Chronic Intermittent Ethanol Exposure Selectively Increases Synaptic Excitability in the Ventral Domain of the Rat Hippocampus

Abstract

Many studies have implicated hippocampal dysregulation in the pathophysiology of alcohol use disorder (AUD). However, over the past twenty years, a growing body of evidence has revealed distinct functional roles of the dorsal (dHC) and ventral (vHC) hippocampal subregions, with the dHC being primarily involved in spatial learning and memory and the vHC regulating anxiety-and depressive-like behaviors. Notably, to our knowledge, no rodent studies have examined the effects of chronic ethanol exposure on synaptic transmission along the dorsal/ventral axis. To that end, we examined the effects of the chronic intermittent ethanol vapor exposure (CIE) model of AUD on dHC and vHC synaptic excitability. Adult male Long Evans rats were exposed to CIE or air for 10 days (12 hrs/day; targeting blood ethanol levels of 175-225 mg%) and recordings were made 24 hours into withdrawal. As expected, this protocol increased anxiety-like behaviors on the elevated plus-maze and successive alleys test. Extracellular recordings revealed marked CIE-associated increases in synaptic excitation in the CA1 region that were exclusively restricted to the ventral domain of the hippocampus. Western blot analysis of synaptoneurosomal fractions revealed that the expression of two proteins that regulate synaptic strength, GluA2 and SK2, were dysregulated in the vHC, but not the dHC, following CIE. Together, these findings suggest that the ventral CA1 region may be particularly sensitive to the maladaptive effects of chronic ethanol exposure and provide new insight into some of the neural substrates that may contribute to the negative affective state that develops during withdrawal.

Effect of Alcohol on Hippocampal-Dependent Plasticity and Behavior: Role of Glutamatergic Synaptic Transmission

“…Chronic alcohol administration has also been associated with impaired performance in the other cognitive tasks such as the Hebb-Williams maze (working memory assessment; Bond and Digiusto, 1976;Fehr et al, 1976), the radial arm maze (spatial memory; Gál and Bárdos, 1994), the spontaneous alternation paradigm (spatial processing), the attentional set shifting (cognitive flexibility, dependent of frontal cortex; Vedder et al, 2015), the step-down passive avoidance task, the Greek cross maze, and the Shuttlebox task (Farr et al, 2005), all of them of which are related with avoidance learning, which involves the limbic system including the hippocampus (Gabriel, 1993). Chronic intermittent ethanol exposure (CIE) in vapor chambers increases the anxiety-like behaviors in the adult male rats, possibly related to the alterations in the synaptic activity of the ventral hippocampus and not of the dorsal hippocampus (Ewin et al, 2019).…”

Chemogenetic inhibition of a monosynaptic projection from the basolateral amygdala to the ventral hippocampus selectively reduces appetitive, but not consummatory, alcohol drinking-related behaviors

“…Both clinical and preclinical studies have shown that increased BLA excitability is a common feature of AUD and comorbid diseases, like generalized anxiety disorder and post-traumatic stress disorder [4,48,49]. Interestingly, BLA projections to the hippocampus are largely restricted to the ventral domain of this brain region and we have recently reported that a model of vulnerability to AUD and a model of alcohol dependence both lead to increases in hippocampal synaptic excitability that are exclusively restricted to the ventral region of the hippocampus [14,50]. Although additional studies will be needed to establish a causal role of BLA-vHC dysregulation in the behavioral phenotypes promoted by these models, these emerging findings are consistent with the idea that maladaptive increases in BLA-vHC synaptic communication may contribute to both the anxiogenic behaviors and excessive alcohol drinking associated with AUD and comorbid affective conditions.…”

Inhibition of the Ventral Hippocampus Increases Alcohol Drinking

“…While human imaging studies do not differentiate dorsal and ventral areas of the hippocampus, preclinical work in the 1980's suggests that the ventral portion of the hippocampus may be more susceptible to ethanol-related plasticity, exhibiting larger reductions in spine density (Lescaudron & Verna 1985). Interestingly, more recent work supports the idea that the vHC may be more vulnerable to ethanol exposure with reports demonstrating increased excitability which was associated with reduced expression of key proteins that regulate synaptic transmission in the vHC (Almonte et al 2017;Ewin et al 2019). Although this appears opposite to the data presented here, given the complex interactions between the hippocampal subregions in the ventral hippocampus (CA1, CA2, CA3 and Subiculum), sorting out the multifaceted effects of ethanol on neuronal function in this area and ultimately determining how these alterations influence behavior will be an important undertaking.…”

“…The work presented here reveals a complexity in hippocampal function with regards to ethanol drinking behavior that requires further study to understand. Much of the work supporting a role for the hippocampus in various behaviors relies on permanent or reversible lesions, however more recent work using newer, more selective technology is emerging that is helping to resolve unanswered questions and, at the same time, reveal the complex function of this heterogenous structure (Barker et al 2019;Britt et al 2012;Ewin et al 2019;Scudder et al 2018;Yu et al 2017). Despite the exciting directions that research in this area is going, many questions regarding ventral hippocampal functional remain unresolved.…”