Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula

AbstractThe lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related disorders such as depression, anxiety and posttraumatic stress disorder. Dynorphin (Dyn)/Kappa opioid receptor (KOR) signaling is a mediator of stress response in reward circuitry. Previously, we have shown that maternal deprivation (MD), a severe early life stress, increases LHb intrinsic excitability while blunting the response of LHb neurons to extra hypothalamic corticotropin-releasing factor (CRF) signaling, another stress mediator. CRF pathways also interact with Dyn/KOR signaling. Surprisingly, there has been little study of direct KOR regulation of the LHb despite its distinct role in stress, reward and aversion processing. To test the functional role of Dyn-KOR signaling in the LHb, we utilized ex-vivo electrophysiology combined with pharmacological tools in rat LHb slices. We show that activation of KORs by a KOR agonist (U50,488) exerts differential effects on the excitability of two distinct subpopulations of LHb neurons that differ in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increases neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreases neuronal excitability in small/negative Ih (Ih-) neurons. Additionally, we found that an intact fast-synaptic transmission is required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission. While stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons, we found that U50, 488 either increased or decreased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreased mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. While total p38 MAPK (a downstream signaling pathway driven by KOR activation) expression was elevated in the LHb of MD rats compared to non-MD controls, we found that application of KOR-specific agonist, U50,488, onto LHb slices was still able to alter phosphorylated p38 MAPK (ph-p38) expression in MD rats similar to non-MD controls. Moreover, we found that the U50,488-mediated increase in LHb neuronal firing observed in non-MD rats was absent following MD. Altogether, this is the first demonstration of the existence of the functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD.

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Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula

Neurobiology of Stress ◽

10.1016/j.ynstr.2020.100267 ◽

2020 ◽

Vol 13 ◽

pp. 100267 ◽

Cited By ~ 1

Author(s):

Sarah C. Simmons ◽

Ryan D. Shepard ◽

Shawn Gouty ◽

Ludovic D. Langlois ◽

William J. Flerlage ◽

...

Keyword(s):

Opioid Receptor ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Kappa Opioid Receptor ◽

Receptor Signaling ◽

Kappa Opioid ◽

Lateral Habenula

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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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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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Early life stress alters transcriptomic patterning across reward circuitry in male and female mice

Nature Communications ◽

10.1038/s41467-019-13085-6 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 12

Author(s):

Catherine Jensen Peña ◽

Milo Smith ◽

Aarthi Ramakrishnan ◽

Hannah M. Cates ◽

Rosemary C. Bagot ◽

...

Keyword(s):

Life Stress ◽

Early Life ◽

Cortical Plasticity ◽

Early Life Stress ◽

Stress Sensitivity ◽

Sensitive Period ◽

Male And Female ◽

Reward Circuitry ◽

Female Mice ◽

Increase Risk

Abstract Abuse, neglect, and other forms of early life stress (ELS) significantly increase risk for psychiatric disorders including depression. In this study, we show that ELS in a postnatal sensitive period increases sensitivity to adult stress in female mice, consistent with our earlier findings in male mice. We used RNA-sequencing in the ventral tegmental area, nucleus accumbens, and prefrontal cortex of male and female mice to show that adult stress is distinctly represented in the brain’s transcriptome depending on ELS history. We identify: 1) biological pathways disrupted after ELS and associated with increased behavioral stress sensitivity, 2) putative transcriptional regulators of the effect of ELS on adult stress response, and 3) subsets of primed genes specifically associated with latent behavioral changes. We also provide transcriptomic evidence that ELS increases sensitivity to future stress through enhancement of known programs of cortical plasticity.

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17. Lifelong Transcriptional, Epigenetic, and Neurophysiological Consequences of Early Life Stress in Mouse Brain Reward Circuitry

Biological Psychiatry ◽

10.1016/j.biopsych.2018.02.034 ◽

2018 ◽

Vol 83 (9) ◽

pp. S7

Author(s):

Catherine Pena ◽

Hope Kronman ◽

Allyson Friedman ◽

Deena Walker ◽

Hannah Cates ◽

...

Keyword(s):

Mouse Brain ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Reward Circuitry ◽

Brain Reward

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Early life stress alters transcriptomic patterning across reward circuitry in male and female mice

10.1101/624353 ◽

2019 ◽

Author(s):

Catherine Jensen Peña ◽

Milo Smith ◽

Aarthi Ramakrishnan ◽

Hannah M. Cates ◽

Rosemary C. Bagot ◽

...

Keyword(s):

Life Stress ◽

Early Life ◽

Cortical Plasticity ◽

Early Life Stress ◽

Stress Sensitivity ◽

Sensitive Period ◽

Male And Female ◽

Reward Circuitry ◽

Female Mice ◽

Increase Risk

ABSTRACTAbuse, neglect, and other forms of early life stress (ELS) significantly increase risk for psychiatric disorders including depression. In this study, we show that ELS in a postnatal sensitive period increases sensitivity to adult stress in female mice, consistent with our earlier findings in male mice. We used RNA-sequencing in the ventral tegmental area, nucleus accumbens, and prefrontal cortex of male and female mice to show that adult stress is distinctly represented in the brain’s transcriptome depending on ELS history. We identify: 1) biological pathways disrupted after ELS and associated with increased behavioral stress sensitivity, 2) putative transcriptional regulators of the effect of ELS on adult stress response, and 3) subsets of primed genes specifically associated with latent behavioral changes. We also provide transcriptomic evidence that ELS increases sensitivity to future stress through enhancement of known programs of cortical plasticity.

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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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Early-Life Neglect Alters Emotional and Cognitive Behavior in a Sex-Dependent Manner and Reduces Glutamatergic Neuronal Excitability in the Prefrontal Cortex

Frontiers in Psychiatry ◽

10.3389/fpsyt.2020.572224 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiuping Sun ◽

Yu Zhang ◽

Xianglei Li ◽

Xinmin Liu ◽

Chuan Qin

Keyword(s):

Life Stress ◽

Early Life ◽

Child Neglect ◽

Neuronal Excitability ◽

Early Life Stress ◽

Reference Memory ◽

Male Rats ◽

Early Weaning ◽

Spatial Reference ◽

Spatial Reference Memory

Early-life neglect in critical developmental periods has been associated with emotional and cognitive consequences. Maternal separation (MS) has been commonly used as a rodent model to identify the developmental effects of child neglect. However, reports have shown considerable variability in behavioral results from MS studies in both mice and rats. Difficulties in developing reliable child neglect models have impeded advances in identifying the effects of early-life stress. Accumulating evidence shows that neuronal intrinsic excitability plays an important role in information processing and storage in the brain. The prefrontal cortex (PFC) integrates information from many cortical and subcortical structures. No studies to date have examined the impact of early-life stress on glutamatergic neuronal excitability in the PFC. This study aimed to develop a reliable child neglect rat model and observe glutamatergic neuronal excitability in the PFC. An MS with early weaning (MSEW) rat model was developed. Rats were separated from the dam for 4 h per day on postnatal days (PNDs) 2–5 and for 8 h per day on PNDs 6–16 and then weaned on PND 17. A battery of behavioral tests was used to assess anxiety-like behavior, coping behavior, working memory, spatial reference memory, and fear memory. The action potentials (APs) of glutamatergic neuronal membranes were recorded. MSEW resulted in anxiety-like behavior, a passive coping strategy and increased fear memory in male rats and decreased locomotor activity in both sexes. MSEW slightly impaired working memory during non-stressful situations in female rats but did not change spatial reference memory or associative learning under stressful circumstances in either sex. MSEW reduced the number of glutamatergic neuron APs in male rats. Our findings showed that MS with early weaning induced anxiety-like behavior in male rats. The reduced glutamatergic neuronal excitability may be associated with the emotional alteration induced by MSEW in male rats. In addition, MSEW induced adaptive modification, which depended on a non-stressful context.

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