Abstract
The development of the amygdala, a central structure of the limbic system, remains poorly understood. We found that two spatially distinct and early-specified telencephalic progenitor pools marked by the homeodomain transcription factor Dbx1 are major sources of neuronal cell diversity in the mature mouse amygdala. We found that Dbx1-positive cells of the ventral pallium generate the excitatory neurons of the basolateral complex and cortical amygdala nuclei. Moreover, Dbx1-derived cells comprise a previously unknown migratory stream that emanates from the preoptic area (POA), a ventral telencephalic domain adjacent to the diencephalic border. The Dbx1-positive, POA-derived population migrated specifically to the amygdala and, as defined by both immunochemical and electrophysiological criteria, generated a unique subclass of inhibitory neurons in the medial amygdala nucleus. Thus, this POA-derived population represents a previously unknown progenitor pool dedicated to the limbic system.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Alheid, G.F. Extended amygdala and basal forebrain. Ann. NY Acad. Sci. 985, 185–205 (2003).
Sah, P., Faber, E.S., Lopez De Armentia, M. & Power, J. The amygdaloid complex: anatomy and physiology. Physiol. Rev. 83, 803–834 (2003).
Swanson, L.W. & Petrovich, G.D. What is the amygdala? Trends Neurosci. 21, 323–331 (1998).
Amaral, D.G., Bauman, M.D. & Schumann, C.M. The amygdala and autism: implications from nonhuman primate studies. Genes Brain Behav. 2, 295–302 (2003).
Baron-Cohen, S. et al. The amygdala theory of autism. Neurosci. Biobehav. Rev. 24, 355–364 (2000).
Rauch, S.L., Shin, L.M. & Phelps, E.A. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research–past, present, and future. Biol. Psychiatry 60, 376–382 (2006).
Bai, J. et al. The role of DCX and LIS1 in migration through the lateral cortical stream of developing forebrain. Dev. Neurosci. 30, 144–156 (2008).
Carney, R.S. et al. Cell migration along the lateral cortical stream to the developing basal telencephalic limbic system. J. Neurosci. 26, 11562–11574 (2006).
Medina, L. et al. Expression of Dbx1, Neurogenin 2, Semaphorin 5A, Cadherin 8, and Emx1 distinguish ventral and lateral pallial histogenetic divisions in the developing mouse claustroamygdaloid complex. J. Comp. Neurol. 474, 504–523 (2004).
Stenman, J., Toresson, H. & Campbell, K. Identification of two distinct progenitor populations in the lateral ganglionic eminence: implications for striatal and olfactory bulb neurogenesis. J. Neurosci. 23, 167–174 (2003).
Bielle, F. et al. Multiple origins of Cajal-Retzius cells at the borders of the developing pallium. Nat. Neurosci. 8, 1002–1012 (2005).
Yun, K., Potter, S. & Rubenstein, J.L. Gsh2 and Pax6 play complementary roles in dorsoventral patterning of the mammalian telencephalon. Development 128, 193–205 (2001).
Carney, R.S.E., Cocas, L.A., Hirata, T., Mansfield, K. & Corbin, J.G. Differential regulation of telencephalic pallial–subpallial boundary patterning by Pax6 and Gsh2. Cereb. Cortex published online, doi:10.1093/cercor/bhn123 (12 August 2008).
Tao, W. & Lai, E. Telencephalon-restricted expression of BF-1, a new member of the HNF-3/fork head gene family, in the developing rat brain. Neuron 8, 957–966 (1992).
Branda, C.S. & Dymecki, S.M. Talking about a revolution: the impact of site-specific recombinases on genetic analyses in mice. Dev. Cell 6, 7–28 (2004).
Joyner, A.L. & Zervas, M. Genetic inducible fate mapping in mouse: establishing genetic lineages and defining genetic neuroanatomy in the nervous system. Dev. Dyn. 235, 2376–2385 (2006).
Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).
Danielian, P.S., Muccino, D., Rowitch, D.H., Michael, S.K. & McMahon, A.P. Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr. Biol. 8, 1323–1326 (1998).
Pierani, A. et al. Control of interneuron fate in the developing spinal cord by the progenitor homeodomain protein Dbx1. Neuron 29, 367–384 (2001).
Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).
Hevner, R.F. et al. Tbr1 regulates differentiation of the preplate and layer 6. Neuron 29, 353–366 (2001).
Porteus, M.H., Bulfone, A., Ciaranello, R.D. & Rubenstein, J.L. Isolation and characterization of a novel cDNA clone encoding a homeodomain that is developmentally regulated in the ventral forebrain. Neuron 7, 221–229 (1991).
del Rio, M.R. & DeFelipe, J. Colocalization of calbindin D-28k, calretinin and GABA immunoreactivities in neurons of the human temporal cortex. J. Comp. Neurol. 369, 472–482 (1996).
McDonald, A.J. & Mascagni, F. Colocalization of calcium-binding proteins and GABA in neurons of the rat basolateral amygdala. Neuroscience 105, 681–693 (2001).
Olmos, J.L., Real, M.A., Medina, L., Guirado, S. & Davila, J.C. Distribution of nitric oxide–producing neurons in the developing and adult mouse amygdalar basolateral complex. Brain Res. Bull. 66, 465–469 (2005).
Tanaka, M. et al. Nitrergic neurons in the medial amygdala project to the hypothalamic paraventricular nucleus of the rat. Brain Res. 777, 13–21 (1997).
Wonders, C.P. & Anderson, S.A. The origin and specification of cortical interneurons. Nat. Rev. Neurosci. 7, 687–696 (2006).
Fuentealba, P. et al. Ivy cells: a population of nitric oxide–producing, slow-spiking GABAergic neurons and their involvement in hippocampal network activity. Neuron 57, 917–929 (2008).
Wang, Y. et al. Anatomical, physiological and molecular properties of Martinotti cells in the somatosensory cortex of the juvenile rat. J. Physiol. (Lond.) 561, 65–90 (2004).
Beierlein, M., Gibson, J.R. & Connors, B.W. Two dynamically distinct inhibitory networks in layer 4 of the neocortex. J. Neurophysiol. 90, 2987–3000 (2003).
Bacci, A., Rudolph, U., Huguenard, J.R. & Prince, D.A. Major differences in inhibitory synaptic transmission onto two neocortical interneuron subclasses. J. Neurosci. 23, 9664–9674 (2003).
Bacci, A., Huguenard, J.R. & Prince, D.A. Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids. Nature 431, 312–316 (2004).
Bian, X., Yanagawa, Y., Chen, W.R. & Luo, M. Cortical-like functional organization of the pheromone-processing circuits in the medial amygdala. J. Neurophysiol. 99, 77–86 (2008).
Corbin, J.G., Nery, S. & Fishell, G. Telencephalic cells take a tangent: nonradial migration in the mammalian forebrain. Nat. Neurosci. 4 Suppl: 1177–1182 (2001).
Marin, O. & Rubenstein, J.L. A long, remarkable journey: tangential migration in the telencephalon. Nat. Rev. Neurosci. 2, 780–790 (2001).
Corbin, J.G. et al. Regulation of neural progenitor cell development in the nervous system. J. Neurochem. 106, 2272–2287 (2008).
Flames, N. et al. Delineation of multiple subpallial progenitor domains by the combinatorial expression of transcriptional codes. J. Neurosci. 27, 9682–9695 (2007).
Choi, G.B. et al. Lhx6 delineates a pathway mediating innate reproductive behaviors from the amygdala to the hypothalamus. Neuron 46, 647–660 (2005).
Molnar, Z. & Butler, A.B. The corticostriatal junction: a crucial region for forebrain development and evolution. Bioessays 24, 530–541 (2002).
Waclaw, R.R. et al. The zinc finger transcription factor Sp8 regulates the generation and diversity of olfactory bulb interneurons. Neuron 49, 503–516 (2006).
Stoykova, A., Fritsch, R., Walther, C. & Gruss, P. Forebrain patterning defects in Small eye mutant mice. Development 122, 3453–3465 (1996).
Toresson, H., Potter, S.S. & Campbell, K. Genetic control of dorsal-ventral identity in the telencephalon: opposing roles for Pax6 and Gsh2. Development 127, 4361–4371 (2000).
Tole, S., Remedios, R., Saha, B. & Stoykova, A. Selective requirement of Pax6, but not Emx2, in the specification and development of several nuclei of the amygdaloid complex. J. Neurosci. 25, 2753–2760 (2005).
Gorski, J.A. et al. Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J. Neurosci. 22, 6309–6314 (2002).
Nery, S., Fishell, G. & Corbin, J.G. The caudal ganglionic eminence is a source of distinct cortical and subcortical cell populations. Nat. Neurosci. 5, 1279–1287 (2002).
Marin, O., Anderson, S.A. & Rubenstein, J.L. Origin and molecular specification of striatal interneurons. J. Neurosci. 20, 6063–6076 (2000).
Xu, Q., Tam, M. & Anderson, S.A. Fate mapping Nkx2.1-lineage cells in the mouse telencephalon. J. Comp. Neurol. 506, 16–29 (2008).
Remedios, R. et al. A stream of cells migrating from the caudal telencephalon reveals a link between the amygdala and neocortex. Nat. Neurosci. 10, 1141–1150 (2007).
Garcia-Lopez, M. et al. Histogenetic compartments of the mouse centromedial and extended amygdala based on gene expression patterns during development. J. Comp. Neurol. 506, 46–74 (2008).
Corbin, J.G., Gaiano, N., Machold, R.P., Langston, A. & Fishell, G. The Gsh2 homeodomain gene controls multiple aspects of telencephalic development. Development 127, 5007–5020 (2000).
Acknowledgements
The authors would like to thank members of the Corbin, Haydar and Zohn laboratories for input during various stages of this project, with a special acknowledgment to J.L. Olmos-Serrano for his expert insight and advice on amygdala anatomy and development. We also gratefully acknowledge T. Haydar, J.L. Olmos-Serrano, I. Zohn and V. Gallo for critical reading of the manuscript. We thank R. Hevner for the Tbr1 antibody (University of Washington), S. Aizawa for the Foxg1 and Lhx2 probes (RIKEN) and M. Matise for the Dbx1 probe (University of Medicine and Dentistry New Jersey/Robert Wood Johnson Medical School). The RC2 monoclonal antibody was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the US National Institute of Child Health and Human Development and maintained by the University of Iowa. We also thank the Children's National Medical Center and Georgetown University Transgenic Cores for the generation of mice. This work was supported by grants from the US National Institutes of Health (J.G.C. and M.M.H.). The Children's National Medical Center microscope core facility is supported by an US National Institutes of Health Intellectual and Developmental Disabilities Research Center grant.
Author information
Authors and Affiliations
Contributions
T.H. generated the Dbx1+/CreERT2 knock-in animals and carried out the fate mapping, slice culture assays, immunohistochemistry and in situ hybridization analysis. G.M.L. provided timed crossed Dbx1+/LacZ embryos and input on the analysis. L.A.C. provided technical assistance for the slice culture migration assays and analysis. P.L. and M.M.H. obtained and analyzed the electrophysiological and biocytin data. J.G.C. carried out the matrigel experiments. The study was conceived and planned by T.H. and J.G.C. The majority of the manuscript was written by T.H. and J.G.C. with the electrophysiology part being written by M.M.H.
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–6 and Supplementary Table 1 (PDF 1795 kb)
Rights and permissions
About this article
Cite this article
Hirata, T., Li, P., Lanuza, G. et al. Identification of distinct telencephalic progenitor pools for neuronal diversity in the amygdala. Nat Neurosci 12, 141–149 (2009). https://doi.org/10.1038/nn.2241
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn.2241
This article is cited by
-
Synchronization of inspiratory burst onset along the ventral respiratory column in the neonate mouse is mediated by electrotonic coupling
BMC Biology (2023)
-
Transcriptionally defined amygdala subpopulations play distinct roles in innate social behaviors
Nature Neuroscience (2023)
-
Specific contribution of neurons from the Dbx1 lineage to the piriform cortex
Scientific Reports (2021)
-
Development of the mouse anterior amygdalar radial unit marked by Lhx9-expression
Brain Structure and Function (2021)
-
Identification of amygdala-expressed genes associated with autism spectrum disorder
Molecular Autism (2020)