Jessica H. Brann
Neurosensory systems create our perceptions of the external world. However, we lack critical knowledge of the neural circuitry governing the operation, fidelity, and regeneration of these sensory systems. My motivation as a neuroscientist is to tease apart the mechanisms underlying the functional recovery of sensation following injury or aging. My laboratory is combining expertise in the olfactory system with interests in the effects of aging on the maintenance and renewal of a unique population of neural stem cells found in the olfactory system.
Neural regeneration is rare in the nervous system, but could have a profound therapeutic impact on recovery from traumatic or pathological induced brain injuries. This sensory system affords a singular opportunity to probe neural stem cell differentiation and functional regeneration of a neural circuit in the face of an ever-changing sensory landscape. In particular, the olfactory system houses two repositories of neural stem cells capable of lifelong proliferation. The first repository is found in the peripheral neuroepithelium, where neural stem cells generate excitatory projection neurons, the olfactory sensory neurons, throughout the life of mammals. These neurons, while specialized for transducing chemical stimuli, are true neurons (not specialized epithelial cells) and possess a long axon that projects to targets in the CNS. The second stem cell population is found in the subventricular zone of the brain, which supplies newborn inhibitory interneurons to the olfactory bulb. My primary research interests have evolved to concentrate on these two areas.
Neurogenesis and Regeneration in the Young Adult and Aged Adult Olfactory Epithelium
The potential of neural stem cells to generate sensory neurons in the young adult olfactory epithelium has been known for more than 30 years, but little research thus far has queried whether a similar process exists in animals older than six months of age. Thus it is possible the regenerative capacity of this tissue may not exist to meet the challenge of replacing worn out cells, but rather may be an extension of postnatal development. Is the observed adult neurogenesis in this tissue really for tissue repair and cell replacement, or is this a case of extended postnatal growth – or some combination of the two?
The epithelia undergo a prolonged period of postnatal growth that is largely complete by six months of age, at which point there is a marked slowing of neurogenesis. However, it was not clear from those data whether age affects the potential for newly generated cells to become neurons. A series of experiments demonstrated the potential for the neural stem cell in aged animals to generate mature neurons did indeed remain intact (Brann and Firestein, 2010).
- (A) Sagittal schematic of the rodent nose depicting the locations of the olfactory epithelium (OE) and the vomeronasal organ (VNO). (B) The OE is composed of five primary cell types, including the horizontal basal cell (HBC; neural stem cell), globose basal cell (GBC), immature olfactory sensory neuron (OSNi), mature olfactory sensory neuron (OSNm), and sustentacular cell (Sus).
While neural stem cells are normally relatively quiescent, the olfactory epithelium is still quite capable of responding dramatically to injury with a robust wave of neuronal proliferation. In young animals, more than 6-8 million new neurons are generated within 3-4 weeks following surgical ablation. This type of challenge had never been delivered to an older animal. We therefore used a variety of ablation techniques (surgical, chemical and genetic) to examine the regenerative capacity of this aged tissue. Proliferation increased, remarkably with the same efficacy in aged mice as in younger controls, generating 400% more daughter cells than in the un-lesioned epithelium and in age-matched controls (Brann and Firestein, 2010; manuscripts in preparation). Therefore, the olfactory system contains a unique reservoir of long-lasting neural stem cells that have developed strategies to cope with environmental and DNA damage, both of which contribute to aging. These cells remain ready to answer a serious injury to the system even at very advanced ages and after long periods of relatively slow proliferation.
These data have exciting implications for clinical research. These neural stem cells are accessible, easily studied, isolated and manipulated. More immediately, these experiments will set the stage for several critical future questions. First, in the adult and aged adult, is the process of differentiation from stem cell to functional neuron the same or different as that observed during development? How is a neuronal fate versus a supporting cell fate determined? Future experiments elucidating this pathway will reveal critical processes underlying excitatory neuronal differentiation and precision of targeting. It also raises fundamental questions about the nature of a regenerated olfactory system. How does this system accomplish the impressive task of generating a new neuron? How does repair or regeneration occur in aged tissue, particularly that following injury?
Neural Circuit Formation and Maintenance in the Olfactory Bulb
The ability for an organism to navigate its surroundings and adapt to an ever-changing environment requires that sensory circuits exhibit plasticity in order to accommodate a variety of stimuli. We strive to decipher the role of this neuronal plasticity as well as understand the ways in which olfactory system copes with a continually changing odor landscape. My laboratory will examine synaptic plasticity in a circuit in the OB, the first relay in the brain for incoming olfactory information. The olfactory system exhibits a remarkable capacity for both structural and functional plasticity. Neural stem cells in the subventricular zone compromise a stem cell niche that supplies new interneurons to the OB. In addition, there is evidence that the synapses between interneurons (periglomerular and granule cells) and primary projection neurons (mitral cells) of the olfactory bulb undergo plasticity as well. This system is thus an excellent model for such studies, as well as circuit development and homeostasis, because it is readily accessible, its projection pathways are relatively well understood, it is amenable to genetic manipulation, and can be readily examined in the context of a salient physiological stimulus.
- Postnatal electroporation can manipulate gene expression in newborn interneurons of the OB. (A-D) Individual neurons can be labeled (B, mRFP), as well as synapses visualized by Homer1b-EGFP (A). Nuclei are labeled by TOTO-3 (C).
Brann JH, Ellis DE, Ku BS, Spinazzi EF and S Firestein. 2015. Injury in aged animals robustly activates quiescent olfactory neural stem cells. Frontiers in Neuroscience. 9:367. (http://www.ncbi.nlm.nih.gov/pubmed/26500487)
Brann JH and SJ Firestein. 2014. A lifetime of neurogenesis in the olfactory system. Frontiers in Neuroscience. 8:182. (http://www.ncbi.nlm.nih.gov/pubmed/25018692)
Mobley, A. S., Bryant, A.K., Richard, M.B., Brann, J.H., Firestein, S.J. and C.A. Greer. 2013.Age-dependent regional changes in the rostral migratory stream. Neurobiology of Aging. 34(7):1873-81. (http://www.ncbi.nlm.nih.gov/pubmed/23419702)
Brann, J.H. and S. Firestein. 2010. Regeneration of new neurons is preserved in aged vomeronasal epithelia. The Journal of Neuroscience. 30:15686. (http://www.ncbi.nlm.nih.gov/pubmed/21084624)
Mast, T.G., Brann, J.H. and D.A. Fadool. 2010. The TRPC2 channel forms protein-protein interactions with Homer and RTP in the rat vomeronasal organ. BMC Neuroscience. 11:61 (http://www.ncbi.nlm.nih.gov/pubmed/20492691)
Chesler A.T., Le Pichon C.E., Brann J.H., Araneda R.C., Zou D.-J., Firestein S. 2008. Selective gene expression by postnatal electroporation during olfactory interneuron neurogenesis. PLoS ONE. 3(1):e1517. (http://www.ncbi.nlm.nih.gov/pubmed/18231603)
Brann, J.H., Saideman, S.R., Valley, M.T. and D. Wiedl. 2007. Strategies for Odor Coding in the Piriform Cortex. The Journal of Neuroscience. 27:1237-1238. (http://www.ncbi.nlm.nih.gov/pubmed/17290509)
Brann, J.H. and D. A. Fadool. 2006. Vomeronasal sensory neurons from S. odoratus utilize the PLC pathway in pheromone transduction. The Journal of Experimental Biology. 209(Pt 10):1914-1927. (http://www.ncbi.nlm.nih.gov/pubmed/16651557)
Labra, A., Brann, J.H. and D. A. Fadool. 2005. Heterogeneity of voltage- and chemo-signal activated response profiles in vomeronasal sensory neurons. The Journal of Neurophysiology 94(4):2535-2548. (http://www.ncbi.nlm.nih.gov/pubmed/15972830)
Farbman, A.I., Brann, J.H., Rozenblat, A., Rochlin, M.W., Weiler, E., Bhattacharyya, M. 2004. Developmental expression of neurotrophin receptor genes in rat geniculate ganglion neurons. The Journal of Neurocytology. 33(3):331-343.
Brann, J.H., Dennis, J.C., Morrison, E.E., and D.A. Fadool. 2002. Type specific inositol 1,4,5- trisphosphate receptor localization in the vomeronasal organ and its interaction with a transient receptor potential channel, TRPC2. Journal of Neurochemistry. 83(6):1452-60. (http://www.ncbi.nlm.nih.gov/pubmed/12472899)
Fadool D.A., M. Wachowiak, and J.H. Brann. 2001. Patch-clamp analysis of voltage- and chemosignal-activated currents in the vomeronasal organ. The Journal of Experimental Biology. 204(Pt 24):4199-4212. (http://www.ncbi.nlm.nih.gov/pubmed/11815645)