Summary Disease tolerance is the ability of the host to reduce the impact of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (“endotoxin tolerance”). We found that a first exposure to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase 2, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR complex-associated Src kinase activity promoted IDO1 phosphorylation and signaling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in gram-negative and gram-positive infections, pointing to a role for AhR in contributing to host fitness.

Dopamine (DA)-containing projections to the cerebral cortex are considered to play an important role in cognitive processes. Using a recently developed monoclonal antiserum directed against DA and an antibody directed against tyrosine hydroxylase in combination with Golgi impregnation and electron microscopy, we have observed that DA and tyrosine hydroxylase afferents establish symmetric membrane specializations with the soma, dendritic shafts, and spines of identified pyramidal cells in the prefrontal, cingulate, and motor cortex of primates. The axospinous contacts invariably formed part of a synaptic complex in which the dendritic spine of a pyramidal neuron was the target of both a DApositive symmetric and an unlabeled asymmetric bouton. This arrangement allows direct DA modulation of the overall excitability of cortical projection neurons by altering local spine responses to excitatory inputs. Dopamine (DA) has been implicated in a wide range of cognitive and affective behaviors and its importance for diseases affecting thought processes, such as schizophrenia, has been repeatedly stressed (1). Although the highest brain concentrations of DA are found in the caudate nucleus, this neurotransmitter is also present in the cerebral cortex, particularly in areas like the prefrontal cortex (2, 3) that are involved in emotional and cognitive processing. In rodents (4) and nonhuman primates (5), experimental depletion of DA has, in fact, been shown to result in cognitive deficits.A more complete understanding of DA's role in cortical function will require detailed knowledge about the cortical targets of DA afferents. The DA innervation of the primate prefrontal cortex has so far been studied only at the light microscopic level (6, 7). These studies reveal rich plexuses of DA-containing fibers in specific layers of the prefrontal cortex in monkeys (6, 7) and humans (8). However, definitive information on the postsynaptic structures innervated by these fibers is lacking. Accordingly, the goal of the present study was to provide ultrastructural data on the nature, distribution, and postsynaptic targets of dopaminergic boutons in the primate neocortex. We have used a recently available monoclonal antiserum directed against DA developed in one of our laboratories (9) as well as an antibody to its rate-limiting enzyme, tyrosine hydroxylase (TH) (10), and combined these methods with Golgi impregnation and electron microscopy (EM) to visualize DA synapses in the primate cortex. MATERIALS AND METHODSFive adult male rhesus monkey (Macaca mulatta) were deeply anesthetized and transcardially perfused using the fixative of Van Eden et al. (11) for DA and that of Somogyi and Takagi (12) for TH. After perfusion, blocks of tissue were taken from the dorsal bank of the principal sulcus (Walker's area 46), the anterior cingulate gyrus (Brodmann's area 24), and the primary motor cortex (Brodmann's area 4) (see Fig. 1) and were then sectioned perpendicular to the pial surface on a vibratome or cryostat. The sections were stai...

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