A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress

Introduction Using proton magnetic resonance spectroscopy imaging, the effects of early life stress on nonhuman primate striatal neuronal integrity were examined as reflected by N-acetyl aspartate (NAA) concentrations. NAA measures were interrogated through examining their relationship to previously documented early life stress markers—cerebrospinal fluid corticotropin-releasing factor concentrations, hippocampal volume, body mass, and behavioral timidity. Rodent models of depression exhibit increases in neurotrophic effects in the nucleus accumbens. We hypothesized that rearing under conditions of early life stress (variable foraging demand, VFD) would produce persistent elevations of NAA concentrations (in absolute or ratio form) in ventral striatum/caudate nucleus (VS/CN) with altered correlation to early life stress markers. Methods Eleven bonnet macaque males reared under VFD conditions and seven age-matched control subjects underwent proton magnetic resonance spectroscopy imaging during young adulthood. Voxels were placed over VS/CN to capture nucleus accumbens. Cisternal cerebrospinal fluid corticotropin-releasing factor concentrations, hippocampal volume, body mass, and response to a human intruder had been previously determined. Results VFD-reared monkeys exhibited significantly increased NAA/creatine concentrations in right VS/CN in comparison to normally reared controls, controlling for multiple comparisons. In comparison to controls, VFD cerebrospinal fluid corticotropin-releasing factor concentrations were directly associated with right VS/CN absolute NAA. Left hippocampal volume was inversely associated with left VS/CN NAA/creatine in VFD reared but not in controls. Disruption of a normative inverse correlation between left VS/CN NAA and body mass was noted in VFD. Only non-VFD subjects exhibited a direct relationship between timidity response to an intruder and right VS/CN NAA. Conclusion Early life stress produced persistent increases in VS/CN NAA, which demonstrated specific patterns of association (or lack thereof) to early life stress markers in comparison to non-VFD subjects. The data are broadly consistent with a stable nonhuman primate phenotype of anxiety and mood disorder vulnerability whereby in vivo indicators of neuronal integrity, although reduced in hippocampus, are increased in striatum. The findings may provide a catalyst for further studies in humans and other species regarding a reciprocal hippocampal/nucleus accumbens relationship in affective disorders.

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Potentiation of glutamatergic synaptic transmission onto lateral habenula neurons following early life stress and intravenous morphine self-administration in rats

10.1101/2020.12.23.424217 ◽

2020 ◽

Author(s):

Ludovic D. Langlois ◽

Rina Y. Berman ◽

Ryan D. Shepard ◽

Sarah C. Simmons ◽

Mumeko C. Tsuda ◽

...

Keyword(s):

Synaptic Transmission ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Sucrose Preference ◽

Male Rats ◽

Self Administration ◽

Lateral Habenula ◽

Glutamatergic Synaptic Transmission ◽

Intravenous Morphine

AbstractEarly life stress (ELS) presents an important risk factor for drug addiction and comorbid depression and anxiety through persistent effects on the mesolimbic dopamine (DA) pathways1. Using an ELS model for child neglect (a single 24 h episode of maternal deprivation, MD) in rats, recent published works from our lab show that MD induces dysfunction in ventral tegmental area (VTA) DA neurons 2–4 and its negative controller, the lateral habenula (LHb) 5–7. In regard to LHb, MD-induced potentiation of glutamatergic synaptic transmission onto LHb neurons shifts the coordination of excitation/inhibition (E/I) balance towards excitation, resulting in an increase in the overall spontaneous neuronal activity with elevation in bursting and tonic firing, and intrinsic excitability of LHb neurons in early adolescent male rats 5–7. Here, we explored how MD affects intravenous morphine self-administration (MSA) acquisition and sucrose preference as well as glutamatergic synaptic function in LHb neurons of adult male rats self-administering morphine. We found that MD-induced increases in LHb neuronal and glutamatergic synaptic activity and E/I ratio persisted into adulthood. Moreover, MD significantly reduced morphine intake, triggered anhedonia-like behavior in the sucrose preference test (SPT), and was associated with persistent glutamatergic potentiation 24h after the last MSA session. MSA also triggered postsynaptic glutamatergic potentiation in LHb neurons of control rats during this time period. Our data highlights that ELS-induced glutamatergic plasticity in LHb may dampen the positive reinforcing properties of natural rewards and opioids, and contribute to the development of anhedonic and dysphoric states associated with opioids.

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Early life adversity and serotonin transporter gene variation interact to affect DNA methylation of the corticotropin-releasing factor gene promoter region in the adult rat brain

Development and Psychopathology ◽

10.1017/s0954579414001345 ◽

2015 ◽

Vol 27 (1) ◽

pp. 123-135 ◽

Cited By ~ 39

Author(s):

Rick H. A. van der Doelen ◽

Ilse A. Arnoldussen ◽

Hussein Ghareh ◽

Liselot van Och ◽

Judith R. Homberg ◽

...

Keyword(s):

Dna Methylation ◽

Serotonin Transporter ◽

Life Stress ◽

Early Life ◽

Gene Promoter ◽

Early Life Stress ◽

Corticotropin Releasing Factor ◽

Mrna Levels ◽

Gene Variation ◽

Gene Environment

AbstractThe interaction between childhood maltreatment and the serotonin transporter (5-HTT) gene linked polymorphic region has been associated with increased risk to develop major depression. This Gene × Environment interaction has furthermore been linked with increased levels of anxiety and glucocorticoid release upon exposure to stress. Both endophenotypes are regulated by the neuropeptide corticotropin-releasing factor (CRF) or hormone, which is expressed by the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central amygdala (CeA). Therefore, we hypothesized that altered regulation of the expression of CRF in these areas represents a major neurobiological mechanism underlying the interaction of early life stress and 5-HTT gene variation. The programming of gene transcription by Gene × Environment interactions has been proposed to involve epigenetic mechanisms such as DNA methylation. In this study, we report that early life stress and 5-HTT genotype interact to affect DNA methylation of the Crf gene promoter in the CeA of adult male rats. Furthermore, we found that DNA methylation of a specific site in the Crf promoter significantly correlated with CRF mRNA levels in the CeA. Moreover, CeA CRF mRNA levels correlated with stress coping behavior in a learned helplessness paradigm. Together, our findings warrant further investigation of the link of Crf promoter methylation and CRF expression in the CeA with behavioral changes that are relevant for psychopathology.

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Corticotropin-Releasing Factor and the Psychobiology of Early-Life Stress

Current Directions in Psychological Science ◽

10.1111/j.1467-8721.2007.00481.x ◽

2007 ◽

Vol 16 (2) ◽

pp. 85-89 ◽

Cited By ~ 26

Author(s):

Charles F. Gillespie ◽

Charles B. Nemeroff

Keyword(s):

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Corticotropin Releasing Factor

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Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome

Psychological Medicine ◽

10.1017/s0033291707001444 ◽

2007 ◽

Vol 38 (7) ◽

pp. 963-973 ◽

Cited By ~ 25

Author(s):

F. Van Den Eede ◽

G. Moorkens ◽

W. Hulstijn ◽

B. Van Houdenhove ◽

P. Cosyns ◽

...

Keyword(s):

Hpa Axis ◽

Life Stress ◽

Early Life ◽

Low Dose ◽

Early Life Stress ◽

Chronic Fatigue ◽

Corticotropin Releasing Factor ◽

Fatigue Syndrome ◽

History Of ◽

Cortisol Responses

BackgroundStudies of hypothalamic–pituitary–adrenal (HPA) axis function in chronic fatigue syndrome (CFS) point to hypofunction, although there are negative reports. Suggested mechanisms include a reduced hypothalamic or supra-hypothalamic stimulus to the HPA axis and enhanced sensitivity to the negative feedback of glucocorticoids. The aim of the current study was to investigate HPA axis function in CFS with the dexamethasone/corticotropin-releasing factor (Dex/CRF) test, in analogy with research in affective disorders.MethodThirty-four well-characterized female CFS patients and 25 healthy control subjects participated in the low-dose Dex/CRF test. Current major depressive episode was an exclusion criterion. History of early-life stress (ELS) was assessed with the Structured Trauma Interview.ResultsSalivary cortisol responses after 0.5 mg Dex were lower in CFS patients than in controls (before 100 μg CRF, p=0.038; after 100 μg CRF, p=0.015). A secondary analysis revealed an influence of early-life stress and of oestrogen intake. After removal of the 10 participants who were taking an oral oestrogen, patients without a history of ELS showed lower cortisol responses than patients with ELS and controls (before CRF, p=0.005; after CRF, p=0.008).ConclusionsCFS is globally associated with reduced cortisol responses in the combined low-dose Dex/CRF test, but this effect is only clearly present in CFS patients without a history of ELS. This study provides further support for an enhanced glucocorticoid negative feedback and/or a reduced central HPA axis drive in CFS. Furthermore, it demonstrates that ELS is an important variable to consider in CFS research.

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Potentiation of glutamatergic synaptic transmission onto lateral habenula neurons following early life stress and intravenous morphine self‐administration in rats

Addiction Biology ◽

10.1111/adb.13064 ◽

2021 ◽

Author(s):

Ludovic D. Langlois ◽

Rina Y. Berman ◽

Ryan D. Shepard ◽

Sarah C. Simmons ◽

Mumeko C. Tsuda ◽

...

Keyword(s):

Synaptic Transmission ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Self Administration ◽

Lateral Habenula ◽

Glutamatergic Synaptic Transmission ◽

Intravenous Morphine

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Targeting Endocannabinoid Signaling in the Lateral Habenula as an Intervention to Prevent Mental Illnesses Following Early Life Stress: A Perspective

Frontiers in Synaptic Neuroscience ◽

10.3389/fnsyn.2021.689518 ◽

2021 ◽

Vol 13 ◽

Author(s):

Ryan D. Shepard ◽

Fereshteh S. Nugent

Keyword(s):

Psychiatric Disorders ◽

Life Stress ◽

Early Life ◽

Neural Circuits ◽

Treatment Strategies ◽

Early Life Stress ◽

Mental Illnesses ◽

Lateral Habenula ◽

Psychiatric Illnesses ◽

New Research

Adverse events and childhood trauma increase the susceptibility towards developing psychiatric disorders (substance use disorder, anxiety, depression, etc.) in adulthood. Although there are treatment strategies that have utility in combating these psychiatric disorders, little attention is placed on how to therapeutically intervene in children exposed to early life stress (ELS) to prevent the development of later psychopathology. The lateral habenula (LHb) has been a topic of extensive investigation in mental health disorders due to its prominent role in emotion and mood regulation through modulation of brain reward and motivational neural circuits. Importantly, rodent models of ELS have been shown to promote LHb dysfunction. Moreover, one of the potential mechanisms contributing to LHb neuronal and synaptic dysfunction involves endocannabinoid (eCB) signaling, which has been observed to critically regulate emotion/mood and motivation. Many pre-clinical studies targeting eCB signaling suggest that this neuromodulatory system could be exploited as an intervention therapy to halt maladaptive processes that promote dysfunction in reward and motivational neural circuits involving the LHb. In this perspective article, we report what is currently known about the role of eCB signaling in LHb function and discuss our opinions on new research directions to determine whether the eCB system is a potentially attractive therapeutic intervention for the prevention and/or treatment of ELS-associated psychiatric illnesses.

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Early-life experiences altered the maturation of the lateral habenula in mouse models, resulting in behavioural disorders in adulthood

Journal of Psychiatry and Neuroscience ◽

10.1503/jpn.200226 ◽

2021 ◽

Vol 46 (4) ◽

pp. E480-E489

Author(s):

Tomoya Nakamura ◽

Kohei Kurosaki ◽

Munenori Kanemoto ◽

Masakiyo Sasahara ◽

Hiroyuki Ichijo

Keyword(s):

Life Stress ◽

Early Life ◽

Life Experiences ◽

Forced Swim Test ◽

High Stress ◽

Early Life Stress ◽

Sensitive Period ◽

Lateral Habenula ◽

Highly Sensitive ◽

Parvalbumin Neurons

Background: Abnormally high activity in the lateral habenula causes anxiety- or depression-like behaviours in animal experimental models. It has also been reported in humans that excessive stress in early life is correlated with the onset of psychiatric disorders in adults. These findings raise the question of whether maturation of the lateral habenula is affected under the influence of early-life experiences, which could govern behaviours throughout life. Methods: We examined the maturation of the lateral habenula in mice based on neuronal activity markers and plastic components: Zif268/Egr1, parvalbumin and perineuronal nets. We examined the effect of early-life stress using repeated maternal deprivation. Results: First, we found a transient highly sensitive period of the lateral habenula under stress. The lateral habenula matured through 4 stages: postnatal days 1–9 (P1–9), P10–20, around P35 and after P35. At P10–20, the lateral habenula was highly sensitive to stress. We also observed experience-dependent maturation of the lateral habenula. Only mice exposed to chronic stress from P10–20 exhibited changes specific to the lateral habenula at P60: abnormally high stress reactivity shown by Zif268/Egr1 and fewer parvalbumin neurons. These mice showed anxiety- or depression-like behaviours in the light–dark box test and forced swim test. Limitations: The effect of parvalbumin neurons in the lateral habenula on behavioural alterations remains unknown. It will be important to understand the “sensitive period” of the neuronal circuits in the lateral habenula and how the period P10–20 is different from P9 or earlier, or P35 or later. Conclusion: In mice, early-life stress in the period P10–20 led to late effects in adulthood: hyperactivity in the lateral habenula and anxiety or depression, indicating differences in neuronal plasticity between stages of lateral habenula maturation.

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