Depression is a polygenic and highly complex psychiatric disorder that remains a major burden on society. Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), are some of the most commonly prescribed drugs worldwide. In this review, we will discuss the evidence that links serotonin and serotonin receptors to the etiology of depression and the mechanisms underlying response to antidepressant treatment. We will then revisit the role of serotonin in three distinct hypotheses that have been proposed over the last several decades to explain the pathophysiology of depression: the monoamine, neurotrophic, and neurogenic hypotheses. Finally, we will discuss how recent studies into serotonin receptors have implicated specific neural circuitry in mediating the antidepressant response, with a focus being placed on the hippocampus.

The ventral hippocampus (vHPC) is a critical hub in networks that process emotional information. While recent studies have indicated that ventral CA1 (vCA1) projection neurons are functionally dissociable, the basic principles of how the inputs and outputs of vCA1 are organized remain unclear. Here we used viral and sequencing approaches to define the logic of the extended vCA1 circuit. Using high-throughput sequencing of genetically barcoded neurons (MAPseq) to map the axonal projections of thousands of vCA1 neurons, we identify a population of neurons that simultaneously broadcast information to multiple areas known to regulate the stress axis and approach/avoidance behavior. Through molecular profiling and viral input-output tracing of vCA1 projection neurons, we show how neurons with distinct projection targets may differ in their inputs and transcriptional signatures. These studies reveal novel organizational principles of the vHPC that may underlie its functional heterogeneity.

The bed nucleus of the stria terminalis (BNST) is a forebrain region highly responsive to stress that expresses corticotropin-releasing hormone (CRH) and is implicated in mood disorders, such as anxiety. However, the exact mechanism by which chronic stress induces CRH-mediated dysfunction in BNST and maladaptive behaviors remains unclear. Here, we first confirmed that selective acute optogenetic activation of the oval nucleus BNST (ovBNST) increases maladaptive avoidance behaviors in male mice. Next, we found that a 6 week chronic variable mild stress (CVMS) paradigm resulted in maladaptive behaviors and increased cellular excitability of ovBNST CRH neurons by potentiating mEPSC amplitude, altering the resting membrane potential, and diminishing M-currents (a voltage-gated K ϩ current that stabilizes membrane potential) in ex vivo slices. CVMS also increased c-fos ϩ cells in ovBNST following handling. We next investigated potential molecular mechanism underlying the electrophysiological effects and observed that CVMS increased CRH ϩ and pituitary adenylate cyclase-activating polypeptide ϩ (PACAP; a CRH upstream regulator) cells but decreased striatal-enriched protein tyrosine phosphatase ϩ (a STEP CRH inhibitor) cells in ovBNST. Interestingly, the electrophysiological effects of CVMS were reversed by CRHR1-selective antagonist R121919 application. CVMS also activated protein kinase A (PKA) in BNST, and chronic infusion of the PKA-selective antagonist H89 into ovBNST reversed the effects of CVMS. Coadministration of the PKA agonist forskolin prevented the beneficial effects of R121919. Finally, CVMS induced an increase in surface expression of phosphorylated GluR1 (S845) in BNST. Collectively, these findings highlight a novel and indispensable stress-induced role for PKA-dependent CRHR1 signaling in activating BNST CRH neurons and mediating maladaptive behaviors.

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Epigenetic mechanisms that modify chromatin conformation have recently been under investigation for their contributions to learning and the formation of memory. For example, the role of enzymes involved in histone acetylation are studied in the formation of long-lasting memories because memory consolidation requires gene expression events that are facilitated by an open state of chromatin. We recently proposed that epigenetic events may control the entry of specific sensory features into long-term memory by enabling transcription-mediated neuronal plasticity in sensory brain areas. Histone deacetylases, like HDAC3, may thereby regulate the specific sensory information that is captured for entry into long-term memory stores (Phan and Bieszczad, 2016). To test this hypothesis, we used an HDAC3-selective inhibitor (RGFP966) to determine whether its application after an experience with a sound stimulus with unique acoustic features could contribute to the formation of a memory that would assist in mediating its later recognition. We gave adult male zebra finches limited exposure to unique conspecific songs (20 repetitions each, well below the normal threshold to form long-term memory), followed by treatment with RGFP966 or vehicle. In different groups, we either made multi-electrode recordings in the higher auditory area NCM (caudal medial nidopallidum), or determined expression of an immediate early gene, zenk (also identified as zif268, egr-1, ngfi-a and krox24), known to participate in neuronal memory in this system. We found that birds treated with RGFP966 showed neuronal memory after only limited exposure, while birds treated with vehicle did not. Strikingly, evidence of neuronal memory in NCM induced by HDAC3-inhibition was lateralized to the left-hemisphere, consistent with our finding that RGFP966-treatment also elevated zenk expression only in the left hemisphere. The present findings show feasibility for epigenetic mechanisms to control neural plasticity underlying the formation of specific memories for conspecific communication sounds. This is the first evidence in zebra finches that epigenetic mechanisms may contribute to gene expression events for memory of acoustically-rich sensory cues.