Alcohol Dependence Modifies Brain Networks Activated During Withdrawal and Reaccess: A c-Fos–Based Analysis in Mice

Roland, Alison V.; Coelho, Cesar A.O.; Haun, Harold L.; Gianessi, Carol A.; López, Marcelo F.; D’Ambrosio, Shannon; Machinski, Samantha; Kroenke, Christopher D.; Frankland, Paul W.; Becker, Howard C.; Kash, Thomas L.

doi:10.1016/j.biopsych.2023.01.018

Cited by 28 publications

(26 citation statements)

References 39 publications

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“…Apart from electrophysiological recordings, we also utilized an additional approach, c-fos immunohistochemistry, to monitor neuronal activity. c-fos is an immediate early gene and a marker of increased neuronal activity, which is widely used to assess patterns of neuronal activity . As expected, a robust increase in c-fos expression in vDG was seen in the Pb-exposed group and the Ctrl + ChR2 group compared to Ctrl mice, while the expression was back to the basal level after photoinhibition in the Pb + eNpHR3.0 group (Figure ).…”

Section: Resultssupporting

confidence: 65%

“…c-fos is an immediate early gene and a marker of increased neuronal activity, which is widely used to assess patterns of neuronal activity. 40 As expected, a robust increase in c-fos expression in vDG was seen in the Pbexposed group and the Ctrl + ChR2 group compared to Ctrl mice, while the expression was back to the basal level after photoinhibition in the Pb + eNpHR3.0 group (Figure 4). These experiment results again demonstrated the effects of Pb exposure and optogenetic stimulation on neuronal activity.…”

Section: Excitatory Neuronal Hyperexcitation In Vdg Caused Pb-induced...supporting

confidence: 73%

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Chronic Pb Exposure Induces Anxiety and Depression-like Behaviors in Mice via Excitatory Neuronal Hyperexcitability in Ventral Hippocampal Dentate Gyrus

Zhou

Huang

et al. 2023

Environ. Sci. Technol.

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Lead (Pb) is a widespread neurotoxic pollutant. Pb exposure is associated with mood disorders, with no well-established neural mechanisms elucidated. In the present study, we aimed to investigate whether excitatory neurons in the dentate gyrus subregion of the ventral hippocampus (vDG) played a key role in Pb-induced anxiety and depression-like behaviors. C57BL/6 mice were exposed to 100 ppm Pb starting on day 1 of pregnancy until experiments were performed using the offspring. Behavioral studies suggested that chronic Pb exposure triggered anxiety and depression-like behaviors. A combination of electrophysiological, optogenetic, and immunohistochemistry experiments was conducted. Results showed that Pb exposure resulted in excitatory neuronal hyperexcitability in vDG and that the behavioral deficits caused by Pb exposure could be rescued by inhibition of excitatory neuronal activity. Moreover, it was found that the action potential (AP) threshold of excitatory neurons was decreased by electrophysiological recordings. Our study demonstrates a significant role for excitatory neurons in vDG in Pb-induced anxiety and depression-like behaviors in mice, which is likely a result of decreased AP threshold. These outcomes can serve as an important basis for understanding mechanisms of anxiety and depression under environmental Pb exposure and help in the design of therapeutic strategies.

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Section: Resultssupporting

confidence: 65%

Section: Excitatory Neuronal Hyperexcitation In Vdg Caused Pb-induced...supporting

confidence: 73%

Chronic Pb Exposure Induces Anxiety and Depression-like Behaviors in Mice via Excitatory Neuronal Hyperexcitability in Ventral Hippocampal Dentate Gyrus

Zhou

Huang

et al. 2023

Environ. Sci. Technol.

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“…Notable regions downregulated by naltrexone included LA and MPN, which were identified as major contributors to digging bouts and duration through multiple linear regression modeling ( Fig. S1) , and the COA was recently identified to normalize its reactivity with re-access to drinking in dependent animals and when chemogenetically silenced reduce drinking in withdrawal (2).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, withdrawal from alcohol, nicotine, cocaine, and methamphetamine leads to coordinated hyperactivity of the extended amygdala network, with a shift from a cortical-driven to a subcortical-driven network, and a reduction of network modularity as a result. Moreover, after resumed access to alcohol, network modularity normalizes relative to abstinence (2). We hypothesized that these network changes may represent relevant biomarkers of withdrawal in dependency and that pharmacological treatments known to show some level of efficacy in animal models relevant to alcohol use disorder should normalize whole-brain functional connectivity.…”

Section: Introductionmentioning

confidence: 99%

Antagonists of the stress and opioid systems restore the functional connectivity of the prefrontal cortex during alcohol withdrawal through divergent mechanisms

Carrette,

Santos,

Brennan

et al. 2023

Preprint

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Chronic alcohol consumption leads to dependence and withdrawal symptoms upon cessation, contributing to persistent use. However, the brain network mechanisms by which the brain orchestrates alcohol withdrawal and how these networks are affected by pharmacological treatments remain elusive. Recent work revealed that alcohol withdrawal produces a widespread increase in coordinated brain activity and a decrease in modularity of the whole-brain functional network using single-cell whole-brain imaging of immediate early genes. This decreased modularity and functional hyperconnectivity are hypothesized to be novel biomarkers of alcohol withdrawal in alcohol dependence, which could potentially be used to evaluate the efficacy of new medications for alcohol use disorder. However, there is no evidence that current FDA-approved medications or experimental treatments known to reduce alcohol drinking in animal models can normalize the changes in whole-brain functional connectivity. In this report, we tested the effect of R121919, a CRF1 antagonist, and naltrexone, an FDA-approved treatment for alcohol use disorder, on whole-brain functional connectivity using the cellular marker FOS combined with graph theory and advanced network analyses. Results show that both R121919 and naltrexone restored the functional connectivity of the prefrontal cortex during alcohol withdrawal, but through divergent mechanisms. Specifically, R121919 increased FOS activation in the prefrontal cortex, partially restored modularity, and normalized connectivity, particularly in CRF1-rich regions, including the prefrontal, pallidum, and extended amygdala circuits. On the other hand, naltrexone decreased FOS activation throughout the brain, decreased modularity, and increased connectivity overall except for the Mu opioid receptor-rich regions, including the thalamus. These results identify the brain networks underlying the pharmacological effects of R121919 and naltrexone and demonstrate that these drugs restored different aspects of functional connectivity of the prefrontal cortex, pallidum, amygdala, and thalamus during alcohol withdrawal. Notably, these effects were particularly prominent in CRF1- and Mu opioid receptors-rich regions highlighting the potential of whole-brain functional connectivity using FOS as a tool for identifying neuronal network mechanisms underlying the pharmacological effects of existing and new medications for alcohol use disorder.

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“…The distinctions between adaptive and maladaptive memories may not be solely attributed to changes within isolated structures or altered connectivity between pairs of structures, but rather to collective changes across multiple structures within the neural network. Combining the quantification of immediate-early genes expression linked to neural activation such as cfos [36] and network-based graph analysis [37][38][39], it is possible to reveal the brain functional connectivity during active cognitive experiences, such as memory recall [40][41][42][43]. In network models of neural systems, brain regions are represented as nodes, and functional connections between nodes are represented as edges.…”

Section: Introductionmentioning

confidence: 99%

Network-Level Changes in the Brain Underlie Fear Memory Strength

Haubrich

Nader

2023

Preprint

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The strength of a fear memory significantly influences whether it drives adaptive or maladaptive behavior in the future. Yet, how mild and strong fear memories differ in underlying biology is not well understood. We hypothesized that this distinction may not be exclusively the result of changes within specific brain regions, but rather the outcome of collective changes in connectivity across multiple regions within the neural network. To test this, rats were fear conditioned in protocols of varying intensities to generate mild or strong memories. Neuronal activation driven by recall was measured using cfos immunohistochemistry in 12 brain regions implicated in fear learning and memory. The interregional coordinated brain activity was computed and graph-based functional networks were generated to compare how mild and strong fear memories differ at the systems level. Our results show that mild fear recall is supported by a well-connected brain network with small-world properties in which the amygdala is well-positioned to be modulated by other regions. In contrast, this connectivity is disrupted in strong fear memories and the amygdala is isolated from other regions. These findings indicate that the neural systems underlying mild and strong fear memories differ, with implications for understanding and treating disorders of fear dysregulation.

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Alcohol Dependence Modifies Brain Networks Activated During Withdrawal and Reaccess: A c-Fos–Based Analysis in Mice

Cited by 28 publications

References 39 publications

Chronic Pb Exposure Induces Anxiety and Depression-like Behaviors in Mice via Excitatory Neuronal Hyperexcitability in Ventral Hippocampal Dentate Gyrus

Chronic Pb Exposure Induces Anxiety and Depression-like Behaviors in Mice via Excitatory Neuronal Hyperexcitability in Ventral Hippocampal Dentate Gyrus

Antagonists of the stress and opioid systems restore the functional connectivity of the prefrontal cortex during alcohol withdrawal through divergent mechanisms

Network-Level Changes in the Brain Underlie Fear Memory Strength

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