"Active coping" strategies may be promoted during therapy for pathological anxiety because they: 1) give the patient control over exposure to aversive stimuli, 2) prevent fearful reactions and feelings, and 3) may produce a more permanent recovery. This is nicely modeled by active avoidance (AA) training where subjects learn to replace initial fear reactions with instrumental actions that prevent exposure to aversive stimuli. However, some excessively fearful subjects never master the AA task. Interestingly, this poor AA phenotype reflects a deficit in performance, rather than learning, since brain lesions that disrupt Pavlovian reactions rescue AA without further training (Choi et al., 2010;Lazaro.Munoz et al., 2010). Thus, defensive responding after AA training appears to depend on competition in fear processing circuits between Pavlovian and instrumental memories. This is consistent with observations that fearful reactions disappear once an AA response is acquired and reappear if the response is not available (Cain and LeDoux, 2007;Lovibond et al., 2008;Solomon and Wynne, 1954). The neural circuitry and mechanisms are well known for Pavlovian fear reactions but are poorly understood for AA, especially in humans. Even less is known about the neural circuits and transmitter systems mediating the competitive selection of active vs. reactive defensive responses. Our long term goal is to elucidate the brain systems, cells, molecules and physiological processes necessary for suppressing Pavlovian fear and establishing permanent active coping responses. We will begin with unbiased imaging of AA related brain activity in rats (c-fos expression) to identify critical response selection points inthe fear circuit. However, we will also test specific hypotheses about the role of amygdala and prefrontal cortex (PFC) norepinephrine in AA expression, given the importance of these regions and this neuromodulator to emotion and defensive behavior. Our objectives are to: 1) identify brain regions and cell populations where activity is associated with good vs. poor AA performance, and 2) determine whether adrenergic signaling influences action vs. reaction selection post training. Based on published and preliminary data, our main hypothesis is that ?-adrenergic receptor signaling in central amgydala (CE) opposes the expression of instrumental actions by promoting competing Pavlovian fear reactions. We will test this by injecting propranolol or isoproterenol into CE and assessing conditioned fear and AA in rats. We expect propranolol to suppress fear reactions and selectively enhance AA in poor avoiders, and isoproterenol to convert good avoiders to high freezing poor avoiders. Other candidate regions will be assessed similarly, but null effects are expected. If successful, these studies will identiy specific brain regions and signaling pathways critical for active coping. They may also suggest an innovative way to temporarily combine ?.blockers with behavior therapy to establish permanent active coping strategies in anxious humans. Further, since avoidance can be maladaptive, these studies may identify a mechanism that is awry in pathological anxiety.

Public Health Relevance

Instrumental active avoidance (AA) depends on the suppression of Pavlovian fear reactions, yet, the brain mechanisms mediating this response competition are unknown. In rats, we will identify critical brain regions and evaluate whether ?-adrenergic receptor signaling impedes AA by promoting competing Pavlovian fear reactions. Given that AA processes likely contribute to both the pathology (e.g. avoidance) and treatment (e.g. active coping) of anxiety, the findings may have therapeutic importance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH097125-02
Application #
8541889
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Vicentic, Aleksandra
Project Start
2012-09-07
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$187,982
Indirect Cost
$67,982
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
Collins, Katherine A; Mendelsohn, Avi; Cain, Christopher K et al. (2014) Taking action in the face of threat: neural synchronization predicts adaptive coping. J Neurosci 34:14733-8
Campese, Vincent D; Kim, Jeanny; Lázaro-Muñoz, Gabriel et al. (2014) Lesions of lateral or central amygdala abolish aversive Pavlovian-to-instrumental transfer in rats. Front Behav Neurosci 8:161
Cain, Christopher K; McCue, Margaret; Bello, Iruma et al. (2014) d-Cycloserine augmentation of cognitive remediation in schizophrenia. Schizophr Res 153:177-83
Martinez, Raquel C R; Gupta, Nikita; Lázaro-Muñoz, Gabriel et al. (2013) Active vs. reactive threat responding is associated with differential c-Fos expression in specific regions of amygdala and prefrontal cortex. Learn Mem 20:446-52