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Iron deficiency in human infancy reportedly leads to developmental delays and changes in neurobiology that may be irreversible. Using a rodent model, the present study examined whether dietary iron deficiency late in pregnancy and during lactation alters sensorimotor development and brain monoaminergic systems. Rats were assigned to 1 of 4 dietary treatments during gestation and lactation: 1) iron sufficient control; 2) prenatal iron deficiency beginning on gestational d 15 (G15); 3) postnatal iron deficiency beginning on postnatal d 4 (P4); 4) iron deficiency beginning on G15 followed by an iron sufficient diet on P4. Developmental milestones, open field behavior, brain iron and proteins, monoamines, and their transporters were evaluated between P6 and P21. Only G15 iron deficient rats had greater dopaminergic activity than controls as indicated by increased tyrosine hydroxylase levels, phosphorylated tyrosine hydroxylase levels, and cellular dopamine in prefrontal cortex and striatum at P15. These rats also showed delayed eye opening, ear development, and reduced locomotor activity. Iron repletion at P4 returned most measures to control levels by the time of weaning. Postnatal iron deficiency reduced striatal and ventral midbrain iron as well as cellular dopamine levels in prefrontal cortex and striatum at P21. Developmental delays in ear development and achievement in bar holding and surface righting also resulted from postnatal iron deficiency. These results indicate that iron deficiency begun at G15 affects early dopamine neurobiology, the development of specific developmental milestones, and behavior in preweaned rats.

Iron deficiency in human infants and in young animal models produces changes in neural functioning that may be related to monoamine metabolism. This study employed both behavioral and biochemical approaches in a design using cross-fostering to examine alterations in dopamine (DA) function when iron deficiency occurs during the neonatal period. We measured brain Fe, dopamine transporters (DAT) and dopamine receptor density in rats made iron deficient, or not, from postnatal day (PND) 4 to PND 14 or 21. Some pups were then weaned to an iron-deficient diet and others to the control diet to examine the reversibility of these effects. Behaviors related to dopamine function were measured. Dopamine [D.sub.2] receptor ([D.sub.2]R), [D.sub.1]R and iron concentrations were ~70, 80 and 30% of control values, respectively, in the nucleus accumbens and striatum in iron-deficient rats at PND 14. The DAT density was also reduced to 50% of control density in the nucleus accumbens but was unchanged in the striatum. By PND 21, there was also a significant 50% lowering of DAT, [D.sub.1]R and [D.sub.2]R densities in the prefrontal cortex (PFC). Iron repletion at PND 21-49 normalized [D.sub.1]R, [D.sub.2]R, and DAT levels in the nucleus accumbens, PFC and ventral midbrain but not in the striatum. In summary, neonatal iron deficiency is associated with changes in DA biology that vary with duration of iron deficiency, and are not completely normalized despite replenishment of iron status. Changes in DA-related behaviors that were persistent after postweaning iron repletion suggest the existence of a critical neonatal developmental period that is expressed by alterations in DA functioning. J. Nutr. 133:1174-1179, 2003. KEY WORDS: * dopamine * dopamine receptors * dopamine transporter * iron deficiency * prefrontal cortex * rats

The article comments on article "Supplier-dependent differences in intermittent voluntary alcohol intake and response to naltrexone in Wistar rats" discusses the y factors associated with animal husbandry can potentially have an impact on behavior.

Ecstasy (3,4-methylenedioxymethylamphetamine; MDMA) is a popular club drug often taken with ethanol (EtOH). We recently found EtOH potentiated the psychomotor effects of MDMA in rats. This potentiation could reflect pharmacodynamic or/and pharmacokinetic processes. To test the latter hypothesis, rats were injected i.p. with 6.6 or 10 mg/kg MDMA with or without 1.5 g/kg EtOH, and were killed at 5, 15 or 60 min after injection. MDMA, its primary metabolite, 3,4-methylenedioxyamphetamine (MDA), and EtOH concentrations were determined in the plasma and the hippocampus, frontal cortex and striatum at each time-point. EtOH potentiated MDMA-induced hyperactivity mainly during the first 60 min post-administration. Fifteen and 60 min after treatment with MDMA and EtOH, MDMA concentrations were greater than afterMDMAalone in the blood and the three brain regions examined. EtOH, however, did not increase the fraction of MDMA converted to MDA, as shown by unaltered MDA/ MDMAratios at eitherMDMAdose. Interestingly, when combined with EtOH, the distribution ofMDMA and MDA in the brain was not homogeneous. Concentrations of both were much higher in the striatum and cortex, than in the hippocampus. Thus, at least part of the potentiation of the MDMA-induced hyperlocomotion by EtOH might be the result of a higher concentration of MDMA and metabolites in the blood and brain. Our results present clear evidence that EtOH increases brain and blood concentrations of MDMA and leads to the possibility of both enhanced MDMA-based neurotoxicity and increased liability for abuse. [ABSTRACT FROM AUTHOR]

Evaluates the effects of dietary iron deficiency (ID) and excess iron on the physical activity of rats. Hemoglobin, hematocrit, liver nonheme iron concentration and body, liver and brain weights of the subjects; Measures of motor activity; Effects of iron deficiency in early life.

Rationale: Autism spectrum disorder (ASD) represents a complex neurodevelopmental condition lacking specific pharmacological interventions. Given the multifaced etiology of ASD, there exist no effective treatment for ASD. Rapamycin (RAPA) can activate autophagy by inhibiting the mTOR pathway and has exhibited promising effects in treating central nervous system disorders; however, its limited ability to cross the blood-brain barrier (BBB) has hindered its clinical efficacy, leading to substantial side effects. Methods: To address this challenge, we designed a drug delivery system utilizing red blood cell membrane (CM) vesicles modified with SS31 peptides to enhance the brain penetration of RAPA for the treatment of autism. Results: The fabricated SCM@RAPA nanoparticles, with an average diameter of 110 nm, exhibit rapid release of RAPA in a pathological environment characterized by oxidative stress. In vitro results demonstrate that SCM@RAPA effectively activate cellular autophagy, reduce intracellular ROS levels, improve mitochondrial function, thereby ameliorating neuronal damage. SS31 peptide modification significantly enhances the BBB penetration and rapid brain accumulation of SCM@RAPA. Notably, SCM@RAPA nanoparticles demonstrate the potential to ameliorate social deficits, improve cognitive function, and reverse neuronal impairments in valproic acid (VPA)-induced ASD models. Conclusions: The therapeutic potential of SCM@RAPA in managing ASD signifies a paradigm shift in autism drug treatment, holding promise for clinical interventions in diverse neurological conditions., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Of the nearly 1 million military personnel who participated in the 1990-1991 Gulf War, between 25% and 35% became ill with what now is referred to as Gulf War Illness (GWI) by the Department of Defense. Symptoms varied from gastrointestinal distress to lethargy, memory loss, inability to concentrate, depression, respiratory, and reproductive problems. The symptoms have persisted for 30 years in those afflicted but the basis of the illness remains largely unknown. Nerve agents and other chemical exposures in the war zone have been implicated but the long-term effects of these acute exposures have left few if any identifiable signatures. The major aim of this study is to elucidate the possible genomic basis for the persistence of symptoms, especially of the neurological and behavioral effects. To address this, we performed a whole genome epigenetic analysis of the proposed cause of GWI, viz., exposure to organophosphate neurotoxicants combined with high circulating glucocorticoids in two inbred mouse strains, C57BL/6J and DBA/2J. The animals received corticosterone in their drinking water for 7 days followed by injection of diisopropylfluorophosphate, a nerve agent surrogate. Six weeks after DFP injection, the animals were euthanized and medial prefrontal cortex harvested for genome-wide DNA methylation analysis using high-throughput sequencing. We observed 67 differentially methylated genes, notably among them, Ttll7, Akr1c14, Slc44a4, and Rusc2, all related to different symptoms of GWI. Our results support proof of principle of genetic differences in the chronic effects of GWI-related exposures and may reveal why the disease has persisted in many of the now aging Gulf War veterans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mozhui, O’Callaghan, Ashbrook, Prins, Zhao, Lu and Jones.)

Purpose: Usher syndrome (US) is characterized by a loss of vision due to retinitis pigmentosa (RP) and deafness. US has three clinical subtypes, but even within each subtype, the severity varies. Myosin VIIA, coded by Myo7a , has been identified as one of the causal genes of US. This study aims to identify pathways and other genes through which Myo7a interacts to affect the presentation of US symptoms., Methods: In this study, we used the retinal tissue of BXD recombinant inbred (RI) mice to examine the expression of Myo7a and perform genetic mapping. Expression quantitative trait locus (eQTL), single nucleotide polymorphism (SNP), and gene correlation analysis were performed using GeneNetwork. Gene set enrichment analysis was performed using WebGestalt, and gene network construction was performed using the Gene Cohesion Analysis Tool., Results: We found Myo7a to be cis -regulated, with varied levels of expression across BXD strains. Here, we propose a genetic network with 40 genes whose expression is highly correlated with Myo7a . Among these genes, six have been linked to retinal diseases, three to deafness, and five share a transcription factor with Myo7a. Gene ontology and pathway analysis revealed a strong connection among ion channel activity, Myo7a , and US., Conclusions: Although Myo7a is a causal gene of US type I, this gene works with many other genes and pathways to affect the severity of US. Many of the genes found in the genetic network, pathways, and gene ontology categories of Myo7a are related to either deafness or blindness. Further investigation is needed to examine the specific relationships between these genes, which may assist in the treatment of US.

The aim of this study was to identify genes that influence iron regulation under varying dietary iron availability. Male and female mice from 20+ BXD recombinant inbred strains were fed iron-poor or iron-adequate diets from weaning until 4 mo of age. At death, the spleen, liver, and blood were harvested for the measurement of hemoglobin, hematocrit, total iron binding capacity, transferrin saturation, and liver, spleen and plasma iron concentration. For each measure and diet, we found large, strain-related variability. A principal-components analysis (PCA) was performed on the strain means for the seven parameters under each dietary condition for each sex, followed by quantitative trait loci (QTL) analysis on the factors. Compared with the iron-adequate diet, iron deficiency altered the factor structure of the principal components. QTL analysis, combined with PosMed (a candidate gene searching system) published gene expression data and literature citations, identified seven candidate genes, Ptprd, Mdm1, Picalm, lip1, Tcerg1, Skp2, and Frzb based on PCA factor, diet, and sex. Expression of each of these is cis-regulated, significantly correlated with the corresponding PCA factor, and previously reported to regulate iron, directly or indirectly. We propose that polymorphisms in multiple genes underlie individual differences in iron regulation, especially in response to dietary iron challenge. This research shows that iron management is a highly complex trait, influenced by multiple genes. Systems genetics analysis of iron homeostasis holds promise for developing new methods for prevention and treatment of iron deficiency anemia and related diseases.

Iron homeostasis is one of the most critical functions in living systems. Too little iron can lead to anemia and tissue-specific disorders, such as splenomegaly. Excessive systemic iron is characteristic of hemochromatosis and is implicated in the brain in Parkinson's disease. With the exception of some single gene diseases like hemochromatosis, we know little about genetic-based, individual differences in iron-related parameters and their impact on biology. To model genetic control of iron homeostasis, we measured liver, spleen, and plasma iron concentrations, hematocrit and hemoglobin, transferrin saturation, and total iron-binding capacity in several BXD/Ty recombinant inbred mouse strains derived from C57BL/6 and DBA/2 progenitors. At 120 days of age, the animals were killed for iron analysis. All measures showed genetic-based variability consistent with polygenic influence. Analysis of principal components of the seven measures revealed three factors that we named availability, transport, and storage. Quantitative trait loci (QTL) analysis revealed one suggestive QTL on chromosome 5 for availability, two suggestive QTL (one on chromosome 1 and the other on chromosome 7) for transport, and one weak QTL on chromosome 2 for storage. The results show that iron homeostasis is a complex trait and is influenced by multiple genes.