Tyrosine hydroxylase activity in the superior cervical ganglion during herpes simplex virus infection: Correlation with viral titers and viral antigen

The activity of tyrosine hydroxylase (TH) was measured in the superior cervical ganglion (SCG) of the mouse during herpes simplex virus (HSV) infection. TH activity remained at control levels or actually increased during acute infection at a time when viral titers of SCG homogenates were at their peak and viral antigen was detected in from one-third to one-half of ganglionic neurons. A rapid decline in TH activity followed and coincided with falling viral titers, disappearance of viral antigen and replacement of neurons by inflammatory cells. Immunization partially prevented this reduction of TH activity. In addition, when mice were immunosuppressed by cyclophosphamide, TH activity was relatively preserved early in the course of infection despite high viral titers in the ganglion and the presence of viral antigen and histopathological alterations in nearly 100% of neurons. These results suggest that a cellular 'luxury function', in this case TH activity, can be preserved and perhaps even augmented during neuronal HSV infection. Indeed, activity of this enzyme may persist until late into the acute phase of infection, perhaps up to the point of cell death induced either by immune-mediated or direct virus-induced cell lysis.     

Antinociception produced by receptor selective opioids: modulation of spinal antinociceptive effects by supraspinal opioids

The effect of intracerebroventricular administration of low-antinociceptive doses of selective μ-(DAMGO) or δ-(DPDPE) opioid agonists on the dose-dependent antinociceptive effects produced by intrathecal administration of sequentially increasing doses of selective μ-, δ-, or κ- (U50, 488H) opioid agonists was evaluated, in the rat, using the Randall-Selitto paw-withdrawal test. When DPDPE or U50,488H was administered intrathecally, the low doses of both intracerebroventricular DAMGO and intracerebroventricular DPDPE markedly enhanced the antinociceptive effects of both intrathecal opiods. In contrast, when DAMGO was administered intrathecally, both intracerebroventricular DAMGO and intracerebroventricular DPDPE, administered in low doses, markedly antagonized the antinociceptive effects of the intrathecal opioid. In addition, the intracerebroventricular administration of low-antinociceptive dose of a second μ-opioid agonist, morphiceptin, antagonized the antinociceptive effects of intrathecal morphiceptin. The antagonism of the antinociceptive effects observed with spinal administration of DAMGO is dose-dependent, with the effect observed only at low doses. Furthermore, the antagonism cannot be explained by a reduction in motor deficits produced by intrathecal administration of DAMGO, because there were no differences in motor deficits, measured with an accelerating Rotarod treadmill, between intrathecal DAMGO administered as a single agent or as part of a combination regimen. The differences in antinociceptive effects obtained with the various supraspinal and spinal combinations are discussed in terms of the interactions that may occur between brainstem and spinal opioid receptor sites.     

Stress-induced changes in pathophysiology and interferon gene expression during primary HSV-1 infection

Herpes simplex viruses (HSV) are the cause of the most common clinically recognized herpesvirus infections. The severity and duration of the primary HSV infection have been correlated with the frequency and severity of subsequent recurrences. Reactivation of latent HSV-1 can occur as a result of physical or emotional stress; however, the effects of stress on the modulation of the clinical pathophysiology of primary HSV-1 infections are not well understood. Although it is known that stress can be immunosuppresive, the immunological mechanisms by which stress modulates early immune responses, such as type I interferon gene expression during a primary HSV-1 infection are still not understood. It was hypothesized that due to suppressed early immune responses, stress would increase the severity of a cutaneous primary HSV-1 infection. In this investigation, a cutaneous HSV-1 model in the SKH-1 mouse was characterized and utilized to study the effect of restraint stress on the modulation of the clinical pathophysiology of primary HSV-1. Despite prolonged viral replication at the site of primary infection, restraint stress decreased the clinical severity of primary HSV-1 in the skin of SKH-1 mice. A decrease in type I and type II IFN expression was found in the skin of acutely infected restrained mice when compared to controls at day 3 post-infection using competitive RT-PCR. Using the glucocorticoid-receptor antagonist RU486, IFN-beta and INF-gamma expression were restored in restrained animals to control levels. Treatment with RU486 also increased the clinical severity of the cutaneous infection to control levels in restrained mice. Thus, RST masked the severity of an HSV-1 infection by decreasing its clinical signs while impairing the ability of the host to control viral replication prolonging the infectious period.     

Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms.

The task of defining schizophrenia pathogenesis has fascinated and frustrated researchers for nearly a century. In recent years, unprecedented advances from diverse fields of study have given credence to both viral and developmental theories. This review considers possible mechanisms by which viral and developmental processes may interact to engender schizophrenia. Many of the current controversies in schizophrenia pathogenesis are reviewed in light of the viral hypothesis, including: epidemiological findings and the role of a genetic diathesis, phenotype heterogeneity, abnormalities in excitatory and inhibitory neurotransmitter systems, anomalous cerebral latereralization, and static vs progressive disease. The importance of animal models in elucidating the impact of viral infections on developing neurons is illustrated by recent studies in which neonatal rats are infected with lymphocytic choriomeningitis virus in order to examine alterations in hippocampal circuitry. Finally, consideration is given to a new hypothesis that some cases of schizophrenia could be instigated by a viral infection that disrupts developing inhibitory circuits, consequently unleashing glutamatergic neurotransmission leading to selective excitotoxicity, and a degenerative disease course.     

Stress-induced modulation of instrumental behavior: from goal-directed to habitual control of action

Actions that are directed at achieving pleasant or avoiding unpleasant states are referred to as instrumental. The acquisition of instrumental actions can be controlled by two anatomically and functionally distinct processes: a goal-directed process that is based on the prefrontal cortex and dorsomedial striatum and encodes the causal relationship between an action and the motivational value of the outcome and a dorsolateral striatum-based habit process that learns associations between actions and antecedent stimuli. Here, we review recent research showing that stress modulates the control of instrumental action in a manner that favors habitual over goal-directed action. At the neuroendocrine level, this stress-induced shift towards habit action requires the concerted action of glucocorticoids and noradrenergic arousal and is most likely accompanied by opposite functional changes in the corticostriatal circuits underlying goal-directed and habitual actions. Although generally adaptive, these changes in the control of instrumental action under stress may promote dysfunctional behaviors and the development of psychiatric disorders such as addiction.     

Stress and the anti-influenza immune response: repeated social defeat augments clonal expansion of CD8(+)T cells during primary influenza A viral infection

Social disruption stress (SDR) prior to primary influenza A virus (IAV) infection augments memory to IAV re-challenge in a T cell-specific manner. However, the effect of SDR on the primary anti-viral immune response has not been elucidated. In this study, SDR-infected (INF) mice terminated viral gene expression earlier and mounted an enhanced pulmonary IAV-specific CD8(+)T cell response versus controls. Additionally, SDR-INF mice had a more pro-inflammatory lung profile prior to and during infection and an attenuated corticosterone response. These data demonstrate neuroendocrine modification of the lung microenvironment and increased antigen-specific T cell activation, clonal expansion and viral control in stress-exposed mice.     

Human influenza viral infection in utero increases nNOS expression in hippocampi of neonatal mice

We investigated the role of maternal exposure to human influenza virus (HI) in C57BL/6 mice on day 9 of pregnancy on hippocampal expression of nNOS in day 0 neonates and compared that to sham-infected pups. Qualitative analysis using polyclonal antibody to nNOS showed overall increases in immunoreactivity (IR) in hippocampal and dentate layers of day 0 infected neonates when compared to sham-infected animals. These increases in nNOS immunoreactivity were pronounced in hippocampal plate, intermediate, molecular, subplate, and dentate areas. Quantitative analysis of specific immunogold silver-enhanced nNOS IR via densitometry showed nNOS IR increases of 26–71.6% in all layers, i.e., hippocampal plate (35.1%), dentate area (71.6%), molecular area (43.75%), subplate (45.7%), and intermediate zone (26%) in infected neonatal brains vs. controls. The changes in levels of nNOS expression in hippocampi of neonates born to mothers exposed to HI virus during the second trimester of pregnancy may reflect the potential for glutamatergic excitotoxicity via activation of NMDA receptors in the developing brains of these neonatal mice. Synapse 29:84–88, 1998. © 1998 Wiley-Liss, Inc.     

Stress-induced modulation of the primary cellular immune response to herpes simplex virus infection is mediated by both adrenal-dependent and independent mechanisms

A murine model of herpes simplex virus (HSV) infection was ussed to examine the role of the adrenal gland in restraint stress-induced suppression of viral immunity. Adrenal-dependent mechanisms were important for suppressing the generation of HSV-specific cytotoxic T lymphocytes (CTL) but not the associated diminished lymphadenopathy in response to local HSV infection. While exogenous corticosterone administration alone was unable to suppress lymphadenopathy and CTL generation in adrenalectomized mice, an adrenal-independent mechanism induced by restraints stress functioned in synergy with corticosterone to suppress lymphadenopathy and CTL development. These results suggest that both adrenal-dependent and independent mechanisms cotribute to stress-induced modulation of HSV immunity.     

Syntactic and semantic modulation of neural activity during auditory sentence comprehension

In previous functional neuroimaging studies, left anterior temporal and temporal-parietal areas responded more strongly to sentences than to randomly ordered lists of words. The smaller response for word lists could be explained by either (1) less activation of syntactic processes due to the absence of syntactic structure in the random word lists or (2) less activation of semantic processes resulting from failure to combine the content words into a global meaning. To test these two explanations, we conducted a functional magnetic resonance imaging study in which word order and combinatorial word meaning were independently manipulated during auditory comprehension. Subjects heard six different stimuli: normal sentences, semantically incongruent sentences in which content words were randomly replaced with other content words, pseudoword sentences, and versions of these three sentence types in which word order was randomized to remove syntactic structure. Effects of syntactic structure (greater activation to sentences than to word lists) were observed in the left anterior superior temporal sulcus and left angular gyrus. Semantic effects (greater activation to semantically congruent stimuli than either incongruent or pseudoword stimuli) were seen in widespread, bilateral temporal lobe areas and the angular gyrus. Of the two regions that responded to syntactic structure, the angular gyrus showed a greater response to semantic structure, suggesting that reduced activation for word lists in this area is related to a disruption in semantic processing. The anterior temporal lobe, on the other hand, was relatively insensitive to manipulations of semantic structure, suggesting that syntactic information plays a greater role in driving activation in this area.     

Immune deviation following stress odor exposure: role of endogenous opioids

Olfactory cues can alter immune function. BALB/c mice exposed to odors produced by footshock stressed donor mice have increased antibody responses and increased splenic interleukin (IL)-4 production following immunization relative to recipients of odors from unstressed animals. Here we document that exposure to stress odors results in analgesia that is blocked by the non-selective opioid receptor antagonist naltrexone. The stress odor-induced increase in antigen-driven IL-4 and antibody is also blocked by oral administration of naltrexone. Thus, we provide evidence that immune deviation can occur following a psychosocial stressor, and that the deviation appears to be mediated by endogenous opioid production.     

Stress-induced opioid analgesia and activity in deer mice: sex and population differences

We compared restraint stress-induced opioid, analgesic and locomotory responses of 4 different populations of male and female deer mice, Peromyscus maniculatus artemisiae and P. m. nebrascensis from mainlands, and P. m. angustus and P. m. triangularis from small islands. All of the deer mice displayed immobilization-induced analgesia which was blocked by the prototypical mu-opiate antagonist, naloxone (1.0 mg/kg). In all of the populations males displayed significantly greater levels of analgesia than females. In addition, the levels of opioid-induced analgesia were significantly greater in the insular than in the mainland male and female deer mice. Restraint also induced significant increases in the locomotor activity of the mainland deer mice, while significantly decreasing the activity of the insular animals. Males displayed significantly greater stress-induced changes in locomotor activity than did females. The stress-induced increases in activity were blocked by the delta-opiate antagonist, ICI 154, 129 (10 mg/kg), while the decreases in activity were inhibited by naloxone. These results demonstrate that there are marked sex and population differences in the stress-induced, opioid-mediated responses of deer mice. These 'pharmaco-ecological' findings also suggest that the island-mainland population differences in behavioral responses and ecological characteristics may, in part, be related to differences in the activity of mu-, delta- and possibly other opioid systems.     

Microglia and memory: modulation by early-life infection

The proinflammatory cytokine interleukin-1β (IL-1β) is critical for normal hippocampus (HP)-dependent cognition, whereas high levels can disrupt memory and are implicated in neurodegeneration. However, the cellular source of IL-1β during learning has not been shown, and little is known about the risk factors leading to cytokine dysregulation within the HP. We have reported that neonatal bacterial infection in rats leads to marked HP-dependent memory deficits in adulthood. However, deficits are only observed if unmasked by a subsequent immune challenge [lipopolysaccharide (LPS)] around the time of learning. These data implicate a long-term change within the immune system that, upon activation with the "second hit," LPS, acutely impacts the neural processes underlying memory. Indeed, inhibiting brain IL-1β before the LPS challenge prevents memory impairment in neonatally infected (NI) rats. We aimed to determine the cellular source of IL-1β during normal learning and thereby lend insight into the mechanism by which this cytokine is enduringly altered by early-life infection. We show for the first time that CD11b(+) enriched cells are the source of IL-1β during normal HP-dependent learning. CD11b(+) cells from NI rats are functionally sensitized within the adult HP and produce exaggerated IL-1β ex vivo compared with controls. However, an exaggerated IL-1β response in vivo requires LPS before learning. Moreover, preventing microglial activation during learning prevents memory impairment in NI rats, even following an LPS challenge. Thus, early-life events can significantly modulate normal learning-dependent cytokine activity within the HP, via a specific, enduring impact on brain microglial function.     

Modulation of natural killer cell activity by restraint stress during an influenza A/PR8 infection in mice

These experiments were designed to examine the influences of restraint stress (RST) on natural killer (NK) activity and to determine its consequences on influenza A/PR8 (A/PR8) viral replication in mice. The data showed that RST delayed the recruitment of NK1.1+ cells into the lung parenchyma during infection. Quantification of MIP-1alpha and MCP-1 gene expression by real-time PCR revealed that RST suppressed the chemokines responsible for NK cell recruitment into the infected tissue. Additionally, RST suppressed the expression of several macrophage-derived cytokines involved in the effector response of NK cells. IL-15, which is the main cytokine involved in NK cell development and homeostasis, and IL-12, which is important for NK cytotoxicity, were both suppressed. As the NK cell response is an important innate response to control viral replication, we hypothesized that the RST-mediated reduction in NK cell numbers and function would enable viral replication to continue unchecked. In fact, there was enhanced viral replication in the lungs of RST animals. Interestingly, expression of the anti-viral type I interferons (IFN-alpha and IFN-beta) was elevated presumably in response to the elevated viral load in the stressed mice. Together, these data show that RST suppressed expression of the cytokine genes involved in the recruitment and activation of NK cells during an experimental influenza viral infections. The consequence of this effect was diminished NK cell function and enhanced viral replication.     

Environmental enrichment attenuates hippocampal neuroinflammation and improves cognitive function during influenza infection

Recent findings from our lab have shown that peripheral infection of adult mice with influenza A/PR/8/34 (H1N1) virus induces a neuroinflammatory response that is paralleled by loss of neurotrophic and glial regulatory factors in the hippocampus, and deficits in cognitive function. Environmental enrichment has been shown to exert beneficial effects on the brain and behavior in many central nervous system (CNS) disorders, but its therapeutic potential during peripheral viral infection remains unknown. Therefore, the objective of the present study was to determine if long-term continuous exposure to environmental enrichment could prevent and/or attenuate the negative effects of influenza infection on the hippocampus and spatial cognition. Mice were housed in enriched or standard conditions for 4 months, and continued to live in their respective environments throughout influenza infection. Cognitive function was assessed in a reversal learning version of the Morris water maze, and changes in hippocampal expression of proinflammatory cytokines (IL-1β, IL-6, TNF-α, IFN-α), neurotrophic (BDNF, NGF), and immunomodulatory (CD200, CX3CL1) factors were determined. We found that environmental enrichment reduced neuroinflammation and helped prevent the influenza-induced reduction in hippocampal CD200. These changes were paralleled by improved cognitive performance of enriched mice infected with influenza when compared to infected mice in standard housing conditions. Collectively, these data are the first to demonstrate the positive impact of environmental enrichment on the brain and cognition during peripheral viral infection, and suggest that enhanced modulation of the neuroimmune response may underlie these beneficial effects.