Paraventricular hypothalamic and amygdalar CRF neurons synapse in the external globus pallidus
Stress evokes directed movement to escape or hide from potential danger. Corticotropin-releasing factor (CRF) neurons are highly activated by stress; however, it remains unclear how this activity participates in stress-evoked movement. The external globus pallidus (GPe) expresses high levels of the primary receptor for CRF, CRFR1, suggesting the GPe may serve as an entry point for stress-relevant information to reach basal ganglia circuits, which ultimately gate motor output. Indeed, projections from CRF neurons are present within the GPe, making direct contact with CRFR1-positive neurons. CRFR1 expression is heterogenous in the GPe; prototypic GPe neurons selectively express CRFR1, while arkypallidal neurons do not. Moreover, CRFR1-positive GPe neurons are excited by CRF via activation of CRFR1, while nearby CRFR1-negative neurons do not respond to CRF. Using monosynaptic rabies viral tracing techniques, we show that CRF neurons in the stress-activated paraventricular nucleus of the hypothalamus (PVN), central nucleus of the amygdala (CeA), and bed nucleus of the stria terminalis (BST) make synaptic connections with CRFR1-positive neurons in the GPe an unprecedented circuit connecting the limbic system with the basal ganglia. CRF neurons also make synapses on Npas1 neurons, although the majority of Npas1 neurons are arkypallidal and do not express CRFR1. Interestingly, prototypic and arkypallidal neurons receive different patterns of innervation from CRF-rich nuclei. Hypothalamic CRF neurons preferentially target prototypic neurons, while amygdalar CRF neurons preferentially target arkypallidal neurons, suggesting that these two inputs to the GPe may have different impacts on GPe output. Together, these data describe a novel neural circuit by which stress-relevant information carried by the limbic system signals in the GPe via CRF to influence motor output.
KeywordsCRF CRH CRFR1 CRHR1 Globus pallidus Stress
The authors thank Z. Mao who provided expertise in confocal microscopy. We thank L. Mangieri and Q. Tong for their valuable input to data interpretation and resource sharing. We thank J. Selever, A. Herman, and B. Arenkiel for their kind gift of viral preparations necessary to perform tracing experiments. This work was supported in part by the National Institute of Neurological Disorders and Stroke Grants NS077989 to MB, NS069777 and NS047085 to CSC, MH112768 to NJJ and CSC, and MH114032 to NJJ. RD was supported by a Zilkha Family Discovery Fellowship in neuroengineering.
AJH and NJJ designed experiments and analyzed the results; RD and MB designed and RD performed electrophysiological recordings. AJH, SR and ZY performed immunohistochemical and viral tracing experiments; AJH, CSC, and NJJ wrote the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest.
- Abdi A, Mallet N, Mohamed FY, Sharott A, Dodson PD, Nakamura KC, Suri S, Avery SV, Larvin JT, Garas FN, Garas SN, Vinciati F, Morin S, Bezard E, Baufreton J, Magill PJ (2015) Prototypic and arkypallidal neurons in the dopamine-intact external globus pallidus. J Neurosci 35:6667–6688CrossRefPubMedPubMedCentralGoogle Scholar
- Dodson PD, Larvin JT, Duffell JM, Garas FN, Doig NM, Kessaris N, Duguid IC, Bogacz R, Butt SJB, Magill PJ (2015) Distinct developmental origins manifest in the specialized encoding of movement by adult neurons of the external globus pallidus. Neuron 86:501–513CrossRefPubMedPubMedCentralGoogle Scholar
- Justice NJ, Yuan ZF, Sawchenko PE, Vale W (2008) Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice: implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system. J Comp Neurol 511:479–496CrossRefPubMedPubMedCentralGoogle Scholar
- Lauterbach EC, Price ST, Wilson AN, Knopik VS, Jackson JG, Kavali CM (1994) Post-stroke major depression: Parkinsonism and thalamocortical systems relations. Biol Psychiatry 35:681Google Scholar
- Müller MB, Zimmermann S, Sillaber I, Hagemeyer TP, Deussing JM, Timpl P, Kormann MSD, Droste SK, Kühn R, Johannes MH, Holsboer F, Wurst W (2003) Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat Neurosci 6:1100–1107CrossRefPubMedGoogle Scholar
- Refojo D, Schweizer M, Kuehne C, Ehrenberg S, Thoeringer C, Vogl AM, Dedic N, Schumacher M, von Wolff G, Avrabos C, Touma C, Engblom D, Schutz G, Nave KA, Eder M, Wotjak CT, Sillaber I, Holsboer F, Wurst W, Deussing JM (2011) Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science 333(6051):1903–1907CrossRefPubMedGoogle Scholar
- Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, Gold LH, Chen R, Marchuk Y, Hauser C, Bentley CA, Sawchenko PE, Koob GF, Vale W, Lee KF (1998) Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20:1093–1102CrossRefPubMedGoogle Scholar
- Taniguchi H, He M, Wu P, Kim S, Paik R, Sugino K, Kvitsiani D, Kvitsani D, Fu Y, Lu J, Lin Y, Miyoshi G, Shima Y, Fishell G, Nelson SB, Huang ZJ (2011) A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron 71:995–1013CrossRefPubMedPubMedCentralGoogle Scholar
- Webster EL, Lewis DB, Torpy DJ, Zachman EK, Rice KC, Chrousos GP (1996) In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: suppression of pituitary ACTH release and peripheral inflammation. Endocrinology 137:5747–5750CrossRefPubMedGoogle Scholar