Sleep Deprivation

PUBLICATIONS

An open system for automatic home-cage behavioral analysis and its application to male and female mouse models of Huntington's disease

Behavioural Brain Research

2013-01-13

Abstract

Changes in routine mouse home-cage behavioral activities have been used recently to study alterations of neural circuits caused by genetic and environmental modifications and by drug administration. Nevertheless, automatic assessment of mouse home-cage behaviors remains challenging due to the cost of proprietary systems and to the difficulty in adjusting systems to different monitoring conditions. Here we present software for the automatic quantification of multiple facets of mouse home-cage behaviors, suitable for continuous 24 h video monitoring. We used this program to assess behavioral changes in male and female R6/2 transgenic mouse models of Huntington's disease over a 10-week period. Consistent with the well-known progressive motor coordination deficits of R6/2 mice, their hanging, rearing, and climbing activity declined as the disease progressed. R6/2 mice also exhibited frequent disturbances in their resting activity compared to wild-type mice, suggesting that R6/2 mice are more restless and wakeful. Behavioral differences were seen earlier for male R6/2 mice than female R6/2 mice, and “behavioral signatures” based on multiple behaviors enabled us to distinguish male R6/2 mice from sex- and age-matched wild-type controls as early as 5 weeks of age. These results demonstrate that the automated behavioral classification software that we developed (“OpenCage”) provides a powerful tool for analyzing natural home-cage mouse behaviors, and for constructing behavioral signatures that will be useful for assessing therapeutic strategies. The OpenCage software is available under an open-source GNU General Public License, allowing other users to freely modify and extend it to suit their purposes.

Highlights

► New software for automatic video-based classification of mouse home-cage behavior. ► Software available under open-source license, allowing free modification by users. ► Motor deficits and circadian disruptions detected in male and female R6/2 mice. ► Characteristic behavioral signatures defined based on multiple facets of behaviors. ► Behavioral signatures distinguished male R6/2 mice from WT as early as 5 weeks.

Dorsolateral septum somatostatin interneurons gate mobility to calibrate context-specific behavioral fear responses

Nature Neuroscience

2014-01-01

ABSTRACT

Adaptive fear responses to external threats rely upon efficient relay of computations underlying contextual encoding to subcortical circuits. Brain-wide analysis of highly coactivated ensembles following contextual fear discrimination identified the dorsolateral septum (DLS) as a relay of the dentate gyrus–CA3 circuit. Retrograde monosynaptic tracing and electrophysiological whole-cell recordings demonstrated that DLS somatostatin-expressing interneurons (SST-INs) receive direct CA3 inputs. Longitudinal in vivo calcium imaging of DLS SST-INs in awake, behaving mice identified a stable population of footshock-responsive SST-INs during contextual conditioning whose activity tracked and predicted non-freezing epochs during subsequent recall in the training context but not in a similar, neutral context or open field. Optogenetic attenuation or stimulation of DLS SST-INs bidirectionally modulated conditioned fear responses and recruited proximal and distal subcortical targets. Together, these observations suggest a role for a potentially hard-wired DLS SST-IN subpopulation as arbiters of mobility that calibrate context-appropriate behavioral fear responses

Long-term effects of oxytetracycline exposure in zebrafish: A multi-level perspective

Chemosphere

2014-01-01

Highlights

• Zebrafish exposed to oxytetracycline present different feeding behavior pattern.
• Oxytetracycline induced fish boldness and hyperactivity in light periods.
• Energetic reserves and oxidative stress enzymes decrease after long-term exposure.
• Bacterial communities of fish gut and exposure water were affected by oxytetracycline.

Abstract

Oxytetracycline (OTC) is a broad-spectrum antibiotic widely used in livestock production. Like many other pharmaceuticals, OTC is not completely metabolized by the organism and thus, increasing amounts of the compound are being detected in the aquatic environment. The assessment of the environmental risk of pharmaceuticals is hindered by their very low concentrations and specific modes of action and thus relevant exposure scenarios and sensitive endpoints are needed. Thus, this work aimed to study the long-term effect of OTC exposure in zebrafish (at behavior and biochemical levels) and associated bacterial communities (fish gut and water bacterial communities). Results revealed that at behavioral level, boldness increase (manifested by increased exploratory behavior of a new environment) was observed in fish exposed to low OTC concentrations. Moreover, changes in fish swimming pattern were observed in light periods (increased stress response: hyperactivity and freezing) probably due to photo-sensibility conferred by OTC exposure. Effects at biochemical level suggest that long-term exposure to OTC interfere with cellular energy allocation mainly by reducing lipids levels and increasing energy consumption. Moreover, evidences of oxidative damage were also observed (reduced levels of TG, GST and CAT). The analysis of water and gut microbiome revealed changes in the structure and diversity of bacterial communities potentially leading to changes in communities' biological function. Some of the effects were observed at the lowest concentration tested, 0.1 μg/L which is a concentration already detected in the environment and thus clearly demonstrating the need of a serious ecotoxicological assessment of OTC effects on non-target organisms.

 

Link to the publication :

https://www.sciencedirect.com/science/article/pii/S0045653519301638

Hypothesis-Driven Investigations of Diverse Pharmacological Targets in Two Mouse Models of Autism

Autism Research

2014-01-01

Autism spectrum disorder is a neurodevelopmental syndrome diagnosed primarily by persistent deficits in social interactions and communication, unusual sensory reactivity, motor stereotypies, repetitive behaviors, and restricted interests. No FDA-approved medical treatments exist for the diagnostic symptoms of autism. Here we interrogate multiple pharmacological targets in two distinct mouse models that incorporate well-replicated autism-relevant behavioral phenotypes. Compounds that modify inhibitory or excitatory neurotransmission were selected to address hypotheses based on previously published biological abnormalities in each model. Shank3B is a genetic model of a mutation found in autism and Phelan-McDermid syndrome, in which deficits in excitatory neurotransmission and synaptic plasticity have been reported. BTBR is an inbred strain model of forms of idiopathic autism in which reduced inhibitory neurotransmission and excessive mTOR signaling have been reported. The GABA-A receptor agonist gaboxadol significantly reduced repetitive self-grooming in three independent cohorts of BTBR. The TrkB receptor agonist 7,8-DHF improved spatial learning in Shank3B mice, and reversed aspects of social deficits in BTBR. CX546, a positive allosteric modulator of the glutamatergic AMPA receptor, and d-cycloserine, a partial agonist of the glycine site on the glutamatergic NMDA receptor, did not rescue aberrant behaviors in Shank3B mice. The mTOR inhibitor rapamycin did not ameliorate social deficits or repetitive behavior in BTBR mice. Comparison of positive and negative pharmacological outcomes, on multiple phenotypes, evaluated for replicability across independent cohorts, enhances the translational value of mouse models of autism for therapeutic discovery. GABA agonists present opportunities for personalized interventions to treat components of autism spectrum disorder. Autism Res 2019. © 2019 The Authors. Autism Research published by International Society for Autism
Research published by Wiley Periodicals, Inc.

 

Lay Summary:

Many of the risk genes for autism impair synapses, the connections between nerve cells in the brain. A
drug that reverses the synaptic effects of a mutation could offer a precision therapy. Combining pharmacological and
behavioral therapies could reduce symptoms and improve the quality of life for people with autism. Here we report reductions
in repetitive behavior by a GABA-A receptor agonist, gaboxadol, and improvements in social and cognitive behaviors
by a TrkB receptor agonist, in mouse models of autism.

NEUROPROTECTIVE COMPOSITION , PREPARATION PROCESS THEREOF AND MEDICAL USES THEREOF

2014-01-01

ABSTRACT

The invention relates to a neuroprotective composition derived from mesenchymal stem cells , especially a neuro protective composition derived from the primary culture of dental pulp mesenchymal stem cells . The invention also relates to a process for preparing the neuroprotective com position , as well as the medical use of the neuroprotective composition in the treatment of Parkinson ' s disease .

 

Link to the publication :

https://patentimages.storage.googleapis.com/cf/7a/95/2fddaa73d87899/US20190167727A1.pdf

Identifcation of pathways that regulate circadian rhythms using a larval zebrafsh small molecule screen

Nature

2014-01-01

The circadian clock ensures that behavioral and physiological processes occur at appropriate times during the 24-hour day/night cycle, and is regulated at both the cellular and organismal levels. To identify pathways acting on intact animals, we performed a small molecule screen using a luminescent reporter of molecular circadian rhythms in zebrafish larvae. We identified both known and novel pathways that affect circadian period, amplitude and phase. Several drugs identified in the screen did not affect circadian rhythms in cultured cells derived from luminescent reporter embryos or in established zebrafish and mammalian cell lines, suggesting they act via mechanisms absent in cell culture. Strikingly, using drugs that promote or inhibit inflammation, as well as a mutant that lacks microglia, we found that inflammatory state affects circadian amplitude. These results demonstrate a benefit of performing drug screens using intact animals and provide novel targets for treating circadian rhythm disorders.

Introduction

Circadian rhythms help ensure that physiological processes and behaviors occur at appropriate times during the 24-hour day/night cycle. These rhythms are generated and sustained at the cellular level by a transcriptional-translational negative-feedback loop that cycles with a period of approximately 24 hours, and are entrained by environmental cues such as light, food availability and temperature1. Molecular circadian oscillations in cells in different tissues and brain regions cycle with distinct phases, suggesting that non-cell autonomous mechanisms transmit circadian information throughout an animal1. While the suprachiasmatic nucleus (SCN) acts as a central circadian pacemaker to regulate circadian rhythms in mammals, it is unclear how the SCN transmits circadian information and if additional non-cell autonomous mechanisms exist. It is also unclear whether some aspects of the vertebrate circadian clock, which has primarily been studied using nocturnal rodents, differ from those in diurnal vertebrates such as humans. Thus, despite extensive research, mechanisms that regulate circadian rhythms remain incompletely understood.

Attempts to identify these mechanisms have primarily used two approaches. Genetic screens in model organisms have identified many components of the molecular circadian clock1. However, this approach may fail to detect genes that regulate aspects of the clock that do not affect the phenotype studied, or genes that have functionally redundant paralogs. Genetic screens are also difficult to perform using vertebrate animals. More recently, luminescent reporters have been used in cell culture to screen for cell autonomous factors that regulate the mammalian molecular circadian oscillator2,3,4,5,6,7,8. However, this approach lacks in vivo relevance and will not detect mechanisms that act non-cell autonomously or do not operate in the cell types used. Thus, alternative approaches could reveal novel mechanisms that regulate the circadian clock.

Most small molecule screens use in vitro or cell culture assays to identify drugs that bind a specific target or affect a specific process. However, these screens do not recreate the complex environment of whole animals and likely fail to identify some mechanisms that regulate the process under study. To overcome these limitations, we and others have used intact zebrafish as a vertebrate model system for small molecule screens9. This approach combines the in vivo relevance of whole-animal assays with moderate-throughput, low-cost drug screening. It also exploits several features of zebrafish larvae, including a relatively simple yet conserved vertebrate brain that lacks a mature blood-brain-barrier10, a small size that allows for screening in multi-well plates, and optical transparency that facilitates the use of luminescent reporters. Importantly, for the purposes of circadian research, the zebrafish molecular circadian oscillator closely resembles that of mammals11.

Here we describe a screen for small molecules that affect molecular circadian rhythms using a luminescent reporter in zebrafish larvae. We also monitor behavioral circadian rhythms using an assay that we previously used to identify drugs that regulate larval zebrafish locomotor behaviors12. We show that small molecules targeting pathways known to affect the circadian clock induce the expected circadian phenotypes in intact zebrafish. We also identify drugs that implicate novel pathways in regulating circadian rhythms in vivo that are absent in cultured cells. Finally, we show that inflammatory state affects circadian amplitude using both drugs and xpr1b mutant zebrafish, which lack microglia. These results reveal an unexpected role for the immune system in regulating the circadian clock.

Results

A screen for small molecules that affect molecular circadian rhythms in zebrafish larvae

A previous study described transgenic zebrafish in which the promoter for the period3 gene regulates expression of firefly luciferase (Tg(per3:luc)), and showed that this line accurately reports molecular circadian rhythms in zebrafish larvae13. To test whether this line could be used to screen for small molecules that affect molecular circadian rhythms, we asked whether compounds that affect the circadian clock in cell culture induce similar effects in zebrafish larvae. We entrained Tg(per3:luc) larvae in 14:10 hour light:dark (LD) conditions for 6 days at 22 °C13. We then placed individual larvae into each well of a 96-well plate, added small molecules or DMSO vehicle control to each well, and monitored luminescence for 72 hours in constant darkness (DD) (Fig. 1A). To validate our assay, we first tested a drug that targets a pathway known to affect circadian period length. Pharmacological inhibition of casein kinase 1 (CK1) increases period length in mammalian cell culture3,5,14, rodents5,15 and zebrafish5,15,16, similar to some ck1 mutant animals17,18,19,20. We tested a compound, A002195858, that inhibits CK1 in vitro (IC50 = 23 nM) and dose-dependently increases period length in mammalian cells (Fig. S2F), and found that it also dose-dependently increases period length in our larval zebrafish assay (Fig. 1B). We also found that the Src kinase inhibitor SU-665621 dose-dependently increases circadian amplitude in our assay (Fig. 1C). These results indicate that Tg(per3:luc) larvae can be used to report drug-induced changes in molecular circadian rhythms, and that phenotypes observed in mammalian cells can also be observed in zebrafish larvae.

Ciproxifan improves working memory through increased prefrontal cortex neural activity in sleep-restricted mice

Elsevier

2014-04-22

Histamine receptor type 3 (H3) antagonists are promising awakening drugs for treatment of sleep disorders.
However, few works have tried to identify their cognitive effects after sleep restriction and their
impact on associated neural networks. To that aim, Bl/6J male mice were submitted to acute sleep restriction
in a shaker apparatus that prevents sleep by transient (20e40 ms) up and down movements.
Number of stimulations (2e4), and delay between 2 stimulations (100e200 ms) were randomized. Each
sequence of stimulation was also randomly administered (10e30 s interval) for 20 consecutive hours
during light (8 h) and dark (12 h) phases. Immediately after 20 h-sleep restriction, mice were injected
with H3 antagonist (ciproxifan 3 mg/kg ip) and submitted 30-min later to a working memory (WM) task
using spatial spontaneous alternation behaviour. After behavioural testing, brains were perfused for Fos
immunohistochemistry to assess neuronal brain activation in the dorsal dentate gyrus (dDG) and the
prefrontal cortex. Results showed that sleep restriction decreased slow wave sleep (from 35.8  1.4% to
9.2  2.7%, p < 0.001) and was followed by sleep rebound (58.2  5.9%, p < 0.05). Sleep restriction did
not modify anxiety-like reactivity and significantly decreased WM at long (30 s) but not short (5 s) intertrial
intervals. Whereas sleep restriction failed to significantly modify immunopositive cells in vehicles,
ciproxifan administration prevented WM deficits in sleep restricted mice through significant increases of
Fos labelling in prelimbic, infralimbic and cingulate 2 cortex.

Mice with a deletion of the major central myelin protein exhibit hypersensitivity to noxious thermal stimuli: involvement of central sensitization

Neurobiology of Disease, Volume 65, May 2014, Pages 55-68

2014-05-01

Null mutations in the gene encoding the major myelin protein of the central nervous system, proteolipid protein 1 (PLP1), cause an X-linked form of spastic paraplegia (SPG2) associated with axonal degeneration. While motor symptoms are the best known manifestations of this condition, its somatosensory disturbances have been described but poorly characterized. We carried out a longitudinal study in an animal model of SPG2 — mice carrying a deletion of the Plp1 gene (Plp-null mice). Plp-null mice exhibited severe early-onset thermal hyperalgesia, in the absence of thermal allodynia. We first performed an electrophysiological testing which showed an early decrease in peripheral and spinal conduction velocities in Plp null mice. Such as the abnormal sensitive behaviors, this slowing of nerve conduction was observed before the development of myelin abnormalities at the spinal level, from 3 months of age, and without major morphological defects in the sciatic nerve. To understand the link between a decrease in nerve velocity and an increased response to thermal stimuli before the appearance of myelin abnormalities, we focused our attention on the dorsal horn of the spinal cord, the site of integration of somatosensory information. Immunohistochemical studies revealed an early-onset activation of astrocytes and microglia that worsened with age, associated later in age with perturbation of the expression of the sensory neuropeptides calcitonin-gene-related peptide and galanin. Taken together, these results represent complementary data supporting the hypothesis that Plp-null mice suffer from ganglionopathy associated with late onset central demyelination but with few peripheral nerve alterations, induced by the glial-cell-mediated sensitization of the spinal cord. The mechanism suggested here could underlie pain experiments in other leukodystrophies as well as in other non-genetic demyelinating diseases such as multiple sclerosis.

Mice with a deletion of the major central myelin protein exhibit hypersensitivity to noxious thermal stimuli: involvement of central sensitization

Bérengère Petita,, Fabrice Giraudetb, Céline Béchona, Laurent Bardinf, Paul Avanb, Odile Boespflug-Tanguyd, Mélina Bégou

Maternal cortisol stimulates neurogenesis and affects larval behaviour in zebrafish

Nature

2017-01-18

Abstract

Excess glucocorticoid transferred from stressed mother to the embryo affects developing vertebrate offspring, but the underlying programming events are unclear. In this study, we tested the hypothesis that increased zygotic glucocorticoid deposition, mimicking a maternal stress scenario, modifies early brain development and larval behaviour in zebrafish (Danio rerio). Cortisol was microinjected into the yolk at one cell-stage, to mimic maternal transfer, and the larvae [96 hours post-fertilization (hpf)] displayed increased activity in light and a reduction in thigmotaxis, a behavioural model for anxiety, suggesting an increased propensity for boldness. This cortisol-mediated behavioural phenotype corresponded with an increase in primary neurogenesis, as measured by incorporation of EdU at 24 hpf, in a region-specific manner in the preoptic region and the pallium, the teleostean homolog of the hippocampus. Also, cortisol increased the expression of the proneural gene neurod4, a marker of neurogenesis, in a region- and development-specific manner in the embryos. Altogether, excess zygotic cortisol, mimicking maternal stress, affects early brain development and behavioural phenotype in larval zebrafish. We propose a key role for cortisol in altering brain development leading to enhanced boldness, which may be beneficial in preparing the offspring to a stressful environment and enhancing fitness.

 

http://www.nature.com/articles/srep40905

Hormetic effect of panaxatriol saponins confers neuroprotection in PC12 cells and zebrafish through PI3K/AKT/mTOR and AMPK/SIRT1/FOXO3 pathways

Nature

2017-01-23

Abstract

Hormesis is an adaptive response of living organisms to a moderate stress. However, its biomedical implication and molecular mechanisms remain to be intensively investigated. Panaxatriol saponins (PTS) is the major bioactive components extracted from Panax notoginseng, a widely used herbal medicine for cerebrovascular diseases. This study aims to examine the hormetic and neuroprotective effects of PTS in PC12 cells and zebrafish Parkinson’s disease (PD) models. Our results demonstrated that PTS stimulated PC12 cell growth by about 30% at low doses, while PTS at high doses inhibited cell growth, which is a typical hormetic effect. Moreover, we found that low dose PTS pretreatment significantly attenuated 6-OHDA-induced cytotoxicity and up-regulated PI3K/AKT/mTOR cell proliferation pathway and AMPK/SIRT1/FOXO3 cell survival pathway in PC12 cells. These results strongly suggested that neuroprotective effects of PTS may be attributable to the hormetic effect induced by PTS through activating adaptive response-related signaling pathways. Notably, low dose PTS could significantly prevent the 6-OHDA-induced dopaminergic neuron loss and improve the behavior movement deficiency in zebrafish, whereas relative high dose PTS exhibited neural toxicity, further supporting the hormetic and neuroprotective effects of PTS. This study indicates that PTS may have the potential in the development of future therapeutic medicines for PD.

 

http://www.nature.com/articles/srep41082

FAAH Inhibition Produces Antidepressant-like efforts of Mice to Acute Stress via Synaptic Long-term Depression

Science Direct

2017-02-14

Abstract

Recent studies have shown that inhibition of fatty acid amide hydrolase (FAAH), the major degradative enzyme of the endocannabinoid N-arachidonoylethanolamine (AEA), produced antidepressant behavioral responses, but its underlying mechanism is not clear. Here we find that a systemic administration of the FAAH inhibitor PF3845 or an intra-CA1 application of AEA elicits an in vivo long-term depression (LTD) at excitatory glutamatergic CA3-CA1 synapses of the hippocampus. The PF3845- and/or AEA-elicited LTD are abolished by the LTD-blocking peptide Tat-GluR2. PF3845 significantly decreases passive behavioral coping of naïve mice to acute inescapable stress, which is also abolished by Tat-GluR2 peptide. However, PF3845 does not significantly affect sucrose assumption ratio of mice receiving chronic administration of corticosterone. These results suggest that FAAH inhibitors are able to produce antidepressant effects in naïve animals in response to acute stress through LTD at hippocampal glutamatergic CA3-CA1 synapses.

 

http://www.sciencedirect.com/science/article/pii/S0166432816310798

NMDA-receptor-dependent plasticity in the bed nucleus of the stria terminalis triggers long-term anxiolysis

Nature

2017-02-25

Abstract

Anxiety is controlled by multiple neuronal circuits that share robust and reciprocal connections with the bed nucleus of the stria terminalis (BNST), a key structure controlling negative emotional states. However, it remains unknown how the BNST integrates diverse inputs to modulate anxiety. In this study, we evaluated the contribution of infralimbic cortex (ILCx) and ventral subiculum/CA1 (vSUB/CA1) inputs in regulating BNST activity at the single-cell level. Using trans-synaptic tracing from single-electroporated neurons and in vivo recordings, we show that vSUB/CA1 stimulation promotes opposite forms of in vivo plasticity at the single-cell level in the anteromedial part of the BNST (amBNST). We find that an NMDA-receptor-dependent homosynaptic long-term potentiation is instrumental for anxiolysis. These findings suggest that the vSUB/CA1-driven LTP in the amBNST is involved in eliciting an appropriate response to anxiogenic context and dysfunction of this compensatory mechanism may underlie pathologic anxiety states.

 

http://www.nature.com/articles/ncomms14456

Glial GLT-1 blockade in infralimbic cortex as a new strategy to evoke rapid antidepressant-like effects in rats

Nature

2017-02-25

Abstract

Ketamine and deep brain stimulation produce rapid antidepressant effects in humans and rodents. An increased AMPA receptor (AMPA-R) signaling in medial prefrontal cortex (mPFC) has been suggested to mediate these responses. However, little research has addressed the direct effects of enhancing glutamate tone or AMPA-R stimulation in mPFC subdivisions. The current study investigates the behavioral and neurochemical consequences of glutamate transporter-1 (GLT-1) blockade or s-AMPA microinfusion in the infralimbic (IL) and prelimbic (PrL) cortex. Owing to the connectivity between the mPFC and raphe nuclei, the role of serotonin is also explored. The bilateral microinfusion of the depolarizing agent veratridine into IL -but not PrL- of rats evoked immediate antidepressant-like responses. The same regional selectivity was observed after microinfusion of dihydrokainic acid (DHK), a selective inhibitor of GLT-1, present in astrocytes. The DHK-evoked antidepressant-like responses appear to be mediated by an AMPA-R-driven enhancement of serotonergic activity, as (i) they were prevented by NBQX 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt) and mimicked by s-AMPA; (ii) DHK and s-AMPA elevated similarly extracellular glutamate in IL and PrL, although extracellular 5-HT and c-fos expression in the midbrain dorsal raphe increased only when these agents were applied in IL; and (iii) DHK antidepressant-like responses were prevented by 5-HT synthesis inhibition and mimicked by citalopram microinfusion in IL. These results indicate that an acute increase of glutamatergic neurotransmission selectively in IL triggers immediate antidepressant-like responses in rats, likely mediated by the activation of IL–raphe pathways, which then results in a fast increase of serotonergic activity.

 

http://www.nature.com/tp/journal/v7/n2/full/tp20177a.html

Neurobehavioral effects of lithium in the rat: Investigation of the effect/concentration relationships and the contribution of the poisoning pattern

Science Direct

2017-03-25

Abstract

Severity of lithium poisoning depends on the ingested dose, previous treatment duration and renal function. No animal study has investigated neurobehavioral differences in relation to the lithium poisoning pattern observed in humans, while differences in lithium pharmacokinetics have been reported in lithium-pretreated rats mimicking chronic poisonings with enhanced brain accumulation in rats with renal failure. Our objectives were: 1)-to investigate lithium-related effects in overdose on locomotor activity, anxiety-like behavior, spatial recognition memory and anhedonia in the rat; 2)-to model the relationships between lithium-induced effects on locomotion and plasma, erythrocyte, cerebrospinal fluid and brain concentrations previously obtained according to the poisoning pattern. Open-field, elevated plus-maze, Y-maze and sucrose consumption tests were used. In acutely lithium-poisoned rats, we observed horizontal (p < 0.001) and vertical hypolocomotion (p < 0.0001), increased anxiety-like behavior (p < 0.05) and impaired memory (p < 0.01) but no altered hedonic status. Horizontal (p < 0.01) and vertical (p < 0.001) hypolocomotion peaked more markedly 24 h after lithium injection and was more prolonged in acute-on-chronically vs. acutely lithium-poisoned rats. Hypolocomotion in chronically lithium-poisoned rats with impaired renal function did not differ from acutely poisoned rats 24 h after the last injection. Interestingly, hypolocomotion/concentration relationships best fitted a sigmoidal Emax model in acute poisoning and a linear regression model linked to brain lithium in acute-on-chronic poisoning. In conclusion, lithium overdose alters rat behavior and consistently induces hypolocomotion which is more marked and prolonged in repeatedly lithium-treated rats. Our data suggest that differences between poisoning patterns regarding lithium-induced hypolocomotion are better explained by the duration of lithium exposure than by its brain accumulation.

 

http://www.sciencedirect.com/science/article/pii/S0278584616303438

Deletion of Numb/Numblike in glutamatergic neurons leads to anxiety-like behavior in mice

Science Direct

2017-03-28

Abstract

Endocytic adaptor protein Numb is the first identified cell fate determinant in Drosophila melanogaster. It has been implicated in Notch signaling pathway and regulation of neural stem cells proliferation in the central nervous system. Numb is also expressed in postmitotic neurons, in vitro studies showed that Numb is involved in neuronal morphologic development, such as neurite growth, axonal growth and spine development. However, in vivo functions of Numb in the postmitotic neurons are largely unknown. Here we show that deletion of Numb/Numblike in glutamatergic neurons causes anxiety-like behavior in mouse. In this study, we conditionally deleted Numb and its homologous gene Numblike in the glutamatergic neurons in dorsal forebrain, and thoroughly characterized the behavioral phenotypes of mutant mice. On a battery of tests for anxiety-like behavior, the conditional double knockout mice showed increased anxiety-like behavior on light/dark exploration and novel open field tests, but not on elevated zero maze tests. The conditional double knockout mice also displayed novelty induced hyperactivity in novel open field test. Control measures of general health, motor functions, startle response, sensorimotor gating, depression-related behaviors did not show differences between genotypes. Our present findings provide new insight into the indispensable functions of Numb/Numblike in the brain and behavior, and suggest that Numb/Numblike may play a role in mediating neuronal functions that underlie behaviors related to anxiety.

 

http://www.sciencedirect.com/science/article/pii/S000689931730094X

Bidirectional regulation over the development and expression of loss of control over cocaine intake by the anterior insula

Psychopharmacology

2017-04-05

Abstract

Rationale

Increasing evidence suggests that the anterior insular cortex (AIC) plays a major role in cocaine addiction, being implicated in both impaired insight and associated decision-making and also craving and relapse. However, the nature of the involvement of the insula in the development and maintenance of cocaine addiction remains unknown, thereby limiting our understanding of its causal role in addiction. We therefore investigated whether pre- and post-training bilateral lesions of the AIC differentially influenced the development and the expression of the escalation of cocaine self-administration during extended access to the drug.

Methods

In a series of experiments, Sprague Dawley rats received bilateral excitotoxic lesions of the AIC either prior to, or after 3 weeks of training under 12-h extended self-administration conditions, which are known to promote a robust escalation of intake. We also investigated the influence of AIC lesions on anxiety, as measured in an elevated plus maze and sensitivity to conditioned stimuli (CS)- or drug-induced reinstatement of an extinguished instrumental response.

Results

Whereas, post-escalation lesions of the AIC, as anticipated, restored control over cocaine intake and prevented drug-induced reinstatement, pre-training lesions resulted in a facilitation of the development of loss of control with no influence over the acquisition of cocaine self-administration or anxiety.

Conclusions

AIC lesions differentially affect the development and maintenance of the loss of control over cocaine intake, suggesting that the nature of the contribution of cocaine-associated interoceptive mechanisms changes over the course of escalation and may represent an important component of addiction.

 

http://link.springer.com/article/10.1007/s00213-017-4593-x

Dopaminergic control of anxiety in young and aged zebrafish

ScienceDirect

2017-04-10

Abstract

Changes in the expression of the dopamine transporter (DAT), or the sensitivity of dopamine receptors, are associated with aging and substance abuse and may underlie some of the symptoms common to both conditions. In this study, we explored the role of the dopaminergic system in the anxiogenic effects of aging and acute cocaine exposure by comparing the behavioral phenotypes of wildtype (WT) and DAT knockout zebrafish (DAT-KO) of different ages. To determine the involvement of specific dopamine receptors in anxiety states, antagonists to D1 (SCH23390) and D2/D3 (sulpiride) were employed. We established that DAT-KO results in a chronic anxiety-like state, seen as an increase in bottom-dwelling and thigmotaxis. Similar effects were produced by aging and acute cocaine administration, both leading to reduction in DAT mRNA abundance (qPCR). Inhibition of D1 activity counteracted the anxiety-like effects associated with DAT deficit, independent of its origin. Inhibition of D2/D3 receptors reduced anxiety in young DAT-KO, enhanced the anxiogenic effects of cocaine in WT, but did not affect aged WT or DAT-KO fish. These findings provide new evidence that the dopaminergic system plays a critical role in anxiety-like states, and suggest that adult zebrafish provide a sensitive diurnal vertebrate model for elucidating the molecular mechanisms of anxiety and a platform for anxiolytic drug screens.

 

http://www.sciencedirect.com/science/article/pii/S009130571630212X

Asenapine modulates mood-related behaviors and 5-HT1A/7 receptors-mediated neurotransmission

CNS Neuroscience & Therapeutics

2017-04-17

Abstract


Aim

Asenapine is a new atypical antipsychotic prescribed for the treatment of psychosis/bipolar disorders that presents higher affinity for serotonergic than dopaminergic receptors. The objective of this study was to investigate its antidepressant-like and antimanic-like properties on relevant animal models of depression and mania and to assess the acute and chronic effect of Asenapine on dorsal raphe nucleus (DRN) 5-HT cell firing activity.
Methods

We assessed the effects of Asenapine using in vivo electrophysiological and behavioral assays in rats.


Results

Behavioral experiments showed that Asenapine had no significant effect on immobility time in the forced swim test (FST) in control rats. In the ACTH-treated rats, a model of antidepressant-resistance, Asenapine failed to alter immobility time in the FST. In contrast in the sleep deprivation (SD) model of mania, acute administration of Asenapine significantly decreased the hyperlocomotion of SD rats. In the DRN, acute administration of Asenapine reduced the suppressant effect of the selective 5-HT7 receptor agonist LP-44 and of the prototypical 5-HT1A receptor agonist 8-OH-DPAT on 5-HT neuronal firing activity. In addition, chronic treatment with Asenapine enhanced DRN 5-HT neuronal firing and this effect was associated with an alteration of the 5-HT7 receptor responsiveness.


Conclusion

These results confirm that Asenapine displays robust antimanic property and effective in vivo antagonistic activity at 5-HT1A/7 receptors.

 

http://onlinelibrary.wiley.com/doi/10.1111/cns.12698/full

NACHO Mediates Nicotinic Acetylcholine Receptor Function throughout the Brain

Cell Reports

2017-04-25

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) participate in diverse aspects of brain function and mediate behavioral and addictive properties of nicotine. Neuronal nAChRs derive from combinations of α and β subunits, whose assembly is tightly regulated. NACHO was recently identified as a chaperone for α7-type nAChRs. Here, we find NACHO mediates assembly of all major classes of presynaptic and postsynaptic nAChR tested. NACHO acts at early intracellular stages of nAChR subunit assembly and then synergizes with RIC-3 for receptor surface expression. NACHO knockout mice show profound deficits in binding sites for α-bungarotoxin, epibatidine, and conotoxin MII, illustrating essential roles for NACHO in proper assembly of α7-, α4β2-, and α6-containing nAChRs, respectively. By contrast, GABAA receptors are unaffected consistent with NACHO specifically modulating nAChRs. NACHO knockout mice show abnormalities in locomotor and cognitive behaviors compatible with nAChR deficiency and underscore the importance of this chaperone for physiology and disease associated with nAChRs.

 

https://www.ncbi.nlm.nih.gov/pubmed/28445721

The modulation of adult neuroplasticity is involved in the mood-improving actions of atypical antipsychotics in an animal model of depression

Translational Psychiatry

2017-06-06

Abstract

Depression is a prevalent psychiatric disorder with an increasing impact in global public health. However, a large proportion of patients treated with currently available antidepressant drugs fail to achieve remission. Recently, antipsychotic drugs have received approval for the treatment of antidepressant-resistant forms of major depression. The modulation of adult neuroplasticity, namely hippocampal neurogenesis and neuronal remodeling, has been considered to have a key role in the therapeutic effects of antidepressants. However, the impact of antipsychotic drugs on these neuroplastic mechanisms remains largely unexplored. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 3 weeks of stress exposure, animals were treated with two different antipsychotics: haloperidol (a classical antipsychotic) and clozapine (an atypical antipsychotic). We demonstrated that clozapine improved both measures of depressive-like behavior (behavior despair and anhedonia), whereas haloperidol aggravated learned helplessness in the forced-swimming test and behavior flexibility in a cognitive task. Importantly, an upregulation of adult neurogenesis and neuronal survival was observed in animals treated with clozapine, whereas haloperidol promoted a downregulation of these processes. Furthermore, clozapine was able to re-establish the stress-induced impairments in neuronal structure and gene expression in the hippocampus and prefrontal cortex. These results demonstrate the modulation of adult neuroplasticity by antipsychotics in an animal model of depression, revealing that the atypical antipsychotic drug clozapine reverts the behavioral effects of chronic stress by improving adult neurogenesis, cell survival and neuronal reorganization.

 

https://www.nature.com/tp/journal/v7/n6/full/tp2017120a.html

Left Habenular Activity Attenuates Fear Responses in Larval Zebrafish

ScienceDirect - Current Biology

2017-07-14

Summary

Fear responses are defensive states that ensure survival of an organism in the presence of a threat. Perception of an aversive cue causes changes in behavior and physiology, such as freezing and elevated cortisol, followed by a return to the baseline state when the threat is evaded [1]. Neural systems that elicit fear behaviors include the amygdala, hippocampus, and medial prefrontal cortex. However, aside from a few examples, little is known about brain regions that promote recovery from an aversive event [2]. Previous studies had implicated the dorsal habenular nuclei in regulating fear responses and boldness in zebrafish [3–7]. We now show, through perturbation of its inherent left-right (L-R) asymmetry at larval stages, that the dorsal habenulo-interpeduncular (dHb-IPN) pathway expedites the return of locomotor activity following an unexpected negative stimulus, electric shock. Severing habenular efferents to the IPN, or only those from the left dHb, prolongs the freezing behavior that follows shock. Individuals with a symmetric, right-isomerized dHb also exhibit increased freezing. In contrast, larvae that have a symmetric, left-isomerized dHb, or in which just the left dHb-IPN projection is optogenetically activated, rapidly resume swimming post shock. In vivo calcium imaging reveals a neuronal subset, predominantly in the left dHb, whose activation is correlated with resumption of swimming. The results demonstrate functional specialization of the left dHb-IPN pathway in attenuating the response to fear.

 

http://www.sciencedirect.com/science/article/pii/S0960982217307194

On the transition from reconsolidation to extinction of contextual fear memories

Learning & Memory

2017-08-17

Abstract

Retrieval of an associative memory can lead to different phenomena. Brief reexposure sessions tend to trigger reconsolidation, whereas more extended ones trigger extinction. In appetitive and fear cued Pavlovian memories, an intermediate “null point” period has been observed where neither process seems to be engaged. Here we investigated whether this phenomenon extends to contextual fear memory. Adult rats were subjected to a contextual fear conditioning paradigm, reexposed to the context 2 d later for 3, 5, 10, 20, or 30 min, with immediate injections of MK-801 or saline following reexposure, and tested on the following day. We observed a significant effect of MK-801 with the 3- and 30-min sessions, impairing reconsolidation and extinction, respectively. However, it did not have significant effects with 5-, 10-, or 20-min sessions, even though freezing decreased from reexposure to test. Further analyses indicated that this is not likely to be due to a variable transition point at the population level. In conclusion, the results show that in contextual fear memories there is a genuine “null point” between the parameters that induce reconsolidation and extinction, as defined by the effects of MK-801, although NMDA receptor-independent decreases in freezing can still occur in these conditions.

 

http://learnmem.cshlp.org/content/24/9/392.full

 

Effect of mTOR silencing in mouse infralimbic cortex on depressive-like behaviour

30th ECNP Congress - Paris 2017

2017-09-02

Background: Over the last years, there has been an increase in the number of scientific publications analyzing the role of different cellular pathways implicated in neural proliferation and plasticity, as well as the brain areas involved in the pathophysiology and treatment of Major Depressive Disorder (MDD). The modulation of neuronal activity in the infralimbic prefrontal cortex (IL) underlies the antidepressant and anxiolytic actions of the N-Methyl-D-aspartate (NMDA) antagonist ketamine, indicating the critical role of this area in the disease [1]. Regarding the glutamatergic system, ketamine, demonstrated a rapid onset of action due to an increased activation of the mammalian target of rapamycin (mTOR) pathway in the medial prefrontal cortex (mPFCx) [2], revolutionizing the treatment perspective of this psychiatric disorder. However, little is known about the role of mTOR in the neurobiology of this pathology.


Aim of the study: We hypothesized that a reduced expression of mTOR in the mPFCx would induce a depressive-like behaviour in mice. In this study, we have silenced mTOR using selective small interfering RNA molecules (siRNAs) administered in the infralimbic (IL) and prelimbic (PL) mPFCx.


Methods: We microinjected siRNAs specifically designed against mTOR (mTOR-siRNA) and artificial cerebrospinal fluid (aCSF) as control unilaterally into infralimbic (IL) or prelimbic (PL) cortices of C57BL/6J mice. We examined the behavioural and molecular effects using in situ hybridization, in vivo microdialysis in dorsal raphe nucleus (DRN), and behavioural tests (forced swimming test, FST, and tail suspension test, TST). Groups were statistically compared by one-way or two-way ANOVA, followed by Tukey's posthoc analysis.


Results: Unilateral infusion of mTOR-siRNA (40 μg/μl) into the IL cortex, induced a depressive-like behaviour 24 h post-administration in the FST (mTOR-siRNA 173.0 ± 6.2 s vs control 149.2 ± 5.2 s, p ˂ 0.05, n = 8–9), and 48 h post-administration in the TST (mTOR-siRNA 187.7 ± 7.4 s vs aCSF 155.2 ± 7.4 s, p ˂ 0.05, n = 7–9). On contrast, the infusion into the PL cortex did not reflect significant changes in the animals’ behaviour, in any of the performed paradigms.
mTOR-siRNA infusion into IL cortex reduced mTOR mRNA levels in the IL (19% vs controls, p ˂ 0.01, n = 5) and PL cortices (15% vs controls, p ˂ 0.05, n = 5), while the infusion into PL cortex decreased the levels of mRNA only in the PL area (16% vs controls; p ˂ 0.05, n = 5). Interestingly, in both IL and PL cortices, the mTOR siRNA administration, reduces the BDNF mRNA levels (7%, p ˂ 0.05 and 12%; p ˂ 0.01, respectively).
The mTOR-siRNA infusion into the IL cortex induced changes in neurotransmitter release in the dorsal raphe nucleus (DRN). After the administration of bicuculline (100 μM), the animals with mTOR silenced in IL cortex displayed an increase of 5-HT release in the DRN (p ˂ 0.05 vs controls, n = 4–5), suggesting a higher inhibitory activity in this brain area.


Conclusions: The present study suggests that mTOR in IL cortex (rodent equivalent of the ventral anterior cingulate cortex (Brodmann 25 area), but not in PL cortex, plays a major role in the depressive-like behaviour. This allows a better understanding of the biological basis of MDD and new approaches for antidepressant drug discovery.

 

https://www.ecnp.eu/presentationpdfs/71/P.2.a.010.pdf

Telmisartan Activates PPARδ to Improve Symptoms of Unpredictable Chronic Mild Stress-Induced Depression in Mice

Nature

2017-10-25

Abstract

Major depression is a common mental disorder that has been established to be associated with a decrease in serotonin and/or serotonin transporters in the brain. Peroxisome proliferator-activated receptor δ (PPARδ) has been introduced as a potential target for depression treatment. Telmisartan was recently shown to activate PPARδ expression; therefore, the effectiveness of telmisartan in treating depression was investigated. In unpredictable chronic mild stress (UCMS) model, treatment with telmisartan for five weeks notably decrease in the time spent in the central and the reduced frequency of grooming and rearing in open filed test (OFT) and the decreased sucrose consumption in sucrose preference test (SPT) compared with the paradigms. Telmisartan also reversed the decrease in PPARδ and 5-HTT levels in the hippocampus of depression-like mice. Administration of PPARδ antagonist GSK0660 and direct infusion of sh-PPARδ into the brain blocked the effects of telmisartan on the improvement of depression-like behavior in these mice. Moreover, telmisartan enhanced the expression of PPARδ and 5HTT in H19-7 cells. In conclusion, the obtained results suggest that telmisartan improves symptoms of stress-induced depression in animals under chronic stress through activation of PPARδ. Therefore, telmisartan may be developed as a potential anti-depressant in the future.

 

Full publication available on nature : https://www.nature.com/articles/s41598-017-14265-4

Developmental plasticity in zebrafish (Danio rerio): effects of early life exposure to a stressor

Thesis submitted to the Faculty of Graduate and Postdoctoral Studies

2017-12-05

Abstract

Experience of stress and/or cortisol, the end-product of activation of the hypothalamic-pituitary-interrenal (HPI) axis, may serve as a cue to trigger developmental plasticity. In fish, most research in this area has focused on effects of maternal stress or maternal cortisol levels on development, particularly with respect to the HPI axis and stress responses, and little attention has been paid to the effects of an endogenous stress response during early life. In the current study, zebrafish (Danio rerio) at four developmental stages (4, 7, 15 or 35 days post fertilization, dpf) were subjected to an air exposure stressor twice a day for two days. Individuals stressed early in life exhibited decreased survival and growth, increased whole-body Na +  and Ca 2+ concentrations, and altered HPI axis activity associated with changes in anxiety-related behaviour at 7 to 35 dpf, with most effects diminishing with increasing age. Stress at 7 dpf was particularly effective at eliciting phenotypic changes, suggesting this age represents a critical window for cortisol to influence development. Finally, stress at 35 dpf induced masculinization, suggesting that cortisol influences sexual differentiation in zebrafish. These findings demonstrate that early-life stress in zebrafish triggers developmental plasticity, with effects on physiology and behaviour mediated by the HPI axis in an age-dependent manner.

 

https://ruor.uottawa.ca/bitstream/10393/36973/3/Hare_Alexander_2017_thesis.pdf

 

Environmental conditions strongly affect brain plasticity

Neuroforum

2017-12-14

Abstract:

During development, experience continuously interacts with genetic information to shape and optimize neuronal circuits and behaviour. Therefore, environmental conditions have a powerful impact on the brain. To date, accumulating evidence shows that raising animals in a so-called “enriched environment” elicits remarkable effects on the brain across molecular, anatomical, and functional levels when compared to animals raised in a “standard cage” environment. In our article, we provide a brief review of the field and illustrate the different results of “enriched” versus standard cage-raised rodents with examples from visual system plasticity. We also briefly discuss parallel studies of enrichment effects in humans. Collectively, these data highlight that results should always be considered in the context of the animals’ environment.

link to the full publication :

http://systemsneuroscience.uni-goettingen.de/dl/[Neuroforum]%20Environmental%20conditions%20strongly%20affect%20brain%20plasticity-1.pdf

 

 

ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines

bioRxiv

2018-01-10

Abstract

Dysfunction of the noradrenergic (NE) neurons is implicated in the pathogenesis of manic-depressive psychosis (MDP). ErbB4 is highly expressed in NE neurons, and its genetic variation has been linked to MDP; however, how ErbB4 regulates NE neuronal function and contributes to MDP pathogenesis is unclear. Here we find that conditional deletion of ErbB4 in locus coeruleus (LC) NE neurons increases neuronal spontaneous firing through NMDA receptor hyperfunction, and elevates catecholamines in the cerebrospinal fluid (CSF). Furthermore, ErbB4-deficient mice present mania-like behaviors, including hyperactivity, reduced anxiety and depression, and increased sucrose preference. These behaviors are completely rescued by the anti-manic drug lithium or antagonists of catecholaminergic receptors. Our study demonstrates the critical role of ErbB4 signaling in regulating LC-NE neuronal function, reinforcing the view that dysfunction of the NE system may contribute to the pathogenesis of mania-associated disorder.

Topographical memory analyzed in mice using the Hamlet Test, a novel complex maze

Neurobiology of Learning and Memory

2018-02-16

Highlights

The Hamlet test is a novel complex environment for testing topographic memory in mice.

Exploration and memory differ in different mouse strains but not gender.

The hippocampus-subiculum-parahippocampal gyrus axis and dopaminergic structures are activated.

Training increased hippocampal neurogenesis (cell proliferation and neuronal maturation).

Topographical disorientation was measured in the Hamlet test using a pharmacological model of Alzheimer's disease.


Abstract

The Hamlet test is an innovative device providing a complex environment for testing topographic memory in mice. Animals were trained in groups for weeks in a small village with a central agora, streets expanding from it towards five functionalized houses, where they can drink, eat, hide, run, interact with a stranger mouse. Memory was tested by depriving mice from water or food and analyzing their ability to locate the Drink/Eat house. Exploration and memory were analysed in different strains, gender, and after different training periods and delays. After 2 weeks training, differences in exploration patterns were observed between strains, but not gender. Neuroanatomical structures activated by training, identified using FosB/ΔFosB immunolabelling, showed an involvement of the hippocampus-subiculum-parahippocampal gyrus axis and dopaminergic structures. Training increased hippocampal neurogenesis (cell proliferation and neuronal maturation) and modified the amnesic efficacy of muscarinic or nicotinic cholinergic antagonists. Moreover, topographical disorientation in Alzheimer's disease was addressed using intracerebroventricular injection of amyloid β25-35 peptide in trained mice. When retested after 7 days, Aβ25-35-treated mice showed memory impairment. The Hamlet test specifically allows analysis of topographical memory in mice, based on complex environment. It offers an innovative tool for various ethological or pharmacological research needs. For instance, it allows to examine topographical disorientation, a warning sign in Alzheimer's disease.

 

Link to the publication :

 

https://www.sciencedirect.com/science/article/pii/S1074742718300340

Gamma Oscillation Dysfunction in mPFC Leads to Social Deficits in Neuroligin 3 R451C Knockin Mice

Neuron

2018-03-01

Summary

Neuroligins (NLs) are critical for synapse formation and function. NL3 R451C is an autism-associated mutation. NL3 R451C knockin (KI) mice exhibit autistic behavioral abnormalities, including social novelty deficits. However, neither the brain regions involved in social novelty nor the underlying mechanisms are clearly understood. Here, we found decreased excitability of fast-spiking interneurons and dysfunction of gamma oscillation in the medial prefrontal cortex (mPFC), which contributed to the social novelty deficit in the KI mice. Neuronal firing rates and phase-coding abnormalities were also detected in the KI mice during social interactions. Interestingly, optogenetic stimulation of parvalbumin interneurons in the mPFC at 40 Hz nested at 8 Hz positively modulated the social behaviors of mice and rescued the social novelty deficit in the KI mice. Our findings suggest that gamma oscillation dysfunction in the mPFC leads to social deficits in autism, and manipulating mPFC PV interneurons may reverse the deficits in adulthood.


Keywords

Autism ; Neuroligin 3 ; social novelty ; mPFC ; gamma oscillation ; PV interneuron ; excitability ; optogenetic ; stimulation

 

https://www.sciencedirect.com/science/article/pii/S0896627318301004

The Inappropriate Occurrence of REM Sleep in Narcolepsy is not due to a Defect in Homeostatic Regulation of REM Sleep

Oxford University Press

2018-03-07

Abstract

Narcolepsy type 1 is a disabling disorder with four primary symptoms: excessive-daytime-sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. The three latter symptoms together with a short REM sleep latency have suggested impairment in REM sleep homeostatic regulation with an enhanced propensity for (i.e. tendency to enter) REM sleep. To test this hypothesis, we challenged REM sleep homeostatic regulation in a recognized model of narcolepsy, the orexin knock-out (Orex-KO) mice and their wild-type (WT) littermates. We first performed 48hrs of REM sleep deprivation using the classic small-platforms-over-water method. We found that narcoleptic mice are similarly REM sleep deprived to WT mice. Although they had shorter sleep latency, Orex-KO mice recovered similarly to WT during the following 10hrs of recovery. Interestingly, Orex-KO mice also had cataplexy episodes immediately after REM sleep deprivation, anticipating REM sleep rebound, at a time of day when cataplexy does not occur in baseline condition. We then evaluated REM sleep propensity using our new automated method of deprivation that performs a specific and efficient REM sleep deprivation. We showed that REM sleep propensity is similar during light phase in Orex-KO and WT mice. However, during the dark phase REM sleep propensity was not suppressed in Orex-KO mice when hypocretin/orexin neuropeptides are normally released. Altogether our data suggest that in addition to the well-known wake-promoting role of hypocretin/orexin, these neuropeptides would also suppress REM sleep. Therefore, hypocretin/orexin deficiency would facilitate the occurrence of REM sleep at any time of day in an opportunistic manner as seen in human narcolepsy.

Keywords


narcolepsy, orexin, cataplexy, neuropeptides, hypocretin, REM sleep homeostasis, sleep deprivation, hypersomnia, anxiety

 

https://academic.oup.com/sleep/advance-article/doi/10.1093/sleep/zsy046/4924327

Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization

Nature medicine

2018-03-12

Abstract

Memories become less precise and generalized over time as memory traces reorganize in hippocampal–cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by so-called 'engram-bearing' dentate granule cells (eDGCs). Here we show, using rodents, that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons (INs) in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (ABLIM3) as a mossy-fiber-terminal-localized cytoskeletal factor whose levels decrease after learning. Downregulation of ABLIM3 expression in DGCs was sufficient to increase connectivity with CA3 stratum lucidum INs (SLINs), promote parvalbumin (PV)-expressing SLIN activation, enhance feedforward inhibition onto CA3 and maintain a fear memory engram in the DG over time. Furthermore, downregulation of ABLIM3 expression in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal–cortical and amygdalar networks and decreased fear memory generalization at remote (i.e., distal) time points. Consistent with the observation of age-related hyperactivity of CA3, learning failed to increase DGC–SLIN connectivity in 17-month-old mice, whereas downregulation of ABLIM3 expression was sufficient to restore DGC–SLIN connectivity, increase PV+ SLIN activation and improve the precision of remote memories. These studies exemplify a connectivity-based strategy that targets a molecular brake of feedforward inhibition in DG–CA3 and may be harnessed to decrease time-dependent memory generalization in individuals with PTSD and improve memory precision in aging individuals.

 

https://www.nature.com/articles/nm.4491

The inappropriate occurrence of REM sleep in narcolepsy is not due to a defect in homeostatic regulation of REM sleep

2018-03-13

Abstract

Narcolepsy type 1 is a disabling disorder with four primary symptoms: excessive-daytime-sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. The three latter symptoms together with a short REM sleep latency have suggested impairment in REM sleep homeostatic regulation with an enhanced propensity for (i.e. tendency to enter) REM sleep. To test this hypothesis, we challenged REM sleep homeostatic regulation in a recognized model of narcolepsy, the orexin knock-out (Orex-KO) mice and their wild-type (WT) littermates. We first performed 48hrs of REM sleep deprivation using the classic small-platforms-over-water method. We found that narcoleptic mice are similarly REM sleep deprived to WT mice. Although they had shorter sleep latency, Orex-KO mice recovered similarly to WT during the following 10hrs of recovery. Interestingly, Orex-KO mice also had cataplexy episodes immediately after REM sleep deprivation, anticipating REM sleep rebound, at a time of day when cataplexy does not occur in baseline condition. We then evaluated REM sleep propensity using our  new  automated  method  of  deprivation  that  performs  a  specific  and  efficient  REM  sleep deprivation. We showed that REM sleep propensity is similar during light phase in Orex-KO and WT mice. However, during the dark phase REM sleep propensity was not suppressed in Orex-KO mice when hypocretin/orexin neuropeptides are normally released. Altogether our data suggest that in addition to the well-known wake-promoting role of hypocretin/orexin, these neuropeptides would also suppress REM sleep. Therefore, hypocretin/orexin deficiency would facilitate the occurrence of REM sleep at any time of day in an opportunistic manner as seen in human narcolepsy.
 
Keywords : narcolepsy / orexin / cataplexy / neuropeptides / hypocretin / REM sleep homeostasis /
sleep deprivation / hypersomnia / anxiety/

 

https://www.ncbi.nlm.nih.gov/pubmed/29522212

Baclofen-induced neuro-respiratory toxicity in the rat: contribution of tolerance and characterization of withdrawal syndrome

Toxicological Sciences

2018-03-21

Abstract

Baclofen, a γ-amino-butyric acid type-B receptor agonist with exponentially increased use at high-dose to facilitate abstinence in chronic alcoholics, is responsible for increasing poisonings. Tolerance and withdrawal syndromes have been reported during prolonged treatment but their contribution to the variability of baclofen-induced neurotoxicity in overdose is unknown. We studied baclofen-induced effects on rat sedation, temperature and ventilation and modeled baclofen pharmacokinetics and effect/concentration relationships aiming to investigate the consequences of repeated baclofen pretreatment and to characterize withdrawal syndrome. Baclofen-induced dose-dependent sedation (P<.01), hypothermia (P<.001) and respiratory depression (P<.01) were altered in repeatedly baclofen-pretreated rats (P<.05). Repeatedly baclofen-pretreated rats did not exhibit respiratory depression following baclofen overdose due to limitations on baclofen-induced increase in inspiratory (P<.01) and expiratory times (P<.01). Only slight hypoxemia without respiratory acidosis was observed. Baclofen discontinuation resulted in hyperlocomotion and non-anxiogenic withdrawal symptoms. Regarding pharmacokinetics, repeated baclofen pretreatment increased the peak concentration (P<.05) and absorption constant rate (P<.05) and reduced the distribution volume (P<.0001) and elimination half-life (P<.05). Analysis of the effect/concentration relationships indicated that plasma baclofen concentration decreases more rapidly than all studied neuro-respiratory effects, in tolerant and non-tolerant rats. Taken together, our findings supported the role of brain distribution in baclofen-induced neurotoxicity expression and its probable involvement in tolerance-related attenuation in addition to physiological adaptations of ventilation. In conclusion, repeated pretreatment attenuates baclofen-attributed neurotoxicity in overdose and results in post-discontinuation withdrawal syndrome. Our findings suggest both pharmacodynamic and pharmacokinetic mechanisms whose relative contributions to the variability of baclofen-induced neurotoxicity in overdose remain to be established.


Keywords : Baclofen, Tolerance, Respiratory depression, Pharmacokinetics, Poisoning, Withdrawal

 

https://academic.oup.com/toxsci/advance-article-abstract/doi/10.1093/toxsci/kfy073/4947790

High frequency stimulation of the anterior vermis modulates behavioural response to chronic stress: Involvement of the prefrontal cortex and dorsal raphe?

Neurobiology of Disease

2018-05-02

Abstract

Some evidence suggests that the cerebellum modulates affect via connectivities with mood-regulating corticolimbic structures, such as the prefrontal cortex and monoamine nuclei. In rats exposed to chronic unpredictable stress (CUS), we examined the neuro-behavioural effects of high frequency stimulation and surgical ablation/disconnection of the cerebellar vermis. CUS reduced sucrose preference, increased novelty-induced feeding suppression and passive coping. These depressive-like behaviours were associated with decreased cerebellar zif268 expression, indicating possible cerebellar involvement in stress pathology. These were paralleled by decreased vermal Purkinje simple and complex spiking activity and raphe serotonergic activity. Protracted (24-h) vermal stimulation reversed these behavioural deficits through serotonin-mediated mechanisms since this effect was abrogated by the serotonin-depleting agent pCPA. Vermal stimulation and disconnection lesion also enhanced serotonergic activity, but did not modify prefrontocortical pyramidal firing. This effect was likely mediated by 5-HT1A receptors (5-HT1AR). Indeed, acute vermal stimulation mimicked the effect of the 5-HT1AR agonist 8-OH-DPAT in inhibiting serotonergic activity, which was prevented by pre-treatment with the 5-HT1AR antagonist WAY100,635. These results demonstrate vermal involvement in depressive-type behaviour via its modulatory action on serotonergic neurons. They further suggest that vermal and mPFC stimulation may bestow therapeutic benefits via parallel pathways.

Keywords

Anhedonia; Antidepressant; Cerebellar vermis; Deep brain stimulation; Dorsal raphe; Electrophysiology

 

https://www.sciencedirect.com/science/article/pii/S0969996118300871

Motor impairments correlate with social deficits and restricted neuronal loss in an environmental model of autism

Oxford University Press

2018-05-12

Abstract


Background

Motor impairments are amongst the earliest and most consistent signs of autism spectrum disorders (ASD) but are not used as diagnostic criteria. In addition, the relationship between motor and cognitive impairments and their respective neural substrates remain unknown.


Methods

Here, we aimed at determining whether a well-acknowledged animal model of ASD, the valproic acid (VPA) model, displays motor impairments and whether they may correlate with social deficits and neuronal loss within motor brain areas. For this, pregnant female mice (C57BL/6J) received VPA (450 mg/kg) at E12.5 and offspring underwent a battery of behavioral analyses before being sacrificed for histological correlates in motor cortex, nigrostriatal pathway and cerebellum.


Results

We show that while VPA male mice show both social and motor impairments, female mice only show motor impairments. Prenatal VPA exposure induces specific cell loss within the motor cortex and cerebellum and that is of higher magnitude in males than in females. Finally, we demonstrate that motor dysfunction correlates with reduced social behavior and that motor and social deficits both correlate with a loss of Purkinje cells within the Crus I cerebellar area.


Conclusions

Our results suggest that motor dysfunction could contribute to social and communication deficits in ASD and that motor and social deficits may share common neuronal substrates in the cerebellum. A systematic assessment of motor function in ASD may potentially help the quantitative diagnosis of ASD and strategies aimed at improving motor behavior may provide a global therapeutic benefit.

 

Keywords: valproic acid, cerebellum, motor cortex, gait, Purkinje cells

 

https://academic.oup.com/ijnp/advance-article/doi/10.1093/ijnp/pyy043/4995459

Stress exposure alters brain mRNA expression of the genes involved in insulin signalling, an effect modified by a high fat/high fructose diet and cinnamon supplement

PLOS One

2018-05-29

Abstract

In occidental societies, high fat and high sugar diets often coincide with episodes of stress. The association is likely to modify brain energy control. Brain insulin signalling is rarely studied in stressed individuals consuming high fat diets. Furthermore the effects of cinnamon supplement are not known in these conditions. Therefore, we exposed rats, over a 12-week period, to a control (C) or a high fat/high fructose (HF/HFr) diet that induces peripheral insulin resistance. A cinnamon supplement (C+CN and HF/HFr +CN) was added or not. After diet exposure, one group of rats was exposed to a 30-min restraint followed by a 10-min open-field test, their combination featuring a moderate stressor, the other rats staying unstressed in their home cages. The insulin signalling in hippocampus and frontal cortex was studied through the mRNA expression of the following genes: insulin receptor (Ir), insulin receptor substrate (Irs1), glucose transporters (Glut1 and Glut3), glycogen synthase (Gys1) and their modulators, Akt1 and Pten. In C rats, stress enhanced the expression of Ir, Irs1, Glut1, Gys1 and Akt1 mRNA. In C+CN rats, stress induced an increase in Pten but a decrease in Gys1 mRNA expression. In HF/HFr rats, stress was associated with an increase in Pten mRNA expression. In HF/HFr+CN rats, stress increased Pten mRNA expression but also decreased Gys1 mRNA expression. This suggests that a single moderate stress favours energy refilling mechanisms, an effect blunted by a previous HF/HFr diet and cinnamon supplement.

 

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197094

Serotonergic mechanisms involved in antidepressant-like responses evoked by GLT-1 blockade in rat infralimbic cortex

Neuropharmacology

2018-06-22

Abstract

Novel fast-acting antidepressant strategies, such as ketamine and deep brain stimulation, enhance glutamatergic neurotransmission in medial prefrontal cortex (mPFC) regions via AMPA receptor (AMPA-R) activation. We recently reported that the regionally-selective blockade of the glial glutamate transporter-1 (GLT-1) by dihydrokainic acid (DHK) microinfusion in rat infralimbic cortex (IL), the most ventral part of the mPFC, evoked immediate (10 min) antidepressant-like responses, which involved AMPA-R activation and were associated to increased serotonin (5-hydroxytryptamine, 5-HT) release. Given the reciprocal connectivity between the mPFC and the serotonergic dorsal raphe nucleus (DR), here we examined the serotoninergic mechanisms involved in the reported antidepressant-like responses of DHK infusion. First, we show that antidepressant-like responses evoked by IL application of DHK and citalopram are mediated by local 5-HT1A receptors (5-HT1A-R), since they are cancelled by previous IL WAY100635 microinfusion. Second, IL DHK microinfusion increases excitatory inputs onto DR, as shown by an increased glutamate and 5-HT release in DR and by a selective increase of c-Fos expression in DR 5-HT neurons, not occurring in putative GABAergic neurons. This view is also supported by an increased 5-HT release in ventral hippocampus following IL DHK microinfusion. Interestingly, antidepressant-like responses evoked by IL DHK lasted for 2 h and could be prolonged for up to 24 h by attenuating self-inhibitory effects via 5-HT1A autoreceptors. In contrast, the antidepressant-like effects of S-AMPA microinfusion in IL were short-lasting. Together, our results further support a prominent role of the IL–DR pathway and of ascending 5-HT pathways in mediating antidepressant-like responses evoked by glutamatergic mechanisms.

 

Link to the publication :

https://www.sciencedirect.com/science/article/pii/S0028390818303319

Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B

Cell

2018-07-26

Summary

Protein phosphorylation is a prevalent and ubiquitous mechanism of regulation. Kinases are popular drug targets, but identifying selective phosphatase inhibitors has been challenging. Here, we used surface plasmon resonance to design a method to enable target-based discovery of selective serine/threonine phosphatase inhibitors. The method targeted a regulatory subunit of protein phosphatase 1, PPP1R15B (R15B), a negative regulator of proteostasis. This yielded Raphin1, a selective inhibitor of R15B. In cells, Raphin1 caused a rapid and transient accumulation of its phosphorylated substrate, resulting in a transient attenuation of protein synthesis. In vitro, Raphin1 inhibits the recombinant R15B-PP1c holoenzyme, but not the closely related R15A-PP1c, by interfering with substrate recruitment. Raphin1 was orally bioavailable, crossed the blood-brain barrier, and demonstrated efficacy in a mouse model of Huntington’s disease. This identifies R15B as a druggable target and provides a platform for target-based discovery of inhibitors of serine/threonine phosphatases.

Keywords
protein phosphatase 1 ; protein quality control ; proteostasis ; protein misfolding ; eukaryotic initiation factor-2 ; PPP1R15B ; neurodegenerative diseases ; stress response ; Huntington’s disease ; drug discovery

 

https://www.sciencedirect.com/science/article/pii/S0092867418307980

Spontaneous resurgence of conditioned fear weeks after successful extinction in brain injured mice

Progress in Neuro-Psychopharmacology and Biological Psychiatry

2018-08-07

Highlights

• Spontaneous fear resurgence occurs months after mild brain injury
• TBI, without neurological deficits, leads to risk-taking and slow learning
• PTSD-like deficits occur in conjunction with myelin changes, but not cell density
• Fronto-cortical Bdnf mRNA exons I and IV decrease 3 weeks after mild brain injury

 

Abstract

Mild traumatic brain injury (TBI) is a major risk factor for post-traumatic stress disorder (PTSD), and both disorders share common symptoms and neurobiological defects. Relapse after successful treatment, known as long-term fear resurgence, is common in PTSD patients and a major therapeutic hurdle. We induced a mild focal TBI by controlled cortical impact (CCI) in male C57BL/6 J mice and used fear conditioning to assess PTSD-like behaviors and concomitant alterations in the fear circuitry. We found for the first time that mild TBI, and to a lesser extent sham (craniotomy), mice displayed a spontaneous resurgence of conditioned fear when tested for fear extinction memory recall, despite having effectively acquired and extinguished conditioned fear 6 weeks earlier in the same context. Other characteristic symptoms of PTSD are risk-taking behaviors and cognitive deficits. CCI mice displayed risk-taking behaviors, behavioral inflexibility and reductions in processing speed compared to naïve mice. In conjunction with these changes there were alterations in amygdala morphology 3 months post-trauma, and decreased myelin basic protein density at the primary lesion site and in distant secondary sites such as the hippocampus, thalamus, and amygdala, compared to sham mice. Furthermore, activity-dependent brain-derived neurotrophic factor (BDNF) transcripts were decreased in the prefrontal cortex, a key region for fear extinction consolidation, following fear extinction training in both TBI and, to a lesser extent, sham mice. This study shows for the first time that a mild brain injury can generate a spontaneous resurgence of conditioned fear associated with defective BDNF signalling in the prefrontal cortex, PTSD-like behaviors, and have enduring effects on the brain.

 

5. Conclusion

We found here that mild TBI, and to a lesser extent craniotomy, produce long-term fear extinction deficits. TBI also induced risk taking behaviors, and reduced processing speed and cognitive flexibility. Three months after TBI, there were morphological changes and myelin loss in the CC, the cortex adjacent to the primary lesion site, and in several areas involved in conditioned fear. Bdnf transcription in the mPFC was reduced by TBI, but also craniotomy. Further studies with this murine model are necessary to determine whether re-equilibrating BDNF signalling few weeks after brain injury can restore the behavioral and neurobiological deficits.

Indeed, alterations of cortico-thalamo-amygdalar myelinated pathways may be linked with the decrease in Bdnf mRNA in cortical areas critical for fear extinction consolidation. Diffusion tensor imaging studies revealed similar alterations in PTSD patients (Sanjuan et al., 2013) while TBI patients display decreased BDNF levels late after injury (Schober et al., 2012). As BDNF induces white matterneuroprotection by promoting myelination via a direct action on oligodendrocytes (Husson et al., 2005; Xiao et al., 2010), the late onset of PTSD symptoms and reduction of processing speed after brain injury (Johnson and Lovell, 2011) might be prevented by treatments that increase cortical trophic factors. Systemic BDNF TrkBagonist (Andero et al., 2011) or neural stem cell cortical transplantation promoting TBI functional recovery via BDNF (Johnson and Lovell, 2011), may provide treatment for symptom relapses in the TBI/PTSD comorbidity.

 

 

Link to the full publication :

https://www.sciencedirect.com/science/article/pii/S0278584618303075

 

Comparison of the effects of PACAP-38 and its analog, acetyl-[Ala15, Ala20] PACAP-38-propylamide, on spatial memory, post-learning BDNF expression and oxidative stress in rat

Brain Research

2018-10-16

Highlights

• P38 but not P38-alg systemic administration produced an enhancement of memory in a spatial learning task.
• Training modulated hippocampal BDNF, and stress oxidative biomarkers.
• P38 and P38-alg yielded different effects on BDNF and stress oxidative biomarkers.
• P38-alg functional impact is different from P38.

Abstract

We compared the effects of single intraveinous injection of pituitary adenylate cyclase-activating polypeptide-38 (P38) to those of its analog, acetyl-[Ala15, Ala20]PACAP-38-propylamide (P38-alg) on spatial memory in the Morris water maze (MWM) using a weak massed-learning procedure, post-training brain derived neurotrophic factor (BDNF) and post-training oxidative stress biomarker assays in male Wistar rats. Acquisition of the MWM task following P38 (30 µg/kg) and P38-alg (30 µg/kg) treatments was similar to control group (Saline: 0.9 % NaCl) and there was no interaction between treatments and performance. However, in the probe test, P38-treated group showed a specific interest for the target quadrant whereas the two other groups exhibited less focused place searching behavior. Moreover, P38 had an anxiogenic effect as measured by the distribution of swimming at the periphery of the pool. The swimming test resulted in a decrease in BDNF contents in the hippocampus. P38 but not P38-alg treatment restored BDNF expression. In terms of oxidative stress, both P38 and P38-alg treatments had antioxidative effects. The activity of antioxidative enzymes in the neocortex was increased. However only P38 reduced the levels of carbonylated proteins (CP). These data show that P38 and P38-alg have different behavioral and neurobiological effects. Thus, P38-alg and other analogs with specific functional profiles, inducing beneficial central effects (e.g. neuroprotection) while minimizing undesired peripheral effects may be useful for potential therapeutical use.

 

Link to the publication :

https://www.sciencedirect.com/science/article/pii/S0166432818310507

Sensory coding is impaired in rat absence epilepsy

The Journal of Physiology

2018-12-13

Abstract

Key points

 

  • Absence epilepsy is characterized by the occurrence of spike‐and‐wave discharges concomitant with an alteration of consciousness and associated with cognitive comorbidities.
  • In a genetic model of absence epilepsy in the rat, the GAERS, we showed that spike‐and‐wave discharges are initiated in the barrel field primary somatosensory cortex that codes whisker‐related information therefore playing an essential role in rodents’ interactions with their environment.
  • Sensory‐information processing is impaired in the epileptic barrel field primary somatosensory cortex of GAERS with a delayed sensory‐evoked potential and a duplicated neuronal response to whisker‐stimulation in in vivo extracellular recordings. Yet, GAERS present no defaults of performance in a texture discrimination task, suggesting the existence of a compensatory mechanism within the epileptic neuronal network.
  • Our results indicate that physiological primary functions are processed differently in an epileptic cortical network.

Abstract

Several neurodevelopmental pathologies are associated with disorganized cortical circuits that may alter primary functions such as sensory processes. Here, we addressed the question whether the function of a cortical area is altered in the seizure onset zone of absence epilepsy, a prototypical form of childhood genetic epilepsy associated with cognitive impairments. We first combined in vivo multichannel electrophysiological recordings and histology to precisely localize the seizure onset zone in the genetic absence epilepsy rat from Strasbourg (GAERS). We then investigated the functionality of this epileptic zone using extracellular silicon probe recordings of sensory evoked local field potentials and multi‐unit activity, as well as a behavioral test of texture discrimination. We show that seizures in this model are initiated in the barrel field part of the primary somatosensory cortex and are associated with high‐frequency oscillations. In this cortex, we found an increased density of parvalbumin‐expressing interneurons in Layer 5 in GAERS compared to non‐epileptic Wistar rats. Its functional investigation revealed that sensory abilities of GAERS are not affected in a texture‐discrimination task while the intracortical processing of sensory‐evoked information is delayed and duplicated. Altogether, these results suggest that absence seizures are associated with an increase of parvalbumin‐inhibitory neurons that may promote the functional relation between epileptic oscillations and high frequency activities. Our findings suggest that cortical circuits operate differently in the epileptic onset zone and may adapt to maintain their ability to process highly specialized information.

 

Link to the Publication :

https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP277297

Deletion of the vesicular monoamine transporter 1 (vmat1/slc18a1) gene affects dopamine signaling

Brain Research

2019-01-24

Highlights

• Vesicular monoamine transporters are involved in presynaptic catecholamine storage and contribute to monoamine neurotransmission.
• Two isoforms exist, VMAT1 and VMAT2, but limited data exist for VMAT1.
• VMAT1 has recently been identified as target for neuropsychiatric disorders.
• This study investigated null-mutant VMAT1 animals for effects on monoamine tissue content, effects on up- and downstream dopaminergic targets and behavioral consequences.
• VMAT1 KO mice have decreased dopamine levels in frontal cortex, increased postsynaptic DRD2 expression and lower frontal cortex tyrosine hydroxylase expression.
• VMAT1 KO mice show a marked behavioral locomotor response when challenged with amphetamine.

Abstract

The vesicular monoamine transporter is involved in presynaptic catecholamine storage and neurotransmission. Two isoforms of the transporter exist, VMAT1 and VMAT2, and both are. expressed in the brain, though VMAT2 expression is more robust and has been more widely studied. In this study we investigated the role of VMAT1 KO on markers of dopaminergic function and neurotransmission, and dopamine-related behaviors.

Null-mutant VMAT1 mice were studied behaviorally using the tail suspension test, elevated zero maze and locomotor activity assessments. Tissue monoamines were measured both ex vivo and by using in vivo microdialysis. Protein expression of tyrosine hydroxylase and D2 dopamine receptors was measured using western blot analysis.

Results show that VMAT1 KO mice have decreased dopamine levels in the frontal cortex, increased postsynaptic D2 expression, and lower frontal cortex tyrosine hydroxylase expression compared to WT mice. VMAT1 KO mice also show an exaggerated behavioral locomotor response to acute amphetamine treatment.

We conclude that dopaminergic signaling is robustly altered in the frontal cortex of VMAT1 null-mutant mice and suggest that VMAT1 may be relevant to the pathogenesis and/or treatment of psychiatric illnesses including schizophrenia and bipolar disease.

 

Link to the publication :

https://www.sciencedirect.com/science/article/pii/S0006899319300459

Apigenin attenuates acrylonitrile-induced neuro-inflammation in rats: Involved of inactivation of the TLR4/NF-κB signaling pathway

International Immunopharmacology

2019-01-25

Highlights

 

• Apigenin protected the brains from acrylonitrile-induced neurotoxicity.
• Apigenin inhibited neuro-inflammation via downregulating the TLR4/NF-κB signaling pathway.
• Apigenin suppressed neuronal apoptosis expressed as inhibiting mitochondria-mediated apoptosis pathway.

 

Abstract

Acrylonitrile (ACN) is often found in the productions of synthetic fibers, rubber, and plastics. Exposure to ACN could cause pathological changes of the nervous system, which appeared early and were very serious. Current studies have found that the neurotoxicity is mainly related to oxidative damage and inflammation induced by ACN. Apigenin (AP) is a flavonoid subtype compound that is less toxic, non-mutagenic, and widely distributed in many types of vegetables and fruits. Studies have confirmed that it has nice antioxidant, anti-inflammatory and anti-apoptotic properties in the nervous system and related disease models, such as Alzheimer's disease. In this study, we used AP (117, 234 and 351 mg·kg1) pretreatment intragastrically to resist the neurotoxicity caused by ACN gavage (46 mg·kg−1) for 28 days, and then detected the oxidative stress, inflammation mediated by the TLR4/NF-κB signaling pathway, and apoptosis to evaluate the protective effect of AP. The results showed that AP could lessen the autonomic activities of rats, and improve the abnormal morphology of neurons induced by ACN. AP could also reduce the oxidative stress, downregulate the TLR4/NF-κB signaling pathway, decrease the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and inhibit the mitochondria-mediated neuron apoptosis. Immunofluorescence result showed that AP could decrease the activation and nuclear transfer of NF-κB induced by ACN. These results suggested that AP could protect the brain against ACN-induced neurotoxicity by inhibiting the TLR4/NF-κB signaling pathway and could exhibit a neuroprotective effect.

 

Link to the publication : https://www.sciencedirect.com/science/article/pii/S1567576919304680

 

Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks

Cell

2019-08-08

Highlights

 

• Identification of rare inherited variants associated with ASD and 16 new ASD risk genes
• Inherited risk reveals both new biological pathways and shared PPI with known genes
• We develop and validate a machine learning algorithm (ARC) to remove WGS artifacts
• NR3C2 mutations define a novel syndromic form of ASD, which we model in zebrafish

 

Summary

We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.

 

Link to the publication : https://www.sciencedirect.com/science/article/pii/S0092867419307809

Stress–glucocorticoid–TSC22D3 axis compromises therapy-induced antitumor immunity

Nature Medecine

2019-09-09

Abstract

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.

 

Link to the publication : https://www.nature.com/articles/s41591-019-0566-4

Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression

Molecular Psychiatry

2019-10-16

Abstract

Current antidepressants act principally by blocking monoamine reuptake by high-affinity transporters in the brain. However, these antidepressants show important shortcomings such as slow action onset and limited efficacy in nearly a third of patients with major depression disorder. Here, we report the development of a prodrug targeting organic cation transporters (OCT), atypical monoamine transporters recently implicated in the regulation of mood. Using molecular modeling, we designed a selective OCT2 blocker, which was modified to increase brain penetration. This compound, H2-cyanome, was tested in a rodent model of chronic depression induced by 7-week corticosterone exposure. In male mice, prolonged administration of H2-cyanome induced positive effects on several behaviors mimicking symptoms of depression, including anhedonia, anxiety, social withdrawal, and memory impairment. Importantly, in this validated model, H2-cyanome compared favorably with the classical antidepressant fluoxetine, with a faster action on anhedonia and better anxiolytic effects. Integrated Z-scoring across these depression-like variables revealed a lower depression score for mice treated with H2-cyanome than for mice treated with fluoxetine for 3 weeks. Repeated H2-cyanome administration increased ventral tegmental area dopaminergic neuron firing, which may underlie its rapid action on anhedonia. H2-cyanome, like fluoxetine, also modulated several intracellular signaling pathways previously involved in antidepressant response. Our findings provide proof-of-concept of antidepressant efficacy of an OCT blocker, and a mechanistic framework for the development of new classes of antidepressants and therapeutic alternatives for resistant depression and other psychiatric disturbances such as anxiety.

 

Link to the publication : 

https://www.nature.com/articles/s41380-019-0548-4

Long‐lasting correction of in vivo LTP and cognitive deficits of mice modelling Down syndrome with an α5‐selective GABAA inverse agonist

British Journal of pharmacology

2019-10-25

Abstract

Background and Purpose

Excessive GABAergic inhibition contributes to cognitive dysfunctions in Down syndrome (DS). Selective negative allosteric modulators (NAMs) of α5‐containing GABAA receptors such as α5IA restore learning and memory deficits in Ts65Dn mice modelling DS. This study aimed at testing long‐lasting effects of α5IA on in vivo long‐term potentiation (LTP) and behavior in Ts65Dn mice.

Experimental Approach

We performed in vivo long‐term potentiation (LTP) recordings for six consecutive days in freely moving Ts65Dn mice and their wild‐type littermates, treated with vehicle or α5IA. In parallel, Ts65Dn mice were subjected to various learning and memory tests (Y‐maze, Morris water maze or the novel object recognition) up to seven days following one single injection of α5IA or vehicle.

Key Results

We found that LTP could not be evoked in vivo in Ts65Dn mice at the hippocampal CA3‐CA1 synapse. However, this deficit was sustainably reversed for at least six consecutive days following a single injection of α5IA. This long‐lasting effect of α5IA was also unveiled when assessing working and long‐term memory deficits in Ts65Dn mice.

Conclusion and Implications

We show for the first time in vivo LTP deficits in Ts65Dn mice. These deficits are restored for at least six days following acute treatment with α5IA and might be the substrate for the long‐lasting pharmacological effects of α5IA demonstrated here on spatial working and long‐term recognition and spatial memory tasks. Altogether, these results highlight the interest of NAMs of α5‐containing GABAA receptors for treating cognitive deficits associated with DS.

 

Link to the publication :

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14903

Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain

Brain

2019-10-30

Abstract

Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/β-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination. We validated in a cohort of preterm-born infants that genomic variation in the Wnt pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a blood–brain barrier penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.

 

Link to the publication :

https://academic.oup.com/brain/article-abstract/142/12/3806/5607702

Rapeseed oil fortified with micronutrients improves cognitive alterations associated with metabolic syndrome

Brain, Behaviour and Immunity

2019-11-02

Highlights

 

• n-3 PUFA/AO intake increased brain n-3 PUFA levels in a MetS model, the db/db mice.
• n-3 PUFA/AO reversed hippocampus-dependent spatial memory deficits in db/db mice.
• n-3 PUFA/AO modulated subunit composition of glutamate receptors in the hippocampus.
• n-3 PUFA/AO may reduce MetS-related memory deficits by changing neuronal plasticity.

 

Abstract

Metabolic syndrome represents a major risk factor for severe comorbidities such as cardiovascular diseases or diabetes. It is also associated with an increased prevalence of emotional and cognitive alterations that in turn aggravate the disease and related outcomes. Identifying therapeutic strategies able to improve those alterations is therefore a major socioeconomical and public health challenge. We previously reported that both hippocampal inflammatory processes and neuronal plasticity contribute to the development of emotional and cognitive alterations in db/db mice, an experimental model of metabolic syndrome that displays most of the classical features of the syndrome. In that context, nutritional interventions with known impact on those neurobiological processes appear as a promising alternative to limit the development of neurobiological comorbidities of metabolic syndrome. We therefore tested here whether n-3 polyunsaturated fatty acids (n-3 PUFAs) associated with a cocktail of antioxidants can protect against the development of behavioral alterations that accompany the metabolic syndrome. Thus, this study aimed: 1) to evaluate if a diet supplemented with the plant-derived n-3 PUFA α-linolenic acid (ALA) and antioxidants (provided by n-3 PUFAs-rich rapeseed oil fortified with a mix of naturally constituting antioxidant micronutrients, including coenzyme Q10, tocopherol, and the phenolic compound canolol) improved behavioral alterations in db/db mice, and 2) to decipher the biological mechanisms underlying this behavioral effect. Although the supplemented diet did not improve anxiety-like behavior and inflammatory abnormalities, it reversed hippocampus-dependent spatial memory deficits displayed by db/db mice in a water maze task. It concomitantly changed subunit composition of glutamatergic AMPA and NMDA receptors in the hippocampus that has been shown to modulate synaptic function related to spatial memory. These data suggest that changes in local neuronal plasticity may underlie cognitive improvements in db/db mice fed the supplemented diet. The current findings might therefore provide valuable data for introducing new nutritional strategies for the treatment of behavioral complications associated with MetS.

 

Link to the publication :

https://www.sciencedirect.com/science/article/pii/S0889159119304635

Histological and behavioral evaluation after traumatic brain injury in mice: a ten months follow-up study

Journal of Neurotrauma

2019-12-13

Traumatic brain injury (TBI) is a chronic pathology, inducing long term deficits that remains understudied in preclinical studies. In this context, exploration, anxiety-like behavior, cognitive flexibility and motor coordination were assessed until 5 and 10 months after an experimental TBI in the adult mouse, using two cohorts. In order to differentiate age, surgery, and remote gray and white matter lesions, three groups, unoperated, sham-operated, and TBI, were studied. TBI induced delayed motor coordination deficits at the pole test, 4.5 months after injury, that could be explained by gray and white matter damages in ipsilateral nigrostriatal structures (striatum, internal capsule) that were spreading to new structures between cohorts, at 5 versus 10 months after the injury. Furthermore, TBI induced an enhanced exploratory behavior during stressful situations (active phase during actimetry test, object exploration in an open field), risk-taking behaviors in the elevated plus maze 5 months after injury, and a cognitive inflexibility in the Barnes maze that persists until 9 months after the injury. These behavioral modifications could be related to the white and gray matter lesions observed in ipsi- and contra-lateral limbic structures (amygdala, hilus/CA4, hypothalamus, external capsule, corpus callosum, cingular cortex) that were spreading to new structures between cohorts, at 5 months versus 10 months after the injury. The present study corroborates clinical findings on TBI, and provides a relevant rodent chronic model which could help validating pharmacological strategies against the chronic consequences of TBI.

 

Link to the publication :

https://www.liebertpub.com/doi/abs/10.1089/neu.2019.6679

Ocean acidification does not impair the behaviour of coral reef fishes

Nature

2020-01-08

Abstract

The partial pressure of CO2 in the oceans has increased rapidly over the past century, driving ocean acidification and raising concern for the stability of marine ecosystems1,2,3. Coral reef fishes are predicted to be especially susceptible to end-of-century ocean acidification on the basis of several high-profile papers4,5 that have reported profound behavioural and sensory impairments—for example, complete attraction to the chemical cues of predators under conditions of ocean acidification. Here, we comprehensively and transparently show that—in contrast to previous studies—end-of-century ocean acidification levels have negligible effects on important behaviours of coral reef fishes, such as the avoidance of chemical cues from predators, fish activity levels and behavioural lateralization (left–right turning preference). Using data simulations, we additionally show that the large effect sizes and small within-group variances that have been reported in several previous studies are highly improbable. Together, our findings indicate that the reported effects of ocean acidification on the behaviour of coral reef fishes are not reproducible, suggesting that behavioural perturbations will not be a major consequence for coral reef fishes in high CO2 oceans.

 

Link to the publication : 

https://www.nature.com/articles/s41586-019-1903-y

Insights into paradoxical (REM) sleep homeostatic regulation in mice using an innovative automated sleep deprivation method

Sleep

2020-01-12

Abstract

Identifying the precise neuronal networks activated during paradoxical sleep (PS, also called REM sleep) has been a challenge since its discovery. Similarly, our understanding of the homeostatic mechanisms regulating PS, whether through external modulation by circadian and ultradian drives or via intrinsic homeostatic regulation, is still limited, largely due to interfering factors rendering the investigation difficult. Indeed, none of the studies published so far were able to manipulate PS without significantly altering slow-wave sleep and/or stress level, thus introducing a potential bias in the analyses. With the aim of achieving a better understanding of PS homeostasis, we developed a new method based on automated scoring of vigilance states—using electroencephalogram and electromyogram features—and which involves closed-loop PS deprivation through the induction of cage floor movements when PS is detected. Vigilance states were analyzed during 6 and 48 h of PS deprivation as well as their following recovery periods. Using this new automated methodology, we were able to deprive mice of PS with high efficiency and specificity, for short or longer periods of time, observing no sign of stress (as evaluated by plasma corticosterone level and sleep latency) and requiring no human intervention or environmental changes. We show here that PS can be homeostatically modulated and regulated while no significant changes are induced on slow-wave sleep and wakefulness, with a PS rebound duration depending on the amount of prior PS deficit. We also show that PS interval duration is not correlated with prior PS episode duration in the context of recovery from PS deprivation.

Link to the publication : 

https://academic.oup.com/sleep/article-abstract/43/7/zsaa003/5700797