Kyle Gobrogge
Tufts University, USA
Title: Functional Identification of a CRF-DA Microcircuit in Mice with Relevance to Drug Abuse
Biography
Biography: Kyle Gobrogge
Abstract
Corticotropin releasing factor (CRF) signaling in the posterior ventral tegmental area (pVTA) mediates stress-induced psychostimulant self-administration. Recently, using a Cre-dependent tract-tracing approach with AAV-Flex-ChR2 in adult CRF-Cre male mice, we localized the source of pVTA-CRF to neurons projecting from the lateral hypothalamus (LH) and dorsal raphe nucleus (DRN) synapsing in the paranigral (PN) and parainterfascicular (PIF) sub-nuclei of the ventral posterior medial (VPM) sub-region of the pVTA. We observed that the DRN-, but not the LH-, VPM-CRF circuit was activated after repeated, but not acute, social defeat stress. Furthermore, we found that repeated optical or chemo-genetic activation of CRF in the VPM was sufficient to engender amphetamine (AMPH)-induced-locomotor behavioral cross-sensitization and escalated cocaine intake. Specifically, we observed that male mice with a history of repeated CRF optical or DREADD stimulation in the VPM displayed a significant increase in distance traveled in an open field test after treatment with a low dose of AMPH (1.5 mg./kg.) compared to saline treated and Cre-/- littermate controls. Subsequent cocaine self-administration experiments demonstrated that repeated DREADD CRF activation in the VPM enhanced drug-seeking behavior. Here we build upon these data by focusing on the DRN-VPM CRF microcircuit by using a combination of techniques. Previously, we observed site-specific increases in CRF-ir in the PN/PIF but not the parabrachial pigmented area of the pVTA following stress. Thus, we bilaterally infused CRF-Cre male mice with the G(q) DREADD virus into the DRN and implanted a unilateral microdialysis probe aimed at the PN/PIF and sampled the VPM for CRF during saline and CNO treatment. Our data demonstrate enhanced CRF release in the VPM of DREADD G(q) infected DRN-CRF neurons, after i.p. CNO injection. These results suggest functional increases in released CRF in the VPM after activation of DRN-CRF neurons projecting to the pVTA. We will extend this work by measuring dopamine (DA) release in the nucleus accumbens shell of mice with a history of DRN-VPM CRF microcircuit activity. These latter experiments aim to ascertain mesocorticolimbic CRF-DA interactions and potential increases in rate of cocaine self-administration and reinstatement after abstinence. At present, our data reveal a site-specific CRF microcircuit exclusively projecting from the DRN to the VPM sub-region of the pVTA, its sensitivity to social defeat stress, and VPM-CRF release presumably altering DAergic output in the forebrain after repeated experiences with brief episodes of social stress.
This research was supported by an NIMH R01 research grant NS073574 to J.M., a NIDA grant 031734 to K.M., the Tufts Center for Neuroscience Research grant P30 NS047243, and a Tufts Collaborates grant. The authors declare no biomedical, financial, or potential conflicts of interest. The experiments were approved by the Institutional Animal Care and Use Committee and were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.