Polymodal Sensory Thalamic Inputs to the Rat Lateral Amygdala are Facilitated by Chronic Ethanol Exposure and Regulate Withdrawal-associated Anxiety

AbstractThalamic projections to the lateral amygdala regulate the acquisition of conditioned aversive and reward-related behaviors. Recent work suggests that exposure to chronic ethanol up-regulates presynaptic function of lateral amygdala stria terminalis inputs which contain projections from somatosensory thalamic nuclei. To understand potential contributions by thalamic inputs and their role in the expression of withdrawal-associated aversive behaviors, we integrated optogenetic and chemogenetic approaches with in vitro measures of synaptic function and anxiety-like behavior. We found that expression of Channelrhodopsin in the caudal extension of the posterior thalamic group (cPO) produced monosynaptic glutamatergic synaptic responses in lateral amygdala principal neurons that could be inhibited by co-expression of the hM4-Gi-DREADD. Chronic ethanol exposure increased glutamate release from these cPO terminals but did not impact inhibition by the DREADD agonist, CNO. Systemic injection of CNO specifically reduced withdrawal-related increases in anxiety-like behaviors in animals expressing the Gi-DREADD in cPO. And, microinjection of CNO directly into the lateral amygdala mimicked this anti-anxiety effect. These findings suggest that the cPO-LA circuit is vulnerable to chronic ethanol exposure and plays an important role in regulating anxiety-like behavior following chronic ethanol exposure.

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Chronic ethanol-mediated decrease in cAMP primes macrophages to enhanced LPS-inducible NF-κB activity and TNF expression: relevance to alcoholic liver disease

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00098.2006 ◽

2006 ◽

Vol 291 (4) ◽

pp. G681-G688 ◽

Cited By ~ 63

Author(s):

Leila Gobejishvili ◽

Shirish Barve ◽

Swati Joshi-Barve ◽

Silvia Uriarte ◽

Zhenyuan Song ◽

...

Keyword(s):

Liver Disease ◽

Alcoholic Liver Disease ◽

Ethanol Exposure ◽

Chronic Ethanol ◽

Production Studies ◽

Chronic Ethanol Exposure ◽

Tnf Α ◽

Tnf Gene ◽

Camp Levels

Increased plasma and hepatic TNF-α activity has been implicated in the pathogenesis of alcoholic liver disease (ALD). We previously reported that monocytes from alcoholic patients show enhanced constitutive as well as LPS-inducible NF-κB activation and TNF-α production. Studies in monocytes have shown that cAMP plays an important role in regulating TNF-α expression, and elevation of cellular cAMP suppresses TNF-α production. The effects of chronic ethanol exposure on the cellular levels of cAMP as well as TNF expression in monocytes were examined in vitro and in rat primary hepatic Kupffer cells obtained from a clinically relevant enteral alcohol feeding model of ALD. Chronic ethanol exposure significantly decreased cellular cAMP levels in both LPS-stimulated and unstimulated monocytes. Consistent with the decrease in cAMP levels, ethanol led to an increase in LPS-inducible TNF-α production by affecting NF-κB activation and induction of TNF mRNA expression, without any change in TNF mRNA stability. Enhancement of cellular cAMP with dibutyryl cAMP abrogated LPS-mediated TNF-α expression in ethanol-treated cells. Importantly, cAMP did not affect LPS-inducible NF-κB activation but significantly decreased its transcriptional activity. Together, these data strongly suggest that ethanol can synergize with LPS to upregulate the induction of TNF gene expression and consequent TNF overproduction by decreasing the cellular cAMP levels in monocytes/macrophages. Furthermore, these data also support the notion that cAMP-elevating agents could constitute an effective therapeutic approach in attenuating or preventing the progression of liver disease in alcoholic patients.

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Feeding rats a diet enriched with saturated fatty acids prevents the inhibitory effects of acute and chronic ethanol exposure on the in vitro uptake of hexoses and lipids

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism ◽

10.1016/0005-2760(91)90210-9 ◽

1991 ◽

Vol 1084 (2) ◽

pp. 122-128 ◽

Cited By ~ 15

Author(s):

A.B.R. Thomson ◽

M. Keelan ◽

M.T. Clandinin

Keyword(s):

Fatty Acids ◽

Saturated Fatty Acids ◽

Ethanol Exposure ◽

Chronic Ethanol ◽

Inhibitory Effects ◽

Chronic Ethanol Exposure ◽

In Vitro Uptake

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Chronic ethanol exposure differentially affects the migratory capacity of hepatic compared to splenic dendritic cells in vitro and in vivo

Alcohol ◽

10.1016/j.alcohol.2006.09.020 ◽

2006 ◽

Vol 39 (2) ◽

pp. 115

Author(s):

Audrey H. Lau ◽

Bridget L. Colvin ◽

Angus W. Thomson

Keyword(s):

Dendritic Cells ◽

Ethanol Exposure ◽

Chronic Ethanol ◽

Chronic Ethanol Exposure ◽

Migratory Capacity

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Withdrawal from Chronic Ethanol Exposure Increases Postsynaptic Glutamate Function of Insular Cortex Projections to the Rat Basolateral Amygdala

10.1101/772053 ◽

2019 ◽

Author(s):

Molly M. McGinnis ◽

Brian C. Parrish ◽

Brian A. McCool

Keyword(s):

Synaptic Plasticity ◽

Negative Affect ◽

Basolateral Amygdala ◽

Glutamate Release ◽

Insular Cortex ◽

Ethanol Exposure ◽

Ethanol Withdrawal ◽

Chronic Ethanol ◽

Chronic Ethanol Exposure ◽

Chronic Intermittent Ethanol

AbstractA key feature of alcohol use disorder (AUD) is negative affect during withdrawal, which often contributes to relapse and is thought to be caused by altered brain function, especially in circuits that are important mediators of emotional behaviors. Both the agranular insular cortex (AIC) and the basolateral amygdala (BLA) regulate emotions and are sensitive to ethanol-induced changes in synaptic plasticity. The AIC and BLA are reciprocally connected, however, and the effects of chronic ethanol exposure on this circuit have yet to be explored. Here, we use a combination of optogenetics and electrophysiology to examine the pre- and postsynaptic changes that occur to AIC – BLA synapses following withdrawal from 7- or 10-days of chronic intermittent ethanol (CIE) exposure. While CIE/withdrawal did not alter presynaptic glutamate release probably from AIC inputs, withdrawal from 10, but not 7, days of CIE increased AMPA receptor-mediated postsynaptic function at these synapses. Additionally, NMDA receptor-mediated currents evoked by electrical stimulation of the external capsule, which contains AIC afferents, were also increased during withdrawal. Notably, a single subanesthetic dose of ketamine administered at the onset of withdrawal prevented the withdrawal-induced increases in both AMPAR and NMDAR postsynaptic function. Ketamine also prevented the withdrawal-induced increases in anxiety-like behavior measured using the elevated zero maze. Together, these findings suggest that chronic ethanol exposure increases postsynaptic function within the AIC – BLA circuit and that ketamine can prevent ethanol withdrawal-induced alterations in synaptic plasticity and negative affect.

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Chronic Ethanol Differentially Modulates Glutamate Release from Dorsal and Ventral Prefrontal Cortical Inputs onto Rat Basolateral Amygdala Principal Neurons

10.1101/558189 ◽

2019 ◽

Author(s):

Molly M. McGinnis ◽

Brian C. Parrish ◽

Ann M. Chappell ◽

Brian A. McCool

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Basolateral Amygdala ◽

Glutamate Release ◽

Ethanol Exposure ◽

Chronic Ethanol ◽

Sprague Dawley ◽

Behavioral Alterations ◽

Release Probability ◽

Chronic Ethanol Exposure

AbstractThe medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) have strong reciprocal connectivity. Projections from the BLA to the mPFC can bidirectionally modulate anxiety-related behaviors but it is unclear if the same is true for mPFC to BLA projections. Our laboratory is specifically interested in withdrawal-related anxiety-like behavior and the underlying synaptic plasticity. Here, we use optogenetics and chemogenetics to characterize the neurophysiological and behavioral alterations produced by chronic ethanol exposure and withdrawal on dorsal mPFC/prelimbic (dmPFC/PL) and ventral mPFC (vmPFC/IL) terminals in the BLA. We exposed adult male Sprague-Dawley rats to chronic intermittent ethanol (CIE) using vapor chambers, measured anxiety-like behavior on the elevated zero maze (EZM), and used electrophysiology to record glutamatergic and GABAergic responses in BLA principal neurons. We found that 24-hour withdrawal following a 7-day CIE exposure significantly increased the glutamate release probability from PL/dmPFC terminals, but significantly decreases the glutamate release probability from IL/vmPFC terminals. Chemogenetic inhibition of PL/dmPFC terminals in the BLA attenuated the increased withdrawal-dependent, anxiety-like behavior. These data demonstrate that chronic ethanol exposure and withdrawal strengthens the PL/dmPFC – BLA pathway but weakens the IL/vmPFC – BLA pathway. Moreover, we provide novel evidence that the PL/dmPFC – BLA pathway can modulate anxiety-like behavior. These findings suggest that mPFC-BLA circuits known to regulate the acquisition of aversive behaviors are up-regulated by chronic ethanol while those involved with the extinction of these behaviors are down-regulated.Significance StatementAccumulating evidence suggests that the medial prefrontal cortex and its projections to the basolateral amygdala bidirectionally modulate fear-related behaviors. Since the neuronal circuits for fear and anxiety are thought to overlap, we sought to examine the role of prelimbic and infralimbic subdivisions of the medial prefrontal cortex and their inputs to the basolateral amygdala in regulating anxiety. Specifically, we focused on alcohol withdrawal-induced anxiety-like behavior, which is a commonly reported cause of relapse in human alcoholics. In our study, we used optogenetics and chemogenetics to demonstrate, for the first time, that withdrawal from chronic ethanol exposure strengthens prelimbic synapses, but weakens infralimbic synapses in the basolateral amygdala and that inhibiting glutamate release from prelimbic terminal in the basolateral amygdala reduces anxiety-like behavior.

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