The cellular and molecular mechanisms underlying development of stress-related anxiety disorders remain largely unknown. It is clear that exposure to stress contributes to the development of anxiety disorders, including post-traumatic stress disorder (PTSD). One approach to studying the pathogenesis of these disorders is to examine how the brain controls and responds to stress in animal models. Studies show that stress responses are critical for the animal's short-term survival, but they can become harmful if uncontrolled, leading to maladaptive coping mechanisms and altered brain physiology, chemistry, and anatomy. These studies were designed to better understand the roles of the p75 neurotrophin receptor (p75NTR) and long-term depression, a form of synaptic plasticity, in mediating development of anxiety and mediating the stress response. These studies focused on 1) the physiological effects of loss of p75NTR in hippocampal physiology and the relationship to cholinergic signaling and 2) how disruption of these processes affects development of anxiety-like behavior and the response to acute stress. In the adult brain, p75NTR is primarily expressed in basal forebrain cholinergic neurons, which are the major source of cholinergic innervation to the hippocampus. Exposure to acute behavioral stress enables a form of synaptic plasticity called long-term depression (LTD) in the adult hippocampus. The biological functions of hippocampal LTD, especially in the adult, remain obscure. Recent findings have suggested that LTD may mediate behavioral flexibility by ensuring adaptive responses to environmental changes. We found that transgenic mice lacking the p75NTR do not exhibit stress-induced long-term depression. We also found that the p75NTR mutants show increased levels of anxiety-like behavior. Inhibiting cholinergic transmission with the muscarinic antagonist scopolamine also blocked stress-enabled LTD in the hippocampus, leading to increased anxiety-like behavior. We then confirmed that these behavioral effects were related to a deficiency in stress-enabled LTD by blocking LTD directly using a specific peptide inhibitor and examining anxiety-like behavior. As expected, administration of the peptide inhibitor reduced stress-induced LTD and exacerbated anxiety-like behavior. Our studies provide an excellent foundation for further exploration of how stress-enabled LTD regulates mood in response to acute stress.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
U.S. National Institute of Mental Health
Zip Code
Martinowich, Keri; Cardinale, Kathleen M; Schloesser, Robert J et al. (2012) Acetylcholinesterase inhibition ameliorates deficits in motivational drive. Behav Brain Funct 8:15
Martinowich, Keri; Schloesser, Robert J; Lu, Yuan et al. (2012) Roles of p75(NTR), long-term depression, and cholinergic transmission in anxiety and acute stress coping. Biol Psychiatry 71:75-83
Lu, Yuan; Ji, Yuanyuan; Ganesan, Sundar et al. (2011) TrkB as a potential synaptic and behavioral tag. J Neurosci 31:11762-71
Martinowich, Keri; Schloesser, Robert J; Manji, Husseini K (2009) Bipolar disorder: from genes to behavior pathways. J Clin Invest 119:726-36
Martinowich, Keri; Lu, Bai (2008) Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 33:73-83
Lu, Bai; Martinowich, Keri (2008) Cell biology of BDNF and its relevance to schizophrenia. Novartis Found Symp 289:119-29;discussion 129-35, 193-5