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

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

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

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.

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

2020 ◽  
Author(s):  
Sarah C. Simmons ◽  
Ryan D. Shepard ◽  
Shawn Gouty ◽  
Ludovic D. Langlois ◽  
Brian M. Cox ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
P38 Mapk ◽  
Life Stress ◽  
Early Life ◽  
Neuronal Excitability ◽  
Early Life Stress ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Lateral Habenula ◽  
Reward Circuitry

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.

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

2020 ◽  
Vol 13 ◽  
pp. 100267 ◽  
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

scholarly journals Adolescent Stress Increases Adult Ethanol Self-administration and Alters Ventral Tegmental Area GABA Signaling

2019 ◽  
Author(s):  
David A Connor ◽  
Ruthie E Wittenberg ◽  
Jillian Drogin ◽  
Allison Mak ◽  
John A Dani
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Alcohol Use Disorders ◽  
Early Life Stress ◽  
Male Rats ◽  
Stress Exposure ◽  
Self Administration ◽  
Adolescent Stress ◽  
Gaba Signaling

AbstractAlcohol use disorders (AUDs) continue to be a significant public health problem. Early life stress and adversity have long-lasting effects on a wide range of behaviors, including responses to drugs of abuse. Epidemiological evidence indicates that exposure to early life stress contributes to alcohol use disorders and, while it is known that stress and alcohol both act on overlapping mesolimbic circuitry, the cellular mechanisms underlying the relationship between stress and alcohol intake are not well understood. Previous work has demonstrated that acute stress increases ethanol intake mediated by changes in GABA signaling within the ventral tegmental area (VTA). Here we investigated if adolescent stress exposure might elicit long-term, persistent increases in ethanol self-administration associated with altered VTA GABA signaling. To this end, we exposed adolescent postnatal day (PND) 28 male rats to 14 days of chronic variable stress (CVS) and then examined operant ethanol self-administration begun at least 30 days later. We found that adolescent stress exposure resulted in significantly increased ethanol self-administration in adulthood. In contrast, adult (PND 82) male rats exposed to the same CVS protocol did not display increased ethanol self-administration that was begun 30 days later. Furthermore, we found that adolescent stress exposure resulted in enhancement of ethanol-induced GABA signaling onto VTA dopamine neurons and impairments in VTA GABA chloride homeostasis. The results indicate that adolescence is a period vulnerable to stress, which produces long-term changes in VTA GABA signaling associated with increased ethanol self-administration behavior.

P.6.a.009 Increased ethanol self-administration associated with synaptic plasticity alterations induced by early life stress in mice

2014 ◽  
Vol 24 ◽  
pp. S657-S658
Author(s):  
M.S. Garcia-Gutierrez ◽  
F. Navarrete ◽  
A. Aracil-Fernández ◽  
A. Bartoll ◽  
J. Lanciego ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Life Stress ◽  
Early Life ◽  
Early Life Stress ◽  
Self Administration

Effects of early life stress on cocaine self-administration in post-pubertal male and female rhesus macaques

2019 ◽  
Vol 236 (9) ◽  
pp. 2785-2796 ◽  
Author(s):  
Alison G. P. Wakeford ◽  
Elyse L. Morin ◽  
Sara N. Bramlett ◽  
Brittany R. Howell ◽  
Kai M. McCormack ◽  
...  
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Rhesus Macaques ◽  
Early Life Stress ◽  
Self Administration ◽  
Male And Female ◽  
Female Rhesus ◽  
Female Rhesus Macaques

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

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.

scholarly journals Early Life Stress Promotes Heroin Seeking But Does Not Alter the Excitability of Insular Pyramidal Cells Targeting the Nucleus Accumbens

2021 ◽  
Vol 15 ◽  
Author(s):  
Jonna M. Leyrer-Jackson ◽  
Paula F. Overby ◽  
Erin K. Nagy ◽  
M. Foster Olive
Keyword(s):  
Nucleus Accumbens ◽  
Adverse Childhood Experiences ◽  
Life Stress ◽  
Early Life ◽  
Pyramidal Neurons ◽  
Early Life Stress ◽  
Self Administration ◽  
Childhood Experiences ◽  
Adverse Childhood ◽  
Seeking Behavior

A number of retrospective studies have demonstrated adverse childhood experiences are associated with increased vulnerability to substance use disorders, including opioid use disorders (OUDs). These adverse childhood experiences, also referred to as early life stress (ELS), can be modeled in laboratory animals by various paradigms including limited bedding and nesting (LBN) procedures. Studies using rodent models of ELS have been shown to recapitulate various aspects of OUDs, including relapse propensity and perseverance of drug-seeking behavior. In the current study, we utilized the LBN paradigm to explore potential effects on heroin self-administration, extinction, and relapse-like behaviors in male and female rats. We also utilized in vitro whole-cell electrophysiology to examine the effects of LBN and repeated heroin administration on the excitability of pyramidal neurons in the anterior insular cortex (AIC) projecting to the nucleus accumbens core (NAc), as recent studies suggest that this circuit may mediate various aspects of OUDs and may be compromised as a result of either ELS or OUDs. We observed that compared to control animals, rats exposed to LBN conditions during postnatal days 2–9 showed increased breakpoints for heroin self-administration under a progressive ratio schedule of reinforcement, impaired extinction of heroin-seeking behavior, and increased reinstatement of heroin-seeking behavior induced by heroin-associated cues. No effect of LBN rearing conditions were observed on the acquisition and maintenance of heroin self-administration, and no sex differences in heroin intake were observed. LBN and control reared animals showed no differences in the excitability of AIC-NAc pyramidal neurons, but animals treated with repeated heroin showed decreased excitability of these neurons through a significant increase in rheobase and reduction in action potentials induced by depolarizing currents. Together, these results suggest that ELS exposure produces exacerbations of heroin seeking behavior without parallel effects on AIC-NAc excitability, although heroin itself reduces the excitability of these neurons.

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