Immune status influences fear and anxiety responses in mice after acute stress exposure

Sarah M. Clark, Joseph Sand, T. Chase Francis, Anitha Nagaraju, Kerry C. Michael, Achsah D. Keegan, Alexander Kusnecov, Todd D. Gould, Leonardo H. Tonelli

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Significant evidence suggests that exposure to traumatic and/or acute stress in both mice and humans results in compromised immune function that in turn may affect associated brain processes. Additionally, recent studies in mouse models of immune deficiency have suggested that adaptive immunity may play a role during traumatic stress exposure and that impairments in lymphocyte function may contribute to increased susceptibility to various psychogenic stressors. However, rodent studies on the relationship between maladaptive stress responses and lymphocyte deficiency have been complicated by the fact that genetic manipulations in these models may also result in changes in CNS function due to the expression of targeted genes in tissues other than lymphocytes, including the brain. To address these issues we utilized mice with a deletion of recombination-activating gene 2 (Rag2), which has no confirmed expression in the CNS; thus, its loss should result in the absence of mature lymphocytes without altering CNS function directly. Stress responsiveness of immune deficient Rag2-/- mice on a BALB/c background was evaluated in three different paradigms: predator odor exposure (POE), fear conditioning (FC) and learned helplessness (LH). These models are often used to study different aspects of stress responsiveness after the exposure to an acute stressor. In addition, immunoblot analysis was used to assess hippocampal BDNF expression under both stressed and non-stressed conditions. Subsequent to POE, Rag2-/- mice exhibited a reduced acoustic startle response compared to BALB/c mice; no significant differences in behavior were observed in either FC or LH. Furthermore, analysis of hippocampal BDNF indicated that Rag2-/- mice have elevated levels of the mature form of BDNF compared to BALB/c mice. Results from our studies suggest that the absence of mature lymphocytes is associated with increased resilience to stress exposure in the POE and does not affect behavioral responses in the FC and LH paradigms. These findings indicate that lymphocytes play a specific role in stress responsiveness dependent upon the type, nature and intensity of the stressor.

Original languageEnglish (US)
Pages (from-to)192-201
Number of pages10
JournalBrain, Behavior, and Immunity
StatePublished - May 2014
Externally publishedYes

Bibliographical note

Funding Information:
Supported by the VA Research Merit Award BX000935 and by the National Institute of Mental Health Research Grant R01MH097676 .


  • Acoustic startle
  • Anxiety
  • BDNF
  • Fear
  • Lymphocytes
  • Open field test
  • Stress
  • Western blots


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