Small amounts of
Sistance in the field and/or the laboratory.
Small amounts of lipopolysaccharide (LPS) from invading bacteria are one of the first signals detected by the body upon infection, and detection of LPS primes the immune system to mount a defence. Following the onset of a typical infection, individuals display a coordinated set of behavioral conditions, known collectively as sickness behavior [1,2,3], that reflect a normal acute Tartrazine web response to inflammation. The profound changes which constitute sickness behavior include loss of motivation for food and drink, diminished social interaction, fatigue, irritability, depression and cognitive impairment [3]. The expression of sickness behavior relies on motivational reorganization of priorities, which are dependent on the biological state of the animal and therefore can lead to diverse behavioral outcomes. Separate from this, sickness behavior also includes an element of altered motility, which is characteristic in sick animals. Under some circumstances, the initial inflammatory response can become uncontrolled and ultimately lead to other deleterious effects including prolonged inflammation and cytokine release which is known to contribute to CNS dysfunction, chronic depressive disorders and neurodegenerative processes [2,4,5]. Although the CNS actions of cytokines have been implicated in sickness behavior [6,7,8], the mechanismsin the brain that trigger this behavioral response are not well understood. The Toll-like receptor 4 (TLR4) and its potent ligand LPS, represent one of the first and best characterized ligand and receptor combinations of the innate immune system [9,10]. TLR4 receptors are expressed on microglia in the CNS and on cells of the immune system throughout the body [2,11]. Systemic LPS acts on the CNS through Mirin site several parallel pathways (reviewed in [11]) including: 1) activation of TLR4 on microglia in regions where the blood brain barrier (BBB) is permeable (e.g. area postrema and circumventricular organ [12]; 2) activation of perivascular cells and endothelial cells of blood vessels in the brain [13]; 3) stimulation of the afferent vagal nerves; and 4) transport across the BBB of cytokines generated by peripheral cells [14]. There is however, disagreement in the literature as to what extent each of these pathways contributes to the effects of the LPS driven inflammatory cascade. Here we show that Tat-coupled interfering peptides block TLR4 signaling to second messengers and subsequent cytokine production normally induced by LPS, block morphological changes in microglia induced by LPS, and also 
prevent LPSinduced sickness behavior. We used multiple indices of sickness behavior including various measures of motor performance (open field and modified SHIRPA screen), as well as indices ofMicroglia and Sickness Behaviormotivation including titrated intracranial self stimulation (ICSS). Remarkably, these newly synthesized peptides prevent changes in behavior and motivation normally caused by inflammatory stimuli by inhibiting TLR4 signaling. These peptides highlight the roll of 10457188 TLR4 and microglia in sickness behavior, and thus may be of therapeutic value in limiting the deleterious impact of excessive inflammation in specific CNS pathologies.ResultsOur goal was to manipulate the impact of LPS binding to TLR4 in vivo, and ultimately to impact the pathways involved in sickness behavior. Considering that LPS may be acting directly on TLR4 receptors in accessible regions of the CNS and in peri.Small amounts of
Sistance in the field and/or the laboratory.
Small amounts of lipopolysaccharide (LPS) from invading bacteria are one of the first signals detected by the body upon infection, and detection of LPS primes the immune system to mount a defence. Following the onset of a typical infection, individuals display a coordinated set of behavioral conditions, known collectively as sickness behavior [1,2,3], that reflect a normal acute response to inflammation. The profound changes which constitute sickness behavior include loss of motivation for food and drink, diminished social interaction, fatigue, irritability, depression and cognitive impairment [3]. The expression of sickness behavior relies on motivational reorganization of priorities, which are dependent on the biological state of the animal and therefore can lead to diverse behavioral outcomes. Separate from this, sickness behavior also includes an element of altered motility, which is characteristic in sick animals. Under some circumstances, the initial inflammatory response can become uncontrolled and ultimately lead to other deleterious effects including prolonged inflammation and cytokine release which is known to contribute to CNS dysfunction, chronic depressive disorders and neurodegenerative processes [2,4,5]. Although the CNS actions of cytokines have been implicated in sickness behavior [6,7,8], the mechanismsin the brain that trigger this behavioral response are not well understood. The Toll-like receptor 4 (TLR4) and its potent ligand LPS, represent one of the first and best characterized ligand and receptor combinations of the innate immune system [9,10]. TLR4 receptors are expressed on microglia in the CNS and on cells of the immune system throughout the body [2,11]. Systemic LPS acts on the CNS through several parallel pathways (reviewed in [11]) including: 1) activation of TLR4 on microglia in regions where the blood brain barrier (BBB) is permeable (e.g. area postrema and circumventricular organ [12]; 2) activation of perivascular cells and endothelial cells of blood vessels in the brain [13]; 3) stimulation of the afferent vagal nerves; and 4) transport across the BBB of cytokines generated by peripheral cells [14]. There is however, disagreement in the literature as to what extent each of these pathways contributes to the effects of the LPS driven inflammatory cascade. Here we show that Tat-coupled interfering peptides block TLR4 signaling to second messengers and subsequent cytokine production normally induced by LPS, block morphological changes in microglia induced by LPS, and also prevent LPSinduced sickness behavior. We used multiple indices of sickness behavior including various measures of motor performance (open field and modified SHIRPA screen), as well as indices ofMicroglia and Sickness Behaviormotivation including titrated intracranial self stimulation (ICSS). Remarkably, these newly synthesized peptides prevent changes in behavior and motivation normally caused by inflammatory stimuli by inhibiting TLR4 signaling. These peptides highlight the roll of 10457188 TLR4 and microglia in sickness behavior, and thus may be of therapeutic value in limiting the deleterious impact of excessive inflammation in specific CNS pathologies.ResultsOur goal was to manipulate the impact of LPS binding to TLR4 in vivo, and ultimately to impact the pathways involved in sickness behavior. Considering that LPS may be acting directly on TLR4 receptors in accessible regions of the CNS and in peri.
