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Striatal Neurons Expressing D1 and D2 Receptors are Morphologically Distinct and Differently Affected by Dopamine Denervation in Mice
The loss of nigrostriatal dopamine neurons in Parkinson’s disease induces a reduction in the number of dendritic spines on medium spiny neurons (MSNs) of the striatum expressing D
1
or D
2
dopamine receptor. Consequences on MSNs expressing both receptors (D
1
/D
2
MSNs) are currently unknown. We looked for changes induced by dopamine denervation in the density, regional distribution and morphological features of D
1
/D
2
MSNs, by comparing 6-OHDA-lesioned double BAC transgenic mice (
Drd1a
-tdTomato/
Drd2
-EGFP) to sham-lesioned animals. D
1
/D
2
MSNs are uniformly distributed throughout the dorsal striatum (1.9% of MSNs). In contrast, they are heterogeneously distributed and more numerous in the ventral striatum (14.6% in the shell and 7.3% in the core). Compared to D
1
and D
2
MSNs, D
1
/D
2
MSNs are endowed with a smaller cell body and a less profusely arborized dendritic tree with less dendritic spines. The dendritic spine density of D
1
/D
2
MSNs, but also of D
1
and D
2
MSNs, is significantly reduced in 6-OHDA-lesioned mice. In contrast to D
1
and D
2
MSNs, the extent of dendritic arborization of D
1
/D
2
MSNs appears unaltered in 6-OHDA-lesioned mice. Our data indicate that D
1
/D
2
MSNs in the mouse striatum form a distinct neuronal population that is affected differently by dopamine deafferentation that characterizes Parkinson’s disease.
Journal Article
The contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson’s disease
Astrocyte dysfunction has previously been linked to multiple neurodegenerative disorders including Parkinson’s disease (PD). Among their many roles, astrocytes are mediators of the brain immune response, and astrocyte reactivity is a pathological feature of PD. They are also involved in the formation and maintenance of the blood-brain barrier (BBB), but barrier integrity is compromised in people with PD. This study focuses on an unexplored area of PD pathogenesis by characterizing the interplay between astrocytes, inflammation and BBB integrity, and by combining patient-derived induced pluripotent stem cells with microfluidic technologies to generate a 3D human BBB chip. Here we report that astrocytes derived from female donors harboring the PD-related LRRK2 G2019S mutation are pro-inflammatory and fail to support the formation of a functional capillary in vitro. We show that inhibition of MEK1/2 signaling attenuates the inflammatory profile of mutant astrocytes and rescues BBB formation, providing insights into mechanisms regulating barrier integrity in PD. Lastly, we confirm that vascular changes are also observed in the human postmortem substantia nigra of both males and females with PD.
Astrocytes are implicated in the maintenance of the blood-brain barrier (BBB). This study established a microfluidic BBB chip and found that astrocytes may play a role in cerebrovascular dysfunction in people with Parkinson’s disease.
Journal Article
Routledge handbook of sports event management
From the Olympic Games to community-level competitions, sports events can be complex and pose a particular set of managerial challenges. 'The Routledge Handbook of Sports Event Management' surveys the management of sports events around the world of every size and scale, from small to mega-events, including one-off and recurring events and single sport and multi-sport events.
Book
Balancing in Neorealism
Does neorealism offer a convincing account of great power balancing behavior? Many scholars argue that it does not. This conclusion rests on a misunderstanding of neorealist theory and an erroneous reading of the evidence. Properly specified, neorealism holds that great powers place an overriding emphasis on the need for self-help. This means that they rely relentlessly both on arming and on imitating the successful military practices of their peers to ensure their security. At the same time, they rarely resort to alliances and treat them with skepticism. There is abundant historical evidence to support these claims. Since 1816, great powers have routinely achieved an effective balance in military capabilities with their relevant competitors and promptly copied the major military innovations of the period. Case studies show that these outcomes are the product of states' efforts to ensure security against increasingly capable rivals. Meanwhile, the diplomatic record yields almost no examples of firm peacetime balancing coalitions over the past 200 years. When alliances have formed, great powers have generally doubted the reliability of their allies and of their opponents' allies. Thus neorealism provides a solid foundation for explaining great power balancing behavior.
Journal Article
Elite youth sport policy and management : a comparative analysis
Elite youth sport competitions have increased significantly in number in recent years, with the Youth Olympic Games representing the high point of this phenomenon. This book examines the global context within which elite youth sport has emerged and continues to grow. It explores elite youth sport policy across fifteen countries, in Europe, the Americas, Africa, and Asia, addressing the questions of how youth talent development is organised and why elite youth sport has become so popular.
Book
Identification of neural oscillations and epileptiform changes in human brain organoids
Brain organoids represent a powerful tool for studying human neurological diseases, particularly those that affect brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes, raising the question of whether organoids possess sufficient neural network complexity to model these conditions. Here, we explore the network-level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex network dynamics reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from induced pluripotent stem cells from individuals with Rett syndrome, accompanied by transcriptomic differences revealed by single-cell analyses. We also rescue key physiological activities with an unconventional neuroregulatory drug, pifithrin-α. Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.
This paper explores neural network and cellular complexity within human cortical and subcortical fusion organoids. The platform is used to model network dysfunction associated with Rett syndrome and to identify new therapeutic candidates.
Journal Article
Altered Cardiac Electrophysiology and SUDEP in a Model of Dravet Syndrome
Dravet syndrome is a severe form of intractable pediatric epilepsy with a high incidence of SUDEP: Sudden Unexpected Death in epilepsy. Cardiac arrhythmias are a proposed cause for some cases of SUDEP, yet the susceptibility and potential mechanism of arrhythmogenesis in Dravet syndrome remain unknown. The majority of Dravet syndrome patients have de novo mutations in SCN1A, resulting in haploinsufficiency. We propose that, in addition to neuronal hyperexcitability, SCN1A haploinsufficiency alters cardiac electrical function and produces arrhythmias, providing a potential mechanism for SUDEP.
Postnatal day 15-21 heterozygous SCN1A-R1407X knock-in mice, expressing a human Dravet syndrome mutation, were used to investigate a possible cardiac phenotype. A combination of single cell electrophysiology and in vivo electrocardiogram (ECG) recordings were performed.
We observed a 2-fold increase in both transient and persistent Na(+) current density in isolated Dravet syndrome ventricular myocytes that resulted from increased activity of a tetrodotoxin-resistant Na(+) current, likely Nav1.5. Dravet syndrome myocytes exhibited increased excitability, action potential duration prolongation, and triggered activity. Continuous radiotelemetric ECG recordings showed QT prolongation, ventricular ectopic foci, idioventricular rhythms, beat-to-beat variability, ventricular fibrillation, and focal bradycardia. Spontaneous deaths were recorded in 2 DS mice, and a third became moribund and required euthanasia.
These data from single cell and whole animal experiments suggest that altered cardiac electrical function in Dravet syndrome may contribute to the susceptibility for arrhythmogenesis and SUDEP. These mechanistic insights may lead to critical risk assessment and intervention in human patients.
Journal Article
Cecal Ligation and Puncture Results in Long-Term Central Nervous System Myeloid Inflammation
Survivors of sepsis often experience long-term cognitive and functional decline. Previous studies utilizing lipopolysaccharide injection and cecal ligation and puncture in rodent models of sepsis have demonstrated changes in depressive-like behavior and learning and memory after sepsis, as well as evidence of myeloid inflammation and cytokine expression in the brain, but the long-term course of neuroinflammation after sepsis remains unclear. Here, we utilize cecal ligation and puncture with greater than 80% survival as a model of sepsis. We found that sepsis survivor mice demonstrate deficits in extinction of conditioned fear, but no acquisition of fear conditioning, nearly two months after sepsis. These cognitive changes occur in the absence of neuronal loss or changes in synaptic density in the hippocampus. Sepsis also resulted in infiltration of monocytes and neutrophils into the CNS at least two weeks after sepsis in a CCR2 independent manner. Cellular inflammation is accompanied by long-term expression of pro-inflammatory cytokine and chemokine genes, including TNFα and CCR2 ligands, in whole brain homogenates. Gene expression analysis of microglia revealed that while microglia do express anti-microbial genes and damage-associated molecular pattern molecules of the S100A family of genes at least 2 weeks after sepsis, they do not express the cytokines observed in whole brain homogenates. Our results indicate that in a naturalistic model of infection, sepsis results in long-term neuroinflammation, and that this sustained inflammation is likely due to interactions among multiple cell types, including resident microglia and peripherally derived myeloid cells.
Journal Article