title: The role of brain-derived neurotrophic factor in learned fear processing: an awake rat fMRI study.
abstract: Brain-derived neurotrophic factor (BDNF) signaling is implicated in the etiology of many psychiatric disorders associated with altered emotional processing. Altered peripheral (plasma) BDNF levels have been proposed as a biomarker for neuropsychiatric disease risk in humans. However, the relationship between peripheral and central BDNF levels and emotional brain activation is unknown. We used heterozygous BDNF knockdown rats (BDNF(+/-)) to examine the effects of genetic variation in the BDNF gene on peripheral and central BDNF levels and emotional brain activation as assessed by awake functional magnetic resonance imaging (fMRI). BDNF(+/-) and control rats were trained to associate a flashing light (conditioned stimulus; CS) with foot-shock, and brain activation in response to the CS was measured 24 h later in awake rats using fMRI. Central and peripheral BDNF levels were decreased in BDNF(+/-) rats compared with control rats. Activation of fear circuitry (amygdala, periaqueductal gray, granular insular) was seen in control animals; however, activation of this circuitry was absent in BDNF(+/-) animals. Behavioral experiments confirmed impaired conditioned fear responses in BDNF(+/-) rats, despite intact innate fear responses. These data confirm a positive correlation [r = 0.86, 95% confidence interval (0.55, 0.96); P = 0.0004] between peripheral and central BDNF levels and indicate a functional relationship between BDNF levels and emotional brain activation as assessed by fMRI. The results demonstrate the use of rodent fMRI as a sensitive tool for measuring brain function in preclinical translational studies using genetically modified rats and support the use of peripheral BDNF as a biomarker of central affective processing.
authors.affiliation: University/BHF Centre for Cardiovascular Sciences.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: A P
authors.initials: AP
authors.lastname: Harris
authors.affiliation: University/BHF Centre for Cardiovascular Sciences.
authors.forename: R J
authors.initials: RJ
authors.lastname: Lennen
authors.affiliation: Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
authors.forename: N M
authors.initials: NM
authors.lastname: Brydges
authors.affiliation: University/BHF Centre for Cardiovascular Sciences.
authors.forename: M A
authors.initials: MA
authors.lastname: Jansen
authors.affiliation: Centre for Clinical Brain Sciences (CCBS) Neuroimaging Sciences.
authors.forename: C R
authors.initials: CR
authors.lastname: Pernet
authors.affiliation: Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinbugh, UK.
authors.forename: H C
authors.initials: HC
authors.lastname: Whalley
authors.affiliation: University/BHF Centre for Cardiovascular Sciences.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Centre for Clinical Brain Sciences (CCBS) Neuroimaging Sciences.
authors.forename: I
authors.initials: I
authors.lastname: Marshall
authors.affiliation: AbbVie, Translational Sciences-Imaging, North Chicago, IL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Baker
authors.affiliation: AbbVie, Translational Sciences-Imaging, North Chicago, IL, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Basso
authors.affiliation: Alexion Pharmaceuticals, Cheshire, CT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Day
authors.affiliation: University/BHF Centre for Cardiovascular Sciences.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: M C
authors.initials: MC
authors.lastname: Holmes
authors.affiliation: Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
authors.forename: J
authors.initials: J
authors.lastname: Hall
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D003214:Conditioning, Classical / Q000502:physiology; D003213:Conditioning, Psychological / Q000502:physiology*; D005239:Fear / Q000502:physiology*; D005260:Female; D007858:Learning / Q000502:physiology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D010775:Photic Stimulation / Q000379:methods; D055647:Rats, Transgenic; D014851:Wakefulness
chemical_list: D019208:Brain-Derived Neurotrophic Factor
keywords: Amygdala; BDNF; Pavlovian conditioning; awake rat fMRI; transgenic rat