Neuroscience
-
The pontine micturition center or Barrington's nucleus (BN) - besides regulating micturition - co-regulates the activity of other pelvic viscera such as the colon and genitals. At present, this issue is gaining particular importance due to: (i) recent findings of α-synuclein in BN, (ii) known urinary dysfunction in parkinsonian patients (part of the so-called non-motor symptoms), other patients with dementia and as in very old individuals; and (iii) its proximity to the pedunculopontine nucleus, a surgical target in deep brain stimulation for Parkinson's disease (PD). ⋯ The involvement of dopaminergic activity (physiologic inhibition of the micturition reflex mediated by dopaminergic D1 activity) that diminishes in Parkinsonism and leads to overactivity of the micturition reflex is also well known. In this review, the integrating role of the BN in the context of vesical and gastrointestinal behavior is revisited, and the principal morpho-functional findings that associate dysfunction with the urinary disorders that appear during the pre-motor stages of PD are summarized.
-
The KCNJ10 gene which encodes an inwardly rectifying K(+) channel Kir4.1 subunit plays an essential role in the inner ear and hearing. Mutations or deficiency of KCNJ10 can cause hearing loss with EAST or SeSAME syndromes. This review mainly focuses on the expression and function of Kir4.1 potassium channels in the inner ear and hearing. ⋯ Kir4.1 deficiency leads to hearing loss with the absence of EP and spiral ganglion neuron degeneration. Deafness mutants show loss-of-function and reduced channel membrane-targeting and currents, which can be rescued upon by co-expression with wild-type Kir4.1. This review provides insights for further understanding Kir potassium channel function in the inner ear and the pathogenesis of deafness due to KCNJ10 deficiency, and also provides insights for developing therapeutic strategies targeting this deafness.
-
Review
Transitioning from genotypes to epigenotypes: why the time has come for medulloblastoma epigenomics.
Recent advances in genomic technologies have allowed for tremendous progress in our understanding of the biology underlying medulloblastoma, a malignant childhood brain tumor. Consensus molecular subgroups have been put forth by the pediatric neuro-oncology community and next-generation genomic studies have led to an improved description of driver genes and pathways somatically altered in these subgroups. In contrast to the impressive pace at which advances have been made at the level of the medulloblastoma genome, comparable studies of the epigenome have lagged behind. ⋯ Past studies of DNA methylation-dependent gene silencing and microRNA expression analyses further support the concept of medulloblastoma as an epigenetic disease. In this Review, we aim to summarize the key findings of past reports pertaining to medulloblastoma epigenetics as well as recent and ongoing genomic efforts linking somatic alterations of the genome with inferred deregulation of the epigenome. In addition, we predict what is on the horizon for medulloblastoma epigenetics and how aberrant changes in the medulloblastoma epigenome might serve as an attractive target for future therapies.
-
Review
Significance of epigenetics for understanding brain development, brain evolution and behaviour.
Two major environmental developments have occurred in mammalian evolution which have impacted on the genetic and epigenetic regulation of brain development. The first of these was viviparity and development of the placenta which placed a considerable burden of time and energy investment on the matriline, and which resulted in essential hypothalamic modifications. Maternal feeding, maternal care, parturition, milk letdown and the suspension of fertility and sexual behaviour are all determined by the maternal hypothalamus and have evolved to meet foetal needs under the influence of placental hormones. ⋯ Moreover, major treatments for schizophrenia over the past 40 years have included the drugs lithium and valproate, both of which we now know are histone deacetylases. It is rarely the heritable dysfunctioning of these epigenetic mechanisms that is at fault, but the timing, duration and place where they are deployed. The timing and complexity in the development of the neocortex makes this region of the brain more vulnerable to perturbations.
-
While the importance of epigenetic mechanisms is well established for numerous aspects of cell differentiation and development, recent findings have shown epigenetic processes to be a critical regulatory component in postmitotic neurons. Particularly intriguing, and potentially significant, are data demonstrating epigenetic regulation of cognitive behaviors. ⋯ Here, we review the evidence for the epigenetic control of cognition and the role of epigenetic dysregulation in mental disorders. A better understanding of epigenetic mechanisms will increase our fundamental knowledge of cognition and also provide new and exciting avenues of treatment for various mental disorders.