This article introduces the history and the long-term goals of the Korea Brain Initiative, which is centered on deciphering the brain functions and mechanisms that mediate the integration and control ...of brain functions that underlie decision-making. The goal of this initiative is the mapping of a functional connectome with searchable, multi-dimensional, and information-integrated features. The project also includes the development of novel technologies and neuro-tools for integrated brain mapping. Beyond the scientific goals this grand endeavor will ultimately have socioeconomic ramifications that not only facilitate global collaboration in the neuroscience community, but also develop various brain science-related industrial and medical innovations.
The Korean Brain Initiative is focused on deciphering the mechanisms that mediate the integration and control of brain functions underlying decision-making, through the mapping of a functional connectome and the development of novel technologies, infrastructure, and collaborative approaches.
The COVID-19 (coronavirus disease 2019) pandemic has dramatically changed our daily lives and activities, including those originally intended to serve for leisure and pleasure. Drinking and online ...gaming became coping behaviors used to rescue ourselves from the stress and restricted lifestyle during the COVID-19 pandemic. However, frequent drinking and gaming can result in the pathological consequences of addiction. Those affected use the stimuli not to obtain pleasure, but rather to avoid the displeasure induced by stress and previous use, often unsuccessfully. This review aims to provide an overview of recent longitudinal cohort studies on alcohol and gaming use during the COVID-19 pandemic, as well as to analyze how the pandemic has affected alcohol and gaming use. There was a substantial risk of alcohol and online gaming overuse during the lockdown, which may depend on the pandemic's duration or overuse patterns. Previous studies have shown that increased alcohol consumption and online gaming are associated with heightened stress and anxiety levels caused by social isolation/quarantine. Over time, frequent or excessive alcohol consumption and gaming could lead to an increased risk of more serious mental health problems. Every effort should be made to mitigate mental health problems and ensure adequate adaptation to these exceptional circumstances. Therefore, it would be helpful to encourage physical activity, social interaction, and collaboration to facilitate psychological and physical health.
Sirtuins (SIRTs), class III histone deacetylases, are well characterized for their control of cellular physiology in peripheral tissues, but their influence in brain under normal and pathological ...conditions remains poorly understood. Here, we establish an essential role for SIRT1 and SIRT2 in regulating behavioral responses to cocaine and morphine through actions in the nucleus accumbens (NAc), a key brain reward region. We show that chronic cocaine administration increases SIRT1 and SIRT2 expression in the mouse NAc, while chronic morphine administration induces SIRT1 expression alone, with no regulation of all other sirtuin family members observed. Drug induction of SIRT1 and SIRT2 is mediated in part at the transcriptional level via the drug-induced transcription factor ΔFosB and is associated with robust histone modifications at the Sirt1 and Sirt2 genes. Viral-mediated overexpression of SIRT1 or SIRT2 in the NAc enhances the rewarding effects of both cocaine and morphine. In contrast, the local knockdown of SIRT1 from the NAc of floxed Sirt1 mice decreases drug reward. Such behavioral effects of SIRT1 occur in concert with its regulation of numerous synaptic proteins in NAc as well as with SIRT1-mediated induction of dendritic spines on NAc medium spiny neurons. These studies establish sirtuins as key mediators of the molecular and cellular plasticity induced by drugs of abuse in NAc, and of the associated behavioral adaptations, and point toward novel signaling pathways involved in drug action.
The nucleus accumbens (NAc) has a central role in the mechanism of action of drugs of abuse. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), with two major ...subpopulations defined-termed D1-type and D2-type MSNs-based on the predominant dopamine receptor expressed. However, very little is known about the contribution of altered GABAergic function in NAc MSNs to the neural and behavioral plasticity that contributes to the lasting actions of drugs of abuse. In the present study, we show that GABAergic activity is selectively modulated in D1-type MSNs of the NAc by signaling of brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine receptor kinase B (TrkB), and that such adaptations control rewarding responses to morphine. Optical activation of D1-type MSNs, or the knockout of TrkB from D1-type MSNs (D1-TrkB KO), enhances morphine reward, effects not seen for D2-type MSNs. In addition, D1-TrkB KO mice, but not D2-TrkB KO mice, display decreased GABAA receptor (GABAAR) subunit expression and reduced spontaneous inhibitory postsynaptic currents (sIPSCs) in D1-type, but not D2-type, MSNs in the NAc. Furthermore, we found that GABAAR antagonism in the NAc enhances morphine reward and that morphine exposure decreases TrkB expression as well as GABAergic activity in D1-type MSNs. Together, these data provide evidence for the enhancement of morphine reward through reduction of inhibitory GABAAR responses, an adaptation mediated by morphine-induced reduction of BDNF-TrkB signaling in D1-type MSNs.
Mechanisms controlling release of brain-derived neurotrophic factor (BDNF) in the mesolimbic dopamine reward pathway remain unknown. We report that phasic optogenetic activation of this pathway ...increases BDNF amounts in the nucleus accumbens (NAc) of socially stressed mice but not of stress-naive mice. This stress gating of BDNF signaling is mediated by corticotrophin-releasing factor (CRF) acting in the NAc. These results unravel a stress context-detecting function of the brain's mesolimbic circuit.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The return of fear following extinction therapy is an important issue associated with the treatment of many fear-related disorders. Fear renewal is a suitable model, with which context-dependent ...modulation of the fear response can be examined. In this model, any context outside of an extinction context (e.g., novel or familiar contexts) could evoke relapse of the fear response. However, brain regions associated with context-dependent modulation are not fully understood. The posterior parietal cortex (PPC) is considered a center for integrating multisensory information and making decisions. To study its role in the contextual modulation of fear relapse, we reversibly inactivated the PPC in mice before they were exposed to various contexts after extinction training. When muscimol was infused into the PPC, fear renewal was impaired in a novel context, but not in a familiar context. Fear relapses were blocked during optogenetic inhibition of the PPC, only when animals were placed in a novel context. We propose that the neural activity of the PPC is necessary for the relapse of a precise response to an extinguished conditioned stimulus in a novel context.
Stressful circumstances are significant contributors to mental illnesses such as major depressive disorder. Anhedonia, defined as loss of the ability to enjoy pleasure in pleasurable situations, ...including rewarding activities or social contexts, is considered a key symptom of depression. Although stress-induced depression is associated with anhedonia in humans and animals, the underlying molecular mechanisms of anhedonic responses remain poorly understood. In this study, we demonstrated that synaptotagmin-4 (SYT4), which is involved in the release of neurotransmitters and neurotrophic factors, is implicated in chronic stress-induced anhedonia. Employing chronic unpredictable stress (CUS), we evaluated two subpopulations of mice, susceptible (SUS, anhedonic) and resilient (RES, nonanhedonic), based on sucrose preference, which was strongly correlated with social reward. The FosTRAP (targeted recombination in active populations) system and optogenetic approach revealed that neural activity in the medial prefrontal cortex (mPFC) was significantly associated with CUS-induced anhedonic behavioral phenotypes. By conducting weighted gene coexpression network analysis of RNA sequencing data from the mPFC of SUS and RES mice, we identified Syt4 as a hub gene in a gene network that was unique to anhedonia. We also confirmed that Syt4 overexpression in the mPFC was pro-susceptible, while Syt4 knockdown was pro-resilient; the pro-susceptible effects of SYT4 were mediated through a reduction in brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the mPFC. These findings suggest that SYT4-BDNF interactions in the mPFC represent a crucial regulatory mechanism of anhedonic susceptibility to chronic stress.
The coronavirus disease 2019 (COVID-19) pandemic has disrupted our everyday life. Along with the fear of getting infected or of having loved ones infected, the lifestyle changes and the socioeconomic ...consequences of the pandemic have profound impact on mental health of the general population. While numerous studies on immediate psychological responses to COVID-19 are being published, there is a lack of discussion on its possible long-term sequelae. In this study, we systematically reviewed and meta-analyzed longitudinal studies that examined mental health of the general population prior to and during the pandemic. Furthermore, we explored the long-term psychiatric implications of the pandemic with data from South Korea. Our analysis showed that the number of suicidal deaths during the pandemic was lower than the previous years in many countries, which is in contrast with the increased depression, anxiety, and psychological distress in the general population in South Korea as well as in other countries. To explain this phenomenon, we propose a possibility of delayed impacts. The post-traumatic stress, long-term consequences of social restrictions, and maladaptive response to the “new normal” are discussed in the paper. COVID-19 being an unprecedented global crisis, more research and international collaboration are needed to understand, to treat, and to prevent its long-term effects on our mental health.
Brain-derived neurotrophic factor (BDNF) is a key positive regulator of neural plasticity, promoting, for example, the actions of stimulant drugs of abuse such as cocaine. We discovered a surprising ...opposite role for BDNF in countering responses to chronic morphine exposure. The suppression of BDNF in the ventral tegmental area (VTA) enhanced the ability of morphine to increase dopamine (DA) neuron excitability and promote reward. In contrast, optical stimulation of VTA DA terminals in nucleus accumbens (NAc) completely reversed the suppressive effect of BDNF on morphine reward. Furthermore, we identified numerous genes in the NAc, a major target region of VTA DA neurons, whose regulation by BDNF in the context of chronic morphine exposure mediated this counteractive function. These findings provide insight into the molecular basis of morphine-induced neuroadaptations in the brain's reward circuitry.
Electrolytic lesions to the amygdala, a limbic structure implicated in stress-related behaviors and memory modulation, have been shown to prevent stress-induced impairments of hippocampal long-term ...potentiation (LTP) and spatial memory in rats. The present study investigated the role of intrinsic amygdalar neurons in mediating stress effects on the hippocampus by microinfusing the GABA(A) receptor agonist muscimol into the amygdala and examining stress effects on Schaffer collateral/commissural-CA1 LTP and spatial memory. The critical period of the amygdalar contribution to stress effects on hippocampal functions was determined by applying muscimol either before stress or immediately after stress. Our results indicate that intra-amygdalar muscimol infusions before uncontrollable restraint-tailshock stress effectively blocked stress-induced physiological and behavioral effects. Specifically, hippocampal slices prepared from vehicle-infused stressed animals exhibited markedly impaired LTP, whereas slices obtained from muscimol-infused stressed animals demonstrated robust LTP comparable with that of unstressed animals. Correspondingly, vehicle-infused stressed animals displayed impaired spatial memory (on a hidden platform version of the Morris water maze task), whereas muscimol-infused stressed animals revealed unimpaired spatial memory. In contrast to prestress muscimol effects, however, immediate poststress infusions of muscimol into the amygdala failed to interfere with stress impairments of LTP and spatial memory. Together, these results suggest that the amygdalar neuronal activity during stress, but not shortly after stress, is essential for the emergence of stress-induced alterations in hippocampal LTP and memory.
PDF
