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Prospective and retrospective timing in mild cognitive impairment and Alzheimer’s disease patients: A systematic review and meta-analysis
GiovannaMioniaRafaelRom?n-CaballerobcJacopoClericiaMariagraziaCapizzid
doi : 10.1016/j.bbr.2021.113354
Volume 410, 23 July 2021, 113354
Performance on timing tasks changes with age. Whether these changes reflect a real “clock” problem due to aging or a secondary effect of the reduced cognitive resources of older adults is still an unsettled question. Research on processing of time in aged populations marked by severe mnemonic and/or attentional deficits, such as patients with Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI), may help elucidate the role of cognitive resources in age-related temporal distortions. To this end, we conducted a systematic review and meta-analysis of timing studies in AD and MCI patients; both prospective and retrospective timing tasks were considered and analysed separately. As concerns prospective timing, a first random-effect model showed a medium overall effect of neurodegeneration on timing performance. When considering the role of moderator variables(i.e., neurodegenerative condition, type of measure, participants' age and years of education, interval length, and type of timing task), mean score appeared to be a less sensitive measure than accuracy and variability, and the observed temporal impairment was smaller in older samples. In addition, AD patients only exhibited medium-to-high impairment on prospective timing tasks, whereas MCI patients did not significantly differ from controls. However, assuming a mean age of 70 years old and absolute error as dependent variable, a second fitted meta-regression model predicted a significant outcome also for MCI patients. Concerning retrospective timing, a significant but small effect of neurodegeneration was observed for retrospective judgments. None of the moderators, however, explained between-studies variability. Collectively, our findings highlight a clear deficit in prospective timing for AD patients and underscore several issues that future work should carefully consider to better investigate the effect of MCI on prospective temporal judgements. Results from retrospective timing also point to a possible impairment of retrospective judgments in neurodegenerative conditions, albeit more studies are needed to substantiate this finding.
Effectiveness and mechanisms of enriched environment in post-stroke cognitive impairment
MeiYuanaYi-ShaGuobYuHanbZhen-KunGaocXin-YaShencXiaBia
doi : 10.1016/j.bbr.2021.113357
Volume 410, 23 July 2021, 113357
Post-stroke cognitive impairment (PSCI) is one of the most common complications of stroke, it is also an important reason for the poor prognosis in stroke patients with motor and speech dysfunction. Enriched Environment (EE), a novel and easy-to-implement rehabilitation treatment strategy, is thought to be a potential intervention for PSCI recently. In this paper, we review the therapeutic effects and related mechanisms of EE in PSCI from the level of animal research and clinical application. Besides, we further discuss the application prospects and limitations of EE in PSCI patients.
CE-123, a novel dopamine transporter inhibitor, attenuates locomotor hyperactivity and improves cognitive functions in rat model of fetal alcohol spectrum disorders
EwaGibula-TarlowskaaVolkerKorzbMalgorzataLopatynska-MazurekaAgnieszkaChlopas-KonowalekcPawelGrocheckiaPredragKalabadfVladimirDragacevicdRobertKotlinskieRados?awKujawskigMicha?SzulcgKamilaCzora-PoczwardowskagPrzemyslaw L.MikolajczakgGertLubecfJolanta H.Kotlinskaa
doi : 10.1016/j.bbr.2021.113326
Volume 410, 23 July 2021, 113326
Perinatal alcohol exposure can lead to fetal alcohol spectrum disorders (FASD), usually first diagnosed in childhood, that are characterized by hyperactivity, impulsivity and learning and memory disability, among others. To test the hypothesis that dopamine signaling is one of the main factors underlying these impairments, a new atypical dopamine transporter (DAT) inhibitor, CE-123 (1, 3 or 10 mg/kg) was assessed for its potential to overcome the ethanol-induced behavioral effects in a rat model of FASD. In the present study, neonatal rats were exposed to alcohol intubations across the neonatal period (postnatal day (PND)4?9, the third trimester equivalent of human gestation) and, after weaning, the animals (male rats) were assigned randomly to three groups. The first group was tested at PND21 (hyperactivity test). A second group was tested at PND45 (anxiety test), at PND47 (locomotor activity test), at PND49 (spatial cognitive test in the Barnes maze) and PND50 (reversal learning in the Barnes maze). The third group was tested at PND50 (dopamine receptor mRNA expression). Our results support the hypothesis that dopamine signaling is associated with FASD because the dopamine (D1, D2 and D5) receptor mRNA expression was altered in the striatum, hippocampus and prefrontal cortex in adult rats exposed to ethanol during neonatal period. CE-123 (3 and 10 mg/kg) inhibited the hyperactivity and ameliorated (10 mg/kg) the impairment of reversal learning in alcohol-exposed rats. Thus, these findings provide support that CE-123 may be a useful intervention for same of the deficits associated with neonatal ethanol exposure.
Rapamycin, but not minocycline, significantly alters ultrasonic vocalization behavior in C57BL/6J pups in a flurothyl seizure model
Samantha L.HodgesaPaige D.WomblebEliesse M.KwokbAlyssa M.DarnerbSavannah S.SengerbMatthew S.BinderbAmanda M.FaustbSiena M.CondonbSuzanne O.NolanbSaul I.QuinterobJoaquin N.Lugoabc
doi : 10.1016/j.bbr.2021.113317
Volume 410, 23 July 2021, 113317
Epilepsy is one of the most common neurological disorders, with individuals having an increased susceptibility of seizures in the first few years of life, making children at risk of developing a multitude of cognitive and behavioral comorbidities throughout development. The present study examined the role of PI3K/Akt/mTOR pathway activity and neuroinflammatory signaling in the development of autistic-like behavior following seizures in the neonatal period. Male and female C57BL/6J mice were administered 3 flurothyl seizures on postnatal (PD) 10, followed by administration of minocycline, the mTOR inhibitor rapamycin, or a combined treatment of both therapeutics. On PD12, isolation-induced ultrasonic vocalizations (USVs) of mice were examined to determine the impact of seizures and treatment on communicative behaviors, a component of the autistic-like phenotype. Seizures on PD10 increased the quantity of USVs in female mice and reduced the amount of complex call types emitted in males compared to controls. Inhibition of mTOR with rapamycin significantly reduced the quantity and duration of USVs in both sexes. Changes in USVs were associated with increases in mTOR and astrocyte levels in male mice, however, three PD10 seizures did not result in enhanced proinflammatory cytokine expression in either sex. Beyond inhibition of mTOR activity by rapamycin, both therapeutics did not demonstrate beneficial effects. These findings emphasize the importance of differences that may exist across preclinical seizure models, as three flurothyl seizures did not induce as drastic of changes in mTOR activity or inflammation as observed in other rodent models.
Stimulation of astrocytic sigma-1 receptor is sufficient to ameliorate inflammation- induced depression
LinGuoab1TianyuGaoa1CeGaoaXiaoxiaJiaaJingNiaChaojunHancYunWanga
doi : 10.1016/j.bbr.2021.113344
Volume 410, 23 July 2021, 113344
Astrocytes play important roles in the development of depression. As a promising target for antidepressant development, sigma-1 receptor (Sig-1R) is reported to promote activation of astrocyte in chronic stress-induced depression in our previous study. However, astrocytes are hyper-activated in inflammation-induced depression, raising concerns of whether stimulation of astrocytic Sig-1R would exert antidepressant-like effect in inflammation-induced depression. Here we reported that specific stimulation of astrocytic Sig-1R using adeno-associated virus (AAV) significantly attenuated lipopolysaccharide (LPS)- induced depressive-like behavior in the forced swim test (FST), tail suspension test (TST), sucrose preference test, and improved the memory function in novel object recognition test. Besides, specific stimulation of astrocytic Sig-1R decreased the activation of astrocyte and microglia, as well as increased brain-derived neurotrophic factor (BDNF) in LPS-induced depression. In primary cultured astrocytes, overexpression of Sig-1R also reduced the expression of IL-1?, TNF-?, iNOS during inflammation-treated astrocyte. Taken together, the results suggest that specific stimulation of astrocytic Sig-1R ameliorates inflammation-induced depressive-like behavior, providing the evidence that astrocytic Sig-1R could represent a reliable therapeutic target for depression.
Effect of chronic intracerebroventricular administration of an aromatase inhibitor on the expression of socio-sexual behaviors in male Japanese quail
LucasCourtaJacquesBalthazartaGregory F.BallbCharlotte A.Cornila
doi : 10.1016/j.bbr.2021.113315
Volume 410, 23 July 2021, 113315
LucasCourtaJacquesBalthazartaGregory F.BallbCharlotte A.Cornila
Association between structural brain features and gene expression by weighted gene co-expression network analysis in conversion from MCI to AD
XuwenWangKexinHuangFanYangDihunChenSupingCaiLiyuHuang
doi : 10.1016/j.bbr.2021.113330
Volume 410, 23 July 2021, 113330
Alzheimer’s disease (AD) is a neurodegenerative disease. Mild cognitive impairment (MCI) represents a state of cognitive function between normal cognition and dementia. Longitudinal studies showed that some MCI patients remained in a state of MCI, and some developed AD. The reason for these different conversions from MCI remains to be investigated. 180 MCI participants were followed for eight years. 143 MCI patients maintained the MCI state (MCI_S), and the remaining thirty-seven MCI patients were re-evaluated as having AD (MCI_AD). We obtained 1,036 structural brain characteristics and 15,481 gene expression values from the 180 MCI participants and applied weighted gene co-expression network analysis (WGCNA) to explore the relationship between structural brain features and gene expression. Regulating mediator effect analysis was employed to explore the relationships among gene expression, brain region measurements and clinical phenotypes. We found that 60 genes from the MCI_S group and 18 genes from the MCI_AD group respectively had the most significant correlations with left paracentral lobule and sulcus (L.PTS) and right subparietal sulcus (R.SubPS) thickness; CTCF, UQCR11 and WDR5B were the mutual genes between the two groups. The expression of CTCF gene and clinical score are completely mediated by L.PTS thickness, and the UQCR11 and WDR5B gene expression levels significantly regulate the mediating effect pathway. In conclusion, the factors affecting the different conversions from MCI are closely related to L.PTS thickness and the CTCF, UQCR11 and WDR5B gene expression levels. Our results add a theoretical foundation of imaging genetics for conversion from MCI to AD.
Abnormalities of cortical structures in patients with postpartum depression: A surface-based morphometry study
YunaLia1TongpengChua1KailiCheaFanghuiDongbYinghongShiaHengMaaFengZhaocNingMaoaHaizhuXiea
doi : 10.1016/j.bbr.2021.113340
Volume 410, 23 July 2021, 113340
Postpartum depression (PPD) is a serious postpartum mental health problem worldwide. However, the cortical structural alterations in patients with PPD remain unclear. This study investigated the cortical structural alterations of PPD patients through multidimensional structural patterns and their potential correlations with clinical severity.
Marijuana improved motor impairments and changes in synaptic plasticity-related molecules in the striatum in 6-OHDA-treated rats
GholamrezaKomeiliaElhamHaghparastabVahidSheibanib
doi : 10.1016/j.bbr.2021.113342
Volume 410, 23 July 2021, 113342
Using marijuana has become popular and is allowed for medical purposes in some countries. The effect of marijuana on Parkinson's disease is controversial and Medical marijuana may benefit for motor and non-motor symptoms of patients with Parkinson's disease. No research has been conducted to fully prove the benefits, risks, and uses of marijuana as a treatment for patients with Parkinson's disease. In the present study, several different approaches, including behavioral measures and the western blot method for protein level assay, were used to investigate whether exposure to marijuana affects the motor and synaptic plasticity impairment induced by 6-OHDA. Marijuana consumption significantly decreased apomorphine-induced contralateral rotation, beam travel time, beam freeze time, and catalepsy time, but significantly increased latency to fall in the rotarod test, balance time, and protein level of PSD-95 and dopamine receptor D1 in the 6-OHDA?+?marijuana group. These results suggest that marijuana may be helpful for motor disorders and synaptic changes in patients with Parkinson's disease.
BDNF gene expression association with suicide and psychiatric disorders in children and adolescents: (Relationship between BDNF gene expression and suicide)
RabiaYilmazaDidem Behice?ztopbElif FundaSenercMerveCikili-UytunbFatmaDaldEmrahYildizeMusaSahpolateGokmenZararsizf
doi : 10.1016/j.bbr.2021.113350
Volume 410, 23 July 2021, 113350
In the current study, it was aimed to investigate the relationship between BDNF gene expression and childhood suicide attempt, childhood traumatic experiences, and problem-solving skills in children and adolescents.
Ghrelin restores memory impairment following olfactory bulbectomy in mice by activating hippocampal NMDA1 and MAPK1 gene expression
SantiagoBianconiabMar?a BelénPorettiabPaulaRodr?guezcGiuliaMaestribPamela ElizabethRodr?guezdSusana Rubialesde Barioglioc1Helgi B.Schi?thbeValeria PaolaCarliniab1
doi : 10.1016/j.bbr.2021.113341
Volume 410, 23 July 2021, 113341
Ghrelin (Ghrl) is an orexigenic peptide with potential roles in the modulation of anxiety- and depressive-like symptoms induced by bilateral olfactory bulbectomy (OB) in rodents. In the present work, we assessed whether intrahippocampal Ghrl could reverse OB-induced depressive-like and amnesic effects by regulating molecular mechanisms related to neuroplasticity. Adult female albino Swiss mice were divided into sham and OB groups, and infused with saline (S) or Ghrl 0.03 nmol/?l, 0.3 nmol/?l, or 3 nmol/?l into the hippocampus before exposition to open-field test (OFT) and tail suspension test (TST) or immediately after training in the object recognition test (ORT). After test phase in ORT, animals were euthanized and their hippocampi were dissected to study the expression of genes related to memory. The OB-S animals presented hyperlocomotion in OFT, increased immobility in TST and memory impairment compared to sham-S (p < 0.05), but acute intrahippocampal infusion of Ghrl 0.3 nmol/?l produced an improvement on these parameters in OB animals (p < 0.05). In addition, this dose of Ghrl reversed OB-induced low expression of NMDA1 and MAPK1 iso1 and up-regulated the expression of CaMKIIa iso1 and iso2, and MAPK1 iso2 (p < 0.05). These results extend the existing literature regarding OB-induced behavioral and neurochemical changes, and provide mechanisms that could underlie the antidepressant effect of Ghrl in this model.
Adult and adolescent C57BL/6J and DBA/2J mice are differentially susceptible to fear learning deficits after acute ethanol or MK-801 treatment
L.R.SeemillerT.J.Gould
doi : 10.1016/j.bbr.2021.113351
Volume 410, 23 July 2021, 113351
Ethanol and other drugs of abuse disrupt learning and memory processes, creating problems associated with drug use and addiction. Understanding individual factors that determine susceptibility to drug-induced cognitive deficits, such as genetic background, age, and sex, is important for prevention and treatment. Comparison of adolescent and adult mice of both sexes across inbred mouse strains can reveal age, sex, and genetic contributions to phenotypes. We treated adolescent and adult, male and female, C57BL/6J and DBA/2J inbred mice with ethanol (1?g/kg or 1.5?g/kg) or MK-801 (0.05?mg/kg or 0.1?mg/kg), an NMDA receptor antagonist, prior to fear conditioning training. Contextual and cued fear retention were tested one day and eight or nine days after training. After ethanol exposure, adult C57BL/6J mice experienced greater deficits in contextual learning than adult DBA/2J mice. C57BL/6?J adolescents were less susceptible to ethanol-induced contextual learning disruptions than C57BL/6J adults, and adolescent males of both strains exhibited greater ethanol-induced contextual learning deficits than adolescent females. After MK-801 exposure, adolescent C57BL/6J mice experienced more severe contextual learning deficits than adolescent DBA/2J mice. Both ethanol and MK-801 had greater effects on contextual learning than cued learning. Collectively, we demonstrate that genetic background contributes to contextual and cued learning outcomes after ethanol or MK-801 exposure. Further, we report age-dependent drug sensitivities that are strain-, sex-, and drug-specific, suggesting that age, sex, and genetic background interact to determine contextual and cued learning impairments after ethanol or MK-801 exposure.
Anxiety biases audiovisual processing of social signals
NaomiHefferaAnkeKarlbCrescentJicolaChrisAshwina1KarinPetrinia1
doi : 10.1016/j.bbr.2021.113346
Volume 410, 23 July 2021, 113346
In everyday life, information from multiple senses is integrated for a holistic understanding of emotion. Despite evidence of atypical multisensory perception in populations with socio-emotional difficulties (e.g., autistic individuals), little research to date has examined how anxiety impacts on multisensory emotion perception. Here we examined whether the level of trait anxiety in a sample of 56 healthy adults affected audiovisual processing of emotion for three types of stimuli: dynamic faces and voices, body motion and dialogues of two interacting agents, and circles and tones. Participants judged emotion from four types of displays – audio-only, visual-only, audiovisual congruent (e.g., angry face and angry voice) and audiovisual incongruent (e.g., angry face and happy voice) – as happy or angry, as quickly as possible. In one task, participants based their emotional judgements on information in one modality while ignoring information in the other, and in a second task they based their judgements on their overall impressions of the stimuli. The results showed that the higher trait anxiety group prioritized the processing of angry cues when combining faces and voices that portrayed conflicting emotions. Individuals in this group were also more likely to benefit from combining congruent face and voice cues when recognizing anger. The multisensory effects of anxiety were found to be independent of the effects of autistic traits. The observed effects of trait anxiety on multisensory processing of emotion may serve to maintain anxiety by increasing sensitivity to social-threat and thus contributing to interpersonal difficulties.
Activation of VTA GABA neurons disrupts reward seeking by altering temporal processing
Andrea K.Shieldsa1MauricioSuarezab1Ken T.WakabayashicCaroline E.Bassab
doi : 10.1016/j.bbr.2021.113292
Volume 410, 23 July 2021, 113292
The role of ventral tegmental area (VTA) dopamine in reward, cue processing, and interval timing is well characterized. Using a combinatorial viral approach to target activating DREADDs (Designer Receptors Exclusively Activated by Designer Drugs, hM3D) to GABAergic neurons in the VTA of male rats, we previously showed that activation disrupts responding to reward-predictive cues. Here we explored how VTA GABA neurons influence the perception of time in two fixed interval (FI) tasks, one where the reward or interval is not paired with predictive cues (Non-Cued FI), and another where the start of the FI is signaled by a constant tone that continues until the rewarded response is emitted (Cued FI). Under vehicle conditions in both tasks, responding was characterized by “scalloping” over the 30?s FI, in which responding increased towards the end of the FI. However, when VTA GABA neurons were activated in the Non-Cued FI, the time between the end of the 30?s interval and when the rats made a reinforced response increased. Additionally, post-reinforcement pauses and overall session length increased. In the Cued FI task, VTA GABA activation produced erratic responding, with a decrease in earned rewards. Thus, while both tasks were disrupted by VTA GABA activation, responding that is constrained by a cue was more sensitive to this manipulation, possibly due to convergent effects on timing and cue processing. Together these results demonstrate that VTA GABA activity disrupts the perception of interval timing, particularly when the timing is set by cues.
Changes in the mesocorticolimbic pathway after low dose reserpine-treatment in Wistar and Spontaneously Hypertensive Rats (SHR): Implications for cognitive deficits in a progressive animal model for Parkinson’s disease
Anderson H.F.F.Le?oaYwlliane S.R.MeurerbThalma A.FreitasacAndré M.MedeirosdVanessa C.Ab?lioaeGeison S.Iz?diofIsaltino M.Conceiç?ocAlessandra M.RibeirogRegina H.Silvaa
doi : 10.1016/j.bbr.2021.113349
Volume 410, 23 July 2021, 113349
Reserpine (RES) is an irreversible inhibitor of VMAT2 used to study Parkinson’s disease (PD) and screening for antiparkinsonian treatments in rodents. Recently, the repeated treatment with a low dose of reserpine was proposed as a model capable of emulating progressive neurochemical, motor and non-motor impairments in PD. Conversely, compared to Wistar rats, Spontaneously Hypertensive Rats (SHR) are resistant to motor changes induced by repeated treatment with a low dose of RES. However, such resistance has not yet been investigated for RES-induced non-motor impairments. We aimed to assess whether SHR would have differential susceptibility to the object recognition deficit induced by repeated low-dose reserpine treatment. We submitted male Wistar and SHR rats to repeated RES treatment (15?s.c. injections of 0.1?mg/kg, every other day) and assessed object memory acquisition and retrieval 48?h after the 6th RES injection (immediately before the appearance of motor impairments). Only RES Wistar rats displayed memory impairment after reserpine treatment. On the other hand, untreated SHR rats displayed object recognition memory deficit, but RES treatment restored such deficits. We also performed immunohistochemistry for tyrosine hydroxylase (TH) and ?-synuclein (?-syn) 48?h after the last RES injection. In a different set of animals submitted to the same treatment, we quantified DA, 5-HT and products of lipid peroxidation in the prefrontal cortex (PFC) and hippocampus (HPC). SHR presented increased constitutive levels of DA in the PFC and reduced immunoreactivity to TH in the medial PFC and dorsal HPC. Corroborating the behavioral findings, RES treatment restored those constitutive alterations in SHR. These findings indicate that the neurochemical, molecular and genetic differences in the SHR strain are potentially relevant targets to the study of susceptibility to diseases related to dopaminergic alterations.
Long-term administration of metformin ameliorates age-dependent oxidative stress and cognitive function in rats
Enam Alhagh CharkhatGorgichaHoumanParsaieaSazinYarmandbFarzanehBaharvandcMaryamSarbishegicd
doi : 10.1016/j.bbr.2021.113343
Volume 410, 23 July 2021, 113343
Aging is an inevitable physiological process, associated with a decline in cognitive function. Recently, metformin, as the first-line treatment for type II diabetes, has been shown to increase the life expectancy of diabetic patients. Therefore, researchers are paying increasing attention to its anti-aging properties. Oxygen free radicals are responsible for oxidative stress, which is a prominent factor in age-associated diseases. This study aimed to evaluate the effects of long-term administration of metformin on age-dependent oxidative stress and cognitive function.
Minocycline alleviates Gulf War Illness rats via altering gut microbiome, attenuating neuroinflammation and enhancing hippocampal neurogenesis
LiangLiuaEr-QiangWangbChengDuaHui-ShengChenaYanLva
doi : 10.1016/j.bbr.2021.113366
Volume 410, 23 July 2021, 113366
Accumulating evidences suggest that deficits in neurogenesis, chronic inflammation and gut microbiome dysregulation contribute to the pathophysiology of Gulf War Illness (GWI). Minocycline has been demonstrated to be a potent neuroprotective agent and could regulate neuroinflammation. The present study intends to investigate whether the treatment of minocycline maintains better cognition and mood function in a rat model of GWI and the potential mechanism. Rats received 28 days of GWI-related chemical exposure and restraint stress, along with daily minocycline or vehicle treatment. Cognitive and mood function, neuroinflammation, neurogenesis and gut microbiota were detected. We found that minocycline treatment induces better cognitive and mood function in the GWI rat model, as indicated by open-field test, elevated plus maze test, novel object recognition test and forced swim test. Moreover, minocycline treatment reversed the altered gut microbiome, neuroinflammation and the decreased hippocampal neurogenesis of rats with GWI. Taken together, our study indicated that minocycline treatment exerts better cognitive and mood function in GWI rat model, which is possibly related to gut microbiota remodeling, restrained inflammation and enhanced hippocampal neurogenesis. These results may establish minocycline as a potential prophylactic or therapeutic agent for the treatment of GWI.
Effect of chronically electric foot shock stress on spatial memory and hippocampal blood brain barrier permeability
ZohrehTaghadosiaAsadollahZarifkarabVahidRazbancMaryamOwjfarddHadiAligholiae
doi : 10.1016/j.bbr.2021.113364
Volume 410, 23 July 2021, 113364
Maintaining blood-brain barrier (BBB) contributes critically to preserving normal brain functions. According to the available evidence, intense or chronic exposure to stress would potentially affect different brain structures, such as the hippocampus, negatively. The purpose of this study was to define the relationship between the BBB permeability of the hippocampus and the performance of spatial learning and memory under chronically electric foot shock stress. Sixteen rats were divided into the control and stress groups equally. Animals in the stress group were exposed to foot shock (1?mA, 1?Hz) for 10-s duration every 60?s (1?h/day) for 10 consecutive days. The anxiety-related behavior, spatial learning, and memory were assessed by an Open Field (OF) and the Morris Water Maze (MWM) respectively. The hippocampal BBB permeability was determined by Evans blue penetration assay. Our results demonstrated that the stress model not only increased locomotor activities in the OF test but reduced spatial learning and memory in MWM. Moreover, these effects coincided with a significant increase in hippocampal BBB permeability. In sum, the stress model can be used in future studies focusing on the relationship between stress and BBB permeability of the hippocampus.
GABAergic regulation of locomotion before and during an ethanol exposure in Drosophila melanogaster
Calvin W.DaackDerekYehMarcBuschChristopher L.Kliethermes
doi : 10.1016/j.bbr.2021.113369
Volume 410, 23 July 2021, 113369
Ethanol at low doses induces a locomotor stimulant response across a range of phylogenetically diverse species. In rodents, this response is commonly used as an index of ethanol’s disinhibitory, anxiolytic, or reinforcing effects, and its expression is regulated by signaling through a number of conserved neurotransmitter systems. In the current experiments, we asked whether ethanol-induced locomotor stimulation in the fruit fly Drosophila melanogaster might be mediated by ionotropic GABA receptors. We measured basal and ethanol-stimulated locomotion in flies expressing RNAi directed against three known subunits of ionotropic GABA receptors, and also examined the effects of picrotoxin feeding on these behaviors. We found that RNAi-mediated knockdown of a subunit of fly ionotropic GABA receptors, RDL, in all neurons resulted in an increased ethanol-induced locomotor stimulant response, while knockdown of two other subunits, LCCH3 and GRD, did not affect the responses. The effect of pan neuronal RDL knockdown was recapitulated with selective RDL knockdown in cholinergic neurons, and increased ethanol-induced locomotor stimulation was also seen by feeding the GABAA antagonist picrotoxin to flies prior to behavioral testing. However, the increase in ethanol-stimulated locomotion in each of these experiments was largely accounted for by decreased baseline activity. Our results indicate that ionotropic GABA receptors might be a conserved mediator of the locomotor stimulant effects of ethanol, but that alternative experimental approaches will be necessary to disentangle effects of GABAergic manipulations on baseline and ethanol-stimulated locomotion in flies.
Altered responsiveness to pups in virgin female mice of the BTBR strain: Insights from pattern of c-Fos expression in brain regions involved in maternal behavior
A.M.Tartaglionea1S.Farioli Vecchiolib1M.C.GiorgiaD.CutulicdG.Calamandreia
doi : 10.1016/j.bbr.2021.113365
Volume 410, 23 July 2021, 113365
BTBR is an inbred mouse strain that displays several behavioral alterations resembling the core symptoms of Autism Spectrum Disorder, including deficit in sociability. In the present study, we investigated whether the pup-induced maternal behavior in virgin female mice, a naturally rewarding behavior, is impaired in this strain similarly to social interaction with adult conspecifics. We firstly assessed the maternal responsiveness towards newly born pups expressed by either virgin female mice of the BTBR strain or of the normo-social B6 strain. Next, we examined in both strains the expression of c-Fos as a marker of neuronal activity in selected brain areas involved in the regulation of maternal behavior in rodents including the olfactory bulb, the medial preoptic area and the paraventricular nucleus (PVN). We also examined the effects of pup presentation on oxytocinergic neurons of the PVN, the major brain site of synthesis of oxytocin, which has a pivotal role in facilitation of maternal response and social responsiveness in general. As a final step, we assessed the c-Fos expression pattern comparing the effect of exposure to pups with that induced by exposure to another social stimulus, focusing on other areas implicated in maternal responsiveness as well as in the affective component of social behavior such as pyriform cortex and central and basolateral amygdala.
Change in prostaglandin signaling during sickness syndrome hyperalgesia after ovariectomy in female rats
I.K.MabaJ.V.CruzA.R.Zampronio
doi : 10.1016/j.bbr.2021.113368
Volume 410, 23 July 2021, 113368
The present study investigated hyperalgesia during sickness syndrome in female rats. Hyperalgesia was induced by an intraperitoneal injection of lipopolysaccharide (LPS) or an intracerebroventricular injection of prostaglandin E2 (PGE2). No differences were found in basal mechanical and thermal thresholds or in LPS-induced hyperalgesia in sham-operated animals in the diestrus or proestrus phase or in ovariectomized (OVX) animals. However, higher levels of PGE2 where found in the cerebrospinal fluid of OVX animals compared to sham-operated females. Intracerebroventricular injection of PGE2 produced rapid mechanical hyperalgesia in sham-operated rats while these responses were observed at later times in OVX animals. The protein kinase A (PKA) inhibitor H-89 reduced mechanical PGE2-induced hyperalgesia in OVX female rats, whereas no effect was observed in sham-operated animals. In contrast, the exchange protein activated by cyclic adenosine monophosphate (cAMP; Epac) inhibitor ESI-09 reduced mechanical PGE2-induced hyperalgesia, whereas no effect was observed in OVX animals. PGE2 also induced thermal hyperalgesia in sham-operated and OVX female rats and a similar effect of ESI-09 was observed. These results suggest that PGE2-induced hyperalgesia that is observed during sickness syndrome has different signaling mechanisms in cycling and OVX female rats involving the activation of the cAMP-Epac or cAMP-PKA pathways, respectively.
Discharge characteristics of neurons of nucleus reuniens across sleep-wake states in the behaving rat
Tatiana D.VienaabRobert P.VertesbcStephanie B.Linleyb
doi : 10.1016/j.bbr.2021.113325
Volume 410, 23 July 2021, 113325
The nucleus reuniens (RE) of the ventral midline thalamus is strongly reciprocally connected with the hippocampus (HF) and medial prefrontal cortex (PFC), serving a critical role in affective and cognitive functioning. While midline thalamic nuclei have been implicated in the modulation of states of arousal and consciousness, few studies have addressed RE’s role in behavioral state control. Accordingly, as a first line of investigation, we examined the discharge properties of RE neurons in behaving rats throughout the sleep-wake cycle. We analyzed 153 units in RE which demonstrated heterogeneity in discharge rates and pattern of activity across sleep wake states. Using a rate ratio of activity in wake vs. REM, we found that the majority of cells displayed state-related changes and were classified into distinct cell types, exhibiting their highest discharge rates during active waking (AW), REM sleep, or maintaining equivalent activity across AW/REM. We further distinguished cells as either slow firing (SF = < 10 Hz) or fast firing (FF =>10 Hz) cells. The majority of cells, independent of state-related preference, were SF. FF RE cells were primarily wake active and wake/REM cell types. This diverse set of RE neurons are likely modulated by key brainstem and hypothalamic nuclei, which in turn, drive RE to exert strong effects on its cortical targets during waking and REM sleep. RE may not only act as a node in HF-PFC circuitry, but also as a critical thalamic link in ascending arousal and attentional networks.
Resurgence of alcohol seeking following abstinence induced by punishment in male and female rats
Gabrielle M.SuttonAnthony N.NistRusty W.NallKaitlyn O.BrowningTimothy A.Shahan
doi : 10.1016/j.bbr.2021.113345
Volume 410, 23 July 2021, 113345
To better approximate the human condition, animal models of relapse to drug and alcohol seeking have increasingly employed negative consequences to generate abstinence. Here we report the first demonstration of relapse to punishment-suppressed alcohol seeking induced by loss of non-drug reward (i.e., resurgence). We also report the first examination of potential sex differences in any form of relapse to alcohol seeking following suppression by punishment. Male and female rats first pressed a lever for 20 % oral alcohol. Next, lever pressing for one group continued to produce alcohol, but also produced occasional footshock. For another group, lever pressing similarly produced alcohol and occasional footshock, and a nose-poke response produced alternative non-drug reward (i.e., food). Males showed similar suppression of alcohol seeking by punishment alone and punishment?+?alternative non-drug reward, whereas females showed less suppression by punishment alone. Finally, when alternative reinforcement and punishment were suspended, resurgence occurred for both sexes in the group that previously had access to non-drug reward. Exposure to and then removal of punishment alone did not produce relapse for males, but it did for females. These results suggest that loss of alternative non-drug reward can generate relapse to alcohol seeking following abstinence induced by negative consequences. Future research should further examine the role of potential sex differences in sensitivity to punishment and how such differences may contribute to relapse more broadly.
Role of acute social stress in the rewarding effects of MDMA in adolescent mice
M.P.Garc?a-PardoaJ.E.De la Rubia Ort?bC.Calpe-L?pezcM.A.Aguilarc
doi : 10.1016/j.bbr.2021.113348
Volume 410, 23 July 2021, 113348
Drug use among adolescents is a serious problem in our society, as some individuals develop dependence and addiction. MDMA/Esctasy is one of the most typically used substances by this age group. It is well known that environmental factors can alter the rewarding properties of drugs and the propensity to drug-related disorders. In this sense, exposure to social stress induces long-term effects in mice, enhancing the rewarding effects of MDMA in the conditioned place preference (CPP) paradigm. On the other hand, previous research has not provided conclusive results regarding the short-term effects of social defeat on MDMA reward in adolescent animals, probably due to the use of very low or very high doses. Thus, in the present study, we set out to evaluate whether exposure to social defeat immediately before each conditioning session with an intermediate dose of MDMA (2.25 mg/kg) modulates the rewarding effect of this drug in adolescent animals. Our results indicate that both control and socially defeated mice acquired CPP, but only stressed mice showed reinstatement. These findings indicate that social defeat induces an increase in the rewarding effect of MDMA, suggesting that this type of stress is a potential factor in the development of MDMA addiction.
High-frequency repetitive transcranial magnetic stimulation enhances layer II/III morphological dendritic plasticity in mouse primary motor cortex
MarcoCambiaghiaLauraCherchiaLauraMasinaCarmenritaInfortunabNicholasBriskicChristinaCaviascocSaraHazavehcZhiyongHancMarioBuffelliaFortunatoBattagliac
doi : 10.1016/j.bbr.2021.113352
Volume 410, 23 July 2021, 113352
High-frequency repeated transcranial magnetic stimulation (HF-rTMS) is a safe non-invasive neuromodulatory technique and there is a body of evidence shows that it can modulate plasticity in different brain areas. One of the most interesting application of HF-rTMS is the modulation of plasticity in primary motor cortex (M1) to promote recovery after brain injuries. However, the underlying mechanism by which HF-rTMS modulates motor cortex plasticity remain to be investigated.
Central amygdala circuits in valence and salience processing
Mi-SeonKongaLarry S.Zweifelab
doi : 10.1016/j.bbr.2021.113355
Volume 410, 23 July 2021, 113355
Behavioral responses to environmental stimuli are dictated by the affective valence of the stimulus, good (positive valence) or bad (negative valence). These stimuli can innately elicit an affective response that promotes approach or avoidance behavior. In addition to innately valenced stimuli, valence can also be assigned to initially neutral stimuli through associative learning. A stimulus of a given valence can vary in salience depending on the strength of the stimulus, the underlying state of the animal, and the context of the stimulus presentation. Salience endows the stimulus with the ability to direct attention and elicit preparatory responses to mount an incentive-based motivated behavior. The central nucleus of the amygdala (CeA) has emerged as an early integration point for valence and salience detection to engage preparatory autonomic responses and behavioral posturing in response to both aversive and appetitive stimuli. There are numerous cell types in the CeA that are involved in valence and salience processing through a variety of connections, and we will review the recent progress that has been made in identifying these circuit elements and their roles in these processes.
Interactions between maternal fluoxetine exposure, the maternal gut microbiome and fetal neurodevelopment in mice
Helen E.VuongElena J.L.ColeyMariaKazantsevMichaela E.CookeTomiko K.RendonJorgeParamoElaine Y.Hsiao
doi : 10.1016/j.bbr.2021.113353
Volume 410, 23 July 2021, 113353
Selective serotonin reuptake inhibitors (SSRIs) are the most widely used treatment by women experiencing depression during pregnancy. However, the effects of maternal SSRI use on early offspring development remain poorly understood. Recent studies suggest that SSRIs can modify the gut microbiota and interact directly with particular gut bacteria, raising the question of whether the gut microbiome impacts host responses to SSRIs. In this study, we investigate effects of prenatal SSRI exposure on fetal neurodevelopment and further evaluate potential modulatory influences of the maternal gut microbiome. We demonstrate that maternal treatment with the SSRI fluoxetine induces widespread alterations in the fetal brain transcriptome during midgestation, including increases in the expression of genes relevant to synaptic organization and neuronal signaling and decreases in the expression of genes related to DNA replication and mitosis. Notably, maternal fluoxetine treatment from E7.5 to E14.5 has no overt effects on the composition of the maternal gut microbiota. However, maternal pretreatment with antibiotics to deplete the gut microbiome substantially modifies transcriptional responses of the fetal brain to maternal fluoxetine treatment. In particular, maternal fluoxetine treatment elevates localized expression of the opioid binding protein/cell adhesion molecule like gene Opcml in the fetal thalamus and lateral ganglionic eminence, which is prevented by maternal antibiotic treatment. Together, these findings reveal that maternal fluoxetine treatment alters gene expression in the fetal brain through pathways that are impacted, at least in part, by the presence of the maternal gut microbiota.
