Chronic intermittent ethanol promotes ventral subiculum hyperexcitability via increases in extrinsic basolateral amygdala input and local network activity

Abstract

The hippocampus, particularly its ventral domain, can promote negative affective states (i.e. stress and anxiety) that play an integral role in the development and persistence of alcohol use disorder (AUD). The ventral hippocampus (vHC) receives strong excitatory input from the basolateral amygdala (BLA) and the BLA-vHC projection bidirectionally modulates anxiety-like behaviors. However, no studies have examined the effects of chronic alcohol on the BLA-vHC circuit. In the present study, we used ex vivo electrophysiology in conjunction with optogenetic approaches to examine the effects of chronic intermittent ethanol exposure (CIE), a well-established rodent model of AUD, on the BLA-vHC projection and putative intrinsic vHC synaptic plasticity. We discovered prominent BLA innervation in the subicular region of the vHC (vSub). CIE led to an overall increase in the excitatory/inhibitory balance, an increase in AMPA/NMDA ratios but no change in paired-pulse ratios, consistent with a postsynaptic increase in excitability in the BLA-vSub circuit. CIE treatment also led to an increase in intrinsic network excitability in the vSub. Overall, our findings suggest a hyperexcitable state in BLA-vSub specific inputs as well as intrinsic inputs to vSub pyramidal neurons which may contribute to the negative affective behaviors associated with CIE.

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

“…Prior findings from our lab have identified profound sex differences in vHC synaptic adaptations promoted by chronic intermittent ethanol exposure (CIE), a rodent model of alcohol dependence. Although withdrawal from CIE was associated with increased anxiety‐like behaviour in both sexes, this adaptation was accompanied by vHC hyperexcitability in male rats and decreased vHC network excitability in females (Bach et al, 2021, 2021; Ewin et al, 2019). Additional studies will be needed to determine how these sexually dimorphic adaptations associated with chronic ethanol exposure relate to motivational (appetitive) aspects of drinking in male and female rats.…”

“…One possible reason for the frequent co-occurrence of these disorders is that their aetiology may involve maladaptive changes in common neural pathways. For example, many studies have reported that both AUD and PTSD are associated with dysregulated activity and connectivity in circuits that include the prefrontal cortex, amygdala and hippocampus (Almonte et al, 2017;Bloodgood et al, 2018;Santos et al, 2019;Skelly et al, 2017). Notably, recent studies have demonstrated that these brain regions are not homogenous structures but, rather, are comprised of distinct populations of cells with unique afferent and efferent connectivity that often encode behaviours with opposing valence (Beyeler et al, 2018;Kim et al, 2016).…”

Subiculum–BNST structural connectivity in humans and macaques

“…Both the hippocampus and the BNST have been associated with alcohol use, with the BNST being specifically implicated in alcohol-related alterations to stress-processing ( Bach et al., 2021 ; Volkow et al., 2016 ). One recent small-scale study reported a greater number of streamlines between the hippocampus and the BNST in early abstinence women than in control women, a finding which was not seen in men ( Flook et al., 2021 ).…”

“…Evidence from both preclinical and human subjects have linked the hippocampus and the BNST to dispositional negativity and addictive behaviours ( Hur et al., 2018 ; Lebow and Chen, 2016 ; Mira et al., 2020 ; Shackman et al., 2016 ). Alcohol consumption in particular has been shown to alter stress processing via drug-induced changes to PVN projecting limbic regions, including alterations to BNST and subiculum receptor signalling ( Bach et al., 2021 ; Centanni et al., 2019 ; Haun et al., 2020 ; Mira et al., 2020 ). However, relationships between the microstructural properties of this putative subiculum-BNST pathway and dispositional negativity / alcohol use in humans are currently unknown.…”

Subiculum – BNST Structural Connectivity in Humans and Macaques

“…Evidence from both preclinical and human subjects have linked the hippocampus and the BNST to dispositional negativity and addictive behaviours (Hur et al, 2018;Lebow & Chen, 2016;Mira et al, 2020;Shackman et al, 2016). Alcohol consumption in particular has been shown to alter stress processing via druginduced changes to PVN projecting limbic regions, including alterations to BNST and subiculum receptor signalling (Bach et al, 2021;Centanni et al, 2019;Haun et al, 2020;Mira et al, 2020). However, relationships between the microstructural properties of this putative subiculum-BNST pathway and dispositional negativity / alcohol use in humans are currently unknown.…”