Learned helplessness activates hippocampal microglia in rats: A potential target for the antidepressant imipramine.

An accumulating body of evidence has demonstrated that inflammation is associated with the pathology of depression. We recently found that psychological stress induces inflammation in the hippocampus of the rat brain through the inflammasome, a component of the innate immune system. Microglia, the resident macrophages in the brain, play a central role in the innate immune system and express inflammasomes; thus, we hypothesized that hippocampal microglia would be key mediators in the development of depression via stress-induced inflammation. To test this hypothesis and to determine how antidepressants modulate microglial function, we used immunohistochemistry to examine the morphological changes that occur in the hippocampal microglia of rats exposed to the learned helplessness (LH) paradigm. We noted significantly increased numbers of activated microglia in the granule cell layer, hilus, CA1, and CA3 regions of the hippocampi of LH rats. Conversely, administering imipramine to LH rats for 7days produced a significant decrease in the number of activated microglia in the hilus, but not in the other examined regions. Nonetheless, there were no significant differences in the combined number of activated and non-activated microglia either in LH or LH+imipramine rats relative to control rats. In addition, treating the naïve rats with imipramine or fluvoxamine produced no discernible microglial changes. These data suggest that stress activates hippocampal microglia, while certain antidepressants decrease the number of activated microglia in the hilus, but not in other hippocampal regions. Therefore, the hilus represents a candidate target region for the antidepressant imipramine.

A pilot study on the effects of cognitive remediation on hemodynamic responses in the prefrontal cortices of patients with schizophrenia: a multi-channel near-infrared spectroscopy study.

The regional neuronal changes taking place between before and after cognitive rehabilitation are still not characterized in schizophrenia patients. In addition, it is not known whether these regional changes are predictive or correlated with treatment response. We conducted a preliminary quasi-experimental study to investigate the effects of a Neuropsychological Educational Approach to Cognitive Remediation (NEAR), one of the cognitive remediation therapies, on neurocognitive functioning assessed by the Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS-J), and on prefrontal and temporal hemodynamic responses during working memory (WM) task (2-back, letter version) using 52-channel near-infrared spectroscopy (NIRS). We assessed 19 patients with schizophrenia or schizoaffective disorder twice with an interval of 6months. Moreover, taking into consideration the possible practice effect, we assessed 12 control patients twice with an interval of 6months. The NEAR group, in comparison with the control group, showed significant improvement in two subcomponents of BACS-J, that is, motor speed and executive function along with the composite scores. The NEAR group also showed a significant increase in brain activation in the bilateral cortical regions associated with WM, and in comparison with the control group the between-group differences were restricted to the right frontopolar area. In addition, the amount of enhancement in some cognitive subcomponents was positively correlated with the magnitude of an increase in hemodynamic response during WM task predominantly in the right hemispheres. These findings suggest that neurocognitive deficits in schizophrenia and their neural dysfunction may be improved by NEAR, and NIRS may be a useful tool to assess the changes of the neural activity underlying the improvement of neurocognitive functioning elicited by neurocognitive rehabilitation.

Association between cognitive insight and prefrontal function during a cognitive task in schizophrenia: a multichannel near-infrared spectroscopy study.

Insight has been studied mostly from a clinical perspective. Recently, the focus of this research field shifted to cognitive insight or the ability to monitor and correct the erroneous convictions of individuals. In this study, we investigated the relationship between cognitive insight and prefrontal function during a cognitive task in 30 patients with clinically stable schizophrenia and 30 age- and gender-matched healthy controls. We measured the changes in hemoglobin concentration in the prefrontal and temporal cortical regions during a verbal fluency task (VFT) by using 52-channel near-infrared spectroscopy (NIRS). Cognitive insight was measured using the Beck Cognitive Insight Scale (BCIS). Regional hemodynamic changes were significantly smaller in the schizophrenia group than in the control group in prefrontal and temporal regions, and significant positive relationship was observed between the score of the BCIS self-reflectiveness subscale and right ventrolateral prefrontal and right temporal functions during the VFT. These results suggest that the right ventrolateral prefrontal and temporal cortical regions are associated with cognitive insight in clinically stable patients with schizophrenia and that NIRS is an efficient medical tool for monitoring these characteristics.

Association between subjective well-being and prefrontal function during a cognitive task in schizophrenia: a multi-channel near-infrared spectroscopy study.

The purpose of this study was to examine the relationship between subjective well-being and prefrontal function during a cognitive task in schizophrenia. Twenty-four patients with clinically stable schizophrenia participated in the study. We measured the change in hemoglobin concentration in the prefrontal region during a verbal fluency task (VFT) by using 52-channel near-infrared spectroscopy (NIRS). The subjective well-being of participants was assessed using the Subjective Well-being under Neuroleptic drug treatment Short form (SWNS). A significant positive relationship was observed between the SWNS score and frontopolar, left ventrolateral, and bilateral dorsolateral prefrontal function during the VFT. These results suggest that the frontopolar and left ventrolateral and bilateral dorsolateral prefrontal cortical regions are associated with the subjective well-being of clinically stable patients with schizophrenia and that NIRS may be an efficient medical tool for monitoring these characteristics.

Hippocampal astrocytes are necessary for antidepressant treatment of learned helplessness rats.

The astrocyte is a major component of the neural network and plays a role in brain function. Previous studies demonstrated changes in the number of astrocytes in depression. In this study, we examined alterations in the number of astrocytes in the learned helplessness (LH) rat, an animal model of depression. The numbers of activated and nonactivated astrocytes in the dentate gyrus (molecular layer, subgranular zone, and hilus), and CA1 and CA3 regions of the hippocampus were significantly increased 2 and 8 days after attainment of LH. Subchronic treatment with imipramine showed a tendency (although not statistically significant) to decrease the LH-induced increment of activated astrocytes in the CA3 region and dentate gyrus. Furthermore, subchronic treatment of naïve rats with imipramine did not alter the numbers of activated and nonactivated astrocytes. However, the antidepressant-like effects of imipramine in the LH paradigm were blocked when fluorocitrate (a reversible inhibitor of astrocyte function) was injected into the dentate gyrus or CA3 region. Injection of fluorocitrate into naive rats failed to induce behavioral deficits in the conditioned avoidance test. These results indicate that astrocytes are responsive to the antidepressant-like effect of imipramine in the dentate gyrus and CA3 region of the hippocampus.

Infusion of neuropeptide Y into CA3 region of hippocampus produces antidepressant-like effect via Y1 receptor.

A couple of papers indicate that patients with depression show a decrease in serum neuropeptide Y (NPY). To study the role of NPY in depression, we examined the effects of infusion of NPY into the hippocampus of learned helplessness (LH) rats (an animal model of depression). Infusion of NPY into the cerebral ventricle of LH rats showed antidepressant-like effects. Infusion of NPY into the CA3 region, but not the dentate gyrus (DG), produced antidepressant-like effects in the LH paradigm. Infusion of NPY did not affect locomotor activity or aversive learning ability. Coadministration of BIBO3304 (a Y1 receptor antagonist) with NPY to the CA3 region blocked the antidepressant-like effects of NPY, whereas coadministration of NPY with BIIE0246 (a Y2 receptor antagonist) to the CA3 region failed to block antidepressant-like effects. Furthermore, infusions of [Leu(31) Pro(34)]PYY (a Y1 and Y5 receptor agonist) alone and BIIE0246 alone into the CA3 region produced the antidepressant-like effects in LH rats. These results suggest that infusion of NPY into the CA3 region of hippocampus of LH rats produces antidepressant-like activity through Y1 receptors and attenuating effects through Y2 receptors.

Subchronic treatment with imipramine ameliorates the decreased number in neuropeptide Y-positive cells in the hippocampus of learned helplessness rats.

Learned helplessness, but not immobilization stress, decreased the numbers of neuropeptide Y (NPY)-positive cells (interneuron), but not calcitonin gene-related peptide (CGRP)-positive cells (mossy cell), in the hilus of the hippocampus. Subchronic treatment of learned helplessness rats, but not naive rats, with imipramine ameliorated the decrease in the number of NPY-positive cells. Therefore, NPY-positive cells in the hippocampus may contribute to depression.

Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects.

Rats exposed to learned helplessness (LH), an animal model of depression, showed a recovery following an intracerebroventricular injection of nor-binaltorphimine dihydrochloride (norBNI; a kappa-opioid antagonist). To investigate the potential role of dynorphin A and dynorphin B, we examined the effects of different stress/depression models on dynorphin A and dynorphin B immunoreactivity in hippocampus and nucleus accumbens (NAc). Immobilization stress (3 h) caused an increase in levels of dynorphin A and dynorphin B immunoreactivity in the hippocampus and the NAc. Forced swim stress also temporally increased dynorphin A levels in the hippocampus. Furthermore, exposure to LH produced a similar increase in dynorphin A and dynorphin B in the hippocampus and NAc. Infusions of norBNI into the dentate gyrus or CA3 regions of hippocampus and into the shell or core regions of NAc produced antidepressant-like effects in the LH paradigm. The degrees of norBNI's effects were stronger in the CA3 region and NAc shell and less effective in the dentate gyrus of hippocampus and NAc core. These results indicate that both dynorphin A and dynorphin B contribute to the effects of stress, and suggest that blockade of kappa-opioid receptors may have therapeutic potential for the treatment of depression.