Le virus T lymphotropique humain de type 1 (HTLV-1) est l’agent étiologique d’une forme rare et très agressive de leucémie de l’adulte (ATL). Le processus leucémogène a longtemps été attribué à la seule action de l’oncoprotéine Tax. Cependant, une nouvelle protéine virale, appelée HBZ (HTLV-1 bZIP factor), a été découverte en 2002. Elle est codée par le brin complémentaire du génome proviral et transcrite en antisens à partir du LTR3’. HBZ s’est avéré être un acteur clef de la prolifération et de la transformation des cellules T infectées, et donc du développement de l’ATL. La présente étude propose de nouvelles pistes quant aux mécanismes par lesquels HBZ induit la survie et la prolifération cellulaire. Nous avons montré que la protéine HBZ stimule l’expression de la neurotrophine BDNF et que les cellules de patients ATL surexpriment à la fois BDNF et son récepteur TrkB. De plus, ces patients présentent une concentration sérique anormalement élevée de la forme mature de BDNF, suggérant l’existence d’une boucle autocrine/paracrine BDNF/TrkB. L’activité de cette boucle a été confirmée in vitro et promeut la survie des cellules infectées par HTLV-1. D’autre part, nous avons découvert qu’HBZ dérégule l’expression du suppresseur de tumeur JunD dans les cellules T infectées, et induit celle de l’isoforme potentiellement oncogène ΔJunD. La production de ΔJunD résulterait d’une altération des mécanismes d’initiation de la traduction par HBZ. Nos résultats montrent aussi que ΔJunD promeut la prolifération et la transformation cellulaire en l’absence de sérum. Nous proposons donc que son expression pourrait contribuer à l’évolution des cellules T infectées en cellules leucémiques. / The human T-lymphotropic virus type 1 (HTLV-1) is associated with a rare and aggressive form of adult leukemia (ATL). For a long time, leukemogenesis was thought to mainly result from the action of the Tax oncoprotein. However, a new viral protein, called HBZ (HTLV-1 bZIP factor), was discovered in 2002. It is encoded by the minus strand of the proviral genome and transcribed in antisens from the 3’LTR. Since its discovery, HBZ came out as a key player in proliferation and transformation of infected T cells, thus contributing to ATL development. In this study we provide new leads regarding the mechanisms of HBZ-induced cell survival and proliferation. On one hand, we show that HBZ stimulates the expression of the BDNF neurotrophin and that ATL cells from patients overexpress both BDNF and its high-affinity receptor TrkB. Moreover, sera from patients exhibited abnormal levels of the mature form of BDNF, suggesting the existence of a BDNF/TrkB paracrine/autocrine loop. That loop was confirmed to be activated in vitro and to support the survival of HTLV-1-infected cells. On the other hand, we discovered that HBZ deregulates the expression of the JunD tumor suppressor in infected T cells and induces that of the ∆JunD isoform, which is potentially oncogenic. ∆JunD production would result from alteration of the translational initiation by HBZ. Our results also show that ∆JunD induces proliferation and transformation of serum starved cells. Finally, we hypothesize that HBZ-induced expression of ∆JunD may influence infected T cells to turn leukemic.

La pratique régulière d’une activité physique (AP) est un important message de santé publique. L’AP améliore non seulement la santé cardiovasculaire via l’augmentation de la production de NO (nitric oxide) par l’endothélium vasculaire mais aussi la santé cérébrale via l’augmentation des taux de BDNF (brain-derived neurotrophic factor) dans le cerveau. Comme la synthèse et la sécrétion de BDNF sont proportionnelles à l’activité neuronale, il est généralement admis que l’élévation des taux cérébraux de BDNF induite par l’AP est à relier à l’hyperactivité neuronale. Nous avons testé l’hypothèse selon laquelle l’élévation du flux sanguin dans les vaisseaux de la circulation cérébrale pendant la réalisation de l’AP contribue à augmenter les taux cérébraux de BDNF. Les expériences ont été menées chez des rats soumis ou non à l’AP (tapis roulant). Nos résultats montrent : 1) que l’augmentation des taux de BDNF induite par l’AP (tapis roulant, 18m/min, 30 min/j, 7j consécutifs) est moindre lorsque l’augmentation du flux sanguin pendant la réalisation de l’AP, est prévenue par un clampage mono- ou bi- carotidien, 2) que l’effet de l’AP sur les taux de BDNF dépend de l’intensité de l’AP ( tapis horizontal versus déclive descendant), 3) que la dysfonction endothéliale (modèle de rat spontanément hypertendu) et le traitement par un inhibiteur de NO synthase diminuent les effets de l’AP sur les taux cérébraux de BDNF et 4) qu’il existe une association positive entre les taux cérébraux de BDNF et la production de NO par l’endothélium vasculaire.L’ensemble de nos résultats suggère que l’augmentation des taux cérébraux de BDNF induite par l’AP met en jeu l’augmentation du flux sanguin dans les vaisseaux de la circulation cérébrale et, plus précisément, l’augmentation de la production endothéliale de NO qui en résulte. Ils fournissent de nouvelles données pour comprendre le lien existant entre fonction endothéliale et performances cognitives, soulevant l’idée selon laquelle les modalités d’AP pour améliorer la santé cérébrale doivent être différentes en cas de pathologies associées à une dysfonction endothéliale. / The regular practice of physical activity (PA) is an important public health message. PA not only improves cardiovascular health through the increase in NO (nitric oxide) production by the vascular endothelium but also through the increase levels in brain BDNF (brain-derived neurotrophic factor) levels. As the synthesis and secretion of BDNF are proportional to neuronal activity, it is generally accepted that PA-induced brain BDNF levels elevation is linked to neuronal hyperactivity. We tested the hypothesis that the increase in blood flow in cerebrovasculature during PA contributes to increase brain BDNF levels. The experiments were carried out in sedentary and trained rats (treadmill). Our results show that: 1) brain BDNF levels elevation induced by PA (treadmill, 18m /min, 30 min /day, 7 consecutive days) is lower when the normal rise of cerebral blood flow during the PA is prevented by occluding one or both common carotid arteries, 2) the effect of PA on brain BDNF levels is dependent on PA intensity (horizontal versus downhill), 3) the presence of endothelial dysfunction (spontaneously hypertensive rat model) as well as NO synthase inhibition decrease the effects of PA on brain BDNF levels and 4) there is a positive association between brain BDNF levels and vascular endothelium NO production .Collectively, our results suggest that increase in brain BDNF levels, induced by PA, involves increase in cerebrovasculature blood flow and more precisely elevation in endothelium NO production. They provide new data for understanding the relationship between endothelial function and cognitive performance, raising the idea that PA modalities to improve brain health might be different in pathologies diseases with endothelial dysfunction.

L’exercice physique (EX) est reconnu comme la stratégie non pharmacologique la plus efficace pour améliorer la santé cérébrale. Les études menées chez l’Homme et l’animal s’accordent pour impliquer le brain-derived neurotrophic factor (BDNF), une neurotrophine dont les taux cérébraux augmentent en réponse à l’EX et qui est unanimement reconnue comme une molécule de signalisation cruciale de la neuroplasticité. Principalement exprimé par les neurones, le BDNF est également très exprimé par la cellule endothéliale et la cellule musculaire. Très largement sollicités lors d’un effort physique, l’endothélium et le muscle pourraient intervenir dans les effets positifs induits par l’EX. Bien qu’il existe aujourd’hui un consensus sur l’implication du BDNF dans les effets cérébraux de l’EX, il n’en existe pas concernant les modalités d’EX à pratiquer pour optimiser de manière efficace la plasticité cérébrale. Dans ce contexte, les objectifs de ces travaux étaient de déterminer l’impact des modalités de l’EX sur les expressions protéiques de BDNF dans différents territoires (cerveau, endothélium, muscle) et d’étudier les mécanismes à l’origine de l’augmentation de BDNF en réponse à l’EX.Nos résultats montrent que 1) l’expression du BDNF dans des vaisseaux périphériques de même territoire vasculaire (diamètre interne différent) est similaire en réponse à l’EX et majoritairement d’origine endothéliale, 2) l’augmentation de l’expression cérébrale de BDNF en réponse à l’EX dépend de l’intensité de l’EX, mais pas du type de contraction (excentrique/concentrique), 3) la mémoire est restaurée par un EX de forte intensité, 4) l’EX n’impacte pas l’expression musculaire de BDNF, mais augmente l’expression du précurseur de l’irisine (FNDC5), 5) l’expression du BDNF dépend de la composition du muscle en fibres musculaires, 6) les effets cérébraux de l’intensité de l’EX ne semblent pas être reliés à la surexpression de l’irisine musculaire.En conclusion, nos données démontrent que l’EX impacte positivement l’expression endothéliale, cérébrale mais pas musculaire de BDNF. Les résultats mettent en évidence l’importance du paramètre intensité de l’EX sur les taux cérébraux de BDNF. Enfin, selon nos données obtenues, l’irisine et le BDNF musculaires ne semblent pas être impliqués dans l’augmentation cérébrale de BDNF en fonction de l’intensité de l’EX. / Physical exercise (EX) is recognized as the most potent non-pharmacological strategy to positively enhance brain health. From Human and animal studies there is a consensus to involve brain-derived neurotrophic factor (BDNF), a neurotrophin strongly expressed in response to EX and implicated in neuroplasticity mechanisms. Mainly expressed by neurons, BDNF is also expressed by endothelial and muscle cells. Largely sought during a physical effort, endothelium and skeletal muscle could be involved in positive effects induced by EX. Although there is a real consensus about BDNF and cerebral effect of EX, the typology of the better regimen of EX to enhance cerebral plasticity is not known. In this context, objectives of this works were to determine the impact of EX modalities on BDNF protein expression in different territory (brain, endothelium and muscle) and to identify mechanisms related in BDNF increases in response to EX.Our results showed that 1) BDNF expression in peripheral vessels from the same vascular territory (distinct internal diameter) is similar in response to EX, 2) cerebral BDNF increases induced by EX is dependent on EX intensity but not on the type of contraction (eccentric/concentric), 3) memory is restored by high intensity EX, 4) after EX, BDNF muscular expression is unchanged while the precursor of irisine (FNDC5) expression is increased, 5) BDNF expression depends on muscular fibers typology, 6) cerebral beneficial effects of EX intensity is might not be related to muscular irisine production.In conclusion, our data demonstrated that EX positively impact endothelial, cerebral but not muscular BDNF expression. Results highlighted the importance of the intensity parameter of EX on cerebral BDNF levels. Finally, according to our data, irisine and BDNF from the muscle might not be related to the cerebral increases of BDNF induced by EX intensity.

La leucémie lymphoïde chronique (LLC) est une hémopathie maligne caractérisée par l’accumulation, dans le sang et les organes lymphoïdes secondaires, de lymphocytes B matures résistants à l’apoptose. Le microenvironnement tumoral de la LLC au sein des organes lymphoïdes secondaires, et notamment les « Nurse-Like Cells » (NLCs), joue un rôle majeur dans la promotion de la survie et de la prolifération des cellules leucémiques. Au cours de cette étude, la surexpression du récepteur de la neurotensine NTSR2, un récepteur couplé aux protéines G, a été caractérisée. Il est activé de façon constitutive dans les cellules leucémiques circulantes, et son activation dépend de son interaction avec le récepteur à activité tyrosine kinase TrkB suite à la liaison de son ligand, le BDNF, tous deux également surexprimés. L’activation de NTSR2-TrkB par le BDNF entraine une signalisation de survie par les voies Src et Akt, aboutissant à la surexpression des protéines anti-apoptotiques Bcl-2 et Bcl-XL. L’inhibition du récepteur NTSR2 dans ces cellules fait diminuer leur viabilité. En présence des NLCs, les expressions de NTSR2, TrkB, BDNF, et de la sortiline, protéine de transport des neurotrophines et des récepteurs Trk, est accentuée. Les NLCs produisent elle-même du BDNF, activent la voie de signalisation Src, et leur rôle protecteur des cellules leucémiques est BDNF-dépendant. L’ensemble de ces travaux met en évidence un rôle capital de NTSR2-TrkB-BDNF dans la signalisation de survie des cellules leucémiques circulantes et au sein du microenvironnement tumoral de la LLC, et pourrait ainsi constituer une nouvelle cible thérapeutique potentielle. / Chronic lymphocytic leukemia (CLL) is a malignant hemopathy characterized by the accumulation of apoptosis resistant mature B lymphocytes in peripheral blood and secondary lymphoid organs. In these secondary lymphoid organs, the tumor microenvironment, notably Nurse-like Cells (NLCs), plays a major role in leukemic cells survival and proliferation promotion. In this study, an overexpression of neurotensin receptor NTSR2, a G-protein coupled receptor, was identified. NTSR2 is constitutively activated in circulating leukemic cells and its activation depends on its interaction with tyrosine kinase activity receptor TrkB upon binding of its ligand, BDNF. Activation of NTSR2-TrkB by BDNF induces survival signaling by Src and Akt pathways, and in term anti-apoptotic proteins Bcl-2 and Bcl-XL overexpression. Inhibition of NTSR2 in those cells impacts their viability. In the presence of NLCs, expressions of NTSR2, TrkB, BDNF, and sortilin, a neurotrophin and Trk receptor transport regulator, are enhanced. NLCs produce BDNF, stimulate Src activation, and their protective role on leukemic cells is BDNF-dependent. Taken together, this study highlights a key role of NTSR2-TrkB-BDNF in leukemic cells survival signaling, both in the circulation or in the tumor microenvironment, and might thus constitute a potential new therapeutic target.

Background: Serotonin (5-HT) and its neurotrophic support system, specifically brain-derived neurotrophic factor (BDNF), are thought to modulate energy homeostasis and susceptibility to obesity. Moreover, a polymorphism (5-HTTLPR) in the serotonin reuptake transporter (5-HTT) gene impairs its transcription, thereby altering serotonergic tone and potentially contributing to such susceptibility. This study aims to investigate the effect of BDNF, biallelic 5-HTTLPR, and central in-vivo 5-HTT availability in highly obese versus non-obese subjects using positron emission tomography (PET) and 5-HTT selective [11C]DASB. Methods: Thirty-eight subjects, 24 obese (body mass index, BMI, >35 kg/m2), otherwise mentally and physically healthy, and 14 non-obese (BMI ≤ 25 kg/m2), age- and sex-matched healthy controls were included in this study. Parametric images of binding potential were generated from PET data. Central 5-HTT availability, 5-HTTLPR genotype, and serum BDNF concentrations were analyzed, first in a volume of interest, then in a voxel-wise manner. Results: Overall, our results showed an absence of a linear correlation between BDNF, in-vivo central 5-HTT availability, and body mass index (BMI). 5-HTTLPR genotyping revealed BDNF and hippocampal 5-HTT availability to be negatively correlated (r = −0.57, p = 0.007) in long allelic homozygotes. However, obese subjects exhibited opposing effects of BDNF levels on 5-HTT availability in the nucleus accumbens (NAcc) relative to our non-obese controls. Conclusions: Our data did not confirm an overall correlation between serum BDNF, in-vivo central 5-HTT availability, 5-HTTLPR, and BMI. However, there is evidence that serotonergic tone linked to BDNF, specifically in the NAcc, is involved in the pathophysiology of obesity, although this needs further exploration over a wide range of reward-related eating behaviors.

<p>Multiple lines of evidence reveal that activation of the tropomyosin related kinase B (TrkB) receptor is a critical molecular mechanism underlying status epilepticus (SE) induced epilepsy development. However, the cellular consequences of such signaling remain unknown. To this point, localization of SE-induced TrkB activation to CA1 apical dendritic spines provides an anatomic clue pointing to Schaffer collateral-CA1 synaptic plasticity as one potential cellular consequence of TrkB activation. Here, we combine two-photon glutamate uncaging with two photon fluorescence lifetime imaging microscopy (2pFLIM) of fluorescence resonance energy transfer (FRET)-based sensors to specifically investigate the roles of TrkB and its canonical ligand brain derived neurotrophic factor (BDNF) in dendritic spine structural plasticity (sLTP) of CA1 pyramidal neurons in cultured hippocampal slices of rodents. To begin, we demonstrate a critical role for post-synaptic TrkB and post-synaptic BDNF in sLTP. Building on these findings, we develop a novel FRET-based sensor for TrkB activation that can report both BDNF and non-BDNF activation in a specific and reversible manner. Using this sensor, we monitor the spatiotemporal dynamics of TrkB activity during single-spine sLTP. In response to glutamate uncaging, we report a rapid (onset less than 1 minute) and sustained (lasting at least 20 minutes) activation of TrkB in the stimulated spine that depends on N-methyl-D-aspartate receptor (NMDAR)-Ca2+/Calmodulin dependent kinase II (CaMKII) signaling as well as post-synaptically synthesized BDNF. Consistent with these findings, we also demonstrate rapid, glutamate uncaging-evoked, time-locked release of BDNF from single dendritic spines using BDNF fused to superecliptic pHluorin (SEP). Finally, to elucidate the molecular mechanisms by which TrkB activation leads to sLTP, we examined the dependence of Rho GTPase activity - known mediators of sLTP - on BDNF-TrkB signaling. Through the use of previously described FRET-based sensors, we find that the activities of ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42) require BDNF-TrkB signaling. Taken together, these findings reveal a spine-autonomous, autocrine signaling mechanism involving NMDAR-CaMKII dependent BDNF release from stimulated dendritic spines leading to TrkB activation and subsequent activation of the downstream molecules Rac1 and Cdc42 in these same spines that proves critical for sLTP. In conclusion, these results highlight structural plasticity as one cellular consequence of CA1 dendritic spine TrkB activation that may potentially contribute to larger, circuit-level changes underlying SE-induced epilepsy.</p> / Dissertation

Primary sensory afferent outgrowth within the developing longitudinal pathway of the spinal cord is important for intrasegmental and intersegmental communication that underlies coordination and development of reflexes and contributes to sensory perception. The endogenous mechanisms that regulate primary sensory afferent extension are the primary focus of this dissertation. This dissertation tested the hypothesis that primary sensory afferent extension in the longitudinal pathway is regulated by sphingosine 1-phosphate type 1 receptor (S1P1R) and tyrosine kinase receptor B (TrkB) through a brain derived neurotrophic factor (BDNF) related mechanism. To test this hypothesis we used embryonic day five (E5) chicken embryos, as this is the developmental time point when sensory afferents are growing along the longitudinal axis of the spinal cord but have not yet turned ventrally to make connections with the grey matter of the spinal cord. Chicken embryos were removed from their in ovo environment to allow for labeling of primary afferent neurons in the thoracic 3/4 (T3/4) dorsal root ganglia (DRG). Tissue was then put into culture with or without various pharmacological agents and subsequently assayed for length of growth of the labeled primary afferent axons along the longitudinal axis of the spinal cord. Results showed both BDNF and fingolimod-p, an S1P1R agonist known to increase BDNF mRNA and protein production/secretion in cortical neurons, increased primary axon extension along the longitudinal pathway. Further, fingolimod-p increased BDNF mRNA production in DRG in this system. Conversely, inhibition of BDNF or S1PRs attenuated primary afferent axon extension along the longitudinal pathway. We found BDNF signaling to be required for fingolimod-p's effects as addition of αBDNF attenuated the effects of fingolimod-p on axon outgrowth. TrkB, the high affinity receptor for BDNF, is expressed in chicken DRG during embryonic development. We hypothesized that TrkB activation by BDNF regulates DRG axon extension in the longitudinal pathway through the PLC-γ signaling pathway. We found inhibition of TrkB and/or PLC-γ signaling pathway attenuated DRG axon extension with or without BDNF stimulation. Additional pathways associated with TrkB activation: mitogen activated kinase (MAPK) and phosphoinositide 3-kinase (PI3K) appeared to either have no effect on DRG axon extension or were involved in DRG axon extension through a mechanism that is not related to TrkB. Collectively, these studies suggest an endogenous mechanism for the regulation of DRG axon outgrowth within the longitudinal pathway. With this mechanism, DRG axon outgrowth may be enhanced or attenuated following manipulation of S1P1R, BDNF and/or TrkB. Further, these findings suggest an action through BDNF on CNS axons as a potential therapeutic effect of fingolimod-p, a treatment for relapsing remitting forms of Multiple Sclerosis

Alcoholism is a complex neurological disorder characterized by loss of control in limiting intake, compulsion to seek and imbibe ethanol, and chronic craving and relapse. It is suggested that the characteristic behaviors associated with the escalation of drug use are caused by long-term molecular adaptations precipitated by the drug’s continual administration. These lasting activity-dependent changes that underlie addiction-associated behavior are thought, in part, to depend on new protein synthesis and remodeling at the synapses. It is well established that mRNA can be transported to neuronal distal processes, where it can undergo localized translation that is regulated in a spatially restricted manner in response to stimulation. Through two avenues of investigation, the research herein demonstrates that behavioral responses to ethanol result, at least in part, from alterations in the synaptic transcriptome which contribute to synaptic remodeling and plasticity. The synaptoneurosome preparation was utilized to enrich for RNAs trafficked to the synapse. Two complementary methods of genomic profiling, microarrays and RNA-Seq, were used to survey the synaptic transcriptome of DBA/2J mice subjected to ethanol-induced behavioral sensitization. A habituating expression profile, characteristic of glucocorticoid-responsive genes, was observed for a portion of synaptically targeted genes determined to be sensitive to repeated ethanol exposure. Other ethanol-responsive genes significantly enriched for at the synapse were related to biological functions such as protein folding and extra-cellular matrix components, suggesting a role for local regulation of synaptic functioning by ethanol. In a separate series of experiments, it was shown that altered trafficking of Bdnf, an ethanol-responsive gene, resulted in aberrant ethanol behavioral phenotypes. In particular, mice lacking dendritically targeted Bdnf mRNA exhibited enhanced sensitivity to low, activating doses and high, sedating doses of ethanol. Together these experiments suggest that ethanol has local regulatory effects at the synapse and lays the foundation for further investigations into the role of the synaptic transcriptome in ethanol-responsive behaviors. Supported by NIAA grants R01AA014717, U01 AA016667 and P20AA017828 to MFM, F31AA021035 to MAO, and NIDA T32DA007027 to WLD.

Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of secreted proteins, which include in addition to BDNF, nerve growth factor (NGF) and neurotrophin 3-6 (NT-3-6). BDNF mediates its functions by activating two cell surface receptors, pan-neurotrophin receptor (P75NTR) and tropomyosin-related kinase B (TrkB) and their downstream intracellular cascades. BDNF is best known for its role in neuronal survival, regulation of neuronal differentiation, migration and activity-dependent synaptic plasticity. However, BDNF is widely expressed in non-neuronal tissues as well. The localization and the function of BDNF in intestinal smooth muscle cells (SMCs) are not well defined. Thus, the main purpose of the present study was the identification and characterization of BDNF in intestinal SMCs. Using xviii biochemical and molecular techniques, we have demonstrated in this study that BDNF is synthesized and released in rabbit intestinal longitudinal SMCs cultures. Furthermore, gut neuropeptides, Pituitary Adenylate Cyclase Activating Peptide (PACAP) and substance P (SP) increased BDNF expression and release in SMCs cultures after 24 hrs and 48 hrs incubation. We have also shown that intracellular Ca2+ levels are essential for SP stimulation of BDNF expression and secretion. Lastly, we have demonstrated that exogenous BDNF enhanced carbachol (CCh)-induced contraction of isolated longitudinal muscle strips, and this was inhibited by preincubation with TrkB inhibitor K252a and PLC inhibitor U73122 sugesting that BDNF sensitize longitudinal SMCs to CCh by activating PLC pathway, which is normally absent in those muscle cells. These results provide new insight into the mechanisms of neurotrophin (BDNF) modulation of gut function, which may lead to new therapeutic avenues for treatment of gastrointestinal disorders, and explain some of the pathological changes associated with inflammation such as hypercontractility associated with gut infection or IBD.

Thesis advisor: Barbara E. Wolfe / Background: Anorexia nervosa (AN) is a serious mental illness with physical and emotional consequences. Currently, there are limited effective treatments available to address this devastating condition. One possible biomarker implicated in this condition is brain derived neurotrophic factor (BDNF), a member of the neuron growth family. Pre-clinical studies indicate administration of BDNF is associated with decreased food intake and weight loss. Serum BDNF levels also have been shown to be reduced in AN compared to healthy controls (HC). In studies of selective serotonin reuptake inhibitors (SSRI's), blood levels of BDNF have been shown to increase following SSRI administration. This study sought to examine the possible relationship between peripheral BDNF levels and influence of an SSRI, and augmentation with 5-hydroxytryptophan (5-HTP) in persons with AN and HC's. Methods: This study examined previously collected samples from an investigation assessing the influence of SSRI administration and augmentation with 5-HTP on serotonin function in AN. The original study utilized a randomized double-blind placebo-controlled design. AN (n=16) and HC (n=49) subjects were randomized to 1 of 3 treatment conditions (fluoxetine, fluoxetine plus 5-HTP, and placebo) for 7 days of drug administration. Blood samples were collected following an overnight fast and stored at -70°C prior to batch analysis (ELISA). Results: Plasma BDNF levels in AN subjects (59.7 (SD 43.3) pg/ml) were not significantly (p=0.24) different from HC's (76.2 (SD 49.0) pg/ml). There were no significant differences between SSRI, SSRI plus 5-HTP, and placebo treatment groups within or between AN and HC groups. Conclusions: Although BDNF levels in AN subjects were lower than HC, the difference was not statistically significant. After 7 days of SSRI, SSRI plus 5-HTP, or placebo, there were no differences in BDNF levels between or within groups. The possibility exists that 7 days is not long enough to see an expressed effect of SSRI's on BDNF. Future studies would benefit from longer duration of SSRI's, assessing potential covariates (e.g. BMI, depression), and a larger sample. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Connell School of Nursing. / Discipline: Nursing.