Social isolation rearing (SIR) provides an excellent model of early life adversity to investigate alterations in brain function. Few studies have investigated the effects of SIR on noradrenaline (NE) projections which arise from the locus coeruleus (LC), a system which regulates arousal and attentional processes, including the processing of novelty. In addition, there is a paucity of information on the effects of SIR in females. In this study we investigated the behavioural response to attentional processing of novelty and glutamate- and GABA-stimulated release of noradrenaline in the prefrontal cortex (PFC) and hippocampus (HC) of male and female rats. Sprague Dawley pups were reared in isolated or socialised housing conditions from weaning on postnatal day 21 (P21). At P78-83 animal behaviour was recorded from the three phases of the novel object recognition (NOR) task. Then at P90-94, NE release was measured in the PFC and HC after stimulating the tissue in vitro with either glutamate or GABA. Behaviourally SIR decreased novelty-related behaviour, male isolates showed effects of SIR during the NOR Test phase while female isolates showed effects of SIR during the Habituation phase. SIR PFC NE release was decreased when glutamate stimulation followed GABA stimulation and tended to increase when GABA stimulation followed glutamate stimulation, differences were predominantly due to male isolates. No SIR differences were found for HC. Early life adversity differentially affects the function of the LCNE system in males and females, evidenced by changes in attentional processing of novelty and stimulated noradrenaline release in the PFC.

EDITORIAL article Front. Neuroanat., 14 February 2019 Volume 13 - 2019 | https://doi.org/10.3389/fnana.2019.00012

In an attempt to better represent the aetiology of fetal alcohol spectrum disorder (FASD) and the associated psychological deficits, prenatal-ethanol exposure was followed by maternal separation in a rat model in order to account for the effects of early-life adversities in addition to in utero alcohol exposure. Extracellular signal-regulated kinase 1/2 (ERK1/2) and glycogen synthase kinase 3-beta (GSK3 beta) are converging points for many signalling cascades and have been implicated in models of FASD and models of early-life stress. Therefore, these kinases may also contribute to the behavioural changes observed after the combination of both developmental insults. In this study, ethanol-dams voluntarily consumed a 0.066% saccharin-sweetened 10% ethanol (EtOH) solution for 10 days prior to pregnancy and throughout gestation while control-dams had ad libitumaccess to a 0.066% saccharin (sacc) solution. Whole litters were randomly assigned to undergo maternal separation (MS) for 3 h/day from P2 to P14 while the remaining litters were left undisturbed (nMS). This resulted in 4 experimental groups: control (sacc + nMS), MS (sacc + MS), EtOH (EtOH + nMS) and EtOH + MS. Throughout development, EtOH-rats weighed less than control rats. However, subsequent maternal separation stress caused EtOH + MSrats to weigh more than EtOH-rats. In adulthood both MS- and EtOH-rats were hyperactive but the combination produced activity levels similar to that of control rats. All treated animals (MS-, EtOH- and EtOH + MS-rats) demonstrated a negative affective state shown by increased number and duration of 22 kHz ultrasonic vocalizations compared to control rats. Prenatal-ethanol exposure increased the P-GSK3 beta/GSK3 beta ratio in the prefrontal cortex (PFC) and maternal separation decreased the P-GSK3 beta/GSK3 beta ratio in the dorsal hippocampus (DH) of adult rats. However, maternal separation stress decreased the effect of prenatal-ethanol exposure on the P-ERK/ERK ratio in the PFC and DH and reduced prenatal-ethanol-induced hyperactivity. Therefore, indicating a significant interaction between prenatal-ethanol exposure and early-life stress on behaviour and the brain and may implicate P-ERK1/2 signalling in exploratory behaviour.

In utero exposure to alcohol has been shown to cause a spectrum of cognitive and behavioral deficits. This study aimed to explore the long-term effects of early-ethanol exposure on proteins in the brain. Male Sprague-Dawley rat pups were exposed to 12% ethanol (4 g/kg/day i.p.) or volume-controlled saline during the third human trimester equivalent (P4–P9). At P31, prefrontal cortex (PFC) and dorsal hippocampus (DH) proteins were analyzed by isobaric tags for relative and absolute quantitation (iTRAQ) and liquid chromatography mass spectrometry (LC-MS). Early-ethanol exposure increased the capacity for metabolism of NADH and oxidative phosphorylation, as shown by an upregulation of NADH dehydrogenase (ubiquinone, 1 alpha subcomplex 9) while simultaneously decreasing the capacity to protect against oxidative stress in the PFC. Early-ethanol exposure decreased the capacity for ATP synthesis (> 2-fold down regulation of ATP synthase) and increased glycogen synthesis in the DH (> 2-fold decrease in glycogen synthase kinase-3β). The effects of early-ethanol exposure on glucose metabolism and ATP production appeared to be region specific. In addition, early-ethanol exposure decreased structural proteins in both the PFC and DH. A greater number of proteins were altered in the DH than in the PFC, indicating that the DH may be more susceptible to the effects of early-ethanol exposure. These proteomic profiles provide valuable insight into the long-term molecular changes in the brain induced by early-ethanol exposure.

Maternal separation (MS) is a well-established rodent model of depression. Chronic constant light (CCL) treatment during adolescence has been shown to reverse the depression-like behaviour induced by MS. We aimed to further delineate the antidepressant effect of light by investigating the involvement of the dopaminergic, serotonergic and orexinergic systems. MS was used to induce changes in adult male Sprague-Dawley rats, some of whom were also treated with CCL for 3 weeks during adolescence. At P80, rats were decapitated and brain tissue collected for analysis of glutamate- and potassium-stimulated dopamine release in the nucleus accumbens (NAc) using an in vitro superfusion technique. Enzyme-linked immunosorbent assays were employed to measure 5-hydroxytryptamine (5-HT) levels in the hypothalamus and prefrontal cortex (PFC). Western blotting was used to measure orexin receptor 1 (OXR-1) and 2 (OXR-2) in the PFC. MS did not affect 5-HT levels in these rats. However, CCL increased hypothalamic 5-HT and reduced 5-HT levels in the PFC. CCL had opposite effects on OXR levels in the PFC of maternally separated and non-separated rats. MS increased OXR-1 and OXR-2 levels in the PFC, an effect that was normalized by CCL treatment. MS reduced glutamate-stimulated dopamine release in the NAc, an effect that was not reversed by CCL. The present results suggest that CCL treatment affects 5-HT and orexinergic systems in the MS model while not affecting the MS-induced decrease in dopamine release in the NAc. The reversal of changes in the orexinergic system may be of particular relevance to the antidepressant effect of CCL in depression.

There have been important advances in our understanding of the genetic architecture of anxiety disorders. At the same time, relatively few genes have reached genome wide significance in anxiety disorders, and there is relatively little work on how exposure to an adverse environment impacts on gene expression in either animal models or human clinical populations. Here we assessed differential expression of genes of the dorsal striatum involved in synaptic transmission in an animal models of early adversity (maternal separation followed by restraint stress), and investigated whether variants in these genes were associated with risk for anxiety disorders, particularly in the presence of environmental stressors. Fifty-two male Sprague Dawley rats underwent maternal separation, and gene expression was studied using array technology. The human homologues of the differentially expressed genes were screened and analysed in a DSM-IV anxiety disorders cohort, and healthy controls (patients, n = 92; controls, n = 194), using blood. Two candidate genes (Mmp9 and Bdnf) were aberrantly expressed in the experimental rodent group relative to controls. Four single nucleotide polymorphisms (SNPs) in the human homologues of these genes were significantly associated with susceptibility for anxiety disorders (MMP9: rs3918242 and BDNF: rs6265, rs10835210 and rs11030107). Three of these (BDNF: rs6265, rs10835210, rs11030107) were found to interact significantly with childhood trauma severity resulting in increased likelihood of an anxiety disorder diagnosis. This study provides insights into the utility of rat models for identifying molecular candidates for anxiety disorders in humans.

The detrimental effects of drug abuse are apparently not limited to individuals but may also impact the vulnerability of their progenies to develop addictive behaviours. Epigenetic signatures, early life experience and environmental factors, converge to influence gene expression patterns in addiction phenotypes and consequently may serve as mediators of behavioural trait transmission between generations. The majority of studies investigating the role of epigenetics in addiction do not consider the influence of social interactions. This shortcoming in current experimental approaches necessitates developing social models that reflect the addictive behaviour in a free-living social environment. Furthermore, this review also reports on the advancement of interventions for drug addiction and takes into account the emerging roles of histone deacetylase (HDAC) inhibitors in the etiology of drug addiction and that HDAC may be a potential therapeutic target at nucleosomal level to improve treatment outcomes.

Neuroscience began with neuroanatomy and neurosurgery in Egypt more than 5000 years ago. Knowledge grew over time and specialized neurosurgery centers were established in north Africa in the eleventh century. However, it was not until the twentieth century that neuroscience research became established in sub-Saharan Africa. In most African countries, clinical research focused on understanding the rationale and improving treatment of epilepsy, infections, nutritional neuropathies, stroke and tumors. Significant advances were made. In the twenty-first century, African knowledge expanded to include all branches of neuroscience, contributing to genetic, biochemical and inflammatory determinants of brain disorders. A major focus of basic neuroscience research has been, and is, investigation of plant extracts, drugs and stress in animal models, providing insight and identifying potential novel therapies. A significant event in the history of African neuroscience was the founding of the Society of Neuroscientists of Africa (SONA) in 1993. The International Brain Research Organization (IBRO) supported SONA conferences, as well as workshops and neuroscience training schools in Africa. Thanks to their investment, as well as that of funding agencies, such as the National Institutes of Health (NIH), International Society for Neurochemistry (ISN), World Federation of Neurosurgical Societies (WFNS), World Federation of Neurology (WFN) and the International League Against Epilepsy (ILAE), neuroscience research is well-established in Africa today. However, in order to continue to develop, African neuroscience needs continued international support and African neuroscientists need to engage in policy and decision-making to persuade governments to fund studies that address the unique regional needs in Africa.

Early life adversity has been associated with the development of various neuropsychiatric disorders in adulthood such as depression and anxiety. The aim of this study was to determine if stress during adulthood can exaggerate the depression-/anxiety-like behaviour observed in the widely accepted maternally separated (MS) Sprague–Dawley (SD) rat model of depression. A further aim was to determine whether the behavioural changes were accompanied by changes in hippocampal brain-derived neurotrophic factor (BDNF) and the protein profile of the prefrontal cortex (PFC). Depression-/anxiety-like behaviour was measured in the elevated plus maze, open field and forced swim test (FST) in the MS SD rats exposed to chronic restraint stress in adulthood. As expected, MS increased immobility of SD rats in the FST but restraint stress did not enhance this effect of MS on SD rats. A proteomic analysis of the PFC revealed a decrease in actin-related proteins in MS and non-separated rats subjected to restraint stress as well as a decrease in mitochondrial energy-related proteins in the stressed rat groups. Since MS during early development causes a disruption in the hypothalamic‐pituitary‐adrenal axis and long-term changes in the response to subsequent stress, it may have prevented restraint stress from exerting its effects on behaviour. Moreover, the decrease in proteins related to mitochondrial energy metabolism in MS rats with or without subsequent restraint stress may be related to stress per se and not depression-like behaviour, because rats subjected to restraint stress displayed similar decreases in energy-related proteins and spent less time immobile in the FST than control rats.

While genetic predisposition is a major factor, it is not known how development of attention-deficit/hyperactivity disorder (ADHD) is modulated by early life stress. The spontaneously hypertensive rat (SHR) displays the behavioral characteristics of ADHD (poorly sustained attention, impulsivity, hyperactivity) and is the most widely studied genetic model of ADHD. We have previously shown that SHR have disturbances in the noradrenergic system and that the early life stress of maternal separation failed to produce anxiety-like behavior in SHR, contrary to control Sprague-Dawley and Wistar-Kyoto (WKY) who showed typical anxiety-like behavior in later life. In the present study we investigated the effect of maternal separation on approach behavior (response to a novel object in a familiar environment) in preadolescent SHR and WKY. We also investigated whether maternal separation altered GABA(A) and NMDA receptor-mediated regulation of norepinephrine release in preadolescent SHR and WKY hippocampus. We found that female SHR, similar to male SHR, exhibited greater exploratory activity than WKY. Maternal separation significantly increased GABAA receptor-mediated inhibition of glutamate-stimulated release of norepinephrine in male and female SHR hippocampus but had no significant effect in WKY. Maternal separation had opposite effects on NMDA receptor-mediated inhibition of norepinephrine release in SHR and WKY hippocampus, as it increased inhibition of both glutamate-stimulated and depolarization-evoked release in SHR hippo campus but not in WKY. The results of the present study show that noradrenergic function is similarly altered by the early life stress of maternal separation in male and female SHR, while GABA- and glutamate-regulation of norepinephrine release remained unaffected by maternal separation in the control, WKY, rat strain. This article is part of a Special Issue entitled SI: Noradrenergic System. (C) 2015 Elsevier B.V. All rights reserved.

Many stress-related psychiatric disorders are more common in women than in men. We aimed to determine how female rats respond to maternal separation (MS; removal of the dam from the litter for 3 h/day from postnatal day (P) 2-14)). A subset of MS females were also exposed to chronic constant light for 3 weeks during adolescence (P42-63) to investigate whether the antidepressant effect of light treatment, previously observed in male rats, could be seen in female rats. Ultrasonic vocalizations (22 kHz) were recorded and the forced swim test was conducted immediately after light exposure (P65-67) and 33 days later (P98-99) to determine depressive-like behaviour. Key proteins in the MAPK signal transduction pathway (MKP-1, phospho-ERK, total ERK) and a synaptosomal marker (synaptophysin) were measured in the ventral hippocampus. We found that MS decreased the duration of 22 kHz vocalizations at P65 which was reversed by subsequent light. Light exposure increased time spent in the inner zone of the open field and the number of 22 kHz calls in response to novelty at P98. MS decreased the time females spent immobile and increased time actively swimming in the forced swim test at P67 but not at P99. MKP-1 and synaptophysin levels remained unchanged while MS decreased phospho-ERK levels in the ventral hippocampus. In contrast to clinical findings, the results suggest that female rats may be resistant to MS-induced depression-like behaviour. The behavioural effects of MS and light treatment in female rats may involve the MAPK/ERK signal transduction pathway.

Developmental stress has been hypothesised to interact with genetic predisposition to increase the risk of developing substance use disorders. Here we have investigated the effects of maternal separation-induced developmental stress using a behavioural proxy of methamphetamine preference in an animal model of attention-deficit/hyperactivity disorder, the spontaneously hypertensive rat, versus Wistar Kyoto and Sprague–Dawley comparator strains.

This study investigates the effects of early exposure to ethanol on cognitive function and neural plasticity‐related proteins in the rat brain. Sprague‐Dawley rats were administered 12% ethanol solution (4 g/kg/day i.p.) or saline from P4 to P9. Vinpocetine, a phosphodiesterase type 1 inhibitor, was tested to determine whether it could reverse any changes induced by early ethanol exposure. Hence, from P25 to P31, ethanol‐exposed male rats were injected with vinpocetine (20 mg/kg/day i.p.) or vehicle (DMSO) prior to undergoing behavioral testing in the open field and Morris water maze (MWM) tests. Ethanol exposure did not adversely affect spatial memory in the MWM. A key finding in this study was a significant ethanol‐induced change in the function of the phosphorylated extracellular signal‐related kinase (P‐ERK) signaling pathway in the prefrontal cortex (PFC) and dorsal hippocampus (DH) of rats that did not display overt behavioral deficits. The P‐ERK/ERK ratio was decreased in the PFC and increased in the DH of ethanol‐exposed rats compared with controls. Rats that received vinpocetine in addition to ethanol did not display any behavioral changes but did show alterations in neural plasticity‐related proteins. Mitogen‐activated protein kinase phosphatase was increased, whereas brain‐derived neurotrophic factor was decreased, in the PFC of vinpocetine‐treated ethanol‐exposed rats, and phosphorylated‐glycogen synthase kinase β and synaptophysin were increased in the DH of these rats. This study provides insight into the long‐term effects of early ethanol exposure and its interaction with vinpocetine in the rat brain. © 2016 Wiley Periodicals, Inc.

© 2016 Russell. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/ zero/1.0/) applies to the data made available in this article, unless otherwise stated. Athena Akrami USA

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common child psychiatric disorders. While it is typically treated with medications that target dopamine and norepinephrine transmission, there is increasing evidence that other neurotransmitter systems, such as glutamate and GABA, may be involved. The aetiology of ADHD is unknown; however, there is evidence that early life stress may contribute to the development of the disorder. In the present study we used proteomic analysis (iTRAQ) followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blot analysis to investigate hippocampal protein profiles of three rat strains: an animal model of ADHD, spontaneously hypertensive rats (SHR), their control Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD). We additionally investigated how these protein profiles are affected by maternal separation, a model of early life stress. Our findings show that solute carrier family 12 member 5 (KCC2) is increased in SHR hippocampus. The glutamate transporter GLT1 splice variant, GLT1b, was increased (proteomic analysis) while total GLT1 (comprised mostly of GLT1a splice variant) was reduced (Western blot analysis) in SHR hippocampus, compared to WKY and SD – a pattern that is consistent with elevated extracellular glutamate levels. Maternal separation increased total GLT1 in hippocampi of SHR, WKY, and SD, and reduced GLT1b in SHR hippocampus. Together these findings provide evidence for disturbed glutamatergic and GABAergic transmission in SHR hippocampus, maternal separation effects on glutamate uptake in hippocampi of all three strains, as well a unique effect of maternal separation on GLT1b levels in SHR hippocampus. These data suggest significant involvement of glutamatergic and GABAergic transmission in the neuropathophysiology of ADHD, and implicates changes in glutamatergic transmission as a result of early life stress.

Background: Developmental stress increases the risk of developing psychological disturbances and is modelled in rodents by maternal separation (MS). Attention-deficit/hyperactivity disorder (ADHD) is characterised by inattention, hyperactivity and impulsivity and is studied using the spontaneously hypertensive rat (SHR). Previous studies suggested that SHR differ from their progenitor strain, the Wistar-Kyoto (WKY), in their response to developmental stress. This study sought to investigate the effects of MS on striatal protein expression, a brain area implicated in the pathophysiology of ADHD and susceptible to developmental stress, in SHR, WKY and Sprague-Dawley (SD) rat strains.Method: Dissected striata of separated and non-separated SHR, WKY and SD (n = 6 per group) were assessed for MS-induced changes in protein expression using isobaric tagging (iTRAQ) and peptide quantification via matrix-assisted laser desorption/ionisation (MALDI) tandem mass spectrometry.Results: Strain and MS-induced differences were observed in proteins related to energy metabolism, neuroprotection, protein folding, protein metabolism, signalling and structure. Striatal SHR protein levels were consistent with delayed neuronal maturation and altered neurotransmission and energy metabolism. MS produced mostly opposite effects on SHR striatal proteins compared to WKY and SD.Comparison with existing methods: Proteomic profiling of protein expression in selected brain areas provides an assessment of overall changes in metabolic pathways that cannot be determined using standard protein isolation techniques. Furthermore, MS-induced changes in protein expression in the striatum of SHR, WKY and SD have not been reported.Conclusions: The results suggest that energy metabolism, neurotransmission and neural development are altered in SHR striatum and that WKY and SD are suitable comparator strains for SHR The strain-dependent effects of MS on striatal protein expression reinforce the importance of gene x environment interactions in determining behavioural outcome. (C) 2015 Elsevier B.V. All rights reserved.

The characteristics of neurological, psychiatric, developmental and substance-use disorders in low- and middle-income countries are unique and the burden that they have will be different from country to country. Many of the differences are explained by the wide variation in population demographics and size, poverty, conflict, culture, land area and quality, and genetics. Neurological, psychiatric, developmental and substance-use disorders that result from, or are worsened by, a lack of adequate nutrition and infectious disease still afflict much of sub-Saharan Africa, although disorders related to increasing longevity, such as stroke, are on the rise. In the Middle East and North Africa, major depressive disorders and post-traumatic stress disorder are a primary concern because of the conflict-ridden environment. Consanguinity is a serious concern that leads to the high prevalence of recessive disorders in the Middle East and North Africa and possibly other regions. The burden of these disorders in Latin American and Asian countries largely surrounds stroke and vascular disease, dementia and lifestyle factors that are influenced by genetics. Although much knowledge has been gained over the past 10 years, the epidemiology of the conditions in low- and middle-income countries still needs more research. Prevention and treatments could be better informed with more longitudinal studies of risk factors. Challenges and opportunities for ameliorating nervous-system disorders can benefit from both local and regional research collaborations. The lack of resources and infrastructure for health-care and related research, both in terms of personnel and equipment, along with the stigma associated with the physical or behavioural manifestations of some disorders have hampered progress in understanding the disease burden and improving brain health. Individual countries, and regions within countries, have specific needs in terms of research priorities.