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Article ; Online: Repetitive mild traumatic brain injury induces persistent alterations in spontaneous synaptic activity of hippocampal CA1 pyramidal neurons.

Langlois, Ludovic D / Selvaraj, Prabhuanand / Simmons, Sarah C / Gouty, Shawn / Zhang, Yumin / Nugent, Fereshteh S

IBRO neuroscience reports

2022 Volume 12, Page(s) 157–162

Abstract: Mild traumatic brain injury (mTBI) or concussion is the most common form of TBI which frequently results in persistent cognitive impairments and memory deficits in affected individuals [1]. Although most studies have investigated the role of hippocampal ... ...

Abstract	Mild traumatic brain injury (mTBI) or concussion is the most common form of TBI which frequently results in persistent cognitive impairments and memory deficits in affected individuals [1]. Although most studies have investigated the role of hippocampal synaptic dysfunction in earlier time points following a single injury, the long-lasting effects of mTBI on hippocampal synaptic transmission following multiple brain concussions have not been well-elucidated. Using a repetitive closed head injury (3XCHI) mouse model of mTBI, we examined the alteration of spontaneous synaptic transmission onto hippocampal CA1 pyramidal neurons by recording spontaneous excitatory AMPA receptor (AMPAR)- and inhibitory GABA
Language	English
Publishing date	2022-02-09
Publishing country	Netherlands
Document type	Journal Article
ISSN	2667-2421
ISSN (online)	2667-2421
DOI	10.1016/j.ibneur.2022.02.002
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Article: Blast-Induced Mild Traumatic Brain Injury Alterations of Corticotropin-Releasing Factor Neuronal Activity in the Mouse Hypothalamic Paraventricular Nucleus.

Simmons, Sarah / Langlois, Ludovic D / Oyola, Mario G / Gouty, Shawn / Wu, T John / Nugent, Fereshteh S

Frontiers in synaptic neuroscience

2022 Volume 13, Page(s) 804898

Abstract: Blast-induced mild traumatic brain injury (mbTBI) is the most common cause of TBI in US service members and veterans. Those exposed to TBI are at greater risk of developing neuropsychiatric disorders such as posttraumatic stress disorder, anxiety and ... ...

Abstract	Blast-induced mild traumatic brain injury (mbTBI) is the most common cause of TBI in US service members and veterans. Those exposed to TBI are at greater risk of developing neuropsychiatric disorders such as posttraumatic stress disorder, anxiety and depressive disorders, and substance use disorders following TBI. Previously, we have demonstrated that mbTBI increases anxiety-like behaviors in mice and dysregulates stress at the level of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN). To expand on how mTBI may dysregulate the stress axis centrally, here PVN CRF neuronal activity was evaluated using whole cell-patch clamp recordings in hypothalamic slices from sham and mbTBI adult male CRF:tdTomato mice 7 days post-injury. We found that mbTBI generally did not affect the neuronal excitability and intrinsic membrane properties of PVN CRF neurons; this injury selectively increased the frequency of spontaneous neuronal firing of PVN CRF neurons localized to the dorsal PVN (dPVN) but not ventral PVN (vPVN). Consistently, mbTBI-induced dPVN CRF hyperactivity was associated with pre- and post-synaptic depression of spontaneous GABAergic transmission onto dPVN CRF neurons suggesting that mbTBI-induced GABAergic synaptic dysfunction may underlie dPVN CRF neuronal hyperactivity and increases in dPVN CRF signaling. The present results provide the first evidence for mbTBI-induced alterations in PVN CRF neuronal activity and GABAergic synaptic function that could mediate hypothalamic CRF dysregulation following mbTBI contributing to stress psychopathology associated with blast injury.
Language	English
Publishing date	2022-01-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2592086-8
ISSN	1663-3563
ISSN	1663-3563
DOI	10.3389/fnsyn.2021.804898
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Article ; Online: Opiates and Plasticity in the Ventral Tegmental Area.

Langlois, Ludovic D / Nugent, Fereshteh S

ACS chemical neuroscience

2017 Volume 8, Issue 9, Page(s) 1830–1838

Abstract: Opioids are among the most effective pain relievers; however, their abuse has been on the rise worldwide evident from an alarming increase in accidental opioid overdoses. This demands for an urgent increase in scientific endeavors for better ... ...

Abstract	Opioids are among the most effective pain relievers; however, their abuse has been on the rise worldwide evident from an alarming increase in accidental opioid overdoses. This demands for an urgent increase in scientific endeavors for better understanding of main cellular mechanisms and circuits involved in opiate addiction. Preclinical studies strongly suggest that memories associated with positive and negative opioid experiences are critical in promoting compulsive opiate-seeking and opiate-taking behaviors, and relapse. Particular focus on synaptic plasticity as the cellular correlate of learning and memory has rapidly evolved in drug addiction field over the past two decades. Several critical addiction-related brain areas are identified, one of which is the ventral tegmental area (VTA), an area intensively studied as the initial locus for drug reward. Here, we provide an update to our previous review on "Opiates and Plasticity" highlighting the most recent discoveries of synaptic plasticity associated with opiates in the VTA. Electrophysiological studies of plasticity of addiction to date have been invaluable in addressing learning processes and mechanisms that underlie motivated and addictive behaviors, and now with the availability of powerful technologies of transgenic approaches and optogenetics, circuit-based studies hold high promise in fostering synaptic studies of opiate addiction.
MeSH term(s)	Analgesics, Opioid/adverse effects ; Analgesics, Opioid/pharmacology ; Animals ; Epigenesis, Genetic ; Humans ; Neuronal Plasticity/drug effects ; Neuronal Plasticity/physiology ; Opiate Alkaloids/adverse effects ; Opiate Alkaloids/pharmacology ; Opioid-Related Disorders/metabolism ; Synapses/drug effects ; Synapses/metabolism ; Ventral Tegmental Area/drug effects ; Ventral Tegmental Area/metabolism
Chemical Substances	Analgesics, Opioid ; Opiate Alkaloids
Language	English
Publishing date	2017--20
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.7b00281
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Article ; Online: Effects of Glutamine, Curcumin and Fish Bioactive Peptides Alone or in Combination on Intestinal Permeability in a Chronic-Restraint Stress Model.

Langlois, Ludovic D / Oddoux, Sarah / Aublé, Kanhia / Violette, Paul / Déchelotte, Pierre / Noël, Antoine / Coëffier, Moïse

International journal of molecular sciences

2023 Volume 24, Issue 8

Abstract: Irritable bowel syndrome (IBS), a multifactorial intestinal disorder, is often associated with a disruption in intestinal permeability as well as an increased expression of pro-inflammatory markers. The aim of this study was to first test the impact of ... ...

Abstract	Irritable bowel syndrome (IBS), a multifactorial intestinal disorder, is often associated with a disruption in intestinal permeability as well as an increased expression of pro-inflammatory markers. The aim of this study was to first test the impact of treatment with glutamine (Gln), a food supplement containing natural curcumin extracts and polyunsaturated n-3 fatty acids (Cur); bioactive peptides from a fish protein hydrolysate (Ga); and a probiotic mixture containing
MeSH term(s)	Animals ; Mice ; Male ; Irritable Bowel Syndrome/metabolism ; Glutamine/pharmacology ; Glutamine/metabolism ; Curcumin/pharmacology ; Curcumin/metabolism ; Intestinal Mucosa/metabolism ; Corticosterone/metabolism ; Cytokines/metabolism ; Permeability ; Fatty Acids, Omega-3/pharmacology ; Fatty Acids, Omega-3/metabolism
Chemical Substances	Glutamine (0RH81L854J) ; Curcumin (IT942ZTH98) ; Corticosterone (W980KJ009P) ; Cytokines ; Fatty Acids, Omega-3
Language	English
Publishing date	2023-04-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24087220
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Article ; Online: AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenula.

Simmons, Sarah C / Flerlage, William J / Langlois, Ludovic D / Shepard, Ryan D / Bouslog, Christopher / Thomas, Emily H / Gouty, Kaitlyn M / Sanderson, Jennifer L / Gouty, Shawn / Cox, Brian M / Dell'Acqua, Mark L / Nugent, Fereshteh S

Communications biology

2024 Volume 7, Issue 1, Page(s) 345

Abstract: The scaffolding A-kinase anchoring protein 150 (AKAP150) is critically involved in kinase and phosphatase regulation of synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a key ... ...

Abstract	The scaffolding A-kinase anchoring protein 150 (AKAP150) is critically involved in kinase and phosphatase regulation of synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a key role in brain's processing of rewarding/aversive experiences, however its role in the lateral habenula (LHb, as an important brain reward circuitry) is completely unknown. Using whole cell patch clamp recordings in LHb of male wildtype and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), here we show that the genetic disruption of PKA anchoring to AKAP150 significantly reduces AMPA receptor-mediated glutamatergic transmission and prevents the induction of presynaptic endocannabinoid-mediated long-term depression in LHb neurons. Moreover, ΔPKA mutation potentiates GABA
MeSH term(s)	Animals ; Male ; Mice ; A Kinase Anchor Proteins/genetics ; A Kinase Anchor Proteins/metabolism ; Corticotropin-Releasing Hormone/metabolism ; Endocannabinoids ; Habenula/metabolism ; Neuronal Plasticity/physiology ; Neurons/physiology ; Receptors, AMPA/genetics ; Receptors, AMPA/metabolism ; Receptors, GABA-A/metabolism ; Synaptic Transmission/physiology
Chemical Substances	A Kinase Anchor Proteins ; Corticotropin-Releasing Hormone (9015-71-8) ; Endocannabinoids ; Receptors, AMPA ; Receptors, GABA-A ; Akap5 protein, mouse
Language	English
Publishing date	2024-03-20
Publishing country	England
Document type	Journal Article
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-024-06041-8
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Article ; Online: Histone deacetylase inhibition reduces ventral tegmental area dopamine neuronal hyperexcitability involving AKAP150 signaling following maternal deprivation in juvenile male rats.

Shepard, Ryan D / Langlois, Ludovic D / Authement, Michael E / Nugent, Fereshteh S

Journal of neuroscience research

2020 Volume 98, Issue 7, Page(s) 1457–1467

Abstract: Traumatic early life stress (ELS) is linked to dopamine (DA) dysregulation which increases the probability of developing psychiatric disorders in adolescence and adulthood. Our prior studies demonstrated that a severe early life stressor, a 24-hr ... ...

Abstract	Traumatic early life stress (ELS) is linked to dopamine (DA) dysregulation which increases the probability of developing psychiatric disorders in adolescence and adulthood. Our prior studies demonstrated that a severe early life stressor, a 24-hr maternal deprivation (MD) in juvenile male rats, could lead to altered DA signaling from the ventral tegmental area (VTA) due to impairment of GABAergic synaptic plasticity (promoting GABAergic long-term depression, LTD) with concomitant changes in the abundance of synaptic regulators including A-kinase anchoring protein (AKAP150). Importantly, these MD-induced synaptic changes in the VTA were accompanied by upregulation of histone deacetylase 2, histone hypoacetylation, and were reversible by HDAC inhibition. Using cell-attached and whole-cell patch clamp recordings, we found that MD stress also increased spontaneous VTA DA neuronal activity and excitability in juvenile male rats without affecting intrinsic excitability. Postsynaptic chemical disruption of AKAP150 and protein kinase A interaction increased VTA DA neuronal excitability in control non-MD rats mimicking the effects of MD on DA cell excitability with similar changes in membrane properties. Interestingly, this disruption decreased MD-induced VTA DA hyperexcitability. This MD-induced DA neuronal hyperexcitability could also be normalized at 24 hr after injection of the class 1 HDAC inhibitor, CI-994. Altogether, our data suggest that AKAP150 plays a critical role in the regulation of VTA DA neuronal excitability and that HDAC-mediated targeting of AKAP150 signaling could normalize VTA DA dysfunction following ELS thereby providing novel therapeutic targets for prevention of later life psychopathology.
MeSH term(s)	A Kinase Anchor Proteins/metabolism ; Action Potentials/drug effects ; Animals ; Benzamides/pharmacology ; Dopaminergic Neurons/drug effects ; Dopaminergic Neurons/metabolism ; Dopaminergic Neurons/physiology ; Histone Deacetylase Inhibitors/pharmacology ; Male ; Maternal Deprivation ; Patch-Clamp Techniques ; Phenylenediamines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Synaptic Transmission/drug effects ; Ventral Tegmental Area/drug effects ; Ventral Tegmental Area/metabolism ; Ventral Tegmental Area/physiology
Chemical Substances	A Kinase Anchor Proteins ; Akap5 protein, rat ; Benzamides ; Histone Deacetylase Inhibitors ; Phenylenediamines ; tacedinaline (UMF554N5FG)
Language	English
Publishing date	2020-03-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	195324-2
ISSN	1097-4547 ; 0360-4012
ISSN (online)	1097-4547
ISSN	0360-4012
DOI	10.1002/jnr.24613
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Article: Dopamine Receptor Activation Is Required for GABAergic Spike Timing-Dependent Plasticity in Response to Complex Spike Pairing in the Ventral Tegmental Area.

Langlois, Ludovic D / Dacher, Matthieu / Nugent, Fereshteh S

Frontiers in synaptic neuroscience

2018 Volume 10, Page(s) 32

Abstract: One of the most influential synaptic learning rules explored in the past decades is activity dependent spike-timing-dependent plasticity (STDP). In STDP, synapses are either potentiated or depressed based on the order of pre- and postsynaptic neuronal ... ...

Abstract	One of the most influential synaptic learning rules explored in the past decades is activity dependent spike-timing-dependent plasticity (STDP). In STDP, synapses are either potentiated or depressed based on the order of pre- and postsynaptic neuronal activation within narrow, milliseconds-long, time intervals. STDP is subject to neuromodulation by dopamine (DA), a potent neurotransmitter that significantly impacts synaptic plasticity and reward-related behavioral learning. Previously, we demonstrated that GABAergic synapses onto ventral tegmental area (VTA) DA neurons are able to express STDP (Kodangattil et al., 2013), however it is still unclear whether DA modulates inhibitory STDP in the VTA. Here, we used whole-cell recordings in rat midbrain slices to investigate whether DA D1-like and/or D2-like receptor (D1R/D2R) activation is required for induction of STDP in response to a complex pattern of spiking. We found that VTA but not Substantia nigra pars compact (SNc) DA neurons exhibit long-term depression (LTD
Language	English
Publishing date	2018-09-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2592086-8
ISSN	1663-3563
ISSN	1663-3563
DOI	10.3389/fnsyn.2018.00032
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Article ; Online: Potentiation of glutamatergic synaptic transmission onto lateral habenula neurons following early life stress and intravenous morphine self-administration in rats.

Langlois, Ludovic D / Berman, Rina Y / Shepard, Ryan D / Simmons, Sarah C / Tsuda, Mumeko C / Gouty, Shawn / Choi, Kwang H / Nugent, Fereshteh S

Addiction biology

2021 Volume 27, Issue 1, Page(s) e13064

Abstract: Early life stress presents an important risk factor for drug addiction and comorbid depression and anxiety through persistent effects on the mesolimbic dopamine pathways. Using an early life stress model for child neglect (a single 24 h episode of ... ...

Abstract	Early life stress presents an important risk factor for drug addiction and comorbid depression and anxiety through persistent effects on the mesolimbic dopamine pathways. Using an early life stress 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 the ventral tegmental area and its negative controller, the lateral habenula (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 in the intrinsic excitability of LHb neurons in early adolescent male rats. 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 behaviour in the sucrose preference test and was associated with persistent glutamatergic potentiation 24 h after the last MSA session. MSA also altered the decay time kinetics of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) currents in LHb neurons of control rats during this time period. Our data highlight that early life stress-induced glutamatergic plasticity in LHb may dampen the positive reinforcing and motivational properties of both natural rewards and opioids, and may contribute to the development of anhedonia and dysphoric states associated with opioids.
MeSH term(s)	Animals ; Male ; Rats ; Dopamine/metabolism ; gamma-Aminobutyric Acid/metabolism ; Glutamic Acid/metabolism ; Habenula/drug effects ; Morphine/pharmacology ; Neurons/drug effects ; Receptors, AMPA/metabolism ; Self Administration ; Synaptic Transmission/drug effects ; Ventral Tegmental Area/metabolism ; Stress, Psychological
Chemical Substances	Dopamine (VTD58H1Z2X) ; gamma-Aminobutyric Acid (56-12-2) ; Glutamic Acid (3KX376GY7L) ; Morphine (76I7G6D29C) ; Receptors, AMPA
Language	English
Publishing date	2021-05-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1324314-7
ISSN	1369-1600 ; 1355-6215
ISSN (online)	1369-1600
ISSN	1355-6215
DOI	10.1111/adb.13064
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Zs.A 4586: Show issues

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Article ; Online: Involvement of Lateral Habenula Dysfunction in Repetitive Mild Traumatic Brain Injury-Induced Motivational Deficits.

Flerlage, William J / Langlois, Ludovic D / Rusnak, Milan / Simmons, Sarah C / Gouty, Shawn / Armstrong, Regina C / Cox, Brian M / Symes, Aviva J / Tsuda, Mumeko C / Nugent, Fereshteh S

Journal of neurotrauma

2022 Volume 40, Issue 1-2, Page(s) 125–140

Abstract: Affective disorders including depression (characterized by reduced motivation, social withdrawal, and anhedonia), anxiety, and irritability are frequently reported as long-term consequences of mild traumatic brain injury (mTBI) in addition to cognitive ... ...

Abstract	Affective disorders including depression (characterized by reduced motivation, social withdrawal, and anhedonia), anxiety, and irritability are frequently reported as long-term consequences of mild traumatic brain injury (mTBI) in addition to cognitive deficits, suggesting a possible dysregulation within mood/motivational neural circuits. One of the important brain regions that control motivation and mood is the lateral habenula (LHb), whose hyperactivity is associated with depression. Here, we used a repetitive closed-head injury mTBI model that is associated with social deficits in adult male mice and explored the possible long-term alterations in LHb activity and motivated behavior 10-18 days post-injury. We found that mTBI increased the proportion of spontaneous tonically active LHb neurons yet decreased the proportion of LHb neurons displaying bursting activity. Additionally, mTBI diminished spontaneous glutamatergic and GABAergic synaptic activity onto LHb neurons, while synaptic excitation and inhibition (E/I) balance was shifted toward excitation through a greater suppression of GABAergic transmission. Behaviorally, mTBI increased the latency in grooming behavior in the sucrose splash test suggesting reduced self-care motivated behavior following mTBI. To show whether limiting LHb hyperactivity could restore motivational deficits in grooming behavior, we then tested the effects of Gi (hM4Di)-DREADD-mediated inhibition of LHb activity in the sucrose splash test. We found that chemogenetic inhibition of LHb glutamatergic neurons was sufficient to reverse mTBI-induced delays in grooming behavior. Overall, our study provides the first evidence for persistent LHb neuronal dysfunction due to an altered synaptic integration as causal neural correlates of dysregulated motivational states by mTBI.
MeSH term(s)	Mice ; Male ; Animals ; Habenula/physiology ; Brain Concussion/complications ; Neurons ; Motivation ; Sucrose/pharmacology
Chemical Substances	Sucrose (57-50-1)
Language	English
Publishing date	2022-09-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	645092-1
ISSN	1557-9042 ; 0897-7151
ISSN (online)	1557-9042
ISSN	0897-7151
DOI	10.1089/neu.2022.0224
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Article: Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula.

Simmons, Sarah C / Shepard, Ryan D / Gouty, Shawn / Langlois, Ludovic D / Flerlage, William J / Cox, Brian M / Nugent, Fereshteh S

Neurobiology of stress

2020 Volume 13, Page(s) 100267

Abstract: 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 ... ...

Abstract	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-, GABA
Language	English
Publishing date	2020-11-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2816500-7
ISSN	2352-2895
ISSN	2352-2895
DOI	10.1016/j.ynstr.2020.100267
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