Risk factors for anxiety disorder are important in determining who ultimately develops the disorder. However, our understanding of risk factors is rudimentary. Identification of the mechanisms of risk factors would be a step forward in understanding the etiology of anxiety disorders. Reduced hippocampal volume, dysfunction of the brain-derived neurotrophin factor (BDNF) system and behavioral inhibition temperament are three anxiety risk factors identified in humans. The risk factor of reduced hippocampal volume is associated with impaired hippocampal-dependent learning, suggesting impaired hippocampal synaptic plasticity in individuals at risk. BDNF is important for synaptic plasticity. Thus, we hypothesize that impaired hippocampal synaptic plasticity may underlie the risk factors of both reduced hippocampal volume and BDNF dysfunction. The Wistar Kyoto (WKY) rat is an inbred strain that is stress sensitive, has a reduced hippocampal volume compared to the outbred Sprague Dawley (SD) rat, has an abnormal BDNF system and expresses a behavioral inhibition. In addition, WKY rats acquire active avoidance to a greater and more persistent degree than SD rats. Abnormal avoidance is a core feature of all anxiety disorders, and the development of abnormal avoidance parallels the trajectory of PTSD (cluster C). Thus, the proposed studies will test whether impaired synaptic plasticity in the hippocampus contributes to the development of abnormal avoidance learning in the presence and absence of behavioral inhibition temperament.
Four aims are proposed.
Aim 1 will determine whether BDNF-induced synaptic plasticity is impaired in the hippocampus of WKY rats and if NMDA and BDNF agonists can attenuate these impairments.
Aim 2 will investigate the effects of drugs acting on NMDA and BDNF-TrkB receptors on avoidance learning.
Aim 3 will determine if opioid-dependent LTP in the hippocampus is impaired in WKY rats. Opioid-dependent LTP does not require NMDA or TrkB receptors.
Aim 4 will investigate whether drugs acting on opioid receptors can affect the development of abnormal avoidance responding. Because opioid-dependent LTP is independent of NMDA and TrkB receptors, the comparison of opioid LTP to NMDA- and BDNF-LTP will determine whether the development of abnormal avoidance requires impairment of a specific type of LTP (i.e., NMDA) or if impairment to any of the various forms of LTP in the hippocampus can lead to the development of abnormal avoidance. The proposed studies will start to elucidate the mechanisms and interactions of three risk factors for anxiety disorders. Understanding the etiology of anxiety disorders and mechanisms of risk factors will help in the development of treatments. This is especially important to the health of veterans because a significant number of veterans are likely to develop anxiety-related disorders as a result of the extreme stress associated with combat service.

Public Health Relevance

Occurrence of anxiety disorders is dependent on the interaction of environment and individual risk factors. The extreme and constant stressors of deployment, war and war time service enhance the likelihood of developing anxiety disorders, and the rates of veterans developing anxiety disorders have been estimated to be 4 times higher than the general population. Accordingly, anxiety disorders are a major focus for VA medical and psychiatry services. Basic research that is focused on a mechanistic account of how vulnerability factors interact with stress leading to psychopathology has the potential to contribute to an understanding of the etiological basis of PTSD and other anxiety disorders. Understanding the etiology of PTSD and anxiety disorders will provide opportunities to prevent and treat these disorders, resulting in significant cost saving to the VA and allowing medical specialists to concentrate their efforts on fewer patients.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000132-06
Application #
8967080
Study Section
Neurobiology A (NURA)
Project Start
2009-04-01
Project End
2018-09-30
Budget Start
2015-10-01
Budget End
2016-09-30
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
VA New Jersey Health Care System
Department
Type
DUNS #
087286308
City
East Orange
State
NJ
Country
United States
Zip Code
Smith, Ian M; Pang, Kevin C H; Servatius, Richard J et al. (2016) Paired-housing selectively facilitates within-session extinction of avoidance behavior, and increases c-Fos expression in the medial prefrontal cortex, in anxiety vulnerable Wistar-Kyoto rats. Physiol Behav 164:198-206
Fragale, Jennifer E C; Khariv, Veronika; Gregor, Danielle M et al. (2016) Dysfunction in amygdala-prefrontal plasticity and extinction-resistant avoidance: A model for anxiety disorder vulnerability. Exp Neurol 275 Pt 1:59-68
Servatius, Richard J; Avcu, Pelin; Ko, Nora et al. (2015) Avoidance expression in rats as a function of signal-shock interval: strain and sex differences. Front Behav Neurosci 9:168
Janke, Kellie L; Cominski, Tara P; Kuzhikandathil, Eldo V et al. (2015) Investigating the Role of Hippocampal BDNF in Anxiety Vulnerability Using Classical Eyeblink Conditioning. Front Psychiatry 6:106
Pang, Kevin C H; Sinha, Swamini; Avcu, Pelin et al. (2015) Long-lasting suppression of acoustic startle response after mild traumatic brain injury. J Neurotrauma 32:801-10
Jiao, Xilu; Beck, Kevin D; Myers, Catherine E et al. (2015) Altered activity of the medial prefrontal cortex and amygdala during acquisition and extinction of an active avoidance task. Front Behav Neurosci 9:249
Beck, Kevin D; Jiao, Xilu; Smith, Ian M et al. (2014) ITI-Signals and Prelimbic Cortex Facilitate Avoidance Acquisition and Reduce Avoidance Latencies, Respectively, in Male WKY Rats. Front Behav Neurosci 8:403
Jiao, Xilu; Beck, Kevin D; Stewart, Amanda L et al. (2014) Effects of psychotropic agents on extinction of lever-press avoidance in a rat model of anxiety vulnerability. Front Behav Neurosci 8:322
Avcu, Pelin; Jiao, Xilu; Myers, Catherine E et al. (2014) Avoidance as expectancy in rats: sex and strain differences in acquisition. Front Behav Neurosci 8:334
Cominski, Tara P; Jiao, Xilu; Catuzzi, Jennifer E et al. (2014) The role of the hippocampus in avoidance learning and anxiety vulnerability. Front Behav Neurosci 8:273