Elsevier

Psychoneuroendocrinology

Volume 76, February 2017, Pages 57-66
Psychoneuroendocrinology

Increased anxiety-like behaviors, but blunted cortisol stress response after neonatal hippocampal lesions in monkeys

https://doi.org/10.1016/j.psyneuen.2016.11.018Get rights and content

Highlights

  • Early hippocampal lesions cause increased anxiety-like and self-directed behaviors.

  • Despite increased anxiety-like behaviors, monkey had a blunted cortisol stress response.

  • Data is similar to adult-onset hippocampal damage in humans and monkeys.

  • Implication for mood and psychiatric disorders with altered hippocampal development.

Abstract

The hippocampus is most notably known for its role in cognition and spatial memory; however it also plays an essential role in emotional behaviors and neuroendocrine responses. The current study investigated the long-term effects of neonatal hippocampal lesions (Neo-Hibo) on emotional and hypothalamic-pituitary-adrenal (HPA) axis functioning. During infancy, unlike controls, Neo-Hibo monkeys exhibited enhanced expression of emotional behaviors (e.g. freezing, anxiety-like, and self-directed behaviors) when exposed to a human intruder (HI task). Upon reaching adulthood, they exhibited reduced freezing and hostility, but increased anxiety-like and self-directed behaviors during the HI task. Neo-Hibo monkeys behaved as if they systematically over-rated the risk inherent in the HI task, which supports Gray and McNaughton’s septo-hippocampal theory of anxiety. Also, in adulthood, the increased levels of anxiety-like behaviors in Neo-Hibo monkeys were associated with a blunted cortisol response to the HI task. Examination of basal HPA axis function revealed that Neo-Hibo monkeys exhibited the typical diurnal cortisol decline throughout the day, but had lower cortisol concentrations in the morning as compared to controls. Taken together these data suggest that an intact hippocampus during development plays a larger role beyond that of inhibitory/negative feedback regulation of the HPA axis stress-activation, and may be critical for HPA axis basal functioning as well as for the stress response. The behavioral and neuroendocrine changes demonstrated in the current study are reminiscent of those seen in human or nonhuman primates with adult-onset hippocampal damage, demonstrating little functional compensation following early hippocampal damage.

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

References (68)

  • J.P. Herman et al.

    Central mechanisms of stress integration: Hierarchical circuitry controlling hypothalamo- pituitary-adrenocortical responsiveness

    Front. Neuroendocrinol.

    (2003)
  • E. Heuer et al.

    Working memory for temporal order is impaired after selective neonatal hippocampal lesions in adult rhesus macaques

    Behav. Brain Res.

    (2013)
  • H. Kober et al.

    Functional grouping and cortical-subcortical interactions in emotion: a meta-analysis of neuroimaging studies

    Neuroimage

    (2008)
  • C.J. Machado et al.

    Behavioral and hormonal reactivity to threat effects of selective amygdala, hippocampal or orbital frontal lesions in monkeys

    Psychoneuroendocrinology

    (2008)
  • Y. Meng et al.

    Alterations of hippocampal projections in adult macaques with neonatal hippocampal lesions: a diffusion tensor imaging study

    Neuroimage

    (2014)
  • V. Mondelli et al.

    Abnormal cortisol levels during the day and cortisol awakening response in first-episode psychosis: the role of stress and of antipsychotic treatment

    Schizophr. Res.

    (2010)
  • S. Nemanic et al.

    Assessment of locus and extent of neurotoxic lesions in monkeys using neuroimaging techniques: A replication

    J. Neurosci. Meth.

    (2002)
  • E.A. Phelps

    Human emotion and memory: Interactions of the amygdala and hippocampal complex

    Curr. Opin. Neurobiol.

    (2004)
  • J. Poppenk et al.

    Long-axis specialization of the human hippocampus

    Trends Cogn. Sci.

    (2013)
  • J. Raper et al.

    Pervasive alterations of emotional and neuroendocrine responses to an acute stressor after neonatal amygdala lesions in rhesus monkeys

    Psychoneuroendocrinology

    (2013)
  • M.M. Sanchez et al.

    Differential rearing affects corpus callosum size and cognitive function of rhesus monkeys

    Brain Res.

    (1998)
  • S. Steudte-Schmiedgen et al.

    Hair cortisol concentrations and cortisol stress reactivity predict PTSD symptom increase after trauma exposure during military deployment

    Psychoneuroendocrinology

    (2015)
  • O.T. Wolf et al.

    No morning cortisol response in patients with severe global amnesia

    Psychoneuroendocrinology

    (2005)
  • M. Aas et al.

    Abnormal cortisol awakening response predicts worse cognitive function in patients with first-episode psychosis

    Psychol. Med.

    (2011)
  • M. Alvarado et al.

    Selective neurotoxic damage to the hippocampal formation impairs acquisition and performance of the transverse patterning task and location memory in rhesus macaques

    Hippocampus

    (2005)
  • D.G. Amaral et al.

    Anatomical Organization of the Primate Amygdaloid Complex, in The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction

  • P. Andersen et al.

    The Hippocampus Book

    (2007)
  • J. Bachevalier et al.

    Spatial memory in monkeys as measured with the visual paired-comparison task: effects of selective hippocampal, perirhinal and areas TH/TF lesions

    Hippocampus

    (2008)
  • M.D. Bauman et al.

    The development of social behavior following neonatal amygdala lesions in rhesus monkeys

    J. Cogn. Neurosci.

    (2004)
  • M.D. Bauman et al.

    Emergence of stereotypies in juvenile monkeys (Macaca mulatta) with neonatal amygdala or hippocampus lesions

    Behav. Neurosci.

    (2008)
  • A. Becker et al.

    Social behavior in rats lesioned with ibotenic acid in the hippocampus: Quantitative and qualitative analysis

    Psychopharmacology

    (1999)
  • M.S. Blank et al.

    Effects of venipuncture on serum levels of prolactin, growth hormones, and cortisol in outdoor compound-housed female rhesus monkeys

    Acta Endocrinol.

    (1983)
  • E. Bliss-Moreau et al.

    Neonatal amygdala or hippocampus lesions influence responsiveness to objects

    Dev. Psychobiol.

    (2010)
  • E. Bliss-Moreau et al.

    Neonatal amygdala lesions result in globally blunted affect in adult rhesus macaques

    Behav. Neurosci.

    (2011)
  • Cited by (17)

    • Neonatal exposures to sevoflurane in rhesus monkeys alter synaptic ultrastructure in later life

      2022, iScience
      Citation Excerpt :

      We focused on hippocampal CA1 and layer III of the dorsolateral prefrontal cortex (dlPFC). We chose CA1 of the hippocampus because impairments in visual recognition and disrupted socioemotional behaviors follow neonatal hippocampal lesions,61,62 and layer III of the dlPFC because the development and function of dlPFC neurons depend on hippocampal integrity.63,64 We used electron microscopy to identify synaptic contacts in ultrathin (70 nm) tissue sections from stratum radiatum of the CA1 field of the hippocampus and layer III of dlPFC.

    • Differential responses toward conditioned and unconditioned stimuli, but decreased hypothalamic-pituitary-adrenal axis responsiveness in neonatal hippocampal lesioned monkeys

      2022, Developmental Cognitive Neuroscience
      Citation Excerpt :

      The combination of a blunted response to ACTH stimulation of the adrenal cortex and blunted response to metyrapone suggests that adult animals with neonatal hippocampal lesions may be suffering from adrenal exhaustion (Kannan, 1988). This may also explain the blunted cortisol response to an acute stressor and flattened diurnal cortisol rhythm detected in these same animals previously (Raper et al., 2017). Electrical stimulation studies as well as those reporting the presence of high glucocorticoid levels in the hippocampus have implicated its key role in the negative feedback control of the HPA axis (Herman et al., 2003).

    • Early intervention with electroacupuncture prevents PTSD-like behaviors in rats through enhancing hippocampal endocannabinoid signaling

      2019, Progress in Neuro-Psychopharmacology and Biological Psychiatry
      Citation Excerpt :

      Atrophy of hippocampus is one of the obvious pathologic changes in patients with PTSD and animal models (Kikuchi et al., 2008; Lindauer et al., 2006) and hippocampal dysfunction might interact with traumatic experience to influence the etiology and maintenance of PTSD (Acheson et al., 2012). In addition, factors impairing hippocampal structure may induce anxiety (Loi et al., 2017; Raper et al., 2017) and the improvement of hippocampal structure and function has been shown to hold the potential to alleviate anxiety and is involved in anti-anxiety drug effects (Mohammad et al., 2018). Importantly, a well-established body of literature supports the role of eCB system in maintaining hippocampal structure and function (Djurisic et al., 2018; Micale et al., 2017; Segev et al., 2018) and the regulation of EA on the hippocampal synaptic plasticity, metabolism and functions as well (Han et al., 2018; Soligo et al., 2017).

    • Persistent alteration in behavioural reactivity to a mild social stressor in rhesus monkeys repeatedly exposed to sevoflurane in infancy

      2018, British Journal of Anaesthesia
      Citation Excerpt :

      Loss of neurones and oligodendrocytes was observed in amygdala and hippocampus,37 structures involved in the development of emotional behaviour. Early loss of neurones and oligodendrocytes could alter the developmental trajectory of the central nervous system in a number of ways, as early lesions have different consequences to lesions later in life as their effects interact with the developmental trajectory of cognitive and emotional processes.22,31,38 It is also possible that surviving neurones function abnormally, as adult rodents that were exposed to anaesthesia in early development have identified electrophysiological and cell morphological abnormalities.13,39,40

    • Visual recognition memory is impaired in rhesus monkeys repeatedly exposed to sevoflurane in infancy

      2017, British Journal of Anaesthesia
      Citation Excerpt :

      Thus, disturbances in emotional behaviour after repeated anaesthesia exposure in infancy, may manifest earlier than impairments in memory. Notably, both impairments in memory and disturbances in emotional behaviour, marked by increased anxiety, manifest after early hippocampal damage in monkeys.17 18 30 This pattern is consistent with an early anaesthesia-induced neurobehavioural deficit being caused by hippocampal dysfunction, although considerable additional work remains to be done to validate this hypothesis.

    View all citing articles on Scopus
    View full text