ABSTRACTRapid-eye-movement sleep (REMs) is characterized by activated electroencephalogram (EEG) ... more ABSTRACTRapid-eye-movement sleep (REMs) is characterized by activated electroencephalogram (EEG) and muscle atonia, accompanied by vivid dreams. REMs is homeostatically regulated, ensuring that any loss of REMs is compensated by a subsequent increase in its amount. However, the neural mechanisms underlying the homeostatic control of REMs are largely unknown. Here, we show that GABAergic neurons in the preoptic area of the hypothalamus projecting to the tuberomammillary nucleus (POAGAD2→TMN neurons) are crucial for the homeostatic regulation of REMs. POAGAD2→TMN neurons are most active during REMs, and inhibiting them specifically decreases REMs. REMs restriction leads to an increased number and amplitude of calcium transients in POAGAD2→TMN neurons, reflecting the accumulation of REMs pressure. Inhibiting POAGAD2→TMN neurons during REMs restriction blocked the subsequent rebound of REMs. Our findings reveal a hypothalamic circuit whose activity mirrors the buildup of homeostatic REM...
Additional file 4: Table S2. List of 526 DEGs with FDR adjusted p-value cutoffs of 0.05 correspon... more Additional file 4: Table S2. List of 526 DEGs with FDR adjusted p-value cutoffs of 0.05 corresponding to genes presented in heatmap format in Fig. 1b according to their log2L/R values.
Additional file 5: Table S3. Comparison of averaged expression values of DEGs between the two mPF... more Additional file 5: Table S3. Comparison of averaged expression values of DEGs between the two mPFC hemispheres, presented in dot plot format in Fig. 1c.
Additional file 6: Table S4. The 526 genes exhibiting laterality listed, according to their log2L... more Additional file 6: Table S4. The 526 genes exhibiting laterality listed, according to their log2L/R values. Laterality genes with positive values are expressed more highly in the left mPFC, and those with negative values are expressed more highly in the right mPFC. The genes used in rank order analysis in Fig. 1e.
Additional file 8: Table S6. GO analysis using GeneMANIA. Genes with leftward or rightward latera... more Additional file 8: Table S6. GO analysis using GeneMANIA. Genes with leftward or rightward laterality were used as input to GeneMANIA, and the associated GO terms were reported.
Additional file 7: Table S5. Differences in the expression of the housekeeping genes, Actb(b-acti... more Additional file 7: Table S5. Differences in the expression of the housekeeping genes, Actb(b-actin), Gapdh(glyceraldehyde-3-phosphate dehydrogenase), B2m ((b2microglobinbetween control and resilient/susceptible mice, summarized as log2FC values and p-values for each gene.
Additional file 3: Table S1. Analysis of DEGs in the two hemispheres of the mPFC in mice with soc... more Additional file 3: Table S1. Analysis of DEGs in the two hemispheres of the mPFC in mice with social defeat stress versus non-stressed mice. Significant DEGs with a FDR adjusted p-value cutoff of 0.05 are shown. AveExpr, averaged expression of microarray genes; t, moderated t-statistic; B, B-statistic.
Additional file 1: Figure S1. Sample preparation for microarrays. a. The distribution of control ... more Additional file 1: Figure S1. Sample preparation for microarrays. a. The distribution of control and socially defeated mice depending on their sociability index (SI). Resilient mice (defined as those exhibiting SI greater than 1) were highly sociable, whereas susceptible mice (defined as those exhibiting SI scores less than 1) were social avoidant. Non-stressed, control mice from social interaction tests showed similar distribution of SI with resilient as previously described [17]. The average SI values for non-defeat control, resilient, and susceptible mice were 1.5, 1.5, and 0.8, respectively. b. The SI values of mice that were selected for the microarray analysis. The average SI of the selected mice were 1.76 (n = 8), 1.61 (n = 8), and 0.5 (n = 7) for the control, resilient, and susceptible groups, respectively. c. Full list of the SI values of the mice used in the microarray analysis.
Additional file 2: Figure S2. RT-qPCR confirmation of lateralized genes, categorized according to... more Additional file 2: Figure S2. RT-qPCR confirmation of lateralized genes, categorized according to hemispheric dominance. Changes in the expression levels of left- and right-dominant genes were confirmed by RT-qPCR analysis. a. The Gapdh-normalized expression of the left-dominant genes, Cux2 and Wfs1, in the mPFC, presented as a bar graph. The expression levels of Cux2 and Wfs1 were higher in the left mPFC of susceptible mice, while the levels of these genes were similar in the left and right mPFC of non-stressed and resilient mice. b. The Gapdh-normalized expression of the right-dominant genes, Ctgf, Mbp, and Rprm, in the mPFC. The expression levels of Ctgf, Mbp, and Rprm were higher in the right mPFC of susceptible mice, while the levels of these genes were similar between the left and right mPFC of non-stressed and resilient mice. c. The left/right (L/R) expression ratios of the left-dominant genes, Cux2 and Wfs1, in the mPFC, presented as a bar graph. The ratios of Cux2 and Wfs1 ...
Functional lateralization of the prefrontal cortex has been implicated in stress and emotional di... more Functional lateralization of the prefrontal cortex has been implicated in stress and emotional disorders, yet underlying gene expression changes remains unknown. Here, we report molecular signatures lateralized by chronic social defeats between the two medial prefrontal cortices (mPFCs). Stressed mice show 526 asymmetrically expressed genes between the mPFCs. This cortical asymmetry selectively occurs in stressed mice with depressed social activity, but not in resilient mice with normal behavior. We have isolated highly asymmetric genes including connective tissue growth factor (CTGF), a molecule that modulates wound healing at the periphery. Knockdown of CTGF gene in the right mPFC by shRNA led to a stress-resistant behavioral phenotype. Overexpression of CTGF in the right mPFC using viral transduction induces social avoidance while the left mPFC thereof prevent stress-induced social avoidance. Our study provides a molecular window into the mechanism of stress-induced socioemotiona...
A salient feature of mammalian sleep is the alternation between rapid eye movement (REM) and non-... more A salient feature of mammalian sleep is the alternation between rapid eye movement (REM) and non-REM (NREM) sleep. However, how these two sleep stages influence each other and thereby regulate the timing of REM sleep episodes is still largely unresolved. Here, we developed a statistical model that specifies the relationship between REM and subsequent NREM sleep to quantify how REM sleep affects the following NREM sleep duration and its electrophysiological features in mice. We show that a lognormal mixture model well describes how the preceding REM sleep duration influences the amount of NREM sleep till the next REM sleep episode. The model supports the existence of two different types of sleep cycles: Short cycles form closely interspaced sequences of REM sleep episodes, whereas during long cycles, REM sleep is first followed by an interval of NREM sleep during which transitions to REM sleep are extremely unlikely. This refractory period is characterized by low power in the theta a...
In the version of this article initially published, a sentence in the fifth paragraph of the Resu... more In the version of this article initially published, a sentence in the fifth paragraph of the Results read, "Immunohistochemistry revealed that VGLUT2 MPA neurons rarely expressed CaMKIIα, which is a putative marker for subcortical glutamatergic neurons." It should have read, "Immunohistochemistry revealed that CaMKIIα MPA neurons rarely expressed VGLUT2, which is a putative marker for subcortical glutamatergic neurons." The error has been corrected in the HTML and PDF versions of the article. In the supplementary information originally posted online, the wrong version of Supplementary Fig. 1 was posted and some of the supplementary videos were interchanged. In the corrected Supplementary Fig. 1, the top right subpanel was added and the original Supplementary Fig. 1a was divided into 1a and 1b, with subsequent panels incremented accordingly. The legend was changed from "a. Schematic illustrating electrical lesioning of the rat anterior hypothalamus. Electrica...
As animals forage, they must obtain useful targets by orchestrating appropriate actions that rang... more As animals forage, they must obtain useful targets by orchestrating appropriate actions that range from searching to chasing, biting and carrying. Here, we reveal that neurons positive for the α subunit of Ca/calmodulin-dependent kinase II (CaMKIIα) in the medial preoptic area (MPA) that send projections to the ventral periaqueductal gray (vPAG) mediate these target-directed actions in mice. During photostimulation of the MPA-vPAG circuit, mice vigorously engaged with 3D objects and chased moving objects. When exposed to a cricket, they hunted down the prey and bit it to kill. By applying a head-mounted object control with timely photostimulation of the MPA-vPAG circuit, we found that MPA-vPAG circuit-induced actions occurred only when the target was detected within the binocular visual field. Using this device, we successfully guided mice to navigate specified routes. Our study explains how the brain yields a strong motivation to acquire a target object along the continuum of hunti...
The infralimbic cortex (IL) is known to facilitate the formation of extinction memory through rec... more The infralimbic cortex (IL) is known to facilitate the formation of extinction memory through reciprocal interactions with the amygdala, which produces fear responses such as freezing. Thus, whether presynaptic input from the amygdala and post-synaptic output of IL neurons are functionally dissociated in extinction memory formation remains unclear. Here, we demonstrated that photostimulation of IL inputs from BLA did not change freezing responses to conditioned stimuli (CS) during training, but did facilitate extinction memory, measured as a reduction in freezing responses to the CS 1 day later. On the other hand, photostimulation of somata of IL neurons induced an immediate reduction in freezing to CS, but this did not affect extinction memory tested the next day. These results provide in vivo evidence for IL-dependent facilitation of extinction memory without post-synaptic modulation of freezing circuits.
Myelination in corpus callosum plays important role for normal brain functions by transferring ne... more Myelination in corpus callosum plays important role for normal brain functions by transferring neurological information between various brain regions. However, the factors controlling expression of myelin genes in myelination are poorly understood. Here, CXXC5, a recently identified protein with CXXC-type zinc finger DNA binding motif, was characterized as a transcriptional activator of major myelin genes. We identified expression of CXXC5 expression was increased by Wnt/β-catenin signaling. CXXC5 specifically expressed in the white matter induced expression of myelin genes through the direct binding of CXXC DNA-binding motif of CXXC5 on the MBP promoter. During the differentiation of neural stem cells (NSCs) of CXXC5(-/-) mice, the expressions of myelin genes were simultaneously reduced. The CXXC5(-/-) mice exhibited severely reduction of myelin genes expression in corpus callosum as well as abnormalities in myelin structure. The disrupted structural integrity of myelin in the CXXC5(-/-) mice resulted in reduced electrical conduction amplitudes at corpus callosum. These findings indicate that the regulation of myelin genes expression by CXXC5 is important for forming myelin structure involved with axonal electrical signal transfer in the corpus callosum. GLIA 2015.
What is already known • Several animal and clinical studies suggest that the neurotoxic effects o... more What is already known • Several animal and clinical studies suggest that the neurotoxic effects of anesthesia during neurodevelopment may lead to neurodevelopmental impairments.
When subjected to stress, some individuals develop maladaptive symptoms whereas others retain nor... more When subjected to stress, some individuals develop maladaptive symptoms whereas others retain normal behavior. The medial prefrontal cortex (mPFC) is known to control these adaptive responses to stress. Here, we show that mPFC neurons in the left hemisphere control stress effects on social behavior. Mice made socially avoidant by the stress of chronic social defeats showed depressed neural activity in the left mPFC. Photoactivation of these neurons reversed social avoidance and restored social activity. Despite social defeats, resilient mice with normal sociability showed normal firing rates in the left mPFC; however, photoinhibition of these neurons induced social avoidance. The same photomodulation administered to the right mPFC caused no significant effects. These results explain how stressed individuals develop maladaptive behaviors through left cortical depression, as reported in mood and anxiety disorders.
ABSTRACTRapid-eye-movement sleep (REMs) is characterized by activated electroencephalogram (EEG) ... more ABSTRACTRapid-eye-movement sleep (REMs) is characterized by activated electroencephalogram (EEG) and muscle atonia, accompanied by vivid dreams. REMs is homeostatically regulated, ensuring that any loss of REMs is compensated by a subsequent increase in its amount. However, the neural mechanisms underlying the homeostatic control of REMs are largely unknown. Here, we show that GABAergic neurons in the preoptic area of the hypothalamus projecting to the tuberomammillary nucleus (POAGAD2→TMN neurons) are crucial for the homeostatic regulation of REMs. POAGAD2→TMN neurons are most active during REMs, and inhibiting them specifically decreases REMs. REMs restriction leads to an increased number and amplitude of calcium transients in POAGAD2→TMN neurons, reflecting the accumulation of REMs pressure. Inhibiting POAGAD2→TMN neurons during REMs restriction blocked the subsequent rebound of REMs. Our findings reveal a hypothalamic circuit whose activity mirrors the buildup of homeostatic REM...
Additional file 4: Table S2. List of 526 DEGs with FDR adjusted p-value cutoffs of 0.05 correspon... more Additional file 4: Table S2. List of 526 DEGs with FDR adjusted p-value cutoffs of 0.05 corresponding to genes presented in heatmap format in Fig. 1b according to their log2L/R values.
Additional file 5: Table S3. Comparison of averaged expression values of DEGs between the two mPF... more Additional file 5: Table S3. Comparison of averaged expression values of DEGs between the two mPFC hemispheres, presented in dot plot format in Fig. 1c.
Additional file 6: Table S4. The 526 genes exhibiting laterality listed, according to their log2L... more Additional file 6: Table S4. The 526 genes exhibiting laterality listed, according to their log2L/R values. Laterality genes with positive values are expressed more highly in the left mPFC, and those with negative values are expressed more highly in the right mPFC. The genes used in rank order analysis in Fig. 1e.
Additional file 8: Table S6. GO analysis using GeneMANIA. Genes with leftward or rightward latera... more Additional file 8: Table S6. GO analysis using GeneMANIA. Genes with leftward or rightward laterality were used as input to GeneMANIA, and the associated GO terms were reported.
Additional file 7: Table S5. Differences in the expression of the housekeeping genes, Actb(b-acti... more Additional file 7: Table S5. Differences in the expression of the housekeeping genes, Actb(b-actin), Gapdh(glyceraldehyde-3-phosphate dehydrogenase), B2m ((b2microglobinbetween control and resilient/susceptible mice, summarized as log2FC values and p-values for each gene.
Additional file 3: Table S1. Analysis of DEGs in the two hemispheres of the mPFC in mice with soc... more Additional file 3: Table S1. Analysis of DEGs in the two hemispheres of the mPFC in mice with social defeat stress versus non-stressed mice. Significant DEGs with a FDR adjusted p-value cutoff of 0.05 are shown. AveExpr, averaged expression of microarray genes; t, moderated t-statistic; B, B-statistic.
Additional file 1: Figure S1. Sample preparation for microarrays. a. The distribution of control ... more Additional file 1: Figure S1. Sample preparation for microarrays. a. The distribution of control and socially defeated mice depending on their sociability index (SI). Resilient mice (defined as those exhibiting SI greater than 1) were highly sociable, whereas susceptible mice (defined as those exhibiting SI scores less than 1) were social avoidant. Non-stressed, control mice from social interaction tests showed similar distribution of SI with resilient as previously described [17]. The average SI values for non-defeat control, resilient, and susceptible mice were 1.5, 1.5, and 0.8, respectively. b. The SI values of mice that were selected for the microarray analysis. The average SI of the selected mice were 1.76 (n = 8), 1.61 (n = 8), and 0.5 (n = 7) for the control, resilient, and susceptible groups, respectively. c. Full list of the SI values of the mice used in the microarray analysis.
Additional file 2: Figure S2. RT-qPCR confirmation of lateralized genes, categorized according to... more Additional file 2: Figure S2. RT-qPCR confirmation of lateralized genes, categorized according to hemispheric dominance. Changes in the expression levels of left- and right-dominant genes were confirmed by RT-qPCR analysis. a. The Gapdh-normalized expression of the left-dominant genes, Cux2 and Wfs1, in the mPFC, presented as a bar graph. The expression levels of Cux2 and Wfs1 were higher in the left mPFC of susceptible mice, while the levels of these genes were similar in the left and right mPFC of non-stressed and resilient mice. b. The Gapdh-normalized expression of the right-dominant genes, Ctgf, Mbp, and Rprm, in the mPFC. The expression levels of Ctgf, Mbp, and Rprm were higher in the right mPFC of susceptible mice, while the levels of these genes were similar between the left and right mPFC of non-stressed and resilient mice. c. The left/right (L/R) expression ratios of the left-dominant genes, Cux2 and Wfs1, in the mPFC, presented as a bar graph. The ratios of Cux2 and Wfs1 ...
Functional lateralization of the prefrontal cortex has been implicated in stress and emotional di... more Functional lateralization of the prefrontal cortex has been implicated in stress and emotional disorders, yet underlying gene expression changes remains unknown. Here, we report molecular signatures lateralized by chronic social defeats between the two medial prefrontal cortices (mPFCs). Stressed mice show 526 asymmetrically expressed genes between the mPFCs. This cortical asymmetry selectively occurs in stressed mice with depressed social activity, but not in resilient mice with normal behavior. We have isolated highly asymmetric genes including connective tissue growth factor (CTGF), a molecule that modulates wound healing at the periphery. Knockdown of CTGF gene in the right mPFC by shRNA led to a stress-resistant behavioral phenotype. Overexpression of CTGF in the right mPFC using viral transduction induces social avoidance while the left mPFC thereof prevent stress-induced social avoidance. Our study provides a molecular window into the mechanism of stress-induced socioemotiona...
A salient feature of mammalian sleep is the alternation between rapid eye movement (REM) and non-... more A salient feature of mammalian sleep is the alternation between rapid eye movement (REM) and non-REM (NREM) sleep. However, how these two sleep stages influence each other and thereby regulate the timing of REM sleep episodes is still largely unresolved. Here, we developed a statistical model that specifies the relationship between REM and subsequent NREM sleep to quantify how REM sleep affects the following NREM sleep duration and its electrophysiological features in mice. We show that a lognormal mixture model well describes how the preceding REM sleep duration influences the amount of NREM sleep till the next REM sleep episode. The model supports the existence of two different types of sleep cycles: Short cycles form closely interspaced sequences of REM sleep episodes, whereas during long cycles, REM sleep is first followed by an interval of NREM sleep during which transitions to REM sleep are extremely unlikely. This refractory period is characterized by low power in the theta a...
In the version of this article initially published, a sentence in the fifth paragraph of the Resu... more In the version of this article initially published, a sentence in the fifth paragraph of the Results read, "Immunohistochemistry revealed that VGLUT2 MPA neurons rarely expressed CaMKIIα, which is a putative marker for subcortical glutamatergic neurons." It should have read, "Immunohistochemistry revealed that CaMKIIα MPA neurons rarely expressed VGLUT2, which is a putative marker for subcortical glutamatergic neurons." The error has been corrected in the HTML and PDF versions of the article. In the supplementary information originally posted online, the wrong version of Supplementary Fig. 1 was posted and some of the supplementary videos were interchanged. In the corrected Supplementary Fig. 1, the top right subpanel was added and the original Supplementary Fig. 1a was divided into 1a and 1b, with subsequent panels incremented accordingly. The legend was changed from "a. Schematic illustrating electrical lesioning of the rat anterior hypothalamus. Electrica...
As animals forage, they must obtain useful targets by orchestrating appropriate actions that rang... more As animals forage, they must obtain useful targets by orchestrating appropriate actions that range from searching to chasing, biting and carrying. Here, we reveal that neurons positive for the α subunit of Ca/calmodulin-dependent kinase II (CaMKIIα) in the medial preoptic area (MPA) that send projections to the ventral periaqueductal gray (vPAG) mediate these target-directed actions in mice. During photostimulation of the MPA-vPAG circuit, mice vigorously engaged with 3D objects and chased moving objects. When exposed to a cricket, they hunted down the prey and bit it to kill. By applying a head-mounted object control with timely photostimulation of the MPA-vPAG circuit, we found that MPA-vPAG circuit-induced actions occurred only when the target was detected within the binocular visual field. Using this device, we successfully guided mice to navigate specified routes. Our study explains how the brain yields a strong motivation to acquire a target object along the continuum of hunti...
The infralimbic cortex (IL) is known to facilitate the formation of extinction memory through rec... more The infralimbic cortex (IL) is known to facilitate the formation of extinction memory through reciprocal interactions with the amygdala, which produces fear responses such as freezing. Thus, whether presynaptic input from the amygdala and post-synaptic output of IL neurons are functionally dissociated in extinction memory formation remains unclear. Here, we demonstrated that photostimulation of IL inputs from BLA did not change freezing responses to conditioned stimuli (CS) during training, but did facilitate extinction memory, measured as a reduction in freezing responses to the CS 1 day later. On the other hand, photostimulation of somata of IL neurons induced an immediate reduction in freezing to CS, but this did not affect extinction memory tested the next day. These results provide in vivo evidence for IL-dependent facilitation of extinction memory without post-synaptic modulation of freezing circuits.
Myelination in corpus callosum plays important role for normal brain functions by transferring ne... more Myelination in corpus callosum plays important role for normal brain functions by transferring neurological information between various brain regions. However, the factors controlling expression of myelin genes in myelination are poorly understood. Here, CXXC5, a recently identified protein with CXXC-type zinc finger DNA binding motif, was characterized as a transcriptional activator of major myelin genes. We identified expression of CXXC5 expression was increased by Wnt/β-catenin signaling. CXXC5 specifically expressed in the white matter induced expression of myelin genes through the direct binding of CXXC DNA-binding motif of CXXC5 on the MBP promoter. During the differentiation of neural stem cells (NSCs) of CXXC5(-/-) mice, the expressions of myelin genes were simultaneously reduced. The CXXC5(-/-) mice exhibited severely reduction of myelin genes expression in corpus callosum as well as abnormalities in myelin structure. The disrupted structural integrity of myelin in the CXXC5(-/-) mice resulted in reduced electrical conduction amplitudes at corpus callosum. These findings indicate that the regulation of myelin genes expression by CXXC5 is important for forming myelin structure involved with axonal electrical signal transfer in the corpus callosum. GLIA 2015.
What is already known • Several animal and clinical studies suggest that the neurotoxic effects o... more What is already known • Several animal and clinical studies suggest that the neurotoxic effects of anesthesia during neurodevelopment may lead to neurodevelopmental impairments.
When subjected to stress, some individuals develop maladaptive symptoms whereas others retain nor... more When subjected to stress, some individuals develop maladaptive symptoms whereas others retain normal behavior. The medial prefrontal cortex (mPFC) is known to control these adaptive responses to stress. Here, we show that mPFC neurons in the left hemisphere control stress effects on social behavior. Mice made socially avoidant by the stress of chronic social defeats showed depressed neural activity in the left mPFC. Photoactivation of these neurons reversed social avoidance and restored social activity. Despite social defeats, resilient mice with normal sociability showed normal firing rates in the left mPFC; however, photoinhibition of these neurons induced social avoidance. The same photomodulation administered to the right mPFC caused no significant effects. These results explain how stressed individuals develop maladaptive behaviors through left cortical depression, as reported in mood and anxiety disorders.
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