Chemical Coding of Neurotransmission

National Institute Of Mental Health

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Abstract

Review articles published from the Section on Molecular Neuroscience (SMN) during the last calendar year summarize recent literature establishing the neuroanatomical basis for the involvement of brain neuropeptides, principally pituitary adenylate cyclase-activating polypeptide (PACAP) which is a major focus of our laboratory, in an array of brain circuits mediating homeostatic and allostatic regulation, with an emphasis on the co-transmitters, such as glutamate and GABA expressed along with PACAP in these circuits. These publications update the foundation of our work on neuropeptide co-transmission in the brain, and ongoing attempts to identify functionally significant signaling functions for PACAP and other neuropeptides within these circuits. In particular, we develop the concept (Eiden et al., Cell. Mol. Life Sci. 79: 492, 2022) that it is critical to identify the full chemotype of peptidergic neurons within defined brain circuits in keeping with evidence that small molecule amine transmitters (SMATs), including the excitatory transmitter glutamate and the inhibitory transmitter GABA, may act cooperatively with neuropeptides to allow information transfer across the synapse required for functional patency of brain circuits mediating behavioral and endocrine responses. Vasopressin magnocellular neurons of the hypothalamus project to both the posterior pituitary, where vasopressin is released as a hormone in response to hydromineral imbalance, and throughout the brain (reviewed in Zhang et al., in Neuroanatomy of Neuroendocrine Systems, p 167-96, 2022, where vasopressin, via ascending projections, is released along with glutamate at synapses within amygdalar, habenular, hippocampal and other brain nuclei comcommitant with state-dependent behavioral adaptations associated with water deprivation and gonadal status. Likewise, a detailed exigesis of PACAP co-transmission (reviewed in Eiden et al., in Neuroanatomy of Neuroendocrine Systems, p 429-86, 2022) summarized the chemoanatomical evidence that PACAP is co-stored mainly in glutamatergic neurons throughout the brain, with storage in GABAergic neurons restricted mainly to olfactory bulb and cerebellum. The primary research articles published by the SMN and collaborators in this calendar year have collectively provided additional evidence for the functional (molecular, cellular, circuit and physiological/behavioral) role(s) of the neuropeptides arginine vasopressin and PACAP at specific brain synapses in rat and mouse, and developed and characterized genetically altered mice to facilitate further investigations of peptidergic neurotransmission in the brain. In collaboration with the Zhang laboratory in the Department of Physiology, UNAM (Hernandez-Perez et al., J. Neuroendocrinol., in press, 2023) a group of excitatory PACAP-expressing neurons have been identified within the lateral olfactory tract (NLOT) that are controlled by input from vasopressinergic neurons of the supraoptic nucleus of the hypothalamus and possess the hallmarks of a functional hub linking hydromineral homeostasis to behavior. A role for vasopressin as a synapse organizer in the limbic system has also been identified (Zhang et a., J. Neuroendocrinol. 34: e13164, 2022). AVP innervates specific cells of the basolateral amygdala, and these respond to AVP with prompt induction of the synaptic protein PSD-95 and the GluA1 AMPA glutamate receptor. Exploring the mechanism(s) of action of vasopressin at their PACAPergic target neurons in NLOT to determine if the synaptic organizer functions of AVP are unique to BLA or extend to other vasopressinergic synapses (e.g. NLOT); whether AVP is able to enhance the firing of PACAPergic neurons of NLOT, and the consequences of activation of NLOT PACAP neurons on their targets in cortex will require translation of this model from rat to mouse, to enable employment of the mouse genetic models to determine whether or not deletion of PACAP from these neurons, as in PACAPergic neurons of PFC and PBn, result in impaired IEG induction or transduction of stressor signaling to behavior as in these other systems. We have also identified a novel role for PACAP signaling through cAMPNCS-RapGEF2 in short- and long-term transcriptional regulation in neuroendocrine cells (Xu et al. J. Neuroendocrinol. 34: e13182, 2022), and plan to extend these observations to PACAPs synaptic action in the central nervous system of the mouse. Based on our discovery of a developmental role for PACAP in locomotor activity independent of its transmitter role in the adult, we tested a new model for PACAP deficiency in the mouse in which PACAP gene deletion occurs following early stages of development and only in neurons (Bakalar et al. J. Neuroendocrinol., in press, 2023), and will begin to employ the Baf53b-Cre::Adcyap1fl/fl mouse in both gain- and loss-of-function experiments to identify PACAPs actions in synaptic information transfer in circuits involved in stress responding. Two glutamatergic circuits have been identified in mouse in which the presence of PACAP is required for IEG (FOS) induction after restraint stress, and mediating endocrine and behavioral sequelae of acute restraint stress (Jiang et al., Biol. Psychiatr. GOS, in press, 2023). The parabrachioamygdalar and frontocorticohypothalamic PACAPergic pathways in the mouse are now independently required to express PACAP to achieve behavioral and endocrine activation, respectively, following restraint stress. Overall, publications from the SMN and our collaborators in this calendar year strengthen the case for specific role(s) of neuropeptide co-transmission in neuronal cellular plasticity underlying stress responding; link this role to FOS induction in neurons engaged in the stress response, and lay a foundation for more detailed examination of the PACAP-dependent post-synaptic events that occur at circuits of stress required to complete their tasks as behavioral and endocrine stress transducers in the brain.