Chemical Coding of Neurotransmission

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

The eleven publications from the Section on Molecular Neuroscience (SMN) in the past calendar year comprise eight primary reports arising from data obtained in the laboratory, and three reviews (as well as two additional book chapters in Masterclasses in Neuroendocrinology Volume 12: Neuroanatomy of Neuroendocrine Systems that have not yet surfaced in the NIDB). Progress in the field contributed by this group, in this calendar year, may be summarized as follows: Bakalar and colleagues compared the behavioral and transcriptomic profiles of mice with neuronal knock-out of the neuropeptide PACAP at various developmental stages to distinguish PAC1 receptor-dependent stress-response signaling deficits from developmentally arising PAC1 receptor-independent motor abnormalities (repetitive jumping), with implications for distinguishing developmental from adult roles for neuropeptide signaling in CNS; L. Zhang and colleagues established the effects of vasopressin released in brain from magnocellular neurons of the hypothalamus at limbic synapses as a synaptic organizer in CNS circuits with both immediate neurotransmitter actions and long-term actions on neuroplasticity through induction of PSD95 and GluA1 protein expression, identifying for the first time this unique dual role of brain vasopressinergic neurons; Xu and colleagues expanded the signaling role of RapGEF2 from that initiated at dopamine and PACAP receptors to VIP, ADBR and GLP-1 receptors, suggesting that this pathway is virtually ubiquitous, like that for protein kinase A activation, for Gs-coupled GPCRs of at least family B and for catecholamines; and Zhang et al. demonstrated in a brain-wide analysis by dual in situ hybridization histochemistry (DISH) that PACAPergic neurons of the brain are almost uniformly glutamatergic throughout the brain except at it rostral pole and in cerebellum, setting the stage for ongoing analysis of neuropeptide/small-molecule amine transmitter (SMAT) interaction in frontocortical-hypothalamic and brain stem-amygdalar PACAPergic circuits devoted to brain processing of endocrine and behavioral responses, respectively, to stress. In aggregate, we and our collaborators are working towards a more detailed understanding of how neuropeptides and SMATs collaborate at synapses within brain circuits dedicated to behavioral responses to aversive and rewarding stimuli, and stress. We are attempting to build a new view of cyclic AMP signaling in which cyclic AMP activates immediate early genes for neuronal plasticity encoding experience by two separate pathways, one dedicated to fos activation and acting through the threonine-serine protein kinase A, and one dedicated to activation of the immediate early gene Egr1/Zif268 via the MAP kinase ERK, and acting through the guanine nucleotide exchanger NCS-RapGEF2. This year in particular, we have explored the role of RapGEF2 in mediating hippocampal associative learning during fear conditioning (Jiang, Shahoha, Tejeda, Ashery and Eiden, BioRxiv doi: https://doi.org/10.1101/2022.04.30.490162); and dopamine-dependent cocaine-induced drug seeking behavior through RapGEF2-dependent activation of ERK. The SMN also participated in collaborative experiments with the UNAM laboratory of Prof. Limei Zhang to investigate the regio-specific expression of ACE2, the receptor for COVID, in rodent brain (Hernandez et al., Exp. Neurol. 345, 113837, 2021).