Exosomal miR-132-3p from Mesenchymal Stromal Cells Improve Synaptic Dysfunction and Cognitive Decline in Vascular Dementia

Background/Aims: Vascular dementia (VD) results in cognition and memory deficit. Exosomes and their carried microRNAs (miRs) contribute to the neuroprotective effects of mesenchymal stromal cells, and miR-132-3p plays a key role in neuron plasticity. Here we investigated the role and underlying mechanism of MSC EX and their miR-132-3p cargo in rescuing cognition and memory deficit in VD mice. Methods: Bilateral carotid artery occlusion was used to generate a VD mouse model. MiR-132-3p and MSC EX levels in the hippocampus and cortex were measured. At 24 h post-VD induction, mice were administered with MSC EX infected with control lentivirus (EXCon), pre-miR-132-3p-expressing lentivirus (EXmiR−132−3p), or miR-132-3p antago lentivirus (EXantagomiR−132−3p) intravenously. Behavioral and cognitive tests were performed and the mice were sacrificed in 21 days after VD. The effects of MSC EX on neuron number, synaptic plasticity, dendritic spine density, and Aβ and p-Tau levels in the hippocampus and cortex were determined. The effects of MSC EX on oxygen-glucose deprivation (OGD)-injured neurons with respect to apoptosis, and neurite elongation and branching were determined. Finally, the expression levels of Ras, phosphorylation of Akt, GSK-3β, and Tau were also measured. Results: Compared with normal mice, VD mice exhibited significantly decreased miR-132-3p and MSC EX levels in the cortex and hippocampus. Compared with EXCon treatment, the infusion of EXmiR−132−3p was more effective at improving cognitive function and increasing miR-132-3p level, neuron number, synaptic plasticity, and dendritic spine density, while decreasing Aβ and p-Tau levels in the cortex and hippocampus of VD mice. Conversely, EXantagomiR−132−3p treatment significantly decreased miR-132-3p expression in cortex and hippocampus, as well as attenuated EXmiR−132−3p treatment-induced functional improvement. In vitro, EXmiR−132−3p treatment inhibited RASA1 protein expression, but increased Ras and the phosphorylation of Akt and GSK-3β, and decreased p-Tau levels in primary neurons by delivering miR-132-3p, which resulted in reduced apoptosis, and increased neurite elongation and branching in OGD-injured neurons. Conclusions: Our studies suggest that miR-132-3p cluster-enriched MSC EX promotes the recovery of cognitive function by improving neuronal and synaptic dysfunction through activation of the Ras/Akt/GSK-3β pathway induced by downregulation of RASA1.

Seasonal changes in the hippocampal formation of hoarding and non-hoarding tits

The hippocampal formation (HF) processes spatial memories for cache locations in food-hoarding birds. Hoarding is a seasonal behavior, and seasonal changes in the HF have been described in some studies, but not in others. One potential reason is that birds may have been sampled during the seasonal hoarding peak in some studies, but not in others. In this study, we investigate the seasonal changes in hoarding and HF in willow tits (Poecile montanus). We compare this to seasonal changes in HF in a closely related non-hoarding bird, the great tit (Parus major). Willow tits near Oulu, Finland, show a seasonal hoarding peak in September and both HF volume and neuron number show a similar peak. HF neuronal density also increases in September, but then remains the same throughout winter. Unexpectedly, the great tit HF also changes seasonally, although in a different pattern: the great tit telencephalon increases in volume from July to August and decreases again in November. Great tit HF volume follows suit, but with a delay. Great tit HF neuron number and density also increase from August to September and stay high throughout winter. We hypothesize that seasonal changes in hoarding birds’ HF are driven by food-hoarding experience (e.g., the formation of thousands of memories). The seasonal changes in great tit brains may also be due to experience-dependent plasticity, responding to changes in the social and spatial environment. Large-scale experience-dependent neural plasticity is therefore probably not an adaptation of food-hoarding birds, but a general property of the avian HF and telencephalon.

Traip Mitotic Function Controls Brain Size

Microcephaly is a developmental failure to achieve proper brain size and neuron number. Mutations in diverse genes are linked to microcephaly, including several with DNA damage repair (DDR) functions; however, it is not well understood how these DDR gene mutations limit brain size. One such gene is TRAIP, which has multiple known functions in DDR. We characterized the Drosophila ortholog Traip, finding that loss of Traip causes a brain-specific defect in the Mushroom Body (MB). Traip mutant (traip-) MBs had reduced size and fewer neurons, but no neurodegeneration, consistent with human primary microcephaly disorders. Reduced neuron numbers in traip- were explained by premature caspase-dependent cell death of MB neuroblasts (MB-NBs). Many traip- MB-NBs had prominent chromosome bridges in anaphase, along with polyploidy, aneuploidy, or micronuclei. We found no evidence for an interphase DNA repair role for Traip in MB-NBs; instead, proper MB development requires Traip function during mitosis, where Traip localizes to centrosomes and mitotic spindles. Our results suggest that proper brain size is ensured by the recently described role for TRAIP in unloading stalled replication forks in mitosis, which suppresses DNA bridges and neural stem cell death to promote proper neuron number. Further, the mitotic nature of traip- MB-NB defects and Traip localization suggest a closer etiological link between DDR microcephaly genes like Traip and the centrosome/spindle-related genes more commonly associated with microcephaly.

Orexin/Hypocretin and Histamine Cross-Talk on Hypothalamic Neuron Counts in Mice

The loss of hypothalamic neurons that produce wake-promoting orexin (hypocretin) neuropeptides is responsible for narcolepsy type 1 (NT1). While the number of histamine neurons is increased in patients with NT1, results on orexin-deficient mouse models of NT1 are inconsistent. On the other hand, the effect of histamine deficiency on orexin neuron number has never been tested on mammals, even though histamine has been reported to be essential for the development of a functional orexin system in zebrafish. The aim of this study was to test whether histamine neurons are increased in number in orexin-deficient mice and whether orexin neurons are decreased in number in histamine-deficient mice. The hypothalamic neurons expressing L-histidine decarboxylase (HDC), the histamine synthesis enzyme, and those expressing orexin A were counted in four orexin knock-out mice, four histamine-deficient HDC knock-out mice, and four wild-type C57BL/6J mice. The number of HDC-positive neurons was significantly higher in orexin knock-out than in wild-type mice (2,502 ± 77 vs. 1,800 ± 213, respectively, one-tailed t-test, P = 0.011). Conversely, the number of orexin neurons was not significantly lower in HDC knock-out than in wild-type mice (2,306 ± 56 vs. 2,320 ± 120, respectively, one-tailed t-test, P = 0.459). These data support the view that orexin peptide deficiency is sufficient to increase histamine neuron number, supporting the involvement of the histamine waking system in the pathophysiology of NT1. Conversely, these data do not support a significant role of histamine in orexin neuron development in mammals.

Interactions between neuroanatomy, cognition, and ecology in Anolis lizards

The interactions between an organism and its environment are mediated by cognition, the substrates of which are in the brain. Cognition is ubiquitous across vertebrates, yet we still know very little about the factors shaping its evolution, particularly outside of birds and mammals. In natural environments, cognition likely impacts organism fitness. Behavioral flexibility, which enables an animal to modulate its behavior to match its environment, may facilitate success in novel habitats, such as in dispersal to islands, biotic invasions, and urban adaptation. Cognitive specializations may also be associated with specific ecological traits, such as habitat complexity. Furthermore, our understanding of the neural substrates of cognition in the brain is primarily limited to studies of relative brain size. The first chapter provides a more in depth introduction to these topics. In this dissertation, I explore the interactions between cognition, neuroanatomy, and ecology in Anolis lizards. Anolis lizards exhibit a diversity of habitat specializations, which is the result of adaptive radiation in the West Indies. As mentioned above, cognitive mechanisms in anoles may play a role in adjusting to novel environments and exploiting new niches. In the second chapter, I modified a detour task to evaluate whether wild, free-living Anolis sagrei can solve a novel detour problem under natural conditions. In the second chapter, I compare the neuron and nonneuron number and density of Anolis cristatellus and Anolis evermanni to see whether differences in neuroanatomy reflect their differential performance on an extractive foraging task. I also explore how these data relate to published observations from other vertebrates. Finally, in the fourth chapter I expand upon two previous studies by evaluating whether neuron number follows the predictions of concerted or mosaic evolution in five species of Puerto Rican Anolis and whether habitat complexity explains differences in neuron density between species. I conclude in the final chapter by summarizing my results and outlining future directions. Taken together, the results presented in this dissertation demonstrate the potential for studying cognition and neuroanatomy in an evolutionary context. The methods applied in my second chapter can be used in the future to explore the connection between cognition and fitness in lizards, which are a tractable model for such studies under natural conditions. My third and fourth chapters took a novel approach by studying neuroanatomical differences between species in neuron number and density, and generated novel insights into brain evolution in Anolis. By studying cognition and the brain in lizards and other ectotherms, we can begin to finally understand factors shaping the evolution of cognition and neuroanatomy across vertebrates.

Increased cortical volume without increased neuron number in heterozygous Chd8 mutant mouse cortex

De novo mutations in the chromatin-remodeling factor CHD8 (Chromodomain-Helicase DNA-binding protein 8) have emerged as a key genetic risk factor for Autism Spectrum Disorder (ASD) and, more generally, neurodevelopmental disorders. Individuals with heterozygous mutations in CHD8 typically present hallmarks of ASD with comorbid cognitive disability and macrocephaly. Knockdown or haploinsufficiency of Chd8 in animal models has recapitulated phenotypes observed in patients, including increased head circumference and brain size. Here, we aimed to determine whether increased neuron numbers or soma size drives increased cortical volume. We performed design-based stereological analyses of cortical structure in adult male and female heterozygous Chd8 mice and wild-type littermate controls. Chd8 haploinsufficient male mice displayed a ~8-12% increase in cortical volume, no differences in cortical neuron number and comparable neuronal soma size. Our study reproduced previous reports of increased brain size associated with CHD8 mutation in humans and mice and are consistent with reported sex-specific impacts of Chd8 mutations in mice and increased burden of CHD8 mutations in human males with ASD. These findings suggest that the nature of the cortical enlargement due to Chd8 haploinsufficiency is complex and appears to be due to a factor other than an increased neuron number or soma size.Lay SummaryWe measured the size and neuron number in the neocortex in mice with heterozygous Chd8 mutation, a model relevant to Autism Spectrum Disorder. We found an increased cortical volume in male mutants, which was not accompanied by increased neuron number or soma size. Our results indicate that the enlarged brain in Chd8 mutant mice is complex, more evident here in males, and is due to factors other than increased neuron number.

Antioxidant Blend of Curcumin and Broccoli Seed Extract Exhibits Protective Effect on Neurodegeneration and Promotes Drosophila Lifespan

Antioxidants and related compounds are anti-inflammatory and exhibit great potential in promoting human health. They are also often considered to be important elements in the process of neurodegeneration. Here we describe a antioxidant blend of Curcumin and Broccoli Seed Extract (BSE). Flies treated with the blend exhibit extended lifespan. RNA-seq analysis of samples from adult fly brains reveals a wide array of new genes with differential expression upon treatment with the blend. Interestingly, abolishing expression of some of the identified genes in dopaminergic (DA) neurons does not affect DA neuron number. Taken together, our findings reveal an antioxidant blend that promotes fly longevity and exhibits protective effect over neurodegeneration, demonstrating the importance of antioxidants in health and pathology.

The evidence for the influence of musical compositions during pregnancy to the structure and functions of the offsprings’ brain

Objective: to compile studies in Surabaya on the effect of Mozart compositions during pregnancy on the number of the offsprings brain neuron, glia, BDNF, apoptotic neurons and, neuronal dendritic density. These series of studies aimed to develop environmental-enrichment model during pregnancy so we can have better brain for the next generation. Better brain means better capacity in processing information, solving the problems, and creating new solutions that depends on the number of neuron, glia, ratio glia/ neuron and synapses. We do believe in the motto of “From Neurons to Nation” Overview: There were 38 studies, in animal models except two in human subjects, all of them with control, prospective, and randomized. The first group consist of analyze the frequency, sequence, time, duration, gestational age, distant, and intensity of Mozart composition. The second group: try to analyze the mechanism and compare with variety of other compositions including other western music(Chopin, Beethoven, Blues, Jazz, Rock) and Indonesian music(Gamelan Jawa, Sunda, Bali, Pop, Religious). The third group: combine with nutrition, reverse sequence, involving cerebrum and cerebellum, and right-left hemisphere. There were no growth restricted, dead, and malformed offsprings in both groups. The BDNF expression, synapsin I expression, the number of neuron, number of glia, and dendritic density of the exposed groups were higher than control. The neuronal apoptotic index were lower in the exposed groupsConclusions: Mozart compositions during pregnancy increased the BDNF, synapsin I, number of neuron, number of glia, dendritic density and, also decreased the neuronal apoptosis in offsprings’ brain