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 Impaired developmental microglial pruning of excitatory synapses on CRH-expressing hypothalamic neurons exacerbates stress responses throughout life

2021 ◽  
Author(s):  
Jessica L Bolton ◽  
Annabel K Short ◽  
Shivashankar Othy ◽  
Cassandra L Kooiker ◽  
Manlin Shao ◽  
...  
Keyword(s):  
Stress Responses ◽  
Life Stress ◽  
Early Life ◽  
Early Life Stress ◽  
Mental Illnesses ◽  
Excitatory Synapses ◽  
Process Dynamics ◽  
Brain Circuits ◽  
Synapse Density ◽  
And Function

The developmental origins of stress-related mental illnesses are well-established, and early-life stress/adversity (ELA) is an important risk factor. However, it is unclear how ELA impacts the maturation of salient brain circuits, provoking enduring vulnerability to stress and stress-related disorders. Here we find that ELA increases the number and function of excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, and implicate disrupted synapse pruning by microglia as a key mechanism. Microglial process dynamics on live imaging, and engulfment of synaptic elements by microglia, were both attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor Mer. Accordingly, selective chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Selective early-life microglial activation also mitigated the adrenal hypertrophy and prolonged stress responses in adult ELA mice, establishing microglial actions during development as powerful contributors to experience-dependent sculpting of stress-related brain circuits.

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 Effects of Early Life Stress on Bone Homeostasis in Mice and Humans

2020 ◽  
Vol 21 (18) ◽  
pp. 6634
Author(s):  
Karin Wuertz-Kozak ◽  
Martin Roszkowski ◽  
Elena Cambria ◽  
Andrea Block ◽  
Gisela A. Kuhn ◽  
...  
Keyword(s):  
Childhood Abuse ◽  
Life Stress ◽  
Early Life ◽  
Stressful Life Events ◽  
Bone Microarchitecture ◽  
Treatment Strategies ◽  
Early Life Stress ◽  
Bone Homeostasis ◽  
Mineral Density ◽  
Depressive Patients

Bone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined for bone microarchitecture (μCT), metabolism (qPCR/ELISA), and neuronal stress mediator expression (qPCR) and compared with a sample of depressive patients with or without early life stress by analyzing bone mineral density (BMD) (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone, and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone microarchitecture. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies.

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.

Early Life Stress Alters Behavior, Immunity, and Microbiota in Rats: Implications for Irritable Bowel Syndrome and Psychiatric Illnesses

2009 ◽  
Vol 65 (3) ◽  
pp. 263-267 ◽  
Author(s):  
Siobhain M. O'Mahony ◽  
Julian R. Marchesi ◽  
Paul Scully ◽  
Caroline Codling ◽  
Anne-Marie Ceolho ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Life Stress ◽  
Early Life ◽  
Early Life Stress ◽  
Psychiatric Illnesses ◽  
Irritable Bowel

scholarly journals Do Adolescent Exposure to Cannabinoids and Early Adverse Experience Interact to Increase the Risk of Psychiatric Disorders: Evidence from Rodent Models

2021 ◽  
Vol 22 (2) ◽  
pp. 730
Author(s):  
Anna Portugalov ◽  
Irit Akirav
Keyword(s):  
Psychiatric Disorders ◽  
Life Stress ◽  
Early Life ◽  
Therapeutic Potential ◽  
Early Life Stress ◽  
Cannabis Use ◽  
Rodent Models ◽  
Long Term Effects ◽  
Self Medication ◽  
Brain And Behavior

There have been growing concerns about the protracted effects of cannabis use in adolescents on emotion and cognition outcomes, motivated by evidence of growing cannabis use in adolescents, evidence linking cannabis use to various psychiatric disorders, and the increasingly perceived notion that cannabis is harmless. At the same time, studies suggest that cannabinoids may have therapeutic potential against the impacts of stress on the brain and behavior, and that young people sometimes use cannabinoids to alleviate feelings of depression and anxiety (i.e., “self-medication”). Exposure to early adverse life events may predispose individuals to developing psychopathology in adulthood, leading researchers to study the causality between early life factors and cognitive and emotional outcomes in rodent models and to probe the underlying mechanisms. In this review, we aim to better understand the long-term effects of cannabinoids administered in sensitive developmental periods (mainly adolescence) in rodent models of early life stress. We suggest that the effects of cannabinoids on emotional and cognitive function may vary between different sensitive developmental periods. This could potentially affect decisions regarding the use of cannabinoids in clinical settings during the early stages of development and could raise questions regarding educating the public as to potential risks associated with cannabis use.

scholarly journals Effects of early life stress on bone homeostasis in mice and humans

2020 ◽  
Author(s):  
Karin Wuertz-Kozak ◽  
Martin Roszkowski ◽  
Elena Cambria ◽  
Andrea Block ◽  
Gisela A. Kuhn ◽  
...  
Keyword(s):  
Childhood Abuse ◽  
Life Stress ◽  
Early Life ◽  
Stressful Life Events ◽  
Bone Microarchitecture ◽  
Treatment Strategies ◽  
Early Life Stress ◽  
Bone Homeostasis ◽  
Mineral Density ◽  
Depressive Patients

AbstractBone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined on bone microarchitecture (μCT), metabolism (qPCR), and neuronal stress mediator expression (qPCR) and contrasted with a sample of depressive patients with or without early life stress by analyzing bone mineral density [BMD] (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone micro-CT. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies.

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