Mathematical models of neuronal growth

The establishment of a functioning neuronal network is a crucial step in neural development. During this process, neurons extend neurites—axons and dendrites—to meet other neurons and interconnect. Therefore, these neurites need to migrate, grow, branch and find the correct path to their target by processing sensory cues from their environment. These processes rely on many coupled biophysical effects including elasticity, viscosity, growth, active forces, chemical signaling, adhesion and cellular transport. Mathematical models offer a direct way to test hypotheses and understand the underlying mechanisms responsible for neuron development. Here, we critically review the main models of neurite growth and morphogenesis from a mathematical viewpoint. We present different models for growth, guidance and morphogenesis, with a particular emphasis on mechanics and mechanisms, and on simple mathematical models that can be partially treated analytically.

Stimulation of Neurite Outgrowth Using Autologous NGF Bound at the Surface of a Fibrous Substrate

Peripheral nerve injury still remains a major clinical challenge, since the available solutions lead to dysfunctional nerve regeneration. Even though autologous nerve grafts are the gold standard, tissue engineered nerve guidance grafts are valid alternatives. Nerve growth factor (NGF) is the most potent neurotrophic factor. The development of a nerve guidance graft able to locally potentiate the interaction between injured neurons and autologous NGF would be a safer and more effective alternative to grafts that just release NGF. Herein, a biofunctional electrospun fibrous mesh (eFM) was developed through the selective retrieval of NGF from rat blood plasma. The neurite outgrowth induced by the eFM-NGF systems was assessed by culturing rat pheochromocytoma (PC12) cells for 7 days, without medium supplementation. The biological results showed that this NGF delivery system stimulates neuronal differentiation, enhancing the neurite growth more than the control condition.

Elevated IL-6 in Pre-Eclampsia Increases Neurite Growth and Mitochondrial Respiration in an in vitro Model of Neuronal Development

Pre-eclampsia (PE) is a common and serious hypertensive disorder of pregnancy, which affects 3-5% of first-time pregnancies and is a leading cause of maternal and neonatal morbidity and mortality. Prenatal exposure to PE is associated with an increased risk of neurodevelopmental disorders in affected offspring, although the cellular and molecular basis of this are largely unknown. In this study we examined the effects of exposure to maternal serum from women with PE or a healthy uncomplicated pregnancy on the survival, neurite growth and mitochondrial function of SH-SY5Y cells. We report that cells exposed to PE serum exhibited increased neurite growth and mitochondrial respiration, two important neurodevelopmental parameters, compared to those treated with control serum. Levels of the pleiotropic cytokine IL-6 were significantly elevated in the PE sera, and cells exposed to PE serum displayed increased phospho-STAT3 levels which is a key intracellular mediator of IL-6 signalling. Finally, we show that treating these cells with IL-6 alone is sufficient to induce a similar neurite growth and respiratory phenotype to PE serum-exposed cells. This suggests that elevated IL-6 seen in maternal serum in PE may be responsible at least in part for its inducing increased neurite growth and mitochondrial respiration in SH-SY5Y cells. Overall, this study demonstrates that there are circulating factors in the serum of women with pre-eclampsia that affect neuronal development and oxygen consumption differently to that of a healthy uncomplicated pregnancy, and that immune dysregulation via elevated IL-6 may be important in mediating these effects.

Inhibitor of Lysyl Oxidase in The Optic Nerve Head Complex Imparts Partial Protection Against Injury in Experimental Glaucoma

Background: Glaucoma is a neurodegenerative disease with the progressive loss of retinal ganglion cells and changes in the optic nerve head (ONH). These changes are exacerbated by an increase in intraocular pressure (IOP). Methods: The effect of scleral and optic nerve softening with beta aminopropionitrile a lysyl oxidase inhibitor (BAPN) and stiffening with genipin, in a model of chronic increase of IOP was evaluated. Changes in optic nerve and retina were evaluated. H&E, Bielschowsky's silver staining and glial fibrillary acid protein (GFAP) staining was performed on optic nerve, retina and scleral structures. Changes in the expression of the Ywhab, Yhwaz (prosurvival genes), C3 complement (complement C3 inflammatory marker), CPG15 (neurite growth and neural survival gene) GFAP (glial activator marker) genes was carried out in the different groups.Results: Protective effect of BAPN was evident by the preservation of the optic nerve structure, and with the conservation of the retinal structures, while deleterious changes were evident in the stiffening of ONH complex, characterized by the increase in the glia, changes in the optic nerve, and disorganization in the retina. BAPN induced a reduction in the expression of Ywhab, Yhwaz (prosurvival genes), C3 and GFAP (inflammatory and glial marker) and CPG15. Conclusions: These findings support the critical involvement of changes in the ONH stiffness in the progression of glaucoma. The control of this variable as a regulatory mechanism in the progression of neural glaucomatous damage must be considered and would be explored as a possible intervention in glaucoma management.

Serotonergic Psychedelics in Neural Plasticity

Psychedelics, compounds that can induce dramatic changes in conscious experience, have been used by humans for centuries. Recent studies have shown that certain psychedelics can induce neural plasticity by promoting neurite growth and synapse formation. In this review, we focus on the role of classical serotonergic psychedelics in neural plasticity and discuss its implication for their therapeutic potentials.

NME1 Protects Against Neurotoxin-, α-Synuclein- and LRRK2-Induced Neurite Degeneration in Cell Models of Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disease characterised by the progressive degeneration of midbrain dopaminergic neurons, coupled with the intracellular accumulation of α-synuclein. Axonal degeneration is a central part of the pathology of PD. While the majority of PD cases are sporadic, some are genetic; the G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is the most common genetic form. The application of neurotrophic factors to protect dopaminergic neurons is a proposed experimental therapy. One such neurotrophic factor is growth differentiation factor (GDF)5. GDF5 is a dopaminergic neurotrophic factor that has been shown to upregulate the expression of a protein called nucleoside diphosphate kinase A (NME1). However, whether NME1 is neuroprotective in cell models of axonal degeneration of relevance to PD is unknown. Here we show that treatment with NME1 can promote neurite growth in SH-SY5Y cells, and in cultured dopaminergic neurons treated with the neurotoxin 6-hydroxydopamine (6-OHDA). Similar effects of NME1 were found in SH-SY5Y cells and dopaminergic neurons overexpressing human wild-type α-synuclein, and in stable SH-SY5Y cell lines carrying the G2019S LRRK2 mutation. We found that the effects of NME1 require the RORα/ROR2 receptors. Furthermore, increased NF-κB-dependent transcription was partially required for the neurite growth-promoting effects of NME1. Finally, a combined bioinformatics and biochemical analysis of the mitochondrial oxygen consumption rate revealed that NME1 enhanced mitochondrial function, which is known to be impaired in PD. These data show that recombinant NME1 is worthy of further study as a potential therapeutic agent for axonal protection in PD.

Physical Cues of Matrices Reeducate Nerve Cells

The behavior of nerve cells plays a crucial role in nerve regeneration. The mechanical, topographical, and electrical microenvironment surrounding nerve cells can activate cellular signaling pathways of mechanical transduction to affect the behavior of nerve cells. Recently, biological scaffolds with various physical properties have been developed as extracellular matrix to regulate the behavior conversion of nerve cell, such as neuronal neurite growth and directional differentiation of neural stem cells, providing a robust driving force for nerve regeneration. This review mainly focused on the biological basis of nerve cells in mechanical transduction. In addition, we also highlighted the effect of the physical cues, including stiffness, mechanical tension, two-dimensional terrain, and electrical conductivity, on neurite outgrowth and differentiation of neural stem cells and predicted their potential application in clinical nerve tissue engineering.

Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue

Activation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NT-3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NT-3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NT-3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NT-3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC +/−). Increasing NT-3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC + /− or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NT-3 is a fat-derived neurotrophic factor that regulates SNS innervation, energy metabolism and obesity.