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. 2008 Sep;33(10):2341-51.
doi: 10.1038/sj.npp.1301649. Epub 2007 Dec 12.

Aging Exacerbates Depressive-Like Behavior in Mice in Response to Activation of the Peripheral Innate Immune System

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Aging Exacerbates Depressive-Like Behavior in Mice in Response to Activation of the Peripheral Innate Immune System

Jonathan P Godbout et al. Neuropsychopharmacology. .
Free PMC article

Abstract

Exposure to peripheral infections may be permissive to cognitive and behavioral complications in the elderly. We have reported that peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes an exaggerated neuroinflammatory response and prolonged sickness behavior in aged BALB/c mice. Because LPS also causes depressive behavior, the purpose of this study was to determine whether aging is associated with an exacerbated depressive-like response. We confirmed that LPS (0.33 mg/kg intraperitoneal) induced a protracted sickness response in aged mice with reductions in locomotor and feeding activities 24 and 48 h postinjection, when young adults had fully recovered. When submitted to the forced swim test 24 h post-LPS, both young adult and aged mice exhibited an increased duration of immobility. However, when submitted to either the forced swim test or the tail suspension test 72 h post-LPS, an increased duration of immobility was evident only in aged mice. This prolonged depressive-like behavior in aged LPS-treated mice was associated with a more pronounced induction of peripheral and brain indoleamine 2,3-dioxygenase and a markedly higher turnover rate of brain serotonin (as measured by the ratio of 5-hydroxy-indoleacetic acid over 5-hydroxy-tryptamine) compared to young adult mice at 24 post-LPS injection. These results provide the first evidence that age-associated reactivity of the brain cytokine system could play a pathophysiological role in the increased prevalence of depression observed in the elderly.

Conflict of interest statement

DISCLOSURE/CONFLICT OF INTEREST

The authors declare that there are no actual or potential conflicts of interest. The authors affirm that there are no financial, personal, or other relationships with other people or organizations that have inappropriately influenced or biased their research.

Figures

Figure 1
Figure 1
Aging prolonged lipopolysaccharide (LPS)-induced deficits in locomotor activity, food intake, and body weight. Young adult and aged mice were injected i.p. with either saline or LPS and (a) locomotor activity, (b) food intake, and (c) body weight were measured at 0, 24, 48, and 72 h after LPS. Bars represent the mean ± SEM (n = 9). Means with different letters (a, b, c, or d) are significantly different (P<0.05) from each other. Bars denoted with the same letter (ie a) are equal to other bars denoted with the same letter (a) and are significantly different from bars denoted with different letters: (b), (c), or (d). Moreover, bars denoted with multiple letters (ie a, b) are significantly different only from bars denoted with a single different letter (c) and (d).
Figure 2
Figure 2
Depressive-like behavior was prolonged in aged mice 72 h following peripheral lipopolysaccharide (LPS) injection. Young adult and aged mice were injected i.p. with either saline or LPS and exposed to the forced swim test (a) 24 or (b) 72 h later. Bars represent the mean ± SEM duration of immobility (n = 8 at 24h and n = 14 at 72 h). In (a) and (b), means with different letters (a or b) are significantly different (P<0.05) from each other. (c) Young adult and aged mice were injected i.p. with either saline or LPS and exposed to the tail suspension test 72 h later. Bars represent the mean ± SEM duration of immobility (n = 6). Means with different letters (a or b) are significantly different (P<0.05) from each other.
Figure 3
Figure 3
Increased tryptophan (TRP) metabolism in the plasma of aged mice in response to peripheral lipopolysaccharide (LPS) injection. (a) Young adult and aged mice were injected i.p. with either saline or LPS and TRP and kynurenine (KYN) were measured in plasma collected 24h later. The table represents the mean ± SEM (n = 6). Means with different letters (a or b) are significantly different (P<0.05) from each other. (b) Metabolism of TRP as measured by the ratio of KYN to TRP. Bars represent mean ± SEM (n = 6). Means with (*) are significantly different (P<0.05).
Figure 4
Figure 4
Increased indoleamine 2,3-dioxygenase (IDO) mRNA expression in brain of aged mice after peripheral lipopolysaccharide (LPS) injection. Young adult and aged mice were injected i.p. with either saline or LPS and IDO mRNA was measured by real-time RT–PCR in whole brain collected at (a) 4 or (b) 24 h later. Bars represent the mean ± SEM (n = 6). Means with (*) are significantly different (P < 0.05).
Figure 5
Figure 5
Elevated indoleamine 2,3-dioxygenase (IDO) enzymatic activity in brain of aged mice in response to peripheral lipopolysaccharide (LPS) injection. Young adult and aged mice were injected i.p. with either saline or LPS and IDO activity was measured in whole brain collected 24 h later. Bars represent the mean ± SEM (n = 6). Means with (*) are significantly different (P<0.05).
Figure 6
Figure 6
Increased serotonin (5-HT) turnover in the brain of aged mice in response to peripheral lipopolysaccharide (LPS) injection. (a) Young adult and aged mice were injected i.p. with either saline or LPS and 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan (TRP) were measured in whole brain collected 24h later. The table represents the mean ± SEM (n = 6). Means with different letters (a, b, or c) are significantly different (P<0.05) from each other. (b) Turnover rate of brain 5-HT as measured by the ratio of 5-HIAA to 5-HT. Bars represent mean ± SEM (n = 6). Means with different letters (a, b, or c) are significantly different (P<0.05) from each other.
Figure 7
Figure 7
Elevated interleukin (IL)-6 in the plasma of aged mice in response to peripheral lipopolysaccharide (LPS) injection. Young adult and aged mice were injected i.p. with either saline or LPS and IL-6 was measured in plasma collected 24 h later. Bars represent the mean ± SEM (n = 6). There was no detectable IL-6 (n.d.) in the plasma of saline-treated mice. Means with (*) are significantly different (P<0.05).
Figure 8
Figure 8
Proposed mechanism for the depressive-like effects of lipopolysaccharide (LPS) in the aged. In the aged, peripheral immune activation by LPS results in an exaggerated production of proinflammatory cytokines including interleukin (IL)-1 β (IL-1 β), interferon-γ (IFNγ), and IL-6 in the brain. These inflammatory cytokines induce the transcription and enzymatic activity of indoleamine 2,3-dioxygenase (IDO). IDO diverts tryptophan (TRP) from synthesis of 5-hydroxytryptophan (5-HTP) and 5-hydroxytryptamine (5-HT) to the generation of TRP metabolites including kynurenine and quinolinic acid that act on glutamate receptors. This impacts both serotonergic and glutamatergic neurotransmission. The disruption in 5-HT metabolism may lead to a higher turnover of 5-HT with a reduction in 5-HT synthesis and increase in 5-HT degradation by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid (5-HIAA). The inflammatory-associated imbalance between serotonergic and glutamatergic neurotransmission ultimately causes protracted depressive-like behavior in the aged.

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