Research Projects

Despite the decades-long theory that we drink to relieve stress, we still do not understand the complex neurobiology that underlies this behavior. Not only do stressors drive both social drinking and relapse in people with alcohol use disorder, but also chronic alcohol drinking itself reciprocally impacts stress systems in the brain. Using preclinical techniques such as: behavioral pharmacology, electrophysiology, circuit mapping, optogenetics, chemogenetics, and fiber photometry, the Hwa Lab studies how external stressors and endogenous stress signaling in the brain governs excessive drinking.

Here are is a sampling of current research projects:

Theoretical Model. Intermittent access to alcohol disrupts responses to predator odor stress, which increases glutamatergic synaptic transmission in dynorphin (Dyn) cells in the dorsal bed nucleus of the stria terminalis (BNST). One major source of the enhanced synaptic drive is the medial prefrontal cortex (mPFC) among others like the basolateral amygdala (BLA) and periaqueductal grey (PAG). Enhanced glutamate may lead to increased synaptic plasticity after alcohol drinking and stress after exposure to TMT predator odor.

Long-term alcohol drinking alters stress engagement of BNST circuit elements. While blunted responses to stress have been identified in alcohol-dependent individuals, few studies have considered mechanisms by which alcohol drinking results in maladaptive stress responses during protracted abstinence. We are investigating how chronic intermittent alcohol drinking can affect stress-related phenotypes using modern, converging neuroscience techniques. Kappa opioid receptor (KOR) signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate promoting a maladaptive behavioral phenotype following heavy alcohol drinking (Hwa et al. 2020). Altered responses to TMT predator odor were associated with enhanced prefrontal cortex (PFC)-driven excitation of dynorphin-containing neurons in the BNST during protracted withdrawal from intermittent alcohol drinking. These findings suggest that corticolimbic connectivity may underlie impaired stress-coping during protracted withdrawal from heavy drinking.

We aim to: 1. Test the role of BNST dynorphin in alcohol-induced alterations in TMT response. 2. Map and test connectivity of whole brain BNST inputs activated by TMT predator odor stress. 3. Compare distinct roles of BNST inputs in stress responses after alcohol. These studies dissociate the contributions of distinct circuits that define abnormal stress reactions after chronic alcohol drinking.


How does intermittent access escalate alcohol drinking? Male C57BL/6J mice drink more alcohol on an intermittent access (IA, red) schedule versus given continuous access (CA, orange). **p<0.01. Adapted from Hwa et al. 2011. IA is hypothesized to increase CRF stress peptide release from the dorsal raphe nucleus (DRN) with reductions in serotonin (5-HT) output in the medial prefrontal cortex (mPFC) based on my published studies (Hwa et al. 2013, 2016). In contrast, CA is not affected by CRF-R1 antagonism, thus hypothesized to have lesser CRF and more serotonin tone at the synapse. Other molecules may also contribute to this theorized framework like opioid peptides and glutamate.

Intermittent schedules as a means of escalation to pathologies of consumption. Does the manner by which people drink alcohol affect future drinking outcomes? Animals given intermittent, or restricted, schedules of access (IA) to highly palatable foods, alcohol, and other drugs of abuse develop signs of dependence over time, suggested by neurochemical markers and behavioral indices of withdrawal. Some have theorized that IA may stimulate and sensitize networks in the brain to promote escalated responses, exhibited by increased intake or enhanced locomotion, to an abused substance. Durations of the access and deprivation intervals may be an important characteristic of IA as a potential schedule that can lead to disorders of consumption. Exploration of how intermittency drives escalated intake would be crucial for both the prevention and treatment of these pathologies of excess intake.

We aim to: 1. Characterize the neural mechanisms underlying intermittent access and contrast with those of continuous access. 2. Differentiate functional connectivity in mice that drink on intermittent versus continuous access schedules. 3. Manipulate brain neuropeptide circuitry to decrease escalated, intermittent drinking. These approaches allow for cell-specific interrogation of different levels of alcohol drinking.

In addition to these current research lines, Dr. Hwa has studied stress, aggression, and alcohol drinking, and importantly, the interaction of these phenomena. Our neurobiological expertise involves how stress neuropeptides, like CRF and dynorphin, modulate neurotransmission of dopamine, serotonin, and glutamate, all nestled within complex drinking or social behavior. You can read about these experiments and techniques in Publications.