Experimental Neurobiology最新文献

The FK506 binding protein 5 (FKBP5) is a co-chaperone that regulates the activity of the glucocorticoid receptor (GR) and has been reported to mediate stress resilience. This study aimed to determine the effects of Fkbp5 deletion on acute stress-induced recognition memory impairment and hippocampal GR signaling. Wild-type and Fkbp5-knockout mice were subjected to acute uncontrollable stress induced by restraint and electrical tail shock. First, we assessed the cognitive status of mice using a novel object recognition task. Next, we measured plasma corticosterone, GR levels, and the levels of GR phosphorylation at serine 211 in the hippocampus. Wild-type mice exhibited stress-induced memory impairments, whereas Fkbp5-knockout mice did not. Plasma corticosterone and GR levels did not differ between the non-stressed wild-type and Fkbp5-knockout mice, but the levels of phosphorylated GR were lower in Fkbp5-knockout mice than in wild-type mice. Wild-type and Fkbp5-knockout mice showed increased nuclear GR levels following stress, indicating GR translocation. However, cytosolic phosphorylated GR levels were lower in the hippocampi of Fkbp5-knockout mice following stress than in those of wild-type mice. These results suggest that FKBP5 deficiency increases resilience to acute stress by altering GR signaling.

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder. Pain catastrophizing, characterized by magnification, rumination, and helplessness, increases perceived pain intensity and mental distress in CRPS patients. As functional connectivity patterns in CRPS remain largely unknown, we aimed to investigate functional connectivity alterations in CRPS patients and their association with pain catastrophizing using a whole-brain analysis approach. Twenty-one patients with CRPS and 49 healthy controls were included in the study for clinical assessment and resting-state functional magnetic resonance imaging. Between-group differences in whole-brain functional connectivity were examined through a Network-based Statistics analysis. Associations between altered functional connectivity and the extent of pain catastrophizing were also assessed in CRPS patients. Relative to healthy controls, CRPS patients showed higher levels of functional connectivity in the bilateral somatosensory subnetworks (components 1~2), but lower functional connectivity within the prefronto-posterior cingulate (component 3), prefrontal (component 4), prefronto-parietal (component 5), and thalamo-anterior cingulate (component 6) subnetworks (p<0.05, family-wise error corrected). Higher levels of functional connectivity in components 1~2 (β=0.45, p=0.04) and lower levels of functional connectivity in components 3~6 (β=-0.49, p=0.047) were significantly correlated with higher levels of pain catastrophizing in CRPS patients. Higher functional connectivity in the somatosensory subnetworks implicating exaggerated pain perception and lower functional connectivity in the prefronto-parieto-cingulo-thalamic subnetworks indicating impaired cognitive-affective pain processing may underlie pain catastrophizing in CRPS.

Connectome, the complete wiring diagram of the nervous system of an organism, is the biological substrate of the mind. While biological neural networks are crucial to the understanding of neural computation mechanisms, recent artificial neural networks (ANNs) have been developed independently from the study of real neural networks. Computational scientists are searching for various ANN architectures to improve machine learning since the architectures are associated with the accuracy of ANNs. A recent study used the hermaphrodite Caenorhabditis elegans (C. elegans) connectome for image classification tasks, where the edge directions were changed to construct a directed acyclic graph (DAG). In this study, we used the whole-animal connectomes of C. elegans hermaphrodite and male to construct a DAG that preserves the chief information flow in the connectomes and trained them for image classification of MNIST and fashion-MNIST datasets. The connectome-inspired neural networks exhibited over 99.5% and 92.6% of accuracy for MNIST and fashion-MNIST datasets, respectively, which increased from the previous study. Together, we conclude that realistic biological neural networks provide the basis of a plausible ANN architecture. This study suggests that biological networks can provide new inspiration to improve artificial intelligences (AIs).

Ca²⁺+ transients can be observed in the distal dendrites of Purkinje cells (PCs) despite their lack of action potential backpropagation. These Ca²⁺+ events in distal dendrites require specific patterns of PC firing, such as complex spikes (CS) or simple spikes (SS) of burst mode. Unlike CS, which can act directly on voltage-gated calcium channels in the dendrites through climbing fiber inputs, the condition that can produce the Ca²⁺+ events in distal dendrites with burst mode SS is poorly understood. Here, we propose the interspike interval threshold (ISIT) for Ca²⁺+ transients in the distal dendrites of PC. We found that to induce the Ca²⁺+ transients in distal dendrites the frequency of spike firing of PC should reach 250 Hz (3 ms ISI). Metabotropic glutamate receptor 1 (mGluR1) activation significantly relieved the ISIT and established cellular conditions in which spike firing with 50 Hz (19 ms ISI) could induce Ca²⁺+ transients in the distal dendrites. In contrast, blocking T-type Ca²⁺+ channels or depleting the endoplasmic reticulum Ca²⁺+ store resulted in a stricter condition in which spike firing with 333 Hz (2 ms ISI) was required. Our findings demonstrate that the PC has strict ISIT for dendritic Ca²⁺+ transients, and this ISIT can be relieved by mGluR1 activation. This strict restriction of ISIT could contribute to the reduction of the signal-to-noise ratio in terms of collecting information by preventing excessive dendritic Ca²⁺+ transients through the spontaneous activity of PC.

Cholesterol metabolism plays an essential role in cellular functions (including as a component of the plasma membrane, as an energy source, and in hormone production) under normal conditions. Dysregulated cholesterol metabolism causes a wide spectrum of pathological conditions, leading to neuropsychiatric disorders, such as anxiety and depression. In addition, patients with neuropsychiatric disorders also have impaired cholesterol metabolism. Therefore, metabolic disturbances are closely associated with the neuropsychiatric disorders. Although immune disturbance, neuroinflammation, a dysregulated neurotransmitter system, and oxidative stress have been suggested as pathophysiology of neuropsychiatric disorders, dysregulation of cholesterol metabolism is also found in patients with psychiatric diseases. As expected, patients with mental illness appear to be at risk of metabolic disorders, including metabolic syndrome, in which cholesterol influences altered neuronal homeostasis, such as neuronal cell toxicity, neuronal cell death, and neuronal structures and functions, including synaptogenesis, neurogenesis, axonogenesis, and action potential. Therefore, reversing impaired or abnormal cholesterol metabolism may help restore neuronal injury found in mental illness. This review is aimed to discuss the links between cholesterol metabolism impairment and neuropsychiatric disorders and provides insights into neuronal dysfunction due to abnormal cholesterol metabolism in neuropsychiatric disorders.

Developing social strategies to share limited resources equally and maximize the long-term benefits of conflict resolution is critical for appropriate social interactions. During social interactions, social decision-making depends not only on the external environment, but also on internal factors, such as hunger, thirst, or fatigue. In particular, hunger, which is related to food as a physical need, plays a dominant role in social decision-making. However, the consequences of food deprivation on social decision-making are not well understood. We have previously shown that mice with rule-observance behavior are capable of resolving conflict during social decision-making by observing a well-established social strategy based on reward zone allocation. Here, we developed a rule-observance behavior paradigm wherein the hunger state is achieved by applying food restrictions on mice prior to social behavior experiments. We found that the hunger state in mice deteriorated the established social strategy by decreasing reaction time, implying an increase in impulsivity. In contrast, the hunger state did not affect reward zone allocation, indicating no effect on spatial memory. This decrease in reaction time led to a significant increase in the percentage of violations during rule observance and a significant decrease in the amount of reward (payoff equity). Our study proposes that the hunger state exerts a detrimental effect on appropriate social decision-making by decreasing reaction time, increasing violation, and decreasing payoff equity in rule-observance behavior.

Trace fear conditioning is characterized by a stimulus-free trace interval (TI) between the conditioned stimulus (CS) and the unconditioned stimulus (US), which requires an array of brain structures to support the formation and storage of associative memory. The entorhinal cortex (EC) has been proposed to provide essential neural code for resolving temporal discontinuity in conjunction with the hippocampus. However, how the CS and TI are encoded at the neuronal level in the EC is not clear. In Exp. 1, we tested the effect of bilateral pre-training electrolytic lesions of EC on trace vs. delay fear conditioning using rats as subjects. We found that the lesions impaired the acquisition of trace but not delay fear conditioning confirming that EC is a critical brain area for trace fear memory formation. In Exp. 2, single-unit activities from EC were recorded during the pre-training baseline and post-training retention sessions following trace or delay conditioning. The recording results showed that a significant proportion of the EC neurons modulated their firing during TI after the trace conditioning, but not after the delay fear conditioning. Further analysis revealed that the majority of modulated units decreased the firing rate during the TI or the CS. Taken together, these results suggest that EC critically contributes to trace fear conditioning by modulating neuronal activity during the TI to facilitate the association between the CS and US across a temporal gap.

In 1998, Korea implemented the Brain Research Promotion Act (BRPA), a law to revamp the field of neuroscience at the national level. However, despite numerous revisions including the definition and classification of neuroscience and the national plans for the training and education systems, the governance for neuroethics has not been integrated into the Act. The ethical issues raised by neuroscience and neurotechnology remain unchallenged, especially given the focus on the industrial purpose of the technology. In the current study, we analyzed the BRPA revision process by using Kingdon's Multiple Streams Framework to determine the problems faced by the process. We propose a new strategy, including neuroethics governance and a national committee, to promote interdisciplinary neuroscience research and strengthen neuroethics in Korea.

The recent, unprecedented advancement in neuroscience has led to new discoveries about the human brain and its function. Yet at the same time, it has spurred novel ethical and regulatory issues, and the field of neuroethics has emerged as an interdisciplinary endeavor to address these issues. Across the globe, extensive efforts have been underway to achieve the integration of neuroscience and Neuroethics, with active engagement not only from academia but also from the government, the public, and industry. However, in some countries, integrating neuroscience and neuroethics has proved to be a particularly challenging task. For example, in South Korea, the government has primarily driven the integration effort, and only a small group of researchers is properly trained for conducting an interdisciplinary evaluation of ethical, legal, social, and cultural implications (ELSCI) of neurotechnology. On the basis of the last few years of experience pursuing a government-funded neuroethics project in South Korea, we developed a new operational framework to provide practical guidance on ELSCI research. This framework consists of the X, Y, and Z axes; the X-axis represents a target neurotechnology, the Y-axis represents different developmental stages of the technology, and the Z-axis represents ELSCI issues that may arise from the development and use of the neurotechnology. Here we also present a step-by-step workflow to apply this matrix framework, from organizing a panel for a target neurotechnology to facilitating stakeholder discussion through public hearings. This framework will enable meaningful integration of neuroscience and neuroethics to promote responsible innovation in neuroscience and neurotechnology.

Amyloid precursor protein (APP) plays an important role in the pathogenesis of Alzheimer's disease (AD), but the normal function of APP at synapses is poorly understood. We and others have found that APP interacts with Reelin and that each protein is individually important for dendritic spine formation, which is associated with learning and memory, in vitro. However, whether Reelin acts through APP to modulate dendritic spine formation or synaptic function remains unknown. In the present study, we found that Reelin treatment significantly increased dendritic spine density and PSD-95 puncta number in primary hippocampal neurons. An examination of the molecular mechanisms by which Reelin regulates dendritic spinogenesis revealed that Reelin enhanced hippocampal dendritic spine formation in a Ras/ERK/CREB signaling-dependent manner. Interestingly, Reelin did not increase dendritic spine number in primary hippocampal neurons when APP expression was reduced or in vivo in APP knockout (KO) mice. Taken together, our data are the first to demonstrate that Reelin acts cooperatively with APP to modulate dendritic spine formation and suggest that normal APP function is critical for Reelin-mediated dendritic spinogenesis at synapses.