{"gene":"ADCYAP1","run_date":"2026-06-09T22:02:41","timeline":{"discoveries":[{"year":2022,"finding":"ADCYAP1+ neurons in the nucleus of the solitary tract and area postrema (NTS-AP) are both necessary and sufficient for sickness behavior responses to LPS (anorexia, adipsia, lethargy, temperature changes): activation of these neurons fully recapitulates LPS-induced sickness, while inhibition significantly diminishes all behavioral responses.","method":"Chemogenetic activation/inhibition of ADCYAP1+ neurons in TRAP2 mice combined with single-nucleus RNA sequencing to identify LPS-activated neural populations; whole-brain activity mapping (FOS expression)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments (activation recapitulates, inhibition diminishes) with cell-type specificity established by snRNA-seq; multiple orthogonal methods in single rigorous study","pmids":["36071158"],"is_preprint":false},{"year":2006,"finding":"Loss of Adcyap1 (PACAP) in mice causes hyperlocomotion and prepulse inhibition deficits; the paradoxical antihyperkinetic effect of amphetamine in Adcyap1−/− mice depends on serotonin 1A (5-HT1A) receptor signaling, and amphetamine increases c-Fos-positive neurons in the prefrontal cortex of these mice, suggesting PACAP normally modulates 5-HT1A-mediated inhibitory prefrontal control of motor activity.","method":"Genetic knockout (Adcyap1−/− mice), prepulse inhibition assay, pharmacological manipulation (amphetamine, 5-HT1A agonist 8-OH-DPAT, fluoxetine), c-Fos immunohistochemistry","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined behavioral phenotype plus pharmacological epistasis placing 5-HT1A downstream; single lab, multiple orthogonal methods","pmids":["16687500"],"is_preprint":false},{"year":2006,"finding":"Adcyap1−/− mice exhibit intense jumping behavior that is suppressed by the SSRI fluoxetine and the serotonin precursor 5-hydroxytryptophan, and these mice show reduced brain 5-HIAA, indicating that PACAP supports serotonergic tone that limits abnormal motor behavior.","method":"Genetic knockout (Adcyap1−/− mice), pharmacological treatment (fluoxetine, 5-HTP), neurochemical measurement of 5-HIAA","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO phenotype with pharmacological rescue and neurochemical correlate; single lab, multiple methods","pmids":["16888223"],"is_preprint":false},{"year":2008,"finding":"Adcyap1−/− mice have markedly reduced white adipose tissue mass, hypoinsulinemia, and increased insulin sensitivity accompanied by decreased adipocyte differentiation marker aP2 and reduced plasma resistin, indicating that PACAP promotes energy storage, adipogenesis, and insulin secretion in vivo.","method":"Genetic knockout (Adcyap1−/− mice), glucose and insulin tolerance tests, fat mass measurement, adipocyte marker mRNA expression (aP2), plasma hormone and adipokine measurements, high-fat diet challenge","journal":"Journal of pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple metabolic phenotypic readouts; single lab","pmids":["18446003"],"is_preprint":false},{"year":2009,"finding":"Forced overexpression of Adcyap1 in insulinoma NIT-1 cells protected them from cytokine-triggered apoptosis, establishing ADCYAP1 as a downstream mediator of DcR3-mediated islet beta cell survival.","method":"Plasmid-mediated overexpression of Adcyap1 in NIT-1 insulinoma cells, cytokine-induced apoptosis assay; DNA microarray identified Adcyap1 upregulation (>700-fold) in DcR3-transgenic islets","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct overexpression with functional apoptosis readout plus microarray identification; single lab, two orthogonal methods","pmids":["20007581"],"is_preprint":false},{"year":2020,"finding":"ADCYAP1 (PACAP) is the most strongly upregulated gene in skin during peripheral nerve regeneration after carpal tunnel release; PACAP signals through its G-protein coupled receptor (PAC1R) expressed on human iPSC-derived sensory neurons and dose-dependently enhances axon outgrowth in vitro.","method":"Transcriptional profiling of serial skin biopsies (pre/post carpal tunnel surgery), human iPSC-derived sensory neuron culture with PACAP treatment, neurite length measurement in vitro","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assay showing dose-dependent axon outgrowth via identified receptor, supported by correlative in vivo transcriptomics; single lab","pmids":["32651949"],"is_preprint":false},{"year":2023,"finding":"Adcyap1/PACAP38 is an intrinsic protective factor in dorsal root ganglion neurons linking neuropathic pain suppression and axonal regeneration: intrathecal PACAP38 mitigates mechanical hyperalgesia and facilitates axon regeneration, while Adcyap1 siRNA knockdown or PAC1R antagonist (PACAP6-38) both worsen pain and delay regeneration in a rat spared nerve crush model.","method":"scRNA-seq of rat DRGs, intrathecal PACAP38 administration, siRNA knockdown of Adcyap1, PAC1R antagonist (PACAP6-38) treatment; behavioral pain testing (mechanical hyperalgesia), axonal regeneration assessment","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (siRNA + receptor antagonist) and gain-of-function (PACAP38) with defined phenotypic readouts; single lab, multiple orthogonal methods","pmids":["37880634"],"is_preprint":false},{"year":2011,"finding":"The ADCYAP1 promoter is hypermethylated in cervical cancer cells and CIN lesions, silencing ADCYAP1 expression; this silencing is reversed by treatment with a DNA methyltransferase inhibitor (5-aza-2'-deoxycytidine) and/or histone deacetylase inhibitor (trichostatin A), establishing promoter hypermethylation as a mechanism of ADCYAP1 transcriptional repression in cervical cancer.","method":"Methylation analysis of CpG islands in ADCYAP1 promoter in cancer cell lines and tissue samples; pharmacological demethylation/HDAC inhibitor treatment followed by gene expression measurement","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — methylation assay plus pharmacological reactivation experiment; single lab, two orthogonal methods","pmids":["21109983"],"is_preprint":false},{"year":2025,"finding":"Gα13 overexpression in medial prefrontal cortex pyramidal neurons downregulates Adcyap1, reducing cAMP/PKA signaling and impairing NMDA receptor function; pharmacological activation with PACAP-38 rescues social deficits and restores synaptic function in Gα13-OE mice, placing ADCYAP1/PACAP downstream of Gα13 in a mPFC cAMP/PKA/NMDAR pathway controlling social behavior.","method":"CRISPR/Cas9-mediated Gα13 overexpression in mPFC pyramidal neurons; RNA-seq identifying Adcyap1 downregulation; pharmacological rescue with PACAP-38; fiber photometry; Golgi staining; whole-cell patch clamp; three-chamber socialization test","journal":"Schizophrenia bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement by genetic epistasis plus pharmacological rescue with multiple orthogonal readouts; single lab","pmids":["40843621"],"is_preprint":false},{"year":2025,"finding":"A Kölliker-Fuse nucleus subpopulation co-expressing Adcyap1 (PACAP) and VGluT1 (Slc17a7) forms calyceal terminals around PKCδ+/GluD1+ extended amygdala neurons and becomes Fos-positive rapidly after acute hypotension, preceding vasopressin-mediated endocrine responses, suggesting PACAP/glutamate co-transmission mediates rapid autonomic compensation to falling blood pressure.","method":"Fos immunohistochemistry at 60 and 120 min after hydralazine-induced hypotension in rats; confocal immunohistochemistry of PACAP+ terminals around EA neurons; RNAscope in situ hybridization for Adcyap1/Slc17a7 co-expression in KF","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlative Fos and anatomical mapping without direct functional manipulation of the PACAP pathway; preprint, single lab","pmids":["bio_10.1101_2025.10.16.682741"],"is_preprint":true}],"current_model":"ADCYAP1-encoded PACAP is a neuropeptide that signals through G-protein coupled receptors (primarily PAC1R) to activate cAMP/PKA signaling, and functions as a pleiotropic regulator: specific brainstem ADCYAP1+ neurons in the NTS-AP are necessary and sufficient for sickness behavior responses to infection; PACAP promotes energy storage and adipogenesis, modulates 5-HT1A-dependent prefrontal inhibitory control of motor activity, protects islet beta cells from apoptosis, drives peripheral sensory axon outgrowth and regeneration, and mediates mPFC synaptic function via a Gα13/Adcyap1/cAMP/PKA/NMDAR pathway controlling social behavior."},"narrative":{"mechanistic_narrative":"ADCYAP1 encodes the neuropeptide PACAP, a pleiotropic signaling molecule that acts through its G-protein coupled receptor PAC1R to coordinate central behavioral programs, peripheral neuronal survival and regeneration, and metabolic energy storage [PMID:32651949, PMID:37880634]. In the brainstem, ADCYAP1+ neurons of the nucleus of the solitary tract and area postrema are both necessary and sufficient for the sickness behavior response to LPS, with chemogenetic activation recapitulating anorexia, adipsia, lethargy and temperature changes and inhibition diminishing them [PMID:36071158]. In the forebrain, PACAP supports serotonergic tone and 5-HT1A-mediated prefrontal inhibitory control of motor activity, such that its loss produces hyperlocomotion, prepulse inhibition deficits and abnormal jumping behavior [PMID:16687500, PMID:16888223], and PACAP signaling lies downstream of Gα13 in an mPFC cAMP/PKA/NMDAR pathway whose disruption impairs social behavior and is rescued by PACAP-38 [PMID:40843621]. In the periphery, PACAP is the most strongly upregulated gene in skin during peripheral nerve regeneration and dose-dependently enhances sensory axon outgrowth via PAC1R, and within dorsal root ganglia it acts as an intrinsic protective factor that suppresses neuropathic pain and facilitates axonal regeneration [PMID:32651949, PMID:37880634]. PACAP also promotes adipogenesis, energy storage and insulin secretion in vivo and protects islet beta cells from cytokine-induced apoptosis [PMID:18446003, PMID:20007581]. ADCYAP1 expression is silenced by promoter hypermethylation in cervical cancer [PMID:21109983].","teleology":[{"year":2006,"claim":"Established that PACAP shapes central motor and sensorimotor gating behavior by supporting serotonergic tone, identifying 5-HT1A as a downstream effector of PACAP-dependent prefrontal inhibitory control.","evidence":"Adcyap1 knockout mice with prepulse inhibition assays, amphetamine/5-HT1A/SSRI pharmacology, neurochemical 5-HIAA measurement and c-Fos immunohistochemistry","pmids":["16687500","16888223"],"confidence":"Medium","gaps":["Did not identify the specific neurons or circuits where PACAP acts on serotonergic signaling","Receptor (PAC1R vs other) mediating the behavioral effect not defined in vivo"]},{"year":2008,"claim":"Defined a peripheral metabolic role for PACAP, showing it promotes white adipose tissue accumulation, adipocyte differentiation and insulin secretion in vivo.","evidence":"Adcyap1 knockout mice analyzed by glucose/insulin tolerance tests, fat mass and adipocyte marker measurement, plasma hormone/adipokine assays","pmids":["18446003"],"confidence":"Medium","gaps":["Tissue site of PACAP action (central vs adipose vs islet) not resolved","Receptor and intracellular pathway mediating adipogenesis not established"]},{"year":2009,"claim":"Placed ADCYAP1 downstream of DcR3 as a beta-cell survival mediator, providing a cell-autonomous anti-apoptotic function.","evidence":"Plasmid overexpression of Adcyap1 in NIT-1 insulinoma cells with cytokine-induced apoptosis assay; DNA microarray identification in DcR3-transgenic islets","pmids":["20007581"],"confidence":"Medium","gaps":["Anti-apoptotic mechanism downstream of PACAP not dissected","Not validated in primary islets or in vivo"]},{"year":2011,"claim":"Identified an epigenetic mechanism silencing ADCYAP1, showing promoter hypermethylation represses its expression in cervical cancer.","evidence":"CpG methylation analysis in cancer cell lines and tissues with pharmacological demethylation/HDAC inhibitor reactivation","pmids":["21109983"],"confidence":"Medium","gaps":["Functional consequence of ADCYAP1 loss for tumorigenesis not tested","Whether silencing is driver or passenger not established"]},{"year":2020,"claim":"Demonstrated that PACAP drives peripheral sensory axon outgrowth via PAC1R, linking it to nerve regeneration.","evidence":"Serial skin biopsy transcriptomics around carpal tunnel surgery plus PACAP treatment of human iPSC-derived sensory neurons with neurite length measurement","pmids":["32651949"],"confidence":"Medium","gaps":["In vivo causal requirement of PACAP for human regeneration not tested","Intracellular signaling driving outgrowth not characterized"]},{"year":2022,"claim":"Resolved the circuit basis of sickness behavior, showing brainstem ADCYAP1+ NTS-AP neurons are necessary and sufficient for the behavioral response to LPS.","evidence":"Chemogenetic gain/loss-of-function in TRAP2 mice, single-nucleus RNA-seq cell typing and whole-brain FOS mapping","pmids":["36071158"],"confidence":"High","gaps":["Whether the PACAP peptide itself (vs other markers of these neurons) mediates the behavior not isolated","Downstream target neurons of the ADCYAP1+ population not fully defined"]},{"year":2023,"claim":"Established PACAP as an intrinsic DRG protective factor coupling neuropathic pain suppression to axonal regeneration through PAC1R.","evidence":"Rat spared nerve crush model with intrathecal PACAP38, Adcyap1 siRNA knockdown and PAC1R antagonist, scRNA-seq, behavioral pain and regeneration readouts","pmids":["37880634"],"confidence":"Medium","gaps":["Signaling cascade downstream of PAC1R in DRG not dissected","Single species/lab"]},{"year":2025,"claim":"Positioned ADCYAP1/PACAP within an mPFC Gα13/cAMP/PKA/NMDAR pathway controlling social behavior, with pharmacological rescue restoring synaptic and behavioral deficits.","evidence":"CRISPR Gα13 overexpression in mPFC pyramidal neurons, RNA-seq, PACAP-38 rescue, fiber photometry, Golgi staining, patch clamp and three-chamber socialization test","pmids":["40843621"],"confidence":"Medium","gaps":["Direct molecular link from Gα13 to Adcyap1 transcription not defined","Single lab"]},{"year":null,"claim":"Whether PACAP/glutamate co-transmission from the Kölliker-Fuse nucleus causally drives rapid autonomic compensation to hypotension remains unresolved.","evidence":"Correlative Fos and anatomical mapping after hydralazine-induced hypotension (preprint)","pmids":[],"confidence":"Low","gaps":["No direct functional manipulation of the PACAP pathway","Causal contribution to blood pressure compensation untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[5,6,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,8]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,8]}],"complexes":[],"partners":["ADCYAP1R1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P18509","full_name":"Pituitary adenylate cyclase-activating polypeptide","aliases":[],"length_aa":176,"mass_kda":18.8,"function":"PACAP is a neuropeptide involved in diverse array of physiological processes through activating the PACAP subfamily of class B1 G protein-coupled receptors: VIP receptor 1 (VIPR1), VIP receptor 2 (VIPR2), and PACAP type I receptor (ADCYAP1R1) (PubMed:11175907, PubMed:23800469, PubMed:32047270, PubMed:36385145). Exerts neuroprotective and general cytoprotective effects due to anti-apoptotic, anti-inflammatory, and antioxidant actions (PubMed:23800469). Promotes neuron projection development through the RAPGEF2/Rap1/B-Raf/ERK pathway (PubMed:23800469). In chromaffin cells, induces long-lasting increase of intracellular calcium concentrations and neuroendocrine secretion (By similarity). Involved in the control of glucose homeostasis, induces insulin secretion by pancreatic beta cells (By similarity). PACAP exists in two bioactive forms from proteolysis of the same precursor protein, PACAP27 and PACAP38, which differ by eleven amino acid residues in the C-terminus (PubMed:32047270)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P18509/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADCYAP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADCYAP1","total_profiled":1310},"omim":[{"mim_id":"607834","title":"ANXIETY","url":"https://www.omim.org/entry/607834"},{"mim_id":"145500","title":"HYPERTENSION, ESSENTIAL","url":"https://www.omim.org/entry/145500"},{"mim_id":"126200","title":"MULTIPLE SCLEROSIS, SUSCEPTIBILITY TO; MS","url":"https://www.omim.org/entry/126200"},{"mim_id":"102981","title":"ADCYAP RECEPTOR, TYPE I; ADCYAP1R1","url":"https://www.omim.org/entry/102981"},{"mim_id":"102980","title":"ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE 1; ADCYAP1","url":"https://www.omim.org/entry/102980"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":11.5},{"tissue":"lymphoid tissue","ntpm":10.3}],"url":"https://www.proteinatlas.org/search/ADCYAP1"},"hgnc":{"alias_symbol":["PACAP"],"prev_symbol":[]},"alphafold":{"accession":"P18509","domains":[{"cath_id":"1.20.5","chopping":"140-172","consensus_level":"medium","plddt":76.1124,"start":140,"end":172}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P18509","model_url":"https://alphafold.ebi.ac.uk/files/AF-P18509-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P18509-F1-predicted_aligned_error_v6.png","plddt_mean":62.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADCYAP1","jax_strain_url":"https://www.jax.org/strain/search?query=ADCYAP1"},"sequence":{"accession":"P18509","fasta_url":"https://rest.uniprot.org/uniprotkb/P18509.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P18509/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P18509"}},"corpus_meta":[{"pmid":"36071158","id":"PMC_36071158","title":"Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/36071158","citation_count":117,"is_preprint":false},{"pmid":"16687500","id":"PMC_16687500","title":"Psychostimulant-induced attenuation of hyperactivity and prepulse inhibition deficits in Adcyap1-deficient mice.","date":"2006","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16687500","citation_count":78,"is_preprint":false},{"pmid":"32651949","id":"PMC_32651949","title":"Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth.","date":"2020","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/32651949","citation_count":52,"is_preprint":false},{"pmid":"18446003","id":"PMC_18446003","title":"Markedly reduced white adipose tissue and increased insulin sensitivity in adcyap1-deficient mice.","date":"2008","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18446003","citation_count":49,"is_preprint":false},{"pmid":"21109983","id":"PMC_21109983","title":"The role of ADCYAP1, adenylate cyclase activating polypeptide 1, as a methylation biomarker for the early detection of cervical cancer.","date":"2011","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21109983","citation_count":28,"is_preprint":false},{"pmid":"28240513","id":"PMC_28240513","title":"Human Papillomavirus Genotypes and Methylation of CADM1, PAX1, MAL and ADCYAP1 Genes in Epithelial Ovarian Cancer Patients.","date":"2017","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/28240513","citation_count":28,"is_preprint":false},{"pmid":"16888223","id":"PMC_16888223","title":"Serotonergic inhibition of intense jumping behavior in mice lacking PACAP (Adcyap1-/-).","date":"2006","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/16888223","citation_count":20,"is_preprint":false},{"pmid":"20007581","id":"PMC_20007581","title":"DcR3 protects islet beta cells from apoptosis through modulating Adcyap1 and Bank1 expression.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20007581","citation_count":15,"is_preprint":false},{"pmid":"29324772","id":"PMC_29324772","title":"Examination of Clock and Adcyap1 gene variation in a neotropical migratory passerine.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29324772","citation_count":12,"is_preprint":false},{"pmid":"37880634","id":"PMC_37880634","title":"Unveiling adcyap1 as a protective factor linking pain and nerve regeneration through single-cell RNA sequencing of rat dorsal root ganglion neurons.","date":"2023","source":"BMC 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Mice","date":"2025-09-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.02.673882","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14886,"output_tokens":2933,"usd":0.044326,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10407,"output_tokens":3003,"usd":0.063555,"stage2_stop_reason":"end_turn"},"total_usd":0.107881,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"ADCYAP1+ neurons in the nucleus of the solitary tract and area postrema (NTS-AP) are both necessary and sufficient for sickness behavior responses to LPS (anorexia, adipsia, lethargy, temperature changes): activation of these neurons fully recapitulates LPS-induced sickness, while inhibition significantly diminishes all behavioral responses.\",\n      \"method\": \"Chemogenetic activation/inhibition of ADCYAP1+ neurons in TRAP2 mice combined with single-nucleus RNA sequencing to identify LPS-activated neural populations; whole-brain activity mapping (FOS expression)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments (activation recapitulates, inhibition diminishes) with cell-type specificity established by snRNA-seq; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"36071158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Loss of Adcyap1 (PACAP) in mice causes hyperlocomotion and prepulse inhibition deficits; the paradoxical antihyperkinetic effect of amphetamine in Adcyap1−/− mice depends on serotonin 1A (5-HT1A) receptor signaling, and amphetamine increases c-Fos-positive neurons in the prefrontal cortex of these mice, suggesting PACAP normally modulates 5-HT1A-mediated inhibitory prefrontal control of motor activity.\",\n      \"method\": \"Genetic knockout (Adcyap1−/− mice), prepulse inhibition assay, pharmacological manipulation (amphetamine, 5-HT1A agonist 8-OH-DPAT, fluoxetine), c-Fos immunohistochemistry\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined behavioral phenotype plus pharmacological epistasis placing 5-HT1A downstream; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16687500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Adcyap1−/− mice exhibit intense jumping behavior that is suppressed by the SSRI fluoxetine and the serotonin precursor 5-hydroxytryptophan, and these mice show reduced brain 5-HIAA, indicating that PACAP supports serotonergic tone that limits abnormal motor behavior.\",\n      \"method\": \"Genetic knockout (Adcyap1−/− mice), pharmacological treatment (fluoxetine, 5-HTP), neurochemical measurement of 5-HIAA\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenotype with pharmacological rescue and neurochemical correlate; single lab, multiple methods\",\n      \"pmids\": [\"16888223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Adcyap1−/− mice have markedly reduced white adipose tissue mass, hypoinsulinemia, and increased insulin sensitivity accompanied by decreased adipocyte differentiation marker aP2 and reduced plasma resistin, indicating that PACAP promotes energy storage, adipogenesis, and insulin secretion in vivo.\",\n      \"method\": \"Genetic knockout (Adcyap1−/− mice), glucose and insulin tolerance tests, fat mass measurement, adipocyte marker mRNA expression (aP2), plasma hormone and adipokine measurements, high-fat diet challenge\",\n      \"journal\": \"Journal of pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple metabolic phenotypic readouts; single lab\",\n      \"pmids\": [\"18446003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Forced overexpression of Adcyap1 in insulinoma NIT-1 cells protected them from cytokine-triggered apoptosis, establishing ADCYAP1 as a downstream mediator of DcR3-mediated islet beta cell survival.\",\n      \"method\": \"Plasmid-mediated overexpression of Adcyap1 in NIT-1 insulinoma cells, cytokine-induced apoptosis assay; DNA microarray identified Adcyap1 upregulation (>700-fold) in DcR3-transgenic islets\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct overexpression with functional apoptosis readout plus microarray identification; single lab, two orthogonal methods\",\n      \"pmids\": [\"20007581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ADCYAP1 (PACAP) is the most strongly upregulated gene in skin during peripheral nerve regeneration after carpal tunnel release; PACAP signals through its G-protein coupled receptor (PAC1R) expressed on human iPSC-derived sensory neurons and dose-dependently enhances axon outgrowth in vitro.\",\n      \"method\": \"Transcriptional profiling of serial skin biopsies (pre/post carpal tunnel surgery), human iPSC-derived sensory neuron culture with PACAP treatment, neurite length measurement in vitro\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assay showing dose-dependent axon outgrowth via identified receptor, supported by correlative in vivo transcriptomics; single lab\",\n      \"pmids\": [\"32651949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Adcyap1/PACAP38 is an intrinsic protective factor in dorsal root ganglion neurons linking neuropathic pain suppression and axonal regeneration: intrathecal PACAP38 mitigates mechanical hyperalgesia and facilitates axon regeneration, while Adcyap1 siRNA knockdown or PAC1R antagonist (PACAP6-38) both worsen pain and delay regeneration in a rat spared nerve crush model.\",\n      \"method\": \"scRNA-seq of rat DRGs, intrathecal PACAP38 administration, siRNA knockdown of Adcyap1, PAC1R antagonist (PACAP6-38) treatment; behavioral pain testing (mechanical hyperalgesia), axonal regeneration assessment\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (siRNA + receptor antagonist) and gain-of-function (PACAP38) with defined phenotypic readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37880634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The ADCYAP1 promoter is hypermethylated in cervical cancer cells and CIN lesions, silencing ADCYAP1 expression; this silencing is reversed by treatment with a DNA methyltransferase inhibitor (5-aza-2'-deoxycytidine) and/or histone deacetylase inhibitor (trichostatin A), establishing promoter hypermethylation as a mechanism of ADCYAP1 transcriptional repression in cervical cancer.\",\n      \"method\": \"Methylation analysis of CpG islands in ADCYAP1 promoter in cancer cell lines and tissue samples; pharmacological demethylation/HDAC inhibitor treatment followed by gene expression measurement\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — methylation assay plus pharmacological reactivation experiment; single lab, two orthogonal methods\",\n      \"pmids\": [\"21109983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Gα13 overexpression in medial prefrontal cortex pyramidal neurons downregulates Adcyap1, reducing cAMP/PKA signaling and impairing NMDA receptor function; pharmacological activation with PACAP-38 rescues social deficits and restores synaptic function in Gα13-OE mice, placing ADCYAP1/PACAP downstream of Gα13 in a mPFC cAMP/PKA/NMDAR pathway controlling social behavior.\",\n      \"method\": \"CRISPR/Cas9-mediated Gα13 overexpression in mPFC pyramidal neurons; RNA-seq identifying Adcyap1 downregulation; pharmacological rescue with PACAP-38; fiber photometry; Golgi staining; whole-cell patch clamp; three-chamber socialization test\",\n      \"journal\": \"Schizophrenia bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement by genetic epistasis plus pharmacological rescue with multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"40843621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A Kölliker-Fuse nucleus subpopulation co-expressing Adcyap1 (PACAP) and VGluT1 (Slc17a7) forms calyceal terminals around PKCδ+/GluD1+ extended amygdala neurons and becomes Fos-positive rapidly after acute hypotension, preceding vasopressin-mediated endocrine responses, suggesting PACAP/glutamate co-transmission mediates rapid autonomic compensation to falling blood pressure.\",\n      \"method\": \"Fos immunohistochemistry at 60 and 120 min after hydralazine-induced hypotension in rats; confocal immunohistochemistry of PACAP+ terminals around EA neurons; RNAscope in situ hybridization for Adcyap1/Slc17a7 co-expression in KF\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlative Fos and anatomical mapping without direct functional manipulation of the PACAP pathway; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.10.16.682741\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ADCYAP1-encoded PACAP is a neuropeptide that signals through G-protein coupled receptors (primarily PAC1R) to activate cAMP/PKA signaling, and functions as a pleiotropic regulator: specific brainstem ADCYAP1+ neurons in the NTS-AP are necessary and sufficient for sickness behavior responses to infection; PACAP promotes energy storage and adipogenesis, modulates 5-HT1A-dependent prefrontal inhibitory control of motor activity, protects islet beta cells from apoptosis, drives peripheral sensory axon outgrowth and regeneration, and mediates mPFC synaptic function via a Gα13/Adcyap1/cAMP/PKA/NMDAR pathway controlling social behavior.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADCYAP1 encodes the neuropeptide PACAP, a pleiotropic signaling molecule that acts through its G-protein coupled receptor PAC1R to coordinate central behavioral programs, peripheral neuronal survival and regeneration, and metabolic energy storage [#5, #6]. In the brainstem, ADCYAP1+ neurons of the nucleus of the solitary tract and area postrema are both necessary and sufficient for the sickness behavior response to LPS, with chemogenetic activation recapitulating anorexia, adipsia, lethargy and temperature changes and inhibition diminishing them [#0]. In the forebrain, PACAP supports serotonergic tone and 5-HT1A-mediated prefrontal inhibitory control of motor activity, such that its loss produces hyperlocomotion, prepulse inhibition deficits and abnormal jumping behavior [#1, #2], and PACAP signaling lies downstream of Gα13 in an mPFC cAMP/PKA/NMDAR pathway whose disruption impairs social behavior and is rescued by PACAP-38 [#8]. In the periphery, PACAP is the most strongly upregulated gene in skin during peripheral nerve regeneration and dose-dependently enhances sensory axon outgrowth via PAC1R, and within dorsal root ganglia it acts as an intrinsic protective factor that suppresses neuropathic pain and facilitates axonal regeneration [#5, #6]. PACAP also promotes adipogenesis, energy storage and insulin secretion in vivo and protects islet beta cells from cytokine-induced apoptosis [#3, #4]. ADCYAP1 expression is silenced by promoter hypermethylation in cervical cancer [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that PACAP shapes central motor and sensorimotor gating behavior by supporting serotonergic tone, identifying 5-HT1A as a downstream effector of PACAP-dependent prefrontal inhibitory control.\",\n      \"evidence\": \"Adcyap1 knockout mice with prepulse inhibition assays, amphetamine/5-HT1A/SSRI pharmacology, neurochemical 5-HIAA measurement and c-Fos immunohistochemistry\",\n      \"pmids\": [\"16687500\", \"16888223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the specific neurons or circuits where PACAP acts on serotonergic signaling\", \"Receptor (PAC1R vs other) mediating the behavioral effect not defined in vivo\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined a peripheral metabolic role for PACAP, showing it promotes white adipose tissue accumulation, adipocyte differentiation and insulin secretion in vivo.\",\n      \"evidence\": \"Adcyap1 knockout mice analyzed by glucose/insulin tolerance tests, fat mass and adipocyte marker measurement, plasma hormone/adipokine assays\",\n      \"pmids\": [\"18446003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue site of PACAP action (central vs adipose vs islet) not resolved\", \"Receptor and intracellular pathway mediating adipogenesis not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed ADCYAP1 downstream of DcR3 as a beta-cell survival mediator, providing a cell-autonomous anti-apoptotic function.\",\n      \"evidence\": \"Plasmid overexpression of Adcyap1 in NIT-1 insulinoma cells with cytokine-induced apoptosis assay; DNA microarray identification in DcR3-transgenic islets\",\n      \"pmids\": [\"20007581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Anti-apoptotic mechanism downstream of PACAP not dissected\", \"Not validated in primary islets or in vivo\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified an epigenetic mechanism silencing ADCYAP1, showing promoter hypermethylation represses its expression in cervical cancer.\",\n      \"evidence\": \"CpG methylation analysis in cancer cell lines and tissues with pharmacological demethylation/HDAC inhibitor reactivation\",\n      \"pmids\": [\"21109983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of ADCYAP1 loss for tumorigenesis not tested\", \"Whether silencing is driver or passenger not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that PACAP drives peripheral sensory axon outgrowth via PAC1R, linking it to nerve regeneration.\",\n      \"evidence\": \"Serial skin biopsy transcriptomics around carpal tunnel surgery plus PACAP treatment of human iPSC-derived sensory neurons with neurite length measurement\",\n      \"pmids\": [\"32651949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo causal requirement of PACAP for human regeneration not tested\", \"Intracellular signaling driving outgrowth not characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the circuit basis of sickness behavior, showing brainstem ADCYAP1+ NTS-AP neurons are necessary and sufficient for the behavioral response to LPS.\",\n      \"evidence\": \"Chemogenetic gain/loss-of-function in TRAP2 mice, single-nucleus RNA-seq cell typing and whole-brain FOS mapping\",\n      \"pmids\": [\"36071158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the PACAP peptide itself (vs other markers of these neurons) mediates the behavior not isolated\", \"Downstream target neurons of the ADCYAP1+ population not fully defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established PACAP as an intrinsic DRG protective factor coupling neuropathic pain suppression to axonal regeneration through PAC1R.\",\n      \"evidence\": \"Rat spared nerve crush model with intrathecal PACAP38, Adcyap1 siRNA knockdown and PAC1R antagonist, scRNA-seq, behavioral pain and regeneration readouts\",\n      \"pmids\": [\"37880634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling cascade downstream of PAC1R in DRG not dissected\", \"Single species/lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned ADCYAP1/PACAP within an mPFC Gα13/cAMP/PKA/NMDAR pathway controlling social behavior, with pharmacological rescue restoring synaptic and behavioral deficits.\",\n      \"evidence\": \"CRISPR Gα13 overexpression in mPFC pyramidal neurons, RNA-seq, PACAP-38 rescue, fiber photometry, Golgi staining, patch clamp and three-chamber socialization test\",\n      \"pmids\": [\"40843621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link from Gα13 to Adcyap1 transcription not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether PACAP/glutamate co-transmission from the Kölliker-Fuse nucleus causally drives rapid autonomic compensation to hypotension remains unresolved.\",\n      \"evidence\": \"Correlative Fos and anatomical mapping after hydralazine-induced hypotension (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct functional manipulation of the PACAP pathway\", \"Causal contribution to blood pressure compensation untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [5, 6, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ADCYAP1R1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}