Physical exercise and antidepressants enhance BDNF targeting in hippocampal CA3 dendrites: further evidence of a spatial code for BDNF splice variants.

Baj, Gabriele; D'Alessandro, Valentina; Musazzi, Laura; Mallei, Alessandra; Sartori, Cesar R; Sciancalepore, Marina; Tardito, Daniela; Langone, Francesco; Popoli, Maurizio; Tongiorgi, Enrico

doi:10.1038/npp.2012.5

Cited by 103Nerve injury and regenerationTreatment of Major DepressionNeuroscience and Neuropharmacology Research

Physical exercise and antidepressants enhance BDNF targeting in hippocampal CA3 dendrites: further evidence of a spatial code for BDNF splice variants.

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Baj, Gabriele, D'Alessandro, Valentina, Musazzi, Laura, Mallei, Alessandra, Sartori, Cesar R, Sciancalepore, Marina, Tardito, Daniela, Langone, Francesco +2 more·2012·Neuropsychopharmacology

DOI 10.1038/npp.2012.5PMC PMC3358751

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Abstract

Brain-derived neurotrophic factor (BDNF) is encoded by multiple BDNF transcripts, whose function is unclear. We recently showed that a subset of BDNF transcripts can traffic into distal dendrites in response to electrical activity, while others are segregated into the somatoproximal domains. Physical exercise and antidepressant treatments exert their beneficial effects through upregulation of BDNF, which is required to support survival and differentiation of newborn dentate gyrus (DG) neurons. While these DG processes are required for the antidepressant effect, a role for CA1 in antidepressant action has been excluded, and the effect on CA3 neurons remains unclear. Here, we show for the first time that physical exercise and antidepressants induce local increase of BDNF in CA3. Voluntary physical exercise for 28 consecutive days, or 2-week treatment with 10 mg/kg per day fluoxetine or reboxetine, produced a global increase of BDNF mRNA and protein in the neuronal somata of the whole hippocampus and a specific increase of BDNF in dendrites of CA3 neurons. This increase was accounted for by BDNF exon 6 variant. In cultured hippocampal neurons, application of serotonin or norepinephrine (10-50 μM) induced increase in synaptic transmission and targeting of BDNF mRNA in dendrites. The increased expression of BDNF in CA3 dendrites following antidepressants or exercise further supports the neurotrophin hypothesis of antidepressants action and confirms that the differential subcellular localization of BDNF mRNA splice variants provides a spatial code for a selective expression of BDNF in specific subcellular districts. This selective expression may be exploited to design more specific antidepressants.

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In animal models, the combination of AE and antidepressant treatment had a stronger impact on up-regulating BDNF than either intervention had individually.
“For example, animal models have demonstrated that the combination of AE and antidepressant treatment had a stronger impact on up-regulating BDNF than either intervention had individually (Russo-Neustadt et al., 2001; Baj et al., 2012)”
From Aerobic Exercise as a Tool to Improve Hippocampal Plasticity and Function in Humans: Practical Implications for Mental Health Treatment (2016) · cites this paper as Baj et al., 2012

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Physical exercise and acute restraint stress differentially modulate hippocampal brain‐derived neurotrophic factor transcripts and epigenetic mechanisms in mice
Ieraci, A., Mallei, A., Musazzi, L., & Popoli, M. (2015) · Hippocampus · doi:10.1002/hipo.22458 · Cited by 94 · see citing works
“…structure of the BDNF gene allows the distinct BDNF exons to be differentially expressed in subcellular localizations, in specific brain regions and in response to distinct stimuli (Russo-Neustadt et al., 2000; Zajac et al., 2010; Lyons and West, 2011; Baj et al., 2012; Musazzi et al., 2014).”
BackgroundInfluential
Individual Differences in Novelty Seeking Predict Subsequent Vulnerability to Social Defeat through a Differential Epigenetic Regulation of Brain-Derived Neurotrophic Factor Expression
Duclot, F., & Kabbaj, M. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0199-13.2013 · Cited by 85 · see citing works
“Furthermore, exercise or repeated treatment with fluoxetine or reboxetine, all exhibiting antidepressant properties, upregulate the hippocampal mRNA levels of transcript VI but not IV (Baj et al., 2012).”
Background
Inwardly Rectifying Potassium Channel Kir4.1 as a Novel Modulator of BDNF Expression in Astrocytes
Ohno, Y., Kinboshi, M., & Shimizu, S. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113313 · Cited by 78 · see citing works
Epigenetic Regulation of BDNF Gene during Development and Diseases
Chen, K.-W., & Chen, L. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18030571 · Cited by 75 · see citing works
“In addition, exon VI was increased in hippocampal CA3, but not CA1 and dentate gyrus neurons in response to the antidepressant drugs fluoxetine and reboxetine [34].”
Background
Gene-environment interactions informing therapeutic approaches to cognitive and affective disorders
Rogers, J., Renoir, T., & Hannan, A. J. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.12.038 · Cited by 69 · see citing works
The Effect of Systemic Chemotherapy on Neurogenesis, Plasticity and Memory
Wigmore, P. (2012) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2012_235 · Cited by 66 · see citing works
Amitriptyline induces brain-derived neurotrophic factor (BDNF) mRNA expression through ERK-dependent modulation of multiple BDNF mRNA variants in primary cultured rat cortical astrocytes and microglia
Hisaoka‐Nakashima, K., Kajitani, N., Kaneko, M., Shigetou, T., Kasai, M., Matsumoto, C., Yokoe, T., Azuma, H., Takebayashi, M., Morioka, N., et al. (2016) · Brain Research · doi:10.1016/j.brainres.2015.12.057 · Cited by 65 · see citing works
“Reboxetine and citalopram increased exon VI in hippocampus (Baj et al., 2012; Russo-Neustadt et al., 2004).”
Expression and Dendritic Trafficking of BDNF-6 Splice Variant are Impaired in Knock-In Mice Carrying Human BDNF Val66Met Polymorphism
Mallei, A., Baj, G., Ieraci, A., Corna, S., Musazzi, L., Lee, F. S., Tongiorgi, E., & Popoli, M. (2015) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyv069 · Cited by 61 · see citing works
“It will also be interesting to assess the behavioral and cellular/molecular effects of chronic antidepressants or physical exercise in Val66Met knockin mice, considering the specific influence exerted by these environmental factors on BDNF-6 expression and targeting (Baj et al., 2012) and its ability to modify the num…”
BackgroundResultInfluential
The absence of 5-HT4 receptors modulates depression- and anxiety-like responses and influences the response of fluoxetine in olfactory bulbectomised mice: Adaptive changes in hippocampal neuroplasticity markers and 5-HT1A autoreceptor
Amigó, J., Díaz, Á., Pilar-Cuéllar, F., Vidal, R., Martín, A., Compan, V., Pazos, Á., & Castro, E. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.08.037 · Cited by 62 · see citing works
Pharmacological treatment with mirtazapine rescues cortical atrophy and respiratory deficits in MeCP2 null mice
Bittolo, T., Raminelli, C. A., Deiana, C., Baj, G., Vaghi, V., Ferrazzo, S., Bernareggi, A., & Tongiorgi, E. (2016) · Scientific Reports · doi:10.1038/srep19796 · Cited by 59 · see citing works
Beyond good and evil: A putative continuum-sorting hypothesis for the functional role of proBDNF/BDNF-propeptide/mBDNF in antidepressant treatment
Diniz, C. R. A. F., Casarotto, P. C., Resstel, L., & Joca, S. R. L. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.04.001 · Cited by 58 · see citing works
Regulation of the spatial code for BDNF mRNA isoforms in the rat hippocampus following pilocarpine‐treatment: A systematic analysis using laser microdissection and quantitative real‐time PCR
Baj, G., Turco, D. D., Schlaudraff, J., Torelli, L., Deller, T., & Tongiorgi, E. (2013) · Hippocampus · doi:10.1002/hipo.22100 · Cited by 55 · see citing works
“In the same study we showed that the transcript containing exon 6 can largely account for this effect (Baj et al., 2012).”
Influential
The Role of Dendritic Brain-Derived Neurotrophic Factor Transcripts on Altered Inhibitory Circuitry in Depression
Oh, H., Piantadosi, S. C., Rocco, B. R., Lewis, D. A., Watkins, S. C., & Sibille, E. L. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.09.026 · Cited by 55 · see citing works
Voluntary Physical Exercise Induces Expression and Epigenetic Remodeling of VegfA in the Rat Hippocampus
Sølvsten, C. A. E., de Paoli, F. V., Christensen, J., & Nielsen, A. L. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0344-y · Cited by 52 · see citing works
Reducing Allostatic Load in Depression and Anxiety Disorders: Physical Activity and Yoga Practice as Add-On Therapies
D’Alessio, L., Korman, G. P., Sarudiansky, M., Guelman, L. R., Scévola, L., Pastore, A., Obregón, A., & Ej, R. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00501 · Cited by 53 · see citing works
Bdnf mRNA splice variants differentially impact CA1 and CA3 dendrite complexity and spine morphology in the hippocampus
Maynard, K. R., Hobbs, J. W., Sukumar, M., Kardian, A., Jimenez, D. V., Schloesser, R. J., & Martinowich, K. (2017) · Brain Structure and Function · doi:10.1007/s00429-017-1405-3 · Cited by 51 · see citing works
Cranial irradiation regulates CREB-BDNF signaling and variant BDNF transcript levels in the mouse hippocampus
Son, Y., Yang, M., Kang, S., Lee, S., Kim, J., Kim, J., Park, S., Kim, J., Jo, S., Jung, U., et al. (2015) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2015.03.002 · Cited by 48 · see citing works
“, 2004), and administration of chemicals or antidepressants (Baj et al., 2012; Nair et al., 2007).”
Effect of agomelatine on memory deficits and hippocampal gene expression induced by chronic social defeat stress in mice
Martin, V., Allaïli, N., Euvrard, M., Marday, T., Riffaud, A., Franc, B., Mocaër, E., Gabriel, C., Fossati, P., Lehéricy, S., et al. (2017) · Scientific Reports · doi:10.1038/srep45907 · Cited by 45 · see citing works
BDNF-TrkB signaling in oxytocin neurons contributes to maternal behavior
Maynard, K. R., Hobbs, J. W., Phan, B. N., Gupta, A., Rajpurohit, S., Williams, C. A., Rajpurohit, A., Shin, J. H., Jaffe, A. E., & Martinowich, K. (2018) · eLife · doi:10.7554/elife.33676 · Cited by 46 · see citing works
“…Bdnf promoters allow for tight temporal, spatial, and stimulus-specific BDNF expression, which is critical for modulating plasticity in specific neural circuits (Baj et al., 2012; Baj, Leone, Chao, & Tongiorgi, 2011; Pattabiraman et al., 2005; Timmusk, Belluardo, Persson, & Metsis, 1994).”
Background
A single bout of exercise increases hippocampalBdnf: influence of chronic exercise and noradrenaline
Venezia, A. C., Quinlan, E. M., & Roth, S. M. (2017) · Genes Brain & Behavior · doi:10.1111/gbb.12394 · Cited by 43 · see citing works
“A similar increase in hippocampal Bdnf expression is observed following treatment with antidepressants, including norepinephrine reuptake inhibitors such as reboxetine (Baj et al. 2012; Larsen et al. 2008; Musazzi et al. 2009; Russo-Neustadt et al. 2004).”
Background
Behavioural and neuroplastic properties of chronic lurasidone treatment in serotonin transporter knockout rats
Luoni, A., Hulsken, S., Cazzaniga, G., Racagni, G., Homberg, J. R., & Riva, M. A. (2012) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145712001332 · Cited by 42 · see citing works
“2e), which is the main neurotrophin transcript that undergoes dendritic targeting (Chiaruttini et al. 2008; Baj et al. 2012).”
Pharmacological characterization of BDNF promoters I, II and IV reveals that serotonin and norepinephrine input is sufficient for transcription activation
Musazzi, L., Rimland, J. M., Ieraci, A., Racagni, G., Domenici, E., & Popoli, M. (2014) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145713001685 · Cited by 39 · see citing works
“: +39 02 5031 8377 Fax: +39 02 5031 8278 Email: laura.musazzi@unimi.it Khundakar and Zetterström, 2006; Calabrese et al., 2007; Wang et al., 2008; Alboni et al., 2010; Baj et al., 2012).”
Background
Chronic Antidepressant Treatment in Normal Mice Induces Anxiety and Impairs Stress-coping Ability
Baek, I., Park, J. Y., & Han, P. (2015) · Experimental Neurobiology · doi:10.5607/en.2015.24.2.156 · Cited by 36 · see citing works
Increased Expression of Brain-Derived Neurotrophic Factor Transcripts I and VI, cAMP Response Element Binding, and Glucocorticoid Receptor in the Cortex of Patients with Temporal Lobe Epilepsy
Martínez-Levy, G. A., Rocha, L., Rodríguez-Pineda, F., Alonso-Vanegas, M. A., Nani, A., Buentello-García, R. M., Briones-Velasco, M., San-Juan, D., Cienfuegos, J., & Cruz-Fuentes, C. S. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0597-0 · Cited by 37 · see citing works
“In a similar way, BDNF VI variant increase in the apical dendrites of CA3 neurons in mice exposed to an antidepressive treatment or voluntary exercise [58], a re-”
BackgroundInfluential
Signaling pathways controlling activity-dependent local translation of BDNF and their localization in dendritic arbors
Baj, G., Pinhero, V., Vaghi, V., & Tongiorgi, E. (2016) · Journal of Cell Science · doi:10.1242/jcs.177626 · Cited by 37 · see citing works
“Accordingly, we have shown that BDNF-6 trafficking to dendrites is increased by physical exercise and chronic antidepressant treatments (Baj et al., 2012).”
Background
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
Serra, M. P., Poddighe, L., Boi, M., Sanna, F., Piludu, M. A., Sanna, F., Corda, M. G., Giorgi, O., & Quartu, M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123745 · Cited by 37 · see citing works
“It has been proposed that the neural substrate of the therapeutic efficacy of antidepressants consists in the integration of the newly-generated neurons in the subgranular zone of the DG to the neural circuitry of the hippocampus [70,96,102].”
Background
Chronic social defeat stress differentially regulates the expression ofBDNFtranscripts and epigenetic modifying enzymes in susceptible and resilient mice
Mallei, A., Ieraci, A., & Popoli, M. (2018) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2018.1500029 · Cited by 35 · see citing works
“P< 0.05; P< 0.01. n¼ 7–15/group. into the soma, whereas BDNF-6 is transported into the dendrites after stimulation (Chiaruttini et al. 2008; Baj et al. 2011; Baj et al. 2012).”
BackgroundInfluential
Beneficial effects of Spirulina platensis, voluntary exercise and environmental enrichment against adolescent stress induced deficits in cognitive functions, hippocampal BDNF and morphological remolding in adult female rats
Moradikor, N., Ghanbari, A., Rashidipour, H., Yousefi, B., Bandegi, A. R., & Rashidy‐Pour, A. (2019) · Hormones and Behavior · doi:10.1016/j.yhbeh.2019.03.004 · Cited by 36 · see citing works
Blues in the Brain and Beyond: Molecular Bases of Major Depressive Disorder and Relative Pharmacological and Non-Pharmacological Treatments
Maffioletti, E., Minelli, A., Tardito, D., & Gennarelli, M. (2020) · Genes · doi:10.3390/genes11091089 · Cited by 36 · see citing works
Short‐term running exercise alters DNA methylation patterns in neuronal nitric oxide synthase and brain‐derived neurotrophic factor genes in the mouse hippocampus and reduces anxiety‐like behaviors
Tomiga, Y., Sakai, K., Ra, S.-G., Kusano, M., Ito, A., Uehara, Y., Takahashi, H., Kawanaka, K., Soejima, H., & Higaki, Y. (2021) · The FASEB Journal · doi:10.1096/fj.202100630r · Cited by 25 · see citing works
Environmental Enrichment Increased Bdnf Transcripts in the Prefrontal Cortex: Implications for an Epigenetically Controlled Mechanism
Costa, G. D. A., Silva, N. K. D. G. T., Marianno, P., Chivers, P., Bailey, A., & Camarini, R. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2023.07.001 · Cited by 34 · see citing works
Expression of BDNF and trkB in the hippocampus of a rat genetic model of vulnerability (Roman low‐avoidance) and resistance (Roman high‐avoidance) to stress‐induced depression
Serra, M. P., Poddighe, L., Boi, M., Sanna, F., Piludu, M. A., Corda, M. G., Giorgi, O., & Quartu, M. (2017) · Brain and Behavior · doi:10.1002/brb3.861 · Cited by 32 · see citing works
“Studies on the BDNF targeting on hippocampal CA3 dendrites (Baj, Pinhero, Vaghi, & Tongiorgi, 2016; Baj et al., 2012; Righi, Tongiorgi, & Cattaneo, 2000) further suggest the possibility of concurrent mechanisms of BDNFmediated trophic support.”
BackgroundInfluential
Increased expression of BDNF transcript with exon VI in hippocampi of patients with pharmaco-resistant temporal lobe epilepsy
Martínez-Levy, G. A., Rocha, L., Lubin, F. D., Alonso-Vanegas, M. A., Nani, A., Buentello-García, R. M., Pérez-Molina, R., Briones-Velasco, M., Recillas-Targa, F., Pérez-Molina, A., et al. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2015.11.046 · Cited by 33 · see citing works
Running during adolescence rescues a maternal separation‐induced memory impairment in female mice: Potential role of differential exon‐specific BDNF expression
Wearick‐Silva, L. E., Marshall, P. R., Viola, T. W., Centeno‐Silva, A., de Azeredo, L. A., Orso, R., Li, X., Donadio, M. V. F., Bredy, T. W., & Grassi‐Oliveira, R. (2016) · Developmental Psychobiology · doi:10.1002/dev.21487 · Cited by 30 · see citing works
“Furthermore, it is important to note that we used whole hippocampus to evaluate the BDNF mRNA levels, where sub regions of hippocampus could present different expression patterns following environmental manipulation (Baj et al., 2012; Nair et al., 2007).”
Method
Chronic Fluoxetine Induces the Enlargement of Perforant Path-Granule Cell Synapses in the Mouse Dentate Gyrus
Kitahara, Y., Ohta, K., Hasuo, H., Shuto, T., Kuroiwa, M., Sotogaku, N., Togo, A., Nakamura, K., & Nishi, A. (2016) · PLoS ONE · doi:10.1371/journal.pone.0147307 · Cited by 30 · see citing works
Influences of prenatal and postnatal stress on adult hippocampal neurogenesis: The double neurogenic niche hypothesis
Ortega‐Martínez, S. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.12.036 · Cited by 29 · see citing works
Improving Cognition with Nutraceuticals Targeting TGF-β1 Signaling
Grasso, M., Caruso, G., Godos, J., Bonaccorso, A., Carbone, C., Castellano, S., Currenti, W., Grosso, G., Musumeci, T., & Caraci, F. (2021) · Antioxidants · doi:10.3390/antiox10071075 · Cited by 29 · see citing works
“Indeed, physical activity from one hand promotes neurogenesis via synthesis and release of BDNF—one of the key neurotrophic factors involved in brain plasticity [63]—and on the other hand it increases TGF-β1 plasma levels [64], thus suggesting that physical activity can be considered as an add-on strategy to the conve…”
Background
Selective Depletion of CREB in Serotonergic Neurons Affects the Upregulation of Brain-Derived Neurotrophic Factor Evoked by Chronic Fluoxetine Treatment
Rafa–Zabłocka, K., Kreiner, G., Bagińska, M., & Nalepa, I. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00637 · Cited by 28 · see citing works
“, 1999), including selective serotonin reuptake inhibitors (SSRIs) (Baj et al., 2012).”
Background
The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits, biochemical changes, and hippocampal synaptic plasticity in an animal model of depression
Bhagya, V., Srikumar, B. N., Raju, T., & Rao, S. (2015) · Journal of Neuroscience Research · doi:10.1002/jnr.23473 · Cited by 28 · see citing works
“, 2000) and upregulates the neuroprotective proteins, such as brain-derived neurotrophic factor (Russo-Neustadt et al., 2004; Wyneken et al., 2006; Baj et al., 2012).”
Background
Low-intensity treadmill exercise and/or bright light promote neurogenesis in adult rat brain.
Kwon, S. J., Park, J., Park, S. Y., Song, K. S., Jung, S. T., Jung, S. B., Park, I. R., Choi, W. S., & Kwon, S. O. (2013) · PubMed Central · doi:10.3969/j.issn.1673-5374.2013.10.007 · Cited by 27 · see citing works
Distinct role of 5′UTR sequences in dendritic trafficking of BDNF mRNA: additional mechanisms for the BDNF splice variants spatial code
Colliva, A., & Tongiorgi, E. (2021) · Molecular Brain · doi:10.1186/s13041-020-00680-8 · Cited by 24 · see citing works
Protective effect of young green barley leaf (Hordeum vulgare L.) on restraint stress-induced decrease in hippocampal brain-derived neurotrophic factor in mice
Yamaura, K., Tanaka, R., Bi, Y., Fukata, H., 大石, 信., Sato, H., Mori, C., & Ueno, K. (2015) · Pharmacognosy Magazine · doi:10.4103/0973-1296.157702 · Cited by 23 · see citing works
Brain-derived neurotrophic factor serum levels in genetically isolated populations: gender-specific association with anxiety disorder subtypes but not with anxiety levels or Val66Met polymorphism
Carlino, D., Francavilla, R., Baj, G., Kulak, K., d’Adamo, P., Ulivi, S., Cappellani, S., Gasparini, P., & Tongiorgi, E. (2015) · PeerJ · doi:10.7717/peerj.1252 · Cited by 23 · see citing works
Self-citation
Repetitive enhancement of serum BDNF subsequent to continuation ECT
Vanicek, T., Kranz, G. S., Vyssoki, B., Komorowski, A., Fugger, G., Höflich, A. S., Micskei, Z., Milovic, S., Lanzenberger, R. R., Eckert, A., et al. (2019) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.13080 · Cited by 22 · see citing works
Anticonvulsant Action and Long-Term Effects of Chronic Cannabidiol Treatment in the Rat Pentylenetetrazole-Kindling Model of Epilepsy
Gáll, Z., Kelemen, K., Tolokán, A., Zolcseak, I., Sável, I., Bod, R.-B., Ferencz, E., Vancea, S., Urkon, M., & Kolcsár, M. (2022) · Biomedicines · doi:10.3390/biomedicines10081811 · Cited by 22 · see citing works
“As confirmed by others, this measurement of stratum pyramidale thickness is robust and constant, because it does not differ across a series of coronal sections collected around the anteroposterior axis of the same animal [58].”
Background
The effect of physical exercise on circulating neurotrophic factors in healthy aged subjects: A meta-analysis and meta-regression
Behrad, S., Dezfuli, S. A. T., Yazdani, R., Hayati, S., & Shanjani, S. M. (2024) · Experimental Gerontology · doi:10.1016/j.exger.2024.112579 · Cited by 19 · see citing works
“Additionally, exercise enhances cardiovascular health, which supports brain function (Baj et al., 2012).”
Temporal endurance of exercise-induced benefits on hippocampus-dependent memory and synaptic plasticity in female mice
Dong, T. N., Kramár, E. A., Beardwood, J. H., Al‐Shammari, A., Wood, M. A., & Keiser, A. A. (2022) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2022.107658 · Cited by 19 · see citing works
Peritoneal endometriosis induces time-related depressive- and anxiety-like alterations in female rats: involvement of hippocampal pro-oxidative and BDNF alterations
Filho, P. W. L. L., Filho, A. J. M. C., Vieira, C. F. X., Oliveira, T. D. Q., Soares, M. V. R., Jucá, P. M., Quevedo, J., Barichello, T., Macêdo, D. S., & Medeiros, F. D. C. (2019) · Metabolic Brain Disease · doi:10.1007/s11011-019-00397-1 · Cited by 18 · see citing works
The role of exercise-related FNDC5/irisin in depression
Liu, Y., Fu, X., Zhao, X., Cui, R., & Yang, W. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1461995 · Cited by 16 · see citing works
BDNF and Lactate as Modulators of Hippocampal CA3 Network Physiology
Griego, E., & Galván, E. J. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01425-6 · Cited by 15 · see citing works
“Postsynaptically, BDNF and TrkB are highly expressed in CA3 pyramidal neurons (Baj et al. 2012; Dolci et al. 2003; Tecuatl et al. 2018).”
Background
Global epigenetic analysis of BDNF Val66Met mice hippocampus reveals changes in dendrite and spine remodeling genes
Mallei, A., Ieraci, A., Corna, S., Tardito, D., Lee, F. S., & Popoli, M. (2018) · Hippocampus · doi:10.1002/hipo.22991 · Cited by 15 · see citing works
Manipulation of a genetically and spatially defined sub-population of BDNF-expressing neurons potentiates learned fear and decreases hippocampal-prefrontal synchrony in mice
Hallock, H. L., Quillian, H. M., Mai, Y., Maynard, K. R., Hill, J. L., & Martinowich, K. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0429-1 · Cited by 14 · see citing works
Blunted response of hippocampal AMPK associated with reduced neurogenesis in older versus younger mice
Jang, S., Kim, H., Jeong, J., Lee, S. K., Kim, E. W., Park, M., Kim, C. H., Lee, J. E., Namkoong, K., & Kim, E. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2016.06.011 · Cited by 14 · see citing works
Exercise and crocin prevent adolescent-stress induced impairment of spatial navigation and dendritic retraction in the hippocampal CA3 area in adult male rats
Ghalandari-Shamami, M., Nourizade, S., Barati, M., Yousefi, B., Pashayi, M., Vafaei, A. A., Kokhaei, P., & Rashidy‐Pour, A. (2021) · Brain Research · doi:10.1016/j.brainres.2020.147274 · Cited by 11 · see citing works
Perceived antidepressant efficacy associated with reduced negative and enhanced neutral mnemonic discrimination
Phillips, T., Castro, M. R., Vas, R., Ferguson, L. A., Harikumar, A., & Leal, S. L. (2023) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2023.1225836 · Cited by 11 · see citing works
“Antidepressants can reverse these synaptic changes by increasing DG neurogenesis and by increasing CA3 dendritic arborization (Baj et al., 2012; Castrén and Hen, 2013; Hill et al., 2015).”
Background
Voluntary wheel running during adolescence prevents the increase in ethanol intake induced by social defeat in male mice
Reguilón, M. D., Perez, C. F., Manzanedo, C., Miñarro, J., & Rodríguez‐Arias, M. (2023) · Psychopharmacology · doi:10.1007/s00213-023-06461-0 · Cited by 12 · see citing works
“Brain-derived neurotrophic factor (BDNF) is considered critical for neuronal and synaptic plasticity throughout the nervous system (Baj et al. 2012; Erickson et al. 2012; Liu and Nusslock 2018; Vaynman et al. 2004).”
Effect of environmental enrichment on aggression and the expression of brain-derived neurotrophic factor transcript variants in group-housed male mice
Aldhshan, M. S., & Mizuno, T. M. (2022) · Behavioural Brain Research · doi:10.1016/j.bbr.2022.113986 · Cited by 9 · see citing works
Anxiolytic-like effect of trans-2-decenoic acid ethyl ester in stress-induced anxiety-like model mice
MAKINO, A., Iinuma, M., Fukumitsu, H., Soumiya, H., Furukawa, Y., & Furukawa, S. (2013) · Biomedical Research · doi:10.2220/biomedres.34.259 · Cited by 9 · see citing works
Effect of Voluntary Wheel-Running Exercise on the Endocrine and Inflammatory Response to Social Stress: Conditioned Rewarding Effects of Cocaine
Perez, C. F., Reguilón, M. D., Miñarro, J., & Rodríguez‐Arias, M. (2022) · Biomedicines · doi:10.3390/biomedicines10102373 · Cited by 8 · see citing works
“Physical activity in running wheels has been previously liked to increase levels of BDNF [14,89,90], and accordingly, we found increases of BDNF in the striatum and the hippocampus of animals exposed to VWR, with even higher hippocampal levels in animals housed with one activity wheel (1 × 4).”
Background
Molecular Regulation and Therapeutic Applications of Brain-Derived Neurotrophic Factor–Tropomyosin-Related Kinase B Signaling in Major Depressive Disorder Though Its Interaction with Vascular Endothelial Growth Factor and N-Methyl-D-Aspartic Acid Receptors: A Narrative Review
Matsuzaka, Y., & Yashiro, R. (2025) · Biologics · doi:10.3390/biologics5010007 · Cited by 8 · see citing works
“The neurotrophin hypothesis proposes that antidepressants require the integration of newly generated granule cells in the DG into the hippocampal circuitry, including the formation of synapses between DG mossy fibers and CA3 dendrites [87].”
Kinetics of Norepinephrine- and Serotonin-Induced BDNF Release in Cultured Embryonic Hippocampal Neurons
Chen, M. J., & Russo-Neustadt, A. (2013) · Neuroscience &amp Medicine · doi:10.4236/nm.2013.44031 · Cited by 9 · see citing works
Chemical LTP induces confinement of BDNF mRNA under dendritic spines and BDNF protein accumulation inside the spines
Bimbi, G., & Tongiorgi, E. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1348445 · Cited by 6 · see citing works
Antidepressants Promote and Prevent Cancers
Lavergne, F., & Jay, T. (2020) · Cancer Investigation · doi:10.1080/07357907.2020.1817481 · Cited by 6 · see citing works
Age-dependent expression pattern in the mammalian brain of a novel, small peptide encoded in the 22q11.2 deletion syndrome region
Kragness, S., Harrison, M. A. A., Westmoreland, J. J., Burstain, A., & Earls, L. R. (2018) · Gene Expression Patterns · doi:10.1016/j.gep.2018.03.004 · Cited by 6 · see citing works
Neurobiological effects of exercise intervention for premenstrual syndrome
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Authors: Baj, G., D'Alessandro, V., Musazzi, L., Mallei, A., Sartori, C. R., Sciancalepore, M., Tardito, D., Langone, F., Popoli, M., & Tongiorgi, E.
Affiliations: University of Trieste (IT)
University of Milan (IT)
Universidade Estadual de Campinas (UNICAMP) (BR)
Corresponding author: Tongiorgi, Enrico
ORCID: Baj, Gabriele
Musazzi, Laura
Mallei, Alessandra
Sciancalepore, Marina
Tardito, Daniela
Popoli, Maurizio
Tongiorgi, Enrico
Venue: Neuropsychopharmacology
Publisher: Springer Science and Business Media LLC
Published: 2012-02-08
Volume: 37
Issue: 7
Pages: 1600-1611
ISSN: 0893-133X (ISSN-L)
1740-634X
DOI: 10.1038/npp.2012.5
PMC: PMC3358751
OpenAlex: W2062574685
Cited by: 103
References: 57
Citations by year: 2026: 2 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 6 · 2021: 5 · 2020: 4 · 2019: 9 · 2018: 15 · 2017: 8 · 2016: 12 · 2015: 13 · 2014: 6 · 2013: 6 · 2012: 5
FWCI: 3.95
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: Neuropsychopharmacology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
BOA (University of Milano-Bicocca) (submittedVersion, other-oa)
IRIS eCampus Telematic University (Università degli Studi eCampus) (submittedVersion)
Funders: Ministero dell’Istruzione, dell’Università e della Ricerca
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: brain-derived neurotrophic factor, dendritic targeting, hippocampal CA3, antidepressants, fluoxetine, reboxetine, serotonin, norepinephrine, synaptic transmission, dentate gyrus, subcellular localization, spatial codes
MeSH terms: Reboxetine, Animals, Antidepressive Agents, Cells, Cultured, Dendrites, Fluoxetine, Male, Morpholines, Synaptic Transmission, Neurons, Norepinephrine, Physical Conditioning, Animal, Serotonin, Up-Regulation, Rats, Sprague-Dawley, Brain-Derived Neurotrophic Factor, Protein Isoforms, Mice, Rats, CA3 Region, Hippocampal

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Physical exercise and antidepressants enhance BDNF targeting in hippocampal CA3 dendrites: further evidence of a spatial code for BDNF splice variants.

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