Early life stress alters emotional learning in a sex- and age-dependent manner with no impact on emotional behaviors.

Neonatal adversity can impact neurodevelopmental trajectories. This study examined the long-term effects of maternal deprivation on day 9 (DEP9), associated or not to a stressor (saline injection [SAL]), on contextual fear conditioning (Experiment 1) and emotional behaviors (Experiment 2) in Wistar rats. Whole litters were either assigned to DEP9 or control groups, and on day 10, half of the litters in each group received an SAL or not (NSAL). DEP9-SAL male adolescents showed the longest freezing time and DEP9 adult males froze more than females. Females exhibited less anxiety-like behavior than males; DEP9-SAL females spent more time in the open arms and DEP9 males visited less the extremity of the open arm in the elevated plus maze. Early life stress increased conditioned and innate fear in males, but not in females, indicating a clear sexual dimorphism in the response to potentially threatening stimuli.

Lack of Autophagy Induction by Lithium Decreases Neuroprotective Effects in the Striatum of Aged Rats.

The pharmacological modulation of autophagy is considered a promising neuroprotective strategy. While it has been postulated that lithium regulates this cellular process, the age-related effects have not been fully elucidated. Here, we evaluated lithium-mediated neuroprotective effects in young and aged striatum. After determining the optimal experimental conditions for inducing autophagy in loco with lithium carbonate (Li2CO3), we measured cell viability, reactive oxygen species (ROS) generation and oxygen consumption with rat brain striatal slices from young and aged animals. In the young striatum, Li2CO3 increased tissue viability and decreased ROS generation. These positive effects were accompanied by enhanced levels of LC3-II, LAMP 1, Ambra 1 and Beclin-1 expression. In the aged striatum, Li2CO3 reduced the autophagic flux and increased the basal oxygen consumption rate. Ultrastructural changes in the striatum of aged rats that consumed Li2CO3 for 30 days included electrondense mitochondria with disarranged cristae and reduced normal mitochondria and lysosomes area. Our data show that the striatum from younger animals benefits from lithium-mediated neuroprotection, while the striatum of older rats does not. These findings should be considered when developing neuroprotective strategies involving the induction of autophagy in aging.

Propranolol failed to prevent severe stress-induced long-term behavioral changes in male rats.

Memories of adverse events can be maladaptive when they lead to exaggerated fear, as observed in post-traumatic stress disorder (PTSD). Fear conditioning and fear sensitization are learning processes thought to play a role in fear-related disorders, and only few animal studies have evaluated the relationship between the associative and non-associative fear memory components on the development and maintenance of PTSD-like behavioral changes. Here we assessed the effects of a single dose of propranolol (10 mg/kg) or saline after fear memory retrieval on the long-term behavioral responses induced by severe stress in male rats. Animals were submitted to contextual fear conditioning (delayed shock group) or not (non-shock group) and underwent fear memory retrieval followed by propranolol or saline administration two weeks later. Rats were then evaluated in different behavioral tests to assess the expression of the conditioned fear response, anxiety-like and exploratory behaviors, and fear response after the presentation of unknown acoustic stimulus. Post-retrieval propranolol did not disrupt the subsequent expression of neither conditioned fear response nor the exploratory deficit and fear sensitization response, indicating that propranolol failed to mitigate long-term behavioral changes induced by severe stress in rats.

Variability in response to severe stress: highly reactive rats exhibit changes in fear and anxiety-like behavior related to distinct neuronal co-activation patterns.

There is an important individual variability in development of posttraumatic stress disorder (PTSD) and this feature needs to be better addressed in preclinical studies. Previously we showed that only rats that explored the context before a foot shock (delayed shock group) exhibited long-lasting behavioral changes. In this study the delayed shock group was segregated using the freezing response upon re-exposure to the shock-paired context and we investigated whether higher reactivity would be related to behavioral alterations and to activation of brain regions using Fos immunoreactivity. The latter allowed the analysis of co-activity patterns among brain regions within each group, by creating connectivity maps. High responder rats (HR) displayed heightened freezing response upon context re-exposure, anxiety-like behavior, impaired exploratory behavior and fear sensitization. Fos analysis showed that HR displayed a negative correlation between the medial prefrontal cortex and the ventral hippocampus (vHPC) after the first context re-exposure. After the second context re-exposure, HR displayed reduced Fos expression in vHPC CA1 area, whereas low responders (LR) showed increased Fos in the paraventricular nucleus of the thalamus. Pearson correlation analyses revealed positive associations between freezing and Fos in the dorsal the periaqueductal gray and vHPC after exposure to unfamiliar acoustic stimulus in a novel environment. Thus, assessment of individual variability allowed the identification of a subset of reactive animals that displayed behavioral modifications relevant to PTSD. Fos correlation and network analyses revealed co-activity patterns in HR rats that may point out to associations of brain areas relevant to the behavioral outcomes.

Corticosterone Assimilation by a Voluntary Oral Administration in Palatable Food to Rats.

Drug delivery in research on nonhuman animals in the laboratory is still challenging because it is usually invasive and stressful. Stress-free voluntary oral drug administration in water lacks precise control of dose and timing of substance ingestion. Voluntary oral consumption of corticosterone has been previously successfully applied in mice using oat flakes, but protocols for oral corticosterone administration in rats remain unavailable. This study assessed the effectiveness of voluntary oral administration to rats of a palatable piece of bread soaked with corticosterone that can be rapidly prepared and is reliably dose- and timing-controllable. After three familiarization days, all rats ate the bread within 120 seconds of presentation, irrespective of the presence or absence of corticosterone or vehicle. Corticosterone plasma levels remained at basal levels with consumption of vehicle-containing bread, and they were significantly increased with corticosterone-containing bread. Hence, the method enabled corticosterone bodily assimilation while avoiding stress, making it a possible alternative for invasive and stressful procedures. This article includes a methodological refinement that lessens unnecessary discomfort to laboratory animals and is potentially suitable for acute and chronic protocol studies.

Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation.

Careaga MBL, Girardi CEN, Suchecki D. Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation. NEUROSCI BIOBEHAV REV -Posttraumatic stress disorder (PTSD) is a psychopathology characterized by exacerbation of fear response. A dysregulated fear response may be explained by dysfunctional learning and memory, a hypothesis that was proposed decades ago. A key component of PTSD is fear conditioning and the study of this phenomenon in laboratory has expanded the understanding of the underlying neurobiological changes in PTSD. Furthermore, traumatic memories are strongly present even years after the trauma and maintenance of this memory is usually related to behavioral and physiological maladaptive responses. Persistence of traumatic memory may be explained by a dysregulation of two memory processes: extinction and reconsolidation. The former may explain the over-expression of fear responses as an imbalance between traumatic and extinction memory. The latter, in turn, explains the maintenance of fear responses as a result of enhancing trauma-related memories. Thus, this review will discuss the importance of fear conditioning for the establishment of PTSD and how failure in extinction or abnormal reconsolidation may contribute to the maintenance of fear response overtime.

Maternal deprivation alters growth, food intake, and neuropeptide Y in the hypothalamus of adolescent male and female rats.

Maternal deprivation (MD) for 24 hr during the neonatal period impairs body weight gain in adolescent and adult rats. It has been previously shown that maternally deprived rats consume less standard and carbohydrate-rich diets. Because neuropeptide Y (NPY) is implicated in feeding behavior, we assessed, prospectively, the effects of maternal deprivation, imposed on postnatal days (PND) 3 (DEP3) or 11 (DEP11), on physical development (snout-anal length and body weight gain, measured once a week) and food intake (assessed daily, during the rest and active phases, from PND 23 to PND 51); NPY-immunoreactivity (NPY-ir) in the arcuate nucleus of the hypothalamus was evaluated in male (at PND 52) and female rats in estrous (at PND 53-60). DEP3 and DEP11 male and female adolescents were smaller, lighter, and ate less during the active phase, than their CTL counterparts. This change in food intake was accompanied by reduced NPY-ir in the arcuate nucleus of the hypothalamus. The present results indicate that maternal deprivation had a negative impact on the physical development and feeding behavior of adolescent rats that may be explained by reduced hypothalamic NPY production.

Neonatal stress-induced affective changes in adolescent Wistar rats: early signs of schizophrenia-like behavior.

Psychiatric disorders are multifactorial diseases with etiology that may involve genetic factors, early life environment and stressful life events. The neurodevelopmental hypothesis of schizophrenia is based on a wealth of data on increased vulnerability in individuals exposed to insults during the perinatal period. Maternal deprivation (MD) disinhibits the adrenocortical response to stress in neonatal rats and has been used as an animal model of schizophrenia. To test if long-term affective consequences of early life stress were influenced by maternal presence, we submitted 10-day old rats, either deprived (for 22 h) or not from their dams, to a stress challenge (i.p. saline injection). Corticosterone plasma levels were measured 2 h after the challenge, whereas another subgroup was assessed for behavior in the open field, elevated plus maze (EPM), social investigation and the negative contrast sucrose consumption test in adolescence (postnatal day 45). Maternally deprived rats exhibited increased plasma corticosterone (CORT) levels which were higher in maternally deprived and stress challenged pups. Social investigation was impaired in maternally deprived rats only, while saline injection, independently of MD, was associated with increased anxiety-like behavior in the EPM and an impaired intake decrement in the negative sucrose contrast. In the open field, center exploration was reduced in all maternally-deprived adolescents and in control rats challenged with saline injection. The most striking finding was that exposure to a stressful stimulus per se, regardless of MD, was linked to differential emotional consequences. We therefore propose that besides being a well-known and validated model of schizophrenia in adult rats, the MD paradigm could be extended to model early signs of psychiatric dysfunction, and would particularly be a useful tool to detect early signs that resemble schizophrenia.