{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:49:28Z","timestamp":1791362968387,"version":"4.3.1"},"reference-count":76,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011033","name":"ANID, Fondecyt Regular folio project n\u00b01240283, Gobierno de Chile","doi-asserted-by":"publisher","award":["PID2023-147693NB-I00"],"award-info":[{"award-number":["PID2023-147693NB-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"ANID, Fondecyt Regular folio project n\u00b01240283, Gobierno de Chile","doi-asserted-by":"publisher","award":["PID2020-114697GB-I00"],"award-info":[{"award-number":["PID2020-114697GB-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"ANID, Fondecyt Regular folio project n\u00b01240283, Gobierno de Chile","doi-asserted-by":"publisher","award":["2021-SGR-00557"],"award-info":[{"award-number":["2021-SGR-00557"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"ANID, Fondecyt Regular folio project n\u00b01240283, Gobierno de Chile","doi-asserted-by":"publisher","award":["ICREA-Academia-2023"],"award-info":[{"award-number":["ICREA-Academia-2023"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the University of Cagliari (Fondo Integrativo per la Ricerca-FIR 2020, 2024)","award":["PID2023-147693NB-I00"],"award-info":[{"award-number":["PID2023-147693NB-I00"]}]},{"name":"the University of Cagliari (Fondo Integrativo per la Ricerca-FIR 2020, 2024)","award":["PID2020-114697GB-I00"],"award-info":[{"award-number":["PID2020-114697GB-I00"]}]},{"name":"the University of Cagliari (Fondo Integrativo per la Ricerca-FIR 2020, 2024)","award":["2021-SGR-00557"],"award-info":[{"award-number":["2021-SGR-00557"]}]},{"name":"the University of Cagliari (Fondo Integrativo per la Ricerca-FIR 2020, 2024)","award":["ICREA-Academia-2023"],"award-info":[{"award-number":["ICREA-Academia-2023"]}]},{"name":"\u201cDirecci\u00f3 General de la Recerca\u201d (DGR; Autonomous Government of Catalonia, Spain)","award":["PID2023-147693NB-I00"],"award-info":[{"award-number":["PID2023-147693NB-I00"]}]},{"name":"\u201cDirecci\u00f3 General de la Recerca\u201d (DGR; Autonomous Government of Catalonia, Spain)","award":["PID2020-114697GB-I00"],"award-info":[{"award-number":["PID2020-114697GB-I00"]}]},{"name":"\u201cDirecci\u00f3 General de la Recerca\u201d (DGR; Autonomous Government of Catalonia, Spain)","award":["2021-SGR-00557"],"award-info":[{"award-number":["2021-SGR-00557"]}]},{"name":"\u201cDirecci\u00f3 General de la Recerca\u201d (DGR; Autonomous Government of Catalonia, Spain)","award":["ICREA-Academia-2023"],"award-info":[{"award-number":["ICREA-Academia-2023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background\/Objectives: The bidirectional selection of the Roman low- (RLA) and Roman high-avoidance (RHA) rat strains for extremely slow vs. very rapid acquisition of the two-way (shuttle-box) avoidance response has generated two divergent phenotypic profiles: RHA rats exhibit a behavioural pattern and gene expression profile in the frontal cortex and hippocampus (HPC) that are relevant to social and attentional\/cognitive schizophrenia-linked symptoms; on the other hand, RLA rats display phenotypic traits linked to increased anxiety and sensitivity to stress-induced depression-like behaviours. The present studies aimed to evaluate the enduring and potentially positive effects of neonatal handling-stimulation (NH) on the traits differentiating these two strains of rats. Methods: We evaluated the effects of NH on anxious behaviour, prepulse inhibition of startle (PPI), spatial working memory, and hormone responses to stress in adult rats of both strains. Furthermore, given the proposed involvement of neuronal\/synaptic plasticity and neurotrophic factors in the development of anxiety, stress, depression, and schizophrenia-related symptoms, using Western blot (WB) we assessed the effects of NH on the content of brain-derived neurotrophic factor (BDNF), its trkB receptor and Polysialilated-Neural Cell Adhesion Molecule (PSA-NCAM), in the prefrontal cortex (PFC), anterior cingulate cortex (ACg), ventral (vHPC), and dorsal (dHPC) hippocampus of adult rats from both strains. Results: NH increased novelty-induced exploration and reduced anxiety, particularly in RLA rats, attenuated the stress-induced increment in corticosterone and prolactin plasma levels, and improved PPI and spatial working memory in RHA rats. These effects correlated to long-lasting increases of BDNF and PSA-NCAM content in PFC, ACg, and vHPC. Conclusions: Collectively, these findings show enduring and distinct NH effects on neuroendocrine and behavioural and cognitive processes in both rat strains, which may be linked to neuroplastic and synaptic changes in the frontal cortex and\/or hippocampus.<\/jats:p>","DOI":"10.3390\/brainsci15080776","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T08:45:18Z","timestamp":1753173918000},"page":"776","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Neonatal Handling Positively Modulates Anxiety, Sensorimotor Gating, Working Memory, and Cortico-Hippocampal Neuroplastic Adaptations in Two Genetically Selected Rat Strains Differing in Emotional and Cognitive Traits"],"prefix":"10.3390","volume":"15","author":[{"given":"Crist\u00f3bal","family":"R\u00edo-\u00c1lamos","sequence":"first","affiliation":[{"name":"Department of Psychology, School of Medicine, Austral University of Chile, Valdivia 5091000, Chile"},{"name":"Department of Psychiatry & Forensic Medicine, Medical Psychology Unit, School of Medicine & Institute of Neurosciences, Autonomous University of Barcelona, 08193 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3343-7861","authenticated-orcid":false,"given":"Maria P.","family":"Serra","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, CA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3382-2508","authenticated-orcid":false,"given":"Francesco","family":"Sanna","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, CA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Piludu","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, Section of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, 09042 Monserrato, CA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4203-313X","authenticated-orcid":false,"given":"Marianna","family":"Boi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, CA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8950-8120","authenticated-orcid":false,"given":"Toni","family":"Ca\u00f1ete","sequence":"additional","affiliation":[{"name":"Department of Psychiatry & Forensic Medicine, Medical Psychology Unit, School of Medicine & Institute of Neurosciences, Autonomous University of Barcelona, 08193 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3922-4039","authenticated-orcid":false,"given":"Daniel","family":"Sampedro-Viana","sequence":"additional","affiliation":[{"name":"Department of Psychiatry & Forensic Medicine, Medical Psychology Unit, School of Medicine & Institute of Neurosciences, Autonomous University of Barcelona, 08193 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3082-0355","authenticated-orcid":false,"given":"Ignasi","family":"Oliveras","sequence":"additional","affiliation":[{"name":"Department of Psychiatry & Forensic Medicine, Medical Psychology Unit, School of Medicine & Institute of Neurosciences, Autonomous University of Barcelona, 08193 Barcelona, Spain"},{"name":"Department of Medicine, Faculty of Medicine and Health Sciences, International University of Catalunya, 08195 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6137-0660","authenticated-orcid":false,"given":"Adolf","family":"Tobe\u00f1a","sequence":"additional","affiliation":[{"name":"Department of Psychiatry & Forensic Medicine, Medical Psychology Unit, School of Medicine & Institute of Neurosciences, Autonomous University of Barcelona, 08193 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria G.","family":"Corda","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, Section of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, 09042 Monserrato, CA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4610-8183","authenticated-orcid":false,"given":"Osvaldo","family":"Giorgi","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, Section of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, 09042 Monserrato, CA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Fern\u00e1ndez-Teruel","sequence":"additional","affiliation":[{"name":"Department of Psychiatry & Forensic Medicine, Medical Psychology Unit, School of Medicine & Institute of Neurosciences, Autonomous University of Barcelona, 08193 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1884-3597","authenticated-orcid":false,"given":"Marina","family":"Quartu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, CA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/0003-3472(65)90038-2","article-title":"Selection for High Rates and Low Rates of Avoidance Conditioning in the Rat","volume":"13","author":"Bignami","year":"1965","journal-title":"Anim. Behav."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.neubiorev.2021.09.042","article-title":"Neurobehavioral and Neurodevelopmental Profiles of a Heuristic Genetic Model of Differential Schizophrenia- and Addiction-Relevant Features: The RHA vs. RLA Rats","volume":"131","author":"Oliveras","year":"2021","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e8","DOI":"10.1017\/pen.2023.7","article-title":"Contribution of the Roman rat lines\/strains to personality neuroscience: Neurobehavioral modeling of internalizing\/externalizing psychopathologies","volume":"6","author":"Oliveras","year":"2023","journal-title":"Personal. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3389\/fnbeh.2019.00145","article-title":"A Genetic Model of Impulsivity, Vulnerability to Drug Abuse and Schizophrenia-Relevant Symptoms with Translational Potential: The Roman High- vs. Low-Avoidance Rats","volume":"13","author":"Giorgi","year":"2019","journal-title":"Front Behav Neurosci"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/0031-9384(94)90059-0","article-title":"Maturation of the Behavioral and Neuroendocrine Differences between the Roman Rat Lines","volume":"55","author":"Castanon","year":"1994","journal-title":"Physiol. Behav."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/0031-9384(82)90072-5","article-title":"Differential Hormonal and Physiological Responses to Stress in Roman High- and Low-Avoidance Rats","volume":"28","author":"Gentsch","year":"1982","journal-title":"Physiol. Behav."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.neubiorev.2014.11.012","article-title":"Behavioral Neuroscience of Psychological Pain","volume":"48","author":"Papini","year":"2015","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.psyneuen.2007.03.012","article-title":"Plasma Corticosterone, Dexamethasone (DEX) Suppression and DEX\/CRH Tests in a Rat Model of Genetic Vulnerability to Depression","volume":"32","author":"Steimer","year":"2007","journal-title":"Psychoneuroendocrinology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1080\/1025389031000111320","article-title":"Divergent Stress Responses and Coping Styles in Psychogenetically Selected Roman High-(RHA) and Low-(RLA) Avoidance Rats: Behavioural, Neuroendocrine and Developmental Aspects","volume":"6","author":"Steimer","year":"2003","journal-title":"Stress"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1037\/bne0000281","article-title":"Differential Involvement of D2 and D3 Receptors during Reinstatement of Cocaine-Seeking Behavior in the Roman High- and Low-Avoidance Rats","volume":"133","author":"Dimiziani","year":"2019","journal-title":"Behav. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Oliveras, I., R\u00edo-\u00c1lamos, C., Ca\u00f1ete, T., Bl\u00e1zquez, G., Mart\u00ednez-Membrives, E., Giorgi, O., Corda, M.G., Tobe\u00f1a, A., and Fern\u00e1ndez-Teruel, A. (2015). Prepulse Inhibition Predicts Spatial Working Memory Performance in the Inbred Roman High- and Low-Avoidance Rats and in Genetically Heterogeneous NIH-HS Rats: Relevance for Studying Pre-Attentive and Cognitive Anomalies in Schizophrenia. Front. Behav. Neurosci., 9.","DOI":"10.3389\/fnbeh.2015.00213"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"111364","DOI":"10.1016\/j.pnpbp.2025.111364","article-title":"Neonatal Handling Enhances Behavioural and Attentional Domains, and Frontocortical Synaptic Maturation in Rat Models of Schizophrenia-like Behaviour and Anxiety-Related Responses","volume":"139","author":"Oliveras","year":"2025","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1017\/S1461145713000205","article-title":"Innately Low D2 Receptor Availability Is Associated with High Novelty-Seeking and Enhanced Behavioural Sensitization to Amphetamine","volume":"16","author":"Tournier","year":"2013","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Serra, M.P., Poddighe, L., Boi, M., Sanna, F., Piludu, M.A., Sanna, F., Corda, M.G., Giorgi, O., and Quartu, M. (2018). Effect of Acute Stress on the Expression of BDNF, TrkB, and PSA-NCAM in the Hippocampus of the Roman Rats: A Genetic Model of Vulnerability\/Resistance to Stress-Induced Depression. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19123745"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Serra, M.P., Sanna, F., Boi, M., Trucas, M., Fern\u00e1ndez-Teruel, A., Corda, M.G., Giorgi, O., and Quartu, M. (2023). Effects of Tail Pinch on BDNF and TrkB Expression in the Hippocampus of Roman Low- (RLA) and High-Avoidance (RHA) Rats. Int J Mol Sci, 24.","DOI":"10.3390\/ijms24119498"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.euroneuro.2023.05.001","article-title":"A Maturational Shift in the Frontal Cortex Synaptic Transcriptional Landscape Underlies Schizophrenia-Relevant Behavioural Traits: A Congenital Rat Model","volume":"74","author":"Batiuk","year":"2023","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1007\/s10519-008-9234-z","article-title":"Diverse Sensitivity of RHA\/Verh and RLA\/Verh Rats to Emotional and Spatial Aspects of a Novel Environment as a Result of a Distinct Pattern of Neuronal Activation in the Fear\/Anxiety Circuit","volume":"39","author":"Meyza","year":"2009","journal-title":"Behav. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.bbr.2018.12.033","article-title":"Volumetric Brain Differences between the Roman Rat Strains: Neonatal Handling Effects, Sensorimotor Gating and Working Memory","volume":"361","author":"Piludu","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1046\/j.1365-2826.1997.t01-1-00571.x","article-title":"Brain Metabolism of Progesterone, Coping Behaviour and Emotional Reactivity in Male Rats from Two Psychogenetically Selected Lines","volume":"9","author":"Steimer","year":"1997","journal-title":"J. Neuroendocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/0006-8993(92)91529-N","article-title":"Vasopressinergic Modulation of Stress Responses in the Central Amygdala of the Roman High-Avoidance and Low-Avoidance Rat","volume":"596","author":"Roozendaal","year":"1992","journal-title":"Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.neubiorev.2004.07.002","article-title":"Inter-Individual vs Line\/Strain Differences in Psychogenetically Selected Roman High-(RHA) and Low-(RLA) Avoidance Rats: Neuroendocrine and Behavioural Aspects","volume":"29","author":"Steimer","year":"2005","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/sj.mp.4001637","article-title":"BDNF in Schizophrenia, Depression and Corresponding Animal Models","volume":"10","author":"Angelucci","year":"2005","journal-title":"Mol. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/mp.2011.107","article-title":"Epigenetic Regulation of the BDNF Gene: Implications for Psychiatric Disorders","volume":"17","author":"Boulle","year":"2012","journal-title":"Mol. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s007020050040","article-title":"Neurotrophic Factors and the Maldevelopmental Hypothesis of Schizophrenic Psychoses. Review Article","volume":"105","author":"Thome","year":"1998","journal-title":"J. Neural. Transm."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Gliwi\u0144ska, A., Czubili\u0144ska-\u0141ada, J., Wi\u0119ckiewicz, G., \u015awi\u0119tochowska, E., Bade\u0144ski, A., Dworak, M., and Szczepa\u0144ska, M. (2023). The Role of Brain-Derived Neurotrophic Factor (BDNF) in Diagnosis and Treatment of Epilepsy, Depression, Schizophrenia, Anorexia Nervosa and Alzheimer\u2019s Disease as Highly Drug-Resistant Diseases: A Narrative Review. Brain Sci., 13.","DOI":"10.3390\/brainsci13020163"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1523\/JNEUROSCI.5377-03.2004","article-title":"Electroconvulsive Seizures Regulate Gene Expression of Distinct Neurotrophic Signaling Pathways","volume":"24","author":"Altar","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7539","DOI":"10.1523\/JNEUROSCI.15-11-07539.1995","article-title":"Regulation of BDNF and TrkB MRNA in Rat Brain by Chronic Electroconvulsive Seizure and Antidepressant Drug Treatments","volume":"15","author":"Nibuya","year":"1995","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0091-3057(96)00169-4","article-title":"Antidepressant-like Effect of Brain-Derived Neurotrophic Factor (BDNF)","volume":"56","author":"Siuciak","year":"1997","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1111\/j.1749-6632.1995.tb44684.x","article-title":"Effects of Stress on Neurotrophic Factor Expression in the Rat Brain","volume":"771","author":"Smith","year":"1995","journal-title":"Ann. N. Y Acad. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0168-0102(97)00030-8","article-title":"Immobilization Stress Reduced the Expression of Neurotrophins and Their Receptors in the Rat Brain","volume":"28","author":"Ueyama","year":"1997","journal-title":"Neurosci. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0306-9877(03)00299-8","article-title":"Down-Regulation of the Trk-B Signal Pathway: The Possible Pathogenesis of Major Depression","volume":"62","author":"Tsai","year":"2004","journal-title":"Med. Hypotheses"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jpsychires.2011.09.022","article-title":"The Role of BDNF in the Pathophysiology and Treatment of Schizophrenia","volume":"46","author":"Favalli","year":"2012","journal-title":"J. Psychiatr. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/S0920-9964(00)00084-0","article-title":"Brain-Derived Neurotrophic Factor and Neurotrophin 3 in Schizophrenic Psychoses","volume":"52","author":"Durany","year":"2001","journal-title":"Schizophr. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.nbd.2015.03.011","article-title":"Evaluation of TrkB and BDNF Transcripts in Prefrontal Cortex, Hippocampus, and Striatum from Subjects with Schizophrenia, Bipolar Disorder, and Major Depressive Disorder","volume":"77","author":"Reinhart","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/S0304-3940(03)00828-0","article-title":"An Association Study of a Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Clozapine Response of Schizophrenic Patients","volume":"349","author":"Hong","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.schres.2017.12.002","article-title":"BDNF as a Marker of Response to Cognitive Remediation in Patients with Schizophrenia: A Randomized and Controlled Trial","volume":"197","author":"Arias","year":"2018","journal-title":"Schizophr. Res."},{"key":"ref_37","first-page":"127","article-title":"BDNF as a biomarker in diagnosis and evaluation of treatment for schizophrenia and depression","volume":"26","author":"Peng","year":"2018","journal-title":"Discov Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3934\/Neuroscience.2023002","article-title":"Brain-Derived Neurotrophic Factor (BDNF) in Schizophrenia Research: A Quantitative Review and Future Directions","volume":"10","author":"Ahmad","year":"2023","journal-title":"AIMS Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1192\/bjp.bp.108.050401","article-title":"Molecular Differentiation of Schizoaffective Disorder from Schizophrenia Using BDNF Haplotypes","volume":"194","author":"Lencz","year":"2009","journal-title":"Br. J. Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1080\/15592294.2015.1117736","article-title":"BDNF Rs6265 Methylation and Genotype Interact on Risk for Schizophrenia","volume":"11","author":"Ursini","year":"2016","journal-title":"Epigenetics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/S0006-8993(02)03176-1","article-title":"Brain-Derived Neurotrophic Factor (BDNF) MRNA in Rats with Neonatal Ibotenic Acid Lesions of the Ventral Hippocampus","volume":"956","author":"Ashe","year":"2002","journal-title":"Brain Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.bbr.2008.11.039","article-title":"The Neonatal Ventral Hippocampal Lesion as a Heuristic Neurodevelopmental Model of Schizophrenia","volume":"204","author":"Tseng","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1002\/jnr.10609","article-title":"Effect of Antipsychotic Drugs on Brain-Derived Neurotrophic Factor Expression under Reduced N-Methyl-D-Aspartate Receptor Activity","volume":"72","author":"Fumagalli","year":"2003","journal-title":"J. Neurosci. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S0091-3057(02)00787-6","article-title":"Early-Life Handling Stimulation and Environmental Enrichment: Are Some of Their Effects Mediated by Similar Neural Mechanisms?","volume":"73","author":"Escorihuela","year":"2002","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/j.1467-6494.1956.tb01289.x","article-title":"A Further Study of Infantile Handling and Adult Avoidance Learning","volume":"25","author":"Levine","year":"1956","journal-title":"J. Pers."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1002\/dev.21241","article-title":"Neonatal Handling: An Overview of the Positive and Negative Effects","volume":"56","author":"Raineki","year":"2014","journal-title":"Dev. Psychobiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.neubiorev.2019.09.026","article-title":"A Novel Neurobehavioral Framework of the Effects of Positive Early Postnatal Experience on Incentive and Consummatory Reward Sensitivity","volume":"107","author":"Fu","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.neuroscience.2013.10.073","article-title":"Sexually Dimorphic Long-Term Effects of an Early Life Experience on AMPA Receptor Subunit Expression in Rat Brain","volume":"257","author":"Katsouli","year":"2014","journal-title":"Neuroscience"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1126\/science.3340858","article-title":"Effect of Neonatal Handling on Age-Related Impairments Associated with the Hippocampus","volume":"239","author":"Meaney","year":"1988","journal-title":"Science"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1159\/000125287","article-title":"Neonatal Handling Alters Adrenocortical Negative Feedback Sensitivity and Hippocampal Type II Glucocorticoid Receptor Binding in the Rat","volume":"50","author":"Meaney","year":"1989","journal-title":"Neuroendocrinology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1159\/000082516","article-title":"Neonatal Handling and Gender Modulate Brain Monoamines and Plasma Corticosterone Levels Following Repeated Stressors in Adulthood","volume":"80","author":"Panagiotaropoulos","year":"2004","journal-title":"Neuroendocrinology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0166-4328(01)00334-5","article-title":"Sex Differences in the Effects of Neonatal Handling on the Animal\u2019s Response to Stress and the Vulnerability for Depressive Behaviour","volume":"129","author":"Papaioannou","year":"2002","journal-title":"Behav. Brain Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.neuroscience.2006.06.019","article-title":"Effects of Neonatal Handling on the Basal Forebrain Cholinergic System of Adult Male and Female Rats","volume":"142","author":"Pondiki","year":"2006","journal-title":"Neuroscience"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/j.neuroscience.2009.09.032","article-title":"Selective Effects of Neonatal Handling on Rat Brain N-Methyl-d-Aspartate Receptors","volume":"164","author":"Stamatakis","year":"2009","journal-title":"Neuroscience"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"146921","DOI":"10.1016\/j.brainres.2020.146921","article-title":"Neonatal Handling Increases Neurogenesis, BDNF and GR in the Hippocampus Favoring Memory Acquisition in Rats","volume":"1745","year":"2020","journal-title":"Brain Res"},{"key":"ref_56","unstructured":"Paxinos, G., and Watson, C. (1998). The Rat Brain in Stereotaxic Coordinates, Academic Press. [6th ed.]."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/S0076-6879(83)03025-6","article-title":"Punch Sampling Biopsy Technique","volume":"103","author":"Palkovits","year":"1983","journal-title":"Methods Enzymol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein Measurement with the Folin Phenol Reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1002\/hipo.22686","article-title":"Tactile Stimulation during Different Developmental Periods Modifies Hippocampal BDNF and GR, Affecting Memory and Behavior in Adult Rats","volume":"27","author":"Antoniazzi","year":"2017","journal-title":"Hippocampus"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1744-859X-4-8","article-title":"Cellular Mechanisms Underlying the Effects of an Early Experience on Cognitive Abilities and Affective States","volume":"4","author":"Garoflos","year":"2005","journal-title":"Ann. Gen. Psychiatry"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.biopsych.2005.11.009","article-title":"Postnatal Stimulation of the Pups Counteracts Prenatal Stress-Induced Deficits in Hippocampal Neurogenesis","volume":"59","author":"Lemaire","year":"2006","journal-title":"Biol. Psychiatry"},{"key":"ref_62","unstructured":"Kline, P. (1994). An Easy Guide to Factor Analysis, Routledge."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"114021","DOI":"10.1016\/j.bbr.2022.114021","article-title":"Different Maturation Patterns for Sensorimotor Gating and Startle Habituation Deficits in Male and Female RHA vs RLA Rats","volume":"434","author":"Oliveras","year":"2022","journal-title":"Behav. Brain Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1080\/10253890701653039","article-title":"Effect of Neonatal Handling on Adult Rat Spatial Learning and Memory Following Acute Stress","volume":"11","author":"Stamatakis","year":"2008","journal-title":"Stress"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/0091-3057(91)90313-Q","article-title":"Roman Strains as a Psychogenetic Model for the Study of Working Memory: Behavioral and Biochemical Data","volume":"40","author":"Willig","year":"1991","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.nlm.2015.11.008","article-title":"Prefrontal-Hippocampal Pathways Underlying Inhibitory Control over Memory","volume":"134","author":"Anderson","year":"2016","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/s41386-021-01132-0","article-title":"The Role of Prefrontal Cortex in Cognitive Control and Executive Function","volume":"47","author":"Friedman","year":"2022","journal-title":"Neuropsychopharmacology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.neubiorev.2004.03.005","article-title":"A Two-Dimensional Neuropsychology of Defense: Fear\/Anxiety and Defensive Distance","volume":"28","author":"McNaughton","year":"2004","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"McNaughton, N., and Gray, J.A. (2024). The Neuropsychology of Anxiety: An Enquiry into the Funtions of the Septo-Hippocampal System, Oxford University Press. [3rd ed.].","DOI":"10.1093\/oso\/9780198843313.001.0001"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e1021242024","DOI":"10.1523\/JNEUROSCI.1021-24.2024","article-title":"Frustrative Nonreward: Behavior, Circuits, Neurochemistry, and Disorders","volume":"44","author":"Papini","year":"2024","journal-title":"J. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Numakawa, T., Odaka, H., and Adachi, N. (2018). Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113650"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1080\/17470919.2010.503618","article-title":"Infantile Experience and Play Motivation","volume":"5","author":"Aguilar","year":"2010","journal-title":"Soc. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/0031-9384(94)E0113-I","article-title":"Effect of Neonatal Handling on Learned Helplessness Model of Depression","volume":"57","author":"Costela","year":"1995","journal-title":"Physiol. Behav."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0024-3205(97)01036-9","article-title":"Neonatal Handling Reduces Emotional Reactivity and Susceptibility to Learned Helplessness. Involvement of Catecholaminergic Systems","volume":"62","author":"Costela","year":"1997","journal-title":"Life Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.biopsych.2006.08.033","article-title":"Neonatal Handling Prevents the Effects of Phencyclidine in an Animal Model of Negative Symptoms of Schizophrenia","volume":"61","author":"Biguet","year":"2007","journal-title":"Biol. Psychiatry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1096\/fj.02-1032fje","article-title":"The Postnatal Environment Can Counteract Prenatal Effects on Cognitive Ability, Cell Proliferation, and Synaptic Protein Expression","volume":"17","author":"Koo","year":"2003","journal-title":"FASEB J."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/8\/776\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:13:37Z","timestamp":1760033617000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/8\/776"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,22]]},"references-count":76,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["brainsci15080776"],"URL":"https:\/\/doi.org\/10.3390\/brainsci15080776","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,22]]}}}