Front Cell Neurosci
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Front Cell Neurosci · Jan 2015
ReviewSystemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration.
The nervous and immune systems have evolved in parallel from the early bilaterians, in which innate immunity and a central nervous system (CNS) coexisted for the first time, to jawed vertebrates and the appearance of adaptive immunity. The CNS feeds from, and integrates efferent signals in response to, somatic and autonomic sensory information. The CNS receives input also from the periphery about inflammation and infection. ⋯ While SB manifestations are transient and self-limited, under states of persistent systemic inflammatory response the cognitive and behavioral changes can become permanent. For example, cognitive decline is almost universal in sepsis survivors, and a common finding in patients with systemic lupus erythematosus. Here, we review recent genetic evidence suggesting an association between neurodegenerative disorders and persistent immune activation; clinical and experimental evidence indicating previously unidentified immune-mediated pathways of neurodegeneration; and novel immunomodulatory targets and their potential relevance for neurodegenerative disorders.
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Front Cell Neurosci · Jan 2015
ReviewLost highway(s): barriers to postnatal cortical neurogenesis and implications for brain repair.
The genesis of the cerebral cortex is a highly complex and tightly-orchestrated process of cell division, migration, maturation, and integration. Developmental missteps often have catastrophic consequences on cortical function. Further, the cerebral cortex, in which neurogenesis takes place almost exclusively prenatally, has a very poor capacity for replacement of neurons lost to injury or disease. ⋯ Herein, we review corticogenesis from the context of regeneration and detail the strategies to promote neurogenesis, including interneuron transplants and glial reprogramming. Such strategies circumvent the "lost highways" which are critical for cortical development but are absent in the adult. These new approaches may provide for the possibility of meaningful clinical regeneration of elements of cortical circuitry lost to trauma and disease.
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Adult neurogenesis has been convincingly demonstrated in two regions of the mammalian brain: the sub-granular zone (SGZ) of the dentate gyrus (DG) in the hippocampus, and the sub-ventricular zone (SVZ) of the lateral ventricles (LV). SGZ newborn neurons are destined to the granular cell layer (GCL) of the DG, while new neurons from the SVZ neurons migrate rostrally into the olfactory bulb (OB). The process of adult neurogenesis persists throughout life and is supported by a pool of neural stem cells (NSCs), which reside in a unique and specialized microenvironment known as "neurogenic niche". ⋯ EVs, and particularly exosomes, are implicated in the transfer of mRNAs, microRNAs (miRNAs), proteins and lipids between cells and thus are able to modify the function of recipient cells. Exosomes appear to play a significant role in different stem cell niches such as the mesenchymal stem cell niche, cancer stem cell niche and pre-metastatic niche; however, their roles in adult neurogenic niches remain virtually unexplored. This review focuses on the current knowledge regarding the functional relationship between cellular and extracellular components of the adult SVZ and SGZ neurogenic niches, and the growing evidence that supports the potential role of exosomes in the physiology and pathology of adult neurogenesis.
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Gastrointestinal (GI) pain is a common clinical problem, for which effective therapy is quite limited. Sensations from the GI tract, including pain, are mediated largely by neurons in the dorsal root ganglia (DRG), and to a smaller extent by vagal afferents emerging from neurons in the nodose/jugular ganglia. Neurons in rodent DRG become hyperexcitable in models of GI pain (e.g., gastric or colonic inflammation), and can serve as a source for chronic pain. ⋯ The contribution of these changes to visceral pain remains to be determined. These results indicate that although visceral pain is unique, it shares basic mechanisms with somatic pain, suggesting that therapeutic approaches to both pain types may be similar. Future research in this field should include additional types of GI injury and also other types of visceral pain.
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Front Cell Neurosci · Jan 2015
Age- and sex-dependent susceptibility to phenobarbital-resistant neonatal seizures: role of chloride co-transporters.
Ischemia in the immature brain is an important cause of neonatal seizures. Temporal evolution of acquired neonatal seizures and their response to anticonvulsants are of great interest, given the unreliability of the clinical correlates and poor efficacy of first-line anti-seizure drugs. The expression and function of the electroneutral chloride co-transporters KCC2 and NKCC1 influence the anti-seizure efficacy of GABAA-agonists. ⋯ This study established a novel neonatal mouse model of PB-resistant seizures that demonstrates age/sex-dependent susceptibility. The age-dependent profile of KCC2 expression and its post-insult downregulation may underlie the PB-resistance reported in this model. Blocking NKCC1 with low-dose BTN following PB treatment failed to improve PB-efficacy.