Experimental and Molecular Medicine/Experimental and molecular medicine, Feb 1, 2024
Stressful circumstances are significant contributors to mental illnesses such as major depressive... more 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.
Mental health is influenced by the gut-brain axis; for example, gut dysbiosis has been observed i... more Mental health is influenced by the gut-brain axis; for example, gut dysbiosis has been observed in patients with major depressive disorder (MDD). Gut microbial changes by fecal microbiota transplantation or probiotics treatment reportedly modulates depressive symptoms. However, it remains unclear how gut dysbiosis contributes to mental dysfunction, and how correction of the gut microbiota alleviates neuropsychiatric disorders. Our previous study showed that chronic consumption of Lactobacillus reuteri ATG-F4 (F4) induced neurometabolic alterations in healthy mice. Here, we investigated whether F4 exerted therapeutic effects on depressive-like behavior by influencing the central nervous system. Using chronic unpredictable stress (CUS) to induce anhedonia, a key symptom of MDD, we found that chronic F4 consumption alleviated CUS-induced anhedonic behaviors, accompanied by biochemical changes in the gut, serum, and brain. Serum and brain metabolite concentrations involved in tryptophan metabolism were regulated by CUS and F4. F4 consumption reduced the elevated levels of serotonin (5-HT) in the brain observed in the CUS group. Additionally, the increased expression of Htr1a, a subtype of the 5-HT receptor, in the medial prefrontal cortex (mPFC) of stressed mice was restored to levels observed in stress-naïve mice following F4 supplementation. We further demonstrated the role of Htr1a using AAV-shRNA to downregulate Htr1a in the mPFC of CUS mice, effectively reversing CUS-induced anhedonic behavior. Together, our findings suggest F4 as a potential therapeutic approach for relieving some depressive symptoms and highlight the involvement of the tryptophan metabolism in mitigating CUS-induced depressive-like behaviors through the action of this bacterium.
IL-1β is a proinflammatory cytokine that contributes to psychological stress responses and has be... more IL-1β is a proinflammatory cytokine that contributes to psychological stress responses and has been implicated in various psychiatric disorders most notably depression. Preclinical studies also demonstrate that IL-1β modulates anxiety-and fear-related behaviors, although these findings are difficult to assess because IL-1β infusions influence locomotor activity and nociception. Here we demonstrate that IL-1RI null mice exhibit a behavioral phenotype consistent with a decrease in anxiety-related behaviors. This includes significant effects in the elevated plus maze, light-dark, and novelty-induced hypophagia tests compared to wild-type mice, with no differences in locomotor activity. With regard to fear conditioning, IL-1RI null mice showed more freezing in auditory and contextual fear conditioning tests, and there was no effect on pain sensitivity. Taken together, the results indicate that the IL-1β/IL-1RI signaling pathway induces anxiety-related behaviors and impairs fear memory.
SummarySocial animals compete for limited resources, resulting in a social hierarchy. Although di... more SummarySocial animals compete for limited resources, resulting in a social hierarchy. Although different neuronal subpopulations in the medial prefrontal cortex (mPFC), a hub brain region of social hierarchy, encode distinct social competition behaviors, their identities and associated molecular underpinnings have not yet been identified. In this study, we found that mPFC neurons projecting to the nucleus accumbens (mPFC-NAc) encode social winning behavior, whereas mPFC neurons projecting to the ventral tegmental area (mPFC-VTA) encode social losing behavior by monitoring and manipulating neural circuit activity. High-throughput single-cell transcriptomic analysis and projection-specific genetic manipulation revealed that the expression level of POU domain, class 3, transcription factor 1 (Pou3f1) in mPFC-VTA neurons controls social hierarchy. Optogenetic activation of mPFC-VTA neurons increasesPou3f1expression and lowers social rank. Together, these data demonstrate that discrete a...
The human brain is constantly active, even at rest. Alpha coherence is an electroencephalography ... more The human brain is constantly active, even at rest. Alpha coherence is an electroencephalography (EEG) rhythm that regulates functional connectivity between different brain regions. However, the relationships between resting-state alpha coherence and N2/P3 components associated with response inhibition and cognitive processes have not been investigated in addictive disorders. The present study investigated the relationships between alpha coherence during the resting state and N2/P3 components of event-related potentials during the Go/Nogo task in healthy controls (HCs) and patients with Internet gaming disorder (IGD). A total of 64 young adults (HC: n = 31; IGD: n = 33) participated in this study. Alpha coherence values at left fronto-central and bilateral centro-temporal electrode sites were significantly correlated with P3 latency in HCs, whereas inverse correlations were observed in patients with IGD. Furthermore, significant differences were observed in the correlation values be...
This study investigated attentional bias toward game-related cues in Internet gaming disorder (IG... more This study investigated attentional bias toward game-related cues in Internet gaming disorder (IGD) using electrophysiological markers of late positive potential (LPP) and identifying the sources of LPP. In addition, the association between LPP and decision-making ability was investigated. The IGD (n = 40) and healthy control (HC; n = 39) participants viewed a series of game-related and neutral pictures, while their event-related potentials (ERPs) were recorded. LPPs were calculated as the mean amplitudes between 400 and 700 ms at the centro-parietal (CP3, CP1, Cpz, CP2, and CP4) and parietal (P3, P1, Pz, P2, and P4) electrode sites. The source activations of LPP were estimated using standardized low-resolution brain electromagnetic tomography (sLORETA). In addition, decision-making ability was evaluated by the Cambridge Gambling Task. Higher LPP amplitudes were found for game-related cues in the IGD group than in the HC group. sLORETA showed that the IGD group was more active in th...
The medial prefrontal cortex (mPFC) plays important roles in social behaviors, but it is not clea... more The medial prefrontal cortex (mPFC) plays important roles in social behaviors, but it is not clear how early social experiences affect the mPFC and its subcortical circuit. We report that mice singly housed for 8 weeks immediately after weaning (SH mice) show a deficit in social recognition, even after 4 weeks of re-socialization. In SH mice, prefrontal infralimbic (IL) neurons projecting to the shell region of nucleus accumbens (NAcSh) showed decreased excitability compared to normally group housed (GH) mice. Furthermore, NAcSh-projecting IL neurons were activated when the mice encountered a familiar conspecific, which was not shown in SH mice. Chemogenetic inhibition of NAcSh-projecting IL neurons in normal mice selectively impaired social recognition without affecting social interaction, whereas activation of these neurons reversed social recognition deficit in SH mice. Therefore, mPFC IL-NAcSh projection is a novel brain circuit affected by early social experience; its activatio...
Global changes in gene expression underlying circuit and behavioral dysregulation associated with... more Global changes in gene expression underlying circuit and behavioral dysregulation associated with cocaine addiction remain incompletely understood. Here, we show how a history of cocaine self-administration (SA) reprograms transcriptome-wide responses throughout the brain's reward circuitry at baseline and in response to context and/or cocaine re-exposure after prolonged withdrawal (WD). We assigned male mice to one of six groups: saline/cocaine SA + 24-hour WD or saline/cocaine SA + 30-day WD + an acute saline/cocaine challenge within the previous drug-paired context. RNA sequencing was conducted on six interconnected brain reward regions. Using pattern analysis of gene expression and factor analysis of behavior, we identified genes that are strongly associated with addiction-related behaviors and uniquely altered by a history of cocaine SA. We then identified potential upstream regulators of these genes. We focused on three patterns of gene expression that reflect responses to...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 6, 2016
ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation o... more ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate thatBaz1b, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression ofBaz1b, along with its associated subunitSmarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 16, 2015
Depression and anxiety disorders are more prevalent in females, but the majority of research in a... more Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences was DNA methyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levels were increased in the NAc of depressed humans, an effect seen in both males and females. Local overexpression of Dnmt3a in NAc rendered male mice more suscepti...
Improved treatment for major depressive disorder (MDD) remains elusive because of the limited und... more Improved treatment for major depressive disorder (MDD) remains elusive because of the limited understanding of its underlying biological mechanisms. It is likely that stress-induced maladaptive transcriptional regulation in limbic neural circuits contributes to the development of MDD, possibly through epigenetic factors that regulate chromatin structure. We establish that persistent upregulation of the ACF (ATP-utilizing chromatin assembly and remodeling factor) ATP-dependent chromatin-remodeling complex, occurring in the nucleus accumbens of stress-susceptible mice and depressed humans, is necessary for stress-induced depressive-like behaviors. We found that altered ACF binding after chronic stress was correlated with altered nucleosome positioning, particularly around the transcription start sites of affected genes. These alterations in ACF binding and nucleosome positioning were associated with repressed expression of genes implicated in susceptibility to stress. Together, our fi...
Electrolytic lesions to the amygdala, a limbic structure implicated in stress-related behaviors a... more 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 GABAAreceptor 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 LT...
IL-1β is a proinflammatory cytokine that contributes to psychological stress responses and has be... more IL-1β is a proinflammatory cytokine that contributes to psychological stress responses and has been implicated in various psychiatric disorders most notably depression. Preclinical studies also demonstrate that IL-1β modulates anxiety-and fear-related behaviors, although these findings are difficult to assess because IL-1β infusions influence locomotor activity and nociception. Here we demonstrate that IL-1RI null mice exhibit a behavioral phenotype consistent with a decrease in anxiety-related behaviors. This includes significant effects in the elevated plus maze, light-dark, and novelty-induced hypophagia tests compared to wild-type mice, with no differences in locomotor activity. With regard to fear conditioning, IL-1RI null mice showed more freezing in auditory and contextual fear conditioning tests, and there was no effect on pain sensitivity. Taken together, the results indicate that the IL-1β/IL-1RI signaling pathway induces anxiety-related behaviors and impairs fear memory.
DFosB, a FosB gene product, is induced in the prefrontal cortex (PFC) by repeated exposure to sev... more DFosB, a FosB gene product, is induced in the prefrontal cortex (PFC) by repeated exposure to several stimuli including antipsychotic drugs such as haloperidol. However, the functional consequences of increased DFosB expression following antipsychotic treatment have not been explored. Here, we assessed whether DFosB induction by haloperidol mediates the positive or negative consequences or clinical-related actions of antipsychotic treatment. We show that individuals with schizophrenia who were medicated with antipsychotic drugs at their time of death display increased DFosB levels in the PFC, an effect that is replicated in rats treated chronically with haloperidol. In contrast, individuals with schizophrenia who were medication-free did not exhibit this effect. Viral-mediated overexpression of DFosB in the PFC of rodents induced cognitive deficits as measured by inhibitory avoidance, increased startle responses in prepulse inhibition tasks, and increased MK-801-induced anxiety-like behaviors. Together, these results suggest that DFosB induction in the PFC by antipsychotic treatment contributes to the deleterious effects of these drugs and not to their therapeutic actions.
Proceedings of the National Academy of Sciences, 2014
Significance We demonstrate that chronic cocaine, including cocaine self-administration, induces ... more Significance We demonstrate that chronic cocaine, including cocaine self-administration, induces poly(ADP-ribose) polymerase-1 (PARP-1) in the nucleus accumbens (NAc). Using a combination of viral-mediated gene transfer and pharmacological tools, we show that upregulation of PARP-1 in NAc dramatically enhances behavioral responses to cocaine, whereas downregulation of PARP-1 has the opposite effect. We used chromatin immunoprecipitation sequencing to map genome-wide binding of PARP-1 in NAc. The data demonstrate upregulation of PARP-1 binding across the genome after cocaine administration and identify numerous target genes for PARP-1. Among these is sidekick-1 (SDK1), previously implicated in regulating synaptic connections during development. We confirm SDK1 induction in NAc after chronic cocaine and demonstrate its ability to promote both cocaine’s behavioral effects and induction of dendritic plasticity in NAc.
Regulating Opioid Responses Different drugs of abuse are thought to highjack similar reward syste... more Regulating Opioid Responses Different drugs of abuse are thought to highjack similar reward systems in the brain using common mechanisms. However, Koo et al. (p. 124 ) now observe that some of the neural mechanisms that regulate opiate reward can be both different and even opposite to those that regulate reward by stimulant drugs. While knockdown of brain-derived neurotrophic factor (BDNF) in the ventral tegmental area in mice antagonized the response to cocaine, the same manipulation strengthened the potential of opiates to increase dopamine neuron excitability. Optogenetic stimulation of dopaminergic terminals in the nucleus accumbens could counteract the effects of BDNF on morphine reward blockade.
Background-Previous work has shown that chronic social defeat stress (CSDS) induces increased pha... more Background-Previous work has shown that chronic social defeat stress (CSDS) induces increased phasic firing of ventral tegmental area (VTA) dopamine neurons that project to the nucleus accumbens (NAc) selectively in mice that are susceptible to the deleterious effects of the stress. In addition, acute optogenetic phasic stimulation of these neurons promotes susceptibility in animals exposed to acute defeat stress. These findings are paradoxical since increased dopamine (DA) signaling in NAc normally promotes motivation and reward, and the influence of chronic phasic VTA firing in the face of chronic stress remains unknown. Methods-We used CSDS with repeated optogenetic activation and pharmacological manipulations of the mesolimbic VTA-NAc pathway to examine the role of brain-derived neurotrophic factor (BDNF) and DA signaling in depressive-like behaviors. BDNF protein expression and DA release were measured in this model. Results-Pharmacological blockade of BDNF-TrkB signaling, but not DA signaling, in NAc prevented CSDS-induced behavioral abnormalities. Chronic optogenetic phasic stimulation of the VTA-NAc circuit during CSDS exacerbated the defeat-induced behavioral symptoms, and these aggravated symptoms were also normalized by BDNF-TrkB blockade in NAc. The aggravated
In the fear conditioning literature, it is generally hypothesized that neurons in the basolateral... more In the fear conditioning literature, it is generally hypothesized that neurons in the basolateral amygdalar complex (BLA) (lateral and basal nuclei) support the formation of conditioned fear memory and project to neurons in the central nucleus (CeA) for the expression of conditioned fear responses. According to this serial processing-transmission view, damage to either BLA or CeA would comparably disrupt the expression of a variety of conditioned fear responses. In the present study, we further investigated the roles of BLA and CeA in fear conditioning by concurrently assessing freezing and 22 kHz ultrasonic vocalization (USV) as dependent measures of fear in rats. Selective neurotoxins, NMDA for the BLA and ibotenic acid for the CeA, were used to destroy intrinsic neurons [evidenced by thionin dye and NeuN (neuronal nuclei) antibody stainings] without damaging the fibers of passage (confirmed by myelin staining). During the 10 tone-footshock paired training, postshock freezing and ...
Often called the second brain, the gut communicates extensively with the brain and vice versa. Th... more Often called the second brain, the gut communicates extensively with the brain and vice versa. The conversation between these two organs affects a variety of physiological mechanisms that are associated with our mental health. Over the past decade, a growing body of evidence has suggested that the gut microbiome builds a unique ecosystem inside the gastrointestinal tract to maintain the homeostasis and that compositional changes in the gut microbiome are highly correlated with several mental disorders. There are ongoing efforts to treat or prevent mental disorders by regulating the gut microbiome using probiotics. These attempts are based on the seminal findings that probiotics can control the gut microbiome and affect mental conditions. However, some issues have yet to be conclusively addressed, especially the causality between the gut microbiome and mental disorders. In this review, we focus on the mechanisms by which the gut microbiome affects mental health and diseases. Furthermore, we discuss the potential use of probiotics as therapeutic agents for psychiatric disorders.
Experimental and Molecular Medicine/Experimental and molecular medicine, Feb 1, 2024
Stressful circumstances are significant contributors to mental illnesses such as major depressive... more 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.
Mental health is influenced by the gut-brain axis; for example, gut dysbiosis has been observed i... more Mental health is influenced by the gut-brain axis; for example, gut dysbiosis has been observed in patients with major depressive disorder (MDD). Gut microbial changes by fecal microbiota transplantation or probiotics treatment reportedly modulates depressive symptoms. However, it remains unclear how gut dysbiosis contributes to mental dysfunction, and how correction of the gut microbiota alleviates neuropsychiatric disorders. Our previous study showed that chronic consumption of Lactobacillus reuteri ATG-F4 (F4) induced neurometabolic alterations in healthy mice. Here, we investigated whether F4 exerted therapeutic effects on depressive-like behavior by influencing the central nervous system. Using chronic unpredictable stress (CUS) to induce anhedonia, a key symptom of MDD, we found that chronic F4 consumption alleviated CUS-induced anhedonic behaviors, accompanied by biochemical changes in the gut, serum, and brain. Serum and brain metabolite concentrations involved in tryptophan metabolism were regulated by CUS and F4. F4 consumption reduced the elevated levels of serotonin (5-HT) in the brain observed in the CUS group. Additionally, the increased expression of Htr1a, a subtype of the 5-HT receptor, in the medial prefrontal cortex (mPFC) of stressed mice was restored to levels observed in stress-naïve mice following F4 supplementation. We further demonstrated the role of Htr1a using AAV-shRNA to downregulate Htr1a in the mPFC of CUS mice, effectively reversing CUS-induced anhedonic behavior. Together, our findings suggest F4 as a potential therapeutic approach for relieving some depressive symptoms and highlight the involvement of the tryptophan metabolism in mitigating CUS-induced depressive-like behaviors through the action of this bacterium.
IL-1β is a proinflammatory cytokine that contributes to psychological stress responses and has be... more IL-1β is a proinflammatory cytokine that contributes to psychological stress responses and has been implicated in various psychiatric disorders most notably depression. Preclinical studies also demonstrate that IL-1β modulates anxiety-and fear-related behaviors, although these findings are difficult to assess because IL-1β infusions influence locomotor activity and nociception. Here we demonstrate that IL-1RI null mice exhibit a behavioral phenotype consistent with a decrease in anxiety-related behaviors. This includes significant effects in the elevated plus maze, light-dark, and novelty-induced hypophagia tests compared to wild-type mice, with no differences in locomotor activity. With regard to fear conditioning, IL-1RI null mice showed more freezing in auditory and contextual fear conditioning tests, and there was no effect on pain sensitivity. Taken together, the results indicate that the IL-1β/IL-1RI signaling pathway induces anxiety-related behaviors and impairs fear memory.
SummarySocial animals compete for limited resources, resulting in a social hierarchy. Although di... more SummarySocial animals compete for limited resources, resulting in a social hierarchy. Although different neuronal subpopulations in the medial prefrontal cortex (mPFC), a hub brain region of social hierarchy, encode distinct social competition behaviors, their identities and associated molecular underpinnings have not yet been identified. In this study, we found that mPFC neurons projecting to the nucleus accumbens (mPFC-NAc) encode social winning behavior, whereas mPFC neurons projecting to the ventral tegmental area (mPFC-VTA) encode social losing behavior by monitoring and manipulating neural circuit activity. High-throughput single-cell transcriptomic analysis and projection-specific genetic manipulation revealed that the expression level of POU domain, class 3, transcription factor 1 (Pou3f1) in mPFC-VTA neurons controls social hierarchy. Optogenetic activation of mPFC-VTA neurons increasesPou3f1expression and lowers social rank. Together, these data demonstrate that discrete a...
The human brain is constantly active, even at rest. Alpha coherence is an electroencephalography ... more The human brain is constantly active, even at rest. Alpha coherence is an electroencephalography (EEG) rhythm that regulates functional connectivity between different brain regions. However, the relationships between resting-state alpha coherence and N2/P3 components associated with response inhibition and cognitive processes have not been investigated in addictive disorders. The present study investigated the relationships between alpha coherence during the resting state and N2/P3 components of event-related potentials during the Go/Nogo task in healthy controls (HCs) and patients with Internet gaming disorder (IGD). A total of 64 young adults (HC: n = 31; IGD: n = 33) participated in this study. Alpha coherence values at left fronto-central and bilateral centro-temporal electrode sites were significantly correlated with P3 latency in HCs, whereas inverse correlations were observed in patients with IGD. Furthermore, significant differences were observed in the correlation values be...
This study investigated attentional bias toward game-related cues in Internet gaming disorder (IG... more This study investigated attentional bias toward game-related cues in Internet gaming disorder (IGD) using electrophysiological markers of late positive potential (LPP) and identifying the sources of LPP. In addition, the association between LPP and decision-making ability was investigated. The IGD (n = 40) and healthy control (HC; n = 39) participants viewed a series of game-related and neutral pictures, while their event-related potentials (ERPs) were recorded. LPPs were calculated as the mean amplitudes between 400 and 700 ms at the centro-parietal (CP3, CP1, Cpz, CP2, and CP4) and parietal (P3, P1, Pz, P2, and P4) electrode sites. The source activations of LPP were estimated using standardized low-resolution brain electromagnetic tomography (sLORETA). In addition, decision-making ability was evaluated by the Cambridge Gambling Task. Higher LPP amplitudes were found for game-related cues in the IGD group than in the HC group. sLORETA showed that the IGD group was more active in th...
The medial prefrontal cortex (mPFC) plays important roles in social behaviors, but it is not clea... more The medial prefrontal cortex (mPFC) plays important roles in social behaviors, but it is not clear how early social experiences affect the mPFC and its subcortical circuit. We report that mice singly housed for 8 weeks immediately after weaning (SH mice) show a deficit in social recognition, even after 4 weeks of re-socialization. In SH mice, prefrontal infralimbic (IL) neurons projecting to the shell region of nucleus accumbens (NAcSh) showed decreased excitability compared to normally group housed (GH) mice. Furthermore, NAcSh-projecting IL neurons were activated when the mice encountered a familiar conspecific, which was not shown in SH mice. Chemogenetic inhibition of NAcSh-projecting IL neurons in normal mice selectively impaired social recognition without affecting social interaction, whereas activation of these neurons reversed social recognition deficit in SH mice. Therefore, mPFC IL-NAcSh projection is a novel brain circuit affected by early social experience; its activatio...
Global changes in gene expression underlying circuit and behavioral dysregulation associated with... more Global changes in gene expression underlying circuit and behavioral dysregulation associated with cocaine addiction remain incompletely understood. Here, we show how a history of cocaine self-administration (SA) reprograms transcriptome-wide responses throughout the brain's reward circuitry at baseline and in response to context and/or cocaine re-exposure after prolonged withdrawal (WD). We assigned male mice to one of six groups: saline/cocaine SA + 24-hour WD or saline/cocaine SA + 30-day WD + an acute saline/cocaine challenge within the previous drug-paired context. RNA sequencing was conducted on six interconnected brain reward regions. Using pattern analysis of gene expression and factor analysis of behavior, we identified genes that are strongly associated with addiction-related behaviors and uniquely altered by a history of cocaine SA. We then identified potential upstream regulators of these genes. We focused on three patterns of gene expression that reflect responses to...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 6, 2016
ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation o... more ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate thatBaz1b, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression ofBaz1b, along with its associated subunitSmarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 16, 2015
Depression and anxiety disorders are more prevalent in females, but the majority of research in a... more Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences was DNA methyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levels were increased in the NAc of depressed humans, an effect seen in both males and females. Local overexpression of Dnmt3a in NAc rendered male mice more suscepti...
Improved treatment for major depressive disorder (MDD) remains elusive because of the limited und... more Improved treatment for major depressive disorder (MDD) remains elusive because of the limited understanding of its underlying biological mechanisms. It is likely that stress-induced maladaptive transcriptional regulation in limbic neural circuits contributes to the development of MDD, possibly through epigenetic factors that regulate chromatin structure. We establish that persistent upregulation of the ACF (ATP-utilizing chromatin assembly and remodeling factor) ATP-dependent chromatin-remodeling complex, occurring in the nucleus accumbens of stress-susceptible mice and depressed humans, is necessary for stress-induced depressive-like behaviors. We found that altered ACF binding after chronic stress was correlated with altered nucleosome positioning, particularly around the transcription start sites of affected genes. These alterations in ACF binding and nucleosome positioning were associated with repressed expression of genes implicated in susceptibility to stress. Together, our fi...
Electrolytic lesions to the amygdala, a limbic structure implicated in stress-related behaviors a... more 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 GABAAreceptor 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 LT...
IL-1β is a proinflammatory cytokine that contributes to psychological stress responses and has be... more IL-1β is a proinflammatory cytokine that contributes to psychological stress responses and has been implicated in various psychiatric disorders most notably depression. Preclinical studies also demonstrate that IL-1β modulates anxiety-and fear-related behaviors, although these findings are difficult to assess because IL-1β infusions influence locomotor activity and nociception. Here we demonstrate that IL-1RI null mice exhibit a behavioral phenotype consistent with a decrease in anxiety-related behaviors. This includes significant effects in the elevated plus maze, light-dark, and novelty-induced hypophagia tests compared to wild-type mice, with no differences in locomotor activity. With regard to fear conditioning, IL-1RI null mice showed more freezing in auditory and contextual fear conditioning tests, and there was no effect on pain sensitivity. Taken together, the results indicate that the IL-1β/IL-1RI signaling pathway induces anxiety-related behaviors and impairs fear memory.
DFosB, a FosB gene product, is induced in the prefrontal cortex (PFC) by repeated exposure to sev... more DFosB, a FosB gene product, is induced in the prefrontal cortex (PFC) by repeated exposure to several stimuli including antipsychotic drugs such as haloperidol. However, the functional consequences of increased DFosB expression following antipsychotic treatment have not been explored. Here, we assessed whether DFosB induction by haloperidol mediates the positive or negative consequences or clinical-related actions of antipsychotic treatment. We show that individuals with schizophrenia who were medicated with antipsychotic drugs at their time of death display increased DFosB levels in the PFC, an effect that is replicated in rats treated chronically with haloperidol. In contrast, individuals with schizophrenia who were medication-free did not exhibit this effect. Viral-mediated overexpression of DFosB in the PFC of rodents induced cognitive deficits as measured by inhibitory avoidance, increased startle responses in prepulse inhibition tasks, and increased MK-801-induced anxiety-like behaviors. Together, these results suggest that DFosB induction in the PFC by antipsychotic treatment contributes to the deleterious effects of these drugs and not to their therapeutic actions.
Proceedings of the National Academy of Sciences, 2014
Significance We demonstrate that chronic cocaine, including cocaine self-administration, induces ... more Significance We demonstrate that chronic cocaine, including cocaine self-administration, induces poly(ADP-ribose) polymerase-1 (PARP-1) in the nucleus accumbens (NAc). Using a combination of viral-mediated gene transfer and pharmacological tools, we show that upregulation of PARP-1 in NAc dramatically enhances behavioral responses to cocaine, whereas downregulation of PARP-1 has the opposite effect. We used chromatin immunoprecipitation sequencing to map genome-wide binding of PARP-1 in NAc. The data demonstrate upregulation of PARP-1 binding across the genome after cocaine administration and identify numerous target genes for PARP-1. Among these is sidekick-1 (SDK1), previously implicated in regulating synaptic connections during development. We confirm SDK1 induction in NAc after chronic cocaine and demonstrate its ability to promote both cocaine’s behavioral effects and induction of dendritic plasticity in NAc.
Regulating Opioid Responses Different drugs of abuse are thought to highjack similar reward syste... more Regulating Opioid Responses Different drugs of abuse are thought to highjack similar reward systems in the brain using common mechanisms. However, Koo et al. (p. 124 ) now observe that some of the neural mechanisms that regulate opiate reward can be both different and even opposite to those that regulate reward by stimulant drugs. While knockdown of brain-derived neurotrophic factor (BDNF) in the ventral tegmental area in mice antagonized the response to cocaine, the same manipulation strengthened the potential of opiates to increase dopamine neuron excitability. Optogenetic stimulation of dopaminergic terminals in the nucleus accumbens could counteract the effects of BDNF on morphine reward blockade.
Background-Previous work has shown that chronic social defeat stress (CSDS) induces increased pha... more Background-Previous work has shown that chronic social defeat stress (CSDS) induces increased phasic firing of ventral tegmental area (VTA) dopamine neurons that project to the nucleus accumbens (NAc) selectively in mice that are susceptible to the deleterious effects of the stress. In addition, acute optogenetic phasic stimulation of these neurons promotes susceptibility in animals exposed to acute defeat stress. These findings are paradoxical since increased dopamine (DA) signaling in NAc normally promotes motivation and reward, and the influence of chronic phasic VTA firing in the face of chronic stress remains unknown. Methods-We used CSDS with repeated optogenetic activation and pharmacological manipulations of the mesolimbic VTA-NAc pathway to examine the role of brain-derived neurotrophic factor (BDNF) and DA signaling in depressive-like behaviors. BDNF protein expression and DA release were measured in this model. Results-Pharmacological blockade of BDNF-TrkB signaling, but not DA signaling, in NAc prevented CSDS-induced behavioral abnormalities. Chronic optogenetic phasic stimulation of the VTA-NAc circuit during CSDS exacerbated the defeat-induced behavioral symptoms, and these aggravated symptoms were also normalized by BDNF-TrkB blockade in NAc. The aggravated
In the fear conditioning literature, it is generally hypothesized that neurons in the basolateral... more In the fear conditioning literature, it is generally hypothesized that neurons in the basolateral amygdalar complex (BLA) (lateral and basal nuclei) support the formation of conditioned fear memory and project to neurons in the central nucleus (CeA) for the expression of conditioned fear responses. According to this serial processing-transmission view, damage to either BLA or CeA would comparably disrupt the expression of a variety of conditioned fear responses. In the present study, we further investigated the roles of BLA and CeA in fear conditioning by concurrently assessing freezing and 22 kHz ultrasonic vocalization (USV) as dependent measures of fear in rats. Selective neurotoxins, NMDA for the BLA and ibotenic acid for the CeA, were used to destroy intrinsic neurons [evidenced by thionin dye and NeuN (neuronal nuclei) antibody stainings] without damaging the fibers of passage (confirmed by myelin staining). During the 10 tone-footshock paired training, postshock freezing and ...
Often called the second brain, the gut communicates extensively with the brain and vice versa. Th... more Often called the second brain, the gut communicates extensively with the brain and vice versa. The conversation between these two organs affects a variety of physiological mechanisms that are associated with our mental health. Over the past decade, a growing body of evidence has suggested that the gut microbiome builds a unique ecosystem inside the gastrointestinal tract to maintain the homeostasis and that compositional changes in the gut microbiome are highly correlated with several mental disorders. There are ongoing efforts to treat or prevent mental disorders by regulating the gut microbiome using probiotics. These attempts are based on the seminal findings that probiotics can control the gut microbiome and affect mental conditions. However, some issues have yet to be conclusively addressed, especially the causality between the gut microbiome and mental disorders. In this review, we focus on the mechanisms by which the gut microbiome affects mental health and diseases. Furthermore, we discuss the potential use of probiotics as therapeutic agents for psychiatric disorders.
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Papers by Ja Wook Koo