Our lab is uncovering some of the factors that lead to depression and determine whether patients will respond to antidepressants. Antidepressants like serotonin-specific reuptake inhibitors (SSRIs) are only effective in 30% of depressed patients and require over three weeks. Thus, better ways of predicting response or alternative treatments are needed. To address these questions, we have examined the genetic and epigenetic regulators of the serotonin system and their effects on behavior and antidepressant response. To do this we use mouse models of mental illness, as well as human samples from collaborators.

One key gene that we study is serotonin-1A (5-HT1A) receptor gene. The 5-HT1A autoreceptor on serotonin neurons inhibits their activity and is associated with depression and resistance to SSRIs.  But in other brain cells, it mediates serotonin actions (see Figure below). The 3-6 week delay in response to SSRIs reflects the time it takes to desensitize the 5-HT1A autoreceptors to allow serotonin activation. Therefore, we first identified the molecular mechanisms that regulate the 5-HT1A gene and identified human 5-HT1A variant (rs6295) that increases 5-HT1A expression and is associated with SSRI-resistant depression. To test whether these transcription changes really affect depression we knocked them out in serotonin neurons of adult mice. This results in SSRI-resistant anxiety and depression-like behaviors.

We are now testing whether other types of antidepressants or direct stimulation of serotonin neurons will reverse the depression in these mice.In addition to genetic changes, we examine how sex and stress affect behavior and response to antidepressants. We find important roles of DNA methylation of the 5-HT1A gene and remodeling of serotonin branches in the brain. We have also examined depression that occurs after a stroke and that responds to SSRI treatment but not exercise. Using this injury model of depression, we are finding that SSRIs enhance neuroplasticity of serotonin branches (see Figure above) for long-lasting recovery from depression and cognitive impairment. By understanding antidepressant actions in these models, we can develop better treatment strategies for depression in humans.

Five Key Publications

Albert lab members in bold
Publications archived at: ResearchGate

1. Vahid-Ansari F, Newman-Tancredi A, Fuentes-Alvarenga AF, Daigle M, Albert PR (2024) Rapid reorganization of serotonin projections and antidepressant response to 5-HT1A-biased agonist NLX-101 in fluoxetine-resistant cF1ko mice. Neuropharmacology 261:110132. PDF

2. Vahid-Ansari F, Zahrai A, Daigle M, Albert PR (2024) Chronic Desipramine Reverses Deficits in Cell Activity, Norepinephrine Innervation, and Anxiety-Depression Phenotypes in Fluoxetine-Resistant cF1ko Mice. J Neurosci 44. PDF

3. Turcotte-Cardin V, Vahid-Ansari F, Luckhart C, Daigle M, Geddes SD, Tanaka KF, Hen R, James J, Merali Z, Beique JC, Albert PR (2019) Loss of adult 5-HT1A autoreceptors results in a paradoxical anxiogenic response to antidepressant treatment. J Neurosci 39, 1334-46. PDF

4. Vahid-Ansari F, Daigle M, Manzini MC, Tanaka KF, Hen R, Geddes SD, Beique JC, James J, Merali Z, Albert PR. (2017) Abrogated Freud-1/CC2D1A repression of 5-HT1A autoreceptors induces fluoxetine-resistant anxiety/depression-like behavior. J Neurosci 37, 11967-11978. PDF

5. Zahrai A, Vahid-Ansari F, Daigle M, Albert PR (2020) Fluoxetine-induced recovery of serotonin and norepinephrine projections in a mouse model of post-stroke depression. Transl Psychiatry 10:334. PDF