Abstract

Anatomical characterization of cocaine and amphetamine related transcript (CART) gene transcription in the human hypothalamus and its relationship to psychiatric disorders

Krolewski DM, Medina A, Myers RM, Schatzberg AF, Bunney WE, Barchas JD, Akil H, Watson SJ
Society for Neuroscience. 2011.

Cocaine and amphetamine related transcript (CART) peptide has been shown to be expressed within the rodent hypothalamic paraventricular nucleus (PVN) which governs the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies suggest that expression changes in PVN localized corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) peptides contribute to an altered HPA axis in humans diagnosed with major depressive disorder (MDD). Therefore, the aim of the present study is to examine the anatomical relationship of CART peptide to that of both CRH and AVP as well as perform quantitative analyses on mRNA abundance in postmortem human subjects diagnosed with psychiatric conditions. To achieve this, frozen hypothalamic blocks from normal controls, MDDs, and schizophrenics (SZ) were sectioned at 10µm on a cryostat and in situ hybridization (ISH) was subsequently performed utilizing radiolabeled cRNA probes for CART, CRH, and AVP. Then, employing a neuropeptide mRNA-based hypothalamic map generated by the Pritzker Neuropsychiatric Research Consortium (Krolewski et al., 2010) as a guide, individual subjects were then anatomically aligned. Our results, as demonstrated by 2 and 3-dimensional reconstruction, show that CART mRNA expression strongly overlaps with that of both CRH and AVP in the PVN, but is not present within the ventrally located supraoptic nucleus. In addition, though no significant differences in CART mRNA levels were observed between control and MDD subjects, preliminary data from a subset of SZ subjects demonstrated heightened expression. Currently, double label ISH experiments are being conducted to determine the extent of CART colocalization with CRH and AVP. The results of this investigation describing both CART mRNA distribution and its regulation will serve to further elucidate prospective changes in HPA axis function in MDD and SZ. The authors want to thank the members of Pritzker Neuropsychiatric Disorder Research Consortium.

Support: The Pritzker Neuropsychiatric Research Consortium and NIMH Conte Center Grant #L99MH60398.