Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression

Abstract

Decreased serotonergic activity has been implicated in anxiety and major depression, and antidepressants directly or indirectly increase the long-term activity of the serotonin system. A key component of serotonin circuitry is the 5-HT1A autoreceptor, which functions as the major somatodendritic autoreceptor to negatively regulate the “gain” of the serotonin system. In addition, 5-HT1A heteroreceptors are abundantly expressed post-synaptically in the prefrontal cortex (PFC), amygdala, and hippocampus to mediate serotonin actions on fear, anxiety, stress, and cognition. Importantly, in the PFC 5-HT1A heteroreceptors are expressed on at least two antagonist neuronal populations: excitatory pyramidal neurons and inhibitory interneurons. Rodent models implicate the 5-HT1A receptor in anxiety- and depression-like phenotypes with distinct roles for pre- and post-synaptic 5-HT1A receptors. In this review, we present a model of serotonin-PFC circuitry that integrates evidence from mouse genetic models of anxiety and depression involving knockout, suppression, over-expression, or mutation of genes of the serotonin system including 5-HT1A receptors. The model postulates that behavioral phenotype shifts as serotonin activity increases from none (depressed/aggressive not anxious) to low (anxious/depressed) to high (anxious, not depressed). We identify a set of conserved transcription factors including Deaf1, Freud-1/CC2D1A, Freud-2/CC2D1B and glucocorticoid receptors that may confer deleterious regional changes in 5-HT1A receptors in depression, and how future treatments could target these mechanisms. Further studies to specifically test the roles and regulation of pyramidal vs. interneuronal populations of 5-HT receptors are needed better understand the role of serotonin in anxiety and depression and to devise more effective targeted therapeutic approaches.

Cholinergic and serotonergic modulations differentially affect large-scale functional networks in the mouse brain

“…When comparing the effect of cholinergic and serotonergic modulation, the frontal and thalamic networks were more affected by the latter. This is consistent with observations in neurological disorders, such as depression and autism, characterized by frontal impairments and aberrant serotonergic functioning (Jeong et al 2009;Albert et al 2014).…”

Translocator protein mediates the anxiolytic and antidepressant effects of midazolam

“…It is interesting that the prefrontal cortex and hippocampus were selected to measure neurosteriod biosynthesis in this study. Both the brain regions play an important role in emotional processing, fear conditioning and explicit memory that are relevant to anxiety and depression (Albert et al, 2014;Dias et al, 2012). Previous studies showed that prefrontal cortex and hippocampus contribute to memory formation in the fear associated network in addition to regulating subsequent expression of fear (Herry et al, 2010;Maren et al, 2013).…”

“…Both the brain regions are important in emotional processing, fear conditioning and explicit memory and play a role in anxiety and depression (Albert et al, 2014;Dias et al, 2012).…”

Chronic l-Dopa Decreases Serotonin Neurons in a Subregion of the Dorsal Raphe Nucleus

“…Chronic L-dopa specifically affected the caudal extent of the dorsal DRN and the PFC, two brain regions involved in affective behaviors (Lowry et al, 2005(Lowry et al, , 2008Warden et al, 2012;Albert et al, 2014). The crosstalk between these two regions is involved in fear and anxiety responses in rats (Hashimoto et al, 1999;Bishop et al, 2004;Amat et al, 2005;Forster et al, 2006) and several preclinical and clinical studies propose that chronic L-dopa therapy for Parkinson's disease could result in mood disturbances, such as anxiety and depression (Damasio et al, 1971;Choi et al, 2000;Borah and Mohanakumar, 2007;Eskow Jaunarajs et al, 2010.…”