Marie-Claude Audet

Social defeat promotes specific cytokine variations within the prefrontal cortex upon subsequent aggressive or endotoxin challenges

Stressful experiences typically have short-lived neuroendocrine and neurochemical effects, but the processes leading to these biological alterations may be sensitized so that later challenges promote exaggerated responses. As stressors and immunogenic insults have both been associated with inflammatory immune variations within the brain, we assessed whether a social defeat stressor would result in augmented corticosterone release and mRNA expression of pro-inflammatory cytokines within the prefrontal cortex (PFC) upon later social defeat (sensitization) or endotoxin (lipopolysaccharide: LPS) challenges (cross-sensitization). In the absence of a prior stressor experience, the social defeat challenge did not affect prefrontal interleukin (IL)-1β or tumor necrosis factor (TNF)-α mRNA expression, but increased that of IL-6, whereas LPS increased the expression of each cytokine. Among mice that had initially been repeatedly defeated, IL-1β and TNF-α expression was enhanced after the social defeat challenge, whereas this was not evident in response to the LPS challenge. In contrast, the initial social defeat stressor had protracted effects in that increase of IL-6 expression was limited upon subsequent challenge with either social defeat or LPS. Previous social stressor experiences also limited the corticosterone rise ordinarily elicited by either social defeat or LPS treatment. It seems that a powerful stressor, such as social defeat, may have persistent effects on later corticosterone and cytokine responses to different types of stressful insults (social versus systemic challenges), but the nature of the effects varies with the specific process assessed.

Interplay between pro-inflammatory cytokines and growth factors in depressive illnesses

The development of depressive disorders had long been attributed to monoamine variations, and pharmacological treatment strategies likewise focused on methods of altering monoamine availability. However, the limited success achieved by treatments that altered these processes spurred the search for alternative mechanisms and treatments. Here we provide a brief overview concerning a possible role for pro-inflammatory cytokines and growth factors in major depression, as well as the possibility of targeting these factors in treating this disorder. The data suggest that focusing on one or another cytokine or growth factor might be counterproductive, especially as these factors may act sequentially or in parallel in affecting depressive disorders. It is also suggested that cytokines and growth factors might be useful biomarkers for individualized treatments of depressive illnesses.

Repeated subchronic exposure to phencyclidine elicits excessive atypical grooming in rats

Self-grooming in rodents is stereotypically sequenced and naturally occurs after arousal, novelty, or stress. Grooming expression and syntax resulting from stressful and appetitive conditions were assessed in male Long Evans rats treated daily with 10mg/kg of phencyclidine (PCP) for 15 days. Approximately 20 h after the 1st, the 8th, and/or the 15th injection, grooming was induced with water sprays, a loud sound, or smearing food. Behaviors expressed during the seconds or minutes that followed induction were videotaped and codified. Results showed that subchronic treatment with PCP amplified the grooming response in all stressful and appetitive conditions, but provoked a disorganization of grooming sequences only under the stressful, water condition. Thus, PCP enhanced grooming expression indiscriminately. However, this behavior had to serve both hygienic and stress managing purposes in order for chain sequencing to become disorganized as a consequence of drug treatment. These results suggest that the detailed examination of grooming expression and organization is an appropriate tool to measure stress-induced behavioral sensitization and motor functions in animal models of neuropsychiatric disorders such as schizophrenia.

Social Agonistic Distress in Male and Female Mice: Changes of Behavior and Brain Monoamine Functioning in Relation to Acute and Chronic Challenges

Stressful events promote several neuroendocrine and neurotransmitter changes that might contribute to the provocation of psychological and physical pathologies. Perhaps, because of its apparent ecological validity and its simple application, there has been increasing use of social defeat (resident-intruder) paradigms as a stressor. The frequency of stress-related psychopathology is much greater in females than in males, but the typical resident-intruder paradigm is less useful in assessing stressor effects in females. An alternative, but infrequently used procedure in females involves exposing a mouse to a lactating dam, resulting in threatening gestures being expressed by the resident. In the present investigation we demonstrated the utility of this paradigm, showing that the standard resident-intruder paradigm in males and the modified version in females promoted elevated anxiety in a plus-maze test. The behavioral effects that reflected anxiety were more pronounced 2 weeks after the stressor treatment than they were 2 hr afterward, possibly reflecting the abatement of the stress-related of hyper-arousal. These treatments, like a stressor comprising physical restraint, increased plasma corticosterone and elicited variations of norepinephrine and serotonin levels and turnover within the prefrontal cortex, hippocampus and central amygdala. Moreover, the stressor effects were exaggerated among mice that had been exposed to a chronic or subchronic-intermittent regimen of unpredictable stressors. Indeed, some of the monoamine changes were more pronounced in females than in males, although it is less certain whether this represented compensatory changes to deal with chronic stressors that could result in excessive strain on biological systems (allostatic overload).

Behavior and Pro-Inflammatory Cytokine Variations Among Submissive and Dominant Mice Engaged in Aggressive Encounters: Moderation by Corticosterone Reactivity

Psychosocial stressors contribute to the pathophysiology of affective disorders and variations of cytokine functioning have been implicated in this process. The present investigation demonstrated, in mice, the impact of stressful aggressive encounters on activity levels, plasma corticosterone and cytokine concentrations, and on cytokine mRNA expression within the prefrontal cortex (PFC) and hippocampus. As glucocorticoids have been tied to cytokine variations, mice were subdivided into low or high corticosterone responders, defined in terms of circulating hormone levels 75 min post-confrontation. Interestingly, stressor-induced effects among low and high responders varied as a function of whether mice were submissive or dominant during the aggressive bout. Agonistic encounters elicited subsequent hyperactivity, particularly among low corticosterone responders and among dominant mice. Plasma levels of corticosterone and interleukin (IL)-6 concomitantly increased after aggressive encounters and varied with dominance status and with the low versus high corticosterone response. Among the low responders corticosterone and IL-6 increases were modest and only apparent among submissive mice, whereas among high responders these elevations were more pronounced and comparable in submissive and dominant mice. Aggressive episodes also increased IL-1β and IL-6 mRNA brain expression. The IL-1β rise was greater in the PFC and hippocampus of submissive mice that were low responders. Among high responders IL-1β and IL-6 increased in both groups, although in the PFC this effect was specific to dominant mice. The data are discussed in terms of their relevance to the impact of aggressive encounters on affective behaviors, and to the role that cytokines might play in this regard.

Neuroendocrine and neurochemical impact of aggressive social interactions in submissive and dominant mice: implications for stress-related disorders

Social conflicts may engender stress-related behavioural and physiological disturbances in the victims of aggression. In addition, stress-like neurochemical changes and ensuing depressive and anxiety symptoms might also be evident in the perpetrators of aggressive acts. The present investigation assessed basal levels of circulating corticosterone and of brain serotonin (5-HT) and norepinephrine (NE) in pre-identified submissive and dominant mice. In addition, brain neurochemical changes were determined following a single or three 15-min aggressive episodes both in submissive mice and in those that dominated the aggressive interplay. Three minutes after single and repeated confrontations, plasma corticosterone levels and 5-HT utilization within the prefrontal cortex (PFC) and hippocampus were increased to a comparable extent in submissive and dominant animals. Interestingly, however, NE utilization within the PFC and hippocampus was augmented to a greater level in submissive mice. These results suggest that 5-HT neuronal functioning was generally responsive to aggressive events, irrespective of social rank, whereas NE neuronal activity within the PFC and hippocampus was more sensitive to the submissive/dominance attributes of the social situation. It is possible that NE and 5-HT variations associated with an aggressive experience contribute to depressive- and anxiety-like manifestations typically observed after such psychosocial stressors, particularly in submissive mice. However, given that 5-HT changes occur irrespective of social rank, these data suggest that a toll is taken on both submissive and dominant mice, leaving them vulnerable to stress-related pathology.

Delayed alternation performance following subchronic phencyclidine administration in rats depends on task parameters

The cognitive effects of subchronic phencyclidine administration in rats are still unsettled in the literature. Possible causes of discrepancies are different drug treatment regimens and task parameters. The current experiment tested whether variations in procedures of the delayed T-maze alternation task result in performance differences following identical PCP treatments. Sixteen rats were trained on a continuous version of the T-maze task where they alternated between successive free-choice runs. Another sixteen were trained on a discrete trials version where each trial started with a forced run followed by a free choice test. After training, half of the rats submitted to each task version were treated daily for 14 days with i.p. injections of PCP (10 mg/kg) and the remaining half received a saline solution. At 48 h after the last injection, the subjects were tested for 10 days in their respective task version. Results showed that rats treated with PCP were impaired relative to controls in the continuous alternation task whereas performance of PCP and Saline groups did not differ in the discrete trials version. Cognitive control from prefrontal cortex and/or striatal response-related processes could have been damaged by PCP exposure. The systematic study of differences in tasks parameters may help reconcile discordant findings on PCPs functional outcomes.

Environmental enrichment in male CD-1 mice promotes aggressive behaviors and elevated corticosterone and brain norepinephrine activity in response to a mild stressor

Housing rodents in an enriched environment (EE) has been typically considered to have positive effects on well-being and cognitive functioning of the animals. However, in some strains of mice, EEs have also been reported to elicit aggression and to promote stress-related outcomes. In the current investigation, we examined whether environmental enrichment would elicit aggression among CD-1 male mice and thus sensitize responses to a subsequent mild stressor. It was first observed that mice housed in an EE for 2 weeks displayed more aggressive behaviors than did mice that had been housed in a standard environment (SE). In the second experiment, it was noted that after 4 weeks of EE or SE housing, mice exhibited comparable plasma corticosterone concentrations as well as levels of brain norepinephrine and its metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), in the absence of a challenge. However, upon exposure to mild stressor (placement in a novel cage), relative to their SE counterparts, EE mice were more active and displayed higher plasma corticosterone concentrations and enhanced MHPG accumulation in the prefrontal cortex and hippocampus. It seems that enrichment in male CD-1 mice promotes aggression, and may sensitize biological processes, possibly increasing vulnerability to stressor-related outcomes.

The differential impact of social defeat on mice living in isolation or groups in an enriched environment: plasma corticosterone and monoamine variations

Social defeat in mice is a potent stressor that promotes the development of depressive- and anxiety-like behaviours, as well as variations of neuroendocrine and brain neurotransmitter activity. Although environmental enrichment may protect against some of the adverse behavioural and biological effects of social defeat, it seems that, among male group-housed mice maintained in an enriched environment (EE), aggressive behaviours may be more readily instigated, thus promoting distress and exacerbating psychopathological features. Thus, although an EE can potentially have numerous beneficial effects, these may depend on the general conditions in which mice were raised. It was observed in the current investigations that EE group-housed BALB/cByJ mice displayed increased anxiety-like behaviours compared to their counterparts maintained in a standard environment (SE). Furthermore, in response to social defeat, EE group-housed male mice exhibited decreased weight gain, exaggerated corticosterone elevations and altered hippocampal norepinephrine utilization compared to their SE counterparts. These effects were not apparent in the individually housed EE mice and, in fact, enrichment among these mice appeared to buffer against serotonin changes induced by social defeat. It is possible that some potentially beneficial effects of enrichment were precluded among group-housed mice, possibly owing to social disturbances that might occur in these conditions. In fact, even if social interaction is an essential feature of enrichment, it seems that some of the positive effects of this housing condition might be optimal when mice are housed individually, particularly with regard to buffering the effects of social defeat.

Impaired social motivation and increased aggression in rats subchronically exposed to phencyclidine

Phencyclidine (PCP) treatment induces social withdrawal in the rat model of schizophrenia but little is known about the qualitative adequacy of behaviors displayed during interactions. Affiliative, avoidance, and aggressive behaviors were examined in rats 20 h after the 1st, the 8th, and the 15th injection of 10 mg/kg of PCP or of a saline vehicle. PCP treatment reduced the initiation of affiliative contacts with a control congener and increased aggressive responses, in the absence of drug outcomes on time spent in social interaction. These results suggest that subchronic PCP administration in rats affects perception and appraisal of social situations as well as motivation to interact. Such pathological behaviors are consistent with the social impairments characteristic of human schizophrenia.