Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis.

The limited success in understanding the pathophysiology of major depression may result from excessive focus on the dysfunctioning of neurons, as compared with other types of brain cells. Therefore, we examined the role of dynamic alterations in microglia activation status in the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We report that following an initial period (2-3 days) of stress-induced microglial proliferation and activation, some microglia underwent apoptosis, leading to reductions in their numbers within the hippocampus, but not in other brain regions, following 5 weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. Blockade of the initial stress-induced microglial activation by minocycline or by transgenic interleukin-1 receptor antagonist overexpression rescued the subsequent microglial apoptosis and decline, as well as the CUS-induced depressive-like behavior and suppressed neurogenesis. Similarly, the antidepressant drug imipramine blocked the initial stress-induced microglial activation as well as the CUS-induced microglial decline and depressive-like behavior. Treatment of CUS-exposed mice with either endotoxin, macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, all of which stimulated hippocampal microglial proliferation, partially or completely reversed the depressive-like behavior and dramatically increased hippocampal neurogenesis, whereas treatment with imipramine or minocycline had minimal or no anti-depressive effects, respectively, in these mice. These findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions.

Sleep enhances plasticity in the developing visual cortex.

During a critical period of brain development, occluding the vision of one eye causes a rapid remodeling of the visual cortex and its inputs. Sleep has been linked to other processes thought to depend on synaptic remodeling, but a role for sleep in this form of cortical plasticity has not been demonstrated. We found that sleep enhanced the effects of a preceding period of monocular deprivation on visual cortical responses, but wakefulness in complete darkness did not do so. The enhancement of plasticity by sleep was at least as great as that produced by an equal amount of additional deprivation. These findings demonstrate that sleep and sleep loss modify experience-dependent cortical plasticity in vivo. They suggest that sleep in early life may play a crucial role in brain development.

Sleep does not enhance the recovery of deprived eye responses in developing visual cortex.

Monocular deprivation (MD) during a critical period of visual development triggers a rapid remodeling of cortical responses in favor of the open eye. We have previously shown that this process is enhanced by sleep and is inhibited when the sleeping cortex is reversibly inactivated. A related but distinct form of cortical plasticity is evoked when the originally deprived eye (ODE) is reopened, and the non-deprived eye is closed during the critical period (reverse monocular deprivation (RMD)). Recent studies suggest that different mechanisms regulate the initial loss of deprived eye responses following MD and the recovery of deprived eye responses following RMD. In this study we investigated whether sleep also enhances RMD plasticity in critical period cats. Using polysomnography combined with microelectrode recordings and intrinsic signal optical imaging in visual cortex we show that sleep does not enhance the recovery of ODE responses following RMD. These findings add to the growing evidence that different forms of plasticity in vivo are regulated by distinct mechanisms and that sleep has divergent roles upon different types of experience-dependent cortical plasticity.

Specific and time-dependent effects of glucocorticoid receptor agonist RU28362 on stress-induced pro-opiomelanocortin hnRNA, c-fos mRNA and zif268 mRNA in the pituitary.

This study examined the effects of the glucocorticoid receptor (GR) agonist RU28362 on stress-induced gene expression in the pituitary of rats to investigate mechanisms of glucocorticoid negative feedback in vivo. In an initial experiment, acute restraint stress produced rapid (within 15 min) induction of c-fos mRNA, zif268 mRNA and pro-opiomelanocortin (POMC) hnRNA within the anterior and intermediate/posterior pituitary as determined by quantitative real-time polymerase chain reaction. Treatment with RU28362 (150 microg/kg, i.p.) 60 min before restraint inhibited adrenocorticotrophic hormone (ACTH) and corticosterone secretion and selectively suppressed the stress-induced increase in POMC hnRNA in the anterior pituitary gland. The failure of RU28362 to surpress the stress-induced rise in c-fos and expression of zif268 mRNA suggests that the central release of ACTH secretagogues was not affected at this time point by treatment with the GR agonist. Rather, the inhibition of ACTH release appeared to be due to a direct effect of RU28362 within the pituitary. A follow-up time-course study varied the interval (10, 60 or 180 min) between RU28362 pretreatment and the onset of restraint. The stress-induced increase in POMC hnRNA was completely blunted by RU28362 treatment within 10 min of treatment, although the stress induced hormone secretion, c-fos mRNA and zif268 mRNA were unaffected. The rapid inhibition of the stress-induced rise in POMC hnRNA in the anterior pituitary appears to reflect direct, GR-mediated suppression of POMC gene expression. RU28362 pretreatment 180 min before restraint onset was sufficient to suppress the stress-induced expression in the anterior pituitary gland of all three genes examined. Thus, the delayed negative feedback effects on hypothalamic-pituitary-adrenal axis activity that emerged after 180 min after glucocorticoid treatment were not evident at 60 min. Taken together, the data suggest that the inhibition of the stress-induced release of ACTH apparent within the first hour of glucocorticoid exposure is effected at the level of the pituitary gland. The delayed glucocorticoid effects evident 180 min after RU28362 treatment may include glucocorticoid actions in the brain and additional actions within the pituitary.

Infusion of nerve growth factor (NGF) into kitten visual cortex increases immunoreactivity for NGF, NGF receptors, and choline acetyltransferase in basal forebrain without affecting ocular dominance plasticity or column development.

Intracerebroventricular or intracortical administration of nerve growth factor (NGF) has been shown to block or attenuate visual cortical plasticity in the rat. In cats and ferrets, the effects of exogenous NGF on development and plasticity of visual cortex have been reported to be small or nonexistent. To determine whether locally delivered NGF affects ocular dominance column formation or the plasticity produced by monocular deprivation in cats at the height of the critical period, we infused recombinant human NGF into the primary visual cortex of kittens using an implanted cannula minipump. NGF had no effect on the normal developmental segregation of geniculocortical afferents into ocular dominance columns as determined both physiologically and anatomically. The plasticity of binocular visual cortical responses induced by monocular deprivation was also normal in regions of immunohistochemically detectable NGF infusion, as measured using intrinsic signal optical imaging and single-unit electrophysiology. Immunohistochemical analysis of the basal forebrain regions of the same animals demonstrated that the NGF infused into cortex was biologically active, producing an increase in the number of NGF-, TrkA-, p75(NTR)-, and choline acetyltransferase-positive neurons in basal forebrain nuclei in the hemisphere ipsilateral to the NGF minipump compared to the contralateral basal forebrain neurons. We conclude that NGF delivered locally to axon terminals of cholinergic basal forebrain neurons resulted in increases in protein expression at the cell body through retrograde signaling.

Neonatal treatments with the serotonin uptake inhibitors clomipramine and zimelidine, but not the noradrenaline uptake inhibitor desipramine, disrupt sleep patterns in adult rats.

Chronic postnatal exposure to clomipramine (CMI), a monoamine uptake inhibitor, results in persistent alterations in adult rat REM sleep. These effects have been ascribed to CMI's ability to block neonatal active sleep (AS). However, these effects have not been obtained with other anti-depressants which also block neonatal AS. We compared the long-term effects on adult rat sleep after postnatal treatments (P8-P21) with either CMI or zimelidine (ZMI, a selective serotonin uptake inhibitor) or desipramine (DMI, a selective noradrenaline uptake inhibitor). ZMI and CMI increased the frequency and decreased the duration of REM sleep bouts, increased the number of nonREM-REM transitions, and increased sigma power in REM and nonREM sleep EEGs in adulthood. In contrast, DMI had no effect on any adult sleep parameters. Since ZMI, DMI and CMI all reduce AS to similar levels, these results suggest that neonatal AS suppression is not responsible for the sleep deficits following CMI or ZMI treatment. However, since ZMI and CMI, but not DMI, increase synaptic concentrations of serotonin, elevated serotonin levels during development may instead be responsible for the long-lasting sleep deficits.

The effects of REM sleep-inhibiting drugs in neonatal rats: evidence for a distinction between neonatal active sleep and REM sleep.

Neonatal active sleep (AS) has been considered to be homologous and continuous with rapid-eye-movement (REM) sleep in adult animals. We have recently proposed an alternative view that AS is an undifferentiated sleep state distinct from REM sleep. To test these opposing views on the relationship of AS and REM sleep, neonatal rats (P11, P14 and P20) were systemically injected with compounds that inhibit REM sleep in adults. Zimelidine (ZMI) and desipramine (DMI) are monoamine uptake inhibitors which increase synaptic concentrations of serotonin and norepinephrine, respectively. Serotonin and norepinephrine inhibit brainstem cholinergic neurons important in REM sleep generation. Atropine (ATR) is a muscarinic receptor antagonist that blocks the post-synaptic effects of cholinergic projections. Only DMI (5 mg/kg) suppressed AS at P11. ZMI (6 mg/kg) and ATR (6 mg/kg) did not suppress AS until P14. These data suggest that serotonergic and cholinergic regulation of AS are absent before P14. The fact that AS in P11 rats is not affected by cholinergic antagonists supports the hypothesis that AS and REM sleep represent different sleep states.

Monocyte 5-HT1A receptors mediate pindobind suppression of natural killer cell activity: modulation by catalase.

Serotonin (5-hydroxytryptamine; 5-HT) modulates constituents of the immune system. 5-HT1A receptor antagonists potently suppress lymphocyte function. NK cell activity (NKCA) was measured after exposure of mononuclear cells to the 5-HT1A receptor antagonist pindobind and the 5-HT(1C/2) receptor antagonist ketanserin. Elutriated monocytes were exposed to pindobind, incubated with peripheral blood lymphocytes (PBL) in the presence or absence of an H2O2 scavenger catalase, and NKCA measured. Pindobind, but not ketanserin, suppressed NKCA in vitro. Pindobind-treated monocytes suppressed NKCA, whereas pindobind treatment of PBL did not affect NKCA. Catalase inhibited pindobind-induced suppression of NKCA. These data are consistent with previous results that 5-HT modulates NKCA via 5-HT1A receptors on monocytes and suggest that 5-HT may abrogate monocyte suppression of NKCA by inhibiting monocyte signals such as H2O2.

The ability to detect deceit generalizes across different types of high-stake lies.

The authors investigated whether accuracy in identifying deception from demeanor in high-stake lies is specific to those lies or generalizes to other high-stake lies. In Experiment 1, 48 observers judged whether 2 different groups of men were telling lies about a mock theft (crime scenario) or about their opinion (opinion scenario). The authors found that observers' accuracy in judging deception in the crime scenario was positively correlated with their accuracy in judging deception in the opinion scenario. Experiment 2 replicated the results of Experiment 1, as well as P. Ekman and M. O'Sullivan's (1991) finding of a positive correlation between the ability to detect deceit and the ability to identify micromomentary facial expressions of emotion. These results show that the ability to detect high-stake lies generalizes across high-stake situations and is most likely due to the presence of emotional clues that betray deception in high-stake lies.

The forced-choice paradigm and the perception of facial expressions of emotion.

The view that certain facial expressions of emotion are universally agreed on has been challenged by studies showing that the forced-choice paradigm may have artificially forced agreement. This article addressed this methodological criticism by offering participants the opportunity to select a none of these terms are correct option from a list of emotion labels in a modified forced-choice paradigm. The results show that agreement on the emotion label for particular facial expressions is still greater than chance, that artifactual agreement on incorrect emotion labels is obviated, that participants select the none option when asked to judge a novel expression, and that adding 4 more emotion labels does not change the pattern of agreement reported in universality studies. Although the original forced-choice format may have been prone to artifactual agreement, the modified forced-choice format appears to remedy that problem.

The dark side of self- and social perception: black uniforms and aggression in professional sports.

Black is viewed as the color of evil and death in virtually all cultures. With this association in mind, we were interested in whether a cue as subtle as the color of a person's clothing might have a significant impact on his or her behavior. To test this possibility, we examined whether professional football and ice hockey teams that wear black uniforms are more aggressive than those that wear nonblack uniforms. An analysis of the penalty records of the National Football League and the National Hockey League indicate that teams with black uniforms in both sports ranked near the top of their leagues in penalties throughout the period of study. On those occasions when a team switched from nonblack to black uniforms, the switch was accompanied by an immediate increase in penalties. The results of two laboratory experiments indicate that this finding can be attributed to both social perception and self-perception processes--that is, to the biased judgments of referees and to the increased aggressiveness of the players themselves. Our discussion focuses on the theoretical implications of these data for an understanding of the variable, or "situated," nature of the self.

Effect of memory perspective on retrospective causal attributions.

Two studies examined whether people's retrospective causal attributions might be mediated by the visual perspective from which events are recalled. In Study 1, pairs of Ss participated in "get-acquainted" conversations and made a series of attribution ratings for their performance. They returned 3 weeks later to rerate their performance on the same attribution scales and to indicate the perspective from which they remembered their earlier conversation. Ss reported either "observer" memories in which they could "see" themselves from the outside or "field" memories in which their field of view matched that of the original situation. Study 2 was identical to Study 1 with the exception that Ss' memory perspectives were manipulated via verbal instructions. In both experiments, conversations that were recalled from an observer's perspective were attributed more dispositionally. These results suggest that the different perspectives from which events can be recalled function much like the divergent visual perspectives available to actors and observers in immediate, everyday experience. Discussion of these results focuses on how they further understanding of the contradictory findings reported in the literature on temporal shifts in attributions.

Behavioral markers and recognizability of the smile of enjoyment.

Ekman and Friesen (1982) predicted that smiles that express enjoyment would be marked by smoother zygomatic major actions of more consistent duration than the zygomatic major actions of nonenjoyment smiles. Study 1 measured the duration and smoothness of smiles shown by female subjects in response to positive emotion films while alone and in a social interaction. Enjoyment smiles in both situations were of more consistent duration and smoother than nonenjoyment smiles. In Study 2 observers who were shown videotapes of enjoyment and nonenjoyment smiles were able to accurately identify enjoyment smiles at rates greater than chance; moreover, accuracy was positively related to increased salience of orbicularis oculi action. In Study 3, another group of observers were asked to record their impressions of the smiling women shown in Study 2. These women were seen as more positive when they showed enjoyment compared with nonenjoyment smiles. These results provide further evidence that enjoyment smiles are entities distinct from smiles in general.

Inhibition training in wolves and dogs.

A theoretical model previously proposed by the first author hypothesizes that dogs (C. familiaris) should perform better than wolves (C. lupus) on training tasks in which (1) cues are arbitrarily selected by the experimenter, (2) reinforcement is administered by the experimenter, and (3) the to-be-learned behavior has no perceptible, functional connection with the reinforcement. To test this hypothesis, four Eastern wolf pups (C. l. lycaon) and four Alaskan Malamute pups (C. familiaris) were administered a passive inhibition task at seven weeks of age and an active inhibition test (leash training) at 11 weeks of age. Significant differences in the predicted direction were obtained for all task variables.

Development of diurnal organization of EEG slow-wave activity and slow-wave sleep in the rat.

This study characterizes the development of diurnal patterns of slow-wave sleep (SWS) distribution and SWS electroencephalographic (EEG) delta-power (DP) density in 12- to 24-day-old rats (P12-P24). Diurnal organization in sleep-wake distribution was established by P20. A decline in SWS DP across the light phase did not appear until P24. Before P20, SWS DP increased across the light phase in a pattern inverse to that typically seen in adult rats. At P20, SWS DP was evenly distributed across the light phase, and at P24, SWS DP declined across the light phase. The transient dissociation between diurnal organization in sleep-wake cycles and SWS DP suggests that circadian and homeostatic sleep regulatory mechanisms develop at different rates in the postnatal period.

Development of REM and slow wave sleep in the rat.

Active sleep (AS) in the neonate has been considered to be an immature form of rapid eye movement (REM) sleep. Quiet sleep (QS) has been thought to represent an immature form of slow wave sleep (SWS). To determine the relationship between the behaviorally determined states of AS and QS and electrographically determined REM sleep and SWS, we examined sleep ontogeny in the developing rat using an experimental routine that permitted long-term recordings and minimized the effects of maternal separation. Under these conditions, a transient state that included electroencephalographic slow wave activity and phasic motor activity was eventually replaced with the mature SWS pattern. Our work suggests that neonatal QS is not an immature form of SWS and that AS is best considered as an undifferentiated behavioral state from which both SWS and REM sleep develop.

Effects of sleep deprivation in neonatal rats.

This investigation represents the first systematic study of sleep homeostasis in developing mammals that spans the preweaning and postweaning periods. Neonatal rats from 12 to 24 days of postnatal life (P12-P24) were anesthetized with Metofane (methoxyflurane) and implanted with miniaturized electroencephalographic (EEG) and electromyographic electrodes. After 48 h of recovery, neonatal rats were sleep deprived for 3 h by either gentle handling or forced locomotion. We find that 3-h sleep deprivation produces dramatically different compensatory responses at different stages of postnatal development. In striking contrast to adult rats, sleep deprivation does not increase slow-wave sleep EEG delta (0.5-4.0 Hz) activity in rats younger than P24. However, P12-P20 rats do show evidence of sleep regulation because they show compensatory increases in sleep time and sleep continuity during recovery. In P12 rats, approximately 90% of total slow wave sleep time lost during the sleep-deprivation period was recovered during subsequent sleep. A similar recovery of active sleep time was observed in P20-P24 rats. These findings suggest not only that sleep is regulated in neonatal rats but that the accumulation and/or discharge of sleep need changes dramatically between the third and fourth postnatal weeks.