Mouse models of stress disorders and addiction

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications & trials

Abstract

Overview. The Laboratory of Behavioral and Genomic Neuroscience continued a program of research in this year (October, 2022 to September, 2023) designed to develop mouse models of emotional disorders and substance use disorder, with focus remaining on corticolimbic circuits. The laboratory was engaged in studies of the circuits underlying risky decisions - behaviors subject to the effects of chronic alcohol on corticolimbic systems. We employed a procedure of measuring choices of mice between large and small rewards, the former being occasionally associated with mild foot shock. Our data show that mice alter their behavior as a function of risk of punishment and require neural activity in cortical and limbic areas. Interestingly, we have shown that alcohol exposure produced marked structural and functional alterations in the same corticolimbic regions we had found in other studies of cognitive behavior. The marked structural and functional changes we observed in these regions after alcohol exposure would support some role for abnormalities in regions such as the prefrontal cortex. In order to test for effects of chronic alcohol on cognitive performance, we exposed mice to alcohol either prior to discrimination learning or before reversal learning. These experiments showed that alcohol exposure produced a significant decrease in the number of errors made during either learning or relearning after reversal. Notably, alcohol-induced facilitation of relearning was limited to the late stage of training, in a pattern of facilitation analogous to that we had earlier found after prefrontal cortex lesions. According to the scheme outlined above, this raises the possibility that enhanced reversal was caused by a alcohol-induced functional lesion of the prefrontal cortex and a resultant loss of competition on stimulus-bound learning mediated by regions, including the dorsal striatum. However, it remains unclear at present whether these changes after alcohol would necessarily result in gain, rather than loss, of a striatal contribution to performance. Further work is being undertaken to define the role of the striatum in order to better explain the behavioral effects of alcohol. Individuals exposed to extreme forms of trauma and neglect are more prone to suffer from emotional disorders, such as anxiety and depression, that are comorbid with alcohol use disorder. It is far from clear exactly how alcohol misuse increases later risk for these neuropsychiatric disorders. Another unresolved question is why some individuals appear especially sensitive to effects of stress, while others are resilient. This inter-individual variation suggests that genetics play a significant role in modulating stress, a notion supported by recent research in humans. Unfortunately, there are inherent limitations to the study of genetic and environmental influences on behavior under tightly controlled conditions in humans. Animal models provide a valuable alternative. The laboratory mouse potentially provides an excellent model system to study neural factors modulating behavior due to the availability of genetically-distinct mouse strains and the capacity for engineering genetic mutants. The Section on Behavioral Science and Genetics seeks to develop mouse models of cognitive abnormalities and alcohol use disorders. Relatedly, a major project examined the role of endocannabinoids as a mechanism underlying individual differences in fear extinction a form of inhibitory learning that aids recovery from psychological trauma. Working in collaboration with the laboratory of Dr. George Kunos, we tested the effects of a novel drug, AM3506, that boosts brain endocannabinoid levels (via prevention of degradation by the enzyme fatty acid amide hydrolase). Our work has found that either systemic or intra-amygdala delivery of this drug facilitates fear extinction in a mouse strain with impaired extinction. Supporting the amygdala as effect-locus, AM3506's extinction-facilitating effects were blocked by intra-amygdala CB1R antagonism and recapitulated by intra-amygdala AM3506. These findings reveal a new potential therapeutic approach to treating trauma. We are currently following this work up with studies on the precise mechanisms involved, with a focus on interactions with the amygdala serotonin system and the antidepressant drug, fluoxetine. Other projects tested the consequences of chronic intermittent ethanol exposure (CIE) for various behaviors including compulsive alcohol-seeking and fear extinction. Our findings suggested a scheme whereby alcohol-induced loss of NMDAR-mediated cortical neuronal bursting disrupts encoding of extinction to impair the behavior. More generally, these observations provide novel evidence of how chronic alcohol disrupts corticoamygdala function, and predict that other behaviors dependent on this circuitry, such as compulsive drug-taking, will be adversely impacted by chronic alcohol. Clinically , our findings could have implications for understanding the neural basis of comorbid AUD and anxiety. For example, loss of cortical modulation of extinction could impair recovery from psychological trauma and the efficacy of extinction-based therapies, increasing risk for anxiety disorders such as PTSD. Persistent anxiety could in turn foster further alcohol misuse, leading to a vicious cycle of misuse and progressively weakening prefrontal function. By the same token, treatments (e.g., endocannabinoid-targeting) that improve recovery from trauma could help break this cycle to reduce anxiety and alcohol use disorder.