Neuroimmune consequences of and contributions to affective mood states
Chronic psychosocial stress in animals alters the activation status of the brain’s immune cells—the microglia — and affects the status of immune cells in the periphery. Neuronal stress circuits engage a bi-directional dialog between the brain and central and peripheral immune systems involving anatomical, humoral, and cellular mechanisms. The neuroimmune communication pathways serve to achieve internal homeostasis. Disequilibrium in the system, if sustained or severe, results in disease. We are studying neuroimmune relationships in chronic stress paradigms to understand how they play out to affect behavior and CNS structure and function. The immune system is divided into an innate arm mediating rapid general immunity and an adaptive arm mediating delayed acquired cellular immunity. We are studying both arms. Stress-activated microglia are studied in a number of in vivo and ex vivo assays. The picture shows an assay for phagocytic activity of an isolated microglial cell.
Our studies of the effect of peripheral immune cells on behavior and stress circuits have focused on the model of adoptive transfer of lymphocytes into mice that lack mature lymphocytes. Cells taken from stressed but not unstressed mice confer an antidepressant effect on the host mice after repopulating the immune organs of the host mouse, as shown in the photograph of the labeled T cells (red) in meninges covering the brain of the host mouse. Studies are underway to understand the mechanisms for this novel effect.
- Lehmann M.L., Weigel T.K., Elkahloun A.G., Herkenham M. Chronic social defeat reduces myelination in the mouse medial prefrontal cortex. Sci Reports, 7: 46548, 2017. Full Text/Abstract
- Lehmann, M.L., Cooper, H.A., Maric, D., Herkenham, M. Social defeat induces depressive-like states and microglial activation without involvement of peripheral macrophages. J. Neuroimmunol.,13: 224, 2016. Full Text/Abstract
- Herkenham, M. and Kigar, S. L., Contributions of the adaptive immune system to mood regulation: mechanisms and pathways of neuroimmune interactions. Prog Neuropsychopharmacol. Biol. Psychiatry, 79: 49-57, 2017. Full Text/Abstract
- Brachman, R.A., Lehmann, M.L., Maric, D., and Herkenham, M. Lymphocytes from chronically stressed mice confer antidepressant-like effects to naïve mice. J. Neurosci., 35: 1530-1538, 2015 Full Text/Abstract
- Listwak, S.J., Rathore, P., and Herkenham, M. Minimal NF-kB activity in neurons. Neuroscience, 250: 282-299, 2013. Full Text/Abstract
Psychosocial Stress, Environmental Enrichment, and Hippocampal Neurogenesis
A naturalistic model of chronic stress that mimics depressive conditions in humans is psychosocial stress, achieved in mice by creating a housing condition in which an aggressive dominant mouse and a subordinate mouse live together separated by a perforated barrier. The persistent conflict results in socially defeated subordinate mice that show behavioral signs of increased anxiety, helplessness, anhedonia, and inappropriate social interaction, assessed in validated behavioral tests. We showed that environmental enrichment — housing in large cages with tubes, toys, and a running wheel — following social defeat restores the normal behavior of the subordinate mice. We found that adult neurogenesis is required for the restorative effects. We also found that the environmental enrichment is protective when it is given prior to the psychosocial stress, and these effects are neurogenesis-dependent and require normal fluctuations in the stress hormone corticosterone. The photomicrograph shows newborn cells (BrdU-positive; yellow) in the germinal layer of the dentate gyrus.
- Lehmann, M.L., Brachman, R.A., Martinowich, K., Schloesser, R.J., and Herkenham, M. Glucocorticoids orchestrate divergent effects on mood through adult neurogenesis. J. Neurosci., 33: 2961-2972, 2013. Full Text/Abstract
- Lehmann, M. L., Geddes, C. E., Lee, J. L., and Herkenham, M. Urine scent marking (USM): A novel test for depressive-like behavior and a predictor of stress resiliency in mice. PLoS ONE, 8(7): e69822, 2013. Full Text/Abstract
- Lehmann, M.L. and Herkenham, M. Environmental enrichment confers stress resiliency to social defeat through an infralimbic cortex-dependent neuroanatomical pathway. J. Neuroscience, 31: 6159-6173, 2011. Full Text/Abstract
- Schloesser, R.J., Lehmann, M., Martinowich, K., Manji, H.K., Herkenham, M. Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress. Mol. Psychiatry, 15: 1152-1163, 2010. Full Text/Abstract