Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated 18F positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for precision medicine-based clinical theranostics. DREADD ligands developed to date are not appropriate for such translational applications. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine. The second-generation DREADD agonist, Compound 21 (C21), was developed to overcome these limitations. We found that C21 has low brain penetrance, weak affinity, and low in vivo DREADD occupancy. To address these drawbacks, we developed two new DREADD agonists, JHU37152 and JHU37160, and the first dedicated positron emission tomography (PET) DREADD radiotracer, [ 18 F]JHU37107. JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [ 18 F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons and at their long-range projections, enabling for the first time, noninvasive and longitudinal neuronal projection mapping and potential for neurotheranostic applications.
Behavioral flexibility and timely reactions to salient stimuli are essential for survival. The subcortical thalamic-basolateral amygdala (BLA) pathway serves as a shortcut for salient stimuli ensuring rapid processing. Here, we show that BLA neuronal and thalamic axonal activity mirror the defensive behavior evoked by an innate visual threat as well as an auditory learned threat. Importantly, perturbing this pathway compromises defensive responses to both forms of threats, in that animals fail to switch from exploratory to defensive behavior. Despite the shared pathway between the two forms of threat processing, we observed noticeable differences. Blocking beta-adrenergic receptors impair the defensive response to the innate but not the learned threats. This reduced defensive response, surprisingly, is reflected in the suppression of the activity exclusively in the BLA, as the thalamic input response remains intact. Our side-by-side examination highlights the similarities and differences between innate and learned threat-processing, thus providing new fundamental insights.
Hebbian plasticity, widely regarded as the cellular mechanism for learning and memory, posits that the formation of a long-lasting memory requires a tight temporal co-activation of pre- and postsynaptic inputs encoding that memory. Here we demonstrate that forms of synaptic manipulation deviating from Hebbian rules can produce a long-lasting memory. To this end, we optogenetically manipulate independently two inputs to the lateral amygdala (LA), a region known to mediate fear memories. We focused on the association of one input to the LA with a foot shock, which does not form a detectable memory. This experience can be converted to a long-lasting memory by induction of synaptic potentiation of the input alone, delivered minutes before, minutes after, or even 24 hours later. Notably, a similar conversion to a long-lasting memory is achieved by potentiating an independent input to the LA delivered minutes, but not 24 hours after the experience. Surprisingly, in a non-associative conditioning paradigm, strong stimulation of an independent input uncovers the aversive memory of the shock. Our results indicate that different forms of plasticity can proactively as well as retroactively impact the persistence of memories, an effect with computational and behavioral implications.
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