Recovery from Posttraumatic Stress Requires Dynamic and Sequential Shifts in Amygdalar Connectivities

Yoon, Sujung,Kim, Jieun E,Hwang, Jaeuk,Kang, Ilhyang,Jeon, Saerom,Im, Jooyeon J,Kim, Bori R,Lee, Sunho,Kim, Geon Ha,Rhim, Hyewhon,Lim, Soo Mee,Lyoo, In Kyoon American College of Neuropsychopharmacology 2017 Neuropsychopharmacology Vol.42 No.2

<P>The neural mechanisms underlying the development and maintenance of posttraumatic stress disorder (PTSD) have long been studied. However, little is known about the neural correlates of the recovery process from PTSD. A 5-year longitudinal study was conducted to investigate the trajectory of structural connectivities of the amygdala in disaster survivors with PTSD. Thirty disaster survivors, who were diagnosed with PTSD, and 29 healthy individuals, who were not exposed to trauma, underwent three waves of assessments including neuroimaging scanning over a 5-year period from the time of the disaster at approximately 1.3-year intervals. All disaster survivors showed significant improvements in PTSD symptoms over time. Using diffusion tensor imaging analysis, a 5-year trajectory of amygdalar structural connectivities with key brain regions was assessed. The amygdala insula connection was initially strengthened and then normalized during recovery, while the amygdala prefrontal cortex (PFC) connection was at first unaffected, then strengthened, and eventually normalized. The lower tract strength of the amygdala thalamus connection normalized during recovery, while that of amygdala hippocampus connection remained low. The greater amygdala PFC connectivity was associated with less PTSD symptom severity. The present longitudinal study revealed that recovery from PTSD parallels dynamic and sequential shifts in amygdalar connectivities with multiple brain regions, suggesting the expanded view of fear circuitry including the insula and-thalamus, beyond the traditional model which primarily involves the amygdala, PFC, and hippocampus.</P>

Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Choi, Yoori,Kim, Hye-Sun,Shin, Ki Young,Kim, Eun-Mee,Kim, Minji,Kim, Hyun-Soo,Park, Cheol Hyoung,Jeong, Yun Ha,Yoo, Jongman,Lee, Jean-Pyo,Chang, Keun-A,Kim, Seonghan,Suh, Yoo-Hun American College of Neuropsychopharmacology 2007 Neuropsychopharmacology Vol.32 No.11

Minocycline is a semi-synthetic tetracycline antibiotic that effectively crosses the blood–brain barrier. Minocycline has been reported to have significant neuroprotective effects in models of cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. In this study, we demonstrate that minocycline has neuroprotective effects in in vitro and in vivo Alzheimer's disease models. Minocycline was found to attenuate the increases in the phosphorylation of double-stranded RNA-dependent serine/threonine protein kinase, eukaryotic translation initiation factor-2 α and caspase 12 activation induced by amyloid β peptide<SUB>1–42</SUB> treatment in NGF-differentiated PC 12 cells. In addition, increases in the phosphorylation of eukaryotic translation initiation factor-2 α were attenuated by administration of minocycline in Tg2576 mice, which harbor mutated human APP695 gene including the Swedish double mutation and amyloid β peptide<SUB>1–42</SUB>-infused rats. We found that minocycline administration attenuated deficits in learning and memory in amyloid β peptide<SUB>1–42</SUB>-infused rats. Increased phosphorylated state of eukaryotic translation initiation factor-2 α is observed in Alzheimer's disease patients' brains and may result in impairment of cognitive functions in Alzheimer's disease patients by decreasing the efficacy of de novo protein synthesis required for synaptic plasticity. On the basis of these results, minocycline may prove to be a good candidate as an effective therapeutic agent for Alzheimer's disease.Neuropsychopharmacology (2007) 32, 2393–2404; doi:10.1038/sj.npp.1301377; published online 4 April 2007

Effect of Ginseng Saponins on Enhanced Dopaminergic Transmission and Locomotor Hyperactivity Induced by Nicotine

Kim, Sang Eun,Shim, Insop,Chung, June-Key,Lee, Myung Chul American College of Neuropsychopharmacology 2006 Neuropsychopharmacology Vol.31 No.8

Several studies have shown that behavioral hyperactivity induced by psychomotor stimulants is prevented by ginseng saponins. In an attempt to investigate whether the effect of ginseng saponins is through their inhibitory action on the enhanced dopaminergic transmission by psychomotor stimulants, we examined the effects of ginseng total saponin (GTS) presynaptically on nicotine-induced dopamine (DA) release in the striatum of freely moving rats using in vivo microdialysis technique and postsynaptically on the in vitro and in vivo binding of [<SUP>3</SUP>H]raclopride to DA D<SUB>2</SUB> receptors. Also, we examined the effects of GTS on nicotine-induced locomotor hyperactivity and on nicotine-induced Fos protein expression in the nucleus accumbens and striatum. Systemic pretreatment with GTS (100 and 400 mg/kg, intraperitoneally (i.p.)) resulted in a dose-dependent inhibition of locomotor hyperactivity induced by nicotine. GTS decreased nicotine-induced DA release in the striatum in a dose-dependent manner. However, GTS had no effects on resting levels of locomotor activity and extracellular DA in the striatum. GTS inhibited the in vitro binding of [<SUP>3</SUP>H]raclopride to rat striatal membranes with an IC<SUB>50</SUB> of 5.14±1.09 μM. High doses of GTS (400 and 800 mg/kg, i.p.) resulted in decreases in the in vivo binding of [<SUP>3</SUP>H]raclopride in the striatum. GTS decreased nicotine-induced Fos protein expression in the nucleus accumbens and striatum, reflecting the inhibition by GTS of nicotine-induced enhancement of dopaminergic transmission. The results of the present study suggest that GTS acts not only on dopaminergic neurons directly or indirectly to prevent nicotine-induced DA release but also postsynaptically by binding to DA D<SUB>2</SUB> receptors. This may explain the blocking effect of GTS on behavioral activation induced by nicotine and conceivably by other psychostimulants. Our data raise the possibility that GTS, by attenuating nicotine-induced enhancement of dopaminergic transmission, may prove to be a useful therapeutic agent for nicotine addiction and warrant further investigation on its effect on nicotine's rewarding property.Neuropsychopharmacology (2006) 31, 1714–1721. doi:10.1038/sj.npp.1300945; published online 26 October 2005

Cerebellar Gray Matter Volume Correlates with Duration of Cocaine Use in Cocaine-Dependent Subjects

Sim, Minyoung E,Lyoo, In Kyoon,Streeter, Chris C,Covell, Julie,Sarid-Segal, Ofra,Ciraulo, Domenic A,Kim, Minue J,Kaufman, Marc J,Yurgelun-Todd, Deborah A,Renshaw, Perry F American College of Neuropsychopharmacology 2007 Neuropsychopharmacology Vol.32 No.10

This study was conducted to explore differences in gray and white matter volume between cocaine-dependent and healthy comparison subjects using optimized voxel-based morphometry (VBM). Brain magnetic resonance imaging (MRI) and neuropsychological function tests were performed for 40 cocaine-dependent subjects (41.4±6.9 years, 27 men) and 41 healthy age- and sex-matched comparison subjects (38.7±8.8 years, 26 men). Optimally normalized whole brain MR images were segmented, modulated, smoothed, and compared between groups with statistical parametric mapping. The cocaine-dependent group had lower gray matter volumes in bilateral premotor cortex (Brodmann area (BA) 6, 8; 16.6%), right orbitofrontal cortex (BA 10, 15.1%), bilateral temporal cortex (BA 20, 38; 15.9%), left thalamus (12.6%), and bilateral cerebellum (13.4%) as well as lower right cerebellar white matter volume (10.0%) relative to the comparison group at a corrected p<0.05 for multiple comparisons. Duration of cocaine use negatively correlated with right and left cerebellar gray matter volumes (r=−0.37, r=−0.39, respectively). In cocaine-dependent subjects, lower cerebellar hemispheric gray and white matter volumes were correlated with deficits in executive function and decreased motor performance. This study reports that cocaine-dependent subjects have lower gray matter volumes in cerebellar hemispheres as well as in frontal, temporal cortex, and thalamus. These findings are the first to suggest that the cerebellum may be vulnerable to cocaine-associated brain volume changes, and that cerebellar deficits may contribute to neuropsychological deficits and motor dysfunction frequently observed in cocaine-dependent subjects.Neuropsychopharmacology (2007) 32, 2229–2237; doi:10.1038/sj.npp.1301346; published online 14 February 2007

Decreased Glutamate/Glutamine Levels May Mediate Cytidine’s Efficacy in Treating Bipolar Depression: A Longitudinal Proton Magnetic Resonance Spectroscopy Study

Yoon, Sujung J,Lyoo, In Kyoon,Haws, Charlotte,Kim, Tae-Suk,Cohen, Bruce M,Renshaw, Perry F American College of Neuropsychopharmacology 2009 Neuropsychopharmacology Vol.34 No.7

Targeting the glutamatergic system has been suggested as a promising new option for developing treatment strategies for bipolar depression. Cytidine, a pyrimidine, may exert therapeutic effects through a pathway that leads to altered neuronal-glial glutamate cycling. Pyrimidines are also known to exert beneficial effects on cerebral phospholipid metabolism, catecholamine synthesis, and mitochondrial function, which have each been linked to the pathophysiology of bipolar depression. This study was aimed at determining cytidine’s efficacy in bipolar depression and at assessing the longitudinal effects of cytidine on cerebral glutamate/glutamine levels. Thirty-five patients with bipolar depression were randomly assigned to receive the mood-stabilizing drug valproate plus either cytidine or placebo for 12 weeks. Midfrontal cerebral glutamate/glutamine levels were measured using proton magnetic resonance spectroscopy before and after 2, 4, and 12 weeks of oral cytidine administration. Cytidine supplementation was associated with an earlier improvement in depressive symptoms (weeks 1–4; p=0.02, 0.001, 0.002, and 0.004, respectively) and also produced a greater reduction in cerebral glutamate/glutamine levels in patients with bipolar depression (weeks 2, 4, and 12; p=0.004, 0.004, and 0.02, respectively). Cytidine-related glutamate/glutamine decrements correlated with a reduction in depressive symptoms (p=0.001). In contrast, these relationships were not observed in the placebo add-on group. The study results suggest that cytidine supplementation of valproate is associated with an earlier treatment response in bipolar depression. Furthermore, cytidine’s efficacy in bipolar depression may be mediated by decreased levels of cerebral glutamate and/or glutamine, consistent with alterations in excitatory neurotransmission.Neuropsychopharmacology (2009) 34, 1810–1818; doi:10.1038/npp.2009.2; published online 4 February 2009

Regional Cortical Thickness and Subcortical Volume Changes Are Associated with Cognitive Impairments in the Drug-Naive Patients with Late-Onset Depression

Lim, Hyun Kook,Jung, Won Sang,Ahn, Kook Jin,Won, Wang Youn,Hahn, Changtae,Lee, Seung Yup,Kim, InSeong,Lee, Chang Uk American College of Neuropsychopharmacology 2012 Neuropsychopharmacology Vol.37 No.3

Previous studies have shown an association between late-onset depression (LOD) and cognitive impairment in older adults. However, the neural correlates of this relationship are not yet clear. The aim of this study was to investigate the differences in both cortical thickness and subcortical volumes between drug-naive LOD patients and healthy controls and explore the relationship between LOD and cognitive impairments. A total of 48 elderly, drug-naive patients with LOD and 47 group-matched healthy control subjects underwent 3T MRI scanning, and the cortical thickness was compared between the groups in multiple locations, across the continuous cortical surface. The subcortical volumes were also compared on a structure-by-structure basis. Subjects with LOD exhibited significantly decreased cortical thickness in the rostral anterior cingulate cortex, the medial orbitofrontal cortex, dorsolateral prefrontal cortex, the superior and middle temporal cortex, and the posterior cingulate cortex when compared with healthy subjects (all p<0.05, false discovery rate corrected). Reduced volumes of the right hippocampus was also observed in LOD patients when compared with healthy controls (p<0.001). There were significant correlations between memory functions and cortical thickness of medial temporal, isthmus cingulate, and precuneus (p<0.001). This study was the first study to explore the relationships between the cortical thickness/subcortical volumes and cognitive impairments of drug-naive patients with LOD. These structural changes might explain the neurobiological mechanism of LOD as a risk factor of dementia.

Frontal Glucose Hypometabolism in Abstinent Methamphetamine Users

Kim, Seog Ju,Lyoo, In Kyoon,Hwang, Jaeuk,Sung, Young Hoon,Lee, Ho Young,Lee, Dong Soo,Jeong, Do-Un,Renshaw, Perry F American College of Neuropsychopharmacology 2005 Neuropsychopharmacology Vol.30 No.7

Changes in relative regional cerebral glucose metabolism (rCMRglc) and their potential gender differences in abstinent methamphetamine (MA) users were explored. Relative rCMRglc, as measured by <SUP>18</SUP>F-fluorodeoxyglucose positron emission tomography, and frontal executive functions, as assessed by Wisconsin card sorting test (WCST), were compared between 35 abstinent MA users and 21 healthy comparison subjects. In addition, male and female MA users and their gender-matched comparison subjects were compared to investigate potential gender differences. MA users had lower rCMRglc levels in the right superior frontal white matter and more perseveration and nonperseveration errors in the WCST, relative to healthy comparison subjects. Relative rCMRglc in the frontal white matter correlated with number of errors in the WCST in MA users. In the subanalysis for gender differences, lower rCMRglc in the frontal white matter and more errors in the WCST were found only in male MA users, not in female MA users, relative to their gender-matched comparison subjects. The current findings suggest that MA use causes persistent hypometabolism in the frontal white matter and impairment in frontal executive function. Our findings also suggest that the neurotoxic effect of MA on frontal lobes of the brain might be more prominent in men than in women.Neuropsychopharmacology (2005) 30, 1383–1391, advance online publication, 23 February 2005; doi:10.1038/sj.npp.1300699

Inactivation of JAK2/STAT3 Signaling Axis and Downregulation of M1 mAChR Cause Cognitive Impairment in klotho Mutant Mice, a Genetic Model of Aging

Park, Seok-Joo,Shin, Eun-Joo,Min, Sun Seek,An, Jihua,Li, Zhengyi,Hee Chung, Yoon,Hoon Jeong, Ji,Bach, Jae-Hyung,Nah, Seung-Yeol,Kim, Won-Ki,Jang, Choon-Gon,Kim, Yong-Sun,Nabeshima, Yo-ichi,Nabeshima, American College of Neuropsychopharmacology 2013 Neuropsychopharmacology Vol.38 No.8

We previously reported cognitive dysfunction in klotho mutant mice. In the present study, we further examined novel mechanisms involved in cognitive impairment in these mice. Significantly decreased janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3) phosphorylation were observed in the hippocampus of klotho mutant mice. A selective decrease in protein expression and binding density of the M1 muscarinic cholinergic receptor (M1 mAChR) was observed in these mice. Cholinergic parameters (ie, acetylcholine (ACh), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE)) and NMDAR-dependent long-term potentiation (LTP) were significantly impaired in klotho mutant mice. McN-A-343 (McN), an M1 mAChR agonist, significantly attenuated these impairments. AG490 (AG), a JAK2 inhibitor, counteracted the attenuating effects of McN, although AG did not significantly alter the McN-induced effect on AChE. Furthermore, AG significantly inhibited the attenuating effects of McN on decreased NMDAR-dependent LTP, protein kinase C βII, p-ERK, p-CREB, BDNF, and p-JAK2/p-STAT3-expression in klotho mutant mice. In addition, k252a, a BDNF receptor tyrosine kinase B (TrkB) inhibitor, significantly counteracted McN effects on decreased ChAT, ACh, and M1 mAChR and p-JAK2/p-STAT3 expression. McN-induced effects on cognitive impairment in klotho mutant mice were consistently counteracted by either AG or k252a. Our results suggest that inactivation of the JAK2/STAT3 signaling axis and M1 mAChR downregulation play a critical role in cognitive impairment observed in klotho mutant mice.

mGluR2/3 in the Lateral Amygdala is Required for Fear Extinction: Cortical Input Synapses onto the Lateral Amygdala as a Target Site of the mGluR2/3 Action

Kim, Jihye,An, Bobae,Kim, Jeongyeon,Park, Sewon,Park, Sungmo,Hong, Ingie,Lee, Sukwon,Park, Kyungjoon,Choi, Sukwoo American College of Neuropsychopharmacology 2015 Neuropsychopharmacology Vol.40 No.13

Various subtypes of metabotropic glutamate receptors (mGluRs) have been implicated in fear extinction, but mGluR2/3 subtype has not been tested. Here, we found that microinjection of an mGluR2/3 antagonist, LY341495, into the lateral amygdala (LA), but not into the adjacent central amygdala (CeA), impaired extinction retention without affecting within-session extinction. In contrast, we failed to detect any significant changes in motility and anxiety during a period when extinction training or retention was performed after LY341495 injection, suggesting that the effect of LY341495 is specific to conditioned responses. Subsequently, on the basis of a previous finding that a long-term potentiation of presynaptic efficacy at cortical input synapses onto the lateral amygdala (C-LA synapses) supports conditioned fear, we tested the hypothesis that activation of mGluR2/3 leads to fear extinction via a long-term weakening of presynaptic functions at C-LA synapses. Fear extinction produced a decrease in C-LA synaptic efficacy, whereas LY341495 infusion into the LA blocked this extinction-induced C-LA efficacy decrease without altering synaptic efficacy at other LA synapses. Furthermore, extinction enhanced paired pulse ratio (PPR) of EPSCs, which inversely correlates with presynaptic release probability, whereas LY341495 infusion into the LA attenuated the extinction-induced increase in PPR, suggesting the presence of mGluR2/3-dependent presynaptic changes after extinction. Consistently, extinction occluded a presynaptic form of depression at C-LA synapses, whereas the LY341495 infusion into the LA rescued this occlusion. Together, our findings suggest that mGluR2/3 is required for extinction retention and that the mGluR2/3 action is mediated by the long-term weakening of release probability at C-LA synapses.

Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex

Aoyama, Yuki,Toriumi, Kazuya,Mouri, Akihiro,Hattori, Tomoya,Ueda, Eriko,Shimato, Akane,Sakakibara, Nami,Soh, Yuka,Mamiya, Takayoshi,Nagai, Taku,Kim, Hyoung-Chun,Hiramatsu, Masayuki,Nabeshima, Toshitak American College of Neuropsychopharmacology 2016 Neuropsychopharmacology Vol.41 No.2

<P>Cigarette smoking during pregnancy is associated with various disabilities in the offspring such as attention deficit/hyperactivity disorder, learning disabilities, and persistent anxiety. We have reported that nicotine exposure in female mice during pregnancy, in particular from embryonic day 14 (E14) to postnatal day 0 (P0), induces long-lasting behavioral deficits in offspring. However, the mechanism by which prenatal nicotine exposure (PNE) affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that PNE disrupted the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and subventricular zones. In addition, using a cumulative 5-bromo-2'-deoxyuridine labeling assay, we evaluated the rate of cell cycle progression causing the impairment of neuronal progenitor proliferation, and uncovered anomalous cell cycle kinetics in mice with PNE. Accordingly, the density of glutamatergic neurons in the medial prefrontal cortex (medial PFC) was reduced, implying glutamatergic dysregulation. Mice with PNE exhibited behavioral impairments in attentional function and behavioral flexibility in adulthood, and the deficits were ameliorated by microinjection of D-cycloserine into the PFC. Collectively, our findings suggest that PNE affects the proliferation and maturation of progenitor cells to glutamatergic neuron during neurodevelopment in the medial PFC, which may be associated with cognitive deficits in the offspring.</P>