Inoculation of Bacillus Calmette-Guerin to mice induces an acute episode of sickness behavior followed by chronic depressive-like behavior

Abstract

Although cytokine-induced sickness behavior is now well-established, the mechanisms by which chronic inflammation and depression are linked still remain elusive. Therefore this study aimed to develop a suitable model to identify the neurobiological basis of depressive-like behavior induced by chronic inflammation, independently of sickness behavior. We chose to measure the behavioral consequences of chronic inoculation of mice with Bacillus Calmette-Guerin (BCG), which has been shown to chronically activate both lung and brain indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme that mediates the occurrence of depressive-like behavior following acute innate immune system activation. BCG inoculation induced an acute episode of sickness (approximately 5 days) that was followed by development of delayed depressive-like behaviors lasting over several weeks. Transient body weight loss, reduction of motor activity and the febrile response to BCG were dissociated temporarily from a sustained increase in the duration of immobility in both forced swim and tail suspension tests, reduced voluntary wheel running and decreased preference for sucrose (a test of anhedonia). Moreover, we show that a distinct pattern of cytokine production and IDO activation parallels the transition from sickness to depression. Protracted depressive-like behavior, but not sickness behavior, was associated with sustained increase in plasma interferon-γ and TNF-α concentrations and peripheral IDO activation. Together, these promising new data establish BCG inoculation of mice as a reliable rodent model of chronic inflammation-induced depressive-like behaviors that recapitulate many clinical observations and provide important clues about the neurobiological basis through which cytokines may have an impact on affective behaviors.

Non-Painful Peripheral Inflammation Blocks Conditioned Place-Preference to Morphine and Nicotine through an Ibuprofen-Sensitive and an Ibuprofen Insensitive Pathway

“…For example, the intraperitoneal CGB administration causes a dose dependent depression as increased immobility in a forced swim and tail suspension tests and a decrease in sucrose consumption [22] [32] [33].…”

From head to tail it's a 2 way street for neuro-immune communication

“…In response to infection, mammalian immune cells can produce neuropeptides, cytokines and neurotransmitters that influence the nervous system and can lead to the development of sickness syndrome and depression. [32][33][34] This bidirectional communication means that dysfunction in the nervous system can have a significant impact on the immune system and vice versa. Indeed analysis of people with the autoimmune condition rheumatoid arthritis reveals an increased incidence of depression.…”

Neuropeptides and the Microbiota-Gut-Brain Axis

“…Experimentally, the impact of peripheral immune challenge on brain function and behaviour can be modelled by systemic administration of LPS or Bacille Calmette-Guérin [18,19,106,108]. The signalling pathways whereby peripheral immune challenge alters brain mechanisms involve proinflammatory cytokines such as interleukin-6, tumour necrosis factor-alpha and interferon-gamma, which reach the brain via the circulation but also excite vagal afferent neurons and lead to the expression of cytokines by cerebral microglial cells and astrocytes [18,19,[106][107][108].…”