally reorganizing the prefrontal corticostriatal circuits that regulate goal-directed decision-making in both rodents and humans (2, 3). Biochemical factors remain unclear, however, and whether the cortical mechanisms of goaldirected decision-making are distinct from those underlying motivation to acquire reward is unresolved, despite relevance to the treatment of stressor-related diseases, such as depression.The Neurotrophic Hypothesis of Depression and Antidepressant Efficacy (4) posits that a stress-related loss of neurotrophic support in major limbic regions underlies depressive symptomatology. The Stress Hypothesis (5) postulates that a major causal factor in depression is the desensitization of low-affinity glucocorticoid receptors (GRs), intracellular ligand-binding transcription factors that, when bound to cortisol [corticosterone (CORT) in rodents], exert a negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis. Accordingly, GR deficiency is associated with hypersensitivity to stressors and depressive-like behavior (6),...

RATIONALE-The heterozygous reeler mouse has been proposed as a genetic mouse model of schizophrenia, based on several neuroanatomical and behavioral similarities between these mice and patients with schizophrenia. However, the effect of reelin haploinsufficiency on one of the cardinal symptoms of schizophrenia, the impairment of prefrontal cortex-dependent cognitive function, has yet to be determined.OBJECTIVE-Here, we investigated multiple aspects of cognitive function in heterozygous reeler mice that are known to be impaired in schizophrenic patients.METHODS-Heterozygous reeler mice were assessed for (1) cognitive flexibility in an instrumental reversal learning task; (2) impulsivity in an inhibitory control task; (3) attentional function in a threechoice serial reaction time task; and (4) working memory in a delayed matching-to-position task.RESULTS-No differences were found between heterozygous reeler mice and wild-type littermate controls in any prefrontal-related cognitive measures. However, heterozygous reeler mice showed deficits in the acquisition of two operant tasks, consistent with a role for reelin in certain forms of learning.CONCLUSIONS-These findings suggest that heterozygous reeler mice may not be an appropriate model for the core prefrontal-dependent cognitive deficits observed in schizophrenia, but may model more general learning deficits that are associated with many psychiatric disorders.

Chronic cocaine use has been proposed to induce long-lasting alterations in cognitive functions dependent on the prefrontal cortex, and these alterations may contribute to the development of addiction. However, the underlying cellular mechanisms remain largely unknown, in part because of the lack of suitable animal models of cocaine-induced cognitive dysfunction that are amenable to molecular manipulations. Here, we characterized the effects of repeated cocaine administration on multiple aspects of cognitive function in C57BL/6 mice. Mice received 14 daily injections of either cocaine or saline, followed by a drug-free period of 2 weeks. They were then assessed for (i) cognitive flexibility in an instrumental reversal learning task; (ii) attentional function and response inhibition in a three-choice serial reaction time task; and (iii) working memory in a delayed matching-to-position task. Prior chronic exposure to cocaine resulted in impairments in reversal learning and working memory. Although there were no effects on attentional function or response inhibition, a shift in the pattern of errors committed was observed. These results indicate that prior chronic cocaine exposure in mice induces long-lasting alterations in cognitive functions associated with the prefrontal cortex.

Anatomically selective medial prefrontal cortical projections regulate the extinction of stimulus–reinforcement associations, but the mechanisms underlying extinction of an instrumental response for reward are less well-defined and may involve structures that regulate goal-directed action. We show brain-derived neurotrophic factor (bdnf) knock-down in the prelimbic, but not orbitofrontal, cortex accelerates the initial extinction of instrumental responding for food and reduces striatal BDNF protein. When knock-down mice were provided with alternative response options to readily obtain reinforcement, extinction of the previously reinforced response was unaffected, consistent with the hypothesis that the prelimbic cortex promotes instrumental action, particularly when reinforcement is uncertain or unavailable.