Increased anxiety-like behaviors, but blunted cortisol stress response after neonatal hippocampal lesions in monkeys
Introduction
Our previous studies have demonstrated that neonatal lesions of the hippocampus critically alter the development of memory processes, including visual recognition memory (Zeamer et al., 2010, Zeamer and Bachevalier, 2013), spatial memory (Blue et al., 2013, Glavis-Bloom et al., 2013), and working memory processes (Heuer and Bachevalier, 2011, Heuer and Bachevalier, 2013). These studies provide strong evidence that damage to the hippocampus has a deleterious and long-lasting effect on the development of memory as it does in adult subjects (Nemanic et al., 2004, Alvarado and Bachevalier, 2005, Bachevalier and Nemanic, 2008). Yet, the hippocampus is also known to play an essential role in emotional and defensive behaviors (Andersen et al., 2007, de Kloet, 2012), as well as in negative control of neuroendocrine response to potential threats (Herman et al., 2003). As reviewed below, such a role has largely been derived from studies of adult animals in which both the hippocampus and hypothalamic-pituitary-adrenal (HPA) axis are fully developed, but little is known about how the hippocampus may also regulate the development of emotional behavior and neuroendocrine response to stress.
When faced with a potential threat, adult rodents and primates with hippocampal lesions exhibit less freezing/fear and more anxiety-like behaviors (Phillips and LeDoux, 1992, Chudasama et al., 2008, Chudasama, 2009, Machado and Bachevalier, 2008, Buchanan et al., 2009, Wang et al., 2013). Also electrical stimulation of the hippocampus reduces glucocorticoid secretion, whereas lesions of the hippocampus prolong the HPA axis response to a stressor (see review Herman et al., 2003) and promote hypersecretion of basal glucocorticoids (Fendler et al., 1961; Sapolsky et al., 1991). Additionally, patients with hippocampal damage exhibit a blunted cortisol awakening response (Buchanan et al., 2004, Wolf et al., 2005) and demonstrate a lack of cortisol response to a psychological stressor (Tuvnes et al., 2003, Buchanan et al., 2009). Although these data provide converging evidence that the hippocampus contributes to the inhibitory/negative feedback regulation of the HPA axis (Herman et al., 2003) and regulates the amplitude of the HPA axis stress response, only a handful of studies have begun to assess whether the hippocampus is critical for the development of emotional and neuroendocrine responses.
Few studies have shown that neonatal hippocampal damage yields abnormal emotional reactivity to objects and social partners (Bauman et al., 2004, Bliss-Moreau et al., 2010, Bliss-Moreau et al., 2011a, Bliss-Moreau et al., 2013), but normal HPA axis response to pharmacological challenges assessed at 2.5–4.5 months after the lesion (Goursaud et al., 2006). Yet, none of these studies have investigated the impact of early hippocampal damage on both behavioral and physiological (HPA axis) stress reactivity. The present study examined whether neonatal hippocampal damage in monkeys alters the development of emotional responses from infancy (2 and 4.5 months) to adulthood (6–8 years) and how these early lesions impacted the HPA axis stress response, as well as the basal HPA rhythm in adulthood. To this end, control animals and animals with neonatal hippocampal lesions that served in our cognitive testing battery, were tested on the Human Intruder (HI) paradigm to assess the effects of neonatal hippocampal lesions on the development of behavioral and neuroendocrine stress reactivity.
Section snippets
Subjects
Twelve rhesus monkeys (Macaca mulatta) surrogate-peer reared in a socially enriched environment that promoted species-specific socioemotional skills were used in this study (Goursaud and Bachevalier, 2007, Rommeck et al., 2011, Burbacher et al., 2013, Raper, 2013). Animals received neonatal neurotoxic lesions of the hippocampus (Neo-Hibo; males = 4, females = 2) or sham operations (Neo-C; males = 3, females = 3) at 7–25 days of age. During infancy, surgical procedures and behavioral testing were
Lesion extent verification
Estimation of hippocampal lesion extent from post-surgical FLAIR images for all 6 Neo-Hibo animals ranged from 3.9% to 87.4% (average, 48.1%), whereas the percentage of volume reduction ranged from 14.8% to 67% (average, 42.7%) at 1-year post-surgery and ranged from 6.4% to 65% (average, 38.5%) in adulthood (8–10 years). Lesion estimates from the post-surgical FLAIR strongly correlated with both 1 year and adult hippocampal volume reduction (r[6] = 0.81, p = 0.025 and r[6] = 0.80, p = 0.27,
Experiment 2: Behavioral reactivity in adulthood
Experiment 1 results reveal that Neo-Hibo animals exhibited more fearful defensive freezing at 2 months of age, less affiliative behaviors at both ages, and more anxiety-like and self-directed behaviors at 4.5 months of age as compared to controls. This suggests that early hippocampal damage did not abolish the animals’ ability to express species typical defensive and emotional behaviors, but altered the magnitude of their expression and their developmental trajectory. To investigate whether
Long-term effects of neonatal hippocampal lesions on emotional reactivity
Group differences in behaviors observed during infancy persisted into adulthood (see Fig. 3). Although control and Neo-Hibo animals both exhibit increased fearful defensive freezing during the Profile condition (Condition: F[2,20] = 48.765, p < 0.001, ηp2 = 0.83, d = 4.42), the freezing was dampened in Neo-Hibo as compared to controls (Group: F[1,10] = 4.89, p = 0.051, ηp2 = 0.33, d = 1.40; Fig. 3A).
For hostile behaviors, there was a Group X Condition interaction (F[2,20] = 4.29, p = 0.033, ηp2 = 0.30, d = 1.31; Fig. 3
Discussion
The present study demonstrates that neonatal hippocampal damage causes lasting alterations in emotional behavior expression and neuroendocrine secretions. Although Neo-Hibo lesions did not impair or delay the emergence of defensive and emotional behaviors in early infancy, it did alter the overall magnitude of their expression, which became more pronounced in adulthood. Reduction in basal cortisol levels and a blunted cortisol stress response was also found in adulthood after early hippocampal
Conclusions
The current study demonstrates that an intact hippocampus is essential during development for acquiring normal emotional behavior expression and HPA axis functioning. Early hippocampal damage results in prolonged alterations of emotions (i.e., increased anxiety-like behaviors) and dampens both the cortisol basal rhythm and stress response. These data suggest that the hippocampus plays a larger role beyond that of inhibitory/negative feedback regulation of the HPA axis. The behavioral and
Acknowledgements
Authors are grateful to Jairus O’Malley, Tammy Humbird, Keith Kline, PhD, Christopher Machado, PhD, and Alyson Zeamer, PhD for their assistance with data collection and coding. Additional thanks goes to Sarah Pruett, PhD in the Yerkes BioMarker Core Laboratory for the use of equipment and assistance with the hormone assays. This research was supported by the National Institute for Mental Health (MH58846), National Institute for Child Health and Development (HD35471), Integrated Training in
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