Prefrontal Cortex Glutamatergic Adaptations in a Mouse Model of Alcohol Use Disorder DOI

M. A. Siddiqi,

Dhruba Podder,

Amanda R. Pahng

et al.

Published: Jan. 1, 2023

Alcohol use disorder (AUD) produces cognitive deficits in emotional processing, decision-making, inhibitory control, and working memory, indicating a shift prefrontal cortex (PFC) function. PFC excitatory neurotransmission is mostly mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type ionotropic glutamate receptors (AMPARs); however preclinical studies have focused on other receptor subtypes. Therefore, here we examined the impact of early withdrawal from chronic ethanol AMPAR function mouse medial (mPFC). Naïve, Non-dependent Dependent male C57BL/6J mice were generated using intermittent vapor-two bottle choice (CIE-2BC) paradigm. We used patch-clamp electrophysiology to measure layer 2/3 prelimbic mPFC pyramidal neurons. Since can be impacted subunit composition or plasticity-related proteins, probed their expression levels. had higher spontaneous postsynaptic current (sEPSC) amplitude kinetics compared Naïve/Non-dependent mice. These effects seen during intoxication after 3-8 days withdrawal, action potential-independent, suggesting direct enhancement Surprisingly, 3 decreased genes encoding GluA1/2 subunits (Gria1/2) Further analysis within group revealed negative correlation between Gria1 mRNA levels intake. Finally, synaptic plasticity proteins (Dlg4 Grip1) with dependence. Collectively, these data establish role for adaptations glutamatergic dysfunction associated Future underlying mechanisms that promote alcohol reinforcement, seeking, drinking relapse behavior may help identify new targets AUD treatment.

Language: Английский

The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission DOI Creative Commons
Vicky Chuong, Mehdi Farokhnia, Sophia Khom

et al.

JCI Insight, Journal Year: 2023, Volume and Issue: 8(12)

Published: May 16, 2023

Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in neurobiology of addictive behaviors, and GLP-1 analogues may be used for treatment alcohol use disorder (AUD). Here, we examined effects semaglutide, a long-acting analogue, on biobehavioral correlates rodents. A drinking-in-the-dark procedure was to test semaglutide binge-like drinking male female mice. We also tested dependence-induced rats, as well acute spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced mice; similar effect observed intake other caloric/noncaloric solutions. rats. increased sIPSC frequency CeA ILC neurons alcohol-naive suggesting enhanced GABA release, but had no overall transmission alcohol-dependent In conclusion, analogue decreased across different models species modulated neurotransmission, providing support clinical testing potentially novel pharmacotherapy AUD.

Language: Английский

Citations

91
Neuroimmune regulation of the prefrontal cortex tetrapartite synapse DOI Creative Commons

A. LISS,

Mahum T. Siddiqi,

Paige Marsland

et al.

Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110335 - 110335

Published: Feb. 1, 2025

The prefrontal cortex (PFC) is an essential driver of cognitive, affective, and motivational behavior. There clear evidence that the neuroimmune system directly influences PFC synapses, in addition to its role as first line defense against toxins pathogens. In this review, we describe core structures form tetrapartite synapse, focusing on signaling microdomain created by astrocytic cradling synapse well emerging extracellular matrix synaptic organization plasticity. Neuroimmune signals (e.g. pro-inflammatory interleukin 1β) can impact function each structure within promote intra-synaptic crosstalk, will provide overview recent advances field. Finally, from post mortem human brain tissue preclinical studies indicate inflammation may be a key contributor dysfunction. Therefore, conclude with mechanistic discussion neuroimmune-mediated maladaptive plasticity neuropsychiatric disorders, focus alcohol use disorder (AUD). Growing recognition system's critical regulator provides strong support for targeting develop new pharmacotherapeutics.

Language: Английский

Citations

1
STING antagonist-loaded renal tubule epithelial cell-mimicking nanoparticles ameliorate acute kidney injury by orchestrating innate and adaptive immunity DOI
Yuqi Shen, Fengmin Yang, Feng Wu

et al.

Nano Today, Journal Year: 2024, Volume and Issue: 55, P. 102209 - 102209

Published: Feb. 26, 2024

Language: Английский

Citations

7
Integrative genomics approach identifies glial transcriptomic dysregulation and risk in the cortex of individuals with Alcohol Use Disorder DOI
Anna S. Warden, Nihal A. Salem, Eric Brenner

et al.

Biological Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

1
Sex-dependent factors of alcohol and neuroimmune mechanisms DOI Creative Commons
Bryan Cruz, Vittoria Borgonetti, Michal Bajo

et al.

Neurobiology of Stress, Journal Year: 2023, Volume and Issue: 26, P. 100562 - 100562

Published: Aug. 3, 2023

Excessive alcohol use disrupts neuroimmune signaling across various cell types, including neurons, microglia, and astrocytes. The present review focuses on recent, albeit limited, evidence of sex differences in biological factors that mediate responses to underlying systems may influence drinking behaviors. Females are more vulnerable than males the neurotoxic negative consequences chronic drinking, reflected by elevations pro-inflammatory cytokines inflammatory mediators. Differences cytokine, microglial, astrocytic, genomic, transcriptomic suggest females reactive neuroinflammatory changes after exposure. growing body supports innate immune modulate synaptic transmission, providing a mechanistic framework examine sex-differences neurocircuitry. Targeting be viable strategy for treating AUD, but research is needed understand sex-specific mechanisms.

Language: Английский

Citations

15
Cell-type brain-region specific changes in prefrontal cortex of a mouse model of alcohol dependence DOI Creative Commons
Nihal A. Salem,

L.A. Manzano,

Michael W. Keist

et al.

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 190, P. 106361 - 106361

Published: Nov. 20, 2023

The prefrontal cortex is a crucial regulator of alcohol drinking, and dependence, other behavioral phenotypes associated with AUD. Comprehensive identification cell-type specific transcriptomic changes in dependence will improve our understanding mechanisms underlying the excessive use refine targets for therapeutic development. We performed single nucleus RNA sequencing (snRNA-seq) Visium spatial gene expression profiling on medial (mPFC) obtained from C57BL/6 J mice exposed to two-bottle choice-chronic intermittent ethanol (CIE) vapor exposure (2BC-CIE, defined as dependent group) paradigm which models including escalation drinking. Gene co-expression network analysis differential identified highly dysregulated networks multiple cell types. Dysregulated modules their hub genes suggest novel understudied studying molecular contributing state. A subtype inhibitory neurons was most alcohol-sensitive type contained downregulated module; this module Cpa6, previously by GWAS be consumption. an astrocytic Gpc5 significantly upregulated alcohol-dependent group. To knowledge, there are no studies linking Cpa6 phenotype. also neuroinflammation related types, specifically enriched microglia, further implicating Here, we present comprehensive atlas mediated mPFC identify type-specific implicated dependence.

Language: Английский

Citations

14
IL-18 Signaling in the Rat Central Amygdala Is Disrupted in a Comorbid Model of Post-Traumatic Stress and Alcohol Use Disorder DOI Creative Commons
Vittoria Borgonetti, Bryan Cruz, Valentina Vozella

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(15), P. 1943 - 1943

Published: July 27, 2023

Alcohol use disorder (AUD) and anxiety disorders are frequently comorbid share dysregulated neuroimmune-related pathways. Here, we used our established rat model of post-traumatic stress (PTSD)/AUD to characterize the interleukin 18 (IL-18) system in central amygdala (CeA). Male female rats underwent novel (NOV) familiar (FAM) shock stress, or no (unstressed controls; CTL) followed by voluntary alcohol drinking PTSD-related behaviors, then all received renewed access prior experiments. In situ hybridization revealed that number CeA positive cells for Il18 mRNA increased, while Il18bp decreased both male FAM stressed versus CTL. No changes were observed Il18r1 expression across groups. Ex vivo electrophysiology showed IL-18 reduced GABAA-mediated miniature inhibitory postsynaptic currents (mIPSCs) frequencies CTL, suggesting GABA release, regardless sex. Notably, this presynaptic effect was lost NOV males, it persisted females. mIPSC amplitude CTL rats, effects. Overall, results suggest with impacts IL-18-system and, sex-related fashion, IL-18's modulatory function at synapses.

Language: Английский

Citations

11
Chronic ethanol alters adrenergic receptor gene expression and produces cognitive deficits in male mice DOI Creative Commons

Alexandria C. Athanason,

Tali Nadav,

Chelsea Cates‐Gatto

et al.

Neurobiology of Stress, Journal Year: 2023, Volume and Issue: 24, P. 100542 - 100542

Published: April 28, 2023

Hyperkateifia and stress-induced alcohol cravings drive relapse in individuals with use disorder (AUD). The brain stress signal norepinephrine (also known as noradrenaline) tightly controls cognitive affective behavior was thought to be broadly dysregulated AUD. locus coeruleus (LC) is a major source of forebrain norepinephrine, it recently discovered that the LC sends distinct projections addiction-associated regions suggesting alcohol-induced noradrenergic changes may more region-specific than originally thought. Here we investigated whether ethanol dependence alters adrenergic receptor gene expression medial prefrontal cortex (mPFC) central amgydala (CeA), these mediate impairment negative state withdrawal. We exposed male C57BL/6J mice chronic intermittent vapor-2 bottle choice paradigm (CIE-2BC) induce dependence, assessed reference memory, anxiety-like transcript levels during 3-6 days Dependence bidirectionally altered mouse α1 β mRNA levels, potentially leading reduced mPFC signaling enhanced influence over CeA. These were accompanied by long-term retention deficits shift search strategy modified Barnes maze task, well greater spontaneous digging hyponeophagia. Current clinical studies are evaluating compounds treatment for AUD-associated hyperkatefia, our findings can contribute refinement therapies increasing understanding specific neural systems symptoms targeted.

Language: Английский

Citations

10
Low to moderate ethanol exposure reduces astrocyte-induced neuroinflammatory signaling and cognitive decline in presymptomatic APP/PS1 mice DOI Creative Commons
Shinwoo Kang, Jeyeon Lee, Dina Ali

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Oct. 14, 2024

Alcohol use disorder has been associated with the development of neurodegenerative diseases, including Alzheimer's disease (AD). However, recent studies demonstrate that moderate alcohol consumption may be protective against dementia and cognitive decline. We examined astrocyte function, low-density lipoprotein (LDL) receptor-related protein 1 (LRP1), NF-κB p65 IKK-α/β signaling pathways in modulating neuroinflammation amyloid beta (Aβ) deposition. assessed apolipoprotein E (ApoE) brain APP/PS1 mice using IHC ELISA response to low ethanol exposure (MEE). First, confirm intracerebral distribution ApoE, we co-stained GFAP, a marker for astrocytes biosynthesize ApoE. sought investigate whether ethanol-induced upregulation LRP1 could potentially inhibit activity IL-1β TNF-α induced towards p65, resulting reduction pro-inflammatory cytokines. To evaluate actual Aβ load brains mice, performed specific antibody (Thioflavin S) on both air- ethanol-exposed groups, subsequently analyzing levels. also measured glucose uptake 18F- fluorodeoxyglucose (FDG)-positron emission tomography (PET). Finally, investigated MEE memory changes Y maze, noble object recognition test, Morris water maze. Our findings reduced astrocytic glial fibrillary acidic (GFAP) ApoE levels cortex hippocampus presymptomatic mice. Interestingly, increased expression was accompanied by dampening IKK-α/β-NF-κB pathway, decreased male Notably, female show anti-inflammatory cytokines IL-4, IL-10 without altering concentrations. In males females, plaques, hallmark AD, were exposed starting at pre-symptomatic stage. Consistently, FDG-PET-based activities normalized deficits suggest benefit AD pathology via expression, reducing attenuating study implies astrocyte-derived LDL cholesterol are critical pathology.

Language: Английский

Citations

4
Age- and cytokine-dependent modulation of GABAergic transmission within the basolateral amygdala of male Sprague Dawley rats. DOI
Marvin R. Diaz, Thaddeus M. Barney, Paige Marsland

et al.

Neuropharmacology, Journal Year: 2025, Volume and Issue: 267, P. 110304 - 110304

Published: Jan. 17, 2025

Language: Английский

Citations

0