Cerebral Response to Peripheral Challenge with a Viral Mimetic

Abstract

It has been well established that peripheral inflammation resulting from microbial infections profoundly alters brain function. This review focuses on experimental systems that model cerebral effects of peripheral viral challenge. The most common models employ the induction of the acute phase response (APR) via intraperitoneal injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC). The ensuing transient surge of blood-borne inflammatory mediators induces a “mirror” inflammatory response in the brain characterized by the upregulated expression of a plethora of genes encoding cytokines, chemokines and other inflammatory/stress proteins. These inflammatory mediators modify the activity of neuronal networks leading to a constellation of behavioral traits collectively categorized as the sickness behavior. Sickness behavior is an important protective response of the host that has evolved to enhance survival and limit the spread of infections within a population. However, a growing body of clinical data indicates that the activation of inflammatory pathways in the brain may constitute a serious comorbidity factor for neuropathological conditions. Such comorbidity has been demonstrated using the PIC paradigm in experimental models of Alzheimer's disease, prion disease and seizures. Also, prenatal or perinatal PIC challenge has been shown to disrupt normal cerebral development of the offspring resulting in phenotypes consistent with neuropsychiatric disorders, such as schizophrenia and autism. Remarkably, recent studies indicate that mild peripheral PIC challenge may be neuroprotective in stroke. Altogether, the PIC challenge paradigm represents a unique heuristic model to elucidate the immune-to-brain communication pathways and to explore preventive strategies for neuropathological disorders.

Neurobehavioral comorbidities of epilepsy: Role of inflammation

“…Many types of peripheral inflammatory processes generate circulating inflammatory cytokines, but for the most part these do not appear to enter the brain. Rather, they create a ‘mirror‐like’ inflammation in the brain through signaling via peripheral afferent nerves or at the blood–brain barrier to cause activation of microglial and other brain inflammatory cells that then synthesize de novo cytokines in the brain (reviewed in Riazi et al, D'Mello and Swain, and Konat). Pioneering work by Vezzani and others has established unequivocally that cytokines and other immune activators in the brain exacerbate brain excitability and seizure generation (reviewed in Vezzani et al …”

CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-α

“…Double-stranded RNA is produced during viral replication 15 and recognized by the mammalian innate immune system primarily through pathogen recognition receptors (PRRs), such as toll-like receptor 3 (TLR3) 16 . The binding of poly(I:C) to PRRs leads to the expression of a series of immune mediators (such as type 1 interferons (IFNs), pro-inflammatory cytokines and chemokines), a process that efficiently mimics the acute phase of viral infection 17 . Similar to that observed in viral infection, peripheral immune stimulation through poly(I:C) has been shown to cause behavioral and cognitive impairments in both developing and adult animals 18 , 19 , 20 , 21 ; however, the underlying mechanisms remain unclear.…”

Presence of mother prompts dissociation of sickness behavior, fever, and hypothalamic gene expression in lipopolysaccharide‐injected guinea pig pups

“…Some sickness behaviors (e.g., shivering, seeking warmth, hunched posture with piloerection) generate or conserve body heat, while others (e.g., lethargy, somnolence) conserve non‐thermal energy. Diverse neuroimmune signaling pathways in the brain stem, limbic, and cortical regions appear to mediate sickness behaviors (Konat, ; Konsman, Luheshi, Bluthé, & Dantzer, ; Maes et al, ) whereas proinflammatory cytokine and prostaglandin signaling affecting the hypothalamus is critical for generating the fever response (Conti, Tabarean, Andrei, & Bartfai, ; Saper, Romanovsky, & Scammell, ).…”