Significance. The ability to learn that some stimuli or situations are associated with dangerous or rewarding outcomes is generally advantageous. However, such learning can also lead to a self-reinforcing cycle of harmful behaviors. Thus, it would be useful to achieve control over the network mechanisms that regulate the acquisition and expression of learned emotional behaviors. This is the objective we pursue here. Background. Principal basolateral amygdala (BLA) neurons are essential for the acquisition and expression of conditioned emotional behaviors. Yet, remarkably few of them are activated by emotionally-valenced stimuli. The solution to this paradox resides in the synchronizing influence of gamma. Indeed, gamma drastically increases firing synchrony, amplifying the impact of BLA cells on their targets. Yet, it barely alters BLA firing rates. Thus, we will study the impact of boosting or dampening BLA gamma on emotional learning. To this end, we will combine optogenetics with programmable multi-channel signal processors, known as ?field programma- ble gate arrays? (FPGAs). Unlike computers, FPGAs allow nearly instantaneous signal analysis and conditional light stimulus delivery, providing unprecedented control over fast neuronal events like gamma, in real time. Approach. Parvalbumin (PV)-expressing interneurons play a critical role in the genesis of gamma. Thus, expression of the excitatory opsin Chronos will be restricted to PV cells, by infusing the virus AAV5-hSyn- FLEX-Chronos-GFP in the BLA of PV-cre rat. Then, to boost or dampen gamma, the optogenetic excitation of PV cells will be timed to coincide with their preferred or non-preferred gamma firing phase, respectively. Proposed work:
In Aim #1, we will determine what gamma sub-band is most strongly expressed in the BLA and in relation to what events (conditioned stimuli or responses). We will record unit and LFP activity while rats learn that different conditioned stimuli predict reward delivery (CS-R) or an impending footshock (CS-S). Our pilot data indicates that the largest changes in gamma power occur in the mid-gamma band and that mid- gamma is differentially related to distinct conditioned responses (CRs). Based on these results, in Aim #2, we will test whether enhancing or dampening BLA mid-gamma during the CS-R or CS-S facilitates or impairs the expression of appetitive and defensive CRs. Last, in Aim 3, we will test whether enhancing or dampening BLA gamma after training facilitates or impairs the consolidation of appetitive and defensive CRs. Indeed, we previously found that in the 30 min following an emotionally arousing learning experience, mid-gamma power increases in the BLA and that the magnitude of this increase correlates with individual variations in memory recall.
In Aims 2 -3, control groups will include random groups where the same trains of light stimuli will be delivered irrespective of ongoing gamma, no-opsin groups where the virus will only drive reporter expression, and other frequency groups to test the frequency specificity of our manipulations.
Although the ability to learn that some stimuli or situations are associated with dangerous or rewarding outcomes is generally beneficial, emotional learning can also lead to a self-reinforcing cycle of harmful behaviors. In addiction for instance, the rewarding properties of drugs lead some individuals to progressively develop impaired control over their substance use despite increasingly detrimental consequences for their finances, health, and social relationships. Similarly, in anxiety disorders, subjects engage in self-perpetuating avoidance behaviors because they cause an immediate reduction in anxiety. In this proposal, we aim to achieve control over the network mechanisms that regulate the acquisition and expression of emotional behaviors by focusing on the influence of gamma oscillations in the basolateral amygdala (BLA). To this end, we will achieve real-time control over gamma oscillations in the BLA by combining optogenetics with programmable multi-channel signal processors that allow nearly instantaneous signal analysis and conditional light stimulus delivery with frequency and phase specificity.
