Effects of chronic antidepressant coadministration on acquisition, memory consolidation, and neurogenesis after repeated Lipopolysaccharide administration

Abstract

Neurogenesis within the hippocampus along with learning/memory are altered by many factors including stress, immune activation, and depression. Chronic dosing with antidepressants has been shown to alleviate many of the symptoms following immune activation. To examine interactions between depression, immune activation, and cognitive dysfunction more closely, the following experiments were conducted. Generally, the current set of experiments examined the effects that repeated bolus injections of LPS have on spatial learning in MWM, memory consolidation in both CFC and MWM, and hippocampal neurogenesis.^The effects of chronic (all experiments), or acute imipramine (Experiments 3 and 4) were also examined to see if they influenced the hypothesized LPS-induced decrements.^Experiment 1 looked at the effects of chronic imipramine (10mg/kg for 21 days) and 4 bolus injections of LPS (1mg/kg) have on Morris water maze acquisition, and hippocampal neurogenesis after a 3-day break (past the point that central or peripheral cytokines are present). Experiment 2 addressed the effects that chronic imipramine and bolus injections of LPS have on neurogenesis after a 3-day break (i.e., prior to any potential effects of behavioral testing). Experiment 3 examined the effects acute verses chronic imipramine coadministration with a single acute bolus injection of LPS (1mg/kg) on memory consolidation in Morris water maze. Experiment 4 was much like Experiment 3 but instead of MWM, a CFC paradigm was used.^Our hypotheses were that LPS-treated animals would show acquisition deficits in MWM, memory consolidation deficits in both MWM and CFC, and show a decline in neurogenesis (at both the initial and survival timepoints).^Moreover, we hypothesized that chronic but not acute administration of imipramine would ameliorate all decrements in MWM, CFC, and neurogenesis as the result from repeated or acute bolus LPS administration. The data revealed that LPS did not show the hypothesized effects nor did imipramine in all four studies. We attribute our negative findings may be due to endotoxin tolerance, monocytic priming, TLR-4 down-regulation and/or stress from both behavioral testing and repeated injections.