Aggressive behavior, brain size and domestication in clonal rainbow trout lines.

Domestication causes behavior and brain size changes in many species. We addressed three questions using clonal rainbow trout lines: What are the mirror-elicited aggressive tendencies in lines with varying degrees of domestication? How does brain size relate to genotype and domestication level? Finally, is there a relationship between aggressive behavior and brain size? Clonal lines, although sampling a limited subset of the species variation, provide us with a reproducible experimental system with which we can develop hypotheses for further research. We performed principal component analyses on 12 continuous behavior and brain/body size variables and one discrete behavioral variable ("yawn") and detected several aggression syndromes. Two behaviors, "freeze" and "escape", associated with high domestication; "display" and "yawn" behavior associated with wild lines and "swim against the mirror" behavior associated with semi-wild and domestic lines. Two brain size traits, total brain and olfactory volume, were significantly related to domestication level when taking total body size into account, with domesticated lines having larger total brain volume and olfactory regions. The aggression syndromes identified indicate that future QTL mapping studies on domestication-related traits would likely be fruitful.

Activity of prefrontal cortex serotonin 2A receptor expressing neurons is necessary for the head-twitch response of mice to psychedelic drug DOI in a sex-dependent manner.

Serotonin 2A receptors (5-HT 2A Rs) mediate the effects of psychedelic drugs. 5-HT 2A R agonists, such as (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), that produce a psychedelic experience in humans induce a head-twitch response (HTR) behavior in rodents. However, it is unknown whether the activity of 5-HT 2A R expressing neurons is sufficient to produce the HTR in the absence of an agonist, or in which brain region 5-HT 2A Rs control the HTR. Here, we use an optogenetic approach to examine whether activation of 5-HT 2A R expressing neurons in the mouse prefrontal cortex (PFC) is sufficient to induce HTRs alone, or may augment the HTR produced by DOI, and if inhibition of these neurons prevents DOI-induced HTRs in mice. We crossed Htr2a -Cre mice to Cre-dependent optogenetic lines Ai32 (channelrhodopsin) and Ai39 (halorhodopsin) to selectively activate and inhibit (respectively) 5-HT 2A R-expressing neurons in the PFC of adult mice. We found that optogenetic stimulation of PFC 5-HT 2A R expressing neurons in the absence of an agonist does not increase HTRs in mice. In both male and female Ai32 mice that received vehicle, there was no difference in HTRs in mice that expressed Htr2a -Cre compared with control mice, indicating that optogenetic activation of 5-HT 2A R+ cells in the PFC was not sufficient to produce HTRs in the absence of an agonist. In female mice, activation of PFC 5-HT 2A R expressing neurons augmented the HTR produced by DOI. However, this result was not seen in male mice. In contrast, inhibition of 5-HT 2A R expressing neurons in the PFC prevented the increase in HTR produced by DOI in male, but not in female, mice. Together, these findings suggest that activation of 5-HT 2A Rs in the PFC is not sufficient to induce HTRs in the absence of a 5-HT 2A R agonist but is necessary for induction of HTRs by a 5-HT 2A R agonist in a sex-dependent manner.

Identification of activity-induced Egr3-dependent genes reveals genes associated with DNA damage response and schizophrenia.

Bioinformatics and network studies have identified the immediate early gene transcription factor early growth response 3 (EGR3) as a master regulator of genes differentially expressed in the brains of patients with neuropsychiatric illnesses ranging from schizophrenia and bipolar disorder to Alzheimer's disease. However, few studies have identified and validated Egr3-dependent genes in the mammalian brain. We have previously shown that Egr3 is required for stress-responsive behavior, memory, and hippocampal long-term depression in mice. To identify Egr3-dependent genes that may regulate these processes, we conducted an expression microarray on hippocampi from wildtype (WT) and Egr3-/- mice following electroconvulsive seizure (ECS), a stimulus that induces maximal expression of immediate early genes including Egr3. We identified 69 genes that were differentially expressed between WT and Egr3-/- mice one hour following ECS. Bioinformatic analyses showed that many of these are altered in, or associated with, schizophrenia, including Mef2c and Calb2. Enrichr pathway analysis revealed the GADD45 (growth arrest and DNA-damage-inducible) family (Gadd45b, Gadd45g) as a leading group of differentially expressed genes. Together with differentially expressed genes in the AP-1 transcription factor family genes (Fos, Fosb), and the centromere organization protein Cenpa, these results revealed that Egr3 is required for activity-dependent expression of genes involved in the DNA damage response. Our findings show that EGR3 is critical for the expression of genes that are mis-expressed in schizophrenia and reveal a novel requirement for EGR3 in the expression of genes involved in activity-induced DNA damage response.