Repeated environmental stress has been proposed to induce neural inflammation together with depression and anxiety. Innate immune receptors, such as Toll-like receptors (TLRs), are activated by exogenous or endogenous ligands to evoke inflammation. Here we show that the loss of TLR2 and TLR4 (TLR2/4) abolished repeated social defeat stress (R-SDS)-induced social avoidance and anxiety in mice. TLR2/4 deficiency mitigated R-SDS-induced neuronal response attenuation, dendritic atrophy, and microglial activation in the medial prefrontal cortex (mPFC). Furthermore, mPFC microglia-specific TLR2/4 knockdown blocked social avoidance. Transcriptome analyses revealed that R-SDS induced IL-1α and TNF-α in mPFC microglia in a TLR2/4-dependent manner, and antibody blockade of these cytokines in the mPFC suppressed R-SDS-induced social avoidance. These results identify TLR2/4 as crucial mediators of R-SDS-induced microglial activation in the mPFC, which leads to neuronal and behavioral changes through inflammation-related cytokines, highlighting unexpected pivotal roles of innate immunity in the mPFC in repeated environmental stress-induced behavioral changes. VIDEO ABSTRACT.

Dopamine D1 receptor subtype mediates acute stress-induced dendritic growth in excitatory neurons of the medial prefrontal cortex and contributes to suppression of stress susceptibility in mice

In the analysis of post-mortem brains of 14 chronic schizophrenic patients and 10 controls, biochemical evidence of a hyperdopaminergic state was found in the basal ganglia of schizophrenics; tyrosine hydroxylase activity was increased with a concomitant increase of homovanillic acid. Unusually high tyrosine hydroxylase activity was noted in 2 schizophrenic cases. The Bmax value of 3H-spiperone binding for schizophrenics was higher than the controls. We also found increased specific binding of 3H-kainic acid to the prefrontal cortex in schizophrenics. A negative correlation existed between 3H-kainic acid binding in the medial frontal cortex, and glutamic acid content in various brain areas. Increased immunoreactivity of substance P was found in more than ten brain areas. Methionine-enkephalin was also increased in three areas of the prefrontal cortex of schizophrenics. These results suggest that the hyperdopaminergic state co-existed with glutamatergic hypofunction and increased neuropeptides in various brain areas of chronic schizophrenic patients.

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Dysphagia is a severe disability affecting daily life in patients with amyotrophic lateral sclerosis (ALS). It is caused by degeneration of both the bulbar motor neurons and cortical motoneurons projecting to the oropharyngeal areas. A previous report showed decreased event-related desynchronization (ERD) in the medial sensorimotor areas in ALS dysphagic patients. In the process of degeneration, brain reorganization may also be induced in other areas than the sensorimotor cortices. Furthermore, ALS patients with dysphagia often show a longer duration of swallowing. However, there have been no reports on brain activity in other cortical areas and the time course of brain activity during prolonged swallowing in these patients. In this case report, we investigated the distribution and the time course of ERD and corticomuscular coherence (CMC) in the beta (15–25 Hz) frequency band during volitional swallow using electroencephalography (EEG) in two patients with ALS. Case 1 (a 71-year-old man) was diagnosed 2 years before the evaluation. His first symptom was muscle weakness in the right hand; 5 months later, dysphagia developed and exacerbated. Since his dietary intake decreased, he was given an implantable venous access port. Case 2 (a 64-year-old woman) was diagnosed 1 year before the evaluation. Her first symptom was open-nasal voice and dysarthria; 3 months later, dysphagia developed and exacerbated. She was given a percutaneous endoscopic gastrostomy. EEG recordings were performed during volitional swallowing, and the ERD was calculated. The average swallow durations were 7.6 ± 3.0 s in Case 1 and 8.3 ± 2.9 s in Case 2. The significant ERD was localized in the prefrontal and premotor areas and lasted from a few seconds after the initiation of swallowing to the end in Case 1. The ERD was localized in the lateral sensorimotor areas only at the initiation of swallowing in Case 2. CMC was not observed in either case. These results suggest that compensatory processes for cortical motor outputs might depend on individual patients and that a new therapeutic approach using ERD should be developed according to the individuality of ALS patients with dysphagia.