Htr2a-Expressing Cells in the Central Amygdala Control the Hierarchy between Innate and Learned Fear

SummaryFear is induced by innate and learned mechanisms involving separate pathways. Here, we used an olfactory-mediated innate-fear versus learned-fear paradigm to investigate how these pathways are integrated. Notably, prior presentation of innate-fear stimuli inhibited learned-freezing response, but not vice versa. Whole-brain mapping and pharmacological screening indicated that serotonin-2A receptor (Htr2a)-expressing cells in the central amygdala (CeA) control both innate and learned freezing, but in opposing directions. In vivo fiber photometry analyses in freely moving mice indicated that innate but not learned-fear stimuli suppressed the activity of Htr2a-expressing CeA cells. Artificial inactivation of these cells upregulated innate-freezing response and downregulated learned-freezing response. Thus, Htr2a-expressing CeA cells serve as a hierarchy generator, prioritizing innate fear over learned fear

Kinase and phosphatase engagement is dissociated between memory formation and extinction

Associative long-term memories (LTMs) support long-lasting behavioural changes resulting from sensory experiences. Retrieval of a stable LTM by means of a large number of conditioned stimulus (CS) alone presentations produces inhibition of the original memory through extinction. Currently, there are two opposing hypotheses to account for the neural mechanisms supporting extinction. The unlearning hypothesis posits that extinction affects the original memory trace by reverting the synaptic changes supporting LTM. On the contrary, the new learning hypothesis proposes that extinction is simply the formation of a new associative memory that inhibits the expression of the original one. We propose that detailed analysis of extinction-associated molecular mechanisms could help distinguish between these hypotheses. Here we will review experimental evidence regarding the role of protein kinases and phosphatases on LTM formation and extinction. Even though kinases and phosphatases regulate both memory processes, their participation appears to be dissociated. LTM formation recruits kinases, but is constrained by phosphatases. Memory extinction presents a more diverse molecular landscape, requiring phosphatases and some kinases, but also being constrained by kinase activity. Based on the available evidence, we propose a new theoretical model for memory extinction: a neuronal segregation of kinases and phosphatases supports a combination of time-dependent reversible inhibition of the original memory (CS-US), with establishment of a new associative memory trace (CS-noUS)

Neuronal diversity of the amygdala and the bed nucleus of the stria terminalis

The amygdala complex is a diverse group of more than 13 nuclei, segregated in five major groups: the basolateral (BLA), central (CeA), medial (MeA), cortical (CoA), and basomedial (BMA) amygdala nuclei. These nuclei can be distinguished depending on their cytoarchitectonic properties, connectivity, genetic, and molecular identity, and most importantly, on their functional role in animal behavior. The extended amygdala includes the CeA and the bed nucleus of the stria terminalis (BNST). Both CeA and the BNST share similar cellular organization, including common neuron types, reciprocal connectivity, and many overlapping downstream targets. In this section, we describe the advances of our knowledge on neuronal diversity in the amygdala complex and the BNST, based on recent functional studies, performed at genetic, molecular, physiological, and anatomical levels in rodent models, especially rats and mice. Molecular and connection property can be used separately, or in combinations, to define neuronal populations, leading to a multiplexed neuronal diversity-supporting different functional roles. © 2020 Elsevier B.V

An enhanced therapeutic effect of repetitive transcranial magnetic stimulation combined with antibody treatment in a primate model of spinal cord injury.

Repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (MI) is expected to provide a therapeutic impact on spinal cord injury (SCI). On the other hand, treatment with antibody against repulsive guidance molecule-a (RGMa) has been shown to ameliorate motor deficits after SCI in rodents and primates. Facilitating activity of the corticospinal tract (CST) by rTMS following rewiring of CST fibers by anti-RGMa antibody treatment may exert an enhanced effect on motor recovery in a primate model of SCI. To address this issue, we examined whether such a combined therapeutic strategy could contribute to accelerating functional restoration from SCI. In our SCI model, unilateral lesions were made between the C6 and the C7 level. Two macaque monkeys were used for each of the combined therapy and antibody treatment alone, while one monkey was for rTMS alone. The antibody treatment was continuously carried out for four weeks immediately after SCI, and rTMS trials applying a thermoplastic mask and a laser distance meter lasted ten weeks. Behavioral assessment was performed over 14 weeks after SCI to investigate the extent to which motor functions were restored with the antibody treatment and/or rTMS. While rTMS without the preceding antibody treatment produced no discernible sign for functional recovery, a combination of the antibody and rTMS exhibited a greater effect, especially at an early stage of rTMS trials, on restoration of dexterous hand movements. The present results indicate that rTMS combined with anti-RGMa antibody treatment may exert a synergistic effect on motor recovery from SCI