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

Autor: Shawn Gouty, Ludovic D. Langlois, Sarah C. Simmons, William J. Flerlage, Fereshteh S. Nugent, Ryan D. Shepard, Brian M. Cox
Rok vydání: 2020
Předmět:
inter-event interval
(IEI)
Physiology
miniature excitatory postsynaptic current
(mEPSC)
corticotropin-releasing factor
(CRF)
Stimulation
Dynorphin
hyperpolarization activated cation current
(HCN
Ih)
Biochemistry
dopamine
(DA)
lcsh:RC346-429
0302 clinical medicine
Endocrinology
Lateral habenula
Premovement neuronal activity
Original Research Article
nucleus accumbens
(NAc)
postnatal age
(PN)
early life stress
(ELS)
Chemistry
lcsh:QP351-495
Glutamate receptor
Kappa opioid receptor
(KOR)
raphe nuclei
(RN)
miniature inhibitory postsynaptic current
(mIPSC)
GABAergic
adverse childhood experiences
(ACE)
hormones
hormone substitutes
and hormone antagonists
fastafterhyperpolarization
(fAHP)
endocrine system
maternal deprivation
(MD)
rostromedial tegmental area
(RMTg)
input resistance
(Rin)
AMPA receptor
Neurotransmission
κ-opioid receptor
lcsh:RC321-571
action potential
(AP)
03 medical and health sciences
Cellular and Molecular Neuroscience
medium afterhyperpolarization
(mAHP)
non-maternally deprived
(non-MD)
Kappa opioid receptor
LHb
serotonin
(5HT)
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Molecular Biology
lcsh:Neurology. Diseases of the nervous system
KOR
dynorphin
(Dyn)
ventral tegmental area
(VTA)
Endocrine and Autonomic Systems
Early life stress
artificial cerebral spinal fluid
(ACSF)
030227 psychiatry
lcsh:Neurophysiology and neuropsychology
nervous system
Neuroscience
030217 neurology & neurosurgery
Zdroj: Neurobiology of Stress
Neurobiology of Stress, Vol 13, Iss, Pp 100267-(2020)
ISSN: 2352-2895
Popis: The 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 spontaneous neuronal activity and intrinsic excitability while blunting the response of LHb neurons to extrahypothalamic 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) exerted differential effects on the excitability of two distinct sub-populations of LHb neurons that differed in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increased neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreasing neuronal excitability in small/negative Ih (Ih-) neurons. We found that an intact fast-synaptic transmission was required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. While AMPAR-, GABAAR-, or NMDAR-mediated synaptic transmission alone was sufficient to mediate the effects of U50,488 on excitability of Ih- neurons, either GABAAR- or NMDAR-mediated synaptic transmission could mediate these effects in Ih+ neurons. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission where stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons while primarily decreased or in some cases increased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreasing mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. Moreover, 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 functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD.
Graphical abstract Image 1
Highlights • Lateral Habenula (LHb) neurons differ in synaptic activity and membrane properties. • Kappa opioid receptors (KOR) alter excitability of distinct LHb neurons. • KOR stimulation alters GABAergic and glutamatergic synaptic signaling in LHb. • Early life stress increases dynorphin A protein in LHb, decreases KOR expression. • Early life stress blunts LHb neuronal responses to KOR signaling.
Databáze: OpenAIRE
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