Homeostatic disruption sparks dopaminergic signaling in NAc
Samantha M. Fortin and Mitchell F. Roitman
(see pages 6841–6853)
Animals need to maintain homeostasis to survive, and that need strongly drives behaviors. For example, the drives to drink water and consume sodium help to maintain the balance of fluids and ions our cells depend on. Dopamine release in the nucleus accumbens (NAc) is an important mediator of motivated behaviors, but how physiological need influences dopaminergic signaling is not fully understood. Fortin and Roitman describe a circuit that could link the two. They used fast-scan cyclic voltammetry to measure dopamine release in the shell of the NAc. When sodium-depleted rats received an intraoral infusion of a hypertonic sodium solution, dopamine concentration sharply increased, but no such increase was seen in control rats. Dopamine did not increase in response to infusions of potassium solution or water, regardless of sodium state. Similarly, in water-restricted rats—but not rats given access to water—oral infusion of water led to a dramatic rise in NAc dopamine. Dopamine did not increase in response to sodium infusion in water-restricted rats, indicating that the signal was specific to the animals' physiological need. Dopamine signaling was also taste-specific. Rats depleted of sodium preferred a sodium to a potassium solution, as expected, but did not distinguish between sodium and lithium solutions, because the channel that transduces sodium taste also passes lithium. Accordingly, dopamine levels also rose in response to oral infusion of lithium but not potassium solution.
Upstream of the NAc, the researchers examined neurons of the prelocus ceruleus (pre-LC) and the inner segment of the external layer of the parabrachial nucleus (PBel-inner) that are activated in response to sodium deprivation and express the transcription factor FoxP2. Although the number of sodium-sensing FoxP2 neurons was similar in the pre-LC and PBel-inner of sodium-depleted and control rats, the level of c-Fos expression—a marker of neuronal firing—was significantly higher in sodium-depleted rats. The authors next labeled cells in the ventral tegmental area (VTA) using a retrograde tracer and found that the pre-LC and PBel-inner neurons activated by sodium depletion indeed projected directly to VTA, a region from which dopaminergic neurons in turn project to the NAc. The mesolimbic circuit investigated by the authors, including the pontine nuclei pre-LC and PBel-inner, the VTA, and the NAc, appears to coordinate behavioral responses to homeostatic imbalance, providing key evidence for dopamine as a mediator of such behaviors.
A mouse model of olfactory epithelial neuronal exhaustion
Kevin M. Child, Daniel B. Herrick, James E. Schwob, Eric H. Holbrook, and Woochan Jang
(see pages 6806–6824)
Stem cells in the olfactory epithelium (OE) normally replenish damaged cells, but with age, the repository is depleted. Without the cells, the epithelium may degenerate, leading to an impaired sense of smell—which has been associated with neurological diseases and increased mortality in elderly people. Child et al. have developed a mouse model of accelerated “neurogenic exhaustion” that mimics pathology seen in the OE of aged humans and mice.
Olfactory epithelium from a 4-month-old control mouse (left) and from a transgenic degeneration mouse. OSNs (green) are sparse or absent in the OE from the degenerating mouse, and patches of respiratory epithelial cells (magenta) are present. See Child et al. for details.
The OE contains two populations of stem cells: globose basal cells (GBCs), which routinely replace damaged cells including olfactory sensory neurons (OSNs); and horizontal basal cells (HBCs), a reserve population only activated with severe injury but with regenerative capacity nonetheless. To recapitulate the aging process in young mice, the researchers continually challenged GBC regeneration by genetically engineering OSNs to express the A subunit of Diptheria toxin (DTA) under control of a tetracycline-sensitive promoter, effectively killing the cells. DTA expression could be terminated by administering the tetracycline analog doxycycline.
In the OE of OMP-tTA/TetO-DTA mice, the usual layer of mature OSNs was thinner or absent compared with control (doxycycline-fed) mice. Staining with various cellular markers revealed that some areas of epithelium had undergone respiratory metaplasia, meaning that it had converted from olfactory to respiratory epithelium (RE). In control mice, the OE was consistently populated with neurons, and the borders between OE and RE were sharply defined, whereas in the DTA-expressing mice, the OE contained patches of RE and bits devoid of neurons. The changes were consistent with those seen in tissue samples from elderly people and from wild-type aged mice.
The authors delineated four grades of severity of degeneration, using markers for mature and immature neurons and other cells found in the OE. Neurons and stem cells were progressively depleted and epithelial architecture was disrupted as time spent expressing DTA increased. Degeneration appeared more severe in anterior than in posterior sections of the epithelium. Inflammatory immune cells were present in the epithelium of DTA-expressing mice at less-severe stages of damage but not after neuronal depletion. Two months after halting DTA expression by feeding mice doxycycline, the OE largely recovered to normal, with slightly more damage remaining in mice expressing DTA for 4 months than for 2 months. The findings suggest new avenues of research to better understand how stem cells' potential to replenish neural tissues recedes with age, not just in the olfactory system but elsewhere in the nervous system.
Footnotes
This Week in The Journal was written by Stephani Sutherland, Ph.D.