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Abstract Background To compare validity evidence for dichotomous and trichotomous versions of a neonatal intubation (NI) procedural skills checklist. Methods NI skills checklists were developed utilizing an existing framework. Experts were trained on scoring using dichotomous and trichotomous checklists, and rated recordings of 23 providers performing simulated NI. Videolaryngoscope recordings of glottic exposure were evaluated using Cormack-Lehane (CL) and Percent of Glottic Opening scales. Internal consistency and reliability of both checklists were analyzed, and correlations between checklist scores, airway visualization, entrustable professional activities (EPA), and global skills assessment (GSA) were calculated. Results During rater training, raters gave significantly higher scores on better provider performance in standardized videos (both p

IntroductionFrequent asthma attacks in children result in unscheduled hospital presentations. Patient centered care coordination can reduce asthma hospital presentations. In 2016, The Sydney Children's Hospitals Network launched the Asthma Follow up Integrated Care Initiative with the aim to reduce pediatric asthma emergency department (ED) presentations by 50% through developing and testing an integrated model of care led by care coordinators (CCs).MethodsThe integrated model of care was developed by a multidisciplinary team at Sydney Children's Hospital Randwick (SCH,R) and implemented in two phases: Phase I and Phase II. Children aged 2–16 years who presented ≥4 times to the ED of the SCH,R in the preceding 12 months were enrolled in Phase I and those who had ≥4 ED presentations and ≥1 hospital admissions with asthma attack were enrolled in Phase II. Phase I included a suite of interventions delivered by CCs including encouraging parents/carers to schedule follow-up visits with GP post-discharge, ensuring parents/carers are provided with standard asthma resource pack, offering referrals to asthma education sessions, sending a letter to the child's GP advising of the child's recent hospital presentation and coordinating asthma education webinar for GPs. In addition, in Phase II CCs sent text messages to parents/carers reminding them to follow-up with the child's GP. We compared the change in ED visits and hospital admissions at baseline (6 months pre-enrolment) and at 6-and 12-months post-enrolment in the program.ResultsDuring December 2016-January 2021, 160 children (99 in Phase I and 61 in Phase II) were enrolled. Compared to baseline at 6- and 12-months post-enrolment, the proportion of children requiring ≥1 asthma ED presentations reduced by 43 and 61% in Phase I and 41 and 66% in Phase II. Similarly, the proportion of children requiring ≥1 asthma hospital admissions at 6- and 12-months post-enrolment reduced by 40 and 47% in Phase I and 62 and 69% in Phase II.ConclusionOur results support that care coordinator led integrated model of asthma care which enables integration of acute and primary care services and provides families with asthma resources and education can reduce asthma hospital presentations in children.

Abstract Background Lung cancer screening can reduce mortality but can be a complex, multi-step process. Poor health literacy is associated with unfavorable outcomes and decreased use of preventative services, so it is important to address barriers to care through efficient and practical education. The readability of lung cancer screening materials for patients is unknown and may not be at the recommended 6th grade reading level set by the American Medical Association. Our goals were to: (1) measure the health literacy of a lung cancer screening population from an urban academic medical center, and (2) examine the readability of online educational materials for lung cancer screening. Methods We performed a retrospective cross sectional study at a single urban academic center. Health literacy was assessed using three validated screening questions. To assess the readability of educational materials, we performed a Google search using the phrase, “What is lung cancer screening?” and the Flesch-Kincaid Grade Level (FKGL) formula was used to estimate the grade level required to understand the text. Results There were 404 patients who underwent lung cancer screening during the study period. The prevalence of inadequate/marginal health literacy was 26.7–38.0%. Fifty websites were reviewed and four were excluded from analysis because they were intended for medical providers. The mean FKGL for the 46 websites combined was 10.6 ± 2.2. Conclusions Low health literacy was common and is likely a barrier to appropriate education for lung cancer screening. The current online educational materials regarding lung cancer screening are written above the recommended reading level set by the American Medical Association.

Abstract Background Over a third of Australian children have long-term health conditions, often involving multiple organ systems and resulting in complex health care needs. Our healthcare system struggles to meet their needs because of sectoral fragmentation and episodic models of care. Children with medical complexity (CMC) currently rely on tertiary paediatric hospitals for most of their healthcare, but this is not sustainable. We evaluated the impacts of Care Coordination on tertiary hospital service use and family outcomes. Methods A pre- and post-implementation cohort evaluation of the Care Coordination service at a tertiary paediatric hospital network, was undertaken. From July 2015 CMC enrolled in the service had access to a Care Coordinator, shared-care plans, linkage with local general practitioners (GPs), and access to a 24-h Hotline from August 2016. CMC were those with ≥4 emergency department (ED) presentations, hospital stays of ≥14 days, or ≥ 10 outpatient appointments in 12 months. Medically fragile infants at risk of frequent future hospital utilisation, and children with medical problems complicated by difficult family psychosocial circumstances were also included. Care Coordinators collected outcomes for each enrolled child. Administrative data on hospital encounters 6 months pre- and post-enrolment were analysed for children aged > 6 months. Results An estimated 557 hospital encounters, were prevented in the 6 months after enrolment, for 534 children aged > 6 months. ED presentations decreased by 40% (Chi2 = 37.95; P

Introduction Although care for neonates with cardiac disease is frequently provided by neonatologists and pediatric cardiologists, training in the multidisciplinary management of neonatal cardiac emergencies is not often included in fellowship training. We created a multidisciplinary simulation curriculum to address the skills needed for neonatal cardiac care. Methods Neonatology and pediatric cardiology fellows participated in 1-hour simulations on 3 different days. They managed a neonate with: (1) cyanosis, (2) cardiogenic shock, and (3) an unstable arrhythmia. Using both remote consultation and bedside evaluation, the participants diagnosed and jointly established a management plan for the infant. During the debrief, facilitators reviewed the clinical decisions and multidisciplinary management skills of the participants. Participants completed pre- and postparticipation surveys to evaluate the curriculum's effect on their confidence in the management of neonatal cardiac disease. Results Thirty-three paired survey responses from 20 participants (11 neonatology and 9 pediatric cardiology) reported a mean overall satisfaction score of 4.6 (SD = 0.7) based on a 5-point Likert scale. Postparticipation confidence scores improved significantly in: (1) the recognition of the signs of congenital heart disease (pre = 4.1, post = 4.5, p = .01), (2) differentiation of cardiac cyanosis from noncardiac cyanosis (pre = 3.9, post = 4.2, p = .05), and (3) confidence in discussing cardiac concerns with consultants (pre = 3.3, post = 4.1, p = .02). Discussion This multidisciplinary simulation improved fellows’ confidence in the management of neonates with cardiac disease and provided an opportunity to practice team work, remote consultation, and cross-disciplinary communication.

Abstract Background Children with medical complexity (CMC) have a wide range of long term health problems and disabilities that have an adverse impact on their quality of life. They have high levels of family identified health care needs and health care utilisation. There is no Australian literature on the experiences of health care providers working in the Australian tertiary, secondary and primary health care system, whilst managing CMC. This information is essential to inform the design of integrated health care systems for these children. We address this knowledge gap by exploring the perceptions and experiences of health care providers on the provision of health care for CMC aged 0 to 18 years. Method A qualitative research study was undertaken. Stakeholder forums, group and individual in depth interviews were undertaken using a semi-structured interview guide. The stakeholder forums were audio recorded and transcribed verbatim. Field notes of the stakeholder forums, group and individual interviews were taken. Inductive thematic analysis was undertaken to identify key themes. Results One hundred and three providers took part in the stakeholder forums and interviews across 3 local health districts, a tertiary paediatric hospital network, and primary health care organisations. Providers expressed concern regarding family capacity to negotiate the system, which was impacted by the medical complexity of the children and psychosocial complexity of their families. Lack of health care provider capacity in terms of their skills, time and availability to manage CMC was also a key problem. These issues occurred within a health system that had impaired capacity in terms of fragmentation of care and limited communication among health care providers. Conclusion When designing integrated care models for CMC, it is essential to understand and address the challenges experienced by their health care providers. This requires adequate training of providers, additional resources and time for coordination of care, improved systems of communication among services, with timely access to key information for parents and providers.

It has been hypothesized that a decrease in the synthesis of new neurons in the adult hippocampus might be linked to major depressive disorder (MDD). This hypothesis arose after it was discovered that antidepressant medications increased the synthesis of new neurons in the brain, and it was noted that the therapeutic effects of antidepressants occurred over a time span that approximates the time taken for the new neurons to become functional. Like antidepressants, exercise also increases the synthesis of new neurons in the adult brain: a 2-3-fold increase in hippocampal neurogenesis has been observed in rats with regular access to a running wheel when they are compared with control animals. We hypothesized, based on the adult-neurogenesis hypothesis of MDD, that exercise should alleviate the symptoms of MDD and that potential mechanisms should exist to explain this therapeutic effect. Accordingly, we evaluated studies that suggest that exercise is an effective treatment for MDD, and we explored potential mechanisms that could link adult neurogenesis, exercise and MDD. We conclude that there is evidence to support the hypothesis that exercise alleviates MDD and that several mechanisms exist that could mediate this effect through adult neurogenesis. [ABSTRACT FROM AUTHOR]

Abstract Methamphetamine addiction is mimicked in rats that self-administer the drug. However, these self-administration (SA) models do not include adverse consequences that are necessary to reach a diagnosis of addiction in humans. Herein, we measured genome-wide transcriptional consequences of methamphetamine SA and footshocks in the rat brain. We trained rats to self-administer methamphetamine for 20 days. Thereafter, lever-presses for methamphetamine were punished by mild footshocks for 5 days. Response-contingent punishment significantly reduced methamphetamine taking in some rats (shock-sensitive, SS) but not in others (shock-resistant, SR). Rats also underwent extinction test at one day and 30 days after the last shock session. Rats were euthanized one day after the second extinction test and the nucleus accumbens (NAc) and dorsal striatum were collected to measure gene expression with microarray analysis. In the NAc, there were changes in the expression of 13 genes in the SRvsControl and 9 genes in the SRvsSS comparison. In the striatum, there were 9 (6 up, 3 down) affected genes in the SRvsSS comparison. Among the upregulated genes was oxytocin in the NAc and CARTpt in the striatum of SR rats. These observations support a regional role of neuropeptides in the brain after a long withdrawal interval when animals show incubation of methamphetamine craving.

Introduction: Asthma is the most common chronic illness of childhood. Frequent asthma attacks may result in unscheduled hospital presentations. Unscheduled hospital presentations are a marker of poorly controlled asthma - a significant burden to the health systems and families. Following hospital presentation, the New South Wales (NSW) clinical practice guideline suggests follow-up with the general practitioner (GPs) within 3-5 days. However many children only have their asthma reviewed in hospitals when there is an acute attack rather than having a planned GP review. Implementation of practice change: The Sydney Children’s Hospitals Network (SCHN) Asthma Follow Up Integrated Care Initiative assembled a multidisciplinary team of clinicians, nurses, GPs, managers, researchers, and consumer representatives. The team created a driver diagram to identify change ideas and developed an integrated model of care to improve post-discharge follow-up of children with non-complex asthma Aim: To reduce emergency department (ED) presentations, through improved asthma management and increased engagement with their GPs. Targeted population and stakeholders: Children aged 2-16 years of age with non-complex asthma or viral induced wheeze (VIW), local health partners and parents/carers. Timeline: December 2016-February 2018 Innovation: The integrated model of care included the following: 1- All children, presenting to ED with non-complex asthma/VIW, for ≥4 times in a 12 month period were flagged in electronic medical record system .Care coordinators (CCs) contacted the parents and requested that their child have a review with their GP, and also offered referral to asthma education sessions. 2- A letter was sent to the child’s GP by the CC advising of the child’s recent hospital presentation. This letter contained asthma best practice points, encouraged influenza vaccination, review of asthma action plan, preventer medication and referral to a paediatrician if necessary. 3- Parents were also given a standardised asthma/ VIW resource pack upon discharge from ED which included individualized Asthma Action Plan, asthma information pack and discharge instructions (including recommended follow-up with a GP). Impact: We compared the number of asthma ED presentations for these children six months pre and post enrolment using Wilcoxon signed-rank test. Outcomes: A total of 57 children were contacted by CCs. The median age of the children was 4 years (IQR 3-5 years). The median numbers of ED presentations in the six months preceding enrolment in the program was 2 (IQR 2-3) and post enrolment was 1 (IQR 0-1). There was a 57% reduction in number of children who presented to the ED ≥4 times in the 12 months period post implementation of the program (z=3.25, p =0.001). Sustainability: The initiative has been adopted as routine clinical practice within SCHN. Transferability: Although the model was evaluated within the SCHN , based on the positive preliminary findings the model can be scaled up across all local health districts of NSW. Conclusion: A comprehensive integrated approach to asthma management may reduce frequent ED presentations due to asthma in children. Lessons learned: It is important to have a collaborative multidisciplinary team, in order to share expertise, understand all view points and effectively implement change.

Introduction: Over a third of Australian children have long-term health conditions, often involving multiple organ systems and resulting in complex health care needs. Our healthcare system struggles to meet their needs because of sectoral fragmentation and episodic models of care. Children with medical complexity (CMC) currently rely on tertiary paediatric hospitals for most of their healthcare, but this is not sustainable. We evaluated the impacts of Care Coordination on tertiary hospital service use and family outcomes. Theory/Methods: A pre- and post-implementation cohort evaluation of the Care Coordination service at a large tertiary paediatric hospitals network in Sydney Australia, was undertaken. From July 2015 CMC enrolled in the service had access to a Care Coordinator, shared-care plans, linkage with local general practitioners (GPs), and access to a 24-hour Hotline. We targeted CMC if they had ≥ 4 emergency department (ED) presentations, hospital stays of ≥14 days, or ≥10 outpatient appointments in the previous year, or who had difficult family psychosocial circumstances. Hospital encounters according to administrative data 6 months pre- and post-enrolment were analysed. Family outcomes were measured in terms of travel distances saved and estimated out-of-pocket and productivity costs saved according to published estimates of AU$589 per day of hospital admission. (1) Results: An estimated 557 hospital encounters were prevented in the 6 months after enrolment, for 534 children aged >6 months. ED presentations decreased by 40% (Chi2=37.95; P

Introduction: Children with medical complexity (CMC) require highly specialised care, often from multiple providers and over many years. This paper describes the first 18 months of development of the Kids Guided Personalised Services (GPS) Integrated Care Program (the Program). This Program aims to improve health care experience; communication and to streamline provision of care. Discussion: Key enablers across the Program were put in place and 5 individual project streams were used to implement change. An extensive formative evaluation process was undertaken to truly understand all perspectives in developing the Program. Conclusion/Key Lessons: This Program supports families who are caring for CMC by developing shared care models that bring together local health services with the tertiary hospitals. The methodology used has resulted in comprehensive system change and transformation; reduced presentations to the Emergency Department (ED), avoidable admissions and travel time. A challenge remains in meaningfully engaging primary health care providers.

Introduction The new model in medical education of longitudinal clinical clerkships can be complemented by high-technology simulation, which provides a safe space for learners to consolidate clinical knowledge and practice decision-making skills, teamwork, and communication. We developed an interdisciplinary training intervention including a simulation case and structured debriefing to link clinical content between pediatrics and obstetrics at a major academic medical center. Methods In this case, a 38-year-old female at 38 weeks gestation presents with onset of labor complicated by shoulder dystocia. After the appropriate maneuvers, a depressed neonate is delivered and requires resuscitation. Major equipment needed includes a high- or low-technology birthing mannequin and an infant mannequin. Results Fifty-four third-year medical students participated in this simulation-based intervention at the completion of their integrated pediatrics and obstetrics clerkship. Ninety-one percent of students agreed that the shoulder dystocia simulation was designed appropriately for their learning level and enhanced their ability to handle a risky delivery. Ninety-four percent agreed that the neonatal resuscitation simulation was designed appropriately for their learning level, and 89% reported an enhanced ability to handle a similar situation in the clinic following the intervention. The average overall ratings were 4.24 (SD = 0.61) and 4.06 (SD = 0.89) on a 5-point scale (1 = poor, 5 = excellent) for the obstetrics and pediatrics simulations, respectively. Discussion The integrated obstetrics and pediatrics scenario is feasible to run and clinically accurate. Two distinct areas of medicine in the third-year curriculum are logically incorporated into one cohesive simulation-based training intervention that students found positive and realistic.

Neuroplastic changes in the dorsal striatum participate in the transition from casual to habitual drug use and might play a critical role in the development of methamphetamine (METH) addiction. We examined the influence of METH self-administration on gene and protein expression that may form substrates for METH-induced neuronal plasticity in the dorsal striatum. Male Sprague–Dawley rats self-administered METH (0.1 mg/kg/injection, i.v.) or received yoked saline infusions during eight 15-h sessions and were euthanized 2 h, 24 h, or 1 month after cessation of METH exposure. Changes in gene and protein expression were assessed using microarray analysis, RT-PCR and Western blots. Chromatin immunoprecipitation (ChIP) followed by PCR was used to examine epigenetic regulation of METH-induced transcription. METH self-administration caused increases in mRNA expression of the transcription factors, c-fos and fosb, the neurotrophic factor, Bdnf, and the synaptic protein, synaptophysin (Syp) in the dorsal striatum. METH also caused changes in ΔFosB, BDNF and TrkB protein levels, with increases after 2 and 24 h, but decreases after 1 month of drug abstinence. Importantly, ChIP-PCR showed that METH self-administration caused enrichment of phosphorylated CREB (pCREB), but not of histone H3 trimethylated at lysine 4 (H3K4me3), on promoters of c-fos, fosb, Bdnf and Syp at 2 h after cessation of drug intake. These findings show that METH-induced changes in gene expression are mediated, in part, by pCREB-dependent epigenetic phenomena. Thus, METH self-administration might trigger epigenetic changes that mediate alterations in expression of genes and proteins serving as substrates for addiction-related synaptic plasticity.

Abstract This resource presents three task-training models for critical neonatal intensive care procedures: chest tube insertion, exchange transfusion, and pericardiocentesis. Practicing in a simulated environment has many advantages when the procedure is rarely encountered and of a critical, high-risk nature. Commercially produced models for these procedures are either not available or are prohibitively expensive. The models described in this submission are constructed from simple materials and easily available products. They are realistic and simple enough to immerse the learner in the procedure, rather than distract them with complex technology. Each model is described in detail so that it can be recreated by users. All key aspects of the design, construction, and use of models are provided. Clear photographs of the models including details about the construction are included in the manuscript. We have used these models in a training program for neonatal fellows, pediatric residents, nurse practitioners, physician assistants, and medical students. Learners in our institution and simulation educators at an international simulation conference have used these models. They have reported increased confidence and have demonstrated mastery of the techniques in live scenarios. These models are intended to allow learners to practice their skills in a low risk environment. Learners are required to repeat the procedures until they feel confident and demonstrate mastery on objective skills assessment.

Methamphetamine (METH) is a widely abused amphetamine analog. Few studies have investigated the molecular effects of METH exposure in adult animals. Herein, we determined the consequences of an injection of METH (10 mg/kg) on transcriptional effects of a second METH (2.5 mg/kg) injection given one month later. We thus measured gene expression by microarray analyses in the nucleus accumbens (NAc) of 4 groups of rats euthanized 2 hours after the second injection: saline-pretreated followed by saline-challenged (SS) or METH-challenged (SM); and METH-pretreated followed by saline-challenged (MS) or METH-challenged (MM). Microarray analyses revealed that METH (2.5 mg/kg) produced acute changes (1.8-fold; P

Methamphetamine (METH) addiction is associated with several neuropsychiatric symptoms. Little is known about the effects of METH on gene expression and epigenetic modifications in the rat nucleus accumbens (NAC). Our study investigated the effects of a non-toxic METH injection (20 mg/kg) on gene expression, histone acetylation, and the expression of the histone acetyltransferase (HAT), ATF2, and of the histone deacetylases (HDACs), HDAC1 and HDAC2, in that structure. Microarray analyses done at 1, 8, 16 and 24 hrs after the METH injection identified METH-induced changes in the expression of genes previously implicated in the acute and longterm effects of psychostimulants, including immediate early genes and corticotropin-releasing factor (Crf). In contrast, the METH injection caused time-dependent decreases in the expression of other genes including Npas4 and cholecystokinin (Cck). Pathway analyses showed that genes with altered expression participated in behavioral performance, cell-to-cell signaling, and regulation of gene expression. PCR analyses confirmed the changes in the expression of c-fos, fosB, Crf, Cck, and Npas4 transcripts. To determine if the METH injection caused post-translational changes in histone markers, we used western blot analyses and identified METH-mediated decreases in histone H3 acetylated at lysine 9 (H3K9ac) and lysine 18 (H3K18ac) in nuclear sub-fractions. In contrast, the METH injection caused time-dependent increases in acetylated H4K5 and H4K8. The changes in histone acetylation were accompanied by decreased expression of HDAC1 but increased expression of HDAC2 protein levels. The histone acetyltransferase, ATF2, showed significant METH-induced increased in protein expression. These results suggest that METH-induced alterations in global gene expression seen in rat NAC might be related, in part, to METH-induced changes in histone acetylation secondary to changes in HAT and HDAC expression. The causal role that HATs and HDACs might play in METH-induced gene expression needs to be investigated further.

Methamphetamine (METH) is a toxic drug of abuse, which can cause significant decreases in the levels of monoamines in various brain regions. However, animals treated with progressively increasing doses of METH over several weeks are protected against the toxic effects of the drug. In the present study, we tested the possibility that this pattern of METH injections might be associated with transcriptional changes in the rat striatum, an area of the brain which is known to be very sensitive to METH toxicity and which is protected by METH preconditioning. We found that the presence and absence of preconditioning followed by injection of large doses of METH caused differential expression in different sets of striatal genes. Quantitative PCR confirmed METH-induced changes in some genes of interest. These include small heat shock 27 kD proteins 1 and 2 (HspB1 and HspB2), brain derived neurotrophic factor (BDNF), and heme oxygenase-1 (Hmox-1). Our observations are consistent with previous studies which have reported that ischemic or pharmacological preconditioning can cause reprogramming of gene expression after lethal ischemic insults. These studies add to the growing literature on the effects of preconditioning on the brain transcriptome.

Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle are used extensively as a model of Parkinson's disease. The present experiments sought to identify genes that were affected in the dopamine (DA)-denervated striatum after 6-hydroxydopamine-induced destruction of the nigrostriatal dopaminergic pathway in the rat. We also examined whether a single injection of methamphetamine (METH) (2.5 mg/kg) known to cause changes in gene expression in the normally DA-innervated striatum could still influence striatal gene expression in the absence of DA. Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle resulted in METH-induced rotational behaviors ipsilateral to the lesioned side and total striatal DA depletion on the lesioned side. This injection also caused decrease in striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels. DA depletion was associated with increases in 5-HIAA/5-HT ratios that were potentiated by the METH injection. Microarray analyses revealed changes (±1.7-fold, p

Abstract Background Cognitive deficits are a hallmark feature of both Down Syndrome (DS) and Alzheimer's Disease (AD). Extra copies of the genes on chromosome 21 may also play an important role in the accelerated onset of AD in DS individuals. Growing evidence suggests an important function for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of Aβ peptides. The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromosome 21, and participates in the maintenance of tissue cholesterol homeostasis. Results To assess the role of ABCG1 in DS-related cognition, we evaluated the cognitive performance of mice selectively over-expressing the ABCG1 gene from its endogenous regulatory signals. Both wild-type and ABCG1 transgenic mice performed equivalently on several behavioral tests, including measures of anxiety, as well as on reference and working memory tasks. No deficits in hippocampal CA1 synaptic plasticity as determined with electrophysiological studies were apparent in mice over-expressing ABCG1. Conclusion These findings indicate that although ABCG1 may play a role in maintaining cellular or tissue cholesterol homeostasis, it is unlikely that excess ABCG1 expression contributes to the cognitive deficits in DS individuals.

Background: Fetal alcohol spectrum disorder (FASD) is one of the leading causes of neurodevelopmental disorder for which there is a pressing need for an effective treatment. Recent studies have investigated the essential nutrient choline as a postnatal treatment option. Supplementation with choline has produced improvements in behavioral tasks related to learning and memory and reverted changes in methylation signature following third-trimester equivalent ethanol exposure. We examined whether there are related improvements in hippocampal synaptic plasticity in vivo., Methods: Sprague-Dawley offspring were administered binge-levels of ethanol from postnatal day (PND) 4 to 9, then treated with choline chloride (100 mg/kg/day) from PND 10 to 30. In vivo electrophysiology was performed on male and female offspring from PND 55 to 70. Long-term potentiation (LTP) was induced in the medial perforant pathway of the dentate gyrus using a theta-burst stimulation (TBS) protocol, and field-evoked postsynaptic potentials (EPSPs) were evoked for 60 min following the conditioning stimulus., Results: Developmental ethanol exposure caused long-lasting deficits in LTP of the slope of the evoked responses and in the amplitude of the population spike potentiation. Neither deficit was rescued by postnatal choline supplementation., Conclusions: In contrast to our prior findings that choline can improve hippocampal plasticity (Nutrients, 2022, 14, 2004), here we found that deficits in hippocampal synaptic plasticity due to developmental ethanol exposure persisted into adulthood despite adolescent choline supplementation. Future research should examine more subtle changes in synaptic plasticity to identify synaptic changes that mirror behavioral improvements., (© 2024 The Author(s). Alcohol, Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.)

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is the leading known single-gene cause of autism spectrum disorder. Patients with FXS display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently, there is no cure for this condition; however, there is an emerging focus on therapies that inhibit mechanistic target of rapamycin (mTOR)-dependent protein synthesis owing to the clinical effectiveness of metformin for alleviating some behavioural symptoms in FXS. Adiponectin (APN) is a neurohormone that is released by adipocytes and provides an alternative means to inhibit mTOR activation in the brain. In these studies, we show that Fmr1 knockout mice, like patients with FXS, show reduced levels of circulating APN and that both long-term potentiation (LTP) and long-term depression (LTD) in the dentate gyrus (DG) are impaired. Brief (20 min) incubation of hippocampal slices in APN (50 nM) was able to rescue both LTP and LTD in the DG and increased both the surface expression and phosphorylation of GluA1 receptors. These results provide evidence for reduced APN levels in FXS playing a role in decreasing bidirectional synaptic plasticity and show that therapies which enhance APN levels may have therapeutic potential for this and related conditions.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Background: Cannabis is increasingly being legalized and socially accepted around the world and is often used with alcohol in social settings. We recently showed that in utero exposure to both substances can alter the density of parvalbumin-expressing interneurons in the hippocampus. Here we investigate the effects of in utero alcohol and cannabis exposure, alone or in combination, on somatostatin- and neuropeptide Y-positive (NPY) interneurons. These are separate classes of interneurons important for network synchrony and inhibition in the hippocampus., Methods: A 2 (Ethanol, Air) × 2 (tetrahydrocannabinol [THC], Vehicle) design was used to expose pregnant Sprague-Dawley rats to either ethanol or air, in addition to either THC or the inhalant vehicle solution, during gestational days 5-20. Immunohistochemistry for somatostatin- and NPY-positive interneurons was performed in 50 μm tissue sections obtained at postnatal day 70., Results: Exposure to THC in utero had region-specific and sex-specific effects on the density of somatostatin-positive interneurons in the adult rat hippocampus. A female-specific decrease in NPY interneuron cell density was observed in the CA1 region following THC exposure. Combined exposure to alcohol and THC reduced NPY neurons selectively in the ventral dentate gyrus hippocampal subfield. However, overall, co-exposure to alcohol and cannabis had neither additive nor synergistic effects on interneuron populations in other areas of the hippocampus., Conclusions: These results illustrate how alcohol and cannabis exposure in utero may affect hippocampal function by altering inhibitory processes in a sex-specific manner., (© 2024 The Authors. Alcohol, Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.)

The reliable induction of long-term potentiation (LTP) in the dentate gyrus (DG) in vitro requires the blockade of the γ-aminobutyric acid A (GABA A ) receptor. In these studies we examined the effectiveness of the specific GABA A receptor antagonist bicuculline methiodide (BMI) in facilitating LTP in the DG from hippocampal slices obtained from either C57Bl/6 mice or Sprague-Dawley rats, two species commonly used for electrophysiology. In the C57Bl/6 mice, maximal short-term potentiation and LTP in the DG were produced with a concentration of 5 µM BMI. In contrast, a concentration of 10 μM BMI was required to produce maximal short-term potentiation and LTP in the DG of Sprague-Dawley rats. These results reveal that there are species differences in the optimal amount of BMI required to produce robust and reliable LTP in the rodent DG in vitro and highlight the need to take consideration of the species being used when choosing concentrations of pharmacological agents to employ for electrophysiological use. NEW & NOTEWORTHY In this report we provide specific neurophysiological evidence for concentrations of GABA A antagonist required to study long-term potentiation in the medial perforant pathway of the dentate gyrus. Two commonly used species, Sprague-Dawley rats and C57Bl/6 mice, require different concentrations of bicuculline methiodide to induce optimal short-term and long-term potentiation.

The metabotropic glutamate receptor 7 (mGluR7) is a presynaptic G-protein-coupled glutamate receptor that modulates neurotransmitter release and synaptic plasticity at presynaptic terminals. It is encoded by GRM7, and recently variants have been identified in patients with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), developmental delay (DD), intellectual disability (ID), and brain malformations. To gain updated insights into the function of GRM7 and the phenotypic spectrum of genetic variations within this gene, we conducted a systematic review of relevant literature utilizing PubMed, Web of Science, and Scopus databases. Among the 14 articles meeting the inclusion criteria, a total of 42 patients (from 28 families) harboring confirmed mutations in the GRM7 gene have been documented. Specifically, there were 17 patients with heterozygous mutations, 20 patients with homozygous mutations, and 5 patients with compound heterozygous mutations. Common clinical features included intellectual behavioral disability, seizure/epilepsy, microcephaly, developmental delay, peripheral hypertonia and hypomyelination. Genotype-phenotype correlation was not clear and each variant had unique characteristics including gene dosage, mutant protein surface expression, and degradation pathway that result with a spectrum of phenotype manifestations through ASD or ADHD to severe DD/ID with brain malformations. Neuroinflammation may play a role in the development and/or progression of GRM7-related neurodegeneration along with excitotoxicity. The clinical and functional data presented here demonstrate that both autosomal dominant and recessive inheritance of GRM7 mutation can cause disease spectrum phenotypes through ASD or ADHD to severe DD/ID and seizure with brain malformations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)

Childhood represents a period of significant growth and maturation for the brain, and is also associated with a heightened risk for mild traumatic brain injuries (mTBI). There is also concern that repeated-mTBI (r-mTBI) may have a long-term impact on developmental trajectories. Using an awake closed head injury (ACHI) model, that uses rapid head acceleration to induce a mTBI, we investigated the acute effects of repeated-mTBI (r-mTBI) on neurological function and cellular proliferation in juvenile male and female Long-Evans rats. We found that r-mTBI did not lead to cumulative neurological deficits with the model. R-mTBI animals exhibited an increase in BrdU + (bromodeoxyuridine positive) cells in the dentate gyrus (DG), and that this increase was more robust in male animals. This increase was not sustained, and cell proliferation returning to normal by PID3. A greater increase in BrdU + cells was observed in the dorsal DG in both male and female r-mTBI animals at PID1. Using Ki-67 expression as an endogenous marker of cellular proliferation, a robust proliferative response following r-mTBI was observed in male animals at PID1 that persisted until PID3, and was not constrained to the DG alone. Triple labeling experiments (Iba1+, GFAP+, Brdu+) revealed that a high proportion of these proliferating cells were microglia/macrophages, indicating there was a heightened inflammatory response. Overall, these findings suggest that rapid head acceleration with the ACHI model produces an mTBI, but that the acute neurological deficits do not increase in severity with repeated administration. R-mTBI transiently increases cellular proliferation in the hippocampus, particularly in male animals, and the pattern of cell proliferation suggests that this represents a neuroinflammatory response that is focused around the mid-brain rather than peripheral cortical regions. These results add to growing literature indicating sex differences in proliferative and inflammatory responses between females and males. Targeting proliferation as a therapeutic avenue may help reduce the short term impact of r-mTBI, but there may be sex-specific considerations., (© 2023. The Author(s).)

Many traumatic brain injury (TBI) survivors face scheduling and transportation challenges when seeking therapeutic interventions. The COVID-19 pandemic created a shift in the use of at-home spaces for work, play, and research, inspiring the development of online therapeutic options. In the current study, we determined the feasibility of an at-home cognitive training tool (NeuroTrackerX) that uses anaglyph three-dimensional (3D) glasses and three-dimensional multiple object tracking (3D-MOT) software. We recruited 20 adults (10 female; mean age = 68.3 years, standard deviation [SD] = 6.75) as the at-home training group. We assessed cognitive health status for participants using a self-report questionnaire and the Mini-Mental State Examination (MMSE), and all participants were deemed cognitively healthy (MMSE >26). At-home participants loaned the necessary equipment (e.g., 3D glasses, computer equipment) from the research facilities and engaged in 10 training sessions over 5 weeks (two times per week). Participant recruitment, retention, adherence, and experience were used as markers of feasibility. For program validation, 20 participants (10 female; mean age = 63.39 years, SD = 12.22), who had previously completed at least eight sessions of the in-lab 3D-MOT program, were randomly selected as the control group. We assessed individual session scores, overall improvement, and learning rates between groups. Program feasibility is supported by high recruitment and retention, 90% participant adherence, and participants' ease of use of the program. Validation of the program is supported. Groups showed no differences in session scores ( p  > 0.05) and percentage improvement ( p  > 0.05) despite the differences in screen size and 3D technology. Participants in both groups showed significant improvements in task performance across the training sessions ( p  < 0.001). NeuroTrackerX provides a promising at-home option for cognitive training in cognitively healthy adults and may be a promising avenue as an at-home therapeutic for TBI survivors. This abstract was previously published on clinicaltrials.gov and can be found at: https://www.clinicaltrials.gov/ct2/show/NCT05278273., Competing Interests: J.F. is Director of the Faubert Lab at the University of Montreal and is a co-founder of CogniSens Athletics Inc, which produces the commercial versions of the NeuroTracker and NeuroTrackerX used in this study. In this capacity, he holds shares in the company., (© Taylor Snowden et al., 2023; Published by Mary Ann Liebert, Inc.)

Over the past decade, ketamine, an NMDA receptor antagonist, has demonstrated fast-acting antidepressant effects previously unseen with monoaminergic-based therapeutics. Concerns regarding psychotomimetic effects limit the use of ketamine for certain patient populations. Reelin, an extracellular matrix glycoprotein, has shown promise as a putative fast-acting antidepressant in a model of chronic stress. However, research has not yet demonstrated the changes that occur rapidly after peripheral reelin administration. To address this key gap in knowledge, male Long-Evans rats underwent a chronic corticosterone (CORT; or vehicle) paradigm (40 mg/kg, 21 d). On day 21, rats were then administered an acute dose of ketamine (10 mg/kg, i.p.), reelin (3 µg, i.v.), or vehicle. Twenty-four hours after administration, rats underwent behavioral or in vivo electrophysiological testing before killing. Immunohistochemistry was used to confirm changes in hippocampal reelin immunoreactivity. Lastly, the hippocampus was microdissected from fresh tissue to ascertain whole cell and synaptic-specific changes in protein expression through Western blotting. Chronic corticosterone induced a chronic stress phenotype in the forced swim test and sucrose preference test (SPT). Both reelin and ketamine rescued immobility and swimming, however reelin alone rescued latency to immobility. In vivo electrophysiology revealed decreases in hippocampal long-term potentiation (LTP) after chronic stress which was increased significantly by both ketamine and reelin. Reelin immunoreactivity in the dentate gyrus paralleled the behavioral and electrophysiological findings, but no significant changes were observed in synaptic-level protein expression. This exploratory research supports the putative rapid-acting antidepressant effects of an acute dose of reelin across behavioral, electrophysiological, and molecular measures., (Copyright © 2023 Johnston et al.)

Traumatic brain injury (TBI) and stress are prevalent worldwide and can both result in life-altering health problems. While stress often occurs in the absence of TBI, TBI inherently involves some element of stress. Furthermore, because there is pathophysiological overlap between stress and TBI, it is likely that stress influences TBI outcomes. However, there are temporal complexities in this relationship (e.g., when the stress occurs) that have been understudied despite their potential importance. This paper begins by introducing TBI and stress and highlighting some of their possible synergistic mechanisms including inflammation, excitotoxicity, oxidative stress, hypothalamic-pituitary-adrenal axis dysregulation, and autonomic nervous system dysfunction. We next describe different temporal scenarios involving TBI and stress and review the available literature on this topic. In doing so we find initial evidence that in some contexts stress is a highly influential factor in TBI pathophysiology and recovery, and vice versa. We also identify important knowledge gaps and suggest future research avenues that will increase our understanding of this inherent bidirectional relationship and could one day result in improved patient care., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cannabis use has risen dramatically in recent years due to global decriminalization and a resurgence in the interest of potential therapeutic benefits. While emerging research is shaping our understanding of the benefits and harms of cannabis, there remains a paucity of data specifically focused on how cannabis affects the female population. The female experience of cannabis use is unique, both in the societal context and because of the biological ramifications. This is increasingly important given the rise in cannabis potency, as well as the implications this has for the prevalence of Cannabis Use Disorder (CUD). Therefore, this scoping review aims to discuss the prevalence of cannabis use and CUD in women throughout their lifespan and provide a balanced prospective on the positive and negative consequences of cannabis use. In doing so, this review will highlight the necessity for continued research that goes beyond sex differences., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A growing body of evidence has implicated progranulin in neurodevelopment and indicated that aberrant progranulin expression may be involved in neurodevelopmental disease. Specifically, increased progranulin expression in the prefrontal cortex has been suggested to be pathologically relevant in male Fmr1 knockout ( Fmr1 KO) mice, a mouse model of Fragile X Syndrome (FXS). Further investigation into the role of progranulin in FXS is warranted to determine if therapies that reduce progranulin expression represent a viable strategy for treating patients with FXS. Several key knowledge gaps remain. The mechanism of increased progranulin expression in Fmr1 KO mice is poorly understood and the extent of progranulin's involvement in FXS-like phenotypes in Fmr1 KO mice has been incompletely explored. To this end, we have performed a thorough characterization of progranulin expression in Fmr1 KO mice. We find that the phenomenon of increased progranulin expression is post-translational and tissue-specific. We also demonstrate for the first time an association between progranulin mRNA and FMRP, suggesting that progranulin mRNA is an FMRP target. Subsequently, we show that progranulin over-expression in Fmr1 wild-type mice causes reduced repetitive behaviour engagement in females and mild hyperactivity in males but is largely insufficient to recapitulate FXS-associated behavioural, morphological, and electrophysiological abnormalities. Lastly, we determine that genetic reduction of progranulin expression on an Fmr1 KO background reduces macroorchidism but does not alter other FXS-associated behaviours or biochemical phenotypes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V.)

Mild traumatic brain injuries (mTBIs) are a prevalent health issue in North America. There is increasing pressure to utilize ecologically valid models of closed-head mTBI in the preclinical setting to increase translatability to the clinical population. The awake closed-headed injury (ACHI) model uses a modified controlled cortical impactor to deliver closed-headed injury, inducing clinically relevant behavioral deficits without the need for a craniotomy or the use of an anesthetic. This technique does not normally induce fatalities, skull fractures, or brain bleeds, and is more consistent with being a mild injury. Indeed, the mild nature of the ACHI procedure makes it ideal for studies investigating repetitive mTBI (r-mTBI). Growing evidence indicates that r-mTBI can result in a cumulative injury that produces behavioral symptoms, neuropathological changes, and neurodegeneration. r-mTBI is common in youths playing sports, and these injuries occur during a period of robust synaptic reorganization and myelination, making the younger population particularly vulnerable to the long-term influences of r-mTBI. Further, r-mTBI occurs in cases of intimate partner violence, a condition for which there are few objective screening measures. In these experiments, synaptic function was assessed in the hippocampus in juvenile rats that had experienced r-mTBI using the ACHI model. Following the injuries, a tissue slicer was utilized to make hippocampal slices to evaluate bidirectional synaptic plasticity in the hippocampus at either 1 or 7 days following the r-mTBI. Overall, the ACHI model provides researchers with an ecologically valid model to study changes in synaptic plasticity following mTBI and r-mTBI.

Prenatal ethanol exposure (PNEE) is a leading cause of neurodevelopmental impairments, yet treatments for individuals with PNEE are limited. Importantly, postnatal supplementation with the essential nutrient choline can attenuate some adverse effects of PNEE on cognitive development; however, the mechanisms of action for choline supplementation remain unclear. This study used an animal model to determine if choline supplementation could restore hippocampal synaptic plasticity that is normally impaired by prenatal alcohol. Throughout gestation, pregnant Sprague Dawley rats were fed an ethanol liquid diet (35.5% ethanol-derived calories). Offspring were injected with choline chloride (100 mg/kg/day) from postnatal days (PD) 10-30, and then used for in vitro electrophysiology experiments as juveniles (PD 31-35). High-frequency conditioning stimuli were used to induce long-term potentiation (LTP) in the medial perforant path input to the dentate gyrus of the hippocampus. PNEE altered synaptic transmission in female offspring by increasing excitability, an effect that was mitigated with choline supplementation. In contrast, PNEE juvenile males had decreased LTP compared to controls, and this was rescued by choline supplementation. These data demonstrate sex-specific changes in plasticity following PNEE, and provide evidence that choline-related improvements in cognitive functioning may be due to its positive impact on hippocampal synaptic physiology.

Choline is an essential nutrient under evaluation as a cognitive enhancing treatment for fetal alcohol spectrum disorders (FASD) in clinical trials. As a result, there is increased pressure to identify therapeutic mechanism(s) of action. Choline is not only a precursor for several essential cell membrane components and signaling molecules but also has the potential to directly affect synaptic mechanisms that are believed important for cognitive processes. In the current work, we study how the direct application of choline can affect synaptic transmission in the dentate gyrus (DG) of hippocampal slices obtained from adolescent ( postnatal days 21-28 ) Sprague-Dawley rats ( Rattus norvegicus ). The acute administration of choline chloride (2 mM) reliably induced a long-term depression (LTD) of field excitatory postsynaptic potentials (fEPSPs) in the DG in vitro. The depression required the involvement of M1 receptors, and the magnitude of the effect was similar in slices obtained from male and female animals. To further study the impact of choline in an animal model of FASD, we examined offspring from dams fed an ethanol-containing diet (35.5% ethanol-derived calories) throughout gestation. In slices from the adolescent animals that experienced prenatal ethanol exposure (PNEE), we found that the choline induced an LTD that uniquely involved the activation of N -methyl-d-aspartate (NMDA) and M1 receptors. This study provides a novel insight into how choline can modulate hippocampal transmission at the level of the synapse and that it can have unique effects following PNEE. NEW & NOTEWORTHY Choline supplementation is a nutraceutical therapy with significant potential for a variety of developmental disorders; however, the mechanisms involved in its therapeutic effects remain poorly understood. Our research shows that choline directly impacts synaptic communication in the brain, inducing a long-term depression of synaptic efficacy in brain slices. The depression is equivalent in male and female animals, involves M1 receptors in control animals, but uniquely involves NMDA receptors in a model of FASD.

Background: We recently showed that alcohol and cannabis can interact prenatally, and in a recent review paper, we identified parvalbumin-positive (PV) interneurons in the hippocampus as a potential point of convergence for these teratogens., Methods: A 2 (Ethanol [EtOH], Air) × 2 (tetrahydrocannabinol [THC], Vehicle) design was used to expose pregnant Sprague-Dawley rats to either EtOH or air, in addition to either THC or the inhalant vehicle solution, during gestational days 5-20. Immunohistochemistry was performed to detect PV interneurons in 1 male and 1 female pup from each litter at postnatal day 70., Results: Significant between-group and subregion-specific effects were found in the dorsal cornu ammonis 1 (CA1) subfield and the ventral dentate gyrus (DG). In the dorsal CA1 subfield, there was an increase in the number of PV interneurons in both the EtOH and EtOH +THC groups, but a decrease with THC alone. There were fewer changes in interneuron numbers overall in the DG, though there was a sex difference, with a decrease in the number of PV interneurons in the THC-exposed group in males. There was also a greater cell layer volume in the DG in the EtOH +THC group than the control group, and in the CA1 region in the EtOH group compared to the control and THC groups., Conclusions: Prenatal exposure to alcohol and THC differentially affects parvalbumin-positive interneuron numbers in the hippocampus, indicating that both individual and combined exposure can impact the balance of excitation and inhibition in a structure critically involved in learning and memory processes., (© 2021 by the Research Society on Alcoholism.)

Administration of exercise mimetic drugs could be a novel therapeutic approach to combat comorbid neurodegeneration and metabolic syndromes. Adiponectin is an adipocyte-secreted hormone. In addition to its antidiabetic effect, adiponectin mediates the antidepressant effect of physical exercise associated with adult hippocampal neurogenesis. The antidiabetic effect of the adiponectin receptor agonist AdipoRon has been demonstrated, but its potential pro-cognitive and neurotrophic effects in the hippocampus under diabetic condition are still unclear. This study reported that chronic AdipoRon treatment for 2 weeks improved hippocampal-dependent spatial recognition memory in streptozotocin-induced diabetic mice. Besides, AdipoRon treatment increased progenitor cell proliferation and neuronal differentiation in the hippocampal dentate gyrus (DG) of diabetic mice. Furthermore, AdipoRon treatment significantly increased dendritic complexity, spine density, and N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) in the dentate region, and increased BDNF levels in the DG of diabetic mice. AdipoRon treatment activated AMPK/PGC-1α signalling in the DG, whereas increases in cell proliferation and LTP were not observed when PGC-1α signalling was pharmacologically inhibited. In sum, chronic AdipoRon treatment partially mimics the benefits of physical exercise for learning and memory and hippocampal neuroplasticity in the diabetic brain. The results suggested that AdipoRon could be a potential physical exercise mimetic to improve hippocampal plasticity and hence rescue learning and memory impairment typically associated with diabetes., (© 2021. The Author(s).)

Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer's disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The use and abuse of cannabis can be associated with significant pathophysiology, however, it remains unclear whether (1) acute administration of Δ-9-tetrahydrocannabinol (THC) during early adulthood alters the cannabinoid type 1 (CB 1 ) receptor localization and expression in cells of the brain, and (2) THC produces structural brain changes. Here we use electron microscopy and a highly sensitive pre-embedding immunogold method to examine CB 1 receptors in the hippocampus cornu ammonis subfield 1 (CA1) 30 min after male mice were exposed to a single THC injection (5 mg/kg). The findings show that acute exposure to THC can significantly decrease the percentage of CB 1 receptor immunopositive terminals making symmetric synapses, mitochondria, and astrocytes. The percentage of CB 1 receptor-labeled terminals forming asymmetric synapses was unaffected. Lastly, CB 1 receptor expression was significantly lower at terminals of symmetric and asymmetric synapses as well as in mitochondria. Structurally, CA1 dendrites were significantly larger, and contained more spines and mitochondria following acute THC administration. The area of the dendritic spines, synaptic terminals, mitochondria, and astrocytes decreased significantly following acute THC exposure. Altogether, these results indicate that even a single THC exposure can have a significant impact on CB 1 receptor expression, and can alter CA1 ultrastructure, within 30 min of drug exposure. These changes may contribute to the behavioral alterations experienced by young individuals shortly after cannabis intoxication., (© 2020 Wiley Periodicals LLC.)

Background: It is becoming increasingly recognized that there is significant interneuron degeneration in Alzheimer's disease. As the hippocampus is integral for learning and memory, we performed a systematic review of primary literature focused on the relationship between Alzheimer's and hippocampal interneurons. In this study, we summarize the experimental work performed to date and identify opportunities for future experiments. Objectives: This PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-style systematic review seeks to summarize the findings of all accessible research focused on cholecystokinin (CCK), neuropeptide Y (NPY), parvalbumin (PV), and somatostatin (SOM) interneurons in the hippocampal formation. Results: One thousand five hundred ninety-three articles were pulled from PubMed, PsycInfo, and Web of Science, based on three blocks of search terms. There were 45 articles that met all the predetermined inclusion/exclusion criteria. There is strong evidence that PV interneurons are affected early in the disease by toxic amyloid beta (Aβ) fragments; SOM interneurons are affected indirectly while the SOM neuropeptide may act to slowly worsen toxic Aβ fragment accumulation, whereas NPY- and CCK-positive interneurons are affected later in the progression of the disease. Conclusions: Fewer studies have been performed on NPY and CCK interneurons, and there is room for further investigations regarding the role of PV interneurons in Alzheimer's to help resolve contradictory findings. This review found that PV interneurons are affected early in the disease, but only in Alzheimer's precursor protein but not tau models. NPY and CCK interneurons were found to be affected later in the disease, and SOM interneurons vary greatly. Future studies may consider reporting immunohistochemical studies inclusive of either cell location or morphology-as well as marker to give a more robust picture of the disease.

AdipoRon, an adiponectin receptor agonist, elicits similar antidiabetic, anti-atherogenic, and anti-inflammatory effects on mouse models as adiponectin does. Since AdipoRon can cross the blood-brain barrier, its chronic effects on regulating hippocampal function are yet to be examined. This study investigated whether AdipoRon treatment promotes hippocampal neurogenesis and spatial recognition memory in a dose-dependent manner. Adolescent male C57BL/6J mice received continuous treatment of either 20 mg/kg (low dose) or 50 mg/kg (high dose) AdipoRon or vehicle intraperitoneally for 14 days, followed by the open field test to examine anxiety and locomotor activity, and the Y maze test to examine hippocampal-dependent spatial recognition memory. Immunopositive cell markers of neural progenitor cells, immature neurons, and newborn cells in the hippocampal dentate gyrus were quantified. Immunosorbent assays were used to measure the serum levels of factors that can regulate hippocampal neurogenesis, including adiponectin, brain-derived neurotrophic factor (BDNF), and corticosterone. Our results showed that 20 mg/kg AdipoRon treatment significantly promoted hippocampal cell proliferation and increased serum levels of adiponectin and BDNF, though there were no effects on spatial recognition memory and locomotor activity. On the contrary, 50 mg/kg AdipoRon treatment impaired spatial recognition memory, suppressed cell proliferation, neuronal differentiation, and cell survival associated with reduced serum levels of BDNF and adiponectin. The results suggest that a low-dose AdipoRon treatment promotes hippocampal cell proliferation, while a high-dose AdipoRon treatment is detrimental to the hippocampus function.

Background: Aldehyde fixation is a common process used to preserve the complex structure of biological samples ex vivo. This method of fixation relies on the formation of covalent bonds between aldehydes and amines present in the biomolecules of the sample. Aldehyde fixation is routinely performed in histological studies, however fixed tissue samples are rarely used for non-histological purposes as the fixation process is thought to make brain tissue unsuitable for traditional proteomic analyses such as Western blot. Advances in antigen-retrieval procedures have allowed detectable levels of protein to be solubilized from formaldehyde fixed tissue, opening the door for aldehyde-fixed samples to be used in both histological and proteomic approaches., New Method: Here, we developed a series of antigen-retrieval steps for use on fixed-brain lysates to make them suitable for analysis by Western blot., Results: Prolonged exposure of the tissue homogenate to high temperature (90 °C for 2 h) in the presence of a concentrated formaldehyde scavenger and ionic detergent was sufficient to reveal a variety of synaptic and non-synaptic proteins on membrane blots., Conclusion: This protocol has significant utility for future studies using fixed tissue samples in a variety of neuropathological conditions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The practice of heading in soccer has become a public concern because of the potential for subconcussive impacts to cause cumulative concussive-like effects; however, experimental evidence for this hypothesis has been mixed. This systematic review used pre-defined search parameters to assess primary literature that examined changes in cognitive, behavioral, structural, and/or biological processes after acute heading exposure in youth and young adult soccer players. The findings were synthesized into a concise and comprehensive summary of the research following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) format, and suggestions for standardization of acute heading protocols are described. A total of 1189 articles were considered for this review, with 19 articles meeting all of the inclusion criteria for full analysis. An attempt was made to identify methods with significant sensitivity and reliability by grouping studies based on their outcome measures. Because of lack of standardization across intervention types and data collection protocols, no sensitive and reliable methods could be identified conclusively to assess the effects of acute heading exposure in soccer players. Based on this review, there is not enough evidence to either support or refute the potential of effects of subconcussive events from acute soccer heading exposure. Recommendations for standardization of acute heading exposure studies based on the included literature are discussed. Standardization is required to better understand the impact of acute heading exposure in soccer players, while allowing for the development of guidelines that mitigate any potential risks and allowing athletes to remain active and develop their skills.

Background and Objectives: We examined how acute ethanol (EtOH) exposure affects long term depression (LTD) in the dentate gyrus (DG) of the hippocampus in juvenile rats. EtOH is thought to directly modulate n-methyl-D-aspartate receptor (NMDAr) currents, which are believed important for LTD induction. LTD in turn is believed to play an important developmental role in the hippocampus by facilitating synaptic pruning., Methods: Hippocampal slices (350 μ m) were obtained at post-natal day (PND) 14, 21, or 28. Field EPSPs (excitatory post-synaptic potential) or whole-cell EPSCs (excitatory post-synaptic conductance) were recorded from the DG (dentate gyrus) in response to medial perforant path activation. Low-frequency stimulation (LFS; 900 pulses; 120 s pulse) was used to induce LTD., Results: Whole-cell recordings indicated that EtOH exposure at 50mM did not significantly impact ensemble NMDAr EPSCs in slices obtained from animals in the PND14 or 21 groups, but it reliably produced a modest inhibition in the PND28 group. Increasing the concentration to 100 mM resulted in a modest inhibition of NMDAr EPSCs in all three groups. LTD induction and maintenance was equivalent in magnitude in all three age groups in control conditions, however, and surprisingly, NMDA antagonist AP5 only reliably blocked LTD in the PND21 and 28 age groups. The application of 50 mM EtOH attenuated LTD in all three age groups, however increasing the concentration to 100 mM did not reliably inhibit LTD., Conclusions: These results indicate that the effect of EtOH on NMDAr-EPSCs recorded from DGCs is both age and concentration dependent in juveniles. Low concentrations of EtOH can attenuate, but did not block LTD in the DG. The effects of EtOH on LTD do not align well with it's effects on NNMDA receptors., Competing Interests: The authors have no conflict to report., (© 2020 – IOS Press and the authors. All rights reserved.)