The Insular Cortex→Bed Nucleus of the Stria Terminalis Pathway during Early Abstinence from Chronic Alcohol Use: A Promising Target for Mitigating Negative Emotions and Relapse Risk

Alcohol use disorder (AUD) is a chronically relapsing disorder characterized by compulsive alcohol consumption and a loss of control over alcohol intake, despite adverse consequences (Koob, 2008). Chronic alcohol use drives adaptations in the brain and body to maintain functional stability in the presence of alcohol, a process known as “allostasis” (Koob, 2008). As a result of these adaptations, subsequent abstinence or abrupt cessation of alcohol use propels the brain into a new state of imbalance. Accordingly, the abstinence phase is a dynamic period marked by significant neurological and behavioral changes that occur over varying timescales, as the brain readjusts to functioning without alcohol. These shifts often manifest as withdrawal symptoms, especially negative emotional states, such as anxiety and depression, which act as primary triggers for cravings and relapse in those recovering from AUD (Koob, 2015). Hence, understanding the neurobiological underpinnings of withdrawal symptoms and their progression is essential in developing temporally specific therapeutic strategies to support sustained recovery from AUD. In a recent article published in The Journal of Neuroscience, Taylor et al. (2024) took a step in this direction by focusing on the temporal changes in neuronal and synaptic function within a specific neural pathway that governs negative emotional states during abstinence, namely, the pathway connecting the insular cortex to the bed nucleus of the stria terminalis (BNST).

Although alcohol consumption initially stimulates the brain's reward systems, facilitating continued use through positive reinforcement mechanisms (Koob, 2008), as alcohol dependence develops, the brain's stress systems become activated, especially during abstinence periods (Koob, 2008). This shift leads individuals to use alcohol as a means of mitigating withdrawal symptoms—a process known as negative reinforcement (Koob, 2008). The BNST, an integral component of these stress systems, is increasingly recognized for its role in regulating the negative emotions experienced during abstinence (Centanni et al., 2019). Neuroadaptive processes within the BNST in response to the absence of alcohol, including the rebalance of neurotransmitter systems and stress hormone levels, are central to these emotional experiences (Centanni et al., 2019). For instance, during abstinence from chronic alcohol use, corticotropin-releasing factor-expressing neurons within the BNST become hyperactive and show an increase in glutamatergic presynaptic transmission, contributing to negative emotional states (Centanni et al., 2019). However, the specific brain regions that provide inputs to and induce neural plasticity in the BNST, thereby influencing these negative emotions, have only recently begun to be investigated.

The insular cortex (IC) has attracted substantial interest from addiction researchers following a seminal study showing that damage to this region significantly disrupts addiction to cigarette smoking, leading to cessation without relapse or persistent cravings (Naqvi et al., 2007). Subsequent rodent studies expanded on this observation, demonstrating the IC's roles not only in the perception of craving or malaise but also in the consolidation of context–drug-effect associative memories (Contreras et al., 2007). As the primary cortical hub for interoception, or sensing internal bodily states, the IC integrates interoceptive signals to create moment-to-moment emotional states (Namkung et al., 2017). In addiction research, the IC is known for encoding and recalling emotional states derived from the interoceptive effects of substance use, as well as internal states during withdrawal or abstinence (Naqvi and Bechara, 2009). Accordingly, the IC, in coordination with relevant downstream regions, forms the neural pathways that underlie behavioral and physiological responses throughout various stages of alcohol addiction and abstinence. Notably, the neural pathway linking the IC to the BNST is emerging as crucial in regulating emotional behaviors during alcohol abstinence, thereby influencing relapse risk (Centanni et al., 2019).

Recent research has delved into the adaptive changes within the IC→BNST circuit during abstinence from chronic alcohol consumption (Centanni et al., 2019). Specifically, using a mouse model of chronic drinking followed by forced abstinence (CDFA), Centanni et al. (2019) showed that chemogenetic inactivation of the IC, inducing a reversible loss of function, reduced both the heightened activity and the spontaneous glutamatergic synaptic transmission that otherwise occurred in dorsal BNST (dBNST) neurons after 15 d of protracted abstinence. This IC inactivation also mitigated the negative emotional behaviors that emerge during protracted abstinence. Furthermore, chemogenetic activation (inducing a gain of function) of dBNST neurons that specifically receive inputs from the IC has been found to replicate these protracted abstinence-induced emotional behaviors. Collectively, these data indicate that synaptic and neuronal changes within the BNST, influenced by inputs from the IC, are responsible for the negative emotional states observed during protracted abstinence from chronic alcohol consumption. However, the nature of adaptive changes occurring in IC neurons that project to the BNST during both early and protracted abstinence periods following chronic alcohol intake has remained unknown.

Taylor et al. (2024) addressed this gap, using the CDFA mouse model to investigate the adaptive changes in excitability and synaptic transmission of IC neurons projecting to the dBNST (IC^→BNST neurons) during both early (24 h) and protracted (2 week) abstinence. They also aimed to elucidate the mechanisms underlying these abstinence-related changes. Early, but not protracted, abstinence from chronic alcohol intake led to increased intrinsic excitability (hyperexcitability) of IC^→BNST neurons, indicating a temporary adaptive response to the abrupt cessation of alcohol intake. However, these neurons did not exhibit any change in spontaneous excitatory or inhibitory synaptic transmission during either early or protracted abstinence periods. These results suggest that the hyperexcitability of IC^→BNST neurons during early abstinence is not due to changes at the synapse level (in terms of neurotransmitter release or reception), but instead may be due to changes in the intrinsic properties of the neurons, such as ion channel function or intracellular signaling pathways. Notably, the hyperexcitability observed during early abstinence did not occur after acute alcohol exposure via intraperitoneal injection 24 h prior to recording, when brain slices were washed with alcohol, or after chronic consumption of a natural reward (sucrose). Hence, the hyperexcitability represents a selective neuroadaptive response to the cessation of long-term alcohol consumption, not a response to the presence of alcohol or to reward cessation in general.

The authors next explored the potential role of big potassium (BK) channels in modulating the excitability of IC^→BNST neurons during early abstinence. They focused on BK channels because alcohol is known to affect them, either through direct binding or indirectly by altering cellular metabolism and calcium signaling (Treistman and Martin, 2009). Interestingly, when control brain slices were treated with a BK channel antagonist, IC^→BNST neurons exhibited hyperexcitability similar to that observed during early abstinence. In contrast, in mice experiencing early abstinence, the effect of BK channel blockade on excitability was occluded, suggesting that the hyperexcitability might be linked to alterations in BK channel function. These findings indicate the potential for reduced BK channel expression in IC^→BNST neurons. Indeed, in situ hybridization revealed a decrease in BK channel mRNA expression in IC^→BNST neurons during early, but not protracted, abstinence. Overall, Taylor et al.'s findings suggest that the hyperexcitability of IC^→BNST neurons during early abstinence results from a temporary decrease in BK channel expression and/or alterations in channel function. Importantly, even though these alterations are temporary, they may initiate neuroadaptive processes that manifest during protracted abstinence or other long-term circuit changes.

This study provides valuable insights into three key pieces of information needed for developing therapeutic strategies to alleviate negative emotions and reduce the risk of relapse during abstinence: (1) identifying the specific neural circuit involved (where); (2) pinpointing the critical time window for intervention (when); and (3) recognizing the potential druggable targets (what). First, the study highlights the IC→BNST circuitry as a potential neural substrate where the allostatic state brought on by chronic alcohol use is reversed, leading to the emergence of negative emotional states during abstinence. Specifically, the increased excitability of IC^→BNST neurons may act as a compensatory mechanism to counterbalance the depressive effects of chronic alcohol, while potentially underlying negative emotional states observed during early abstinence (Vranjkovic et al., 2018). This hyperexcitability might be crucial in driving neural plasticity, resulting in increased neuronal activity and excitatory synaptic transmission in the dBNST. This, in turn, could contribute to the emergence of negative emotions observed during protracted abstinence (Centanni et al., 2019). Secondly, the study highlights the early abstinence phase as a critical period for mitigating long-term negative emotions and reducing relapse risk. This is supported by previous research showing that administering ketamine during early abstinence can effectively prevent negative emotional behaviors in later stages of abstinence (Vranjkovic et al., 2018). Lastly, the research points to BK channels as a promising target for mechanism-guided therapy aimed at reducing negative emotions and lowering relapse risk in individuals recovering from AUD.

Additional research is indispensable, including experiments aimed at determining whether reversing the hyperexcitability of IC^→BNST neurons can mitigate the negative emotional behaviors observed during early abstinence (Vranjkovic et al., 2018). Furthermore, experiments should be designed to assess whether counteracting this hyperexcitability affects the heightened neuronal activity and excitatory synaptic transmission within the BNST during later abstinence stages and whether this can help alleviate negative emotional behaviors or long-term risk of relapse. If these causal relationships are established, it becomes crucial to conduct investigations into the efficacy of targeted administration of BK channel agonists, both locally in the IC and systemically, during early abstinence. The objective of these studies would be to ascertain whether such treatments can effectively prevent the onset of negative emotional behaviors during both early and extended abstinence, as well as inhibit the development of increased neuronal activity and synaptic transmission within the BNST during prolonged absence.