Chronic stress affects numerous brain areas involved in memory, emotion, and motivation, such as the hippocampus, amygdala, and prefrontal cortex; it abnormally alters a variety of cellular events, including dendritic morphology and gene expression patterns; and, it can precipitate several maladaptive states, such as depression- and anxiety-like behaviors. Yet, the neural circuitry sufficient to mitigate or even prevent such phenotypes is unclear. In both mice and humans, the hippocampus has been implicated in storing and retrieving positive memories and in modulating stress-related states. Promisingly, the recent work of the PI has demonstrated that artificially stimulating cells in the hippocampus that previously were active during positive memory formation are sufficient to increase reward-like behavior and motivation. To that end, in this DP5 proposal, a novel experimental bridge will be built between artificially activated positive memories and animal models of psychiatric disorders. The recently developed virus system by the PI will be utilized in which the promoter of the immediate early gene c-Fos drives the expression of the light-sensitive ion channel channelrhodopsin-2 in a manner that is under the control of the antibiotic Doxycycline. In the absence of Doxycycline, learning-induced neuronal activity selectively labels active c-Fos-expressing neurons with channelrhodopsin-2, thus conferring activity-dependent and inducible labeling of, in addition to optical control over, hippocampus cells and their corresponding axon terminals. The experimental goals of this project are threefold and combine in vivo optogenetics, in vitro immunohistochemistry, and a battery of behavioral assays. First, the hypothesis will be tested that optically modulating a defined set of positive or negative memory bearing hippocampus cells is sufficient to ameliorate or mimic the effects of chronic stress at the cellular and behavioral levels. Next, the goal is to test whether or not activating memory bearing hippocampus axon terminals?which route distinct mnemonic information to the amygdala, prefrontal cortex, and nucleus accumbens?can differentially modulate independent features of psychiatric disease-like states, such as social impairments, anxiety-like, and anhedonic-related behavior. Finally, the goal is to test if chronically stimulating positive memory bearing hippocampus cells prior to stress can prevent such maladaptive behaviors from precipitating, while subsequently performing a brain-wide anatomical and histological analysis to identify key cellular loci mediating memory's putative prophylactic capacity.
This proposal aims to build a novel experimental bridge between artificially activated memories and animal models of psychiatric disorders. By genetically engineering cells that process positive or negative memories to respond to pulses of light, subsequent optical activation of these memories will be respectively leveraged to reverse or mimic the effects of chronic stress on social, anxiety-like, and hedonic behavior. By identifying, manipulating, and characterizing the circuits supporting memory formation and retrieval, it is thereby possible to resolve the circuit-level biological mechanisms mediating memory's promising capacity to bi-directionally modulate a medley of maladaptive cellular and behavioral states.
|Denny, Christine A; Lebois, Evan; Ramirez, Steve (2017) From Engrams to Pathologies of the Brain. Front Neural Circuits 11:23|