The development and evolution of inhibitory neurons in primate cerebrum.

Neuroanatomists have long speculated that expanded primate brains contain an increased morphological diversity of inhibitory neurons (INs)1, and recent studies have identified primate-specific neuronal populations at the molecular level2. However, we know little about the developmental mechanisms that specify evolutionarily novel cell types in the brain. Here, we reconstruct gene expression trajectories specifying INs generated throughout the neurogenic period in macaques and mice by analysing the transcriptomes of 250,181 cells. We find that the initial classes of INs generated prenatally are largely conserved among mammals. Nonetheless, we identify two contrasting developmental mechanisms for specifying evolutionarily novel cell types during prenatal development. First, we show that recently identified primate-specific TAC3 striatal INs are specified by a unique transcriptional programme in progenitors followed by induction of a distinct suite of neuropeptides and neurotransmitter receptors in new-born neurons. Second, we find that multiple classes of transcriptionally conserved olfactory bulb (OB)-bound precursors are redirected to expanded primate white matter and striatum. These classes include a novel peristriatal class of striatum laureatum neurons that resemble dopaminergic periglomerular cells of the OB. We propose an evolutionary model in which conserved initial classes of neurons supplying the smaller primate OB are reused in the enlarged striatum and cortex. Together, our results provide a unified developmental taxonomy of initial classes of mammalian INs and reveal multiple developmental mechanisms for neural cell type evolution.

Individual differences in amygdala volumes predict changes in functional connectivity between subcortical and cognitive control networks throughout adolescence.

Adolescence is a critical period of structural and functional neural maturation among regions serving the cognitive control of emotion. Evidence suggests that this process is guided by developmental changes in amygdala and striatum structure and shifts in functional connectivity between subcortical (SC) and cognitive control (CC) networks. Herein, we investigate the extent to which such developmental shifts in structure and function reciprocally predict one another over time. 179 youth (9-15 years-old) completed annual MRI scans for three years. Amygdala and striatum volumes and connectivity within and between SC and CC resting state networks were measured for each year. We tested for reciprocal predictability of within-person and between-person changes in structure and function using random-intercept cross-lagged panel models. Within-person shifts in amygdala volumes in a given year significantly and specifically predicted deviations in SC-CC connectivity in the following year, such that an increase in volume was associated with decreased SC-CC connectivity the following year. Deviations in connectivity did not predict changes in amygdala volumes over time. Conversely, broader group-level shifts in SC-CC connectivity were predictive of subsequent deviations in striatal volumes. We did not see any cross-predictability among amygdala or striatum volumes and within-network connectivity measures. Within-person shifts in amygdala structure year-to-year robustly predicted weaker SC-CC connectivity in subsequent years, whereas broader increases in SC-CC connectivity predicted smaller striatal volumes over time. These specific structure function relationships may contribute to the development of emotional control across adolescence.

Quantitative trait locus mapping identifies a locus linked to striatal dopamine and points to collagen IV alpha-6 chain as a novel regulator of striatal axonal branching in mice.

Dopaminergic neurons (DA neurons) are controlled by multiple factors, many involved in neurological disease. Parkinson's disease motor symptoms are caused by the demise of nigral DA neurons, leading to loss of striatal dopamine (DA). Here, we measured DA concentration in the dorsal striatum of 32 members of Collaborative Cross (CC) family and their eight founder strains. Striatal DA varied greatly in founders, and differences were highly heritable in the inbred CC progeny. We identified a locus, containing 164 genes, linked to DA concentration in the dorsal striatum on chromosome X. We used RNAseq profiling of the ventral midbrain of two founders with substantial difference in striatal DA-C56BL/6 J and A/J-to highlight potential protein-coding candidates modulating this trait. Among the five differentially expressed genes within the locus, we found that the gene coding for the collagen IV alpha 6 chain (Col4a6) was expressed nine times less in A/J than in C57BL/6J. Using single cell RNA-seq data from developing human midbrain, we found that COL4A6 is highly expressed in radial glia-like cells and neuronal progenitors, indicating a role in neuronal development. Collagen IV alpha-6 chain (COL4A6) controls axogenesis in simple model organisms. Consistent with these findings, A/J mice had less striatal axonal branching than C57BL/6J mice. We tentatively conclude that DA concentration and axonal branching in dorsal striatum are modulated by COL4A6, possibly during development. Our study shows that genetic mapping based on an easily measured Central Nervous System (CNS) trait, using the CC population, combined with follow-up observations, can parse heritability of such a trait, and nominate novel functions for commonly expressed proteins.

Neurodevelopment of the incentive network facilitates motivated behaviour from adolescence to adulthood.

The ability to enhance motivated performance through incentives is crucial to guide and ultimately optimise the outcome of goal-directed behaviour. It remains largely unclear how motivated behaviour and performance develops particularly across adolescence. Here, we used computational fMRI to assess how response speed and its underlying neural circuitry are modulated by reward and loss in a monetary incentive delay paradigm. We demonstrate that maturational fine-tuning of functional coupling within the cortico-striatal incentive circuitry from adolescence to adulthood facilitates the ability to enhance performance selectively for higher subjective values. Additionally, during feedback, we found developmental sex differences of striatal representations of reward prediction errors in an exploratory analysis. Our findings suggest that a reduced capacity to utilise subjective value for motivated behaviour in adolescence is rooted in immature information processing in the incentive system. This indicates that the neurocircuitry for coordination of incentivised, motivated cognitive control acts as a bottleneck for behavioural adjustments in adolescence.

Cellular-resolution gene expression profiling in the neonatal marmoset brain reveals dynamic species- and region-specific differences.

Precise spatiotemporal control of gene expression in the developing brain is critical for neural circuit formation, and comprehensive expression mapping in the developing primate brain is crucial to understand brain function in health and disease. Here, we developed an unbiased, automated, large-scale, cellular-resolution in situ hybridization (ISH)-based gene expression profiling system (GePS) and companion analysis to reveal gene expression patterns in the neonatal New World marmoset cortex, thalamus, and striatum that are distinct from those in mice. Gene-ontology analysis of marmoset-specific genes revealed associations with catalytic activity in the visual cortex and neuropsychiatric disorders in the thalamus. Cortically expressed genes with clear area boundaries were used in a three-dimensional cortical surface mapping algorithm to delineate higher-order cortical areas not evident in two-dimensional ISH data. GePS provides a powerful platform to elucidate the molecular mechanisms underlying primate neurobiology and developmental psychiatric and neurological disorders.

Increased wiring cost during development is driven by long-range cortical, but not subcortical connections.

The brain undergoes a protracted, metabolically expensive maturation process from childhood to adulthood. Therefore, it is crucial to understand how network cost is distributed among different brain systems as the brain matures. To address this issue, here we examined developmental changes in wiring cost and brain network topology using resting-state functional magnetic resonance imaging (rsfMRI) data longitudinally collected in awake rats from the juvenile age to adulthood. We found that the wiring cost increased in the vast majority of cortical connections but decreased in most subcortico-subcortical connections. Importantly, the developmental increase in wiring cost was dominantly driven by long-range cortical, but not subcortical connections, which was consistent with more pronounced increase in network integration in the cortical network. These results collectively indicate that there is a non-uniform distribution of network cost as the brain matures, and network resource is dominantly consumed for the development of the cortex, but not subcortex from the juvenile age to adulthood.

Heterogeneity in brain functional changes of cognitive processing in ADHD across age: A systematic review of task-based fMRI studies.

This review aims to establish the cognitive processing of patients with attention-deficit hyperactive disorder (ADHD) across age. Functional magnetic resonance imaging (fMRI) studies on children and adult populations were conducted, thus delineating deficits that could have been maintained and ameliorated across age. This allowed for the examination of the correlation between patterns of brain activation and the corresponding development of functional heterogeneity in ADHD. A systematic literature search of fMRI studies on ADHD was conducted using the PubMed and Scopus electronic databases based on PRISMA guidelines. References and citations were verified in Scopus database. The present study has identified 14 studies on children, 16 studies on adults, and one study on both populations of ADHD consisting of 1371 participants. Functional heterogeneity is present in ADHD across age, which can manifest either as different brain activation patterns, intra-subject variability, or both. This is shown in the increased role of the frontal regions and the specialized network in adults with ADHD from inefficient non-specific activation in childhood. Functional heterogeneity may manifest when delayed maturation is insufficient to normalize frontal lobe functions.

VGluT2 Expression in Dopamine Neurons Contributes to Postlesional Striatal Reinnervation.

A subset of adult ventral tegmental area dopamine (DA) neurons expresses vesicular glutamate transporter 2 (VGluT2) and releases glutamate as a second neurotransmitter in the striatum, while only few adult substantia nigra DA neurons have this capacity. Recent work showed that cellular stress created by neurotoxins such as MPTP and 6-hydroxydopamine can upregulate VGluT2 in surviving DA neurons, suggesting the possibility of a role in cell survival, although a high level of overexpression could be toxic to DA neurons. Here we examined the level of VGluT2 upregulation in response to neurotoxins and its impact on postlesional plasticity. We first took advantage of an in vitro neurotoxin model of Parkinson's disease and found that this caused an average 2.5-fold enhancement of Vglut2 mRNA in DA neurons. This could represent a reactivation of a developmental phenotype because using an intersectional genetic lineage-mapping approach, we find that >98% of DA neurons have a VGluT2+ lineage. Expression of VGluT2 was detectable in most DA neurons at embryonic day 11.5 and was localized in developing axons. Finally, compatible with the possibility that enhanced VGluT2 expression in DA neurons promotes axonal outgrowth and reinnervation in the postlesional brain, we observed that DA neurons in female and male mice in which VGluT2 was conditionally removed established fewer striatal connections 7 weeks after a neurotoxin lesion. Thus, we propose here that the developmental expression of VGluT2 in DA neurons can be reactivated at postnatal stages, contributing to postlesional plasticity of dopaminergic axons.SIGNIFICANCE STATEMENT A small subset of dopamine neurons in the adult, healthy brain expresses vesicular glutamate transporter 2 (VGluT2) and thus releases glutamate as a second neurotransmitter in the striatum. This neurochemical phenotype appears to be plastic as exposure to neurotoxins, such as 6-OHDA or MPTP, that model certain aspects of Parkinson's disease pathophysiology, boosts VGluT2 expression in surviving dopamine neurons. Here we show that this enhanced VGluT2 expression in dopamine neurons drives axonal outgrowth and contributes to dopamine neuron axonal plasticity in the postlesional brain. A better understanding of the neurochemical changes that occur during the progression of Parkinson's disease pathology will aid the development of novel therapeutic strategies for this disease.

Striatal circuit development and its alterations in Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder that usually starts during midlife with progressive alterations of motor and cognitive functions. The disease is caused by a CAG repeat expansion within the huntingtin gene leading to severe striatal neurodegeneration. Recent studies conducted on pre-HD children highlight early striatal developmental alterations starting as soon as 6 years old, the earliest age assessed. These findings, in line with data from mouse models of HD, raise the questions of when during development do the first disease-related striatal alterations emerge and whether they contribute to the later appearance of the neurodegenerative features of the disease. In this review we will describe the different stages of striatal network development and then discuss recent evidence for its alterations in rodent models of the disease. We argue that a better understanding of the striatum's development should help in assessing aberrant neurodevelopmental processes linked to the HD mutation.

Neural Stem Cells Direct Axon Guidance via Their Radial Fiber Scaffold.

Neural stem cells directly or indirectly generate all neurons and macroglial cells and guide migrating neurons by using a palisade-like scaffold made of their radial fibers. Here, we describe an unexpected role for the radial fiber scaffold in directing corticospinal and other axons at the junction between the striatum and globus pallidus. The maintenance of this scaffold, and consequently axon pathfinding, is dependent on the expression of an atypical RHO-GTPase, RND3/RHOE, together with its binding partner ARHGAP35/P190A, a RHO GTPase-activating protein, in the radial glia-like neural stem cells within the ventricular zone of the medial ganglionic eminence. This role is independent of RND3 and ARHGAP35 expression in corticospinal neurons, where they regulate dendritic spine formation, axon elongation, and pontine midline crossing in a FEZF2-dependent manner. The prevalence of neural stem cell scaffolds and their expression of RND3 and ARHGAP35 suggests that these observations might be broadly relevant for axon guidance and neural circuit formation.

Histaminergic Control of Corticostriatal Synaptic Plasticity during Early Postnatal Development.

A reduction in the synthesis of the neuromodulator histamine has been associated with Tourette's syndrome and obsessive-compulsive disorder. Symptoms of these disorders are thought to arise from a dysfunction or aberrant development ofcorticostriatal circuits. Here, we investigated how histamine affects developing corticostriatal circuits, both acutely and longer-term, during the first postnatal weeks, using patch-clamp and field recordings in mouse brain slices (C57Bl/6, male and female). Immunohistochemistry for histamine-containing axons reveals striatal histaminergic innervation by the second postnatal week, and qRT-PCR shows transcripts for H1, H2, and H3 histamine receptors in striatum from the first postnatal week onwards, with pronounced developmental increases in H3 receptor expression. Whole-cell patch-clamp recordings of striatal spiny projection neurons and histamine superfusion demonstrates expression of functional histamine receptors from the first postnatal week onwards, with histamine having diverse effects on their electrical properties, including depolarization of the membrane potential while simultaneously decreasing action potential output. Striatal field recordings and electrical stimulation of corticostriatal afferents revealed that histamine, acting at H3 receptors, negatively modulates corticostriatal synaptic transmission from the first postnatal week onwards. Last, we investigated effects of histamine on longer-term changes at developing corticostriatal synapses and show that histamine facilitates NMDA receptor-dependent LTP via H3 receptors during the second postnatal week, but inhibits synaptic plasticity at later developmental stages. Together, these results show that histamine acutely modulates developing striatal neurons and synapses and controls longer-term changes in developing corticostriatal circuits, thus providing insight into the possible etiology underlying neurodevelopmental disorders resulting from histamine dysregulation.SIGNIFICANCE STATEMENT Monogenic causes of neurologic disorders, although rare, can provide opportunities to both study and understand the brain. For example, a nonsense mutation in the coding gene for the histamine-synthesizing enzyme has been associated with Tourette's syndrome and obsessive-compulsive disorder, and dysfunction of corticostriatal circuits. Nevertheless, the etiology of these neurodevelopmental disorders and histamine's role in the development of corticostriatal circuits have remained understudied. Here we show that histamine is an active neuromodulator during the earliest periods of postnatal life and acts at developing striatal neurons and synapses. Crucially, we show that histamine permits NMDA receptor-dependent corticostriatal synaptic plasticity during an early critical period of postnatal development, which suggests that genetic or environmental perturbations of histamine levels can impact striatal development.

Nolz1 expression is required in dopaminergic axon guidance and striatal innervation.

Midbrain dopaminergic (DA) axons make long longitudinal projections towards the striatum. Despite the importance of DA striatal innervation, processes involved in establishment of DA axonal connectivity remain largely unknown. Here we demonstrate a striatal-specific requirement of transcriptional regulator Nolz1 in establishing DA circuitry formation. DA projections are misguided and fail to innervate the striatum in both constitutive and striatal-specific Nolz1 mutant embryos. The lack of striatal Nolz1 expression results in nigral to pallidal lineage conversion of striatal projection neuron subtypes. This lineage switch alters the composition of secreted factors influencing DA axonal tract formation and renders the striatum non-permissive for dopaminergic and other forebrain tracts. Furthermore, transcriptomic analysis of wild-type and Nolz1-/- mutant striatal tissue led to the identification of several secreted factors that underlie the observed guidance defects and proteins that promote DA axonal outgrowth. Together, our data demonstrate the involvement of the striatum in orchestrating dopaminergic circuitry formation.

Abnormal development of cerebellar-striatal circuitry in Huntington disease.

OBJECTIVE: To test the hypothesis that the trajectory of functional connections over time of the striatum and the cerebellum differs between presymptomatic patients with the Huntington disease (HD) gene expansion (GE) and patients with a family history of HD but without the GE (GNE), we evaluated functional MRI data from the Kids-HD study. METHODS: We utilized resting-state, functional MRI data from participants in the Kids-HD study between 6 and 18 years old. Participants were divided into GE (CAG 36-59) and GNE (CAG <36) groups. Seed-to-seed correlations were calculated among 4 regions that provide input signals to the anterior cerebellum: (1) dorsocaudal putamen, (2) globus pallidus externa, (3) subthalamic nucleus, and (4) pontine nuclei; and 2 regions that represented output from the cerebellum: the dentate nucleus to the (1) ventrolateral thalamus and (2) dorsocaudal putamen. Linear mixed effects regression models evaluated differences in developmental trajectories of these connections over time between groups. RESULTS: Four of the six striatal-cerebellum correlations showed significantly different trajectories between groups. All showed a pattern where in the early age ranges (6-12 years) there was hyperconnectivity in the GE compared to the GNE, with those trajectories showing linear decline in the latter half of the age range. CONCLUSION: These results parallel previous findings showing striatal hypertrophy in children with GE as early as age 6. These findings support the notion of developmentally higher connectivity between the striatum and cerebellum early in the life of the child with HD GE, possibly setting the stage for cerebellar compensatory mechanisms.

Single-Cell Analysis of Foxp1-Driven Mechanisms Essential for Striatal Development.

The striatum is a critical forebrain structure integrating cognitive, sensory, and motor information from diverse brain regions into meaningful behavioral output. However, the transcriptional mechanisms underlying striatal development at single-cell resolution remain unknown. Using single-cell RNA sequencing (RNA-seq), we examine the cellular diversity of the early postnatal striatum and show that Foxp1, a transcription factor strongly linked to autism and intellectual disability, regulates the cellular composition, neurochemical architecture, and connectivity of the striatum in a cell-type-dependent fashion. We also identify Foxp1-regulated target genes within distinct cell types and connect these molecular changes to functional and behavioral deficits relevant to phenotypes described in patients with FOXP1 loss-of-function mutations. Using this approach, we could also examine the non-cell-autonomous effects produced by disrupting one cell type and the molecular compensation that occurs in other populations. These data reveal the cell-type-specific transcriptional mechanisms regulated by Foxp1 that underlie distinct features of striatal circuitry.

Maturation of the human striatal dopamine system revealed by PET and quantitative MRI.

The development of the striatum dopamine (DA) system through human adolescence, a time of increased sensation seeking and vulnerability to the emergence of psychopathology, has been difficult to study due to pediatric restrictions on direct in vivo assessments of DA. Here, we applied neuroimaging in a longitudinal sample of n = 146 participants aged 12-30. R2', an MR measure of tissue iron which co-localizes with DA vesicles and is necessary for DA synthesis, was assessed across the sample. In the 18-30 year-olds (n = 79) we also performed PET using [11C]dihydrotetrabenazine (DTBZ), a measure of presynaptic vesicular DA storage, and [11C]raclopride (RAC), an indicator of D2/D3 receptor availability. We observed decreases in D2/D3 receptor availability with age, while presynaptic vesicular DA storage (as measured by DTBZ), which was significantly associated with R2' (standardized coefficient = 0.29, 95% CI = [0.11, 0.48]), was developmentally stable by age 18. Our results provide new evidence for maturational specialization of the striatal DA system through adolescence.

Regular Aerobic Exercise-Alleviated Dysregulation of CAMKIIα Carbonylation to Mitigate Parkinsonism via Homeostasis of Apoptosis With Autophagy.

This study investigated carbonylation of proteins with oxidative modification profiling in the striatum of aging and Parkinson disease (PD) rats, as well as the long-term effects of regular aerobic exercise on the carbonylation process and the damaging effects of PD vs habitual sedentary behavior. Regular aerobic exercise improved the PD rats' rotational behavior, increased tyrosine hydroxylase expression in both the striatum and substantia nigra pars compacta, and decreased α-synuclein expression significantly. Interestingly, apoptotic nuclei and autophagosomes were increased in the aerobic exercise PD rat striatum. Carbonylated protein Ca2+/calmodulin-dependent protein kinase alpha (CAMKIIα) was present in the middle-aged and aged groups but only in the sedentary, not the exercise, PD rat striatum. Notably, CAMKIIα was characterized by a 4-hydroxynonenal adduct. Regular aerobic exercise upregulated CAMKIIα expression level, activated the CAMK signaling pathway, and promoted the expression of autophagy markers Beclin1 and microtubule-associated proteins 1 A/1B light chain 3II. Aberrant carbonylation of CAMKII initiated age-related changes and might be useful as a potential biomarker of PD. Regular aerobic exercise alleviated protein carbonylation modification of CAMKIIα and regulated the CAMK signaling pathway, thereby affecting and regulating the homeostasis of apoptosis and autophagy in the striatum to alleviate the neurodegenerative process of PD lesions.

Huntington's disease associated resistance to Mn neurotoxicity is neurodevelopmental stage and neuronal lineage dependent.

Manganese (Mn) is essential for neuronal health but neurotoxic in excess. Mn levels vary across brain regions and neurodevelopment. While Mn requirements during infanthood and childhood are significantly higher than in adulthood, the relative vulnerability to excess extracellular Mn across human neuronal developmental time and between distinct neural lineages is unknown. Neurological disease is associated with changes in brain Mn homeostasis and pathology associated with Mn neurotoxicity is not uniform across brain regions. For example, mutations associated with Huntington's disease (HD) decrease Mn bioavailability and increase resistance to Mn cytotoxicity in human and mouse striatal neuronal progenitors. Here, we sought to compare the differences in Mn cytotoxicity between control and HD human-induced pluripotent stem cells (hiPSCs)-derived neuroprogenitor cells (NPCs) and maturing neurons. We hypothesized that there would be differences in Mn sensitivity between lineages and developmental stages. However, we found that the different NPC lineage specific media substantially influenced Mn cytotoxicity in the hiPSC derived human NPCs and did so consistently even in a non-human cell line. This limited the ability to determine which human neuronal sub-types were more sensitive to Mn. Nonetheless, we compared within neuronal subtypes and developmental stage the sensitivity to Mn cytotoxicity between control and HD patient derived neuronal lineages. Consistent with studies in other striatal model systems the HD genotype was associated with resistance to Mn cytotoxicity in human striatal NPCs. In addition, we report an HD genotype-dependent resistance to Mn cytotoxicity in cortical NPCs and hiPSCs. Unexpectedly, the HD genotype conferred increased sensitivity to Mn in early post-mitotic midbrain neurons but had no effect on Mn sensitivity in midbrain NPCs or post-mitotic cortical neurons. Overall, our data suggest that sensitivity to Mn cytotoxicity is influenced by HD genotype in a human neuronal lineage type and stage of development dependent manner.

Neuropilin 2 Signaling Mediates Corticostriatal Transmission, Spine Maintenance, and Goal-Directed Learning in Mice.

The striatum represents the main input structure of the basal ganglia, receiving massive excitatory input from the cortex and the thalamus. The development and maintenance of cortical input to the striatum is crucial for all striatal function including many forms of sensorimotor integration, learning, and action control. The molecular mechanisms regulating the development and maintenance of corticostriatal synaptic transmission are unclear. Here we show that the guidance cue, Semaphorin 3F and its receptor Neuropilin 2 (Nrp2), influence dendritic spine maintenance, corticostriatal short-term plasticity, and learning in adult male and female mice. We found that Nrp2 is enriched in adult layer V pyramidal neurons, corticostriatal terminals, and in developing and adult striatal spiny projection neurons (SPNs). Loss of Nrp2 increases SPN excitability and spine number, reduces short-term facilitation at corticostriatal synapses, and impairs goal-directed learning in an instrumental task. Acute deletion of Nrp2 selectively in adult layer V cortical neurons produces a similar increase in the number of dendritic spines and presynaptic modifications at the corticostriatal synapse in the Nrp2-/- mouse, but does not affect the intrinsic excitability of SPNs. Furthermore, conditional loss of Nrp2 impairs sensorimotor learning on the accelerating rotarod without affecting goal-directed instrumental learning. Collectively, our results identify Nrp2 signaling as essential for the development and maintenance of the corticostriatal pathway and may shed novel insights on neurodevelopmental disorders linked to the corticostriatal pathway and Semaphorin signaling.SIGNIFICANCE STATEMENT The corticostriatal pathway controls sensorimotor, learning, and action control behaviors and its dysregulation is linked to neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here we demonstrate that Neuropilin 2 (Nrp2), a receptor for the axon guidance cue semaphorin 3F, has important and previously unappreciated functions in the development and adult maintenance of dendritic spines on striatal spiny projection neurons (SPNs), corticostriatal short-term plasticity, intrinsic physiological properties of SPNs, and learning in mice. Our findings, coupled with the association of Nrp2 with ASD in human populations, suggest that Nrp2 may play an important role in ASD pathophysiology. Overall, our work demonstrates Nrp2 to be a key regulator of corticostriatal development, maintenance, and function, and may lead to better understanding of neurodevelopmental disease mechanisms.

Characterization of Neurodevelopmental Abnormalities in iPSC-Derived Striatal Cultures from Patients with Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is an inherited neurodegenerative disease and is characterized by atrophy of certain regions of the brain in a progressive manner. HD patients experience behavioral changes and uncontrolled movements which can be primarily attributed to the atrophy of striatal neurons. Previous publications describe the models of the HD striatum using induced pluripotent stem cells (iPSCs) derived from HD patients with a juvenile onset (JHD). In this model, the JHD iPSC-derived striatal cultures had altered neurodevelopment and contained a high number of nestin expressing progenitor cells at 42 days of differentiation. OBJECTIVE: To further characterize the altered neurodevelopmental phenotype and evaluate potential phenotypic reversal. METHODS: Differentiation of human iPSCs towards striatal fate and characterization by means of immunocytochemistry and stereological quantification. RESULTS: Here this study demonstrates a distinct delay in the differentiation of the JHD neural progenitor population. However, reduction of the JHD aberrant progenitor populations can be accomplished either by targeting the canonical Notch signaling pathway or by treatment with HTT antisense oligonucleotides (ASOs). CONCLUSIONS: In summary, this data is postulated to reflect a potential overall developmental delay in JHD.

The balance of apoptosis and autophagy via regulation of the AMPK signal pathway in aging rat striatum during regular aerobic exercise.

The objective was to analyze the effects of aerobic exercise on aging striatum stress resistance, and the adaptive mechanisms related to neurodegenerative diseases, and the occurrence, and development of neural degeneration. The 10-weeks of regular moderate-intensity aerobic exercise intervention were carried out in the aerobic exercise runner Sprague-Dawley rats. Apoptotic nuclei appeared in the striatum of aged rats, showing a tendency to relate to aging. The apoptotic index of the striatum in young, middle-aged, and old-aged rats of the aerobic exercise groups increased by 205.56%, 57%, and 68.24%. Autophagy markers Beclin l and LC 3-II expression, AMPKα1 and pAMPKα1 expression increased significantly in all age-exercise groups. The ratio of AMPKα1/pAMPKα1 increased after exercise, and the tendency of exercise to alter autophagy and cell apoptosis increased with aging. Then SirT2 mRNA was significantly upregulated in the aerobic exercise runner groups. In conclusion, we showed that the balance of autophagy and apoptosis were closely regulated by regular aerobic exercise, which affected the development of aging, and via regulation of the AMPK/SirT2 signaling pathway.