Elsevier

Biological Psychiatry

Volume 60, Issue 8, 15 October 2006, Pages 803-811
Biological Psychiatry

Original article
Depressive Behavior in Mice Due to Immune Stimulation is Accompanied by Reduced Neural Activity in Brain Regions Involved in Positively Motivated Behavior

https://doi.org/10.1016/j.biopsych.2006.04.020Get rights and content

Background

Immune stimulation inhibits positively motivated behavior and induces depressive illness. To help clarify the mechanism of these effects, neural activity in response to a positive stimulus was examined in brain regions associated with positively motivated activity defined on the basis of prior behavioral studies of central α1-adrenoceptor action.

Methods

Mice pretreated with either lipopolysaccharide or, for comparison, reserpine were exposed to a motivating stimulus (fresh cage) and subsequently assayed for fos expression and mitogen-activated protein kinase (MAPK) phosphorylation, two measures associated with α1-adrenoceptor-dependent neural activity, in several positive-activity-related (motor, piriform, cingulate cortex, nucleus accumbens, locus coeruleus) and stress-related brain regions (paraventricular hypothalamus, bed nucleus stria terminalis).

Results

Both lipopolysaccharide and reserpine pretreatment abolished fresh cage-induced fos expression and MAPK activation in the positive activity-related brain regions but enhanced these measures in the stress-related areas.

Conclusions

The results support the hypothesis that immune activation reduces α1-adrenoceptor-related signaling and neural activity in brain regions associated with positive activity while it increases these functions in stress-associated areas. It is suggested that neural activities of these two types of brain regions are mutually antagonistic and that a reciprocal shift toward the stress regions is a factor in the loss of positively motivated behaviors in sickness behavior and depressive illness.

Section snippets

Subjects

Swiss Webster male mice, 8–10 weeks old, were subjects. The animals were housed singly with nesting material in standard mouse cages at a room temperature of 22 ± 1°C under a 12/12-hour light/dark cycle (lights on 0500 hours) for 5 days before all procedures. Food and water were available ad libitum.

Experiment 1. Effect of LPS on Exploration of Fresh Cage

All experiments were performed between 0800 hours and 1100 hours to obtain low baseline values for fos and MAPK responses. Mice received an i.p. injection of either vehicle (water) or LPS (20 or 100

Exp. 1. Behavior

The effect of LPS on exploration of the fresh cage is shown in Figure 2. As the two measures of gross movements and number of cage crosses were highly correlated (r = .98, p < .001) only the former measure is presented. Vehicle injected animals showed a high and sustained level of activity lasting 90–120 min. Lipopolysaccharide produced a dose-dependent reduction of gross movements for the duration of the experiment (overall F2,12 = 44.25, p < .001, linear with dose, F1,12 = 86.92, p < .001).

Effects of LPS and Reserpine

Discussion

The current results show that LPS pretreatment blocks fresh cage-induced neural activation in brain regions involved in α1-adrenoceptor-induced behavioral activation. In agreement with previous studies cited above, the fresh cage stimulus was found to induce marked fos expression in the M2, Pir and Cing cortices, and NAc regions in which α1-adrenoceptors stimulate gross behavioral activity and local fos expression. Fresh cage exposure also increased fos expression in the PVH and BNST although

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