{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T16:23:33Z","timestamp":1754151813667,"version":"3.41.2"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>We used the chemogenetic tools for the activation of norepinephrine (NE) release in the prefrontal cortex (PFC) of dopamine transporter knockout (DAT-KO) rats. The objective of this study was to evaluate the effect of chemogenetic activation of NE release in the PFC on the performance of a spatial behavior task by DAT-KO rats. The rats DAT-KO rats with deletion of DAT gene were created as a valuable model for persistently elevated extracellular DA levels. The DAT-KO rats show marked behavioral abnormalities: impulsivity, stereotypy and reduced learning ability. Such hyperdopaminergia is thought to be one of the causes of disorders such as schizophrenia, mania and attention deficit hyperactivity disorder (ADHD). The Locus Coeruleus (LC) is a critical area in the brain that plays an important role in control of several physiological and behavioral processes due to the existence of extensive connections to cortical and subcortical structures. Its activity can modulate both norepinephrine and dopamine neurotransmission, particularly in the PFC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>We used canine adenovirus type 2 (CAV2) to selectively activate LC-NA neurons in DAT-KO rats. The chemogenetic modulation of spatial learning in knockout and wild-type (WT) rats was tested in the Hebb-Williams maze. Variables such as the distance traveled, time taken to reach the goal box, number of errors and the perseverative patterns of activity were analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Norepinephrine release from the LC to the PFC reduced hyperactive behavioral patterns in rats lacking the dopamine transporter (DAT-KO rats) with spontaneously elevated dopamine transmission. These manipulations in hyperdopaminergic mutants also caused amelioration of cognitive abnormalities in spatial learning task by decrease the perseverative activity and the number of visits to the error zones. Furthermore, chemogenetic activation of NE neurotransmission in these animals significantly improved their performance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The results obtained in this study highlight an important modulatory role of NE transmission from LC to PFC on hyperactivity and cognitive dysfunctions of hyperdopaminergic DAT-KO rats lacking the dopamine transporter.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2025.1615208","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T05:22:16Z","timestamp":1753075336000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Chemogenetic tools for modulation of spatial learning in dopamine transporter deficient rats"],"prefix":"10.3389","volume":"19","author":[{"given":"Arina A.","family":"Gromova","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taisiia S.","family":"Shemiakova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikhail G.","family":"Khotin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evgeniia N.","family":"Petrunina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasia D.","family":"Belskaya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raul R.","family":"Gainetdinov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia P.","family":"Kurzina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna B.","family":"Volnova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1016\/j.bbr.2018.11.028","article-title":"Behavioral characterization of DAT-KO rats and evidence of asocial-like phenotypes in DAT-HET rats: the potential involvement of norepinephrine system","volume":"359","author":"Adinolfi","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1002\/CNE.23270","article-title":"Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex","volume":"521","author":"Agster","year":"2013","journal-title":"J. Comp. Neurol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"107327","DOI":"10.1016\/J.NLM.2020.107327","article-title":"Guanfacine\u2019s mechanism of action in treating prefrontal cortical disorders: successful translation across species","volume":"176","author":"Arnsten","year":"2020","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.4103\/1673-5374.270297","article-title":"Locus coeruleus-norepinephrine: basic functions and insights into Parkinson\u2019s disease","volume":"15","author":"Bari","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1270","DOI":"10.3390\/BIOMEDICINES12061270","article-title":"Rats lacking the dopamine transporter display inflexibility in innate and learned behavior","volume":"12","author":"Belskaya","year":"2024","journal-title":"Biomed"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/S00441-017-2649-1","article-title":"Locus coeruleus","volume":"373","author":"Benarroch","year":"2017","journal-title":"Cell Tissue Res."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/S0165-0173(03)00143-7","article-title":"The locus coeruleus\u2013noradrenergic system: modulation of behavioral state and state-dependent cognitive processes","volume":"42","author":"Berridge","year":"2003","journal-title":"Brain Res. Rev."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"893","DOI":"10.2147\/ndt.s2627","article-title":"Attention-deficit-hyperactivity disorder and reward deficiency syndrome","volume":"4","author":"Blum","year":"2008","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1173326","DOI":"10.3389\/FNSYS.2023.1173326","article-title":"Prefrontal modulation of anxiety through a lens of noradrenergic signaling","volume":"17","author":"Bouras","year":"2023","journal-title":"Front. Syst. Neurosci."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1016\/J.TINS.2005.09.002","article-title":"Network reset: a simplified overarching theory of locus coeruleus noradrenaline function","volume":"28","author":"Bouret","year":"2005","journal-title":"Trends Neurosci."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"638007","DOI":"10.3389\/FNCIR.2021.638007","article-title":"Locus Coeruleus norepinephrine in learned behavior: anatomical modularity and spatiotemporal integration in targets","volume":"15","author":"Breton-Provencher","year":"2021","journal-title":"Front. Neural Circuits"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1111\/BPH.14146","article-title":"The use of chemogenetics in behavioural neuroscience: receptor variants, targeting approaches and caveats","volume":"175","author":"Campbell","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1526","DOI":"10.1038\/nn.2682","article-title":"Tuning arousal with optogenetic modulation of locus coeruleus neurons","volume":"13","author":"Carter","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3389\/fpsyt.2018.00043","article-title":"Behavioral phenotyping of dopamine transporter knockout rats: compulsive traits, motor stereotypies, and anhedonia","volume":"9","author":"Cinque","year":"2018","journal-title":"Front. Psych."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1101\/LM.053578.122","article-title":"Differences in learning and memory between middle-aged female and male rats","volume":"29","author":"Colettis","year":"2022","journal-title":"Learn. Mem."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.1176\/AJP.148.11.1474","article-title":"Dopamine in schizophrenia: a review and reconceptualization","volume":"148","author":"Davis","year":"1991","journal-title":"Am. J. Psychiatry"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"e145-57","DOI":"10.1016\/j.biopsych.2011.02.036","article-title":"The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit\/ hyperactivity disorder","volume":"69","author":"Del Campo","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"115","DOI":"10.2174\/157015906776359559","article-title":"On the origin of cortical dopamine: is it a co-transmitter in noradrenergic neurons?","volume":"4","author":"Devoto","year":"2006","journal-title":"Curr. Neuropharmacol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"100946","DOI":"10.1016\/j.mex.2020.100946","article-title":"Immunohistochemical amplification of mCherry fusion protein is necessary for proper visualization","volume":"7","author":"Falcy","year":"2020","journal-title":"MethodsX"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1126\/science.283.5400.397","article-title":"Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity","volume":"283","author":"Gainetdinov","year":"1999","journal-title":"Science"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1126\/SCIENCE.AAN2475","article-title":"Chemogenetics revealed: DREADD occupancy and activation via converted clozapine","volume":"357","author":"Gomez","year":"2017","journal-title":"Science"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"e29808","DOI":"10.7554\/eLife.29808","article-title":"Functional dichotomy in spinal-vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats","volume":"6","author":"Hirschberg","year":"2017","journal-title":"eLife"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1016\/J.NEUROSCIENCE.2009.08.004","article-title":"The role of rat dorsomedial prefrontal cortex in spatial working memory","volume":"164","author":"Horst","year":"2009","journal-title":"Neuroscience"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"3276","DOI":"10.1152\/JN.01192.2011","article-title":"Working with memory: evidence for a role for the medial prefrontal cortex in performance monitoring during spatial delayed alternation","volume":"108","author":"Horst","year":"2012","journal-title":"J. Neurophysiol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/J.BIOPSYCH.2016.07.014","article-title":"The role of genes, stress, and dopamine in the development of schizophrenia","volume":"81","author":"Howes","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"157","DOI":"10.3390\/BIOMEDICINES9020157","article-title":"Early adolescence prefrontal cortex alterations in female rats lacking dopamine transporter","volume":"9","author":"Illiano","year":"2021","journal-title":"Biomed"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"ENEURO.0063","DOI":"10.1523\/ENEURO.0063-24.2024","article-title":"The projection-specific noradrenergic modulation of perseverative spatial behavior in adult male rats","volume":"11","author":"Kabanova","year":"","journal-title":"eNeuro"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"6237","DOI":"10.1111\/EJN.16550","article-title":"Partial chemogenetic inhibition of the locus coeruleus due to heterogeneous transduction of noradrenergic neurons preserved auditory salience processing in wild-type rats","volume":"60","author":"Kabanova","year":"","journal-title":"Eur. J. Neurosci."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"925049","DOI":"10.3389\/FNMOL.2022.925049","article-title":"Attention-deficit\/hyperactive disorder updates","volume":"15","author":"Kessi","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"393","DOI":"10.3892\/mmr.2013.1531","article-title":"Swimming exercise alleviates the symptoms of attention-deficit hyperactivity disorder in spontaneous hypertensive rats","volume":"8","author":"Ko","year":"2013","journal-title":"Mol. Med. Rep."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1038\/s41583-024-00869-z","article-title":"Neurobiology of attention-deficit hyperactivity disorder: historical challenges and emerging frontiers","volume":"25","author":"Koirala","year":"2024","journal-title":"Nat. Rev. Neurosci."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"112642","DOI":"10.1016\/j.bbr.2020.112642","article-title":"Deficit in working memory and abnormal behavioral tactics in dopamine transporter knockout rats during training in the 8-arm maze","volume":"390","author":"Kurzina","year":"2020","journal-title":"Behav. Brain Res."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"503","DOI":"10.3389\/FPSYT.2022.851296","article-title":"Modulation of spatial memory deficit and hyperactivity in dopamine transporter knockout rats via \u03b12A-adrenoceptors","volume":"13","author":"Kurzina","year":"2022","journal-title":"Front. Psych."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"654469","DOI":"10.3389\/FNBEH.2021.654469","article-title":"A new paradigm for training hyperactive dopamine transporter knockout rats: influence of novel stimuli on object recognition","volume":"15","author":"Kurzina","year":"2021","journal-title":"Front. Behav. Neurosci."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1959","DOI":"10.1523\/jneurosci.1931-17.2018","article-title":"Pronounced hyperactivity, cognitive dysfunctions, and BDNF dysregulation in dopamine transporter Knock-out rats","volume":"38","author":"Leo","year":"2018","journal-title":"J. Neurosci."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/J.NEUBIOREV.2020.07.038","article-title":"The role of norepinephrine in the pathophysiology of schizophrenia","volume":"118","author":"M\u00e4ki-Marttunen","year":"2020","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"e18247","DOI":"10.7554\/ELIFE.18247","article-title":"Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior","volume":"6","author":"McCall","year":"2017","journal-title":"eLife"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/J.TINS.2018.12.004","article-title":"Schizophrenia, dopamine and the striatum: from biology to symptoms","volume":"42","author":"McCutcheon","year":"2019","journal-title":"Trends Neurosci."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1093\/SCHBUL\/SBX180","article-title":"Defining the locus of dopaminergic dysfunction in schizophrenia: a Meta-analysis and test of the mesolimbic hypothesis","volume":"44","author":"McCutcheon","year":"2018","journal-title":"Schizophr. Bull."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-021-95497-3","article-title":"Chemogenetic modulation of histaminergic neurons in the tuberomamillary nucleus alters territorial aggression and wakefulness","volume":"11","author":"Naganuma","year":"2021","journal-title":"Sci. Rep."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"45","DOI":"10.3389\/FNINT.2018.00045","article-title":"Dopaminergic modulation of goal-directed behavior in a rodent model of attention-deficit\/hyperactivity disorder","volume":"12","author":"Natsheh","year":"2018","journal-title":"Front. Integr. Neurosci."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1093\/brain\/awu022","article-title":"Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood","volume":"137","author":"Ng","year":"2014","journal-title":"Brain"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1515\/REVNEURO.2010.21.2.119","article-title":"Cortical GABA, striatal dopamine and midbrain serotonin as the key players in compulsiveand anxiety disorders - results from in vivo imaging studies","volume":"21","author":"Nikolaus","year":"2010","journal-title":"Rev. Neurosci."},{"key":"ref44","first-page":"17337","article-title":"Relationship of neurotransmitters to the symptoms of major depressive disorder","volume":"69","author":"Nutt","year":"2008","journal-title":"J. Clin. Psychiatry"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.2147\/DDDT.S221126","article-title":"Evaluating guanfacine hydrochloride in the treatment of attention deficit hyperactivity disorder (Adhd) in adult patients: design, development and place in therapy","volume":"15","author":"Ota","year":"2021","journal-title":"Drug Des. Devel. Ther."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1038\/s41583-020-0360-9","article-title":"Locus coeruleus: a new look at the blue spot","volume":"21","author":"Poe","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1038\/sj.npp.1300724","article-title":"Novelty seeking and stereotypic activation of behavior in mice with disruption of the Dat1 gene","volume":"30","author":"Pogorelov","year":"2005","journal-title":"Neuropsychopharmacology"},{"key":"ref48","first-page":"35","article-title":"Operant conditioning","volume":"43","author":"Pritchett","year":"2004","journal-title":"J. Am. Assoc. Lab. Anim. Sci."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"547","DOI":"10.3390\/LIFE13020547","article-title":"Sex differences in behavior and learning abilities in adult rats","volume":"13","author":"Pupikina","year":"2023","journal-title":"Life"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"5806","DOI":"10.1523\/JNEUROSCI.0552-08.2008","article-title":"Noradrenergic innervation of the dorsal medial prefrontal cortex modulates Hypothalamo-pituitary-adrenal responses to acute emotional stress","volume":"28","author":"Radley","year":"2008","journal-title":"J. Neurosci."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"504957","DOI":"10.3389\/FNMOL.2019.00334","article-title":"Dopamine and noradrenaline in the brain; overlapping or dissociate functions?","volume":"12","author":"Ranjbar-Slamloo","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"2329","DOI":"10.1038\/s41380-022-01471-4","article-title":"Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits","volume":"27","author":"Reinwald","year":"2022","journal-title":"Mol. Psychiatry"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1146\/ANNUREV.NEURO.051508.135535","article-title":"The neuropsychopharmacology of fronto-executive function: monoaminergic modulation","volume":"32","author":"Robbins","year":"2009","journal-title":"Annu. Rev. Neurosci."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"2322","DOI":"10.1523\/JNEUROSCI.3038-04.2005","article-title":"Noradrenaline and dopamine elevations in the rat prefrontal cortex in spatial working memory","volume":"25","author":"Rossetti","year":"2005","journal-title":"J. Neurosci."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/J.NEURON.2016.01.040","article-title":"DREADDs for neuroscientists","volume":"89","author":"Roth","year":"2016","journal-title":"Neuron"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"Unit9.35","DOI":"10.1002\/0471142301.ns0935s54","article-title":"Overview of animal models of attention deficit hyperactivity disorder (ADHD)","volume":"54","author":"Russell","year":"2011","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/nrn2573","article-title":"The locus coeruleus and noradrenergic modulation of cognition","volume":"103","author":"Sara","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"269","DOI":"10.3389\/FPSYT.2022.799433","article-title":"The lack of dopamine transporter is associated with conditional associative learning impairments and striatal proteomic changes","volume":"13","author":"Savchenko","year":"2022","journal-title":"Front. Psych."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"806","DOI":"10.3390\/BIOM13050806","article-title":"Dopamine transporter deficient rodents: perspectives and limitations for neuroscience","volume":"13","author":"Savchenko","year":"2023","journal-title":"Biomol. Ther."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"1770","DOI":"10.1038\/SJ.NPP.1300255","article-title":"Inhibitory action of clozapine on rat ventral tegmental area dopamine neurons following increased levels of endogenous kynurenic acid","volume":"28","author":"Schwieler","year":"2003","journal-title":"Neuropsychopharmacology"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1037\/BNE0000433","article-title":"Dreadds: use and application in behavioral neuroscience","volume":"135","author":"Smith","year":"2021","journal-title":"Behav. Neurosci."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"84","DOI":"10.31363\/2313-7053-2019-4-1-84-85","article-title":"Dopamine transporter knockout rats as the new preclinical model of hyper- and hypo-dopaminergic disorders","author":"Sukhanov","year":"2019","journal-title":"V.M. Bekhterev Rev. Psychiatry Med. Psychol."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1007\/s13311-012-0132-y","article-title":"Reinforcement, dopamine and rodent models in drug development for ADHD","volume":"9","author":"Tripp","year":"2012","journal-title":"Neurotherapeutics"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1038\/nn.4642","article-title":"Modular organization of the brainstem noradrenaline system coordinates opposing learning states","volume":"20","author":"Uematsu","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1242\/dmm.027623","article-title":"Towards trans-diagnostic mechanisms in psychiatry: neurobehavioral profile of rats with a loss-of-function point mutation in the dopamine transporter gene","volume":"10","author":"Vengeliene","year":"2017","journal-title":"Dis. Model. Mech."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1155\/NP.2004.97","article-title":"Dysfunctions in dopamine systems and ADHD: evidence from animals and modeling","volume":"11","author":"Viggiano","year":"2004","journal-title":"Neural Plast."},{"key":"ref68","doi-asserted-by":"publisher","first-page":"110659","DOI":"10.1016\/J.CELREP.2022.110659","article-title":"Prefrontal pyramidal neurons are critical for all phases of working memory","volume":"39","author":"Vogel","year":"2022","journal-title":"Cell Rep."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"222","DOI":"10.3390\/BIOMEDICINES11010222","article-title":"Noradrenergic modulation of learned and innate behaviors in dopamine transporter knockout rats by Guanfacine","volume":"11","author":"Volnova","year":"2023","journal-title":"Biomedicines"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-023-42777-3","article-title":"Striatum-projecting prefrontal cortex neurons support working memory maintenance","volume":"14","author":"Wilhelm","year":"2023","journal-title":"Nat. Commun."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/J.BRAINRESBULL.2006.06.007","article-title":"Negative symptoms: a review of schizophrenia, melancholic depression and Parkinson\u2019s disease","volume":"70","author":"Winograd-Gurvich","year":"2006","journal-title":"Brain Res. Bull."},{"key":"ref72","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/J.BRAINRES.2016.01.005","article-title":"Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex","volume":"1641","author":"Xing","year":"2016","journal-title":"Brain Res."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/J.NEURON.2019.05.034","article-title":"Rapid reconfiguration of the functional connectome after Chemogenetic locus Coeruleus activation","volume":"103","author":"Zerbi","year":"2019","journal-title":"Neuron"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1615208\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T05:22:18Z","timestamp":1753075338000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1615208\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,21]]},"references-count":73,"alternative-id":["10.3389\/fnins.2025.1615208"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2025.1615208","relation":{},"ISSN":["1662-453X"],"issn-type":[{"type":"electronic","value":"1662-453X"}],"subject":[],"published":{"date-parts":[[2025,7,21]]},"article-number":"1615208"}}