Prior studies examining multiple memory systems in the brain have had great difficulty elucidating the specific neural connections that influence the consolidation and synaptic plasticity for different kinds of learning. The present proposal will utilize optogenetic manipulations of specific pathways connecting different brain regions in rats immediately after the rats have undergone different kinds of learning. Specifically, this proposal will build upon the evidence that the basolateral amygdala (BLA) influences consolidation for many different kinds of learning, including spatial/contextual, emotional, and cued-response learning, whereas other regions are involved in memory for more discrete forms of learning. Additional evidence indicates that the BLA influences consolidation through regulation of synaptic plasticity in these other brain regions, including modulation of activity-regulated cytoskeletal-associated protein (Arc), which has been shown to mediate some of the BLA's effects on memory consolidation. Based on these prior findings, the present studies will investigate how distinct BLA projections to different parts of the hippocampus and caudate modulate memory consolidation and Arc expression in downstream brain regions following different kinds of learning. Follow-up experiments will determine whether the increased Arc expression is necessary for the memory modulation. To do so, the current proposal will utilize optogenetic control of activity in specific BLA projections immediately after different learning tasks to directly examine in each Aim: 1) how the candidate pathways influence consolidation for the specific type of learning and 2) how the pathways influence Arc expression in downstream regions and whether the Arc expression is necessary for the memory modulation.
Aim 1 will determine how BLA projections to different parts of the hippocampal formation influence consolidation and Arc expression for the context vs. footshock learning in a modified contextual fear conditioning task.
Aim 2 will determine how BLA projections to part of the hippocampal formation and the caudate influence consolidation and Arc expression for spatial vs. cued-response learning. In both aims, optogenetic stimulation/inhibition will be given to each candidate pathway immediately after the relevant training to determine its role in influencing consolidation. Moreover, each aim will examine whether such optogenetic manipulations alter Arc expression in different downstream structures and whether reducing Arc levels in those regions prevents the memory-modulating effects of the optogenetic manipulations, providing a critical complementary set of experiments that will improve our model for understanding how the BLA influences memory and plasticity-related proteins such as Arc in other regions. The findings from these studies will provide, for the first time, knowledge for how the specific pathways from the BLA to other brain regions influence memory consolidation and synaptic plasticity. Moreover, these experiments will provide a first step to creating an understanding of the functional connections within the brain underlying consolidation processes.

Public Health Relevance

Multiple mental health disorders, including post-traumatic stress disorder, phobias, anxiety, and depression, involves in alterations in amygdala functioning and basic memory processes. Developing our knowledge about the specific and distinct neural pathways emanating from the amgydala involved in different memory processes is therefore crucial for improving our understanding of these disorders and developing new treatments. The present studies will use an innovative approach to target the functional connections among brain regions involved in different kinds of learning and memory, thereby providing a better understanding for how to develop treatments for disorders and injuries that affect memory processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH104384-04
Application #
9428456
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Vicentic, Aleksandra
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Iowa
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
LaLumiere, Ryan T; McGaugh, James L; McIntyre, Christa K (2017) Emotional Modulation of Learning and Memory: Pharmacological Implications. Pharmacol Rev 69:236-255
Goodman, Jarid; McIntyre, Christa K (2017) Impaired Spatial Memory and Enhanced Habit Memory in a Rat Model of Post-traumatic Stress Disorder. Front Pharmacol 8:663
Muller Ewald, Victória A; LaLumiere, Ryan T (2017) Neural systems mediating the inhibition of cocaine-seeking behaviors. Pharmacol Biochem Behav :
Gutman, Andrea L; Nett, Kelle E; Cosme, Caitlin V et al. (2017) Extinction of Cocaine Seeking Requires a Window of Infralimbic Pyramidal Neuron Activity after Unreinforced Lever Presses. J Neurosci 37:6075-6086
Johnson, Shane B; Emmons, Eric B; Anderson, Rachel M et al. (2016) A Basal Forebrain Site Coordinates the Modulation of Endocrine and Behavioral Stress Responses via Divergent Neural Pathways. J Neurosci 36:8687-99
Huff, Mary L; Emmons, Eric B; Narayanan, Nandakumar S et al. (2016) Basolateral amygdala projections to ventral hippocampus modulate the consolidation of footshock, but not contextual, learning in rats. Learn Mem 23:51-60
Alvarez-Dieppa, Amanda C; Griffin, Kimberly; Cavalier, Sheridan et al. (2016) Vagus Nerve Stimulation Enhances Extinction of Conditioned Fear in Rats and Modulates Arc Protein, CaMKII, and GluN2B-Containing NMDA Receptors in the Basolateral Amygdala. Neural Plast 2016:4273280