RESUMO
Peripherally administered inflammatory stimuli, such as lipopolysaccharide (LPS), induce the synthesis and release of proinflammatory cytokines and chemokines in the periphery and the central nervous system, and trigger a variety of neurobiological responses. Indeed, prior reports indicate that peripheral LPS administration in rats disrupts contextual fear memory consolidation processes, potentially due to elevated cytokine expression. We used a similar, but partially olfaction-based, contextual fear conditioning paradigm to examine the effects of LPS on memory consolidation and reconsolidation in mice. Additionally, interleukin-1ß (IL-1ß), brain-derived neurotrophic factor (BDNF), and zinc finger (Zif)-268 mRNA expression in the hippocampus and the cortex, along with peripheral cytokines and chemokines, were assessed. As hypothesized, LPS administered immediately or 2 h, but not 12 h, post-training impaired memory consolidation processes that support the storage of the conditioned contextual fear memory. Additionally, as hypothesized, LPS administered immediately following the fear memory trace reactivation session impaired memory reconsolidation processes. Four hours post-injection, both central cytokine and peripheral cytokine and chemokine levels were heightened in LPS-treated animals, with a simultaneous decrease in BDNF, but not Zif-268, mRNA. Collectively, these data reinforce prior work showing LPS- and cytokine-related effects on memory consolidation, and extend this work to memory reconsolidation.
Assuntos
Endotoxinas/farmacologia , Lipopolissacarídeos/farmacologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Quimiocinas/biossíntese , Condicionamento Operante/efeitos dos fármacos , Citocinas/biossíntese , Discriminação Psicológica/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Medo/psicologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Interleucina-1beta/biossíntese , Aprendizagem/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Redução de Peso/efeitos dos fármacosRESUMO
Poly I:C, a viral mimetic, is a synthetic double-stranded RNA that is known to cause activation of the innate immune system, resulting in the emergence of sickness behaviors in otherwise healthy adult mice. However, the way in which such effects of poly I:C manifest themselves in aged mice are not currently known. We hypothesized that poly I:C administration would lead to burrowing deficits, but that these deficits would be exaggerated in aged subjects (19-months old) compared to young subjects (4-months old) that received the same dose. In order to associate these behavioral decrements with inflammatory factors, we measured mRNA expression of IL-1ß and IL-6 in the hippocampus and parietal cortex and peripheral protein expression of IL-6, TNF-α, MCP-1, MIP-1α, and IL-1ß in the serum. After exposure to poly I:C, aged subjects demonstrated significant impairments in their burrowing behavior, compared to younger subjects administered the same dose. These behavioral decrements coincided with increased expression of IL-6 among animals exposed to poly I:C and increased expression of IL-1ß among aged animals in the hippocampus and cortex. Furthermore, we observed an increase in peripheral poly I:C-induced IL-6, TNF-α, MCP-1, and MIP-1α, but not IL-1ß. These results indicate that virus-mediated immune activation in the aging body can lead to increased sickness behavior. Furthermore, these data indicated a possible dissociation between the effects of poly I:C on sickness behaviors in aged mice, with central expression of IL-1ß potentially playing a role in age-related impairments.