Hisahito Ishida

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 κ‐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 norBNIs 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 κ‐opioid receptors may have therapeutic potential for the treatment of depression.

Hippocampal synapsin I, growth-associated protein-43, and microtubule-associated protein-2 immunoreactivity in learned helplessness rats and antidepressant-treated rats

Learned helplessness rats are thought to be an animal model of depression. To study the role of synapse plasticity in depression, we examined the effects of learned helplessness and antidepressant treatments on synapsin I (a marker of presynaptic terminals), growth-associated protein-43 (GAP-43; a marker of growth cones), and microtubule-associated protein-2 (MAP-2; a marker of dendrites) in the hippocampus by immunolabeling. (1) Learned helplessness rats showed significant increases in the expression of synapsin I two days after the attainment of learned helplessness, and significant decreases in the protein expression eight days after the achievement of learned helplessness. Subchronic treatment of naïve rats with imipramine or fluvoxamine significantly decreased the expression of synapsin I. (2) Learned helplessness increased the expression of GAP-43 two days and eight days after learned helplessness training. Subchronic treatment of naïve rats with fluvoxamine but not imipramine showed a tendency to decrease the expression of synapsin I. (3) Learned helplessness rats showed increased expression of MAP-2 eight days after the attainment of learned helplessness. Naïve rats subchronically treated with imipramine showed a tendency toward increased expression of MAP-2, but those treated with fluvoxamine did not. These results indicate that the neuroplasticity-related proteins synapsin I, GAP-43, and MAP-2 may play a role in the pathophysiology of depression and the mechanisms of antidepressants.

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.

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.

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.

Pregnenolone and dehydroepiandrosterone administration in neonatal rats alters the immunoreactivity of hippocampal synapsin I, neuropeptide Y and glial fibrillary acidic protein at post-puberty

It is well documented that neurosteroids administered during the neonatal period influence the development of several brain systems. In our previous study, pregnenolone administered to rats during the neonatal period altered adenosinergic and dopaminergic functions in the striatum and cerebral cortex. The present study examined the effects of the treatment with pregnenolone and dehydroepiandrosterone (DHEA) from the postnatal day (P) 3-P7 on synapsin I (a marker for presynaptic terminals) and glial fibrillary acidic protein (GFAP: a marker for astroglia) levels in the hippocampus of Sprague-Dawley rats at 3 and 7 weeks of age. In addition, neuropeptide Y and dynorphin A immunoreactivity was measured. The administration of pregnenolone and DHEA to neonatal rats significantly altered the expression of synapsin I in the dentate gyrus and CA3 region at post-puberty but not at pre-puberty. A significantly greater expression of GFAP-immunoreactive astrocytes or processes was demonstrated in the pregnenolone- and DHEA-treated groups at both pre-puberty and post-puberty. A significant increase in the number and size of GFAP-immunoreactive astrocytes and in the extension of arborization was seen in the overall hippocampus. The number of neuropeptide Y-positive cells in the hilus region was also significantly increased in the neurosteroid-treated group at post-puberty. No differences were detected in dynorphin A immunoreactivity among the experimental groups. These results of this study suggest that pregnenolone and DHEA play an important role in the development of hippocampus.

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.

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.

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.