This conference proceedings text features research papers that address novel applications of computer, physical, engineering and mathematical models for solving modern challenging problems in life sciences. All the papers, presented at the Computational Models for Life Sciences conference held in 2007, have been peer-reviewed. They cover a huge range of topics, including image analysis, computer vision, and pattern analysis and classification, among many others.
Abstract Cerebral dopamine neurotrophic factor (CDNF) is expressed in the brain and is neuroprotective. We have previously shown that CDNF is also expressed in the bowel and that its absence leads to degeneration and autophagy in the enteric nervous system (ENS), particularly in the submucosal plexus. We now demonstrate that enteric CDNF immunoreactivity is restricted to neurons (submucosal > myenteric) and is not seen in glia, interstitial cells of Cajal, or smooth muscle. Expression of CDNF, moreover, is essential for the normal development and survival of enteric dopaminergic neurons; thus, expression of the dopaminergic neuronal markers, dopamine, tyrosine hydroxylase, and dopamine transporter are deficient in the ileum of Cdnf −/− mice. The normal age‐related decline in proportions of submucosal dopaminergic neurons is exacerbated in Cdnf −/− animals. The defect in Cdnf −/− animals is not dopamine‐restricted; proportions of other submucosal neurons (NOS‐, GABA‐, and CGRP‐expressing), are also deficient. The deficits in submucosal neurons are reflected functionally in delayed gastric emptying, slowed colonic motility, and prolonged total gastrointestinal transit. CDNF is expressed selectively in isolated enteric neural crest‐derived cells (ENCDC), which also express the dopamine‐related transcription factor Foxa2. Addition of CDNF to ENCDC promotes development of dopaminergic neurons; moreover, survival of these neurons becomes CDNF‐dependent after exposure to bone morphogenetic protein 4. The effects of neither glial cell‐derived neurotrophic factor (GDNF) nor serotonin are additive with CDNF. We suggest that CDNF plays a critical role in development and long‐term maintenance of dopaminergic and other sets of submucosal neurons.
Abstract The terminal portion of the bowel of the lethal spotted mutant mouse (ls/ls) lacks an enteric nervous system due to the failure of neural crest precursors to colonize this region during embryonic life. As a result, the mouse develops congenital megacolon. We have postulated that the defect occurs because the microenvironment of the aganglionic segment is segmentally abnormal and does not permit the migration and/or survival of the enteric neural or glial precursors in the affected zone. We have examined the terminal segment of adult ls/ls and control mice by light and electron microscopy to determine if the defect is associated with identifiable structural abnormalities that persist to maturity. A striking abnormality is an overgrowth of the muscularis mucosa in the adult ls/ls mouse, particularly in the outer longitudinal layer. Electron microscopy also reveals an extensive thickening of the basal lamina around smooth muscle cells. In addition, nerves that are derived from fibers that are extrinsic to this area are abnormal. Large bundles of nerve fibers, some of which contain myelinated axons, large‐caliber unmyelinated axons, and abundant collagen, are prominent in the intermuscular region of the aganglionic segments and often reach into the submucosa. The supporting cells of the unmyelinated and myelinated nerves in the aganglionic segment have voluminous perineural cytoplasm typical of immature Schwann cells. They also exhibit intermediate filaments in their cytoplasm. Otherwise they have the typical morphology of peripheral Schwann cells, rather than enteric glia, including individual ensheathment of axons and a surrounding basal lamina. We suggest that the extracellular matrix and/or cells of mesenchymal origin of the terminal bowel of the ls/ls mouse may prevent the ingrowth of the normal precursors of the glia as well as neurons of the enteric nervous system, but may permit or even encourage the ingrowth of abnormal numbers of extrinsic axons.
As information about the world traverses the brain, the signals exchanged between neurons are passed and modulated by synapses, or specialized contacts between neurons. While neurotransmitter-based synapses tend to exert either excitatory or inhibitory pulses of influence on the postsynaptic neuron, electrical synapses, composed of plaques of gap junction channels, continuously transmit signals that can either excite or inhibit a coupled neighbor. A growing body of evidence indicates that electrical synapses, similar to their chemical counterparts, are modified in strength during physiological neuronal activity. The synchronizing role of electrical synapses in neuronal oscillations has been well established, but their impact on transient signal processing in the brain is much less understood. Here we constructed computational models based on the canonical feedforward neuronal circuit and included electrical synapses between inhibitory interneurons. We provided discrete closely-timed inputs to the circuits, and characterize the influence of electrical synapse strength on both subthreshold summation and spike trains in the output neuron. Our simulations highlight the diverse and powerful roles that electrical synapses play even in simple circuits. Because these canonical circuits are represented widely throughout the brain, we expect that these are general principles for the influence of electrical synapses on transient signal processing across the brain.
'/%3e%3c/defs%3e%3cpath fill='%23012169' d='M0 0h10080v5040H0z'/%3e%3cpath stroke='%23fff' stroke-width='.6' d='m0 0 6 3m0-3L0 3' clip-path='url(%23b)' transform='scale(840)'/%3e%3cpath stroke='%23e4002b' stroke-width='.4' d='m0 0 6 3m0-3L0 3' clip-path='url(%23c)' transform='scale(840)'/%3e%3cpath stroke='%23fff' stroke-width='840' d='M2520 0v2520M0 1260h5040'/%3e%3cpath stroke='%23e4002b' stroke-width='504' d='M2520 0v2520M0 1260h5040'/%3e%3cg fill='%23fff'%3e%3cuse xlink:href='%23d' x='2520' y='3780'/%3e%3cuse xlink:href='%23a' x='7560' y='4200'/%3e%3cuse xlink:href='%23a' x='6300' y='2205'/%3e%3cuse xlink:href='%23a' x='7560' y='840'/%3e%3cuse xlink:href='%23a' x='8680' y='1869'/%3e%3cuse xlink:href='%23e' x='8064' y='2730'/%3e%3c/g%3e%3c/svg%3e)