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Depression and anxiety are two of the most common mental health disorders, often sharing symptoms and administrations. Most pharmacological agents available to treat these disorders target monoamine systems. Currently, finding the most effective treatment for an individual is a process of trial and error. Therefore, to better understand how disease etiology may predict treatment response, we studied mice exposed developmentally to the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX). These mice show the murine equivalent of anxiety- and depression-like symptoms in adulthood and here we report that these mice are also behaviorally resistant to the antidepressant-like effects of adult SSRI administration. We investigated whether tianeptine (TIA), which exerts its therapeutic effects through the mu-opioid receptor (MOR) instead of directly targeting monoaminergic systems, would be more effective in this model.We injected C57BL/6J (C57) pups with either FLX (10 mg/kg, i.p) or vehicle from postnatal (PN) day 2 to 11, a period in which mouse brain development parallels that of the third trimester of a human pregnancy. Prior work established that adult 129SvEv (129) mice exposed to FLX in this time period (PN-FLX) showed increased avoidant and decreased hedonic behaviors, which correspond to anxiety- and depressive-like symptoms in humans, respectively. We performed baseline testing in adulthood in C57 PN-FLX animals and confirmed a similar avoidant phenotype to that reported in 129 PN-FLX mice. We then treated these animals with chronic FLX (18 mg/kg in the drinking water) and evaluated effects on two tasks that measure avoidant behavior – the open field and novelty suppressed feeding (NSF) tasks. This administration failed to improve, and even exacerbated, avoidance symptoms in PN-FLX mice. The same animals then underwent chronic administration with TIA (30 mg/kg, 2x/day, i.p.) as an alternative treatment strategy. TIA administration decreased avoidance behavior as measured in the open field and NSF. Overall, this demonstrates that TIA may be a promising alternative treatment to typical antidepressants, especially in patients whose serotonergic system has been altered.

Cognitive functions, such as working memory, are disrupted in most psychiatric disorders. Many of these processes are believed to depend on the medial prefrontal cortex (mPFC). Traditionally, maze-based behavioral tasks, which have a strong exploratory component, have been used to study the role of the mPFC in working memory in mice. In maze tasks, mice navigate through the environment and require a significant amount of time to complete each trial, thereby limiting the number of trials that can be run per day. Here, we show that an operant-based delayed nonmatch to sample (DNMS) working memory task, with shorter trial lengths and a smaller exploratory component, is also mPFC-dependent. We created excitotoxic lesions in the mPFC of mice and found impairments in both the acquisition of the task, with no delay, and in the performance with delays introduced. Importantly, we saw no differences in trial length, reward collection, or lever-press latencies, indicating that the difference in performance was not due to a change in motivation or mobility. Using this operant DNMS task will facilitate the analysis of working memory and improve our understanding of the physiology and circuit mechanisms underlying this cognitive process. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Serotonin (5-HT) neurons project from the raphe nuclei throughout the brain where they act to maintain homeostasis. Here, we study 5-HT inputs into the bed nucleus of the stria terminalis (BNST), a major subdivision of the extended amygdala that has been proposed to regulate responses to anxiogenic environments in humans and rodents. While the dorsal part of the BNST (dBNST) receives dense 5-HT innervation, whether and how 5-HT in the dBNST normally modulates anxiety remains unclear. Using optogenetics, we demonstrate that activation of 5-HT terminals in the dBNST reduces anxiety in a highly anxiogenic environment. Further analysis revealed that optogenetic inhibition of 5-HT inputs into the dBNST increases anxiety in a less anxiogenic environment. We found that 5-HT predominantly hyperpolarizes dBNST neurons, reducing their activity in a manner that can be blocked by a 5-HT1A antagonist. Finally, we demonstrate that activation of 5-HT1A receptors in the dBNST is necessary for the anxiolytic effect observed following optogenetic stimulation of 5-HT inputs into the dBNST. These data reveal that 5-HT release in the dBNST modulates anxiety-like behavior via 5-HT1A receptors under naturalistic conditions.

Lifelong homeostatic setpoints for mood-related behaviors emerge during adolescence. Serotonin (5-HT) plays an important role in refining the formation of brain circuits during sensitive developmental periods. In rodents, the role of 5-HT1A receptors in general and autoreceptors in particular has been characterized in anxiety. However, less is known about the role of 5-HT1A receptors in depression-related behavior. Here, we show that whole-life suppression of heteroreceptor expression results in a broad depression-like behavioral phenotype accompanied by physiological and cellular changes within medial prefrontal cortex-dorsal raphe proper (mPFC-DRN) circuitry. These changes include increased basal 5-HT in a mPFC that is hyporesponsive to stress and decreased basal 5-HT levels and firing rates in a DRN hyperactivated by the same stressor. Remarkably, loss of heteroreceptors in the PFC at adolescence is sufficient to recapitulate this depression-like behavioral syndrome. Our results suggest that targeting mPFC 5-HT1A heteroreceptors during adolescence in humans may have lifelong ramifications for depression and its treatment.

Type III Nrg1, a member of the Nrg1 family of signaling proteins, is expressed in sensory neurons, where it can signal in a bi-directional manner via interactions with the ErbB family of receptor tyrosine kinases (ErbB RTKs) [1]. Type III Nrg1 signaling as a receptor (Type III Nrg1 back signaling) can acutely activate phosphatidylinositol-3-kinase (PtdIns3K) signaling, as well as regulate levels of α7* nicotinic acetylcholine receptors, along sensory axons [2]. Transient receptor potential vanilloid 1 (TRPV1) is a cation-permeable ion channel found in primary sensory neurons that is necessary for the detection of thermal pain and for the development of thermal hypersensitivity to pain under inflammatory conditions [3]. Cell surface expression of TRPV1 can be enhanced by activation of PtdIns3K [4], [5], [6], making it a potential target for regulation by Type III Nrg1. We now show that Type III Nrg1 signaling in sensory neurons affects functional axonal TRPV1 in a PtdIns3K-dependent manner. Furthermore, mice heterozygous for Type III Nrg1 have specific deficits in their ability to respond to noxious thermal stimuli and to develop capsaicin-induced thermal hypersensitivity to pain. Cumulatively, these results implicate Type III Nrg1 as a novel regulator of TRPV1 and a molecular mediator of nociceptive function.