EARLY LIFE STRESS EXPOSURE YIELDS PERSISTENT PHYSIOLOGICAL, MORPHOLOGICAL, AND BEHAVIORAL CHANGES IN PRECLINICAL RODENT MODELS
Chairs & Presenters:
Jennifer Quinn (Chair and Presenter)
Details of Research Subjects: Stress, Adversity
Ages of Research Subjects: infancy, adolescence, adult
Topics: Stress, Adversity
Early life adversity is a known risk factor for a number of mental health disorders, leading to impaired cognitive, behavioral, and social functioning later in life. Animal models provide a way to systematically and comprehensively assess the impacts of stress on brain physiology and morphology, as well as behavior, in a controlled manner. Most current animal models of early life stress in rodents employ chronic separation or deprivation conditions aimed at mimicking maternal neglect, abuse, or both. However, the precise timing and duration of early stress exposure are likely to influence outcome severity, in line with human studies suggesting a cumulative impact of stress effects on vulnerability to psychopathology. In addition, sex disparities in prevalence, symptomatology, and treatment efficacy for mental health disorders associated with early adversity underscore the need for animal models demonstrating parallel sex-specific effects. In this symposium, we will explore these factors with regard to early life stress exposure at several critical developmental timepoints: early postnatal, preweaning, and adolescence. We will highlight physiological, morphological, and behavioral changes resulting from these varied early stress experiences. This symposium will be of wide interest to ISDP attendees, where there is a strong tradition of bridging across findings from preclinical animal models to human clinical populations. ¬†
AMYGDALA CRF CELLS MEDIATE THE EFFECTS OF NEONATAL PAIN ON SUBSEQUENT STRESS-INDUCED TACTILE HYPERSENSITIVITY
Michael A. Burman, Department of Psychology, University of New England (Primary Presenter), S. M. Davis, J. Zuke, E. Russo, M. Berchulski
We‚Äôve adopted a rodent model of neonatal intensive care unit (NICU)-like treatments in which neonatal rats are exposed to 4 hind-paw pricks a day over postnatal days (PND) 1-7, subjected to a 3-day fear conditioning protocol on PND 24-27 and sensory tested using Von Frey and Hargreaves methods on PND 28.¬† In the initial experiments, rats were returned to the dam between pain episodes.¬† These subjects showed reductions in conditioned freezing and an age-dependent stress-induced tactile hypersensitivity that was strongest in juvenile rats and declined with age, when compared to control subjects.¬† Moreover, juvenile rats that received neonatal pain spent more time on the open arms of an elevated plus maze.¬† In a separate set of experiments, subjects were kept in an incubator between pain episodes (a maternal separation model).¬† Here, neonatal pain subjects demonstrated an adolescent increase in conditioned freezing and a sex-dependent decrease in time spent on the open arms, but retained a modest stress-induced tactile hypersensitivity.¬† Finally, we‚Äôve begun the process of investigating the neural substrates of these phenomena.¬† Neonatal pain appears to activate CRF expression within the central nucleus of the amygdala, but not the hypothalamus, in male rats.¬† Female rats trend towards the opposite pattern.¬† Moreover, antagonizing CRF receptors 1 or 2 in the amygdala prior to fear conditioning in juvenile rats reverses the otherwise observed hypersensitivity.¬† Together these findings suggest that amygdala CRF signaling may be a critical mechanism by which neonatal pain exerts its lasting effects.¬†
SOCIAL BUFFERING ATTENUATES CORTICOSTERONE LEVELS AND AMYGDALA ACTIVITY FOLLOWING STRESS EXPOSURE IN JUVENILE RATS.
Dragana I. Claflin, Department of Psychology, Wright State University. (Primary Presenter), A. M. Costello, D. M. Gallimore, A. A. Koraym, A. P. Shoemaker, M. B Hennessy, J. J. Quinn
Aversive conditioning procedures activate the endocrine stress response (e.g., corticosterone release) and engage fear processing neural systems via the amygdala. This activation underlies the emergence of at least one form of avoidance conditioning (Moriceau & Sullivan, 2006), though its role in development of eyeblink classical conditioning (EBCC) is unknown. The age at which EBCC first emerges (Day 17) is delayed when pups are returned to the mother and home cage between sessions (Stanton et al.,1992). This suggests the mother may buffer corticosterone and amygdala responses in the EBCC paradigm. We observed that repeated unilateral periorbital shock, such as used during EBCC, elevated plasma corticosterone in 17-day-old rats. The corticosterone elevation was significantly reduced both 20 and 60 minutes following return to the home cage with cage-mates and mother, but social isolation in a novel environment instead prolonged CORT elevation. Activation of the central nucleus of amygdala was measured using immunohistochemical analysis of brain tissue for production of the immediate early gene zif-268. Greater activation of both the left and right amygdala was observed in isolated rats one hour after shock, relative to both home-cage controls and rats receiving shock but immediately returned to the social environment of the home cage. Beyond contributing to the literature on social buffering as a powerful psychological and physiological method of reducing stress and fear in young mammals, the findings also suggest that maternal buffering of corticosterone and amygdala responses may modulate developmental emergence of EBCC by reducing the aversive impact of the learning experience. ¬†
SEX DIFFERENCES IN THE PERSISTENT IMPACTS OF ACUTE EARLY LIFE STRESS ON FEAR MEMORY IN ADULTHOOD
Jennifer J. Quinn, Department of Psychology, Miami University (Primary Presenter), B. L. Minshall, C. A. Riddle, D. I. Claflin
Posttraumatic stress disorder (PTSD) represents a spectrum of debilitating anxiety symptoms resulting from exposure to one or more traumatic events. Individuals living with PTSD are more likely to have experienced trauma as a child. This demonstrates the importance of early adversity as a risk factor for developing PTSD later in life. We have established a rodent model of acute early life stress (ELS) which produces robust and persistent behavioral phenotypes relevant to the debilitating symptoms observed in patients with PTSD. In the model, rats or mice are exposed to 15 footshocks on postnatal day 17. In adulthood, previously stressed male and female animals demonstrate robust stress-enhanced fear learning (SEFL). However, moderate ELS (4 footshocks) reveals a female vulnerability toward adult SEFL, where females but not males demonstrate SEFL. This female vulnerability is not due to differences in learning or footshock responsivity during the ELS session. Further, previously-stressed females demonstrate an increased propensity for fear incubation in adulthood (over a 30 day period) compared to previously-stressed males.¬† Animals not previously exposed to ELS show no evidence of fear incubation in adulthood. These data suggest that exposure to an acute stressor early in life can produce long-lasting alterations in future threat responding, and females appear to be more vulnerable to these effects.
PREWEANING STRESS SENSITIZES ADULT FEAR AND DRUG-RELATED LEARNING DESPITE THE LACK OF CONTEXTUAL FEAR MEMORY
Michael S. Fanselow, Department of Psychology, UCLA. (Primary Presenter), M. C. Cobb, A. N. Hoffman, P. J. Kennedy.
Previous research (e.g., Rudy¬†& Morledge, 1994) indicates that preweanling rats do not acquire contextual fear conditioning.¬† Here we report that rats receiving a single significant contextual fear conditioning experience at postnatal day 19 also show no evidence of contextual fear memory as adults.¬† However, these same rats show profound alterations in adult behavior along with corresponding neurobiological changes.¬† These early-life stressed rats show a dramatic enhancement in the acquisition of adult fear conditioning and increased baseline anxiety.¬†¬†As adults, these preweaning stressed rats acquired and extinguished operant responding for intravenous cocaine normally.¬†¬†However, they were more motivated for drug reward, evidenced by increased effort to obtain a single unit dose, and more likely to reinstate operant responding following exposure to a mild stressor or cues previously associated with drug availability.
SEX-DEPENDENT EFFECTS OF ADOLESCENT STRESS ON DENDRITIC MORPHOLOGY IN ADULT PREFRONTAL CORTEX
Cara L. Wellman, Department of Psychological and Brain Sciences, Indiana University (Primary Presenter), M. R. Breach, K. M. Moench
Adolescence is an important period for HPA axis development and synapse maturation and reorganization in the prefrontal cortex (PFC). Thus, stress during adolescence could alter stress-sensitive brain regions such as the PFC as well as the impact of future stressors on these brain regions. Given that women are more susceptible to many stress-linked psychological disorders in which dysfunction of PFC is implicated, and that this increased vulnerability emerges in adolescence, stress during adolescence could have sex-dependent effects. Therefore, we investigated the effects of adolescent social instability stress (SIS) on dendritic morphology of Golgi-stained pyramidal cells in the medial PFC (mPFC) of adult male and female rats. We then examined dendritic reorganization following chronic restraint stress (CRS) with and without a rest period in adult rats that had been stressed during adolescence. Adolescent SIS differentially altered mPFC of males and females, with females showing reduced apical dendritic length and males showing reduced basilar dendritic length. CRS in adulthood failed to produce immediate dendritic remodeling in SIS rats. However, CRS followed by a rest period reduced apical dendritic length in adolescently-stressed adult males, whereas CRS followed by rest produced apical outgrowth in adolescently-stressed adult females. Thus, stress during adolescence differentially alters development of the mPFC in males and females and results in novel stress-induced dendritic changes in adulthood. Such long-term morphological effects likely influence prefrontally-mediated, stress-sensitive behaviors.