scholarly journals Persistent autism-relevant phenotype produced by in utero and lactational exposure of female mice to the commercial PBDE mixture, DE-71

2021 ◽  
Author(s):  
Elena V. Kozlova ◽  
Matthew C. Valdez ◽  
Maximillian E. Denys ◽  
Anthony E. Bishay ◽  
Julia M. Krum ◽  
...  
Keyword(s):  
Recognition Memory ◽  
Polybrominated Diphenyl Ethers ◽  
Psychosocial Functioning ◽  
Female Offspring ◽  
In Utero ◽  
Autism Spectrum ◽  
Social Recognition ◽  
Mass Spectrometry Analysis ◽  
Exposure Model ◽  
Commercial Mixture

Polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent organic pollutants (POPs) that are known neuroendocrine disrupting chemicals with adverse neurodevelopmental effects. PBDEs may act as risk factors for autism spectrum disorders (ASD), characterized by abnormal psychosocial functioning, although direct evidence is currently lacking. Using a translational exposure model, we tested the hypothesis that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in female offspring. C57Bl6/N mouse dams (F0) were exposed to DE-71 via oral administration of 0 (VEH/CON), 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d from 3 wk prior to gestation through lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (ppb) to F1 female offspring brain tissue at postnatal day (PND) 15 which was reduced by PND 110. Neurobehavioral testing of social novelty preference (SNP) and social recognition memory (SRM) revealed that adult L-DE-71 F1 offspring display altered short- and long-term SRM, in the absence of reduced sociability, and increased repetitive behavior. These effects were concomitant with reduced olfactory discrimination of social odors. Additionally, L-DE-71 exposure also altered short-term novel object recognition memory but not anxiety or depressive-like behavior. Moreover, F1 L-DE-71 displayed downregulated mRNA transcripts for oxytocin (Oxt) in the bed nucleus of the stria terminalis (BNST) and supraoptic nucleus, vasopressin (Avp) in the BNST and upregulated Avp1ar in BNST, and Oxtr in the paraventricular nucleus. Our work demonstrates that developmental PBDE exposure produces ASD-relevant neurochemical, olfactory processing and behavioral phenotypes that may result from early neurodevelopmental reprogramming within central social and memory networks.

scholarly journals Cariprazine alleviates core behavioral deficits in the prenatal valproic acid exposure model of autism spectrum disorder

2021 ◽  
Author(s):  
Viktor Román ◽  
Nika Adham ◽  
Andrew G. Foley ◽  
Lynsey Hanratty ◽  
Bence Farkas ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Communication ◽  
Partial Agonist ◽  
Social Play ◽  
Autism Spectrum ◽  
Social Recognition ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Exposure Model ◽  
Behavioral Deficits

Abstract Rationale Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction and restricted, repetitive behaviors. The unmet medical need in ASD is considerable since there is no approved pharmacotherapy for the treatment of these deficits in social communication, interaction, and behavior. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, is already approved for the treatment of schizophrenia and bipolar I disorder in adults; investigation in patients with ASD is warranted. Objectives The aim of this study was to investigate the effects of cariprazine, compared with risperidone and aripiprazole, in the rat prenatal valporic acid (VPA) exposure model on behavioral endpoints representing the core and associated symptoms of ASD. Methods To induce the ASD model, time-mated Wistar rat dams were treated with VPA during pregnancy. Male offspring were assigned to groups and studied in a behavioral test battery at different ages, employing social play, open field, social approach-avoidance, and social recognition memory tests. Animals were dosed orally, once a day for 8 days, with test compounds (cariprazine, risperidone, aripiprazole) or vehicle before behavioral assessment. Results Cariprazine showed dose-dependent efficacy on all behavioral endpoints. In the social play paradigm, only cariprazine was effective. On the remaining behavioral endpoints, including the reversal of hyperactivity, risperidone and aripiprazole displayed similar efficacy to cariprazine. Conclusions In the present study, cariprazine effectively reversed core behavioral deficits and hyperactivity present in juvenile and young adult autistic-like rats. These findings indicate that cariprazine may be useful in the treatment of ASD symptoms.

scholarly journals Maternal Transfer of Environmentally Relevant Polybrominated Diphenyl Ethers (PBDEs) Produces a Diabetic Phenotype and Disrupts Glucoregulatory Hormones and Hepatic Endocannabinoids in Adult Mouse Female Offspring

2020 ◽  
Author(s):  
Elena V. Kozlova ◽  
Bhuvaneswari D. Chinthirla ◽  
Pedro A. Pérez ◽  
Nicholas V. DiPatrizio ◽  
Donovan A. Argueta ◽  
...  
Keyword(s):  
Polybrominated Diphenyl Ethers ◽  
Ex Vivo ◽  
Time Windows ◽  
Female Offspring ◽  
Exposure Model ◽  
Maternal Transfer ◽  
Tissue Mass ◽  
Brown Adipose ◽  
Diphenyl Ethers

AbstractPolybrominated diphenyl ethers (PBDEs) are brominated flame retardant chemicals and environmental contaminants with endocrine-disrupting properties that are associated with diabetes and metabolic syndrome in humans. However, their diabetogenic actions are not completely characterized or understood. In this study, we investigated the effects of DE-71, a commercial penta-mixture of PBDEs, on glucose regulatory parameters in a perinatal exposure model using female C57Bl/6 mice. Results from in vivo glucose and insulin tolerance tests and ex vivo analyses showed that DE-71 produced fasting hyperglycemia, glucose intolerance, reduced sensitivity and delayed glucose clearance after insulin challenge, and exaggerated hepatic endocannabinoid tone in F1 offspring exposed to 0.1 mg/kg DE-71 relative to control. DE-71 effects on F0 dams were more limited indicating that indirect exposure to developing offspring is more detrimental. Other ex vivo glycemic correlates occur more generally in exposed F0 and F1, i.e., reduced plasma insulin and altered glucoregulatory endocrines, exaggerated sympathoadrenal activity, decreased thermogenic brown adipose tissue mass and reduced hepatic glutamate dehydrogenase enzymatic activity. Hepatic PBDE congener analysis indicated maternal transfer of BDE-28 and −153 to F1 at a collective level of 200 ng/g lipid, in range with maximum values detected in serum of human females. Given the persistent diabetogenic phenotype, especially pronounced in female offspring after developmental exposure to environmentally relevant levels of DE-71, additional animal studies should be conducted that further characterize PBDE-induced diabetic pathophysiology and identify critical developmental time windows of susceptibility. Longitudinal human studies should also be conducted to determine the risk of long-lasting metabolic consequences after maternal transfer of PBDEs during early-life development.

scholarly journals Maternal transfer of environmentally relevant polybrominated diphenyl ethers (PBDEs) produces a diabetic phenotype and disrupts glucoregulatory hormones and hepatic endocannabinoids in adult mouse female offspring

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Elena V. Kozlova ◽  
Bhuvaneswari D. Chinthirla ◽  
Pedro A. Pérez ◽  
Nicholas V. DiPatrizio ◽  
Donovan A. Argueta ◽  
...  
Keyword(s):  
Polybrominated Diphenyl Ethers ◽  
Ex Vivo ◽  
Time Windows ◽  
Female Offspring ◽  
Exposure Model ◽  
Maternal Transfer ◽  
Tissue Mass ◽  
Brown Adipose ◽  
Diphenyl Ethers

Abstract Polybrominated diphenyl ethers (PBDEs) are brominated flame retardant chemicals and environmental contaminants with endocrine-disrupting properties that are associated with diabetes and metabolic syndrome in humans. However, their diabetogenic actions are not completely characterized or understood. In this study, we investigated the effects of DE-71, a commercial penta-mixture of PBDEs, on glucoregulatory parameters in a perinatal exposure model using female C57Bl/6 mice. Results from in vivo glucose and insulin tolerance tests and ex vivo analyses revealed fasting hyperglycemia, glucose intolerance, reduced sensitivity and delayed glucose clearance after insulin challenge, decreased thermogenic brown adipose tissue mass, and exaggerated hepatic endocannabinoid tone in F1 offspring exposed to 0.1 mg/kg DE-71 relative to control. DE-71 effects on F0 dams were more limited indicating that indirect exposure to developing offspring is more detrimental. Other ex vivo glycemic correlates occurred more generally in exposed F0 and F1, i.e., reduced plasma insulin and altered glucoregulatory endocrines, exaggerated sympathoadrenal activity and reduced hepatic glutamate dehydrogenase enzymatic activity. Hepatic PBDE congener analysis indicated maternal transfer of BDE-28 and -153 to F1 at a collective level of 200 ng/g lipid, in range with maximum values detected in serum of human females. Given the persistent diabetogenic phenotype, especially pronounced in female offspring after developmental exposure to environmentally relevant levels of DE-71, additional animal studies should be conducted that further characterize PBDE-induced diabetic pathophysiology and identify critical developmental time windows of susceptibility. Longitudinal human studies should also be conducted to determine the risk of long-lasting metabolic consequences after maternal transfer of PBDEs during early-life development.

scholarly journals Different cholinergic cell groups in the basal forebrain regulate social interaction and social recognition memory

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kana Okada ◽  
Kayo Nishizawa ◽  
Tomoko Kobayashi ◽  
Shogo Sakata ◽  
Kouichi Hashimoto ◽  
...  
Keyword(s):  
Social Interaction ◽  
Recognition Memory ◽  
Basal Forebrain ◽  
Social Behaviour ◽  
Cholinergic Neurons ◽  
Social Recognition ◽  
Social Ability ◽  
Cell Groups ◽  
Cholinergic Cell ◽  
Social Recognition Memory

AbstractSocial behaviour is a complex construct that is reported to include several components of social approach, interaction and recognition memory. Alzheimer’s disease (AD) is mainly characterized by progressive dementia and is accompanied by cognitive impairments, including a decline in social ability. The cholinergic system is a potential constituent for the neural mechanisms underlying social behaviour, and impaired social ability in AD may have a cholinergic basis. However, the involvement of cholinergic function in social behaviour has not yet been fully understood. Here, we performed a selective elimination of cholinergic cell groups in the basal forebrain in mice to examine the role of cholinergic function in social interaction and social recognition memory by using the three-chamber test. Elimination of cholinergic neurons in the medial septum (MS) and vertical diagonal band of Broca (vDB) caused impairment in social interaction, whereas ablating cholinergic neurons in the nucleus basalis magnocellularis (NBM) impaired social recognition memory. These impairments were restored by treatment with cholinesterase inhibitors, leading to cholinergic system activation. Our findings indicate distinct roles of MS/vDB and NBM cholinergic neurons in social interaction and social recognition memory, suggesting that cholinergic dysfunction may explain social ability deficits associated with AD symptoms.

scholarly journals Short- and Long-Term Social Recognition Memory Are Differentially Modulated by Neuronal Histamine

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 555
Author(s):  
Barbara Rani ◽  
Bruna Silva-Marques ◽  
Rob Leurs ◽  
Maria Beatrice Passani ◽  
Patrizio Blandina ◽  
...  
Keyword(s):  
Recognition Memory ◽  
Histamine Release ◽  
Histidine Decarboxylase ◽  
Acetylcholinesterase Inhibitor ◽  
Social Recognition ◽  
Amnesic Effect ◽  
Brain Histamine ◽  
Monogamous Species ◽  
Social Recognition Memory

The ability of recognizing familiar conspecifics is essential for many forms of social interaction including reproduction, establishment of dominance hierarchies, and pair bond formation in monogamous species. Many hormones and neurotransmitters have been suggested to play key roles in social discrimination. Here we demonstrate that disruption or potentiation of histaminergic neurotransmission differentially affects short (STM) and long-term (LTM) social recognition memory. Impairments of LTM, but not STM, were observed in histamine-deprived animals, either chronically (Hdc−/− mice lacking the histamine-synthesizing enzyme histidine decarboxylase) or acutely (mice treated with the HDC irreversible inhibitor α-fluoromethylhistidine). On the contrary, restriction of histamine release induced by stimulation of the H3R agonist (VUF16839) impaired both STM and LTM. H3R agonism-induced amnesic effect was prevented by pre-treatment with donepezil, an acetylcholinesterase inhibitor. The blockade of the H3R with ciproxifan, which in turn augmented histamine release, resulted in a procognitive effect. In keeping with this hypothesis, the procognitive effect of ciproxifan was absent in both Hdc−/− and αFMH-treated mice. Our results suggest that brain histamine is essential for the consolidation of LTM but not STM in the social recognition test. STM impairments observed after H3R stimulation are probably related to their function as heteroreceptors on cholinergic neurons.

Brain regions activated during consolidation of social recognition memory

2010 ◽  
Vol 68 ◽  
pp. e291
Author(s):  
Toshiyuki Tanimizu ◽  
Kazune Kadoma ◽  
Yue Zhang ◽  
Hotaka Fukushima ◽  
Satoshi Kida
Keyword(s):  
Recognition Memory ◽  
Brain Regions ◽  
Social Recognition ◽  
Social Recognition Memory

AUTISM SPECTRUM DISORDERS FOLLOWING IN UTERO EXPOSURE TO ANTIEPILEPTIC DRUGS

Neurology ◽  
2009 ◽  
Vol 73 (12) ◽  
pp. 997-997 ◽  
Author(s):  
M. L. Evatt ◽  
M. R. DeLong ◽  
W. B. Grant ◽  
J. J. Cannell ◽  
V. Tangpricha
Keyword(s):  
Autism Spectrum Disorders ◽  
Antiepileptic Drugs ◽  
In Utero ◽  
Autism Spectrum ◽  
In Utero Exposure ◽  
Spectrum Disorders

scholarly journals Targeting the RHOA pathway improves learning and memory in Kctd13 and 16p11.2 deletion mouse models

2020 ◽  
Author(s):  
Sandra Martin Lorenzo ◽  
Valérie Nalesso ◽  
Claire Chevalier ◽  
Marie-Christine Birling ◽  
Yann Herault
Keyword(s):  
Object Recognition ◽  
Recognition Memory ◽  
Mouse Models ◽  
Copy Number Variants ◽  
Gene Copy Number ◽  
Chronic Administration ◽  
Autism Spectrum ◽  
Gene Copy ◽  
List Type ◽  
Object Recognition Memory

ABSTRACTGene copy number variants (CNV) have an important role in the appearance of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in the 16p11.2 deletion through the regulation of the RHOA pathway. Here, we target the pathway and rescue the cognitive phenotypes of the 16p11.2 deletion mouse models. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase (ROCK), in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 region. We focused our attention on the most robust cognitive phenotypes seen in the 16p11.2 models and we showed that a chronic fasudil treatment can restore object recognition memory in both mouse models but does not change other behavioural traits. These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the pertinence of the RHOA pathway as a therapeutic path and reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 CNV models.HIGHLIGHTS- Kctd13 haploinsufficiency recapitulates most of the behaviour phenotypes found in the 16p11.2 Del/+ models- Fasudil treatment restores Kctd13 and 16p11.2 Del/+ mutant phenotypes in novel location and novel object recognition memory tests- Fasudil treatment restores the RhoA pathway in Kctd13+/- and 16p11.2 Del/+ models

scholarly journals A Temporal Activity of CA1 Neurons Underlying Short-Term Memory for Social Recognition Altered in PTEN Mouse Models of Autism Spectrum Disorder

2021 ◽  
Vol 15 ◽  
Author(s):  
An-Ping Chai ◽  
Xue-Feng Chen ◽  
Xiao-Shan Xu ◽  
Na Zhang ◽  
Meng Li ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Short Term Memory ◽  
Autism Spectrum ◽  
Social Recognition ◽  
Neuronal Firing ◽  
Spectrum Disorder ◽  
Long Term Memory ◽  
Short Term ◽  
Term Memory ◽  
Ca1 Neurons

Memory-guided social recognition identifies someone from previous encounters or experiences, but the mechanisms of social memory remain unclear. Here, we find that a short-term memory from experiencing a stranger mouse lasting under 30 min interval is essential for subsequent social recognition in mice, but that interval prolonged to hours by replacing the stranger mouse with a familiar littermate. Optogenetic silencing of dorsal CA1 neuronal activity during trials or inter-trial intervals disrupted short-term memory-guided social recognition, without affecting the ability of being sociable or long-term memory-guided social recognition. Postnatal knockdown or knockout of autism spectrum disorder (ASD)-associated phosphatase and tensin homolog (PTEN) gene in dorsal hippocampal CA1 similarly impaired neuronal firing rate in vitro and altered firing pattern during social recognition. These PTEN mice showed deficits in social recognition with stranger mouse rather than littermate and exhibited impairment in T-maze spontaneous alternation task for testing short-term spatial memory. Thus, we suggest that a temporal activity of dorsal CA1 neurons may underlie formation of short-term memory to be critical for organizing subsequent social recognition but that is possibly disrupted in ASD.

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