Cylindrical spirals and other concentric structures of skeletal muscle in patients with neurological diseases.

Cylindrical spirals (CSs) are ultrastructurally distinct, intracytoplasmic inclusions characterized by concentrically wrapped lamellae, which are rarely found in skeletal muscle biopsies on electron microscopy (EM). CSs are often confused with other EM concentric structures including concentric laminated bodies and mitochondrial concentric cristae (MCC), due to similarities in these ultrastructures. In this study, we found CSs in 9 muscle biopsies from 9 patients, accounting for 0.5% of the biopsies examined routinely by EM. The frequency of CSs in these muscles varied from sparse and segregated to focally frequent and aggregated. CS-associated features included muscle fiber denervation atrophy in all 9 cases, fiber type grouping in 7/8 cases, tubular aggregates in 3/9 cases, and MCC in 2/9 cases. We also compared the concentric structures and highlighted their differences to distinguish CSs from other similar structures. Clinically, 8 out of 9 patients were adults aged 41-74 years and only one patient was 17 month-old. CSs were associated with several neurological diseases including Huntington's disease, amyotrophic lateral sclerosis, Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes, and other complex neurological disorders with neuropathy/encephalopathy, as well as anti-MDA5+ dermatomyositis. Eight of nine patients had genetic findings such as trinucleotide repeat expansion of huntingtin gene, ALS2 variant, MT-TL1 m.3243A > G mutation, and PMP 22 gene deletion. These results suggest that CSs may be highly variable in frequency and likely are under-reported/under-detected; they may be associated with neurogenic myopathy or central/peripheral nervous system disorders including some genetic neurological/neuromuscular diseases. Our findings of more CS-associated neurological diseases and an association of CSs with muscle neurogenic features may contribute to a better understanding of the clinico-pathological significance of CSs.

Neurofilaments in neurologic disorders and beyond.

Many neurologic diseases can initially present as a diagnostic challenge and even when a diagnosis is made, monitoring of disease activity, progression and response to therapy may be limited with existing clinical and paraclinical assessments. As such, the identification of disease specific biomarkers provides a promising avenue by which diseases can be effectively diagnosed, monitored and used as a prognostic indicator for long-term outcomes. Neurofilaments are an integral component of the neuronal cytoskeleton, where assessment of neurofilaments in the blood, cerebrospinal fluid (CSF) and diseased tissue has been shown to have value in providing diagnostic clarity, monitoring disease activity, tracking progression and treatment efficacy, as well as lending prognostic insight into long-term outcomes. As such, this review attempts to provide a glimpse into the structure and function of neurofilaments, their role in various neurologic and non-neurologic disorders, including uncommon conditions with recent knowledge of neurofilament-related pathology, as well as their applicability in future clinical practice.

The effect of hemorrhage on the development of the postnatal mouse cerebellum.

Recent studies have shown that hemorrhagic injury in the preterm cerebellum leads to long-term neurological sequelae, such as motor, affective, and cognitive dysfunction. How cerebellar hemorrhage (CBH) affects the development and function of the cerebellum is largely unknown. Our study focuses on developing a mouse model of CBH to determine the anatomical, behavioral, and molecular phenotypes resulting from a hemorrhagic insult to the developing cerebellum. To induce CBH in the postnatal mouse cerebellum, we injected bacterial collagenase, which breaks down surrounding blood vessel walls, into the fourth ventricle at postnatal day two. We found a reduction in cerebellar size during postnatal growth, a decrease in granule cells, and persistent neurobehavioural abnormalities similar to abnormalities reported in preterm infants with CBH. We further investigated the molecular pathways that may be perturbed due to postnatal CBH and found a significant upregulation of genes in the inflammatory and sonic hedgehog pathway. These results point to an activation of endogenous mechanisms of injury and neuroprotection in response to postnatal CBH. Our study provides a preclinical model of CBH that may be used to understand the pathophysiology of preterm CBH and for potential development of preventive therapies and treatments.

Bi-parental care contributes to sexually dimorphic neural cell genesis in the adult mammalian brain.

Early life events can modulate brain development to produce persistent physiological and behavioural phenotypes that are transmissible across generations. However, whether neural precursor cells are altered by early life events, to produce persistent and transmissible behavioural changes, is unknown. Here, we show that bi-parental care, in early life, increases neural cell genesis in the adult rodent brain in a sexually dimorphic manner. Bi-parentally raised male mice display enhanced adult dentate gyrus neurogenesis, which improves hippocampal neurogenesis-dependent learning and memory. Female mice display enhanced adult white matter oligodendrocyte production, which increases proficiency in bilateral motor coordination and preference for social investigation. Surprisingly, single parent-raised male and female offspring, whose fathers and mothers received bi-parental care, respectively, display a similar enhancement in adult neural cell genesis and phenotypic behaviour. Therefore, neural plasticity and behavioural effects due to bi-parental care persist throughout life and are transmitted to the next generation.

PDGFRα expression distinguishes GFAP-expressing neural stem cells from PDGF-responsive neural precursors in the adult periventricular area.

Jackson et al. (2006) have reported that adult glial fibrillary acid protein (GFAP)-expressing neural stem cells (NSCs) also express platelet-derived growth factor (PDGF) receptor-α (PDGFRα), and that their stimulation by PDGF induced the formation of a glioma-like mass. Here, we reexamined the relationship between PDGFRα and GFAP expression within the three-dimensional organization of the adult periventricular area. Using four independent PDGFRα antibodies, we found that adult mouse GFAP-expressing NSCs and PDGFRα-expressing cells represent two distinct populations of neural precursors. Examination of the adult periventricular area in a mouse line that expresses nuclear-localized enhanced green fluorescent protein under the control of the PDGFRα promoter confirmed that GFAP-expressing NSCs do not express PDGFRα. Furthermore, PDGF-responsive neural precursors were found at least one cell layer subjacent to the ependymal layer, and were evenly distributed across the lateral ventricular wall, which contrasts with the reported patchy and often ependymal localization of adult GFAP-expressing NSCs. Adult human PDGFRα-expressing neural precursors were also found not to express GFAP. PDGF-responsive neural precursors, but not GFAP-expressing NSCs, responded to infusions of PDGF by generating glioma-like masses. Our results do not support the view that GFAP-expressing NSCs are the origin of glioma-like masses that form after intraventricular PDGF infusion.

A novel pathway regulates memory and plasticity via SIRT1 and miR-134.

The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies. Its mammalian homologue, SIRT1, seems to have evolved complex systemic roles in cardiac function, DNA repair and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 has a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, whereas its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of cAMP response binding protein (CREB) expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and brain-derived neurotrophic factor (BDNF), thereby impairing synaptic plasticity. These findings demonstrate a new role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signalling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of central nervous system disorders.

Paternal recognition of adult offspring mediated by newly generated CNS neurons.

In mammals, olfaction is often used to distinguish individuals on the basis of their unique odor types (genetically programmed body odors). Parental-offspring recognition behavior is mediated, in part, by learning and processing of different odor types and is crucial for reproductive success. Maternal recognition behavior and associated brain plasticity has been well characterized, but paternal recognition behavior and brain plasticity is poorly understood. We found that paternal-adult offspring recognition behavior in mice was dependent on postnatal offspring interaction and was associated with increased neurogenesis in the paternal olfactory bulb and hippocampus. Newly generated paternal olfactory interneurons were preferentially activated by adult offspring odors. Disrupting prolactin signaling abolished increased paternal neurogenesis and adult offspring recognition. Rescuing this neurogenesis restored recognition behavior. Thus, neurogenesis in the paternal brain may be involved in offspring recognition.

Identity crisis for adult periventricular neural stem cells: subventricular zone astrocytes, ependymal cells or both?

A population of neural stem cells (NSCs) resides adjacent to the lateral ventricles in the adult mammalian brain. Despite knowledge of their existence since the early 1990s, their identity remains controversial, with evidence suggesting that they may be ependymal cells, glial fibrillary acidic protein (GFAP)-expressing subventricular zone (SVZ) cells or several distinct NSC populations. This issue has major implications for the therapeutic use of NSCs as well as for the study and treatment of brain cancers. Recent studies have both shed light on the issue and added to the controversy.

Male pheromone-stimulated neurogenesis in the adult female brain: possible role in mating behavior.

The regulation of female reproductive behaviors may involve memories of male pheromone signatures, formed in part by neural circuitry involving the olfactory bulb and hippocampus. These neural structures are the principal sites of adult neurogenesis; however, previous studies point to their independent regulation by sensory and physiological stimuli. Here we report that the pheromones of dominant (but not subordinate) males stimulate neuronal production in both the olfactory bulb and hippocampus of female mice, which are independently mediated by prolactin and luteinizing hormone, respectively. Neurogenesis induced by dominant-male pheromones correlates with a female preference for dominant males over subordinate males, whereas blocking neurogenesis with the mitotic inhibitor cytosine arabinoside eliminated this preference. These results suggest that male pheromones are involved in regulating neurogenesis in both the olfactory bulb and hippocampus, which may be important for female reproductive success.

White matter plasticity and enhanced remyelination in the maternal CNS.

Myelination, the process in which oligodendrocytes coat CNS axons with a myelin sheath, represents an important but poorly understood form of neural plasticity that may be sexually dimorphic in the adult CNS. Remission of multiple sclerosis during pregnancy led us to hypothesize that remyelination is enhanced in the maternal brain. Here we report an increase in the generation of myelin-forming oligodendrocytes and in the number of myelinated axons in the maternal murine CNS. Remarkably, pregnant mice have an enhanced ability to remyelinate white matter lesions. The hormone prolactin regulates oligodendrocyte precursor proliferation and mimics the regenerative effects of pregnancy. This suggests that maternal white matter plasticity imparts a striking ability to repair demyelination and identifies prolactin as a potential therapeutic agent.