The impact of maternal neglect on genetic hyperactivity

Majdak, Petra; Grogan, Elizabeth L.; Gogola, Joseph V.; Sorokina, Anastassia; Tse, Stephen; Rhodes, Justin S.

doi:10.1016/j.bbr.2016.07.033

Cited by 6 publications

(9 citation statements)

References 57 publications

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“…Analysis of distances traveled within the 2 hours following injections of either saline or 0.25 mg/kg amphetamines, indicated a significant effect of the baseline activity covariate (F 1,12 = 139.6, p<0.0001) and significant effect of line after correcting for baseline activity (F 1,12 = 11.8, p = 0.0049). Consistent with our previous reports [ 13 , 14 ], amphetamines tended to reduce activity in High-Active mice by 40%, while increasing activity in Control mice by approximately 2-fold, though the interaction was not statistically significant (F 1,12 = 2.5, p = 0.14) given the small sample size of n = 5 per group intended for RNA-seq comparisons.…”

Section: Resultssupporting

confidence: 91%

“…One way to remove this confound in future studies is to develop and analyze additional replicate lines of mice [ 21 ]. It is alternatively possible to estimate rates of genetic drift without replicate lines if certain assumptions are made about heritability, effective population size, and inbreeding coefficients [ 13 , 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…Mice were phenotyped as per previous work [ 13 , 14 ] for home cage activity when they were approximately 3 months old. At approximately 6.5 months of age, all the mice were re-phenotyped for home cage activity using the same procedure, 6 days of continuous video-tracking.…”

Section: General Husbandrymentioning

confidence: 99%

“…Our model includes a High-Active line, selectively bred for 17 generations for increased home cage activity and a Control, unselected line, maintained over the same period. Features of the model relevant for exploring ADHD etiology include polygenicity of the ADHD-like phenotypes, hyperactivity in a habituated environment, motor impulsivity, and symptoms ameliorated with therapeutic doses of amphetamines [ 13 , 14 ]. The goal of the present study was to document differences in gene expression between the High-Active and Control mice in the striatum and in response to amphetamines, in order to develop a more coherent hypothesis for how patterns of differentially expressed genes in the striatum might contribute to ADHD-like behavior.…”

Section: Introductionmentioning

confidence: 99%

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Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling

Sorokina¹,

Saul²,

Goncalves³

et al. 2018

PLoS ONE

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Despite the prevalence and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), genetic etiology remains elusive. Clinical evidence points in part to reduced function of the striatum, but which specific genes are differentially expressed and how they sculpt striatal physiology to predispose ADHD are not well understood. As an exploratory tool, a polygenic mouse model of ADHD was recently developed through selective breeding for high home cage activity. Relative to the Control line, the High-Active line displays hyperactivity and motor impulsivity which are ameliorated with amphetamine. This study compared gene expression in the striatum between Control and High-Active mice to develop a coherent hypothesis for how genes might affect striatal physiology and predispose ADHD-like symptoms. To this end, striatal transcriptomes of High-Active and Control mice were analyzed after mice were treated with saline or amphetamines. The pseudogene Gm6180 for n-cofilin (Cfl1) displayed 20-fold higher expression in High-Active mice corresponding with reduced Cfl1 expression suggesting synaptic actin dysregulation. Latrophilin 3 (Lphn3), which is associated with ADHD in human populations and is involved in synapse structure, and its ligand fibronectin leucine rich transmembrane protein 3 (Flrt3), were downregulated in High-Active mice. Multiple genes were altered in High-Active mice in a manner predicted to downregulate the canonical Wnt pathway. A smaller and different set of genes including glyoxalase (Glo1) were differentially regulated in High-Active as compared to Control in response to amphetamine. Together, results suggest genes involved in excitatory synapse regulation and maintenance are downregulated in ADHD-like mice. Consistent with the molecular prediction, stereological analysis of the striatum from a separate set of mice processed for imunohistochemical detection of synaptophysin revealed approximately a 46% reduction in synaptophysin immunoreactivity in High-Active relative to Control. Results provide a new set of molecular targets related to synapse maintenance for the next generation of ADHD medicines.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: General Husbandrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling

Sorokina¹,

Saul²,

Goncalves³

et al. 2018

PLoS ONE

Self Cite

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“…2C,D). In a previous report, highly active dams also neglected their pups, including a high rate of cannibalization 40 .…”

Section: Scientific Reports |mentioning

confidence: 97%

Impaired experience-dependent maternal care in presynaptic active zone protein CAST-deficient dams

Hagiwara

Sugiyama

Ohtsuka

2020

Sci Rep

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Although sociological studies affirm the importance of parental care in the survival of offspring, maltreatment-including child neglect-remains prevalent in many countries. While child neglect is well known to affect child development, the causes of maternal neglect are poorly understood. Here, we found that female mice with a deletion mutation of CAST (a presynaptic release-machinery protein) showed significantly reduced weaning rate when primiparous and a recovered rate when multiparous. Indeed, when nurturing, primiparous and nulliparous CAST knock out (KO) mice exhibited less crouching time than control mice and moved greater distances. contrary to expectations, plasma oxytocin (OXT) was not significantly reduced in CAST KO mice even though terminals of magnocellular neurons in the posterior pituitary expressed CAST. We further found that compared with control mice, CAST KO mice drank significantly less water when nurturing and had a greater preference for sucrose during pregnancy. We suggest that deficiency in presynaptic release-machinery protein impairs the facilitation of some maternal behaviours, which can be compensated for by experience and learning.Parental care is essential for the survival of mammalian offspring and influences their adult lives mentally and physically. Naturally, both parents have responsibilities from nest building to feeding, but because they lactate, the primary responsibility for parental care falls to mothers 1 . As nursing is essential for mammalian survival, the basic neural mechanisms underlying maternal care are likely conserved throughout the mammalian evolutionary tree. Therefore, studying these neural mechanisms in non-human mammalian models such as gene-transgenic mice 2 can help us understand human maternal care and prevent neglect. In rodents, maternal behaviours such as nest building, gathering pups together in the nest, keeping them warm, and nursing are critical for pup survival.Complex maternal behaviours require highly motivated and flexible neural systems and have frequently been associated the neuropeptide oxytocin (OXT), which is secreted in both the periphery and the brain 2-5 . Indeed, considerable evidence indicates that OXT promotes maternal behaviour, while OXT deficiency (OXT KO in rats) results in impaired milk ejection without obvious defects in parturition 3 . Similarly, a null mutation of the OXT receptor in mice led to defects in lactation and maternal behaviour 6,7 . Additionally, mice deficient in CD38 (a transmembrane glycoprotein with ADP-ribosyl cyclase activity) also showed defects in maternal behaviour correlating with the reduction of plasma OXT levels 8 . Therefore, OXT and its receptor system are essential for the regulation of maternal behaviour. However, OXT is just one of the many critical players; complex maternal behaviours are also regulated by other neuromodulators including dopamine, serotonin, norepinephrine, and corticotropin-releasing factor, which have been associated with maternal motivation and stress-induced anti-maternal be...

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The impact of maternal neglect on genetic hyperactivity

Cited by 6 publications

References 57 publications

Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling

Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling

Impaired experience-dependent maternal care in presynaptic active zone protein CAST-deficient dams

The impact of early-life environment on absence epilepsy and neuropsychiatric comorbidities

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