The preBötzinger complex, often abbreviated as preBötC, is a functionally and anatomically specialized site in the ventral-lateral region of the lower medulla oblongata (i.e., lower brainstem). The preBötC is part of the ventral respiratory group of respiratory related interneurons. Its foremost function is to generate the inspiratory breathing rhythm in mammals. In addition, the preBötC is widely and paucisynaptically connected to higher brain centers that regulate arousal and excitability more generally such that respiratory brain function is intimately connected with many other rhythmic and cognitive functions of the brain and central nervous system. Further, the preBötC receives mechanical sensory information from the airways that encode lung volume as well as pH, oxygen, and carbon dioxide content of circulating blood and the cerebrospinal fluid.

The preBötC is approximately colocated with the hypoglossal (XII) cranial motor nucleus as well as the 'loop' portion of the inferior olive in the anterior-posterior axis. The caudal border of the preBötC is slightly caudal to the obex, where the brainstem merges with the cervical spinal cord.

The initial description of the preBötC was widely disseminated in a 1991 paper in Science, but its discovery predates that paper by one year. The team was led by Jack L. Feldman and Jeffrey C. Smith at the University of California, Los Angeles (UCLA), but the Science paper also included UCLA coauthor Howard Ellenberger, as well as Klaus Ballanyi and Diethelm W. Richter from Göttingen University in Germany. The region derives its name from a neighboring medullary region involved in expiratory breathing rhythm dubbed Bötzinger complex, which was named after the Silvaner (Bötzinger) variety of wine, featured at the conference at which that region was named (click here to hear a BBC interview with Jack Feldman on the topic of Bötzinger / preBötzinger nomenclature).

The first definition of the preBötC was based largely on functional criteria. If the central neuraxis from pons to lumbar spinal cord is removed from a newborn rodent, then basic neural motor patterns can be generated and recorded using microelectrodes in vitro. The breathing rhythm emerges spontaneously with robust and continuous motor activity measurable on any cranial or spinal motor nerve that innervates breathing related musculature.

By isolating a rhythmically active newborn rat brainstem-spinal cord in a microsectioning vibratome, Smith and colleagues performed a series of 75 μm-thick transverse sections while monitoring inspiratory-related motor rhythms. The preBötC represented the portion of the ventral-lateral lower brainstem that was necessary and sufficient to generate inspiratory related rhythm and motor output in vitro. Surprisingly, if microsections were applied from the anterior and posterior regions of the neuraxis simultaneously, a transverse section of thickness ~500 μm – which retained the preBötC and XII motoneurons – generated a rhythm and motor pattern that was almost identical to the rhythm and pattern in the full brainstem-spinal cord preparation. Perturbations that elevated excitability in preBötC sped up respiratory rhythm, whereas perturbations that depressed its excitability slowed the rhythm down. The authors concluded that these preBötC-retaining slice preparations preserved the core network generating inspiratory rhythm as well as premotor and motor neurons that define a minimal breathing-related circuit suitable for studies under controlled conditions in vitro. Breathing slices became a widely exploited preparation for such studies that continue to be used by laboratories worldwide to the present day.

Anatomical observations advanced understanding of the preBötC by providing specific markers expressed by its constituent neurons, which helped understand its approximate borders. The superset of markers is based largely on neuropeptides and peptide receptors, whose expression patterns have come to define the borders of preBötC and its constituent rhythm-generating and output pattern-related interneurons . preBötC neurons selectively express neurokinin-1 receptors (NK1Rs), μ-opioid receptors (μORs), as well as  somatostatin (SST) and SST2a-type receptors. Of course, selectively does not mean exclusively or entirely. Each marker has limitations as a defining feature of the preBötC core, but generally speaking, the neuropeptide-related markers below have proved to be both reliable and of great utility in the quest to define preBötC structure and function.

Peptide markers have been used to probe preBötC function. Substance P (SP) accelerated inspiratory rhythms in vitro by depolarizing putatively rhythmogenic preBötC neurons. SP also depolarized preBötC neurons whose function is premotor-related, i.e., those neurons transmit the nascent inspiratory rhythm to motoneurons outside the preBötC. The net result was that SP sped up the rhythm and elevated the baseline level neural activity in XII nerve recordings in vitro.

The expression of NK1Rs by preBötC neurons was used to test its inspiratory rhythm-generating, role. SP, conjugated to the ribosomal toxin saporin, was injected into the preBötC of adult rats. Over the course of a week, this intervention caused progressive breathing deficits that ultimately resulted in severely pathological (i.e., ataxic) breathing. SP-saporin-injected rats also experienced sleep deficits and extraordinary sensitivity to anesthesia.