Che Ming Yeh

Estrogen modulates sexually dimorphic contextual fear extinction in rats through estrogen receptor β

Females and males are different in brain and behavior. These sex differences occur early during development due to a combination of genetic and hormonal factors and continue throughout the lifespan. Previous studies revealed that male rats exhibited significantly higher levels of contextual fear memory than female rats. However, it remains unknown whether a sex difference exists in the contextual fear extinction. To address this issue, male, normally cycling female, and ovariectomized (OVX) female Sprague‐Dawley rats were subjected to contextual fear conditioning and extinction trials. Here we report that although male rats exhibited higher levels of freezing than cycling female rats after contextual fear conditioning, female rats subjected to conditioning in the proestrus and estrus stage exhibited an enhancement of fear extinction than male rats. An estrogen receptor (ER) β agonist diarylpropionitrile but not an ERα agonist propyl‐pyrazole‐triol administration also enhanced extinction of contextual fear in OVX female rats, suggesting that estrogen‐mediated facilitation of extinction involves the activation of ERβ. Intrahippocampal injection of estradiol or diarylpropionitrile before extinction training in OVX female rats remarkably reduced the levels of freezing response during extinction trials. In addition, the locomotion or anxiety state of female rats does not vary across the ovarian cycle. These results reveal a crucial role for estrogen in mediating sexually dimorphic contextual fear extinction, and that estrogen‐mediated enhancement of fear extinction involves the activation of ERβ.

Prenatal stress alters hippocampal synaptic plasticity in young rat offspring through preventing the proteolytic conversion of pro‐brain‐derived neurotrophic factor (BDNF) to mature BDNF

Non‐technical summary  Prenatal stress (PS) has been associated with a higher risk for the development of various neurological and psychiatric disorders later in life, but the underlying mechanisms are not yet fully understood. Our results support an action mode in which PS downregulates tissue plasminogen activator levels within the hippocampus, inhibiting the proteolytic conversion of pro‐brain‐derived neurotrophic factor (pro‐BDNF) to the mature form of BDNF, thereby leading to long‐lasting alterations of the properties of synaptic plasticity. Our findings bolster the idea that stressful experience during gestation or early in life may lead to long‐lasting malfunction of the hippocampus and our PS model may be useful for the development of more effective intervention and prevention strategies.

Cocaine Withdrawal Impairs Metabotropic Glutamate Receptor-Dependent Long-Term Depression in the Nucleus Accumbens

Neuroadaptation in the nucleus accumbens (NAc), a central component of the mesolimbic dopamine (DA) system, has been implicated in the development of cocaine-induced psychomotor sensitization and relapse to cocaine seeking. However, little is known about the cellular and synaptic mechanisms underlying such adaptation. Using a mouse model of behavioral sensitization, we show that animals withdrawn from repeated cocaine exposure have a selective deficit in the ability to elicit metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) in the shell of the NAc in response to bath application of the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG). Experiments conducted in the presence of the selective mGluR1 antagonists 7-(hydroxyimino)cyclopropachromen-carboxylate ethyl ester and (S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid, or the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine, demonstrated that the impaired DHPG-LTD is likely attributable to a loss of mGluR5 function. Quantitative real-time reverse transcriptase-PCR and Western blot analysis revealed significant downregulation of mGluR5, but not mGluR1, mRNA and protein levels in the NAc shell. The inhibitory effect of repeated cocaine exposure on DHPG-LTD was selectively prevented when cocaine was coadministered with the selective D1-like DA receptor antagonist (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Furthermore, the levels of brain-derived neurotrophic factor (BDNF) protein in the NAc shell increased progressively after cocaine withdrawal, and the impairment of DHPG-LTD in the NAc shell was not found in slices from BDNF-knock-out mice after cocaine withdrawal. These results suggest that withdrawal from repeated cocaine exposure may result in increased BDNF levels in the NAc shell, which leads to a selective downregulation of mGluR5 and thereby impairs the induction of mGluR-dependent LTD.

Neonatal dexamethasone treatment exacerbates hypoxic-ischemic brain injury.

BackgroundThe synthetic glucocorticoid dexamethasone (DEX) is commonly used to prevent chronic lung disease in prematurely born infants. Treatment regimens usually consist of high doses of DEX for several weeks, notably during a critical period of brain development. Therefore, there is some concern about adverse effects of this clinical practice on fetal brain development. In this study, using a clinically relevant rat model, we examined the impact of neonatal DEX treatment on subsequent brain injury due to an episode of cerebral hypoxia-ischemia (HI).ResultsWe found that a 3-day tapering course (0.5, 0.3 and 0.1 mg/kg) of DEX treatment in rat pups on postnatal days 1–3 (P1-3) exacerbated HI-induced brain injury on P7 by a glucocorticoid receptor-mediated mechanism. The aggravating effect of neonatal DEX treatment on HI-induced brain injury was correlated with decreased glutamate transporter-1 (GLT-1)-mediated glutamate reuptake. The expression levels of mRNA and protein of GLT-1 were significantly reduced by neonatal DEX treatment. We also found that the administration of β-lactam antibiotic ceftriaxone increased GLT-1 protein expression and significantly reduced HI-induced brain injury in neonatal DEX-treated rats.ConclusionsThese results suggest that early DEX exposure may lead the neonatal brain to be more vulnerable to subsequent HI injury, which can be ameliorated by administrating ceftriaxone.

A single in vivo cocaine administration impairs 5-HT1B receptor-induced long-term depression in the nucleus accumbens

The nucleus accumbens (NAc) is a crucial forebrain nucleus implicated in reward‐based decision‐making. While NAc neurons are richly innervated by serotonergic fibers, information on the functional role of serotonin 5‐hydroxytryptamine (5‐HT) in the NAc is still sparse. Here, we demonstrate that brief application of 5‐HT or 5‐HT1B receptor agonist CP 93129 induced a long‐term depression (LTD) of glutamatergic transmission in NAc neurons. This LTD was presynaptically mediated and inducible by endogenous 5‐HT. Remarkably, a single cocaine exposure impaired the induction of LTD by 5‐HT or CP 93129. The inhibition was blocked when a selective dopamine D1 receptor antagonist SCH23390 was coadministered with cocaine. Cocaine treatment resulted in increased phosphorylation of presynaptic proteins, rabphilin 3A and synapsin 1, and significantly attenuated CP 93129‐induced decrease in rabphilin 3A and synapsin 1 phosphorylation. Application of cAMP‐dependent protein kinase inhibitor KT5720 caused a prominent synaptic depression in NAc neurons of mice with a history of cocaine exposure. Our results reveal a novel 5‐HT1B receptor‐mediated LTD in the NAc and suggest that cocaine exposure may result in elevated phosphorylation of presynaptic proteins involved in regulating glutamate release, which counteracts the presynaptic depressant effects of 5‐HT1B receptors and thereby impairs the induction of LTD by 5‐HT.

Conditional deletion of Eps8 reduces hippocampal synaptic plasticity and impairs cognitive function.

ABSTRACT Epidermal growth factor receptor substrate 8 (Eps8) is a multifunctional protein involved in actin cytoskeleton regulation and is abundantly expressed in many brain regions. However, the functional significance of Eps8 in the brain has only just begun to be elucidated. Here, we demonstrate that genetic deletion of Eps8 (Eps8−/−) from excitatory neurons leads to impaired performance in a novel object recognition test. Consistently, Eps8−/− mice displayed a deficit in the maintenance of long‐term potentiation in the CA1 region of hippocampal slices, which was rescued by bath application of N‐methyl‐d‐aspartate receptor (NMDAR) antagonist 2‐amino‐5‐phosphonopentanoate. While Eps8−/− mice showed normal basal synaptic transmission, a significant increase in the amplitude and a significantly slower decay kinetic of NMDAR‐mediated excitatory postsynaptic currents (EPSCs) were observed in hippocampal CA1 neurons. Furthermore, a significant increase in the expression of ifenprodil‐sensitive NMDAR‐mediated EPSCs was observed in neurons from Eps8−/− mice compared with those from wild‐type mice. Eps8 deletion led to decreased mature mushroom‐shaped dendritic spine density but increased complexity of basal dendritic trees of hippocampal CA1 pyramidal neurons. These results implicate NMDAR hyperfunction in the cognitive deficits observed in Eps8−/− mice and demonstrate a novel role for Eps8 in regulating hippocampal long‐term synaptic plasticity and cognitive function. This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’. HIGHLIGHTSEps8 deletion results in NMDA receptor hyperfunction.Eps8 deletion promotes decay of long‐term potentiation.Eps8 deletion leads to cognitive deficits.

Repeated transcranial direct current stimulation improves cognitive dysfunction and synaptic plasticity deficit in the prefrontal cortex of streptozotocin-induced diabetic rats

BACKGROUND Cognitive dysfunction is commonly observed in diabetic patients. We have previously reported that anodal transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex can facilitate visuospatial working memory in diabetic patients with concomitant diabetic peripheral neuropathy and mild cognitive impairment, but the underlying mechanisms remain unclear. OBJECTIVE We investigated the cellular mechanisms underlying the effect of tDCS on cognitive decline in streptozotocin (STZ)-induced diabetic rats. METHODS STZ-induced diabetic rats were subjected to either repeated anodal tDCS or sham stimulation over the medial prefrontal cortex (mPFC). Spatial working memory performance in delayed nonmatch-to-place T maze task (DNMT), the induction of long-term potentiation (LTP) in the mPFC, and dendritic morphology of Golgi-stained pyramidal neurons in the mPFC were assessed. RESULTS Repeated applications of prefrontal anodal tDCS improved spatial working memory performance in DNMT and restored the impaired mPFC LTP of diabetic rats. The mPFC of tDCS-treated diabetic rats exhibited higher levels of brain-derived neurotrophic factor (BDNF) protein and N-Methyl-d-aspartate receptor (NMDAR) subunit mRNA and protein compared to sham stimulation group. Furthermore, anodal tDCS significantly increased dendritic spine density on the apical dendrites of mPFC layer V pyramidal cells in diabetic rats, whereas the complexity of basal and apical dendritic trees was unaltered. CONCLUSIONS Our findings suggest that repeated anodal tDCS may improve spatial working memory performance in streptozotocin-induced diabetic rats through augmentation of synaptic plasticity that requires BDNF secretion and transcription/translation of NMDARs in the mPFC, and support the therapeutic potential of tDCS for cognitive decline in diabetes mellitus patients.

Acute food deprivation enhances fear extinction but inhibits long-term depression in the lateral amygdala via ghrelin signaling

Fear memory-encoding thalamic input synapses to the lateral amygdala (T-LA) exhibit dynamic efficacy changes that are tightly correlated with fear memory strength. Previous studies have shown that auditory fear conditioning involves strengthening of synaptic strength, and conversely, fear extinction training leads to T-LA synaptic weakening and occlusion of long-term depression (LTD) induction. These findings suggest that the mechanisms governing LTD at T-LA synapses may determine the behavioral outcomes of extinction training. Here, we explored this hypothesis by implementing food deprivation (FD) stress in mice to determine its effects on fear extinction and LTD induction at T-LA synapses. We found that FD increased plasma acylated ghrelin levels and enhanced fear extinction and its retention. Augmentation of fear extinction by FD was blocked by pretreatment with growth hormone secretagogue receptor type-1a antagonist D-Lys(3)-GHRP-6, suggesting an involvement of ghrelin signaling. Confirming previous findings, two distinct forms of LTD coexist at thalamic inputs to LA pyramidal neurons that can be induced by low-frequency stimulation (LFS) or paired-pulse LFS (PP-LFS) paired with postsynaptic depolarization, respectively. Unexpectedly, we found that FD impaired the induction of PP-LFS- and group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD, but not LFS-induced LTD. Ghrelin mimicked the effects of FD to impair the induction of PP-LFS- and DHPG-induced LTD at T-LA synapses, which were blocked by co-application of D-Lys(3)-GHRP-6. The sensitivity of synaptic transmission to 1-naphthyl acetyl spermine was not altered by either FD or ghrelin treatment. These results highlight distinct features of fear extinction and LTD at T-LA synapses.

Sex difference in stress-induced enhancement of hippocampal CA1 long-term depression during puberty

Females and males react differently to stress. Our previous studies revealed that acute stress facilitates the induction of long‐term depression (LTD) in hippocampal CA1 region. However, it remains unknown whether sex difference exists in the effect of stress on LTD. Using an acute unpredictable and inescapable restraint‐tailshock stress paradigm, we report here that hippocampal slices from stressed male rats expressed larger LTD by low‐frequency stimulation (LFS) than controls, whereas such effect was not observed in female rats during puberty. The facilitatory effect of stress on LTD was prevented when animals were submitted to bilateral adrenalectomy. However, no sex difference in the magnitudes of LTD induced by direct application of N‐methy‐D‐aspartate or a combination of LFS with the glutamate uptake inhibitor D,L‐threo‐β‐benzyloxyaspartate was observed in slices from naive rats. Female rats exhibited significantly higher basal but not stress‐evoked levels of plasma corticosterone than male rats. In addition, the expression levels of glucocorticoid receptors in hippocampal CA1 region were significantly lower in female than male rats. Moreover, female rats showed less responsiveness to stress‐ or dexamethasone‐induced suppression of glutamate uptake in hippocampal synaptosomal preparations than male rats. Importantly, female rats that were masculinized with testosterone at birth responded to stress like male rats did, demonstrating an enhancement of LTD. In contrast, ovariectomized female rats failed to restore theability of stress to facilitate LTD. These results reveal an obvious sex difference in stress‐induced modification of hippocampal synaptic plasticity, which depends on organizational effect of testosterone during early development.

Important Roles of Ring Finger Protein 112 in Embryonic Vascular Development and Brain Functions.

Rnf112 is a member of the RING finger protein family. The expression of Rnf112 is abundant in the brain and is regulated during brain development. Our previous study has revealed that Rnf112 can promote neuronal differentiation by inhibiting the progression of the cell cycle in cell models. In this study, we further revealed the important functions of Rnf112 in embryo development and in adult brain. Our data showed that most of the Rnf112−/− embryos exhibited blood vascular defects and died in utero. Upon further investigation, we found that the survival rate of homozygous Rnf112 knockout mice in 129/sv and C57BL/6 mixed genetic background was increased. The survived newborns of Rnf112−/− mice manifested growth retardation as indicated by smaller size and a reduced weight. Although the overall organization of the brain did not appear to be severely affected in Rnf112−/− mice, using in vivo 3D MRI imaging, we found that when compared to wild-type littermates, brains of Rnf112−/− mice were smaller. In addition, Rnf112−/− mice displayed impairment of brain functions including motor balance, and spatial learning and memory. Our results provide important aspects for the study of Rnf112 gene functions.