Chronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal networks

Abstract

Growing evidence suggests that adult-born granule cells integrate into hippocampal networks and are required for proper cognitive function. Although neuroinflammation is involved in many disorders associated with cognitive impairment, it remains unknown whether it impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. Under similar behavioral conditions, exploration-induced expression of the immediate-early gene Arc in hippocampal cells has been linked to cellular activity observed by electrophysiological recording. By detecting exploration-induced Arc protein expression, we investigated whether neuroinflammation alters the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. Neuroinflammation was induced in rats by intra-cerebroventricular infusion of lipopolysaccharide for 28 days. Animals received bromodeoxyuridine injections starting on day 29 (five days) and were euthanized two months later. Persistent lipopolysaccharide-induced neuroinflammation was reliably detected by microglial activation in the hippocampus. Neuroinflammation did not impact the number of adult-born neurons but did alter their migration pattern through the granule cell layer. There was a positive correlation between the density of activated microglia and alterations in the fraction of existing granule neurons expressing Arc, suggesting that neuroinflammation induced a long-term disruption of hippocampal network activity. The proportion of adult-born neurons expressing behaviorally induced Arc was significantly lower in lipopolysaccharide-treated rats than in controls. This observation supports the fact that neuroinflammation significantly impacts adult-born neurons recruitment into hippocampal networks encoding spatial information.

Novel connection between newborn granule neurons and the hippocampal CA2 field

“…Although electrophysiological or optogenetics approaches will be needed to demonstrate the newborn granule neuron-CA2 functional connectivity and whether these connections could affect hippocampal behavior, these experiments provide further confirmation of their existence and possibility of function. Indeed, our data suggest that both neuroprotective and deleterious stimuli modulate this connection simultaneously to both AHN and hippocampal-dependent memory regulation (Belarbi et al, 2012;Cassilhas et al, 2012). Our findings reveal a novel mechanism of hippocampal plasticity, which may have important functional and behavioral consequences.…”

Stem Cell Transplantation Reverses Chemotherapy-Induced Cognitive Dysfunction

“…For all cohorts, stem cell grafting reduced significantly, the number of activated microglia compared to CYP treated cohorts, and showed a trend toward reduced microglia compared to controls. Thus, the capability of grafted stem cells to attenuate neuroinflammation provides one plausible explanation for their beneficial effects in the irradiated brain, and likely involves the quenching of chemokine signaling in the brain to dampen the recruitment and/or activation of resident microglia (32,33). …”

Behavioral and monoamine perturbations in adult male mice with chronic inflammation induced by repeated peripheral lipopolysaccharide administration

“…Chronic central LPS challenge models have successfully replicated key components of the characteristic neurodegenerative pattern seen in PD and have demonstrated significant early microglial activation followed by delayed and time-dependent nigral dopaminergic neuron degeneration [33, 34] and a long-term disruption of AD-relevant hippocampal network activity [35, 36]. Peripheral administration of a single high dose (5 mg/kg) of LPS resulted in long-lasting neuroinflammation and nigral dopaminergic neurodegeneration [37].…”