Dopaminergic modulation of sensitivity to immediate and delayed punishment during decision-making.

Effective decision-making involves careful consideration of all rewarding and aversive outcomes. Importantly, negative outcomes often occur later in time, leading to underestimation, or "discounting," of these consequences. Despite the frequent occurrence of delayed outcomes, little is known about the neurobiology underlying sensitivity to delayed punishment during decision-making. The Delayed Punishment Decision-making Task (DPDT) addresses this by assessing sensitivity to delayed versus immediate punishment in rats. Rats initially avoid punished reinforcers, then select this option more frequently when delay precedes punishment. We used DPDT to examine effects of acute systemic administration of catecholaminergic drugs on sensitivity to delayed punishment in male and female adult rats. Cocaine did not affect choice of rewards with immediate punishment but caused a dose-dependent reduction in choice of delayed punishment. Neither activation nor blockade of D1-like dopamine receptor affected decision-making, but activation of D2-like dopamine receptors reduced choice of delayed punishment. D2 blockade did not attenuate cocaine's effects on decision-making, suggesting that cocaine's effects are not dependent on D2 receptor activation. Increasing synaptic norepinephrine via atomoxetine also reduced choice of delayed (but not immediate) punishment. Notably, when DPDT was modified from ascending to descending pre-punishment delays, these drugs did not affect choice of delayed or immediate punishment, although high-dose quinpirole impaired behavioral flexibility. In summary, sensitivity to delayed punishment is regulated by both dopamine and norepinephrine transmission in task-specific fashion. Understanding the neurochemical modulation of decision-making with delayed punishment is a critical step toward treating disorders characterized by aberrant sensitivity to negative consequences.

A dual-pathway architecture enables chronic stress to promote habit formation.

Chronic stress can change how we learn and, thus, how we make decisions by promoting the formation of inflexible, potentially maladaptive, habits. Here we investigated the neuronal circuit mechanisms that enable this. Using a multifaceted approach in male and female mice, we reveal a dual pathway, amygdala-striatal, neuronal circuit architecture by which a recent history of chronic stress shapes learning to disrupt flexible goal-directed behavior in favor of inflexible habits. Chronic stress inhibits activity of basolateral amygdala projections to the dorsomedial striatum to impede the action-outcome learning that supports flexible, goal-directed decisions. Stress also increases activity in direct central amygdala projections to the dorsomedial striatum to promote the formation of rigid, inflexible habits. Thus, stress exerts opposing effects on two amygdala-striatal pathways to promote premature habit formation. These data provide neuronal circuit insights into how chronic stress shapes learning and decision making, and help understand how stress can lead to the disrupted decision making and pathological habits that characterize substance use disorders and other psychiatric conditions.

The survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5.

B cells have essential functions in multiple sclerosis and in its mouse model, experimental autoimmune encephalomyelitis, both as drivers and suppressors of the disease. The suppressive effects are driven by a regulatory B cell (Breg) population that functions, primarily but not exclusively, via the production of IL-10. However, the mechanisms modulating IL-10-producing Breg abundance are poorly understood. Here we identify SLAMF5 for controlling IL-10+ Breg maintenance and function. In EAE, the deficiency of SLAMF5 in B cells causes accumulation of IL10+ Bregs in the central nervous system and periphery. Blocking SLAMF5 in vitro induces both human and mouse IL-10-producing Breg cells and increases their survival with a concomitant increase of a transcription factor, c-Maf. Finally, in vivo SLAMF5 blocking in EAE elevates IL-10+ Breg levels and ameliorates disease severity. Our results suggest that SLAMF5 is a negative moderator of IL-10+ Breg cells, and may serve as a therapeutic target in MS and other autoimmune diseases.

SLAMF9 regulates pDC homeostasis and function in health and disease.

SLAMF9 belongs to the conserved lymphocytic activation molecule family (SLAMF). Unlike other SLAMs, which have been extensively studied, the role of SLAMF9 in the immune system remained mostly unexplored. By generating CRISPR/Cas9 SLAMF9 knockout mice, we analyzed the role of this receptor in plasmacytoid dendritic cells (pDCs), which preferentially express the SLAMF9 transcript and protein. These cells display a unique capacity to produce type I IFN and bridge between innate and adaptive immune response. Analysis of pDCs in SLAMF9-/- mice revealed an increase of immature pDCs in the bone marrow and enhanced accumulation of pDCs in the lymph nodes. In the periphery, SLAMF9 deficiency resulted in lower levels of the transcription factor SpiB, elevation of pDC survival, and attenuated IFN-α and TNF-α production. To define the role of SLAMF9 during inflammation, pDCs lacking SLAMF9 were followed during induced experimental autoimmune encephalomyelitis. SLAMF9-/- mice demonstrated attenuated disease and delayed onset, accompanied by a prominent increase of immature pDCs in the lymph node, with a reduced costimulatory potential and enhanced infiltration of pDCs into the central nervous system. These results suggest the crucial role of SLAMF9 in pDC differentiation, homeostasis, and function in the steady state and during experimental autoimmune encephalomyelitis.