Perinatal asphyxia leads to acute kidney damage and increased renal susceptibility in adulthood.

Perinatal asphyxia (PA) poses a significant threat to multiple organs, particularly the kidneys. Diagnosing PA-associated kidney injury remains challenging, and treatment options are inadequate. Furthermore, there is a lack of long-term follow-up data regarding the renal implications of PA. In this study, 7-day-old male Wistar rats were exposed to PA using a gas mixture (4% O2; 20% CO2 in N2 for 15 min) to investigate molecular pathways linked to renal tubular damage, hypoxia, angiogenesis, heat shock response, inflammation, and fibrosis in the kidney. In a second experiment, adult rats with a history of PA were subjected to moderate renal ischemia-reperfusion (IR) injury to test the hypothesis that PA exacerbates renal susceptibility. Our results revealed an increased gene expression of renal injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), hypoxic and heat shock factors (hypoxia-inducible factor-1α, heat shock factor-1, and heat shock protein-27), proinflammatory cytokines (interleukin-1ß, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1), and fibrotic markers (transforming growth factor-ß, connective tissue growth factor, and fibronectin) promptly after PA. Moreover, a machine learning model was identified through random forest analysis, demonstrating an impressive classification accuracy (95.5%) for PA. Post-PA rats showed exacerbated functional decline and tubular injury and more intense hypoxic, heat shock, proinflammatory, and profibrotic response after renal IR injury compared with controls. In conclusion, PA leads to subclinical kidney injury, which may increase the susceptibility to subsequent renal damage later in life. In addition, the parameters identified through random forest analysis provide a robust foundation for future biomarker research in the context of PA.NEW & NOTEWORTHY This article demonstrates that perinatal asphyxia leads to subclinical kidney injury that permanently increases renal susceptibility to subsequent ischemic injury. We identified major molecular pathways involved in perinatal asphyxia-induced renal complications, highlighting potential targets of therapeutic approaches. In addition, random forest analysis revealed a model that classifies perinatal asphyxia with 95.5% accuracy that may provide a strong foundation for further biomarker research. These findings underscore the importance of multiorgan follow-up for perinatal asphyxia-affected patients.

The neural background of hyper-emotional aggression induced by post-weaning social isolation.

Post-weaning social isolation in rats is believed to model symptoms of early social neglect-induced externalizing problems including aggression-related problems. We showed earlier that rats reared in social isolation were hyper-aroused during aggressive contacts, delivered substantially more attacks that were poorly signaled and were preferentially aimed at vulnerable body parts of opponents (head, throat and belly). Here we studied the neural background of this type of aggression by assessing the expression of the activation marker c-Fos in 22 brain areas of male Wistar rats submitted to resident-intruder conflicts. Post-weaning social isolation readily produced the behavioral alterations noticed earlier. Social isolation significantly increased the activation of brain areas that are known to directly or indirectly control inter-male aggression. Particularly, the medial and lateral orbitofrontal cortices, anterior cingulate cortex, bed nucleus of the stria terminalis, medial and basolateral amygdala, hypothalamic attack area, hypothalamic paraventricular nucleus and locus coeruleus showed increased activations. This contrasts our earlier findings obtained in rats with experimentally induced hypoarousal, where abnormal attack patterns were associated with over-activated central amygdala, lateral hypothalamus, and ventrolateral periaqueductal gray that are believed to control predatory attacks. We have observed no similar activation patterns in rats socially isolated from weaning. In summary, these findings suggest that despite some phenotypic similarities, the neuronal background of hypo and hyperarousal-associated abnormal forms of aggression are markedly different. While the neuronal activation patterns induced by normal rivalry and hypoarousal-driven aggression are qualitative different, hyperarousal-associated aggression appears to be an exaggerated form of rivalry aggression.

Temporal changes in c-Fos activation patterns induced by conditioned fear.

Mechanisms underlying shock-induced conditioned fear - a paradigm frequently used to model posttraumatic stress disorder, PTSD - are usually studied shortly after shocks. Some of the brain regions relevant to conditioned fear were activated in all the c-Fos studies published so far, but the overlap between the activated regions was small across studies. We hypothesized that discrepant findings were due to dynamic neural changes that followed shocks, and a more consistent picture would emerge if consequences were studied after a longer interval. Therefore, we exposed rats to a single session of footshocks and studied their behavioral and neural responses one and 28 days later. The neuronal activation marker c-Fos was studied in 24 brain regions relevant for conditioned fear, e.g. in subdivisions of the prefrontal cortex, hippocampus, amygdala, hypothalamic defensive system, brainstem monoaminergic nuclei and periaqueductal gray. The intensity of conditioned fear (as shown by the duration of contextual freezing) was similar at the two time-points, but the associated neuronal changes were qualitatively different. Surprisingly, however, Multiple Regression Analyses suggested that conditioned fear-induced changes in neuronal activation patterns predicted the duration of freezing with high accuracy at both time points. We suggest that exposure to electric shocks is followed by a period of plasticity where the mechanisms that sustain conditioned fear undergo qualitative changes. Neuronal changes observed 28 days but not 1 day after shocks were consistent with those observed in human studies performed in PTSD patients.

Brain mechanisms involved in predatory aggression are activated in a laboratory model of violent intra-specific aggression.

Callous-unemotional violence associated with antisocial personality disorder is often called 'predatory' because it involves restricted intention signaling and low emotional/physiological arousal, including decreased glucocorticoid production. This epithet may be a mere metaphor, but may also cover a structural similarity at the level of the hypothalamus where the control of affective and predatory aggression diverges. We investigated this hypothesis in a laboratory model where glucocorticoid production is chronically limited by adrenalectomy with glucocorticoid replacement (ADXr). This procedure was proposed to model important aspects of antisocial violence. Sham and ADXr rats were submitted to resident/intruder conflicts, and the resulting neuronal activation patterns were investigated by c-Fos immunocytochemistry. In line with earlier findings, the share of attacks aimed at vulnerable targets (head, throat and belly) was dramatically increased by ADXr, while intention signaling by offensive threats was restricted. Aggressive encounters activated the mediobasal hypothalamus, a region involved in intra-specific aggression, but sham and ADXr rats did not differ in this respect. In contrast, the activation of the lateral hypothalamus that is tightly involved in predatory aggression was markedly larger in ADXr rats; moreover, c-Fos counts correlated positively with the share of vulnerable attacks and negatively with social signaling. Glucocorticoid deficiency increased c-Fos activation in the central amygdala, a region also involved in predatory aggression. In addition, activation patterns in the periaqueductal gray - involved in autonomic control - also resembled those seen in predatory aggression. These findings suggest that antisocial and predatory aggression are not only similar but are controlled by overlapping neural mechanisms.

Inhibition of anandamide hydrolysis by cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester (URB597) reverses abuse-related behavioral and neurochemical effects of nicotine in rats.

Emerging evidence suggests that the rewarding, abuse-related effects of nicotine are modulated by the endocannabinoid system of the brain. For example, pharmacological blockade or genetic deletion of cannabinoid CB(1) receptors can reduce or eliminate many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of Delta(9)-tetrahydrocannabinol and nicotine that are ineffective when given alone can induce conditioned place preference when given together. These previous studies have used systemically administered CB(1) receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB(1) receptors throughout the brain. A more functionally selective way to alter endocannabinoid activity is to inhibit fatty acid amide hydrolase (FAAH), thereby magnifying and prolonging the effects of the endocannabinoid anandamide only when and where it is synthesized and released on demand. Here, we combined behavioral and neurochemical approaches to evaluate whether the FAAH inhibitor URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) could alter the abuse-related effects of nicotine in rats. We found that URB597, at a dose (0.3 mg/kg) that had no behavioral effects by itself, prevented development of nicotine-induced conditioned place preference (CPP) and acquisition of nicotine self-administration. URB597 also reduced nicotine-induced reinstatement in both CPP and self-administration models of relapse. Furthermore, in vivo microdialysis showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the terminal area of the brain's mesolimbic reward system. These findings suggest that FAAH inhibition can counteract the addictive properties of nicotine and that FAAH may serve as a new target for development of medications for treatment of tobacco dependence.

Lasting changes in social behavior and amygdala function following traumatic experience induced by a single series of foot-shocks.

Neuronal plasticity within the amygdala mediates many behavioral effects of traumatic experience, and this brain region also controls various aspects of social behavior. However, the specific involvement of the amygdala in trauma-induced social deficits has never been systematically investigated. We exposed rats to a single series of electric foot-shocks--a frequently used model of trauma--and studied their behavior in the social avoidance and psychosocial stimulation tests (non-contact versions of the social interaction test) at different time intervals. Social interaction-induced neuronal activation patterns were studied in the prefrontal cortex (orbitofrontal and medial), amygdala (central, medial, and basolateral), dorsal raphe and locus coeruleus. Shock exposure markedly inhibited social behavior in both tests. The effect lasted at least 4 weeks, and amplified over time. As shown by c-Fos immunocytochemistry, social interactions activated all the investigated brain areas. Traumatic experience exacerbated this activation in the central and basolateral amygdala, but not in other regions. The tight correlation between the social deficit and amygdala activation patterns suggest that the two phenomena were associated. A real-time PCR study showed that CRF mRNA expression in the amygdala was temporarily reduced 14, but not 1 and 28 days after shock exposure. In contrast, amygdalar NK1 receptor mRNA expression increased throughout. Thus, the trauma-induced social deficits appear to be associated with, and possibly caused by, plastic changes in fear-related amygdala subdivisions.

The effect of neurokinin1 receptor blockade on territorial aggression and in a model of violent aggression.

BACKGROUND: Neurokinin1 (NK1) receptor blockers were recently proposed for the treatment of anxiety and depression. Disparate data suggest that NK1 receptors are also involved in the control of aggressiveness, but their role is poorly known. METHODS: We evaluated the aggression-induced activation of NK1 neurons by double-labeling brain sections for NK1 receptors and c-Fos in two laboratory models of aggression. We also studied the effects of the NK1 antagonist L-703,606 in these models. RESULTS: Aggressive encounters activated a large number of NK1 receptor-expressing neurons in areas relevant for aggression control. The activation was aggression-specific, because the effects of psychosocial encounters (that allowed sensory but not physical contacts) were markedly weaker. In the medial amygdala, the activation of neurons expressing NK1 receptors showed a marked positive correlation with the occurrence of violent attacks. In resident/intruder conflicts, NK1 blockade lowered the number of hard bites, without affecting milder forms of attack. In the model of violent aggression, attacks on vulnerable body parts of opponents (the main indicators of violence in this model) were decreased to the levels seen in control subjects. Autonomic deficits seen in the model of violent aggression were also ameliorated. The effects of the compound were not secondary to changes in locomotion or in the behavior of intruders. CONCLUSIONS: Our data show that neurons expressing NK1 receptors are involved in the control of aggressiveness, especially in the expression of violent attacks. This suggests that NK1 antagonists-beyond anxiety and depression-might also be useful in the treatment of aggressiveness and violence.