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One way to associate peptide\u2010deficiency phenotypes with either role is first to assess potential phenotypes in so\u2010called constitutive knockout mice, and then proceed to specify, regionally and temporally, where and when neuropeptide expression is required to prevent these phenotypes<jats:italic>.<\/jats:italic> We have previously demonstrated that the well\u2010known constellation of behavioral and metabolic phenotypes associated with constitutive pituitary adenylate cyclase\u2010activating peptide (PACAP) knockout mice are accompanied by transcriptomic alterations of two types: those that distinguish the PACAP\u2010null phenotype from wild\u2010type (WT) in otherwise quiescent mice (cPRGs), and gene induction that occurs in response to acute environmental perturbation in WT mice that do not occur in knockout mice (aPRGs). Comparing constitutive PACAP knockout mice to a variety of temporally and regionally specific PACAP knockouts, we show that the prominent hyperlocomotor phenotype is a consequence of early loss of PACAP expression, is associated with <jats:italic>Fos<\/jats:italic> overexpression in hippocampus and basal ganglia, and that a thermoregulatory effect previously shown to be mediated by PACAP\u2010expressing neurons of medial preoptic hypothalamus is independent of PACAP expression in those neurons in adult mice. In contrast, PACAP dependence of weight loss\/hypophagia triggered by restraint stress, seen in constitutive PACAP knockout mice, is phenocopied in mice in which PACAP is deleted after neuronal differentiation. Our results imply that PACAP has a prominent role as a trophic factor early in development determining global central nervous system characteristics, and in addition a second, discrete set of functions as a neurotransmitter in the fully developed nervous system that support physiological and psychological responses to stress.<\/jats:p>","DOI":"10.1111\/jne.13286","type":"journal-article","created":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T07:50:30Z","timestamp":1683013830000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Constitutive and conditional deletion reveals distinct phenotypes driven by developmental versus neurotransmitter actions of the neuropeptide PACAP"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8257-4427","authenticated-orcid":false,"given":"Dana","family":"Bakalar","sequence":"first","affiliation":[{"name":"Section on Molecular Neuroscience, 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