VTA-projecting cerebellar neurons mediate stress-dependent depression-like behaviors.

Although cerebellar alterations have been implicated in stress symptoms, the exact contribution of the cerebellum to stress symptoms remains to be elucidated. Here, we demonstrated the crucial role of cerebellar neurons projecting to the ventral tegmental area (VTA) in the development of chronic stress-induced behavioral alterations in mice. Chronic chemogenetic activation of inhibitory Purkinje cells in crus I suppressed c-Fos expression in the DN and an increase in immobility in the tail suspension test or forced swimming test, which were triggered by chronic stress application. The combination of adeno-associated virus-based circuit mapping and electrophysiological recording identified network connections from crus I to the VTA via the dentate nucleus (DN) of the deep cerebellar nuclei. Furthermore, chronic inhibition of specific neurons in the DN that project to the VTA prevented stressed mice from showing such depression-like behavior, whereas chronic activation of these neurons alone triggered behavioral changes that were comparable with the depression-like behaviors triggered by chronic stress application. Our results indicate that the VTA-projecting cerebellar neurons proactively regulate the development of depression-like behavior, raising the possibility that cerebellum may be an effective target for the prevention of depressive disorders in human.

Recent Advances in the Understanding of Specific Efferent Pathways Emerging From the Cerebellum.

The cerebellum has a long history in terms of research on its network structures and motor functions, yet our understanding of them has further advanced in recent years owing to technical developments, such as viral tracers, optogenetic and chemogenetic manipulation, and single cell gene expression analyses. Specifically, it is now widely accepted that the cerebellum is also involved in non-motor functions, such as cognitive and psychological functions, mainly from studies that have clarified neuronal pathways from the cerebellum to other brain regions that are relevant to these functions. The techniques to manipulate specific neuronal pathways were effectively utilized to demonstrate the involvement of the cerebellum and its pathways in specific brain functions, without altering motor activity. In particular, the cerebellar efferent pathways that have recently gained attention are not only monosynaptic connections to other brain regions, including the periaqueductal gray and ventral tegmental area, but also polysynaptic connections to other brain regions, including the non-primary motor cortex and hippocampus. Besides these efferent pathways associated with non-motor functions, recent studies using sophisticated experimental techniques further characterized the historically studied efferent pathways that are primarily associated with motor functions. Nevertheless, to our knowledge, there are no articles that comprehensively describe various cerebellar efferent pathways, although there are many interesting review articles focusing on specific functions or pathways. Here, we summarize the recent findings on neuronal networks projecting from the cerebellum to several brain regions. We also introduce various techniques that have enabled us to advance our understanding of the cerebellar efferent pathways, and further discuss possible directions for future research regarding these efferent pathways and their functions.

Direct pharmacological Akt activation rescues Alzheimer's disease like memory impairments and aberrant synaptic plasticity.

Amyloid ß (Aß) is a key mediator for synaptic dysfunction and cognitive impairment implicated in Alzheimer's disease (AD). However, the precise mechanism of the toxic effect of Aß is still not completely understood. Moreover, there is currently no treatment for AD. Protein kinase B (PKB, also termed Akt) is known to be aberrantly regulated in the AD brain. However, its potential function as a therapeutic target for AD-associated memory impairment has not been studied. Here, we examined the role of a direct Akt activator, SC79, in hippocampus-dependent memory impairments using Aß-injected as well as 5XFAD AD model mice. Oligomeric Aß injections into the 3rd ventricle caused concentration-dependent and time-dependent impairments in learning/memory and synaptic plasticity. Moreover, Aß aberrantly regulated caspase-3, GSK-3ß, and Akt signaling, which interact with each other in the hippocampus. Caspase-3 and GSK-3ß inhibitor ameliorated memory impairments and synaptic deficits in Aß-injected AD model mice. We also found that pharmacological activation of Akt rescued memory impairments and aberrant synaptic plasticity in both Aß-treated and 5XFAD mice. These results suggest that Akt could be a therapeutic target for memory impairment observed in AD.

The reemergence of long-term potentiation in aged Alzheimer's disease mouse model.

Mouse models of Alzheimer's disease (AD) have been developed to study the pathophysiology of amyloid ß protein (Aß) toxicity, which is thought to cause severe clinical symptoms such as memory impairment in AD patients. However, inconsistencies exist between studies using these animal models, specifically in terms of the effects on synaptic plasticity, a major cellular model of learning and memory. Whereas some studies find impairments in plasticity in these models, others do not. We show that long-term potentiation (LTP), in the CA1 region of hippocampal slices from this mouse, is impared at Tg2576 adult 6-7 months old. However, LTP is inducible again in slices taken from Tg2576 aged 14-19 months old. In the aged Tg2576, we found that the percentage of parvalbumin (PV)-expressing interneurons in hippocampal CA1-3 region is significantly decreased, and LTP inhibition or reversal mediated by NRG1/ErbB signaling, which requires ErbB4 receptors in PV interneurons, is impaired. Inhibition of ErbB receptor kinase in adult Tg2576 restores LTP but impairs depotentiation as shown in aged Tg2576. Our study suggests that hippocampal LTP reemerges in aged Tg2576. However, this reemerged LTP is an insuppressible form due to impaired NRG1/ErbB signaling, possibly through the loss of PV interneurons.

Cognitive function and activities of daily living in people affected by leprosy: A cross-sectional, population-based, case-control study.

OBJECTIVES: There has been controversy regarding whether or not people affected by leprosy have more cognitive dysfunction than healthy individuals. The purpose of this study was to assess cognitive functions and activities of daily living (ADL) in people affected by leprosy relative to a control population living in rural areas. MATERIALS AND METHODS: We assessed cognitive functions and ADL using the Korean Mini-Mental State Examination (K-MMSE), Korean Dementia Screening Questionnaire (KDSQ), and Seoul-Instrumental ADL (S-IADL). Higher scores of K-MMSE and lower scores of both KDSQ and S-IADL are indicative of better functioning. We assessed 224 persons living in Sorokdo who were affected by leprosy and 448 age- and gender-matched control subjects living in Namwon of the Chonbuk province. RESULTS: After adjusting for age, gender, and educational status, the K-MMSE score was found to be significantly higher in people affected by leprosy than in control subjects (23.14 ± 4.89 vs. 22.25 ± 4.62, respectively, P = 0.022). Items related to memory in the KDSQ showed no differences between the groups, but people affected by leprosy had a better score in division for other cognitive functions than controls. On items related to ADL in the KDSQ and S-IADL, people affected by leprosy performed significantly worse compared with controls. CONCLUSIONS: Our results suggest that although people affected by leprosy have a lower capacity of ADL, they may have better cognitive functions than normal controls.