The wiring of the nervous system is arguably the most challenging question in developmental biology. In recent years there has been tremendous progress in elucidating how the axons of neurons seek out, recognize, and establish connections with their targets in the developing nervous system. This process can be broken down into cell fate determination, axon/dendrite guidance, synapse formation, and activity dependent modification of synaptic circuit.

Once axons have reached their targets, it is now understood that a key aspect of developmental plasticity is the refining and sculpting of connections between neurons in order to enhance the function of neuronal networks. A later event in the development of the vertebrate nervous system is the optimization of these networks by accelerating the speed of nerve impulse conduction. This is the role of the glia, particularly the myelin-forming glia-oligodendrocytes in the CNS and Schwann cells in the PNS. They achieve this by inducing the assembly of macromolecular complexes at the nodes of Ranvier, which are highly enriched in voltage-gated sodium channels. A second key role for glia is in supporting the health and survival of axons. This aspect of glial function has become particularly evident from studies on demyelinating diseases in which loss of axonal contact is associated with axonal degeneration.

Contact-mediated signals from glia instruct dendrites to become receptive to synaptic partners. Glia-derived factors coordinate the assembly presynaptic structures and the precise apposition of presynaptic and postsynaptic specializations. Glial cells stimulate the process of synapse formation in vitro and in vivo. Glial cells also provide cues that are required for synaptic maturation and remodeling of spines both during development and in the adult.

A major feature of degenerative neurological disease, both in the CNS and PNS, is the production of mutant proteins whose folding and associations are believed to disrupt normal neuronal and glial function. Recent developments in our understanding of how misfolded proteins are handled by cells, including the unfolded protein response, have had immediate and obvious relevance to potential therapeutic interventions in both the CNS and PNS.

Sleep and exercise help grow brain cells. And scientists are studying the effects of sleep on brain growth and pain:

  • The mechanisms by which changes in sleep may impact nociception
  • The mechanisms by which hypothalamic neurons or other mechanisms involved in sleep regulation may affect nociceptive pathways
  • The mechanisms by which brain regions associated with sleep dysregulation may contribute to pain
  • The mechanisms by which deficient sleep or circadian dysregulation may impact central pain-modulatory processes
  • Neural/glial mechanisms underlying the effect of sleep on the transition from acute to chronic pain
  • The relationship between sleep and microbiome impacting pain and analgesia
  • The mechanisms by which pharmacologic interventions for sleep may impact chronic pain
  • The mechanisms by which nonpharmacologic or complementary and integrative health approaches for sleep regulation may impact chronic pain
  • The mechanisms underlying comorbidity of sleep disturbances, pain, and psychiatric disorders such as depression, posttraumatic stress disorders, and other conditions
  • The mechanisms by which complementary approaches, alone or in combination with medications, interact with sleep to increase or mitigate pain
  • The impact of chronotype (“morningness” versus “eveningness”) on perception of pain
  • The impact of circadian misalignment (“social jet lag”) on perception of pain
  • The effect of comorbid conditions with sleep on pain
  • The relationship between glymphatic function and pain
  • Identify pain mechanisms and pathways closely-coupled to sleep disordered breathing (SDB) pathobiology; elucidate mechanisms through which SDB-induced pathobiology increase pain sensitivity or significantly influence the effectiveness of pharmacotherapeutic interventions for acute pain and chronic pain. What mechanisms mediate changes in cognitive perception of pain through sleep fragmentation, sleep deprivation, or circadian disturbances associated with SDB?
  • Identify mechanisms through which sleep and breathing disturbances closely coupled to Sickle Cell Disease (SCD) increase the frequency of chest pain crises and interfere with management of pain in this and other blood disorders
  • Elucidate sleep and circadian mechanisms that contribute to the severity of pain in heart, lung, and blood diseases such as SCD and COPD.  Does sleep duration, quality, or timing contribute to the severity of acute and chronic hyper-reactive inflammation?
  • Identify specific cellular mechanisms through which sleep and circadian disturbances diminish physiological resilience to pain in heart, lung, blood, and sleep disorders.