Hofbauer cells and fetal brain microglia share transcriptional profiles and responses to maternal diet-induced obesity.

Maternal immune activation is associated with adverse offspring neurodevelopmental outcomes, many mediated by in utero microglial programming. As microglia remain inaccessible throughout development, identification of noninvasive biomarkers reflecting fetal brain microglial programming could permit screening and intervention. We used lineage tracing to demonstrate the shared ontogeny between fetal brain macrophages (microglia) and fetal placental macrophages (Hofbauer cells) in a mouse model of maternal diet-induced obesity, and single-cell RNA-seq to demonstrate shared transcriptional programs. Comparison with human datasets demonstrated conservation of placental resident macrophage signatures between mice and humans. Single-cell RNA-seq identified common alterations in fetal microglial and Hofbauer cell gene expression induced by maternal obesity, as well as sex differences in these alterations. We propose that Hofbauer cells, which are easily accessible at birth, provide insights into fetal brain microglial programs and may facilitate the early identification of offspring vulnerable to neurodevelopmental disorders.

Propranolol attenuates the establishment of conditioned context aversions: differential effects compared to MK-801 in an animal model of anticipatory nausea and vomiting.

Cancer patients often experience anticipatory nausea and vomiting (ANV) due to Pavlovian conditioning. Both N-methyl-D-aspartate and beta-adrenergic receptors are known to mediate memory formation, but their role in the development of ANV remains unclear. This study used a conditioned context aversion (CCA) paradigm, an animal model for ANV, to assess whether administration of the beta-adrenergic receptor antagonist propranolol or the N-methyl-D-aspartate receptor antagonist MK-801 immediately after CCA training has an effect on the later expression of CCA in CD1 male mice. In experiment 1, three groups were injected with lithium chloride (LiCl) to induce aversion in a novel context, resulting in CCA. A control group was injected with sodium chloride (NaCl). Following conditioning, two of the LiCl-treated groups received different doses of MK-801 (0.05 or 0.2 mg/kg), while the remaining LiCl-treated and NaCl-treated groups received a second NaCl injection. In experiment 2, two groups were injected with LiCl, and one group was injected with NaCl. After conditioning, one of the LiCl-treated groups received a propranolol injection (10 mg/kg). The remaining LiCl-treated and NaCl-treated groups received NaCl injections. Water consumption was measured in all groups 72 h later within the conditioning context. Postconditioning administration of propranolol, but not MK-801, attenuated CCA, as revealed by similar levels of water consumption in animals that received LiCl and propranolol relative to NaCl-treated animals. These findings suggest that beta-adrenergic receptor activation is crucial for the development of CCA. Therefore, propranolol may represent a novel therapeutic approach for cancer patients at high risk of ANV.

Memory Impairing Effect of Propranolol on Consolidation and Reconsolidation for Various Learning Tasks.

Newly acquired memory traces have been thought to become stable and resistant to interruption after they are stored in long-term memory. However, according to a recent research drugs such as beta-adrenergic receptor antagonists enable memories to be updated and rewritten when administered during consolidation and reconsolidation. Propranolol is a widely used beta-adrenergic receptor antagonist that disrupts the consolidation and reconsolidation processes of memory formation as it inhibits protein synthesis in the central nervous system. This review aims to discuss the memory impairing effect of the systemic and intracerebral administration of propranolol during the consolidation and reconsolidation processes associated with different learning tasks. In doing so, this review will help elucidate the effects of propranolol on different stages of memory formation. Since learning and maladaptive memories underpin some of the most common psychological disorders, such as phobias, post-traumatic stress disorder, addiction, drug-seeking behavior, and so on, a thorough understanding of propranolol's memory-impairing effect has significant clinical value and the potential to help people suffering from these disorders.

Genetic and environmental influences on one-trial conditioned context aversion in mice.

Anticipatory nausea (AN) is caused by an association between contextual cues and the experience of nausea (the side effects of chemotherapy or radiation treatment) and it develops predominantly in female patients undergoing chemotherapy. Preclinical studies in rodents show that the administration of an illness-inducing agent in the presence of novel contextual cues can cause conditioned context aversion (CCA) and this has been proposed to model AN. The literature also suggests that brief pre-exposure to a novel context prior to shock delivery is critical in the development of contextual fear conditioning in rodents (a phenomenon known as Immediate Shock Deficit), but this has not been assessed in CCA. The aim of present study was to develop a CCA paradigm to assess this in outbred (CD1) and inbred (C57BL/6J) mice and evaluate potential sex differences. The results revealed that a single conditioning trial in which a distinctive context was paired with LiCl-induced illness was sufficient to elicit a conditioned response in both female and male CD1 outbred mice, but not in C57BL/6J inbred mice. In addition, CCA was facilitated when animals had prior experience with the context. Finally, outbred female mice showed longer and more robust retention of CCA than male mice, which parallels clinical findings. The results indicate the importance of using CD1 outbred mice as an animal model of AN as well as examining sex differences in the CCA paradigm. Similar findings in humans encourage the future use of this novel CCA preclinical mouse model.

Hofbauer cells and fetal brain microglia share transcriptional profiles and responses to maternal diet-induced obesity.

Maternal immune activation is associated with adverse offspring neurodevelopmental outcomes, many mediated by in utero microglial programming. As microglia remain inaccessible throughout development, identification of noninvasive biomarkers reflecting fetal brain microglial programming could permit screening and intervention. We used lineage tracing to demonstrate the shared ontogeny between fetal brain macrophages (microglia) and fetal placental macrophages (Hofbauer cells) in a mouse model of maternal diet-induced obesity, and single-cell RNA-seq to demonstrate shared transcriptional programs. Comparison with human datasets demonstrated conservation of placental resident macrophage signatures between mice and humans. Single-cell RNA-seq identified common alterations in fetal microglial and Hofbauer cell gene expression induced by maternal obesity, as well as sex differences in these alterations. We propose that Hofbauer cells, which are easily accessible at birth, provide novel insights into fetal brain microglial programs, and may facilitate the early identification of offspring vulnerable to neurodevelopmental disorders in the setting of maternal exposures.

Mismatch between obesogenic intrauterine environment and low-fat postnatal diet may confer offspring metabolic advantage.

OBJECTIVE: Mismatch between a depleted intrauterine environment and a substrate-rich postnatal environment confers an increased risk of offspring obesity and metabolic syndrome. Maternal diet-induced obesity (MATOB) is associated with the same outcomes. These experiments tested the hypothesis that a mismatch between a nutrient-rich intrauterine environment and a low-fat postnatal environment would ameliorate offspring metabolic morbidity. METHODS: C57BL6/J female mice were fed either a 60% high-fat diet (HFD) or a 10% fat control diet (CD) for 14-week pre-breeding and during pregnancy/lactation. Offspring were weaned to CD. Weight was evaluated weekly; body composition was determined using EchoMRI. Serum fasting lipids and glucose and insulin tolerance tests were performed. Metabolic rate, locomotor, and sleep behavior were evaluated with indirect calorimetry. RESULTS: MATOB-exposed/CD-weaned offspring of both sexes had improved glucose tolerance and insulin sensitivity compared to controls. Males had improved fasting lipids. Females had significantly increased weight and body fat percentage in adulthood compared to sex-matched controls. Females also had significantly increased sleep duration and reduced locomotor activity compared to males. CONCLUSIONS: Reduced-fat dietary switch following intrauterine and lactational exposure to MATOB was associated with improved glucose handling and lipid profiles in adult offspring, more pronounced in males. A mismatch between a high-fat prenatal and low-fat postnatal environment may confer a metabolic advantage. The amelioration of deleterious metabolic programming by strict offspring adherence to a low-fat diet may have translational potential.

Perinatal exposure to maternal obesity: Lasting cardiometabolic impact on offspring.

Evidence from epidemiological, clinical, and animal model studies clearly demonstrates that prenatal and lactational maternal obesity and high-fat diet consumption are associated with cardiometabolic morbidity in offspring. Fetal and offspring sex may be an important effect modifier. Adverse offspring cardiometabolic outcomes observed in the setting of maternal obesity include an increased risk for obesity, features of metabolic syndrome (hypertension, hyperglycemia and insulin resistance, hyperlipidemia, increased adiposity), and non-alcoholic fatty liver disease. This review article synthesizes human and animal data linking maternal obesity and high-fat diet consumption in pregnancy and lactation to adverse cardiometabolic outcomes in offspring. We review key mechanisms underlying skeletal muscle, adipose tissue, pancreatic, liver, and central brain reward programming in obesity-exposed offspring, and how such malprogramming contributes to offspring cardiometabolic morbidity.

Fetal brain and placental programming in maternal obesity: A review of human and animal model studies.

Both human epidemiologic and animal model studies demonstrate that prenatal and lactational exposure to maternal obesity and high-fat diet are associated with adverse neurodevelopmental outcomes in offspring. Neurodevelopmental outcomes described in offspring of obese women include cognitive impairment, autism spectrum disorder (ASD), attention deficit hyperactivity disorder, anxiety and depression, disordered eating, and propensity for reward-driven behavior, among others. This review synthesizes human and animal data linking maternal obesity and high-fat diet consumption to abnormal fetal brain development, and neurodevelopmental and psychiatric morbidity in offspring. It highlights key mechanisms by which maternal obesity and maternal diet impact fetal and offspring development, and sex differences in offspring programming. In addition, we review placental effects of maternal obesity, and the role the placenta might play as an indicator vs mediator of fetal programming.

Intracerebral Delivery of Brain-Derived Neurotrophic Factor Using HyStem®-C Hydrogel Implants Improves Functional Recovery and Reduces Neuroinflammation in a Rat Model of Ischemic Stroke.

Ischemic stroke is a leading cause of death and disability worldwide. Potential therapeutics aimed at neural repair and functional recovery are limited in their blood-brain barrier permeability and may exert systemic or off-target effects. We examined the effects of brain-derived neurotrophic factor (BDNF), delivered via an extended release HyStem®-C hydrogel implant or vehicle, on sensorimotor function, infarct volume, and neuroinflammation, following permanent distal middle cerebral artery occlusion (dMCAo) in rats. Eight days following dMCAo or sham surgery, treatments were implanted directly into the infarction site. Rats received either vehicle, BDNF-only (0.167 µg/µL), hydrogel-only, hydrogel impregnated with 0.057 µg/µL of BDNF (hydrogel + BDNFLOW), or hydrogel impregnated with 0.167 µg/µL of BDNF (hydrogel + BDNFHIGH). The adhesive removal test (ART) and 28-point Neuroscore (28-PN) were used to evaluate sensorimotor function up to two months post-ischemia. The hydrogel + BDNFHIGH group showed significant improvements on the ART six to eight weeks following treatment and their behavioral performance was consistently greater on the 28-PN. Infarct volume was reduced in rats treated with hydrogel + BDNFHIGH as were levels of microglial, phagocyte, and astrocyte marker immunoexpression in the corpus striatum. These data suggest that targeted intracerebral delivery of BDNF using hydrogels may mitigate ischemic brain injury and restore functional deficits by reducing neuroinflammation.

Acquisition and retention of conditioned aversions to context and taste in laboratory mice.

We compared the rate of acquisition and strength of retention of conditioned context aversion (CCA) with conditioned taste aversion (CTA) using pigmented, genetically heterogeneous mice (derived from Large and Small strains). Extending previous findings, in Experiment 1, mice accustomed to drinking from large glass bottles in the colony room learned to avoid graduated tubes after a single conditioning trial when drinking from these novel tubes was paired with injections of LiCl. The results also showed that CCA could be developed even when there was a 30-minute delay between conditioned stimulus and unconditioned stimulus. Retention of the aversion lasted for 4 weeks in both Immediate and Delay groups. Studies of conditioned saccharin aversion were conducted in Experiment 2. CTA acquisition was very similar to that observed in CCA and duration of aversion retention was similar in the CCA and CTA Delay groups, although at least 2 weeks longer in the Immediate group. Thus, CCA acquisition and retention characteristics are closer to those seen for CTA than has previously been reported. In Experiment 3, we examined whether albino mice (which are known to have weaker visual abilities compared to pigmented mice) would develop CCA comparable to those of pigmented mice. The development of conditioned aversion and its duration of retention was similar in albinos and pigmented mice. Nonspecific aversion emerged as an important contributor to strength of aversion during retention trials in both CCA and CTA paradigms with pigmented (but not albino) mice and deserves additional scrutiny in this field of inquiry.

Conditioned context aversion learning in the laboratory mouse.

It is well known that pairing of large contextual changes with illness can cause conditioned context aversion in laboratory rats. The aim of present study was to develop a paradigm to study this phenomenon in laboratory mice, a species widely employed in neurobehavioral studies. Genetically heterogeneous mice, drinking from plastic bottles in the colony room, learned to avoid glass bottles after a single conditioning trial when drinking from these was paired with injections of lithium chloride. The aversion was independent of any difference in the taste of water in plastic vs. glass bottles. When the variation in the visual stimulus was less distinct, development of a strong aversion required two conditioning trials and was not retained as well. The results also showed that conditioned context aversion, just like conditioned taste aversion, could also be developed across a 30-minute CS-UCS delay. The fact that taste was not a factor in distinguishing drinking from glass and plastic water bottles raises the possibility that, contextual stimuli, not taste, may have been the CS when rats (in Garcia's original experiments) avoided drinking from plastic bottles that had been paired with radiation. The development of contextual aversion conditioning protocols for mice will enable the molecular resources available for this species to be exploited. Furthermore, representation of the CS by discrete rather than the multimodal CSs typically used in most studies on contextual conditioning offers more focus when considering its neuroanatomical basis.