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Introduction: Adherence counselling with point‐of‐care (POC) drug‐level feedback using a novel tenofovir assay may support pre‐exposure prophylaxis (PrEP) adherence; however, perceptions of urine testing and its impact on adherence are not well studied. We qualitatively examined how POC tenofovir testing was experienced by transgender women (TGW) in Uganda. Methods: Within a cluster randomized trial of peer‐delivered HIV self‐testing, self‐sampling for sexually transmitted infections and PrEP among HIV‐negative TGW showing overall low PrEP prevention‐effective adherence (NCT04328025), we conducted a nested qualitative sub‐study of the urine POC assay among a random sample of 30 TGW (August 2021−February 2022). TGW interviews explored: (1) experiences with POC urine tenofovir testing and (2) perceptions of PrEP adherence counselling with drug‐level feedback. We used an inductive content analytic approach for analysis. Results: Median age was 21 years (interquartile range 20–24), and 70% engaged in sex work. Four content categories describe how TGW experienced POC urine tenofovir testing: (1) Urine tenofovir testing was initially met with scepticism: Testing urine to detect PrEP initially induced anxiety, with some perceptions of being intrusive and unwarranted. With counselling, however, participants found POC testing acceptable and beneficial. (2) Alignment of urine test results and adherence behaviours: Drug‐level feedback aligned with what TGW knew about their adherence. Concurrence between pill taking and tenofovir detection in urine reinforced confidence in test accuracy. (3) Interpretation of urine tenofovir results: TGW familiar with the interpretation of oral‐fluid HIV self‐tests knew that two lines on the test device signified positivity (presence of HIV). However, two lines on the urine test strip indicated a positive result for non‐adherence (absence of tenofovir), causing confusion. Research nurses explained the difference in test interpretation to participants' satisfaction. (4) White coat dosing: Some TGW deliberately chose not to attend scheduled clinic appointments to avoid detecting their PrEP non‐adherence during urine testing. They restarted PrEP before returning to clinic, a behaviour called "white coat dosing." Conclusions: Incorporating POC urine testing into routine PrEP adherence counselling was acceptable and potentially beneficial for TGW but required attention to context. Additional research is needed to identify effective strategies for optimizing adherence monitoring and counselling for this population. [ABSTRACT FROM AUTHOR]

Introduction: Effective use of pre‐exposure prophylaxis (PrEP) has been low among adolescent girls and young women (AGYW) in sub‐Saharan Africa. The MTN‐034/REACH trial offered AGYW a menu of adherence support strategies and achieved high adherence to both daily oral PrEP and the monthly dapivirine vaginal ring. Understanding how these strategies promoted product use could inform the design of adherence support systems in programmatic settings. Methods: REACH was a randomized crossover trial evaluating the safety of and adherence to the ring and oral PrEP among 247 HIV‐negative AGYW (ages 16–21) in South Africa, Uganda and Zimbabwe from January 2019 to September 2021 (NCT03593655). Adherence support included monthly counselling sessions with drug‐level feedback (DLF) plus optional daily short message service (SMS) reminders, weekly phone or SMS check‐ins, peer support clubs, "peer buddies" and additional counselling. Counsellors documented adherence support choices and counselling content on standardized forms. Through focus groups, serial in‐depth interviews (IDIs) and single IDIs (n = 119 total), we explored participants' experiences with adherence support and how it encouraged product use. Results: Participants received counselling at nearly all visits. DLF was provided at 54.3% of sessions and, across sites, 49%–68% received results showing high adherence for oral PrEP, and 73%–89% for the ring. The most popular support strategies were in‐person clubs and weekly calls, followed by online clubs, additional counselling and SMS. Preferences differed across sites but were similar for both products. Qualitative results demonstrated that the REACH strategies supported adherence by providing information about HIV and PrEP, continually motivating participants, and supporting the development of behavioural skills and self‐efficacy, aligning with the Information, Motivation, and Behavioural Skills (IMB) model. Effectiveness was supported by three foundational pillars: strong interpersonal relationships with counsellors; ongoing, easily accessible support and resources; and establishing trust in the counsellors and study products through counsellor relationships, peer‐to‐peer exchange and DLF. Conclusions: Implementation programmes could support effective PrEP use by offering a small menu of counsellor‐ and peer‐based support options that are youth‐friendly and developmentally appropriate. The same menu options can support both ring and oral PrEP users, though content should be tailored to the individual products. [ABSTRACT FROM AUTHOR]

Prenatal opioid exposures lead to extensive cognitive and emotion-regulation problems in children, persisting at least through school-age. Methadone, an opioid typically used for the treatment of opioid use disorder, has been approved for use in pregnant women for several decades. Importantly, however, the impacts of prenatal methadone exposure (PME), particularly on offspring as they progress into adulthood, has not been extensively examined. In recent years, children and young animal models have shown cognitive deficits related to PME, including evidence of hippocampal dysfunction. The present work aims to examine the persistent nature of these deficits, as well as determine how they may differ by sex. Pregnant Sprague-Dawley rats either received subcutaneous methadone or water injections twice daily from gestational days 3-20 or were left undisturbed. Following postnatal day 70, male and female offspring were behaviourally tested for impairments in recognition memory using the Novel Object Recognition task and working spatial memory through Spontaneous Alternation. Additionally, using whole-cell patch-clamp electrophysiology, hippocampal dentate granule cell function was examined in adult offspring. Results indicate that methadone-exposed females showed decreased excitability and increased inhibition of dentate granule cells compared to naïve controls, while males did not. These findings were accompanied by impairments in female working spatial memory and altered behaviour in the Object Recognition task. Overall, this work supports the continued investigation of the long-term effects of PME on adult male and female learning and memory, as well as promotes further exploration of adult hippocampal function as a neural mechanism impacted by this exposure. [ABSTRACT FROM AUTHOR]

Synapses between neurons are malleable biochemical structures, strengthening and diminishing over time dependent on the type of information they receive. This phenomenon known as synaptic plasticity underlies learning and memory, and its different forms, long‐term potentiation (LTP) and long‐term depression (LTD), perform varied cognitive roles in reinforcement, relearning and associating memories. Moreover, both LTP and LTD can exist in an early transient form (early‐LTP/LTD) or a late persistent form (late‐LTP/LTD), which are triggered by different induction protocols, and also differ in their dependence on protein synthesis and the involvement of key molecular players. Beyond homosynaptic modifications, synapses can also interact with one another. This is encapsulated in the synaptic tagging and capture hypothesis (STC), where synapses expressing early‐LTP/LTD present a 'tag' that can capture the protein synthesis products generated during a temporally proximal late‐LTP/LTD induction. This 'tagging' phenomenon forms the framework of synaptic interactions in various conditions and accounts for the cellular basis of the time‐dependent associativity of short‐lasting and long‐lasting memories. All these synaptic modifications take place under controlled neuronal conditions, regulated by subcellular elements such as epigenetic regulation, proteasomal degradation and neuromodulatory signals. Here, we review current understanding of the different forms of synaptic plasticity and its regulatory mechanisms in the hippocampus, a brain region critical for memory formation. We also discuss expression of plasticity in hippocampal CA2 area, a long‐overlooked narrow hippocampal subfield and the behavioural correlate of STC. Lastly, we put forth perspectives for an integrated view of memory representation in synapses. [ABSTRACT FROM AUTHOR]

Memory has an essential function in human life as it helps individuals remember and recognize their surroundings. It is also the major form of cognition that controls behavior. As memory is a function that is highly characteristic of humans, how it was established is of particular interest. Recent progress in the field of neurosciences, together with the technological advancement of genome‐wide approaches, has led to the accumulation of evidence regarding the presence and similar/distinct mechanisms of memory among species. However, the understanding of the evolution of memory obtained utilizing these genome‐wide approaches remains unclear. The purpose of this review was to provide an overview of the literature on the evolution of the memory system among species and the genes involved in this process. This review also discusses possible approaches to study the evolution of memory systems to guide future research. [ABSTRACT FROM AUTHOR]

Disruption of prefrontal glutamate receptor interacting protein (GRIP), which anchors GluA2‐containing AMPA receptors (AMPARs) into the synaptic membrane, potentiates cue‐induced cocaine seeking in both males and females. Protein interacting with C kinase 1 (PICK1) plays an opposing role to that of GRIP, removing AMPARs from the synapse. Consistent with our hypothesis that disruption of PICK1 in the mPFC would lead to a decrease in addiction‐like behaviour, we found that conditional deletion of PICK1 in the mPFC attenuates cue‐induced cocaine seeking in male mice. However, prefrontal PICK1 deletion had the opposite effect in females, leading to an increase in cue‐induced reinstatement of cocaine seeking. We did not see any effects of PICK1 knockdown on sucrose taking or seeking, suggesting the sex‐specific effects do not generalise to natural reinforcers. These findings suggest the role of PICK1 in the prefrontal cortex of females may not be consistent with its accepted role in males. To determine whether these sex differences were influenced by gonadal hormones, we gonadectomised a cohort of males and found that removal of circulating androgens eliminated the effect of prefrontal PICK1 knockdown. As there was no effect of gonadectomy on its own on any of the behavioural measures collected, our results suggest that androgens may be involved in compensatory downstream effects of PICK1 knockdown. Taken together, these results highlight the need for consideration of sex as a biological variable when examining mechanisms underlying all behaviours, as convergent sex differences can reveal different mechanisms where behavioural sex differences do not exist. [ABSTRACT FROM AUTHOR]

We previously showed a hydroxamic acid‐based histone deacetylase inhibitor (HDACi), compound 13, provides neuroprotection against chronic cerebral hypoperfusion (CCH) both in vitro under oxygen‐glucose deprivation (OGD) conditions and in vivo under bilateral common carotid artery occlusion (BCCAO) conditions. Intriguingly, the protective effect of this HDACi is via H3K14 or H4K5 acetylation–mediated differential BDNF isoform activation. BDNF is involved in cell proliferation and differentiation in development, synaptic plasticity and in learning and memory related with receptors or synaptic proteins. B6 mice underwent BCCAO and were randomized into 4 groups; a sham without BCCAO (sham), BCCAO mice injected with DMSO (DMSO), mice injected with HDACi‐compound 13 (compound 13) and mice injected with suberoylanilide hydroxamic acid (SAHA). The cortex and hippocampus of mice were harvested at 3 months after BCCAO, and levels of BDNF, AMPA receptor and dopamine receptors (D1, D2 and D3) were studied using Western blotting analysis or immunohistochemistry. We found that the AMPA receptor plays a key role in the molecular mechanism of this process by modulating HDAC. This protective effect of HDACi may be through BDNF; therefore, activation of this downstream signalling molecule, for example by AMPA receptors, could be a therapeutic target or intervention applied under CCH conditions. [ABSTRACT FROM AUTHOR]

Opioid use by pregnant women is an understudied consequence associated with the opioid epidemic, resulting in a rise in the incidence of neonatal opioid withdrawal syndrome (NOWS) and lifelong neurobehavioral deficits that result from perinatal opioid exposure. There are few preclinical models that accurately recapitulate human perinatal drug exposure and few focus on fentanyl, a potent synthetic opioid that is a leading driver of the opioid epidemic. To investigate the consequences of perinatal opioid exposure, we administered fentanyl to mouse dams in their drinking water throughout gestation and until litters were weaned at postnatal day (PD) 21. Fentanyl-exposed dams delivered smaller litters and had higher litter mortality rates compared with controls. Metrics of maternal care behavior were not affected by the treatment, nor were there differences in dams' weight or liquid consumption throughout gestation and 21 days postpartum. Twenty-four hours after weaning and drug cessation, perinatal fentanyl-exposed mice exhibited signs of spontaneous somatic withdrawal behavior and sex-specific weight fluctuations that normalized in adulthood. At adolescence (PD 35), they displayed elevated anxiety-like behaviors and decreased grooming, assayed in the elevated plus maze and sucrose splash tests. Finally, by adulthood (PD 55), they displayed impaired performance in a two-tone auditory discrimination task. Collectively, our findings suggest that perinatal fentanyl-exposed mice exhibit somatic withdrawal behavior and change into early adulthood reminiscent of humans born with NOWS. [ABSTRACT FROM AUTHOR]

Introduction: Young men who have sex with men (MSM) and transgender women (TGW) face stigmas that hinder access to healthcare. The aim of the study was to understand age‐related determinants of healthcare needs and engagement among MSM and TGW. Methods: The TRUST/RV368 cohort provides integrated prevention and treatment services for HIV and other sexually transmitted infections (STIs) tailored to the needs of sexual and gender minorities. MSM and TGW aged ≥16 years in Abuja and ≥18 years Lagos, Nigeria, completed standardized behavioural questionnaires and were tested for HIV, Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) every three months for up to 18 months. Logistic regression was used to estimate adjusted odds ratios (aORs) for associations of age and other factors with outcomes of interest upon enrolment, including HIV care continuum steps – HIV testing, ART initiation and viral suppression <1000 copies/mL. Cox proportional hazards models were used to calculate adjusted hazard ratios (aHRs) for associations with incident infections. Results: Between March 2013 and February 2019, 2123 participants were enrolled with median age 23 (interquartile range 21 to 27) years. Of 1745 tested, 865 (49.6%) were living with HIV. HIV incidence was 11.6/100 person‐years [PY], including 23.1/100PY (95% CI 15.5 to 33.1) among participants aged 16 to 19 years and 23.8/100 PY (95% CI 13.6 to 39.1) among TGW. Compared to participants aged ≥25 years, those aged 16 to 19 years had decreased odds of prior HIV testing (aOR 0.40 [95% CI 0.11 to 0.92]), disclosing same‐sex sexual practices to healthcare workers (aOR 0.53 [95% CI 0.36 to 0.77]) and receiving HIV prevention information (aOR 0.60 [95% CI 0.41 to 0.87]). They had increased odds of avoiding healthcare (aOR 1.94 [95% CI 1.3 to 2.83]) and engaging in transactional sex (aOR 2.76 [95% CI 1.92 to 3.71]). Age 16 to 19 years was independently associated with increased incidence of HIV (aHR 4.09 [95% CI 2.33 to 7.49]), NG (aHR 3.91 [95% CI 1.90 to 8.11]) and CT (aHR 2.74 [95% CI 1.48 to 5.81]). Conclusions: Young MSM and TGW demonstrated decreased healthcare engagement and higher incidence of HIV and other STIs as compared to older participants in this Nigerian cohort. Interventions to address unique obstacles to healthcare engagement by adolescents and young adults are needed to curb the spread of HIV and other STIs among MSM and TGW in Nigeria. [ABSTRACT FROM AUTHOR]

Introduction: Strategies are needed to curb the increasing HIV incidence in young men who have sex with men (YMSM) and transgender women (YTGW) worldwide. We assessed the impact of youth‐friendly services (YFS) and a mobile phone application (app) on adherence to pre‐exposure prophylaxis (PrEP) in YMSM and YTGW in Thailand. Methods: A randomized control trial was conducted in YMSM and YTGW aged 15 to 19 years. Participants were provided daily oral tenofovir disoproxil fumerate/emtricitabine (TDF/FTC), condoms and randomized to receive either YFS or YFS plus a PrEP app (YFS + APP), whose features included self‐assessment of HIV acquisition risk, point rewards and reminders for PrEP and clinic appointments. Clinic visits occurred at zero, one, three and six months and telephone contact at two, four and five months. HIV testing was performed at every clinic visit. PrEP adherence was evaluated with intracellular tenofovir diphosphate (TFV‐DP) concentrations in dried blood spot (DBS) samples at months 3 and 6. The primary endpoint assessed was "PrEP adherence" defined as TFV‐DP DBS concentrations ≥700 fmol/punch (equivalent to ≥4 doses of TDF/week). Results: Between March 2018 and June 2019, 489 adolescents were screened at three centres in Bangkok. Twenty‐seven (6%) adolescents tested positive for HIV and 200 (41%) adolescents participated in the study. Of these, 147 were YMSM (74%) and 53 YTGW (26%). At baseline, median age was 18 years (IQR 17 to 19), 66% reported inconsistent condom use in the past month. Sexually transmitted infection prevalence was 23%. Retention at six months was 73%. In the YFS + APP arm, median app use duration was three months (IQR 1 to 5). PrEP adherence at month 3 was 51% in YFS and 54% in YFS + APP (p‐value 0.64) and at month 6 was 44% in YFS and 49% in YFS + APP (p‐value 0.54). No HIV seroconversions occurred during 75 person years of follow‐up. Conclusions: Youth‐friendly PrEP services enabled good adherence among half of adolescent PrEP users. However, the mobile phone application tested did not provide additional PrEP adherence benefit in this randomized trial. Adolescent risk behaviours are dynamic and require adaptive programmes that focus on "prevention‐effective adherence." [ABSTRACT FROM AUTHOR]

Emerging evidence implicates that low levels of ATP in the extracellular space may contribute to the pathophysiology of major depressive disorder (MDD). The concentration of extracellular ATP is regulated by its hydrolase ectonucleotide tri(di)phosphohydrolase (ENTPD). However, the role of ENTPD in depression remains poorly understood. Here we examine the role of CD39 (known as ENTPD1) in mouse depression‐like behavior induced by chronic social defeat stress (CSDS). We demonstrate that CSDS enhances the expression and activity of CD39 in hippocampus. The CD39 functional analog apyrase also induces depression‐like behavior, which can be ameliorated by ATP replenishment. Pharmacological inhibition and genetic silencing of CD39 has an antidepressant‐like effect via increasing hippocampal extracellular ATP concentration, accompanied with an increase in hippocampal neurogenesis and dendritic spine numbers in defeated mice. These results suggest that hippocampal CD39 contributes to CSDS‐induced depression‐like behavior via hydrolyzing extracellular ATP, indicating that CD39 may be a promising new target for the treatment of depression. Synopsis: The hippocampal ATP hydrolase CD39 contributes to chronic social defeat stress‐induced depression‐like behavior via hydrolyzing extracellular ATP, suggesting that CD39 may be a potential target for the treatment of depression. CD39 expression and activity are increased by chronic social defeat stress (CSDS) in mice.The CD39 analog apyrase induces depression‐like behaviors of mice.Pharmacological inhibition and knockdown of CD39 have antidepressant‐like effects, promote hippocampal neurogenesis and prevent stubby spine loss by CSDS. [ABSTRACT FROM AUTHOR]

The modified Wenyang Huayu decoction has been widely used to treat vascular dementia in China for thousands of years. We have previously proved that a modified version, Wuzang Wenyang Huayu decoction has the potential to be a more effective clinical treatment that can attenuate cerebral ischaemic injury. However, the global transcript profile and signalling conduction pathways regulated by this recipe remains unclear. This study established a two‐vessel occlusion rat model by bilateral common carotid artery occlusion. Two groups of rats were intragastrically treated Wuzang Wenyang Huayu 2.5 g/kg vs or Piracetam 0.15 g/kg for 2 weeks. Learning and memory abilities were measured with Morris water maze. Neuronal plasticity was observed by HE staining. Differentially expressed transcripts of rat hippocampus were analysed by transcriptomics with Illumina HiSeq2500 platform. Results showed that Wuzang Wenyang Huayu decoction significantly alleviated learning, memory deficits, coordination dysfunction and prevented hippocampus cellular injury; Results further revealed the increased gene expression in KEGG metabolic pathways (MT‐ND2. MT‐ND3, MT‐ND4, MT‐ND4L, MT‐ND5 and MT‐ATP8) and genes involved in signal transduction, carcinogenesis, immune system, endocrine system, nervous system etc (Results further revealed differential expression of genes involved in various systems, including MT‐ND2) Our discovery is likely to provide new insights to molecular mechanisms of Wuzang Wenyang Huayu regarding hippocampal transcripts in a murine vascular dementia model. [ABSTRACT FROM AUTHOR]

Abstract: Memories are stored in synapses that consist of axon terminals and dendritic spines. Dendritic spines are postsynaptic structures of synapses and are essential for synaptic plasticity and cognition. Therefore, extensive investigations concerning the functions and structures of spines have been performed. Sex steroids and stress steroids have been shown to modulate hippocampal synapses. Although the rapid modulatory action of sex steroids on synapses has been studied in hippocampal neurones over several decades, the essential molecular mechanisms have not been fully understood. Here, a description of kinase‐dependent signalling mechanisms is provided that can explain the rapid nongenomic modulation of dendritic spinogenesis in rat and mouse hippocampal slices by the application of sex steroids, including dihydrotestosterone, testosterone, oestradiol and progesterone. We also indicate the role of synaptic (classic) sex steroid receptors that trigger these rapid synaptic modulations. Moreover, we describe rapid nongenomic spine modulation by applying corticosterone, which is an acute stress model of the hippocampus. The explanations for the results obtained are mainly based on the optical imaging of dendritic spines. Comparisons are also performed with results obtained from other types of imaging, including electron microscopic imaging. Relationships between spine modulation and modulation of cognition are discussed. We recognise that most of rapid effects of exogenously applied oestrogen and androgen were observed in steroid‐depleted conditions, including acute slices of the hippocampus, castrated male animals and ovariectomised female animals. Therefore, the previously observed effects can be considered as a type of recovery event, which may be essentially similar to hormone replacement therapy under hormone‐decreased conditions. On the other hand, in gonadally intact young animals with high levels of endogenous sex hormones, further supplementation of sex hormones might not be effective, whereas the infusion of blockers for steroid receptors or kinases may be effective, with respect to suppressing sex hormone functions, thus providing useful information regarding molecular mechanisms. [ABSTRACT FROM AUTHOR]

Hippocampal dendritic spine density rapidly increases following estradiol (E2) treatment, but the types of spines and trafficking of synaptic markers have received little investigation. We assessed rapid effects of E2 over time on the density of four spine types (stubby, filopodial, long thin, and mushroom) and trafficking of AMPA receptor subunit GluA2 and PSD95 on tertiary, apical dendrites in CA1. Castrated male rats received 20 μg kg−1 of E2 or vehicle and were sacrificed 30 or 120 min later. Images of Golgi-Cox impregnated and PSD95/GluA2 stained dendrites were captured under the confocal microscope and quantified with IMARIS-XT. Stubby and filopodial spine densities did not change following treatment. Long-thin spines significantly decreased at 30 min while mushroom spines significantly increased at 120 min. GluA2, PSD95, and GluA2/PSD95 colocalization levels in stubby or long thin spines did not change, but filopodial spines had significantly reduced GluA2 levels at 30 min. Mushroom spines showed significantly increased levels for GluA2, PSD95 and GluA2/PSD95 colocalization at 120 min. Because GluA2 is important for memory consolidation, current results present novel data suggesting that trafficking of GluA2 to mushroom spines provides one mechanism contributing to estradiol's ability to enhance learning and memory by the PI3 signaling pathway. [ABSTRACT FROM AUTHOR]

Pathogenesis in tauopathies involves the accumulation of tau in the brain and progressive synapse loss accompanied by cognitive decline. Pathological tau is found at synapses, and it promotes synaptic dysfunction and memory deficits. The specific role of toxic tau in disrupting the molecular networks that regulate synaptic strength has been elusive. A novel mechanistic link between tau toxicity and synaptic plasticity involves the acetylation of two lysines on tau, K274, and K281, which are associated with dementia in Alzheimer's disease (AD). We propose that an increase in tau acetylated on these lysines blocks the expression of long-term potentiation at hippocampal synapses leading to impaired memory in AD. Acetylated tau could inhibit the activity-dependent recruitment of postsynaptic AMPA-type glutamate receptors required for plasticity by interfering with the postsynaptic localization of KIBRA, a memory-associated protein. Strategies that reduce the acetylation of tau may lead to effective treatments for cognitive decline in AD. [ABSTRACT FROM AUTHOR]

ABSTRACT Anxiety disorders are presumably associated with negative memory. Psychological therapies are widely used to treat this mental deficit in human beings based on the view that positive memory competes with negative memory and relieves anxiety status. Cellular and molecular processes underlying psychological therapies remain elusive. Therefore, we have investigated its mechanisms based on a mouse model in which food reward at one open-arm of the elevated plus-maze was used for training mice to form reward memory and challenge the open arms. Mice with the reward training showed increased entries and stay time in reward open-arm versus neutral open-arm as well as in open-arms versus closed-arms. Accompanying with reward memory formation and anxiety relief, glutamatergic synaptic transmission in dentate gyrus in vivo and dendritic spines in granule cells became upregulated. This synaptic up-regulation was accompanied by the expression of more protein kinase C (PKC) in the dendritic spines. The inhibition of PKC by chelerythrine impaired the formation of reward memory, the relief of anxiety-related behavior and the up-regulation of glutamate synapses. Our results suggest that reward-induced positive memory relieves mouse anxiety-related behavior by strengthening synaptic efficacy and PKC in the hippocampus, which imply the underlying cellular and molecular processes involved in the beneficial effects of psychological therapies treating anxiety disorders. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT There is no evidence on the precise role of synaptic Zn2+ signaling on the retention and recall of recognition memory. On the basis of the findings that intracellular Zn2+ signaling in the dentate gyrus is required for object recognition, short-term memory, the present study deals with the effect of spatiotemporally blocking Zn2+ signaling in the dentate gyrus after LTP induction and learning. Three-day-maintained LTP was impaired 1 day after injection of clioquinol into the dentate gyrus, which transiently reduced intracellular Zn2+ signaling in the dentate gyrus. The irreversible impairment was rescued not only by co-injection of ZnCl2, which ameliorated the loss of Zn2+ signaling, but also by pre-injection of Jasplakinolide, a stabilizer of F-actin, prior to clioquinol injection. Simultaneously, 3-day-old space recognition memory was impaired 1 day after injection of clioquinol into the dentate gyrus, but not by pre-injection of Jasplakinolide. Jasplakinolide also rescued both impairments of 3-day-maintained LTP and 3-day-old memory after injection of ZnAF-2DA into the dentate gyrus, which blocked intracellular Zn2+ signaling in the dentate gyrus. The present paper indicates that the blockade and/or loss of intracellular Zn2+ signaling in the dentate gyrus coincidently impair maintained LTP and recognition memory. The mechanism maintaining LTP via intracellular Zn2+ signaling in dentate granule cells, which may be involved in the formation of F-actin, may retain space recognition memory. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aim Anxiety is one of common mood disorders, in which the deficit of serotonergic and GABAergic synaptic functions in the amygdala and prefrontal cortex is believed to be involved. The pathological changes at the glutamatergic synapses and neurons in these brain regions as well as their underlying mechanisms remain elusive, which we aim to investigate. Methods An agonist of kainate-type glutamate receptors, kainic acid, was applied to induce anxiety-related behaviors. The morphology and functions of glutamatergic synapses in the prelimbic region of mouse prefrontal cortex were analyzed using cellular imaging and electrophysiology. Results After kainate-induced anxiety is onset, the signal transmission at the glutamatergic synapses is upregulated, and the dendritic spine heads are enlarged. In terms of the molecular mechanisms, the upregulated synaptic plasticity is associated with the expression of more protein kinase C ( PKC) in the dendritic spines. Chelerythrine, a PKC inhibitor, reverses kainate-induced anxiety and anxiety-related glutamatergic synapse upregulation. Conclusion The activation of glutamatergic kainate-type receptors leads to anxiety-related behaviors and glutamatergic synapse upregulation through protein kinase C in the prelimbic region of the mouse prefrontal cortex. [ABSTRACT FROM AUTHOR]

ABSTRACT Bisphenol-A (BPA), a common environmental endocrine disruptor, modulates estrogenic, androgenic, and antiandrogenic effects throughout the lifespan. We recently showed that low dose BPA exposure during adolescence increases anxiety and impairs spatial memory independent of sex. In this study, six week old Sprague Dawley rats ( n = 24 males, n = 24 females) received daily subcutaneous injections (40 µg/kg bodyweight) of BPA or vehicle for one week. Serum corticosterone levels in response to a 1 h restraint stress and spine density were examined at age 7 (cohort 1) and 11 (cohort 2) weeks. Adolescent BPA exposure did not alter stress dependent corticosterone responses but decreased spine density on apical and basal dendrites of pyramidal cells in the medial prefrontal cortex (mPFC) and hippocampal CA1 region (CA1). Sex differences in spine density were observed on basal dendrites of the mPFC and CA1 with females having greater spine density than males. This sex difference was further augmented by both age and treatment, with results indicating that BPA-dependent decreases in spine density were more pronounced in males than females on mPFC basal dendrites. Importantly, the robust neuronal alterations were observed in animals exposed to BPA levels below the current U.S.E.P.A. recommended safe daily limit. These results are the first demonstrating that BPA given during adolescence leads to enduring effects on neural morphology at adulthood. Given that humans are routinely exposed to low levels of BPA through a variety of sources, the decreased spine density reported in both male and female rats after BPA exposure warrants further investigation. Synapse 68:498-507, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Prkcz has been identified as a gene whose expression is positively correlated with ethanol ( Et OH) consumption in mice and is also induced by Et OH. Two proteins are produced from Prkcz: protein kinase M zeta ( PKMζ), which is expressed in the nervous system and protein kinase C zeta ( PKCζ), which is expressed in other tissues. We examined Prkcz−/− mice that lack PKCζ and PKMζ to investigate the role of this gene in behavioral responses to Et OH. Methods Male Prkcz−/− and wild-type littermates were tested for Et OH consumption using 4 procedures: 24-hour intermittent access, 4-hour limited intermittent access, 4-day drinking-in-the-dark, and 24-hour continuous access. We also assessed the acute hypnotic effect of Et OH, Et OH reward, and taste preference for sweet-, bitter-, salty-, and umami-flavored solutions. Finally, we determined whether Et OH could increase PKMζ and PKCζ transcripts and protein expression in wild-type mice using quantitative PCR and Western blot analysis. Results Prkcz−/− mice consumed more Et OH than their wild-type littermates in both intermittent access procedures, but not in the drinking-in-the-dark or 24-hour continuous access procedures. Et OH exposure increased Prkcz transcripts in cultured PC12 cells, and intermittent Et OH consumption increased PKMζ protein in the ventral striatum of wild-type mice. Conclusions Absence of PKMζ in the brain is associated with increased Et OH intake during procedures that incorporate intermittent consumption sessions every other day. Our data suggest that Et OH induces PKMζ, which acts in a negative feedback loop to limit binge-like Et OH consumption. [ABSTRACT FROM AUTHOR]

Direct phosphorylation of GluA1 by PKC controls α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor (AMPAR) incorporation into active synapses during long-term potentiation (LTP). Numerous signalling molecules that involved in AMPAR incorporation have been identified, but the specific PKC isoform(s) participating in GluA1 phosphorylation and the molecule triggering PKC activation remain largely unknown. Here, we report that the atypical isoform of PKC, PKCλ, is a critical molecule that acts downstream of phosphatidylinositol 3-kinase (PI3K) and is essential for LTP expression. PKCλ activation is required for both GluA1 phosphorylation and increased surface expression of AMPARs during LTP. Moreover, p62 interacts with both PKCλ and GluA1 during LTP and may serve as a scaffolding protein to place PKCλ in close proximity to facilitate GluA1 phosphorylation by PKCλ. Thus, we conclude that PKCλ is the critical signalling molecule responsible for GluA1-containing AMPAR phosphorylation and synaptic incorporation at activated synapses during LTP expression. [ABSTRACT FROM AUTHOR]

Background Sorafenib is the standard treatment of advanced hepatocarcinoma ( HCC) in cirrhotic patients with preserved liver function. It shares many adverse effects with other tyrosine-kinase ( TK) inhibitors and antiangiogenic drugs. TK inhibitors could have a direct toxicity on CNS, both by interfering with TK-related pathways and by inhibiting angiogenesis. Aims The aim of this study was to investigate whether sorafenib administration can be associated to metabolic encephalopathy in patients with cirrhosis. Methods We retrospectively reviewed medical records of all cirrhotic patients treated with sorafenib for HCC afferent at our Department from January 2009 to December 2011. Results Among 62 patients, we identified 10 patients with clinically significant cognitive impairment. Seven of these were clearly diagnosed with overt hepatic encephalopathy ( HE), one with brain metastases and two with drug-related toxic-metabolic encephalopathy. These last two cases were characterized by severe cognitive impairment, mood alteration and memory deficit. Clinical exam, blood tests and brain CT excluded organic causes of encephalopathy and precipitating factors of HE. Sorafenib discontinuation was associated with complete reversal of the syndrome, which recurred on drug re-administration in one case. Conclusions Our study suggests that sorafenib may be a precipitating factor of metabolic encephalopathy in cirrhotic patients with advanced HCC. This neurological syndrome appears to be not responsive to the conventional treatment for HE, but it is fully reversible by drug discontinuation. It can be speculated that the potential direct neuronal action of sorafenib may represent a trigger for the onset of metabolic encephalopathy in a subset of cirrhotic patients. [ABSTRACT FROM AUTHOR]

Key points Volatile anaesthetics, such as sevoflurane, have been shown to reduce neuronal damage when administered as preconditioning protective agents before hypoxia or ischaemia., Most rapid onset protective effects of anaesthetics have been thought to be due to direct effects on ion channels in the neurons and do not require the activation of biochemical pathways or protein synthesis, We found that sevoflurane activates the mammalian target of rapamycin (mTOR) biochemical pathway, increasing the rapid synthesis and activation of the protein kinase, PKMζ, a PKC isoform critical for maintaining long-term potentiation and long-term memory storage; this, in turn, increases the activity of KATP channels, and induces an increased hyperpolarization during hypoxia. This reduces and delays the hypoxic depolarization and improves neuronal recovery from hypoxia., Thus, it would be advantageous to choose an anaesthetic, such as sevoflurane, that rapidly preconditions and protects neurons from hypoxia and ischaemia for surgeries in which the brain is at risk for damage., Abstract Anaesthetic preconditioning occurs when a volatile anaesthetic, such as sevoflurane, is administered before a hypoxic or ischaemic insult; this has been shown to improve neuronal recovery after the insult. We found that sevoflurane-induced preconditioning in the rat hippocampal slice enhances the hypoxic hyperpolarization of CA1 pyramidal neurons, delays and attenuates their hypoxic depolarization, and increases the number of neurons that recover their resting and action potentials after hypoxia. These altered electrophysiological effects and the improved recovery corresponded with an increase in the amount of a constitutively active, atypical protein kinase C isoform found in brain, protein kinase M zeta (PKMζ). A selective inhibitor of this kinase, zeta inhibitory peptide (ZIP), blocked the increase in the total amount of PKMζ protein and the amount of the activated form of this kinase, phospho-PKMζ (p-PKMζ); it also blocked the altered electrophysiological effects and the improved recovery. We found that both cycloheximide, a general protein synthesis inhibitor, and rapamycin, a selective inhibitor of the mTOR pathway for regulating protein synthesis, blocked the increase in p-PKMζ, the electrophysiological changes, and the improved recovery due to sevoflurane-induced preconditioning. Glibenclamide, a KATP channel blocker, when present only during the hypoxia, prevented the enhanced hyperpolarization, the delayed and attenuated hypoxic depolarization, and the improved recovery following sevoflurane-induced preconditioning. To examine the function of persistent PKMζ and KATP channel activity after the preconditioning was established, we administered 4% sevoflurane for 30 min and then discontinued it for 30 min before 10 min of hypoxia. When either tolbutamide, a KATP channel blocker, or ZIP were administered at least 15 min after the washout of sevoflurane, there was little recovery compared with sevoflurane alone. Thus, continuous KATP channel and PKMζ activity are required to maintain preconditioning protection. We conclude that sevoflurane induces activation of the mTOR pathway, increasing the new protein synthesis of PKMζ, which is constitutively phosphorylated to its active form, leading to an increased KATP channel-induced hyperpolarizaton. This hyperpolarization delays and attenuates the hypoxic depolarization, improving the recovery of neurons following hypoxia. Thus, sevoflurane acts via a metabotropic pathway to improve recovery following hypoxia. [ABSTRACT FROM AUTHOR]

The persistent activity of protein kinase Mzeta (PKMζ), a brain-specific, constitutively active protein kinase C isoform, maintains synaptic long-term potentiation (LTP). Structural remodeling of the postsynaptic density is believed to contribute to the expression of LTP. We therefore examined the role of PKMζ in reconfiguring PSD-95, the major postsynaptic scaffolding protein at excitatory synapses. In primary cultures of hippocampal neurons, PKMζ activity was critical for increasing the size of PSD-95 clusters during chemical LTP (cLTP). Increasing PKMζ activity by overexpressing the kinase in hippocampal neurons was sufficient to increase PSD-95 cluster size, spine size, and postsynaptic AMPAR subunit GluA2. Overexpression of an inactive mutant of PKMζ did not increase PSD-95 clustering, and applications of the ζ-pseudosubstrate inhibitor ZIP reversed the PKMζ-mediated increases in PSD-95 clustering, indicating that the activity of PKMζ is necessary to induce and maintain the increased size of PSD-95 clusters. Thus the persistent activity of PKMζ is both necessary and sufficient for maintaining increases of PSD-95 clusters, providing a unified mechanism for long-term functional and structural modifications of synapses. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Diacylglycerol (DAG) is an important signaling molecule at neuronal synapses. Generation of synaptic DAG is triggered by the activation of diverse surface receptors including N-methyl- D-aspartate (NMDA) receptors and metabotropic glutamate receptors. The action of DAG is terminated by enzymatic conversion of DAG to phosphatidic acid (PA) by DAG kinases (DGKs). DGKζ, one of many mammalian DGKs, is localized to synapses through direct interaction with the postsynaptic scaffolding protein PSD-95, and regulates dendritic spine maintenance by promoting DAG-to-PA conversion. However, a role for DGKζ in the regulation of synaptic plasticity has not been explored. We report here that Schaffer collateral-CA1 pyramidal synapses in the hippocampus of DGKζ-knockout (DGKζ−/−) mice show enhanced long-term potentiation (LTP) and attenuated long-term depression (LTD). The attenuated LTD at DGKζ−/− synapses involves both NMDA receptors and metabotropic glutamate receptors. These changes in LTP and LTD were reversed by phospholipase C inhibition, which blocks DAG production. Similar reversals in both LTP and LTD were also induced by inhibition of protein kinase C, which acts downstream of DAG. These results suggest that DGKζ regulates hippocampal LTP and LTD by promoting DAG-to-PA conversion, and establish that phospholipase C and protein kinase C lie upstream and downstream, respectively, of DGKζ-dependent regulation of hippocampal LTP and LTD. © 2010 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Synaptic plasticity, or changes in synaptic strength, is thought to underlie learning and memory. Imaging studies, mainly in brain slices, have revealed that long-term synaptic plasticity of excitatory synapses in hippocampal neurons is coupled with structural plasticity of dendritic spines, which is thought to be essential for inducing and regulating functional plasticity. Using pharmacological and genetic manipulation, the signalling network underlying structural plasticity has been extensively studied. Furthermore, the recent advent of fluorescence resonance energy transfer (FRET) imaging techniques has provided a readout of the dynamics of signal transduction in dendritic spines undergoing structural plasticity. These studies reveal the signalling pathways relaying Ca(2+) to the functional and structural plasticity of dendritic spines. [ABSTRACT FROM AUTHOR]

The effect of daily varied stress from days 13-21 of gestation in Wistar rats was investigated by tests of learning and memory and anxiogenic behaviour in the 60-day-old offspring of both sexes. Prenatal stress decreased the anogenital distance in males at 1 day of age. Anxiogenic behaviour in the elevated plus maze was seen in prenatally-stressed rats of both genders. There was no significant gender difference in the rate of spatial learning in the Morris water maze but prenatal stress only slowed that of males. In the object recognition test with an inter-trial interval of 40 min, females but not males, discriminated between a familiar and novel object. Prenatal stress did not affect object discrimination in females but feminised that in males. Maternal adrenalectomy with replacement of basal corticosterone levels in the drinking fluid prevented all of the above effects of prenatal stress in the offspring. To mimic the peak corticosterone levels and time course of elevation in response to stress, corticosterone (3 mg/kg) was injected twice (0 and 30 min) on days 13-16 and once on days 17-20 of gestation to adrenalectomised mothers. This treatment re-instated anxiogenic behaviour similar to that induced by prenatal stress, indicating that it is mediated by exposure of the foetal brain to raised levels of corticosterone. However, steroid administration to adrenalectomised dams did not decrease anogenital distance, feminise object recognition memory or slow spatial learning in their male offspring. The findings indicate that other adrenal hormones are necessary to induce these effects of prenatal stress. [ABSTRACT FROM AUTHOR]

Continuous activity of the atypical protein kinase C isoform M zeta (PKMζ) is necessary for maintaining long-term memory acquired in aversively or appetitively motivated associative learning tasks, such as active avoidance, aversive taste conditioning, auditory and contextual fear conditioning, radial arm maze, and watermaze. Whether unreinforced, nonassociative memory will also require PKMζ for long-term maintenance is not known. Using recognition memory for object location and object identity, we found that inactivating PKMζ in dorsal hippocampus abolishes 1-day and 6-day-old long-term recognition memory for object location, while recognition memory for object identity was not affected by this treatment. Memory for object location persisted for no more than 35 days after training. These results suggest that the dorsal hippocampus mediates long-term memory for where, but not what things have been encountered, and that PKMζ maintains this type of spatial knowledge as long as the memory exists. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

We have previously demonstrated that dopamine agonist, SKF38396 (SKF), can substitute for progesterone in the facilitation of female reproductive behaviour in oestradiol benzoate-primed female rats and mice. We also reported that both progesterone- and SKF-initiated signalling were mediated by the cAMP-dependent protein kinase A signal transduction cascade. As the rapid effects of progesterone are also mediated by calcium-dependent kinases, calcium- and calmodulin-dependent kinase (CaMKII) and protein kinase (PKC), we sought to determine whether SKF-initiated signalling also recruited calcium as a second messenger. We measured the changes in the activation of CaMKII and PKC in the ventromedial nucleus (VMN) of the hypothalamus and preoptic area (POA) of the rat brain, which are the two regions implicated in the regulation of female reproductive behaviour in rodents. We measured the basal activities representing the activation of the kinases by in vivo treatments, as well as the total kinase activities assayed in the presence of exogenous cofactors in vitro. We report that, in contrast to progesterone-initiated signalling, there was no recruitment of calcium by SKF in the hypothalamus, as shown by the absence of changes in CaMKII activities in the VMN and POA. Furthermore, SKF-treatment resulted in a rapid increase in calcium-independent basal PKC activity in the VMN but not the POA. These rapid changes were not the result of changes in PKC protein levels or phosphorylation status. These data indicate that progesterone- and SKF-recruit distinct signalling molecules within the same regions of the brain to activate region-specific signal transduction pathways. [ABSTRACT FROM AUTHOR]

SQSTM1/p62 is a multidomain/scaffold for the atypical protein kinase Cs (aPKC). Phosphorylation of AMPA receptors by PKC has been shown to regulate their insertion in the postsynaptic membrane. Here, we directly tested whether p62 could interact with AMPA receptor subunits and influence their trafficking and phosphorylation. GluR1 receptor intracellular loop L2-3 and the ZZ-type zinc finger domain of p62 are essential for the interaction between these two proteins. In this context, both p62 and aPKC-mediated phosphorylation were necessary for surface delivery of the receptor. Our findings reveal that p62 is the first protein identified that interacts with a region of the GluR receptor other than the C-terminal tail. Furthermore, mice deficient in p62 displayed impaired hippocampal CA1 long-term potentiation (LTP), along with diminished surface expression of GluR1 and phosphorylation of S818. Lastly, we identify a conserved sequence (ISExSL) shared by all p62 interacting-aPKC substrates. These findings support a model where p62 interaction and aPKC phosphorylation act together to mediate AMPA receptor trafficking and long-term synaptic plasticity in the hippocampus. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The article presents a study which concerns the research approaches on cognitive dysfunction in systematic lupus erythemathosus (SLE). It notes that neuropsychiatric SLE (NPSLE) was thought to be a single entity in the 1950s and 1960s, and that characterization on such patients demonstrated diverse pathogenic mechanisms in the 1970s. The results of the study show that new advances in the process of researches conducted will provide guidance to future investigations.

Protein kinase Mζ (PKMζ), a constitutively active, atypical PKC isoform, enhances synaptic strength during the maintenance of long-term potentiation (LTP). Here we examine the mechanism by which PKMζ increases synaptic transmission. Postsynaptic perfusion of PKMζ during whole-cell recordings of CA1 pyramidal cells strongly potentiated the amplitude of AMPA receptor (AMPAR)-mediated miniature EPSCs (mEPSCs). Nonstationary fluctuation analysis of events recorded before and after PKMζ enhancement showed that the kinase doubled the number of functional postsynaptic AMPAR channels. After sustained potentiation, application of a PKMζ inhibitor reversed the increase in functional channel number to basal levels, suggesting that persistent increase of PKMζ is required to maintain the postsynaptic localization of a mobile subpopulation of receptors. The kinase did not affect other sites of LTP expression, including presynaptic transmitter release, silent synapse conversion, or AMPAR unit conductance. Thus PKMζ functions specifically to establish and maintain long-term increases in active postsynaptic AMPAR number. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Local protein synthesis in dendrites has emerged as a key mechanism contributing to enduring forms of synaptic plasticity. Although the translational capability of dendrites has been appreciated for over 20 years, it is only recently that significant progress has been made in elucidating mechanisms that contribute to its regulation. It is clear from work over the last few years that the control of translation in dendrites is complex, involving a host of unique (and often surprising) mechanisms that can operate together or in parallel to tightly control gene expression in time and space. Here, we discuss the strategies used by neurons to regulate translation in dendrites and how these are implemented in the service of long-term information storage. © 2005 Wiley Periodicals, Inc. J Neurobiol 64: 116-131, 2005 [ABSTRACT FROM AUTHOR]

Local dendritic protein synthesis provides a mechanism by which the effects of gene expression can be spatially restricted within synaptodendritic compartments of neurons. In the present study, we show that long-term potentiation (LTP), induced by two strong tetanic trains, can be produced in isolated CA1 apical dendrites and that new protein synthesis is critical for this dendritic LTP. LTP in isolated dendrites is also blocked by rapamycin, an inhibitor of growth-related protein synthesis, similar to that observed for LTP in the intact hippocampal slice. These results show that increased dendritic translation of proteins is a critical molecular mechanism for hippocampal LTP. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

To assess the long-term results in patients treated using a modified ureterosigmoidostomy (Mainz II). The Mainz II has a good outcome if used as the primary procedure. In patients with an existing ureterosigmoidostomy who are incontinent, detubularization of the rectosigmoid alone is unlikely to restore continence. [ABSTRACT FROM AUTHOR]

Studies in PKCζ‐deficient mice and new work on PKCλ regulation of AMPA receptors necessitate revisiting the roles of atypical PKC family members in synaptic plasticity and memory. [ABSTRACT FROM AUTHOR]