BDNF in the ventral hippocampus and the acute and chronic actions of alcohol

MODIFIED SPECIFIC AIMS

Alcohol has been consumed by humans for more than 4000-years. Luckily, approximately 85%-90% of individuals who consume alcohol socially never develop alcohol use disorder (AUD) symptoms. Using rodents as a model system, we were the first to identify the existence of endogenous signaling pathways that protect against the development of AUD-associated phenotypes and termed these the STOP pathways (Reviews, [1-3]).

Among the STOP genes is Brain-Derived Neurotrophic Factor (BDNF), a neurotrophic factor that through the activation of its receptor TrkB, plays an important role in synaptic plasticity and learning and memory [4]. For example, we found that BDNF signaling in the dorsolateral striatum (DLS) gates the transition from moderate to excessive alcohol use [5-11], and that malfunctioning of BDNF signaling in the DLS and medial prefrontal cortex (mPFC) drives the escalation of alcohol use [12-14].

We also found that mice carrying a common polymorphism (Val68/MetBDNF), which inhibits the normal function of BDNF [15, 16], consume alcohol compulsively [17]. Recently, we found that the anxiolytic actions of alcohol are attenuated in mice carrying the Met68BDNF allele [18](Fig.1). We further found that Met68BDNF mice exhibit increased social anxiety [18](Fig.2-3), and increased alcohol preference vs. social interaction (Fig.4).

Importantly, we found that these behavioral phenotypes are rescued by overexpression of wildtype BDNF in the ventral hippocampus (vHP) of Met68BDNF mice [18](Figs.5-6). We also found that acutely alcohol increases BDNF expression (Fig.7) and activates TrkB signaling in the vHP (Fig.8), whereas chronically alcohol inhibits BDNF/TrkB signaling in the vHP (Figs.9-10).

This proposal is aimed at testing the hypothesis that BDNF in the vHP and/or vHP circuitries in female and/or male mice contributes to the acute anxiolytic and social actions of alcohol, and that malfunction of BDNF in the vHP and/or in vHP projecting neurons promotes alcohol-induced anxiogenesis, social anxiety and alcohol preference over social interaction.

Aim 1 Determine whether BDNF in the vHP and in vHP neurons projecting to the basolateral amygdala and/or lateral septum promotes anxiolysis and whether disruption of BDNF signaling in the vHP and vHP projecting neurons promotes anxiogenesis in males and female mice. We found that acute alcohol administration is less anxiolytic in mice carrying the Met68BDNF allele [18] (Fig.1), a phenotype which was rescued by overexpression of wildtype BDNF in the vHP of male Met68BDNF mice [18](Fig.5).

The vHP plays a role in anxiety [20-22] and anxiolysis [23] in part via its projections to the basolateral amygdala (BLA) and lateral septum (LS), respectively. Using viral tools in combination with behavioral paradigms, we will examine the hypothesis that BDNF in vHP neurons and/or in VHP neurons that project to the BLA and/or LS contributes to alcohol-induced anxiolysis, and that when BDNF signaling in the vHP and/or vHP projecting neurons is disrupted, alcohol promotes anxiogenesis (Model 1).

Aim 2 will examine whether alcohol promotes social behaviors via BDNF in the vHP and/or in vHP neurons projecting to the medial prefrontal cortex and/or lateral septum. We will also determine whether dysregulation of BDNF signaling in the vHP promotes social anxiety and alcohol preference over social interaction in male and female mice. The vHP is associated with social behavior [24-26].

We, and others, found that mice and humans carrying the Met66 (Human) Met68 (mice) allele exhibit social anxiety [18, 27] in male mice (Figs.2-3). We also discovered that male Met68BDNF mice prefer alcohol over social interaction [18](Fig.4), a phenotype that was rescued by overexpression of wildtype Val68BDNF in the vHP of Met68BDNF mice [18](Fig.6).

The vHP projects to the mPFC and LS, and both regions play a role in social behaviors [25, 26, 28]. Using viral approaches with behavioral paradigms, we will examine the hypothesis that BDNF in the vHP and/or in vHP projecting to the mPFC and/or LS contributes to social behavior and that malfunctioning of BDNF signaling in the vHP and/or vHP projecting neurons causes social anxiety and increases alcohol preference vs. social interaction in female and/or male mice (Model 1).

Except for our recent findings [18], nothing is known about the interaction between alcohol and BDNF in the vHP. The experiments described herein will shed the light on the contribution of the vHP circuitry in general and BDNF in the vHP in specific to alcohol-dependent phenotypes in male and female mice.

MODIFIED HEALTH RELEVANCE SECTION