Physiological paradigm for assessing reward prediction and extinction using cortical direct current potential responses in rats.

Anticipating positive outcomes is a core cognitive function in the process of reward prediction. However, no neurophysiological method objectively assesses reward prediction in basic medical research. In the present study, we established a physiological paradigm using cortical direct current (DC) potential responses in rats to assess reward prediction. This paradigm consisted of five daily 1-h sessions with two tones, wherein the rewarded tone was followed by electrical stimulation of the medial forebrain bundle (MFB) scheduled at 1000 ms later, whereas the unrewarded tone was not. On day 1, both tones induced a negative DC shift immediately after auditory responses, persisting up to MFB stimulation. This negative shift progressively increased and peaked on day 4. Starting from day 3, the negative shift from 600 to 1000 ms was significantly larger following the rewarded tone than that following the unrewarded tone. This negative DC shift was particularly prominent in the frontal cortex, suggesting its crucial role in discriminative reward prediction. During the extinction sessions, the shift diminished significantly on extinction day 1. These findings suggest that cortical DC potential is related to reward prediction and could be a valuable tool for evaluating animal models of depression, providing a testing system for anhedonia.

Chronic antidepressant treatment rescues abnormally reduced REM sleep theta power in socially defeated rats.

The effects of chronic antidepressant (AD) treatment on sleep disturbances in rodent chronic stress models have not been thoroughly investigated. Here, we show that chronic social defeat stress (SDS) in rats induces prolonged social avoidance, alterations in sleep architecture (increased total rapid eye movement [REM] sleep duration, bout, and shortened REM latency), and contextual but not cued fear memory deficits, even 1 month after the last SDS. These abnormalities were associated with changes in electroencephalography (EEG) spectral powers, including reduced REM sleep theta power during the light phase. Chronic treatment with two different classes of antidepressants (ADs), imipramine and fluoxetine, significantly ameliorated these behavioral, sleep, and EEG abnormalities. Interestingly, REM theta power was normalized by chronic (1 month) but not 1 week AD administration and solely correlated with the ratio (an objective indicator) of social interaction 1 month after the last SDS. These data suggest that reductions in REM sleep theta power, an EEG parameter that has never been directly investigated in humans, is a core sleep symptom in socially defeated rats, and, potentially, also in patients with stress-related psychiatric disorders, including major depressive and posttraumatic stress disorders.

Essential roles of plexin-B3+ oligodendrocyte precursor cells in the pathogenesis of Alzheimer's disease.

The role of oligodendrocyte lineage cells, the largest glial population in the adult central nervous system (CNS), in the pathogenesis of Alzheimer's disease (AD) remains elusive. Here, we developed a culture method for adult oligodendrocyte progenitor cells (aOPCs). Fibroblast growth factor 2 (FGF2) promotes survival and proliferation of NG2+ aOPCs in a serum-free defined medium; a subpopulation (~5%) of plexin-B3+ aOPCs was also found. FGF2 withdrawal decreased NG2+, but increased plexin-B3+ aOPCs and Aß1-42 secretion. Plexin-B3+ aOPCs were distributed throughout the adult rat brain, although less densely than NG2+ aOPCs. Spreading depolarization induced delayed cortical plexin-B3+ aOPC gliosis in the ipsilateral remote cortex. Furthermore, extracellular Aß1-42 accumulation was occasionally found around plexin-B3+ aOPCs near the lesions. In AD brains, virtually all cortical SPs were immunostained for plexin-B3, and plexin-B3 levels increased significantly in the Sarkosyl-soluble fractions. These findings suggest that plexin-B3+ aOPCs may play essential roles in AD pathogenesis, as natural Aß-secreting cells.

Delayed increase of brain noradrenaline after acute footshock stress in rats.

Several lines of evidence strongly suggest that accumulation of noradrenaline (NA) in the brain may underlie the hyperarousal symptoms experienced in post-traumatic stress disorder. In animal experiments, however, the effect of stress on NA content appears complex; acute stress reduces the level, while chronic stress tends to increase it. To explain this discrepancy, it is necessary to observe the long-term effects of acute stress on NA metabolism in the brain. In this study, rats were exposed to intermittent intense footshock stress for 1 h, and the brain NA content was measured for 7 days after the stress stimulus. Hypothalamic NA content was immediately reduced and recovered within 24 h. However, a significant NA increase was observed 7 days after the footshock. In the cerebral cortex and hippocampus, an increase in NA content was observed 1 day after the stress and lasted for at least 7 days. The fact that the content of 3-methoxy-4-hydroxyphenylglycol, a major NA metabolite, only transiently increased in all these regions possibly reflects NA release. These results indicate that increase in the brain NA content can be induced by acute stress, though its emergence is delayed. Importantly, this suggests that both acute and chronic stress may lead to NA accumulation under the same mechanism.

Ergothioneine, a metabolite of the gut bacterium Lactobacillus reuteri, protects against stress-induced sleep disturbances.

The relationships between depression and gut microbiota, particularly those involving the immune system, have become a major focus of recent research. Here, we analyzed changes in gut microbiota and their sulfur metabolites in the feces of a depression rat model using the modified 14-day social defeat stress (SDS) paradigm. Our results showed that SDS increased fecal Lactobacillus reuteri in correlation with ergothioneine levels at around day 11, which continued for at least 1 month following SDS administration. In vitro study further revealed that L. reuteri is capable of producing ergothioneine. Although the known anti-inflammatory and anti-oxidative actions of ergothioneine suggested that the increased fecal ergothioneine levels may be related to intestinal anti-inflammatory defense mechanisms, no change was observed in the plasma ergothioneine levels during the same observation period, indicating that the defense mechanisms may not be sufficiently reflected in the body. As ergothioneine is a natural ingredient that is absorbed mainly from the upper gastrointestinal tract, we hypothesized that oral ergothioneine may exert antidepressant effects. As expected, oral administration of ergothioneine prior to and during the SDS paradigm had a preventative effect on SDS-induced depressive behaviors, such as social avoidance and depression-like sleep abnormalities, particularly those of rapid eye movement sleep. These findings indicate that ergothioneine, a metabolite of L. reuteri, may be a common substance in the microbiota-gut-brain axis that prevents stress-induced sleep disturbances, especially those associated with depression.

Decrease in heart rate variability response to task is related to anxiety and depressiveness in normal subjects.

AIMS: Previous studies have shown that heart rate variability (HRV) measurement is useful in investigating the pathophysiology of various psychiatric disorders. The present study further examined its usefulness in evaluating the mental health of normal subjects with respect to anxiety and depressiveness. METHODS: Heart rate (HR) and HRV were measured tonometrically at the wrist in 43 normal subjects not only in the resting condition but also during a task (random number generation) to assess the responsiveness. For HRV measurement, high-frequency (HF; 0.15-0.4 Hz) and low-frequency (LF; 0.04-0.15 Hz) components of HRV were obtained using MemCalc, a time series analysis technique that combines a non-linear least square method with maximum entropy method. For psychological evaluation of anxiety and depressiveness, two self-report questionnaires were used: State-Trait Anxiety Inventory (STAI) and Self-Rating Depression Scale (SDS). RESULTS: No significant relation was observed between HR and HRV indices, and the psychological scores both in the resting and task conditions. By task application, HF decreased, and LF/HF and HR increased, and significant correlation with psychological scores was found in the responsiveness to task measured by the ratio of HRV and HR indices during the task to that at rest (task/rest ratio). A positive relationship was found between task/rest ratio for HF, and STAI and SDS scores. Task/rest ratio of HR was negatively correlated with STAI-state score. CONCLUSION: Decreased HRV response to task application is related to anxiety and depressiveness. Decreased autonomic responsiveness could serve as a sign of psychological dysfunction.

Neuronal activity in the parietal cortex of EL and DDY mice.

To elucidate the mechanism of epileptogenesis, seizures were investigated in the EL mouse, which is an excellent model for epilepsy. In these mice, epileptic seizures initiate in the parietal cortex, where markers of GABA-mediated inhibition are reduced compared with the parietal cortex of DDY mice (the parent strain). This is the first report on units of neuronal activity in the parietal cortex of EL and DDY mice (14 each) using an extracellular microelectrode in vivo under moderate pentobarbital anesthesia. The parietal cortex neurons of the EL mice were less active at rest than those of the DDY mice, but they responded more actively to proprioceptive afferent input from muscle stimulation than the DDY neurons. Three types of spontaneous firing were classified in both EL and DDY cortical neurons: periodically firing, Type A; continuously firing, Type B; and random firing, Type C. The proportions of these three types of neurons were almost the same in the EL mice as in the DDY mice. The peak frequency of the periodical cycle of Type A neurons in the EL mice (375 ms) was longer than that of the Type A neurons in the DDY mice (225 ms). Four patterns of responses to stimulation were observed in the parietal cortex neurons. More excitatory patterns were observed in the EL mice than in the DDY mice. The trans-laminar distribution of cells with different response patterns was also different between the EL and DDY mice. These characteristics of parietal cortex neurons may help determine the seizure susceptibility or ictogenesis in EL mice because the mechanisms underlying these patterns could provide the basis for hypersynchronized discharges in epileptic seizures.