Two-hit model of postintensive care syndrome induced by lipopolysaccharide challenge and subsequent chronic unpredictable stress in mice

Parvabumin interneuron-mediated hippocampal network activity disruption in a two-hit model with relevance to postintensive care syndrome: prevention by fluoxetine

“…The combined stress protocol was selected as we described previously [9]. It is based on a two-hit conception, in which LPS injection as the first hit and subsequent modified chronic unpredictable stress as the second hit.…”

“…For stress exposure, we selected certain relevant stressors that are frequently existed in critically ill patients living in the ICU. As our previous study described [9], animals were housed singly and exposed to four of the following stressors daily in a random order for 21 consecutive days ( Table 1). The control, non-stressed mice groups were reared under similar conditions but received no stressors.…”

“…Accumulating evidence has documented that corticolimbic GABAergic dysfunction is implicated in the etiology of mood disorders, including schizophrenia, depression, and other related neuropsychiatric diseases [11][12][13][14]. Thus, the present study investigated whether GABAergic interneurons and its relevant neural activities are affected by our recently established animal model of PICS [9]. In addition, we examined whether pharmacological intervention with serotonergic system by fluoxetine, a selective serotonin reuptake inhibitor [15], could attenuate the neural and behavioral disturbances of PICS.…”

“…An earlier study reported that nearly 50% of patients experience symptoms of depression, anxiety, post-traumatic stress disorder, and cognitive impairment, which may persist for years [8]. Based on these findings, we recently have developed one clinically relevant animal model of PICS based on two-hit conception [9]. The "two-hit" hypothesis states that initial insult sensitizes the vulnerable brain to subsequent stress so that the two hits have synergistic toxic effects.…”

“…The "two-hit" hypothesis states that initial insult sensitizes the vulnerable brain to subsequent stress so that the two hits have synergistic toxic effects. Because bacterial infection remains the leading cause of ICU admission by epidemiological study [10], we thus subjected animals to lipopolysaccharide (LPS) injection as the first hit and subsequent chronic unpredictable stress as the second hit [9]. This model displayed reproducible anxiety-and depression like behavior and cognitive impairments, which mimics clinical features of human PICS [9].…”