Brain-derived neurotrophic factor (BDNF) is implicated in trauma and stressor-related disorders. These psychiatric conditions include phobias as well as post-traumatic stress disorder, and are characterized by abnormalities in negative valence systems. The biological mechanisms associated with these symptoms are clustered around the constructs of fear and threat, which can be examined in mouse models of fear- conditioning and extinction. Although BDNF is highly associated with impaired fear regulation, how it regulates the underlying circuitry to influence behavior is not well understood. BDNF regulates neural plasticity in the developing and adult brain, and is enriched in regions associated with emotional control including amygdala (AMY), hippocampus (HPC) and prefrontal cortex (PFC). BDNF signaling is complex, including production of multiple transcripts from at least nine different promoters (I through IX). Each of these transcripts contains a 5' non-coding exon spliced to a common coding exon. In response to neuronal activity, the binding of cis-acting calcium-dependent transcription factors and epigenetic chromatin remodeling induces BDNF expression from promoter-IV. Activity-dependent Bdnf transcription plays a role in the homeostatic regulation of neuronal excitability and induction of synaptic plasticity. It has been proposed that aberrant synaptic plasticity in limbic circuits underlies generation of the impaired fear regulation observed in trauma and stressor-related disorders. Our data show that disruption of BDNF from promoter-IV causes resistance to extinction of learned fear, and is accompanied by alterations in HPC and PFC neural activity patterns. These data provide rationale for determining whether this locus can be selectively targeted in disorders associated with impaired fear regulation. Synaptic dysfunction can alter coordination of neuronal oscillations that mediate fear-related behavior, but the molecular and cellular events that control these oscillations have not been fully elucidated. In this proposal we aim to identify network level alterations in fear-related circuits downstream of impaired activity-dependent production of BDNF, and to further reveal the BDNF-dependent cellular and molecular mechanisms that control synchronized network activity in those circuits. These studies then determine whether BDNF-dependent circuits can be directly manipulated to regulate fear expression and extinction. We will assess whether transgenic interventions and novel pharmacological strategies that restore BDNF signaling are able to reverse abnormal fear behavior. The results of these studies are likely to reveal fundamental mechanisms by which activity-dependent BDNF production impacts fear circuit function and behavior. These are critical data because understanding the mechanisms that control the expression and extinction of fear is vital for rational development of improved treatments for anxiety and trauma-related disorders.
The unmet need for effective treatments for mental illnesses associated with impaired regulation of fear is a serious health problem. The proposed research is relevant to the NIH's mission to transform the understanding and treatment of mental illness through basic research for prevention, recovery and cure because it will contribute important information about the cellular and molecular mechanisms that regulate the expression of fear. Our proposed research seeks to understand how brain-derived neurotrophic factor (BDNF) signaling affects neural circuits that are implicated in anxiety as well as trauma and stressor-related disorders, with the ultimate goal of therapeutically targeting this signaling pathway.
