BACKGROUND:Neuro-related proteins are promising biomarkers and therapeutic targets for Parkinson's disease (PD), yet their specific roles remain uncertain. METHODS:We conducted Mendelian randomisation by integrating protein quantitative trait loci with genome-wide association study data from 33,647 patients with PD and 449,056 controls for risk, 28,568 patients for age at onset (AAO), and 4093 patients for progression. Subsequent analyses included genetic colocalisation, protein-protein interaction, functional enrichment, tissue and cell-specific expression profiling, and druggability assessment. In an case-control study (30 patients with PD, 14 controls), plasma neuro-related proteins were measured using the Olink platform. FINDINGS:59 neuro-related proteins were associated with PD: 4 (CLEC1B, IL5RA, SNCG, CDH17) associated with risk, 7 with AAO, and 58 with progression. Colocalisation supported shared variants for TDGF1, PVR, and IL5RA with the progression. 47 proteins were evaluated as druggable targets. Pathway analysis highlighted cytokine-receptor interactions, neuroimmune modulation, and axon guidance. BMP-4, DDR1, GDNF, LAT, and MANF were found to be differentially expressed in patients with PD and correlated with the symptom severity. INTERPRETATION:This integrative genetic-proteomic-clinical framework identifies neuro-related proteins significantly associated with PD, offering mechanistic insights and prioritising therapeutic targets. FUNDING:National Natural Science Foundation of China (NO: U24A20694, NO: 82471433), and Scientific Research Foundation of Guangzhou (NO: 202206010005) to QW; and National Natural Science Foundation of China (NO: 82401641) to BD; and Basic and Applied Basic Research of Guangdong (NO: 2025A1515012456) to WLY; and Ministry of Education Academic Research Fund Tier 1 (RG111/24) to JNF; and National Medical Research Council grants to EKT.

Epidemiological studies have shown developmental vitamin D (DVD)-deficiency increases the risk of later onset of schizophrenia, and animal models reveal that DVD-deficiency impairs dopaminergic neuron maturation. In contrast, vitamin D treatment promotes dopaminergic neuron differentiation in cellular models. Vitamin D also modulates DNA methylation. This study investigates whether maternal vitamin D status influences differentiation of the dopamine-rich ventral mesencephalon via this epigenetic process.Mesencephalon was examined from both DVD-deficient rat dams at gestational day (GD) 14 and dams to which the active form of vitamin D was administered at GD 13. We show that from a panel of DNA methylation or demethylation enzymes, DVD-deficiency increased, whilst vitamin D decreased DNMT3A expression. We then examined the effects of increasing or decreasing DNMT3A on dopaminergic and cell cycle-related genes in mesencephalic neural cultures. DNMT3A overexpression reduced expression of cyclin D1 (CCND1) and CDKN1A (P21), while silencing DNMT3A increased expression of these important cell-cycling genes. Methylation analysis of the promoters of these genes revealed heightened cytosine methylation (5mC) at CCND1 and CDKN1A promoters in DVD-deficient embryos, but vitamin D treatment had no direct impact on these methylation patterns.We conclude that DVD-deficiency’s adverse effects on early brain development may be due to heightened methylation of important cell cycle genes via increased DNMT3A. Although the active form of vitamin D decreased DNMT3A expression in utero, the absence of any silencing effect on these same cell cycle genes suggests this hormone may affect early brain differentiation via more direct transcriptional regulatory pathways via its canonical receptor.

Circadian disturbances are implicated in dysregulation of arousal and general neurobiological function, contributing to conditions such as bipolar disorder (BD). However, the behavioural and biological consequences of circadian disruption on arousal dysfunction remain poorly quantified. Here, we developed a novel unpredictable circadian disruption (UCD) protocol – consisting of unpredictable exposure to light and sound – to investigate its impact on locomotor activity and its association with metabolic, inflammatory, stress, and circadian markers in the nucleus accumbens (NAc). Forty-eight Wistar rats were exposed to UCD or control conditions, with or without corticosterone administration, for five weeks. Body weight was tracked throughout the study. Locomotor activity was assessed over the final two weeks (nine sessions) in an open-field arena. Real-time PCR was used to quantify NAc gene expression of inflammatory, metabolic, stress, and circadian markers, while liquid chromatography-mass spectrometry (LC-MS) measured neurotransmitter and central carbon metabolite concentrations. UCD animals exhibited initial hyperactivity at three weeks, followed by hypoactivity at four weeks. UCD was associated with increased NAc expression of inflammatory, stress, and circadian markers. Male UCD animals showed significant weight gain, an effect reversed in females. UCD also induced increases in NAc insulin resistance markers and reductions in central carbon metabolites, indicating disrupted striatal glucose metabolism. These findings highlight the central effects of circadian disruption on locomotor behaviour, stress, and immunometabolic signalling, offering mechanistic insights into arousal dysfunction in BD. Highlights: ### Competing Interest Statement The authors have declared no competing interest. The University of Queensland, https://ror.org/00rqy9422, Research Training Program stipend and tuition fee offset scholarship

Melatonin has emerged as a promising pharmacological candidate for bipolar disorder (BD), though its mechanisms of action remain incompletely understood. Its antioxidant, anti-inflammatory, and anti-dopaminergic properties suggest potential relevance to BD pathophysiology. This study investigated melatonin’s effects on dopamine signalling, metabolism, and oxidative stress under inflammatory and hyperdopaminergic conditions in differentiated SH-SY5Y neuronal cells. Cells were pretreated with 100nM melatonin or vehicle for 2 hours, then exposed to vehicle, IL-6 (20ng/mL), dopamine (5µM or 500µM), or dopamine (500µM) with ascorbic acid (1mM) for 12 or 24 hours. Dopaminergic markers were assessed via real-time PCR and HPLC; metabolic outcomes were measured using Seahorse assay, central carbon metabolomics, in-cell Western assay, and glucose uptake assay; and oxidative stress was evaluated via reactive oxygen species (ROS), superoxide (SOX), and total antioxidant capacity (TAC) assays. IL-6 increased dopamine levels, p-Erk1/2/Erk1/2, p-AMPK/AMPK, nucleotide pools, and TAC, while reducing dopamine turnover, SV2C expression, and spare respiratory capacity. Melatonin alone increased nucleotides and NADH, while reducing dopamine turnover, ROS, and glucose-1-phosphate. In IL-6 conditions, melatonin pretreatment enhanced spare respiratory capacity, glucose uptake, and NADH, while reducing dopamine, TAC, p-AMPK/AMPK, p-GSK3β/GSK3β, and non-mitochondrial oxygen consumption. High-dose dopamine (500µM) elevated SOX, p-Erk1/2/Erk1/2, insulin receptor-α, GLUT1, glycolytic ATP (glycoATP), and non-mitochondrial oxygen consumption. Melatonin pretreatment attenuated p-Erk1/2/Erk1/2 and GLUT1 elevations. Combined dopamine and ascorbic acid further increased glycolytic intermediates, ROS, p-AMPK/AMPK, and TAC, while reducing p-Erk1/2/Erk1/2, p-mTOR, GLUT1, glucose uptake, and glycoATP. Overall, melatonin mitigated IL-6-induced dopaminergic, oxidative, and metabolic alterations, and partially protected against dopamine-induced metabolic shifts. These findings suggest melatonin may alleviate manic symptoms in BD via both direct dopaminergic modulation and indirect antioxidant and metabolic regulatory effects. ### Competing Interest Statement The authors have declared no competing interest. The University of Queensland, https://ror.org/00rqy9422, Research Training Program stipend and tuition fee offset scholarship

ARTICLE HIGHLIGHTS:The present study reveals a previously unknown molecular mechanism linking prediabetes to neurodegeneration, addressing a critical gap in understanding metabolic-neurological interplay. We investigated whether PTP1B mediates prediabetes-induced cognitive impairment. PTP1B impaired synaptic signaling and synaptic ultrastructure in hippocampal neurons, contributing to cognitive decline in prediabetes. PTP1B is a novel therapeutic target for prediabetes-associated neurodegeneration.

Mitochondrial dysfunction and lipid metabolic disturbance may promote pathologic α-synuclein (α-syn) aggregation, accelerating the progression of Parkinson's disease (PD). Whether extracellular matrices are associated with those pathological mechanisms in PD remains elusive. Here, we aimed to identify if cellular fibronectin (cFn), a component of extracellular matrices, contributes to α-syn abnormality via inducing mitochondrial energy depletion or disrupting lipid homeostasis. In Our study, 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-treated PD mice and human neuronal SH-SY5Y cells were used. Astrocyte-derived cFn protein delivery and AAV-mediated cFn knockdown mouse models were established to validate the functional role of cFn. Mitochondrial dysfunction was detected by transmission electron microscopy (TEM), and the level of poly (ADP‒ribose) (PAR) polymerase-1(PARP1), pathologic α-syn and cFn-induced lipid dysmetabolism was determined. We demonstrated that excessive cFn accumulated in the SNpc of MPTP-treated mice, and cFn rather than plasma Fn (pFn) exacerbated neuronal mitochondrial dysfunction and α-syn accumulation. Mechanically, cFn induced PARP1 activation via integrin α4β1, which contributed to neuronal NAD ​+ ​depletion and pathologic α-syn aggregation. Furthermore, cFn induced an increase in free fatty acids (FAs) and triglycerides (TAG) in neurons by binding to integrin α4β1, which synergistically contributed to α-syn abnormality. We revealed that cFn induced stearoyl-CoA desaturase (SCD) activation via integrin α4β1, which was interacted with SCD. Genetically depleting cFn suppressed PARP1 activation and SCD elevation, which further rescued the mitochondrial disruption and α-syn abnormalities in MPTP-treated mice. Overall, our findings suggest that cFn exacerbates α-syn aggregation via integrin α4β1-mediated PARP1 and SCD elevation. cFn-targeting therapy may be a promising strategy for treating PD.

Epidemiological studies often link circulatory levels of 25 hydroxy vitamin D with an overwhelming variety of disorders. Of such studies, an increasing number are now linking blood 25 hydroxy vitamin D levels with certain brain disorders. Prominent amongst such disorders are schizophrenia and Parkinson’s disease. The neurotransmitter dopamine is central to understanding the eitiology of both disorders with schizophrenia representing increased subcortical dopamine function and Parkinson’s disease a disorder with the pathological hallmark of dopamine cellular pathology. Our group have established the epidemiology linking vitamin D deficiency in utero and later onset of schizophrenia. We have clarified many of the mechanisms behind how vitamin D effects dopamine neuron positioning, differentiation and survival. In this study we confirm vitamin D differentiates the dendritic architecture of dopamine neurons, that vitamin D may represent a requirement for drug-mediated dopamine release and that vitamin D may sculpt presynaptic proteins related to fast or phasic dopamine release.

The main cause of second-generation antipsychotic (SGA)-induced obesity is considered due to the antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling. It is reported that 5-HT2cR interacted with GHSR1a, however it is unknown whether one of the SGA olanzapine alters the 5-HT2cR/GHSR1a interaction, affecting orexigenic neuropeptide signalling in the hypothalamus. We found that olanzapine treatment increased average energy intake and body weight gain in mice; olanzapine treatment also increased orexigenic neuropeptide (NPY) and GHSR1a signaling molecules, pAMPK, UCP2, FOXO1 and pCREB levels in the hypothalamus. By using confocal fluorescence resonance energy transfer (FRET) technology, we found that 5-HT2cR interacted/dimerised with the GHSR1a in the hypothalamic neurons. As 5-HT2cR antagonist, both olanzapine and S242084 decreased the interaction between 5-HT2cR and GHSR1a and activated GHSR1a signaling. The 5-HT2cR agonist lorcaserin counteracted olanzapine-induced attenuation of interaction between 5-HT2cR and GHSR1a and inhibited activation of GHSR1a signalling and NPY production. These findings suggest that 5-HT2cR antagonistic effect of olanzapine in inhibition of the interaction of 5-HT2cR and GHSR1a, activation GHSR1a downstream signaling and increasing hypothalamic NPY, which may be the important neuronal molecular mechanism underlying olanzapine-induced obesity and target for prevention metabolic side effects of antipsychotic management in psychiatric disorders.

Obesity has reached pandemic proportions and is a risk factor for neurodegenerative diseases, including Alzheimer's disease. Chronic inflammation is common in obese patients, but the mechanism between inflammation and cognitive impairment in obesity remains unclear. Accumulative evidence shows that protein-tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. We investigated the causal role of PTP1B in obesity-induced cognitive impairment and the beneficial effect of PTP1B inhibitors in counteracting impairments of cognition, neural morphology, and signaling. We showed that obese individuals had negative relationship between serum PTP1B levels and cognitive function. Furthermore, the PTP1B level in the forebrain increased in patients with neurodegenerative diseases and obese cognitive impairment mice with the expansion of white matter, neuroinflammation and brain atrophy. PTP1B globally or forebrain-specific knockout mice on an obesogenic high-fat diet showed enhanced cognition and improved synaptic ultrastructure and proteins in the forebrain. Specifically, deleting PTP1B in leptin receptor-expressing cells improved leptin synaptic signaling and increased BDNF expression in the forebrain of obese mice. Importantly, we found that various PTP1B allosteric inhibitors (e.g., MSI-1436, well-tolerated in Phase 1 and 1b clinical trials for obesity and type II diabetes) prevented these alterations, including improving cognition, neurite outgrowth, leptin synaptic signaling and BDNF in both obese cognitive impairment mice and a neural cell model of PTP1B overexpression. These findings suggest that increased forebrain PTP1B is associated with cognitive decline in obesity, whereas inhibition of PTP1B could be a promising strategy for preventing neurodegeneration induced by obesity.

Vitamin D has been identified as a key factor in dopaminergic neurogenesis and differentiation. Consequently, developmental vitamin D (DVD) deficiency has been linked to disorders of abnormal dopamine signalling with a neurodevelopmental basis such as schizophrenia. Here we provide further evidence of vitamin D's role as a mediator of dopaminergic development by showing that it increases neurite outgrowth, neurite branching, presynaptic protein re-distribution, dopamine production and functional release in various in vitro models of developing dopaminergic cells including SH-SY5Y cells, primary mesencephalic cultures and mesencephalic/striatal explant co-cultures. This study continues to establish vitamin D as an important differentiation agent for developing dopamine neurons, and now for the first time shows chronic exposure to the active vitamin D hormone increases the capacity of developing neurons to release dopamine. This study also has implications for understanding mechanisms behind the link between DVD deficiency and schizophrenia.

One of the most robust neurochemical abnormalities reported in patients with schizophrenia is an increase in dopamine (DA) synthesis and release, restricted to the dorsal striatum (DS). This hyper functionality is strongly associated with psychotic symptoms and progresses in those who later transition to schizophrenia. To understand the implications of this progressive neurobiology on brain function, we have developed a model in rats which we refer to as EDiPs (Enhanced Dopamine in Prodromal schizophrenia). The EDiPs model features a virally mediated increase in dorsal striatal (DS) DA synthesis capacity across puberty and into adulthood. This protocol leads to progressive changes in behaviour and neurochemistry. Our aim in this study was to explore if increased DA synthesis capacity alters the physiology of DA release and DS connectivity. Using fast scan cyclic voltammetry to assess DA release we show that evoked/phasic DA release is increased in the DS of EDiPs rats, whereas tonic/background levels of DA remain unaffected. Using quantitative immunohistochemistry methods to quantify DS synaptic architecture we show a presynaptic marker for DA release sites (Bassoon) was elevated within TH axons specifically within the DS, consistent with the increased phasic DA release in this region. Alongside changes in DA systems, we also show increased density of vesicular glutamate transporter 1 (VGluT1) synapses in the EDiPs DS suggesting changes in cortical connectivity. Our data may prove relevant in understanding the long-term implications for DS function in response to the robust and prolonged increases in DA synthesis uptake and release reported in schizophrenia.

Developmental vitamin D (DVD)-deficiency is an epidemiologically established risk factor for autism. Emerging studies also highlight the involvement of gut microbiome/gut physiology in autism. The current study aims to examine the effect of DVD-deficiency on a broad range of autism-relevant behavioural phenotypes and gut health. Vitamin D deficient rat dams exhibited altered maternal care, DVD-deficient pups showed increased ultrasonic vocalizations and as adolescents, social behaviour impairments and increased repetitive self-grooming behaviour. There were significant impacts of DVD-deficiency on gut health demonstrated by alterations to the microbiome, decreased villi length and increased ileal propionate levels. Overall, our animal model of this epidemiologically validated risk exposure for autism shows an expanded range of autism-related behavioural phenotypes and now alterations in gut microbiome that correlate with social behavioural deficits raising the possibility that DVD-deficiency induced ASD-like behaviours are due to alterations in gut health.

BackgroundDietary fiber is fermented in the lower gastrointestinal tract, potentially impacting the microbial ecosystem and thus may improve elements of cognition and brain function via the gut-brain axis. β-glucans, soluble dietary fiber, have different macrostructures and may exhibit different effects on the gut-brain axis. This study aimed to compare the effects of β-glucans from mushroom, curdlan and oats bran, representing β-(1,3)/(1,6)-glucan, β-(1,3)-glucan or β-(1,3)/(1,4)-glucan, on cognition and the gut-brain axis.MethodsC57BL/6J mice were fed with either control diet or diets supplemented with β-glucans from mushroom, curdlan and oats bran for 15 weeks. The cognitive functions were evaluated by using the temporal order memory and Y-maze tests. The parameters of the gut-brain axis were examined, including the synaptic proteins and ultrastructure and microglia status in the hippocampus and prefrontal cortex (PFC), as well as colonic immune response and mucus thickness and gut microbiota profiles.ResultsAll three supplementations with β-glucans enhanced the temporal order recognition memory. Brain-derived neurotrophic factor (BDNF) and the post-synaptic protein 95 (PSD95) increased in the PFC. Furthermore, mushroom β-glucan significantly increased the post-synaptic thickness of synaptic ultrastructure in the PFC whilst the other two β-glucans had no significant effect. Three β-glucan supplementations decreased the microglia number in the PFC and hippocampus, and affected complement C3 and cytokines expression differentially. In the colon, every β-glucan supplementation increased the number of CD206 positive cells and promoted the expression of IL-10 and reduced IL-6 and TNF-α expression. The correlation analysis highlights that degree of cognitive behavior improved by β-glucan supplementations was significantly associated with microglia status in the hippocampus and PFC and the number of colonic M2 macrophages. In addition, only β-glucan from oat bran altered gut microbiota and enhanced intestinal mucus.ConclusionsWe firstly demonstrated long-term supplementation of β-glucans enhanced recognition memory. Comparing the effects of β-glucans on the gut-brain axis, we found that β-glucans with different molecular structures exhibit differentia actions on synapses, inflammation in the brain and gut, and gut microbiota. This study may shed light on how to select appropriate β-glucans as supplementation for the prevention of cognitive deficit or improving immune function clinically.

Twenty of the last one hundred years of vitamin D research have involved investigations of the brain as a target organ for this hormone. Our group was one of the first to investigate brain outcomes resulting from primarily restricting dietary vitamin D during brain development. With the advent of new molecular and neurochemical techniques in neuroscience, there has been increasing interest in the potential neuroprotective actions of vitamin D in response to a variety of adverse exposures and how this hormone could affect brain development and function. Rather than provide an exhaustive summary of this data and a listing of neurological or psychiatric conditions that vitamin D deficiency has been associated with, here, we provide an update on the actions of this vitamin in the brain and cellular processes vitamin D may be targeting in psychiatry and neurology.

Schizophrenia is a neurodevelopmental disorder associated with abnormal dopamine (DA) signalling and disruptions in early brain development. We have shown that developmental vitamin D-deficiency (DVD-deficiency) increases the risk of schizophrenia in offspring and impairs various aspects of brain development in rodents, particularly that of DA neurons, however the molecular basis of these impairments remains unclear. Here, we explore whether small non-coding microRNAs (miRNAs) are involved. miRNAs regulate gene expression post-transcriptionally via translational repression and destabilisation of mRNA. While dysregulation of multiple miRNAs has been reported in post-mortem brain of patients with schizophrenia, the biological pathways affected by these small RNAs are not clear. Here we identified differential expression of 18 miRNAs in DA neurons isolated from DVD-deficient embryos. Three miRNAs were selected for further functional studies of dopaminergic neuron differentiation based on their interactions with transcripts involved in neuronal maturation. In particular, we show upregulation of miR-181c-5p suppresses neurite outgrowth of dopaminergic neurons. These findings provide further evidence that an environmental risk factor for schizophrenia - DVD-deficiency - disrupts the development of DA neurons and suggests increased miRNA expression may be one possible mechanism. This disruption potentially underlies the long-term alterations in DA mediated brain function in DVD-deficient offspring, and by inference in schizophrenia.

Dopaminergic (DA) dysfunction is a significant feature in the pathophysiology of schizophrenia. Established developmental risk factors for schizophrenia such as maternal immune activation (MIA) or developmental vitamin D (DVD) deficiency, when modelled in animals, reveal the differentiation of early DA neurons in foetal brains is delayed suggesting this may be a convergent aetiological pathway. Here we have assessed the effects of prenatal hypoxia, another well-known developmental risk factor for schizophrenia, on developing DA systems. Pregnant mice were exposed to a hypoxic environment of 10% oxygen for 48 h from embryonic day 10 (E10) to E12. Embryonic brains were collected and the positioning of mesencephalic cells, expression of DA specification and maturation factors were examined along with the expression of factors that may govern the migration of these neurons. We show that prenatal hypoxia results in a decrease in dopaminergic progenitors retards early DA neuron lateral migration and reduces expression of the receptors known to govern this process. A second time-point, postnatal day 10 (P10) was also examined in order to assess whether prenatal hypoxia alters early presynaptic architecture in the developing striatum. We show reduced expression of tyrosine hydroxylase (TH) in the postnatal striatum along with increases in the density of high-probability DA release sites within TH varicosities. These findings add to the emerging literature showing that multiple epidemiologically validated environmental risk factors for schizophrenia may induce early alterations to develop DA systems. This may represent a possible convergent mechanism in the onset of presynaptic DA dysfunction in patients.

Obesity has become a public health epidemic worldwide and is associated with many diseases with high mortality including hypertension, diabetes, and heart disease. High-fat diet (HFD)-induced energy imbalance is one of the primary causes of obesity, but the underlying mechanisms are not fully elucidated. Our study showed that HFD reduced the level of hydrogen sulfide (H2S) and its catalytic enzyme cystathionine β-synthase (CBS) in mouse hypothalamus and plasma. We found that HFD activated mTOR, IKK/NF-κB, the main pathway regulating inflammation. Activation of inflammatory pathway promoted the production of pro-inflammatory cytokines including IL-6, IL-1β, and TNF-α, which caused cell damage and loss in the hypothalamus. The disturbance of the hypothalamic neuron circuits resulted in body weight gain in HFD-induced mice. Importantly, we also showed that restoration of H2S level with NaHS or activation of CBS with SAMe attenuated HFD-induced activation of mTOR, IKK/NF-κB signaling, which reduced the inflammation and the neuronal cell loss in the hypothalamus, and also inhibited body weight gain in mice. The same effects were obtained by inhibiting mTOR or NF-κB, which suggested that mTOR and NF-κB were the critical molecular factors involved in hypothalamic inflammation. Taken together, this study identified that HFD-induced hypothalamus inflammation plays a critical role in the development of obesity. Moreover, the inhibition of hypothalamic inflammation by regaining H2S level could be a potential therapeutic to prevent the development of obesity.

The dopaminergic (DA) system is important for a range of brain functions and subcortical DA development precedes many cortical maturational processes. The dysfunction of DA systems has been associated with neuropsychiatric disorders such as schizophrenia, depression, and addiction. DA neuron cell fate is controlled by a complex web of transcriptional factors that dictate DA neuron specification, differentiation, and maturation. A growing body of evidence suggests that these transcriptional factors are under the regulation of newly discovered non-coding RNAs. However, with regard to DA neuron development, little is known of the roles of non-coding RNAs. The long non-coding RNA (lncRNA) HOX-antisense intergenic RNA myeloid 1 (HOTAIRM1) is present in adult DA neurons, suggesting it may have a modulatory role in DA systems. Moreover, HOTAIRM1 is involved in the neuronal differentiation in human stem cells suggesting it may also play a role in early DA neuron development. To determine its role in early DA neuron development, we knocked down HOTAIRM1 using RNAi in vitro in a human neuroblastoma cell line, and in vivo in mouse DA progenitors using a novel in utero electroporation technique. HOTAIRM1 inhibition decreased the expression of a range of key DA neuron specification factors and impaired DA neuron differentiation and maturation. These results provide evidence of a functional role for HOTAIRM1 in DA neuron development and differentiation. Understanding of the role of lncRNAs in the development of DA systems may have broader implications for brain development and neurodevelopmental disorders such as schizophrenia.