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 (VGLUT3ϩ) 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)ϩ neurons abolished the increase in DRv TPH2ϩ neurons and ameliorated stress-induced anhedonia in susceptible rats. These findings show that activation of amygdalar CRHϩ 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.

critical feedback on the research and Dr.Byung Kook Lim for his valuable feedback and the use of his slide-scanning microscope. ABSTRACTChronic 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 SIGNIFICANCE STATEMENTDepression 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.

Previous work revealed an inverse correlation between tobacco smoking and Parkinson’s disease (PD) that is associated with nicotine-induced neuroprotection of dopaminergic (DA) neurons against nigrostriatal damage in PD primates and rodent models. Nicotine, a neuroactive component of tobacco, can directly alter the activity of midbrain DA neurons and induce non-DA neurons in the substantia nigra (SN) to acquire a DA phenotype. Here, we investigated the recruitment mechanism of nigrostriatal GABAergic neurons to express DA phenotypes, such as transcription factor Nurr1 and DA-synthesizing enzyme tyrosine hydroxylase (TH), and the concomitant effects on motor function. Wild-type and α-syn-overexpressing (PD) mice treated with chronic nicotine were assessed by behavioral pattern monitor (BPM) and immunohistochemistry/in situ hybridization to measure behavior and the translational/transcriptional regulation of neurotransmitter phenotype following selective Nurr1 overexpression or DREADD-mediated chemogenetic activation. We found that nicotine treatment led to a transcriptional TH and translational Nurr1 upregulation within a pool of SN GABAergic neurons in wild-type animals. In PD mice, nicotine increased Nurr1 expression, reduced the number of α-syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicit de novo translational upregulation of Nurr1. Retrograde labeling revealed that a fraction of these GABAergic neurons projects to the dorsal striatum. Finally, concomitant depolarization and Nurr1 overexpression within GABA neurons were sufficient to mimic nicotine-mediated dopamine plasticity. Revealing the mechanism of nicotine-induced DA plasticity protecting SN neurons against nigrostriatal damage could contribute to developing new strategies for neurotransmitter replacement in PD.

In order to respond appropriately to threats in the environment, the brain must rapidly determine whether a stimulus is important and whether it is positive or negative, and then use that information to direct behavioral responses. Neurons in the amygdala have long been implicated in valence encoding and in fear responses to threatening stimuli, but show transient firing responses in response to these stimuli that do not match the timescales of associated behavioral responses. For decades, there has been a logical gap in how behavioral responses could be mediated without an ensemble representation of the internal state of valence that has rapid onset, high signal-to-noise, and is sustained for the duration of the behavioral state. Here, we present the amygdalostriatal transition zone (ASt) as a missing piece of this highly conserved process that is of paramount importance for survival, which does exactly this: represents an internal state (e.g. fear) that can be expressed in multiple motor outputs (e.g. freezing or escape). The ASt is anatomically positioned as a 'shortcut' to connect the corticolimbic system (important for evaluation) with the basal ganglia (important for action selection) with the inputs of the amygdala and the outputs of the striatum - ideally poised for evaluating and responding to environmental threats. From in vivo cellular resolution recordings that include both electrophysiology and calcium imaging, we find that ASt neurons are unique in that they are sparse coding, extremely high signal-to-noise, and also maintain a sustained response for negative valence stimuli for the duration of the defensive behavior - a rare but essential combination. We further show that photostimulation of the ASt is sufficient to drive freezing and avoidance behaviors. Using single-nucleus RNA sequencing and in situ RNA labelling we generate a comprehensive profile of cell types and gene expression in the ASt, and find the ASt is genetically distinct from adjacent striatal and amygdalar structures. We also find that the ASt has a greater proportion of neurons expressing Drd2 than neurons expressing Drd1a, a unique feature compared to other regions of the striatum. Using in vivo calcium imaging, we show that that this Drd2+ population robustly encodes stimuli of negative valence, and in loss-of-function experiments find that optogenetic inhibition of Drd2+ ASt neurons causes a striking reduction in cue-conditioned fear responses. Together, our findings identify the ASt as a previously-unappreciated critical missing link for encoding learned associations and directing ongoing behavior.