{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T21:10:06Z","timestamp":1768770606659,"version":"3.49.0"},"reference-count":41,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2015,2,11]],"date-time":"2015-02-11T00:00:00Z","timestamp":1423612800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NS051187"],"award-info":[{"award-number":["NS051187"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2015,4]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\"><jats:list-item><jats:p>Signalling mechanisms for coincidence detection of paired stimuli during classical conditioning are fundamental for understanding the mechanisms of associative learning.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Bidirectional 3\u2010phosphoinositide\u2010dependent kinase\u20101 (PDK1) activity is signalled by TrkB neurotrophin receptors for paired stimuli and p75<jats:sup>NTR<\/jats:sup>for unpaired stimuli.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Adenosine 2A receptors modulate PDK1 responses directly as G\u00a0proteins and by transactivation of TrkB.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Convergence of protein kinase\u00a0A and PDK1 activity initiates signalling of paired stimuli during classical conditioning.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>How the neural substrates for detection of paired stimuli are distinct from unpaired stimuli is poorly understood and a fundamental question for understanding the signalling mechanisms for coincidence detection during associative learning. To address this question, we used a neural correlate of eyeblink classical conditioning in an isolated brainstem from the turtle, in which the cranial nerves are directly stimulated in place of using a tone or airpuff. A bidirectional response is activated in &lt;5\u00a0min of training, in which phosphorylated 3\u2010phosphoinositide\u2010dependent kinase\u20101 (p\u2010PDK1) is increased in response to paired and decreased in response to unpaired nerve stimulation and is mediated by the opposing actions of neurotrophin receptors TrkB and p75<jats:sup>NTR<\/jats:sup>. Surprisingly, blockade of adenosine\u00a02A (A<jats:sub>2A<\/jats:sub>) receptors inhibits both of these responses. Pairing also induces substantially increased surface expression of TrkB that is inhibited by Src family tyrosine kinase and A<jats:sub>2A<\/jats:sub>receptor antagonists. Finally, the acquisition of conditioning is blocked by a PDK1 inhibitor. The unique action of A<jats:sub>2A<\/jats:sub>receptors to function directly as G\u00a0proteins and in receptor transactivation to control distinct TrkB and p75<jats:sup>NTR<\/jats:sup>signalling pathways allows for convergent activation of PDK1 and protein kinase\u00a0A during paired stimulation to initiate classical conditioning.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jphysiol.2014.282947","type":"journal-article","created":{"date-parts":[[2015,1,9]],"date-time":"2015-01-09T13:24:16Z","timestamp":1420809856000},"page":"1581-1595","source":"Crossref","is-referenced-by-count":8,"title":["Coincidence detection in a neural correlate of classical conditioning is initiated by bidirectional 3\u2010phosphoinositide\u2010dependent kinase\u20101 signalling and modulated by adenosine receptors"],"prefix":"10.1113","volume":"593","author":[{"given":"Joyce","family":"Keifer","sequence":"first","affiliation":[{"name":"Neuroscience Group, Division of Basic Biomedical Sciences, University of South 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