Physiology & Development of Chronic Fear (Behavioral Neuroendocrinology Lab) Sonia Cavigelli (PI) Rebecca Crouse (Res Tech II) Michael Caruso (Grad Student)
Temperament, Physiology, and Health Animal A Individual A interest physiology approach health Stimuli fear physiology Individual B withdraw health Overarching Question: How do individual difference in behavior and physiology influence health trajectories?
Current Lab Projects The Physiology & Development of Behavioral Inhibition (Cavigelli) Adolescent Asthma & Adult Fear (Crouse) Adolescent Social Stress & Adult Fear (Caruso)
The Physiology & Development of Behavioral Inhibition Sonia A. Cavigelli Christina M. Ragan Kerry C. Michael
Behavioral Inhibition / Shyness in Children Behavioral Inhibition: withdrawal or extreme motor inhibition in response to unfamiliar objects, people, events ~ 15% of children - stable trait: across time & situations (physical/social) - identify in infancy or childhood http://www.education.umd.edu/edhd/faculty/fox/discoveryhealth.php
BI: Health & Physiology Health Risks: - allergies, perhaps asthma - mood disorders (anxiety, depression, ) - in older adults, evidence of faster mortality rates Physiology (fear/stress reactivity ) - glucocorticoid (cortisol) levels (HPA) - cardiovascular reactivity - amygdala activity - short allele of 5-HTT promoter (5-HTTLPR)
Behavioral Inhibition ~ Chronic glucocorticoid elevation Kagan et al. 1987
Consequences of chronic glucocorticoid elevation Allostatic load hypothesis: cumulative wear-and-tear of physiological systems (McEwen & Stellar 1993) e.g.» Hippocampal cell death» Cognitive impairment» Altered immune function» Reduced androgen production» Shortened life span?
Developing an Animal Model - Evidence of temperament/personality: behavioral stability across conditions & time - Experimental manipulations & controls: - environment - physiology - genetics - and interactions - Longitudinal studies - birth to death McClintock, 1982
Background: Behavioral Stability & Underlying Physiological Biases Questions: tests of rodent behavioral inhibition: - trait emerges in infancy and is stable? - associated with physiology? - glucocorticoid production? - pro-inflammatory response? - cardiovascular function? - relation to life span? - relation to maternal care experience?
Test of Behavioral Inhibition Non-Social Social Adapted from: Takahashi, 1992 & 1994 Cavigelli & McClintock (2003), PNAS, 100: 16131 Cavigelli et al. (2007), Physiology & Behavior, 92: 897
Approach Latency in Social Arena Behavioral & Glucocorticoid Responses Young Adults Sprage-Dawley male rats (4 mos): - latency to explore in Novel Non-Social and Social Arenas - glucocorticoid production 2.75 2.5 2.25 2 1.75 1.5 1.25 1.75 NON-INHIBITED MIXED INHIBITED 20 % Corticosterone (ng/ml 500 450 400 350 300 250 200 150 NON-INHIBITED HI/HI INHIBITED HI/LO LO/HI LO/LO.5 100.25 -.5 0.5 1 1.5 2 2.5 Approach Latency in Non-Social Arena 50 0 0 min 40 min 24 hr Time Cavigelli et al. (2007), Physiology & Behavior, 92: 897
Behavioral Stability Young Adults r 59 = 0.39 p < 0.01 Cavigelli et al. (2009), Physiology & Behavior, 98: 205
Glucocorticoid Stability Young Adults Cavigelli et al. (2007), Physiology & Behavior, 92: 897 Cavigelli et al. (2009), Physiology & Behavior, 98: 205
Swelling Response to KLH (mm) - Day 1 IL-6 (pg/ml) Pro-Inflammatory Response 3500 3000 2500 Inhibited Neophilic Non-Inhibited Neophobic 2000 1500 1000 Plasma TNF-a (pg/ml) 35 30 25 20 15 10 5 0 High CORT Neophobic Low CORT Neophilic Inhibited Non-Inhibited 500 0 At Tail Clip 24-hrs later 0 2 4 6 8 10 0.5 12 Hours post-lps injection 0.6 0.4 0.3 0.2 0.1 0 Non-Inhibited Neophilic t 14 = 4.07 p <.01 Neophobic Inhibited Time Cavigelli et al. (2008); Michael et al. (in prep)
Life Span 32% shorter lifespan Cavigelli et al. (2009), Physiology & Behavior, 98: 205
Conclusions 1) Behavioral inhibition in outbred rodent model: a) identify at weaning (did not show data) b) stable over time 2) Peripheral biological correlates of BI (could account for health-related outcomes) a) constant ~30% increase in glucocorticoid production b) elevated pro-inflammatory response c) elevated cardiovascular response to novelty 3) Shortened life span
Neonate-Mother Interactions Predict Inhibition? Questions: - Does early neonatal or maternal behavior predict offspring inhibition in rodent model? (high sibling BI variance: analyses conducted within litters)
Within-litter variance in neonate perioral contact & maternal licking (2-3 fold differences within litters) Ragan et al. (2012), Developmental Psychobiology, 54: 199 Cavigelli et al. (2010), Behavioural Processes, 84: 696
Mothers preferentially-lick neonate sibs that make frequent perioral contact Ragan et al. (2012), Developmental Psychobiology, 54: 199
Latency to Physical Novelty in Adulthood Latency to Physical Novelty in Adulthood Neonate & mother behaviors predict adult sibling inhibition (opposite direction of prediction) F01 F02 F04 F10 F01 F02 F04 F10 6 6 5 5 4 4 3 3 2 2 1 1 0 0 0.05 0.1 0.15 0.2 0.25 0.3 Perioral Contact/Hrs. Observed r 68 = 0.27, p < 0.05 0 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 Licks/Hrs. Observed r 68 = 0.27, p < 0.05 Similar β values in multiple regression Ragan et al. (2012), Developmental Psychobiology, 54: 199
Final Conclusions Rodent BI similar behavioral and physiological characteristics as human behavioral inhibition rodent model allows for experimental, longitudinal/developmental, and intervention studies Physiological correlates of BI may account for differential health outcomes (asthma, anxiety) neuronal, immune, cardiovascular Future research environmental conditions that alter physiology / minimize negative health outcomes focus on early social interactions & epigenetics
Funding: NICHD NIMH NIA PSU Collaborators: Robert H. Bonneau (Hershey Med. Ctr) Laura C. Klein (Penn State Univ.) Eric Loken (Penn State Univ.) Martha K. McClintock (U. Chicago) Noah Sandstrom (Williams Coll.) Cynthia Stifter (Penn State Univ.) David J. Vandenbergh (Penn State U) Jason R. Yee (U. Chicago) Students: Kerry C. Michael Catherine E. Barrett Colleen Kovacsics Many undergraduate assistants
Research Technician: Rebecca Crouse Asthma and Anxiety Mechanisms behind asthmainternalizing disorder co-morbidity: novel mouse model
Possible Mechanisms? 1. Highly stressful experiences of potentially life-threatening respiratory distress with severely labored breathing 2. Chronically-elevated inflammatory responses in the airways
How does Early-Life Stress Affect Neuroendocrine Development? - Michael Caruso Adolescence is associated with a marked increase Social behavior (Spear, 2000) Psychopathology (Kessler et al., 2005) Human and rodent adolescents have unique glucocorticoid responses to stress Sensitive period for adverse effects of stress? Social stressors more relevant for developmental stage? Romeo (2010)
Adolescent vs. Children Stroud et al. (2009) Gunnar et al. (2009)