Connectivity and molecular profiles of Foxp2- and Dbx1-lineage neurons in the accessory olfactory bulb and medial amygdala.

In terrestrial vertebrates, the olfactory system is divided into main (MOS) and accessory (AOS) components that process both volatile and nonvolatile cues to generate appropriate behavioral responses. While much is known regarding the molecular diversity of neurons that comprise the MOS, less is known about the AOS. Here, focusing on the vomeronasal organ (VNO), the accessory olfactory bulb (AOB), and the medial amygdala (MeA), we reveal that populations of neurons in the AOS can be molecularly subdivided based on their ongoing or prior expression of the transcription factors Foxp2 or Dbx1, which delineate separate populations of GABAergic output neurons in the MeA. We show that a majority of AOB neurons that project directly to the MeA are of the Foxp2 lineage. Using single-neuron patch-clamp electrophysiology, we further reveal that in addition to sex-specific differences across lineage, the frequency of excitatory input to MeA Dbx1- and Foxp2-lineage neurons differs between sexes. Together, this work uncovers a novel molecular diversity of AOS neurons, and lineage and sex differences in patterns of connectivity.

Transcriptionally defined amygdala subpopulations play distinct roles in innate social behaviors.

Social behaviors are innate and supported by dedicated neural circuits, but the molecular identities of these circuits and how they are established developmentally and shaped by experience remain unclear. Here we show that medial amygdala (MeA) cells originating from two embryonically parcellated developmental lineages have distinct response patterns and functions in social behavior in male mice. MeA cells expressing the transcription factor Foxp2 (MeAFoxp2) are specialized for processing male conspecific cues and are essential for adult inter-male aggression. By contrast, MeA cells derived from the Dbx1 lineage (MeADbx1) respond broadly to social cues, respond strongly during ejaculation and are not essential for male aggression. Furthermore, MeAFoxp2 and MeADbx1 cells show differential anatomical and functional connectivity. Altogether, our results suggest a developmentally hardwired aggression circuit at the MeA level and a lineage-based circuit organization by which a cell's embryonic transcription factor profile determines its social information representation and behavioral relevance during adulthood.

Hardwired to attack: Transcriptionally defined amygdala subpopulations play distinct roles in innate social behaviors.

Social behaviors are innate and supported by dedicated neural circuits, but it remains unclear whether these circuits are developmentally hardwired or established through social experience. Here, we revealed distinct response patterns and functions in social behavior of medial amygdala (MeA) cells originating from two embryonically parcellated developmental lineages. MeA cells in male mice that express the transcription factor Foxp2 (MeAFoxp2) are specialized for processing male conspecific cues even before puberty and are essential for adult inter-male aggression. In contrast, MeA cells derived from the Dbx1-lineage (MeADbx1) respond broadly to social cues and are non-essential for male aggression. Furthermore, MeAFoxp2 and MeADbx1 cells show differential anatomical and functional connectivity. Altogether, our results support a developmentally hardwired aggression circuit at the level of the MeA and we propose a lineage-based circuit organization by which a cell's embryonic transcription factor profile determines its social information representation and behavior relevance during adulthood.

Serotonergic Plasticity in the Dorsal Raphe Nucleus Characterizes Susceptibility and Resilience to Anhedonia.

Chronic stress induces anhedonia in susceptible but not resilient individuals, a phenomenon observed in humans as well as animal models, but the molecular mechanisms underlying susceptibility and resilience are not well understood. We hypothesized that the serotonergic system, which is implicated in stress, reward, and antidepressant therapy, may play a role. We found that plasticity of the serotonergic system contributes to the differential vulnerability to stress displayed by susceptible and resilient animals. Stress-induced anhedonia was assessed in adult male rats using social defeat and intracranial self-stimulation, while changes in serotonergic phenotype were investigated using immunohistochemistry and in situ hybridization. Susceptible, but not resilient, rats displayed an increased number of neurons expressing the biosynthetic enzyme for serotonin, tryptophan-hydroxylase-2 (TPH2), in the ventral subnucleus of the dorsal raphe nucleus (DRv). Further, a decrease in the number of DRv glutamatergic (VGLUT3+) neurons was observed in all stressed rats. This neurotransmitter plasticity is activity-dependent, as was revealed by chemogenetic manipulation of the central amygdala, a stress-sensitive nucleus that forms a major input to the DR. Activation of amygdalar corticotropin-releasing hormone (CRH)+ neurons abolished the increase in DRv TPH2+ neurons and ameliorated stress-induced anhedonia in susceptible rats. These findings show that activation of amygdalar CRH+ neurons induces resilience, and suppresses the gain of serotonergic phenotype in the DRv that is characteristic of susceptible rats. This molecular signature of vulnerability to stress-induced anhedonia and the active nature of resilience could be targeted to develop new treatments for stress-related disorders like depression.SIGNIFICANCE STATEMENT Depression and other mental disorders can be induced by chronic or traumatic stressors. However, some individuals are resilient and do not develop depression in response to chronic stress. A complete picture of the molecular differences between susceptible and resilient individuals is necessary to understand how plasticity of limbic circuits is associated with the pathophysiology of stress-related disorders. Using a rodent model, our study identifies a novel molecular marker of susceptibility to stress-induced anhedonia, a core symptom of depression, and a means to modulate it. These findings will guide further investigation into cellular and circuit mechanisms of resilience, and the development of new treatments for depression.