Effect of working memory on evaluation-related frontocentral negativity.

Recent results suggest that a negative ERP potential emerges not only on error trials, but is also found after correct responses. There is broad evidence that this component is generated in the anterior cingulate cortex (ACC). The present study aimed to explore the influence of working memory demands on the evaluation process probably reflected by the negative potential. To this purpose, a modified continuous performance task (CPT) was used, with variations of the delay between cues and imperative stimuli. Data were analyzed using conventional averaging techniques as well as source localization with LORETA (low resolution brain electromagnetic tomography). Results suggest a significant effect of working memory delay on the amplitude of the post-response negative ERP component. Its source was located in the anterior cingulate cortex, with the exact location being dependent upon working memory demands. The results support the notion of a general response evaluation system reflected by a post-response negative component. The findings of a working memory dependent modification of this potential suggest a functional link between the medial frontal cortex and the lateral frontal regions primarily involved in working memory processing.

5-HT1A receptors on mature dentate gyrus granule cells are critical for the antidepressant response.

Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants, but the mechanisms by which they influence behavior are only partially resolved. Adult hippocampal neurogenesis is necessary for some of the responses to SSRIs, but it is not known whether mature dentate gyrus granule cells (DG GCs) also contribute. We deleted the serotonin 1A receptor (5HT1AR, a receptor required for the SSRI response) specifically from DG GCs and found that the effects of the SSRI fluoxetine on behavior and the hypothalamic-pituitary-adrenal (HPA) axis were abolished. By contrast, mice lacking 5HT1ARs only in young adult-born GCs (abGCs) showed normal fluoxetine responses. Notably, 5HT1AR-deficient mice engineered to express functional 5HT1ARs only in DG GCs responded to fluoxetine, indicating that 5HT1ARs in DG GCs are sufficient to mediate an antidepressant response. Taken together, these data indicate that both mature DG GCs and young abGCs must be engaged for an antidepressant response.

Fear erasure in mice requires synergy between antidepressant drugs and extinction training.

Antidepressant drugs and psychotherapy combined are more effective in treating mood disorders than either treatment alone, but the neurobiological basis of this interaction is unknown. To investigate how antidepressants influence the response of mood-related systems to behavioral experience, we used a fear-conditioning and extinction paradigm in mice. Combining extinction training with chronic fluoxetine, but neither treatment alone, induced an enduring loss of conditioned fear memory in adult animals. Fluoxetine treatment increased synaptic plasticity, converted the fear memory circuitry to a more immature state, and acted through local brain-derived neurotrophic factor. Fluoxetine-induced plasticity may allow fear erasure by extinction-guided remodeling of the memory circuitry. Thus, the pharmacological effects of antidepressants need to be combined with psychological rehabilitation to reorganize networks rendered more plastic by the drug treatment.