Prenatal Alcohol Exposure Inhibits Transient Expression of Autophagy and Synaptic Proteins in Developing Brain.

Introduction: Neuronal apoptosis and consequent inhibition of autophagy, with loss of synaptic connections are central events in the genesis of fetal alcohol spectrum disorders (FASD). However, studies of molecular mechanisms of autophagy in human fetal brain are limited. Recently, prenatal exposure to EtOH was associated with reduced miRNA-9 levels in fetal brain-derived exosomes (FB- Es) isolated from maternal plasma, which correlated with small eyes, an anatomical hallmark of fetal alcohol syndrome (FAS).

Fetal Brain-Derived Exosomal miRNAs from Maternal Blood: Potential Diagnostic Biomarkers for Fetal Alcohol Spectrum Disorders (FASDs).

Fetal alcohol spectrum disorders (FASDs) are leading causes of neurodevelopmental disability but cannot be diagnosed early in utero. Because several microRNAs (miRNAs) are implicated in other neurological and neurodevelopmental disorders, the effects of EtOH exposure on the expression of these miRNAs and their target genes and pathways were assessed. In women who drank alcohol (EtOH) during pregnancy and non-drinking controls, matched individually for fetal sex and gestational age, the levels of miRNAs in fetal brain-derived exosomes (FB-Es) isolated from the mothers' serum correlated well with the contents of the corresponding fetal brain tissues obtained after voluntary pregnancy termination.

Combined RhoA morpholino and ChABC treatment protects identified lamprey neurons from retrograde apoptosis after spinal cord injury.

Previously, we reported that RhoA knockdown by morpholino antisense oligonucleotides (MOs), and enzymatic digestion of chondroitin sulfate proteoglycans (CSPGs) at the site of injury with chondroitinase ABC (ChABC), each can reduce retrograde neuronal apoptosis after spinal cord transection in the lamprey. To elucidate the mechanisms in neuronal survival and axon regeneration, we have investigated whether these two effects are additive . We used lampreys as a spinal cord injury model.

Maternal Blood Lipid Biomarkers of Oligodendrocyte Pathology to Predict Fetal Alcohol Spectrum Disorders.

Introduction: Up to 9.9% of children have fetal alcohol spectrum disorders (FASD), the most frequent cause of intellectual disability in the US. FASD may involve abnormal brain development, including dysmyelination, suggesting abnormal development of oligodendrocytes (OLs), which make myelin and are rich in lipids.

Exosomal Lipid Biomarkers of Oligodendrocyte Pathology to Predict Scoliosis in Children with Cerebral Palsy.

Introduction: Cerebral Palsy (CP), the most common cause of disability in children, is phenotypically heterogeneous. Approximately 20% of cases develop severe scoliosis. A pathological hallmark of CP is periventricular leukomalacia (PVL), which is due to dysmyelination, suggesting the possibility of a lipidomic abnormality.

Molecular Markers in Maternal Blood Exosomes Allow Early Detection of Fetal Alcohol Spectrum Disorders.

Prenatal alcohol exposure can cause developmental abnormalities (fetal alcohol spectrum disorders; FASD), including small eyes, face and brain, and neurobehavioral deficits. These cannot be detected early in pregnancy with available imaging techniques. Early diagnosis could facilitate development of therapeutic interventions.

Transcriptomes of Injured Lamprey Axon Tips: Single-Cell RNA-Seq Suggests Differential Involvement of MAPK Signaling Pathways in Axon Retraction and Regeneration after Spinal Cord Injury.

Axotomy in the CNS activates retrograde signals that can trigger regeneration or cell death. Whether these outcomes use different injury signals is not known. Local protein synthesis in axon tips plays an important role in axon retraction and regeneration.

The Composition and Cellular Sources of CSPGs in the Glial Scar After Spinal Cord Injury in the Lamprey.

Axon regrowth after spinal cord injury (SCI) is inhibited by several types of inhibitory extracellular molecules in the central nervous system (CNS), including chondroitin sulfate proteoglycans (CSPGs), which also are components of perineuronal nets (PNNs). The axons of lampreys regenerate following SCI, even though their spinal cords contain CSPGs, and their neurons are enwrapped by PNNs. Previously, we showed that by 2 weeks after spinal cord transection in the lamprey, expression of CSPGs increased in the lesion site, and thereafter, decreased to pre-injury levels by 10 weeks.

The GLT-1 enhancer clavulanic acid suppresses cocaine place preference behavior and reduces GCPII activity and protein levels in the rat nucleus accumbens.

The β-lactam antibiotic ceftriaxone (CTX) is a glutamate transporter subtype 1 (GLT-1) enhancer that reduces cocaine reinforcing efficacy and relapse in rats, but pharmacokinetic liabilities limit translational utility. An attractive alternative is clavulanic acid (CLAV), a structurally related β-lactamase inhibitor and component of FDA-approved Augmentin. CLAV retains the GLT-1 enhancing effects of CTX but displays greater oral bioavailability, brain penetrability and negligible antibacterial activity.

Oligodendrocyte pathology in fetal alcohol spectrum disorders.

The pathology of fetal alcohol syndrome and the less severe fetal alcohol spectrum disorders includes brain dysmyelination. Recent studies have shed light on the molecular mechanisms underlying these white matter abnormalities. Rodent models of fetal alcohol syndrome and human studies have shown suppressed oligodendrocyte differentiation and apoptosis of oligodendrocyte precursor cells.

Chondroitinase ABC Promotes Axon Regeneration and Reduces Retrograde Apoptosis Signaling in Lamprey.

Paralysis following spinal cord injury (SCI) is due to failure of axonal regeneration. It is believed that axon growth is inhibited by the presence of several types of inhibitory molecules in central nervous system (CNS), including the chondroitin sulfate proteoglycans (CSPGs). Many studies have shown that digestion of CSPGs with chondroitinase ABC (ChABC) can enhance axon growth and functional recovery after SCI.

HIV-1 and HIV-1-Tat Induce Mitochondrial DNA Damage in Human Neurons.

Introduction: Mitochondrial dysregulation is a key event in HIV-1 infection. Recent studies have suggested that age-related neurodegenerative disorders are associated with increased mitochondrial DNA (mtDNA) damage. As accelerated ageing was found in HIV-1 patients, we hypothesized that HIV-1 infection or HIV-1 proteins can lead to mtDNA damage.

Activated Erk Is an Early Retrograde Signal After Spinal Cord Injury in the Lamprey.

We previously reported that spinal cord transection (TX) in the lamprey causes mRNA to accumulate in the injured tips of large reticulospinal (RS) axons. We sought to determine whether this mRNA accumulation results from phosphorylation and transport of retrograde signals, similar to what has been reported in mammalian peripheral nerve. Extracellular signal-regulated protein kinase (Erk), mediates the neurite outgrowth-promoting effects of many neurotrophic factors.

Source of Early Regenerating Axons in Lamprey Spinal Cord Revealed by Wholemount Optical Clearing with BABB.

Many studies of axon regeneration in the lamprey focus on 18 pairs of large identified reticulospinal (RS) neurons, whose regenerative abilities have been individually quantified. Their axons retract during the first 2 weeks after transection (TX), and many grow back to the site of injury by 4 weeks. However, locomotor movements begin before 4 weeks and the lesion is invaded by axons as early as 2 weeks post-TX.

Mechanisms of Axon Elongation Following CNS Injury: What Is Happening at the Axon Tip?

After an injury to the central nervous system (CNS), functional recovery is limited by the inability of severed axons to regenerate and form functional connections with appropriate target neurons beyond the injury. Despite tremendous advances in our understanding of the mechanisms of axon growth, and of the inhibitory factors in the injured CNS that prevent it, disappointingly little progress has been made in restoring function to human patients with CNS injuries, such as spinal cord injury (SCI), through regenerative therapies. Clearly, the large number of overlapping neuron-intrinsic and -extrinsic growth-inhibitory factors attenuates the benefit of neutralizing any one target.

Advances in the Signaling Pathways Downstream of Glial-Scar Axon Growth Inhibitors.

Axon growth inhibitors generated by reactive glial scars play an important role in failure of axon regeneration after CNS injury in mature mammals. Among the inhibitory factors, chondroitin sulfate proteoglycans (CSPGs) are potent suppressors of axon regeneration and are important molecular targets for designing effective therapies for traumatic brain injury or spinal cord injury (SCI). CSPGs bind with high affinity to several transmembrane receptors, including two members of the leukocyte common antigen related (LAR) subfamily of receptor protein tyrosine phosphatases (RPTPs).

PTPσ Knockdown in Lampreys Impairs Reticulospinal Axon Regeneration and Neuronal Survival After Spinal Cord Injury.

Traumatic spinal cord injury (SCI) results in persistent functional deficits due to the lack of axon regeneration within the mammalian CNS. After SCI, chondroitin sulfate proteoglycans (CSPGs) inhibit axon regrowth putative interactions with the LAR-family protein tyrosine phosphatases, PTPσ and LAR, localized on the injured axon tips. Unlike mammals, the sea lamprey, , robustly recovers locomotion after complete spinal cord transection (TX).

Heterogeneity in the regenerative abilities of central nervous system axons within species: why do some neurons regenerate better than others?

Some neurons, especially in mammalian peripheral nervous system or in lower vertebrate or in vertebrate central nervous system (CNS) regenerate after axotomy, while most mammalian CNS neurons fail to regenerate. There is an emerging consensus that neurons have different intrinsic regenerative capabilities, which theoretically could be manipulated therapeutically to improve regeneration. Population-based comparisons between "good regenerating" and "bad regenerating" neurons in the CNS and peripheral nervous system of most vertebrates yield results that are inconclusive or difficult to interpret.