Overview. In this year (October, 2010 to September, 2011) the Section on Behavioral Science and Genetics continued a program of research designed to develop mouse models of emotional disorders and addiction, with focus on the glutamate system. Individuals exposed to extreme forms of trauma and neglect are more prone to suffer from emotional disorders, such as anxiety and depression, and more likely to develop addiction to alcohol and illicit drugs of abuse. However, it is far from clear exactly how stress increase 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 controled conditions in humans. Animal models provide a valuable alternative. The laboratory mouse potentially provides an excellent model system to study genetic 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 emotional abnormalities and addiction A series of studies were conducted with the goal of a developing a mouse model of stress that produced reliable effects on emotional behaviors and executive functions. The long-term goal of these studies is to develop a model that can be applied to genetically-modified mice (including NMDA KO mice described below) to study gene x stress interactions underlying emotion and addiction. Study 1 was a comparison of the effects of fear extinction across 8 genetically-distinct mouse strains.
The aim was to gather information on which strains are suitable for studies of fear inhibition and at the same time provide insight into genetic factors modulating of this process. Study 2 assessed knockout mice lacking the NR2B receptor subunits on tests for pairwise visual discrimination and reversal learning. This will inform as to the role of NR2B-containing receptors in mediating prefrontal cortex mediated cognitive flexibility. The role of glutamate NMDA receptors in mediating emotional behaviors and the behavioral effects of ethanol. Glutamate neurotransmission via NMDA receptors plays a major role in brain development, in mediating the behavioral effects of ethanol and, it is increasingly thought, modulating emotional behaviors. Therefore, the NMDA receptor represents a potential mechanism underlying the effects of stress on subsequent changes in emotion- and reward-related behaviors. The goal of initial studies was to identify which NMDA receptor subtypes are critical mediators of NMDA receptor effects on ethanol sensitivity and emotional behavior in mice and, therefore, which subtypes should be the focus of future studies of the effects of postnatal stress on possible NMDA receptor-mediated changes in these behaviors. Study 1 examined the effects of chronic exposure to ethanol on NMDAR-related behavioral and electrophysiological endpoints. For the behavioral experiments, a combination of pharmacological (NR2B antagonists) and gene mutant (NR2B KO mice) was employed. Study 2 examined the differential contribution of the NMDA receptor anchoring protein to mediation of ethanol sensitivity and the ability of NMDA receptor-blockade to potentiate ethanol sensitivity (as measured by sedation/hypnosis). Another 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 close collaboration with the laboratory of Dr. George Kunos, we tested the effects of a novel drug that boosts brain endocannabinoid levels (via prevention of degradation by the enzyme fatty acid amide hydrolase). Our preliminary 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, AM3506s 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 and have been submitted for publication.

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Bukalo, Olena; Holmes, Andrew (2018) Everything in Its Right Place: A Prefrontal-Midbrain Circuit for Contextual Fear Discrimination. Neuron 97:732-733
B Potash, James; Holmes, Andrew; Andrews, Anne Milasincic (2018) Dennis L Murphy, MD. Neuropsychopharmacology 43:1193-1194
Bloodgood, Daniel W; Sugam, Jonathan A; Holmes, Andrew et al. (2018) Fear extinction requires infralimbic cortex projections to the basolateral amygdala. Transl Psychiatry 8:60
Gunduz-Cinar, Ozge; Brockway, Emma; Lederle, Lauren et al. (2018) Identification of a novel gene regulating amygdala-mediated fear extinction. Mol Psychiatry :
Lowery-Gionta, Emily G; Crowley, Nicole A; Bukalo, Olena et al. (2018) Chronic stress dysregulates amygdalar output to the prefrontal cortex. Neuropharmacology 139:68-75
Bergstrom, Hadley C; Lipkin, Anna M; Lieberman, Abby G et al. (2018) Dorsolateral Striatum Engagement Interferes with Early Discrimination Learning. Cell Rep 23:2264-2272
Holmes, A (2018) G2B reviews: Epigenetics, epitranscriptomics, microRNAs and more: Emerging approaches to the study of genes, brain and behavior. Genes Brain Behav 17:e12453
Holmes, Andrew (2017) Sex and Orexins: Uncovering a Mechanism Underlying Sex Differences in Stress Susceptibility. Biol Psychiatry 81:642-644
Craske, Michelle G; Stein, Murray B; Eley, Thalia C et al. (2017) Correction: Anxiety disorders. Nat Rev Dis Primers 3:17100
Patel, Sachin; Hill, Mathew N; Cheer, Joseph F et al. (2017) The endocannabinoid system as a target for novel anxiolytic drugs. Neurosci Biobehav Rev 76:56-66

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