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.
|DePoy, Lauren; Daut, Rachel; Wright, Tara et al. (2015) Chronic alcohol alters rewarded behaviors and striatal plasticity. Addict Biol 20:345-8|
|Graybeal, Carolyn; Bachu, Munisa; Mozhui, Khyobeni et al. (2014) Strains and stressors: an analysis of touchscreen learning in genetically diverse mouse strains. PLoS One 9:e87745|
|Bukalo, Olena; Pinard, Courtney R; Holmes, Andrew (2014) Mechanisms to medicines: elucidating neural and molecular substrates of fear extinction to identify novel treatments for anxiety disorders. Br J Pharmacol :|
|Debrouse, Lauren; Hurd, Benita; Kiselycznyk, Carly et al. (2013) Probing the modulation of acute ethanol intoxication by pharmacological manipulation of the NMDAR glycine co-agonist site. Alcohol Clin Exp Res 37:223-33|
|Brigman, Jonathan L; Wright, Tara; Talani, Giuseppe et al. (2010) Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J Neurosci 30:4590-600|
|Mozhui, Khyobeni; Karlsson, Rose-Marie; Kash, Thomas L et al. (2010) Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability. J Neurosci 30:5357-67|
|Holmes, Andrew; Wellman, Cara L (2009) Stress-induced prefrontal reorganization and executive dysfunction in rodents. Neurosci Biobehav Rev 33:773-83|
|Brigman, Jonathan L; Ihne, Jessica; Saksida, Lisa M et al. (2009) Effects of Subchronic Phencyclidine (PCP) Treatment on Social Behaviors, and Operant Discrimination and Reversal Learning in C57BL/6J Mice. Front Behav Neurosci 3:2|
|Camp, M; Norcross, M; Whittle, N et al. (2009) Impaired Pavlovian fear extinction is a common phenotype across genetic lineages of the 129 inbred mouse strain. Genes Brain Behav 8:744-752|
|Karlsson, Rose-Marie; Tanaka, Kohichi; Saksida, Lisa M et al. (2009) Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia. Neuropsychopharmacology 34:1578-89|
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