(DBBS Faculty Member)
Anatomy and Neurobiology
Molecular Development of Neural Circuits
The Simplest Behavior: Neural Circuits, Development, and Evolution
All behaviors are generated by neurons. We are focusing on understanding the neural circuitry, molecular development, and evolution of the simplest mammalian behavior, Breathing.
Using the hindbrain network that generates the breathing rhythm as a model system, we are trying to answer three basic questions:
1. Does behavioral phenotype = molecular genotype?
Can we use the tools of molecular genetics and electrophysiology to identify specific groups of neurons and show they are uniquely responsible for the generation of specific behaviors?
2. Are neural circuits underlying behavior genetically hardwired?
Can we use the tools of developmental neurobiology to understand how the neurons and connectivity of a functional neural network form from an undifferentiated neural epithelium?
3. How do neural circuits evolve?
Can we use our understanding of the molecular development of specific neural circuits in mammals to identify evolutionarily conserved or related population in other species?
Breathing is hypothesized to be generated within a small region of the brainstem called the preBötzinger Complex. Within this area, we identified a very small population of glutamatergic neurons expressing the Neurokinin 1 receptor (Gray et al, Science 1999). We went on to show that these ~600 neurons were necessary for normal breathing in adult rats (Gray et al., NatNeuro 2001). We hypothesize these neurons are uniquely responsible for generating the breathing rhythm in mammals.
In order to identify genes that might be causally involved in the specification and formation of respiratory circuits, we performed a genome-scale, anatomical screen of transcription factor expression in the developing mouse CNS. We directly visualized the expression of over 1000 unique transcription factors by in situ hybridization, at multiple developmental ages across the whole neural axis (Gray et al., Science 2004). Transcription factors are known to control and maintain cellular identity. As such, their expression may be causal to the specification of neurons within a circuit and their connectivity. We hypothesize this specific class of genes can be used as a “read-out” of the underlying genetic organization of the bran and specific circuits. Figure 2 shows an example of how different transcription factors define neuronal populations.
From this screen we have identified over 200 transcription factor genes expressed in subsets of neurons. We are focusing on a subset of these genes preliminary experiments suggest may play a role in respiratory circuitry. Our goal is to use transcription factor promoters to drive recombinase gene expression in subsets of neurons
Gray PA, Hayes JA, Ling GY, Llona I, Tupal S, Picardo MC, Ross SE, Hirata T, Corbin JG, EugenĂn J, Del Negro CA (2010 Nov 3). Developmental origin of preBĂ¶tzinger complex respiratory neurons. J Neurosci. 30 (44): 14883-95. Full Article >
Gray PA (2008 May). Transcription factors and the genetic organization of brain stem respiratory neurons. J Appl Physiol. 104 (5): 1513-21. Full Article >
Gray PA, Fu H, Luo P, Zhao Q, Yu J, Ferrari A, Tenzen T, Yuk DI, Tsung EF, Cai Z, Alberta JA, Cheng LP, Liu Y, Stenman JM, Valerius MT, Billings N, Kim HA, Greenberg ME, McMahon AP, Rowitch DH, Stiles CD, Ma Q (2004 Dec 24). Mouse brain organization revealed through direct genome-scale TF expression analysis. Science. 306 (5705): 2255-7. Full Article >
Pagliardini S, Ren J, Gray PA, Vandunk C, Gross M, Goulding M, Greer JJ (2008 Oct 22). Central respiratory rhythmogenesis is abnormal in lbx1- deficient mice. J Neurosci. 28 (43): 11030-41. Full Article >
Geerling JC, Stein MK, Miller RL, Shin JW, Gray PA, Loewy AD (2010 Nov 22). FoxP2 expression defines dorsolateral pontine neurons activated by sodium deprivation. Brain Res. Full Article >
Gray PA, Janczewski WA, Mellen N, McCrimmon DR, Feldman JL (2001 Sep). Normal breathing requires preBotzinger complex neurokinin-1 receptor-expressing neurons. Nat Neurosci. 4 (9): 927-30. Full Article >
Paul Gray, Ph.D.
Office Location: 954 McDonnell
Office Phone: 314-362-9063
Campus Box: 8108