Biology subjects

Mangieri, R. A.

Publications and source records attributed to Mangieri, R. A..

4 recordsLinked to original sources

bioRxiv2025

Alcohol Dependence-Induced Astrocyte Immune Activation in the Nucleus Accumbens

Astrocytes play many physiological roles in the brain including maintenance of brain homeostasis, modulation of synapse formation and function, and regulation of the blood brain barrier permeability. Upon brain exposure to noxious stimuli, astrocytes can become reactive and activate neuroimmune responses. The nucleus accumbens (NAc) is a critical region involved in reward processing and is integrally involved in the establishment and maintenance of alcohol (ethanol, EtOH) dependence. Here we used the chronic intermittent ethanol - two-bottle choice (CIE-2BC) drinking model to induce EtOH dependence in Aldh1l1-eGFP/Rpl10a mice, which allow the pull-down of astrocyte specific RNA using translating ribosome affinity purification (TRAP) procedure. NAc astrocyte translating RNA and bulk-tissue RNA was analyzed by RNA-Seq to identify genes altered by EtOH dependence or EtOH drinking in astrocytes and the bulk NAc. The number of differentially regulated genes was greater in the astrocyte-specific analysis compared to the bulk-tissue suggesting the cell-type specific approach enables greater resolution of the effects of EtOH. In the astrocyte-specific translatome of EtOH dependent animals, genes related to neuroimmune activation were highly enriched with overall activation of pathways related to interferon and interleukin signaling. In addition, pathways relating to oxidative stress and glutathione related responses were enriched in NAc astrocytes from dependent animals. In contrast, the astrocyte response to EtOH drinking identified pathways related to homeostatic changes. These findings highlight the profound immune activation in NAc astrocytes during EtOH dependence which are distinct from the response to lower levels of EtOH exposure. This study identifies astrocyte pathways and genes involved in the transition from alcohol drinking to alcohol dependence and identify potential novel cell type-specific targets that underlie vulnerability to alcohol use.

neuroscience↗

bioRxiv2021

Synaptic Plasticity in the Agranular Insular Cortex Predicts Escalated Ethanol Consumption

The Agranular Insular Cortex (AIC) is implicated in alcohol use disorder and pharmacologically relevant concentrations of acute ethanol inhibit N-methyl-D-aspartate receptor (NMDAR)-mediated glutamatergic synaptic transmission and plasticity onto layer 2/3 AIC pyramidal neurons. However, it is not known whether the actions of ethanol on glutamatergic synapses are means by which chronic ethanol alters mechanisms of learning and memory in AIC as alcohol drinking transitions from controlled to problematic. We utilized the chronic intermittent ethanol (CIE) vapor model of ethanol exposure in adult male mice, alone or in combination with voluntary ethanol consumption, to determine whether glutamatergic synapses on layer 2/3 AIC pyramidal neurons are differentially regulated by different durations and intensities of chronic ethanol exposure. We observed evidence of both ethanol- and age-related metaplasticity of AIC layer 2/3 glutamatergic synapses, as only young adult, ethanol-naive mice exhibited NMDAR-dependent long term depression ex vivo. Our findings also indicated that voluntary ethanol consumption alone can elicit glutamatergic plasticity in vivo. We found that the ratio of NMDAR- to AMPAR-mediated postsynaptic currents was reduced not only in CIE-treated, but also in air-treated, chronically drinking mice relative to ethanol-naive controls. Furthermore, lower NMDA/AMPA ratios were predictive of greater escalation of ethanol consumption. These findings suggest that even moderate exposure to ethanol may elicit plasticity in the agranular insular cortex that contributes to the progression toward uncontrolled drinking.

neuroscience↗

bioRxiv2021

The FDA-approved drug apremilast suppresses alcohol intake: clinical and pre-clinical validation

Treatment options for Alcohol Use Disorders (AUD) have minimally advanced since 2004, while the annual deaths and economic toll have become alarmingly high. Bringing potential therapeutics beyond the bench and into the clinic for AUD requires rigorous pharmacological screening across molecular, behavioral, pre-clinical, and clinical studies in neuroscience. The repurposing of FDA-approved compounds is an effective and expedited means of screening pharmacotherapies for AUD. Here, we demonstrate that apremilast, a phosphodiesterase type 4 inhibitor that is FDA approved for psoriasis and psoriatic arthritis, reduces binge-like alcohol intake and behavioral measures of motivation in unique, preclinical genetic risk models for drinking to intoxication and reduces excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. In a double blind, placebo-controlled human laboratory study in non-treatment seeking individuals with AUD, apremilast significantly reduced the number of drinks per day. Lastly, using site-directed drug infusions and electrophysiology we determined that apremilast may act by increasing neural activity in the nucleus accumbens, an important alcohol-related brain region, to reduce alcohol intake in mice. These results demonstrate that apremilast reduces excessive alcohol drinking across a spectrum of AUD severity and support its importance as a potential therapeutic for AUD.

animal behavior and cognition↗

bioRxiv2020

Estradiol enhances ethanol stimulation of ventral tegmental area dopamine neuron firing without limiting ethanol inhibition onto those neurons

Females can progress to alcohol and other substance use disorders more quickly than males. The ovarian hormone 17{beta}-estradiol (E2) contributes to sex differences observed in drug use and abuse and may be a principal driver of these differences. However, it is not entirely clear how E2 acts to affect processing of ethanol reward, and several brain regions and mechanisms are implicated. We sought to clarify the role of E2 in modulating the response of ventral tegmental area dopamine neurons to ethanol. To this end, we recorded spontaneous action potentials and inhibitory post synaptic currents from dopaminergic neurons in acute horizontal brain slices from ovariectomized (OVX) dopamine neuron reporter mice (Pitx3-eGFP) treated with either vehicle (VEH) or E2. On the basis of prior work, we hypothesized that E2 administration would cause dopamine cells from OVX+E2 animals to show a more substantial ethanol-induced increase in firing rate compared to control animals. Our data confirmed that ethanol stimulation of the firing rate of dopamine neurons from OVX+E2 mice was greater than that of OVX+VEH animals. Further, we hypothesized that the firing rate increase would be accompanied by a concomitant decrease in ethanol stimulated inhibition onto those same neurons. We found that although ethanol caused the expected increase in GABAA receptor-mediated synaptic inhibition in both groups, there was no difference in this response between OVX+E2 and OVX+VEH animals. Our findings lend additional support for the ability of E2 to enhance ventral tegmental area dopamine neuron responses to ethanol and suggest that this effect is not mediated by an E2-elicited suppression of synaptic inhibition.

neuroscience↗