Patients with depression and rodents exposed to chronic stress exhibit functional and structural changes in diverse brain regions, including atrophy of the prefrontal cortex and hippocampus. Glucocorticoids, systemic inflammation and brain inflammation have been shown to cause region‐specific changes in molecular signaling in neurons and alter the activity dynamics of neural networks composed of stress‐related brain regions, resulting in depressive‐like behaviors. These neural activity dynamics are also altered by the accumulation of environmental factors, which contribute to the formation of vulnerability and resilience to stress. In this paper, I discuss the mechanisms of stress‐induced changes in neuronal function and morphology, and introduce an ultrastructural analysis of synapses using three‐dimensional electron microscopy which is useful for elucidating the effects of neuronal morphological changes on neural circuit networks. In the future, it will be important to focus on the functional and structural changes in each specific neural circuit due to the accumulation of stress and environmental factors to elucidate the mechanisms of stress pathology and vulnerability and resilience to stress.

View full abstract

Advances in genomic analysis technologies have led to the identification of a number of genomic variants that are strongly associated with the pathogenesis of mental disorders. In order to elucidate the pathological mechanisms of mental disorders, it is necessary to unravel the changes in brains caused by these risk variants from various aspects. One of the approaches is the used of iPS cells. As more and more findings are reported by using iPS cells in mental disorder research, it has become clear that neuronal cells derived patients with risk variants share a common phenotype of neurodevelopmental abnormalities such as in neurite elongation, synaptic function, and neuronal migration. Small abnormalities at the molecular and cellular levels in developing brain may be vulnerability for the onset of mental disorders. In this article, we discuss the trend and future of research on mental disorders using iPS cells with risk variants.

View full abstract

Behavioral flexibility refers to the ability to adapt behavior in response to changes in the environment. Since behavioral flexibility is impaired in many neuropsychiatric disorders, it is important to elucidate its neural mechanisms. Flexible behavior in response to situations can be categorized into reversal learning and set‐shifting, in which attention is shifted to a new strategy. Here, we focused on the nucleus accumbens, which is involved in cognitive learning behaviors based on reward and aversion information, and outlined the neural circuit mechanisms involved in behavioral flexibility. The attentional set‐shift task revealed that the indirect pathways of the nucleus accumbens are important for reversal learning rather than set‐shifting. We also showed that the indirect pathways are important for flexible cognitive learning in the touch‐screen visual discrimination learning task. These results indicate that neural circuit plasticity is important in the pathophysiology of neuropsychiatric disorders.

View full abstract

Pentosidine (PEN) , type of AGEs with fluorescence, possesses a cross‐linked structure between lysine and arginine residues in proteins. PEN accumulation is associated with aging and various diseases such as diabetes mellitus. We previously reported that PEN levels in the peripheral blood of a subpopulation of patients with schizophrenia is significantly higher than that in healthy controls. However, the precursor of PEN accumulated in schizophrenia is unknown, and consequently the molecular pathogenesis of schizophrenia caused by PEN accumulation has not been clarified. To elucidate the origin of PEN, we performed metabolome analysis with plasma and identified glucuronic acid (GlcA) as a new precursor of PEN. Furthermore, GlcA has been associated with the diagnosis of schizophrenia. GlcA was significantly associated with mean disease duration and total negative symptom score in the Positive and Negative Syndrome Scale (PANSS) . Moreover, we showed that AKR activity to degrade GlcA was decreased in patients with schizophrenia, and its activity was negatively correlated with GlcA levels in the plasma, suggesting that the decreased AKR activity in patients with schizophrenia increases GlcA levels in the plasma, leading to PEN accumulation. This study indicates that GlcA is a novel source of PEN in schizophrenia. Our findings are expected to elucidate the aging process and pathology of all diseases associated with PEN accumulation.

View full abstract

Repetitive head trauma can induce chronic traumatic encephalopathy (CTE) . CTE is defined as tauopathy because of neuropathologic findings indicative of tau deposition, such as neurofibrillary tangles. Single moderate to severe traumatic brain injury can also produce CTE-like psychiatric and neurological symptoms and neuropathological changes in the chronic phase. Tau imaging in the chronic phase of single moderate to severe single traumatic brain injury shows focal accumulation of tau tracer at the depths of cerebral sulci in some cases. Neuroinflammation can be one of the factors involved in tau pathology in traumatic brain injury. In selecting reference tissues for tau imaging, it is important to consider that the cerebellum is an area where tau can accumulate in CTE.

View full abstract

Auguste Deter, first described by Alois Alzheimer in 1906, developed delusional jealousy and affective symptoms in her 40s, followed by cognitive impairment such as memory loss, aphasia, and visuospatial deficits. In modern times, psychiatric symptoms of Alzheimer’s disease are considered a peripheral symptom of cognitive impairment known as Behavioral and Psychological Symptoms of Dementia (BPSD) that emerge after some degree of cognitive decline. Previous studies on psychiatric symptoms in Alzheimer’s disease mainly focused on cases with advanced cognitive impairment. However, recent cohort studies have reported that the onset of psychiatric symptoms in late life is a risk factor for the development of dementia. In addition, postmortem brain studies have revealed the presence of tauopathy and synucleinopathy in late‐life psychiatric disorders. This paper reviews these previous studies and touches on our group’s attempt to conduct amyloid and tau PET studies on patients with late‐life psychiatric disorders. Our findings suggest that some patients with late‐life psychiatric disorders have tau lesions linked to various AD subtypes and non‐AD tauopathies indicative of distinct early‐stage frontotemporal lobar degeneration subcategories.

View full abstract