Biology subjects

Flanigan, M. E.

Publications and source records attributed to Flanigan, M. E..

6 recordsLinked to original sources

bioRxiv2024

Dynamic regulation of CeA gene expression during acute and protracted abstinence from chronic binge drinking of male and female C57BL/6J mice.

Binge alcohol consumption is a major risk factor for developing Alcohol Use Disorder (AUD) and is associated with alcohol-related problems like accidental injury, acute alcohol poisoning, and black-outs. While there are numerous brain regions that have been shown to play a role in this AUD in humans and animal models, the central nucleus of the amygdala (CeA) has emerged as a critically important locus mediating binge alcohol consumption. In this study, we sought to understand how relative gene expression of key signaling molecules in the CeA changes during different periods of abstinence following bouts of binge drinking. To test this, we performed drinking in the dark (DID) on two separate cohorts of C57BL/6J mice and collected CeA brain tissue at one day (acute) and 7 days (protracted) abstinence after DID. We used qRTPCR to evaluate relative gene expression changes of 25 distinct genes of interest related to G protein-coupled receptors (GPCRs), neuropeptides, ion channel subunits, and enzymes that have been previously implicated in AUD. Our findings show that during acute abstinence CeA punches collected from female mice had upregulated relative mRNA expression of the gamma-aminobutyric acid receptor subunit alpha 2 (Gabra2), and the peptidase, angiotensinase c (Prcp). CeA punches from male mice at the same time point in abstinence had upregulated relative mRNA encoding for neuropeptide-related molecules, neuropeptide Y (Npy) and somatostatin (Sst), as well as the neuropeptide Y receptor Y2 (Npyr2) but downregulated, Glutamate ionotropic receptor NMDA type subunit 1 (Grin1). After protracted abstinence CeA punches collected from female mice had increased mRNA expression of corticotropin releasing hormone (Crh) and Npy. While CeA punches collected from male mice at the same timepoint had upregulated relative mRNA expression of Npy2r and downregulated mRNA expression of Gabra2, Grin1 and opioid receptor kappa 1 (Oprk1). Our findings support that there are differences in how the CeA of male and female respond to binge-alcohol exposure, highlighting the need to understand the implications of such differences in the context of AUD and binge drinking behavior.

neuroscience↗

bioRxiv2023

Bed Nucleus of the Stria Terminalis (BNST) neurons containing the serotonin 5HT2c receptor modulate operant alcohol self-administration behavior in mice

The serotonin 5HT2c receptor has been widely implicated in the pathophysiology of alcohol use disorder (AUD), particularly alcohol seeking and the affective consequences of chronic alcohol consumption. However, little is known about the brain sites in which 5HT2c exerts its effects on specific alcohol-related behaviors, especially in females. Here, we investigated the effects of site-specific manipulation of the 5HT2c receptor system in the BNST on operant alcohol self-administration behaviors in adult mice of both sexes, including the acquisition and maintenance of fixed-ratio responding, motivation for alcohol (progressive ratio), and quinine-adulterated responding for alcohol on a fixed-ratio schedule (punished alcohol seeking). Knockdown of 5HT2c in the BNST did not affect the acquisition or maintenance of operant alcohol self-administration, nor did it affect progressive ratio responding for alcohol. This manipulation had only a subtle effect on responding for quinine alcohol selectively in females. On the other hand, chemogenetic inhibition of BNST 5HT2c-containing neurons (BNST5HT2c) increased operant alcohol self-administration behavior in both sexes on day 2, but not day 9, of testing. It also increased operant responding for 1000 M quinine-adulterated alcohol selectively in males. Importantly, chemogenetic inhibition of BNST5HT2c did not alter operant sucrose responding or motivation for sucrose in either sex. We then performed cell-type specific anterograde tracing, which revealed that BNST5HT2c project to similar regions in males and females, many of which have been previously implicated in AUD. We next used chemogenetics and quantification of the immediate early gene cFos to characterize the functional influence of BNST5HT2c inhibition on vlPAG activity. We show that chemogenetic inhibition of BNST5HT2c reduces vlPAG cFos in both sexes, but that this reduction is more robust in males. Together these findings suggest that BNST5HT2c neurons, and to a small extent the BNST 5HT2c receptor, serve to promote aversive responses to alcohol consumption, potentially through sex-dependent disinhibition of vlPAG neurons.

neuroscience↗

bioRxiv2022

Sex-specific regulation of binge drinking and affective behaviors by subcortical serotonin 5HT2c receptors

Serotonin 5HT2c receptors have been implicated in the pathophysiology of both mood disorders and alcohol use disorder, but the circuits mediating the effects of systemic pharmacological manipulations of this receptor on behavior have not been identified. Binge alcohol consumption induces discrete social and arousal disturbances in human populations, which are thought to promote increased drinking. However, whether models of binge drinking in rodents can induce these same long-term negative behavioral symptoms is unknown. In this study, we employed multiple anatomical, physiological, and behavioral approaches to identify two populations of neurons expressing serotonin 5HT2c receptors, one in the lateral habenula (LHb5HT2c) and one in the bed nucleus of the stria terminalis (BNST5HT2c), that display coordinated in-vivo responses to social, arousal, and alcohol-related stimuli and are physiologically modulated by binge alcohol consumption in a sex-specific manner. Critically, these physiological changes were associated with sex-specific behavioral disturbances that closely mirror social and arousal symptoms observed in humans during abstinence from binge drinking. Specifically, we observed that one week of abstinence from three weeks of binge alcohol drinking induced social recognition deficits in females and potentiated acoustic startle responses in males. While both populations of neurons (BNST and LHb) and the 5HT2c receptor itself contribute to the sex-specific effects of alcohol on social and arousal behaviors to some degree, the primary causal mechanism underlying these phenomena appears to be excessive activation of LHb5HT2c neurons. These findings may have implications for the development of sex-specific treatments for mood and alcohol use disorders targeting the brains serotonin system.

neuroscience↗

bioRxiv2020

LRRK2 mutation alters behavioral, synaptic and non-synaptic adaptations to acute social stress

Parkinsons disease (PD) risk is increased by stress and certain gene mutations, including the most prevalent PD-linked mutation LRRK2-G2019S. Both PD and stress increase risk for psychiatric symptoms, yet it is unclear how PD-risk genes alter neural circuitry in response to stress that may promote psychopathology. Here we show significant differences between adult G2019S knockin and wildtype (wt) mice in stress-induced behaviors, with an unexpected uncoupling of depression-like and hedonic-like responses in G2019S mice. Moreover, mutant spiny projection neurons in nucleus accumbens (NAc) lack an adaptive, stress-induced change in excitability displayed by wt neurons, and instead show stress-induced changes in synaptic properties that wt neurons lack. Some synaptic alterations in NAc are already evident early in postnatal life. Thus, G2019S alters the magnitude and direction of behavioral responses to stress that may reflect unique modifications of adaptive plasticity in cells and circuits implicated in psychopathology in humans.

neuroscience↗

bioRxiv2019

Extended Amygdala Kappa Opioid Receptor Signaling Gates Alcohol-induced Stress Impairments in Mice

"The authors have withdrawn their manuscript because they identified errors in the methods and data reporting that make the results and conclusions unreliable. The published version of this preprint has already been retracted. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author."

neuroscience↗

bioRxiv2019

Divergent behavioral responses in protracted opioid withdrawal in male and female C57BL/6J mice

Persons suffering from opioid use disorder (OUD) experience long-lasting dysphoric symptoms well into extended periods of withdrawal. This protracted withdrawal syndrome is notably characterized by heightened anxiety. Here we investigate if an exacerbated withdrawal model of acute morphine dependence results in lasting behavioral adaptation 6 weeks into forced abstinence. We found that our exacerbated morphine withdrawal paradigm produced distinct impairments in elevated-plus maze, open field, and social interaction tests in male and female mice. These findings will be relevant for future investigation examining the neural mechanisms underlying these behaviors, and will aid in uncovering physiological sex differences in response to opioid withdrawal.

neuroscience↗