Overview. In this year (October, 2012 to September, 2013) the Laboratory of Behavioral and Genomic Neuroscience 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. The initial results led to the identification of a mouse strain, 129S1, that we have subsequently employed to test behavioral and pharmacological manipulations (including an endocannabinoid-acting drug in collaboration with Dr. George Kunos) that reverse emotional abnormalities. 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. Preliminary results showed that alcohol impaired NMDAR-mediation of a form of emotional regulation (fear extinction) regulated by the prefrontal cortex. Study 2 examined the effects of chronic alcohol on a form of choice learning mediated by the dorsal striatum and prefrontal cortex. Results thus far show that alcohol facilitates this learning and does so in concert with dendritic and synaptic plasticity changes in dorsal striatum. 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. We are currently following this work up with studies on the precise mechanisms involved.

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Project End
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Budget End
Support Year
10
Fiscal Year
2013
Total Cost
$1,534,680
Indirect Cost
Name
National Institute on Alcohol Abuse and Alcoholism
Department
Type
DUNS #
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Maren, Stephen; Holmes, Andrew (2016) Stress and Fear Extinction. Neuropsychopharmacology 41:58-79
Holmes, Andrew (2016) The developmental origins of complex behavior and neuropsychiatric disease. Genes Brain Behav 15:5-6
Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma et al. (2016) Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids. Neuropsychopharmacology 41:1598-609
Hartley, N D; Gunduz-Cinar, O; Halladay, L et al. (2016) 2-arachidonoylglycerol signaling impairs short-term fear extinction. Transl Psychiatry 6:e749
Gamble-George, Joyonna Carrie; Baldi, Rita; Halladay, Lindsay et al. (2016) Cyclooxygenase-2 inhibition reduces stress-induced affective pathology. Elife 5:
Knoll, Allison T; Halladay, Lindsay R; Holmes, Andrew J et al. (2016) Quantitative Trait Loci and a Novel Genetic Candidate for Fear Learning. J Neurosci 36:6258-68
Didion, John P; Morgan, Andrew P; Yadgary, Liran et al. (2016) R2d2 Drives Selfish Sweeps in the House Mouse. Mol Biol Evol 33:1381-95
Izquierdo, A; Brigman, J L; Radke, A K et al. (2016) The neural basis of reversal learning: An updated perspective. Neuroscience :
Jury, Nicholas J; DiBerto, Jeffrey F; Kash, Thomas L et al. (2016) Sex differences in the behavioral sequelae of chronic ethanol exposure. Alcohol :
Thompson, Shannon M; Josey, Megan; Holmes, Andrew et al. (2015) Conditional loss of GluN2B in cortex and hippocampus impairs attentional set formation. Behav Neurosci 129:105-12

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