More than a number: Incorporating the aged phenotype to improve in vitro and in vivo modeling of neurodegenerative disease.

Age is the number one risk factor for developing a neurodegenerative disease (ND), such as Alzheimer's disease (AD) or Parkinson's disease (PD). With our rapidly ageing world population, there will be an increased burden of ND and need for disease-modifying treatments. Currently, however, translation of research from bench to bedside in NDs is poor. This may be due, at least in part, to the failure to account for the potential effect of ageing in preclinical modelling of NDs. While ageing can impact upon physiological response in multiple ways, only a limited number of preclinical studies of ND have incorporated ageing as a factor of interest. Here, we evaluate the aged phenotype and highlight the critical, but unmet, need to incorporate aspects of this phenotype into both the in vitro and in vivo models used in ND research. Given technological advances in the field over the past several years, we discuss how these could be harnessed to create novel models of ND that more readily incorporate aspects of the aged phenotype. This includes a recently described in vitro panel of ageing markers, which could help lead to more standardised models and improve reproducibility across studies. Importantly, we cannot assume that young cells or animals yield the same responses as seen in the context of ageing; thus, an improved understanding of the biology of ageing, and how to appropriately incorporate this into the modelling of ND, will ensure the best chance for successful translation of new therapies to the aged patient.

Neuronanomedicine for Alzheimer's and Parkinson's disease: Current progress and a guide to improve clinical translation.

Neuronanomedicine is an emerging multidisciplinary field that aims to create innovative nanotechnologies to treat major neurodegenerative disorders, such as Alzheimer's (AD) and Parkinson's disease (PD). A key component of neuronanomedicine are nanoparticles, which can improve drug properties and demonstrate enhanced safety and delivery across the blood-brain barrier, a major improvement on existing therapeutic approaches. In this review, we critically analyze the latest nanoparticle-based strategies to modify underlying disease pathology to slow or halt AD/PD progression. We find that a major roadblock for neuronanomedicine translation to date is a poor understanding of how nanoparticles interact with biological systems (i.e., bio-nano interactions), which is partly due to inconsistent reporting in published works. Accordingly, this review makes a set of specific recommendations to help guide researchers to harness the unique properties of nanoparticles and thus realise breakthrough treatments for AD/PD.

Long-Term Impact of Diffuse Traumatic Brain Injury on Neuroinflammation and Catecholaminergic Signaling: Potential Relevance for Parkinson's Disease Risk.

Traumatic brain injury (TBI) is associated with an increased risk of developing Parkinson's disease (PD), though the exact mechanisms remain unclear. TBI triggers acute neuroinflammation and catecholamine dysfunction post-injury, both implicated in PD pathophysiology. The long-term impact on these pathways following TBI, however, remains uncertain. In this study, male Sprague-Dawley rats underwent sham surgery or Marmarou's impact acceleration model to induce varying TBI severities: single mild TBI (mTBI), repetitive mild TBI (rmTBI), or moderate-severe TBI (msTBI). At 12 months post-injury, astrocyte reactivity (GFAP) and microglial levels (IBA1) were assessed in the striatum (STR), substantia nigra (SN), and prefrontal cortex (PFC) using immunohistochemistry. Key enzymes and receptors involved in catecholaminergic transmission were measured via Western blot within the same regions. Minimal changes in these markers were observed, regardless of initial injury severity. Following mTBI, elevated protein levels of dopamine D1 receptors (DRD1) were noted in the PFC, while msTBI resulted in increased alpha-2A adrenoceptors (ADRA2A) in the STR and decreased dopamine beta-hydroxylase (DßH) in the SN. Neuroinflammatory changes were subtle, with a reduced number of GFAP+ cells in the SN following msTBI. However, considering the potential for neurodegenerative outcomes to manifest decades after injury, longer post-injury intervals may be necessary to observe PD-relevant alterations within these systems.

Leakage beyond the primary lesion: A temporal analysis of cerebrovascular dysregulation at sites of hippocampal secondary neurodegeneration following cortical photothrombotic stroke.

We have previously demonstrated that a cortical stroke causes persistent impairment of hippocampal-dependent cognitive tasks concomitant with secondary neurodegenerative processes such as amyloid-ß accumulation in the hippocampus, a region remote from the primary infarct. Interestingly, there is emerging evidence suggesting that deposition of amyloid-ß around cerebral vessels may lead to cerebrovascular structural changes, neurovascular dysfunction, and disruption of blood-brain barrier integrity. However, there is limited knowledge about the temporal changes of hippocampal cerebrovasculature after cortical stroke. In the current study, we aimed to characterise the spatiotemporal cerebrovascular changes after cortical stroke. This was done using the photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Cerebrovascular morphology as well as the co-localisation of amyloid-ß with vasculature and blood-brain barrier integrity were assessed in the cortex and hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed transient cerebrovascular remodelling in the peri-infarct area up to 28 days post-stroke. Importantly, the cerebrovascular changes were extended beyond the peri-infarct region to the ipsilateral hippocampus and were sustained out to 84 days post-stroke. When investigating vessel diameter, we showed a decrease at 84 days in the peri-infarct and CA1 regions that were exacerbated in vessels with amyloid-ß deposition. Lastly, we showed sustained vascular leakage in the peri-infarct and ipsilateral hippocampus, indicative of a compromised blood-brain-barrier. Our findings indicate that hippocampal vasculature may represent an important therapeutic target to mitigate the progression of post-stroke cognitive impairment.

"Chemobrain" in childhood cancer survivors-the impact on social, academic, and daily living skills: a qualitative systematic review.

PURPOSE: To examine children's experiences of chemotherapy-induced cognitive impairment--colloquially "chemobrain"--and the impact on children's social, academic, and daily living skills via a qualitative systematic review. Experiencing chemotherapy as a child, when the brain is still developing, may cause lifelong detriment to survivors' lives. There is a significant gap in understanding their lived experience, including the self-identified barriers that children face following treatment. Such a gap can only be fully bridged by listening to the child's own voice and/or parent proxy report through an exploration of the qualitative research literature. METHODS: A search of MEDLINE, Embase, PsycINFO, and CINAHL databases was conducted. Inclusion criteria were qualitative studies with a focus on children (0-18 years) during and/or following chemotherapy treatment and explored children's experiences of chemobrain. RESULTS: Two synthesized findings were identified from six studies. (1) Chemobrain has an academic and psychosocial impact, which may not be understood by education providers. (2) Children and their parents have concerns about their reintegration and adaptation to school, social lives, and their future selves as independent members of society. Children's experiences primarily related to changes in their academic and social functioning. CONCLUSION: This review highlights two important considerations: (1) the lived experiences of pediatric childhood cancer survivors guiding where future interventions should be targeted, and (2) a need to perform more qualitative research studies in this area, as well as to improve the quality of reporting among the existing literature, given that this is a current gap in the field.

Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke?

Ischaemic stroke involves the rapid onset of focal neurological dysfunction, most commonly due to an arterial blockage in a specific region of the brain. Stroke is a leading cause of death and common cause of disability, with over 17 million people worldwide suffering from a stroke each year. It is now well-documented that neuroinflammation and immune mediators play a key role in acute and long-term neuronal tissue damage and healing, not only in the infarct core but also in distal regions. Importantly, in these distal regions, termed sites of secondary neurodegeneration (SND), spikes in neuroinflammation may be seen sometime after the initial stroke onset, but prior to the presence of the neuronal tissue damage within these regions. However, it is key to acknowledge that, despite the mounting information describing neuroinflammation following ischaemic stroke, the exact mechanisms whereby inflammatory cells and their mediators drive stroke-induced neuroinflammation are still not fully understood. As a result, current anti-inflammatory treatments have failed to show efficacy in clinical trials. In this review we discuss the complexities of post-stroke neuroinflammation, specifically how it affects neuronal tissue and post-stroke outcome acutely, chronically, and in sites of SND. We then discuss current and previously assessed anti-inflammatory therapies, with a particular focus on how failed anti-inflammatories may be repurposed to target SND-associated neuroinflammation.

Are the protective benefits of vitamin D in neurodegenerative disease dependent on route of administration? A systematic review.

Background: The clinical and preclinical exploration of the therapeutic properties of vitamin D have significantly increased in the past decade, owing to the growing associative evidence suggesting vitamin D is neuroprotective. However, whether depletion of vitamin D contributes to the onset of neurological disorders or is a symptom of neurological disease has yet to be defined. Much remains unclear about the causal role of vitamin D and the method of use and forms of vitamin D.Objectives: We sought to quantitatively assess if neuroprotective benefits from vitamin D in neurodegenerative diseases are dependent on route of administration: comparing the effect of endogenously sourced vitamin D from UV exposure to exogenously derived vitamin D through synthetic supplementation.Design: We systematically searched PubMed, Embase and PsycInfo databases which included both pre-clinical and clinical studies investigating vitamin D in neurodegenerative diseases. Articles were subject to strict inclusion criteria and objectively assessed for quality. Additionally, Medline data was analysed to identify trends in topic publications and linguistic characteristics of papers.Results: From a total of 231 screened articles, we identified 73 appropriate for review based on inclusion criteria: original studies that investigated vitamin D levels or levels of vitamin D supplementation in neurodegenerative diseases or investigated past/present sun exposure in disease cohorts. Results indicate there is insufficient evidence to comprehensively reflect on a potential neuroprotective role for vitamin D and if this was dependent on route of administration. The majority of current data supporting neuroprotective benefits from vitamin D are based on pre-clinical and observational studies. Solid evidence is lacking to support the current hypothesis that the beneficial effect of UV exposure results from the synthesis of vitamin D. Sun exposure, independent of vitamin D production, may be protective against multiple Sclerosis, Parkinson's disease and Alzheimer's disease. Yet, further research is required to elucidate the beneficial mechanism of actions of UV exposure. The literature of vitamin D and amyotrophic lateral sclerosis was limited, and no conclusions were drawn. Therefore, in cases where UV-derived vitamin D was hypothesized to be the beneficial mediator in the neuroprotective effects of sun exposure, we propose results are based only on associative evidence.Conclusion: On the basis of this systematic review, strong recommendations regarding therapeutic benefits of vitamin D in neurodegenerative disease cannot be made. It is unclear if vitamin D mediates a protective benefit in neurodegenerative disease or whether it is an associative marker of UV exposure, which may contribute to as of yet unidentified neuroprotective factors.

Infants who die in shared sleeping situations differ from those who die while sleeping alone.

AIM: To determine whether there are differences between infants who are sharing a sleeping surface with others, compared to those who die alone. METHODS: A literature review was undertaken of PubMed and Google Scholar databases using search terms: sudden infant death syndrome, SIDS, co-sleeping and overlaying. RESULTS: Statistically significant differences were found between the two groups in the sex ratios, and in staining of brain sections for ß-amyloid precursor protein (ß-APP), glial fibrillary acidic protein (GFAP) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL). There were also higher numbers of nucleated red blood cells (nRBCs) in the peripheral blood of infants who died while co-sleeping. CONCLUSION: The results demonstrate differences between infants who are sharing a sleeping surface with others, compared to those who die alone. It is likely, therefore, that lethal mechanisms for some shared sleepers are not the same as for SIDS infants sleeping alone, and may involve suffocation.

Can neuroimmune mechanisms explain the link between ultraviolet light (UV) exposure and addictive behavior?

High ultraviolet (UV) light exposure on the skin acts as a reinforcing stimulus, increasing sun-seeking behavior and even addiction-like sun seeking behavior. However, the physiological mechanisms that underlie this process remain to be defined. Here, we propose a novel hypothesis that neuroimmune signaling, arising from inflammatory responses in UV-damaged skin cells, causes potentiated signaling within the cortico-mesolimbic pathway, leading to increased sun-seeking behaviors. This hypothesized UV-induced, skin-to-brain signaling depends upon cell stress signals, termed alarmins, reaching the circulation, thereby triggering the activation of innate immune receptors, such as toll-like receptors (TLRs). This innate immune response is hypothesized to occur both peripherally and centrally, with the downstream signaling from TLR activation affecting both the endogenous opioid system and the mesolimbic dopamine pathway. As both neurotransmitter systems play a key role in the development of addiction behaviors through their actions at key brain regions, such as the nucleus accumbens (NAc), we hypothesize a novel connection between UV-induced inflammation and the activation of pathways that contribute to the development of addiction. This paper is a review of the existing literature to examine the evidence which suggests that chronic sun tanning resembles a behavioral addiction and proposes a novel pathway by which persistent sun-seeking behavior could affect brain neurochemistry in a manner similar to that of repeated drug use.

Does neuroinflammation drive the relationship between tau hyperphosphorylation and dementia development following traumatic brain injury?

A history of traumatic brain injury (TBI) is linked to an increased risk for the later development of dementia. This encompasses a variety of neurodegenerative diseases including Alzheimer's Disease (AD) and chronic traumatic encephalopathy (CTE), with AD linked to history of moderate-severe TBI and CTE to a history of repeated concussion. Of note, both AD and CTE are characterized by the abnormal accumulation of hyperphosphorylated tau aggregates, which are thought to play an important role in the development of neurodegeneration. Hyperphosphorylation of tau leads to destabilization of microtubules, interrupting axonal transport, whilst tau aggregates are associated with synaptic dysfunction. The exact mechanisms via which TBI may promote the later tauopathy and its role in the later development of dementia are yet to be fully determined. Following TBI, it is proposed that axonal injury may provide the initial perturbation of tau, by promoting its dissociation from microtubules, facilitating its phosphorylation and aggregation. Altered tau dynamics may then be exacerbated by the chronic persistent inflammatory response that has been shown to persist for decades following the initial impact. Importantly, immune activation has been shown to play a role in accelerating disease progression in other tauopathies, with pro-inflammatory cytokines, like IL-1ß, shown to activate kinases that promote tau hyperphosphorylation. Thus, targeting the inflammatory response in the sub-acute phase following TBI may represent a promising target to halt the alterations in tau dynamics that may precede overt neurodegeneration and later development of dementia.

Toll like receptor 4 activation can be either detrimental or beneficial following mild repetitive traumatic brain injury depending on timing of activation.

A history of repeated concussion has been linked to the later development of neurodegeneration, which is associated with the accumulation of hyperphosphorylated tau and the development of behavioral deficits. However, the role that exogenous factors, such as immune activation, may play in the development of neurodegeneration following repeated mild traumatic brain injury (rmTBI) has not yet been explored. To investigate, male Sprague-Dawley rats were administered three mTBIs 5days apart using the diffuse impact-acceleration model to generate ∼100G. Sham animals underwent surgery only. At 1 or 5days following the last injury rats were given the TLR4 agonist, lipopolysaccharide (LPS, 0.1mg/kg), or saline. TLR4 activation had differential effects following rmTBI depending on the timing of activation. When given at 1day post-injury, LPS acutely activated microglia, but decreased production of pro-inflammatory cytokines like IL-6. This was associated with a reduction in neuronal injury, both acutely, with a restoration of levels of myelin basic protein (MBP), and chronically, preventing a loss of both MBP and PSD-95. Furthermore, these animals did not develop behavioral deficits with no changes in locomotion, anxiety, depressive-like behavior or cognition at 3months post-injury. Conversely, when LPS was given at 5days post-injury, it was associated acutely with an increase in pro-inflammatory cytokine production, with an exacerbation of neuronal damage and increased levels of aggregated and phosphorylated tau. At 3months post-injury, there was a slight exacerbation of functional deficits, particularly in cognition and depressive-like behavior. This highlights the complexity of the immune response following rmTBI and the need to understand how a history of rmTBI interacts with environmental factors to influence the potential to develop later neurodegeneration.

Evolution and significance of the triple risk model in sudden infant death syndrome.

Sudden infant death syndrome (SIDS) is a leading cause of death in infants, although the mechanisms leading to death remain unclear. Multiple theories have emerged over time, with one of the most influential hypotheses being the triple risk model. This model, first devised in 1972 and later revised in 1994 by Filiano and Kinney, is still widely used in assisting with conceptualising and understanding sudden death in infancy. This model has evolved over time, with each version stressing that SIDS is likely to occur when certain risk factors coincide, suggesting that the lethal mechanisms in SIDS are likely to be multifactorial. All versions of the triple risk model from 1972 to the present have emphasised the complexity of SIDS and serve as useful guides for current and future research into the enigma of sudden and unexpected death in infancy.

APOE ε4 and risk for Alzheimer's disease: do regionally distributed white matter hyperintensities play a role?

BACKGROUND: We previously demonstrated that parietal lobe white matter hyperintensities (WMH) increase the risk for Alzheimer's disease (AD). Here, we examined whether individuals with apolipoprotein E gene (APOE ε4) have increased parietal WMH volume. METHODS: Participants were from the Washington Heights-Inwood Columbia Aging Project (WHICAP; n = 694, 47 with dementia) in northern Manhattan and the Etude Santé Psychologique Prévalence Risques et Traitement study (ESPRIT; n = 539, 8 with dementia) in Montpellier. The association between regional WMH and APOE ε4 was examined separately in each group and then in a combined analysis. RESULTS: In WHICAP, ε4 carriers had higher WMH volume particularly in parietal and occipital lobes. In ESPRIT, ε4 carriers had elevated WMH particularly in parietal and temporal lobes. In the combined analysis, ε4 carriers had higher WMH in parietal and occipital lobes. Increased WMH volume was associated with increased frequency of dementia irrespective of APOE ε4 status; those with the ε4 were more likely to have dementia if they also had increased parietal WMH. CONCLUSIONS: APOE ε4 is associated with increased parietal lobe WMH.

Protective roles of peroxiporins AQP0 and AQP11 in human astrocyte and neuronal cell lines in response to oxidative and inflammatory stressors.

In addition to aquaporin (AQP) classes AQP1, AQP4 and AQP9 known to be expressed in mammalian brain, our recent transcriptomic analyses identified AQP0 and AQP11 in human cortex and hippocampus at levels correlated with age and Alzheimer's disease (AD) status; however, protein localization remained unknown. Roles of AQP0 and AQP11 in transporting hydrogen peroxide (H2O2) in lens and kidney prompted our hypothesis that up-regulation in brain might similarly be protective. Established cell lines for astroglia (1321N1) and neurons (SHSY5Y, differentiated with retinoic acid) were used to monitor changes in transcript levels for human AQPs (AQP0 to AQP12) in response to inflammation (simulated with 10-100 ng/ml lipopolysaccharide [LPS], 24 h), and hypoxia (5 min N2, followed by 0 to 24 h normoxia). AQP transcripts up-regulated in both 1321N1 and SHSY5Y included AQP0, AQP1 and AQP11. Immunocytochemistry in 1321N1 cells confirmed protein expression for AQP0 and AQP11 in plasma membrane and endoplasmic reticulum; AQP11 increased 10-fold after LPS and AQP0 increased 0.3-fold. In SHSY5Y cells, AQP0 expression increased 0.2-fold after 24 h LPS; AQP11 showed no appreciable change. Proposed peroxiporin roles were tested using melondialdehyde (MDA) assays to quantify lipid peroxidation levels after brief H2O2. Boosting peroxiporin expression by LPS pretreatment lowered subsequent H2O2-induced MDA responses (∼50%) compared with controls; conversely small interfering RNA knockdown of AQP0 in 1321N1 increased lipid peroxidation (∼17%) after H2O2, with a similar trend for AQP11 siRNA. Interventions that increase native brain peroxiporin activity are promising as new approaches to mitigate damage caused by aging and neurodegeneration.

Cognitive function in different motor subtypes of Parkinson's disease: A systematic review protocol.

Background and Aims: As the fastest-growing neurological disorder globally, a better understanding of Parkinson's disease (PD) is needed to improve patient outcomes and reduce the increasing economic and healthcare burden associated with the disease. Whilst classified as a movement disorder, this disease is highly heterogeneous, encompassing a broad range of both motor and non-motor symptoms (NMS). Cognitive impairment, presenting as either mild cognitive impairment or PD-dementia, is one of the most prevalent and disabling NMS. To better understand heterogeneity in PD, researchers have sought to identify subtypes of individuals who share similar symptom profiles. To date, this research has predominantly focused on motor subtyping, with many studies comparing these motor subtypes on non-motor outcomes, such as cognitive impairment. However, despite evidence of a motor-cognitive relationship in healthy aging, findings regarding the presence of a motor-cognitive relationship in PD are inconsistent. In our proposed systematic review, we will investigate motor subtyping studies that have evaluated the relationship between motor and cognitive function in PD. We aim to examine what is currently known about the relationship between motor and cognitive impairment in PD and evaluate the state of the field with respect to the subtyping methods and quality of cognitive assessment tools used. Methods: Systematic literature searches will be conducted in PubMed, PsycINFO, CINAHL, Scopus, and Web of Science. Results: Results will be synthesized using meta-analysis and, where meta-analysis is not feasible, narrative synthesis. Conclusion: Despite the preponderance of motor subtyping research in PD, our study will be the first to systematically review evidence regarding the association between motor subtypes and cognitive impairment. Understanding the nature of the motor-cognitive relationship in PD may lead to important insights regarding shared underlying disease pathology, which would have significant implications for early diagnosis, prognosis, and treatment of cognitive impairment in PD.

Anatomical distribution of Fyn kinase in the human brain in Parkinson's disease.

INTRODUCTION: Fyn kinase is an Src family kinase (SFK) widely expressed in many tissues, including the CNS. Recently, Fyn kinase activation has been associated with pathological mechanisms underlying neurodegenerative diseases and, as such, the role of Fyn dysfunction is under investigation. In particular, Fyn is implicated as a major upstream regulator of neuroinflammation in Parkinson's Disease (PD). Chronic neuroinflammation has been observed not just in the substantia nigra (SN), but also in several key regions of the brain, with disruption associated with symptoms presentation in PD. This study aimed to characterise the anatomical distribution of Fyn in key brain regions affected in PD, namely the prefrontal cortex, hippocampus, striatum and SN. METHODS: Fresh and fixed post-mortem PD brain samples (n = 10) were collected and compared with neurologically healthy age-matched controls (n = 7) to assess markers of Fyn activity and neuroinflammation. RESULTS: Increased Fyn phosphorylation was observed in SN and striatum of post-mortem samples from PD patients compared with controls. No such increase was observed in the prefrontal cortex or hippocampus. In contrast with previous findings, no increase in microglial activation or astrocyte reactivity was observed in PD brains across regions. CONCLUSION: Taken together, these results indicate that Fyn dysfunction may be involved in the pathological processes observed in PD; however, this appears to be independent of inflammatory mechanisms. Further investigations are required to elucidate if increased Fyn activity is a potential cause or consequence of pathological processing in PD.

Influence of cognitive reserve on cognitive and motor function in α-synucleinopathies: A systematic review and multilevel meta-analysis.

Cognitive reserve has shown promise as a justification for neuropathologically unexplainable clinical outcomes in Alzheimer's disease. Recent evidence suggests this effect may be replicated in conditions like Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. However, the relationships between cognitive reserve and different cognitive abilities, as well as motor outcomes, are still poorly understood in these conditions. Additionally, it is unclear whether the reported effects are confounded by medication. This review analysed studies investigating the relationship between cognitive reserve and clinical outcomes in these α-synucleinopathy cohorts, identified from MEDLINE, Scopus, psycINFO, CINAHL, and Web of Science. 85 records, containing 176 cognition and 31 motor function effect sizes, were pooled using multilevel meta-analysis. There was a significant, positive association between higher cognitive reserve and both better cognition and motor function. Cognition effect sizes differed by disease subtype, cognitive reserve measure, and outcome type; however, no moderators significantly impacted motor function. Review findings highlight the clinical implications of cognitive reserve and importance of engaging in reserve-building behaviours.

Application of diceCT to Study the Development of the Zika Virus-Infected Mouse Brain.

Zika virus (ZIKV) impacts the developing brain. Here, a technique was applied to define, in 3D, developmental changes in the brains of ZIKV-infected mice. Postnatal day 1 mice were uninfected or ZIKV-infected, then analysed by iodine staining and micro-CT scanning (diffusible iodine contrast-enhanced micro-CT; diceCT) at 3-, 6-, and 10-days post-infection (dpi). Multiple brain regions were visualised using diceCT: the olfactory bulb, cerebrum, hippocampus, midbrain, interbrain, and cerebellum, along with the lens and retina of the eye. Brain regions were computationally segmented and quantitated, with increased brain volumes and developmental time in uninfected mice. Conversely, in ZIKV-infected mice, no quantitative differences were seen at 3 or 6 dpi when there were no clinical signs, but qualitatively, diverse visual defects were identified at 6-10 dpi. By 10 dpi, ZIKV-infected mice had significantly lower body weight and reduced volume of brain regions compared to 10 dpi-uninfected or 6 dpi ZIKV-infected mice. Nissl and immunofluorescent Iba1 staining on post-diceCT tissue were successful, but RNA extraction was not. Thus, diceCT shows utility for detecting both 3D qualitative and quantitative changes in the developing brain of ZIKV-infected mice, with the benefit, post-diceCT, of retaining the ability to apply traditional histology and immunofluorescent analysis to tissue.

Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment.

We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37-38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37-38 deletion male (Thoc2Δ/Y) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2Δ/Y mouse brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of THOC2 syndrome.

Deep brain stimulation of the subthalamic nucleus reverses oral tremor in pharmacological models of parkinsonism: interaction with the effects of adenosine A2A antagonism.

Deep brain stimulation (DBS) of the subthalamic nucleus is increasingly being employed as a treatment for parkinsonian symptoms, including tremor. The present studies used tremulous jaw movements, a pharmacological model of tremor in rodents, to investigate the tremorolytic effects of subthalamic DBS in rats. Subthalamic DBS reduced the tremulous jaw movements induced by the dopamine D2 family antagonist pimozide and the D1 family antagonist ecopipam, as well as the cholinomimetics pilocarpine and galantamine. The ability of DBS to suppress tremulous jaw movements was dependent on the neuroanatomical locus being stimulated (subthalamic nucleus vs. a striatal control site), as well as the frequency and intensity of stimulation used. Importantly, administration of the adenosine A2A receptor antagonist MSX-3 reduced the frequency and intensity parameters needed to attenuate tremulous jaw movements. These results have implications for the clinical use of DBS, and future studies should determine whether adenosine A2A antagonism could be used to enhance the tremorolytic efficacy of subthalamic DBS at low frequencies and intensities in human patients.