BDNF in Ventrolateral Orbitofrontal Cortex to Dorsolateral Striatum Circuit Moderates Alcohol Consumption and Gates Alcohol Habit.

BDNF plays a crucial role in shaping the structure and function of neurons. BDNF signaling in the dorsolateral striatum (DLS) is part of an endogenous pathway that protects against the development of alcohol use disorder (AUD). Dysregulation of BDNF levels in the cortex or dysfunction of BDNF/TrkB signaling in the DLS results in the escalation of alcohol drinking and compulsive alcohol use.

Prosapip1 in the dorsal hippocampus mediates synaptic protein composition, long-term potentiation, and spatial memory.

Prosapip1 is a brain-specific protein localized to the postsynaptic density, where it promotes dendritic spine maturation in primary hippocampal neurons. However, nothing is known about the role of Prosapip1 in vivo. To examine this, we utilized the Cre-loxP system to develop a Prosapip1 neuronal knockout mouse.

The Small G-Protein Rac1 in the Dorsomedial Striatum Promotes Alcohol-Dependent Structural Plasticity and Goal-Directed Learning in Mice.

The small G-protein Ras-related C3 botulinum toxin substrate 1 (Rac1) promotes the formation of filamentous actin (F-actin). Actin is a major component of dendritic spines, and we previously found that alcohol alters actin composition and dendritic spine structure in the nucleus accumbens (NAc) and the dorsomedial striatum (DMS). To examine if Rac1 contributes to these alcohol-mediated adaptations, we measured the level of GTP-bound active Rac1 in the striatum of mice following 7 weeks of intermittent access to 20% alcohol.

Sex Differences In The Interaction Between Alcohol And mTORC1.

The kinase mechanistic target of rapamycin complex 1 (mTORC1) plays an essential role in learning and memory by promoting mRNA to protein translation of a subset of synaptic proteins at dendrites. We generated a large body of data in male rodents indicating that mTORC1 is critically involved in mechanisms that promote numerous adverse behaviors associated with alcohol use disorder (AUD) including heavy alcohol use. For example, we found that mTORC1 is activated in the nucleus accumbens (NAc) and orbitofrontal cortex (OFC) of male mice and rats that were subjected to 7 weeks of intermittent access to 20% alcohol two-bottle choice (IA20%2BC).

Paradoxical mTORC1-Dependent microRNA-mediated Translation Repression in the Nucleus Accumbens of Mice Consuming Alcohol Attenuates Glycolysis.

mTORC1 promotes protein translation, learning and memory, and neuroadaptations that underlie alcohol use and abuse. We report that activation of mTORC1 in the nucleus accumbens (NAc) of mice consuming alcohol promotes the translation of microRNA (miR) machinery components and the upregulation of microRNAs (miRs) expression including miR-34a-5p. In parallel, we detected a paradoxical mTORC1-dependent repression of translation of transcripts including Aldolase A, an essential glycolytic enzyme.

The small G-protein Rac1 in the dorsomedial striatum promotes alcohol-dependent structural plasticity and goal-directed learning in mice.

Unlabelled: The small G-protein Rac1 promotes the formation of filamentous actin (F-Actin). Actin is a major component of dendritic spines, and we previously found that alcohol alters actin composition and dendritic spine structure in the nucleus accumbens (NAc) and the dorsomedial striatum (DMS). To examine if Rac1 contributes to these alcohol-mediated adaptations, we measured the level of GTP-bound active Rac1 in the striatum of mice following 7 weeks of intermittent access to 20% alcohol.

Leucine-rich repeat kinase 2 limits dopamine D1 receptor signaling in striatum and biases against heavy persistent alcohol drinking.

The transition from hedonic alcohol drinking to problematic drinking is a hallmark of alcohol use disorder that occurs only in a subset of drinkers. This transition requires long-lasting changes in the synaptic drive and the activity of striatal neurons expressing dopamine D1 receptor (D1R). The molecular mechanisms that generate vulnerability in some individuals to undergo the transition are less understood.

Identification of Novel BDNF-Specific Corticostriatal Circuitries.

Brain-derived neurotrophic factor (BDNF) is released from axon terminals originating in the cerebral cortex onto striatal neurons. Here, we characterized BDNF neurons in the corticostriatal circuitry. First, we used -Cre and Ribotag transgenic mouse lines to label BDNF-positive neurons in the cortex and detected expression in all the subregions of the prefrontal cortex (PFC).

The BDNF Val68Met polymorphism causes a sex specific alcohol preference over social interaction and also acute tolerance to the anxiolytic effects of alcohol, a phenotype driven by malfunction of BDNF in the ventral hippocampus of male mice.

Background: The brain-derived neurotrophic factor (BDNF) Valine 66 to Methionine human polymorphism results in impaired activity-dependent BDNF release and has been linked to psychiatric disorders including depression and anxiety. We previously showed that male knock-in mice carrying the mouse Methionine homolog (Met68BDNF) exhibit excessive and compulsive alcohol drinking behaviors as compared to the wild-type Val68BDNF mice.

Objective: Here, we set out to determine the potential mechanism for the heightened and compulsive alcohol drinking phenotypes detected in Met68BDNF mice.

Alcohol and the brain: from genes to circuits.

Alcohol use produces wide-ranging and diverse effects on the central nervous system. It influences intracellular signaling mechanisms, leading to changes in gene expression, chromatin remodeling, and translation. As a result of these molecular alterations, alcohol affects the activity of neuronal circuits.

Monte Carlo renormalization-group calculation for the d=3 Ising model using a modified transformation.

We present a simple approach to high-accuracy calculations of critical properties for the three-dimensional Ising model, without prior knowledge of the critical temperature. The iterative method uses a modified block-spin transformation with a tunable parameter to improve convergence in the Monte Carlo renormalization group trajectory. We found experimentally that the iterative method enables the calculation of the critical temperature simultaneously with a critical exponent.

Investigating the link between serum concentrations of brain-derived neurotrophic factor and behavioral measures in anxious alcohol-dependent individuals.

Brain-derived neurotrophic factor (BDNF) plays a role in different neurophysiological processes, including those involved in alcohol- and anxiety-related behaviors. Preclinical and clinical studies indicate that chronic excessive alcohol use leads to a downregulation of BDNF production in the periphery and in the brain. In addition, a decrease in BDNF concentrations in the blood has been reported to be associated with increased anxiety levels.

cAMP-Fyn signaling in the dorsomedial striatum direct pathway drives excessive alcohol use.

Fyn kinase in the dorsomedial striatum (DMS) of rodents plays a central role in mechanisms underlying excessive alcohol intake. The DMS is comprised of medium spiny neurons (MSNs) that project directly (dMSNs) or indirectly (iMSNs) to the substantia nigra. Here, we examined the cell-type specificity of Fyn's actions in alcohol use.

Differential correlation of serum BDNF and microRNA content in rats with rapid or late onset of heavy alcohol use.

Heavy alcohol use reduces the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex of rodents through the upregulation of microRNAs (miRs) targeting BDNF mRNA. In humans, an inverse correlation exists between circulating blood levels of BDNF and the severity of psychiatric disorders including alcohol abuse. Here, we set out to determine whether a history of heavy alcohol use produces comparable alterations in the blood of rats.

Growth Factors and Alcohol Use Disorder.

Neurotrophic growth factors were originally characterized for their support in neuronal differentiation, outgrowth, and survival during development. However, it has been acknowledged that they also play a vital role in the adult brain. Abnormalities in growth factors have been implicated in a variety of neurological and psychiatric disorders, including alcohol use disorder (AUD).

mTORC1 in the orbitofrontal cortex promotes habitual alcohol seeking.

The mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in dendritic translation and in learning and memory. We previously showed that heavy alcohol use activates mTORC1 in the orbitofrontal cortex (OFC) of rodents (Laguesse et al., 2017a).

Protein Translation and Psychiatric Disorders.

Although historically research has focused on transcription as the central governor of protein expression, protein translation is now increasingly being recognized as a major factor for determining protein levels within cells. The central nervous system relies on efficient updating of the protein landscape. Thus, coordinated regulation of mRNA localization, initiation, or termination of translation is essential for proper brain function.

The Fyn kinase inhibitor, AZD0530, suppresses mouse alcohol self-administration and seeking.

Fyn is a member of the Src family of protein tyrosine kinases (PTKs) that plays an important role not only in normal synaptic functions but also in brain pathologies including alcohol use disorder. We previously reported that repeated cycles of binge drinking and withdrawal activate Fyn in the dorsomedial striatum (DMS) of rodents, and that Fyn signaling in the DMS contributes to rat alcohol intake and relapse. Here, we used AZD0530, a CNS penetrable inhibitor of Src PTKs developed for the treatment of Alzheimer disease and cancer and tested its efficacy to suppress alcohol-dependent molecular and behavioral effects.

D1 receptor hypersensitivity in mice with low striatal D2 receptors facilitates select cocaine behaviors.

Vulnerability for cocaine abuse in humans is associated with low dopamine D2 receptor (D2R) availability in the striatum. The mechanisms driving this vulnerability are poorly understood. In this study, we found that downregulating D2R expression selectively in striatal indirect-pathway neurons triggers a multitude of changes in D1 receptor (D1R)-expressing direct-pathway neurons, which comprise the other main subpopulation of striatal projection neurons.

Increasing Brain-Derived Neurotrophic Factor (BDNF) in medial prefrontal cortex selectively reduces excessive drinking in ethanol dependent mice.

The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) has been implicated in a number of neuropsychiatric disorders, including alcohol use disorder. Studies have shown that BDNF activity in cortical regions, such as the medial prefrontal cortex (mPFC) mediates various ethanol-related behaviors. We previously reported a significant down-regulation in Bdnf mRNA in mPFC following chronic ethanol exposure compared to control mice.