10 research outputs found
A Role for the Chemokine RANTES in Regulating CD8 T Cell Responses during Chronic Viral Infection
RANTES (CCL5) is a chemokine expressed by many hematopoietic and non-hematopoietic cell types that plays an important role in homing and migration of effector and memory T cells during acute infections. The RANTES receptor, CCR5, is a major target of anti-HIV drugs based on blocking viral entry. However, defects in RANTES or RANTES receptors including CCR5 can compromise immunity to acute infections in animal models and lead to more severe disease in humans infected with west Nile virus (WNV). In contrast, the role of the RANTES pathway in regulating T cell responses and immunity during chronic infection remains unclear. In this study, we demonstrate a crucial role for RANTES in the control of systemic chronic LCMV infection. In RANTES−/− mice, virus-specific CD8 T cells had poor cytokine production. These RANTES−/− CD8 T cells also expressed higher amounts of inhibitory receptors consistent with more severe exhaustion. Moreover, the cytotoxic ability of CD8 T cells from RANTES−/− mice was reduced. Consequently, viral load was higher in the absence of RANTES. The dysfunction of T cells in the absence of RANTES was as severe as CD8 T cell responses generated in the absence of CD4 T cell help. Our results demonstrate an important role for RANTES in sustaining CD8 T cell responses during a systemic chronic viral infection
Selective Enhancement of Dopamine Release in the Ventral Pallidum of Methamphetamine-Sensitized Mice
Drugs of abuse induce
sensitization, which is defined as enhanced
response to additional drug following a period of withdrawal. Sensitization
occurs in both humans and animal models of drug reinforcement and
contributes substantially to the addictive nature of drugs of abuse,
because it is thought to represent enhanced motivational wanting for
drug. The ventral pallidum, a key member of the reward pathway, contributes
to behaviors associated with reward, such as sensitization. Dopamine
inputs to the ventral pallidum have not been directly characterized.
Here we provide anatomical, neurochemical, and behavioral evidence
demonstrating that dopamine terminals in the ventral pallidum contribute
to reward in mice. We report subregional differences in dopamine release,
measured by <i>ex vivo</i> fast-scan cyclic voltammetry:
rostral ventral pallidum exhibits increased dopamine release and uptake
compared with caudal ventral pallidum, which is correlated with tissue
expression of dopaminergic proteins. We then subjected mice to a methamphetamine-sensitization
protocol to investigate the contribution of dopaminergic projections
to the region in reward related behavior. Methamphetamine-sensitized
animals displayed a 508% and 307% increase in baseline dopamine release
in the rostral and caudal ventral pallidum, respectively. Augmented
dopamine release in the rostral ventral pallidum was significantly
correlated with sensitized locomotor activity. Moreover, this presynaptic
dopaminergic plasticity occurred only in the ventral pallidum and
not in the ventral or dorsal striatum, suggesting that dopamine release
in the ventral pallidum may be integrally important to drug-induced
sensitization
The Pyramid of Nonprofit Responsibility: The Institutionalization of Organizational Responsibility Across Sectors
acceptedVersio