Ventromedial prefrontal cortex regulates depressive-like behavior and rapid eye movement sleep in the rat

Abstract

Major depressive disorder (MDD) is a debilitating disease with symptoms like persistent depressed mood and sleep disturbances. The prefrontal cortex (PFC) has been implicated as an important structure in the neural circuitry of MDD, with pronounced abnormalities in blood flow and metabolic activity in PFC subregions, including the subgenual cingulate cortex (sgACC, or Brodmann area 25). In addition, deep brain stimulation in the sgACC has recently been shown to alleviate treatment-resistant depression. Depressed patients also show characteristic changes in sleep: insomnia, increased rapid-eye-movement (REM) sleep and shortened REM sleep latency. We hypothesized that sleep changes and depressive behavior may be a consequence of the abnormal PFC activity in MDD. The rat ventromedial PFC (vmPFC, prelimbic and infralimbic cortices) is considered to be the homolog of the human sgACC, so we examined the effect of excitotic lesions in the vmPFC on sleep-wake and depressive behavior. We also made lesions in the adjacent dorsal region (dmPFC) to compare the effect of this similar but distinct mPFC region. We found that both dmPFC and vmPFC lesions led to increased REM sleep, but only vmPFC-lesioned animals displayed increased sleep fragmentation, shortened REM latency and increased immobility in the forced swim test. Anatomic tracing suggests that the mPFC projects to the pontine REM-off neurons that interact with REM-on neurons in the dorsal pons. These results support our hypothesis that neuronal loss in the rat vmPFC resembles several characteristics of MDD and may be a critical area for modulating both mood and sleep.

Effect of antidepressant drugs on the vmPFC-limbic circuitry

“…Vialou and colleagues demonstrate that CCK likely released by GABAergic interneurons produces low neuronal activity in the vmPFC by social defeat (Vialou et al, 2014). Our recent study (Chang et al , 2014) shows that lesions of the vmPFC but not the dmPFC reduce REM sleep latency and increase REM sleep amounts and immobile time in forced swim test (FST) in rats. These REM sleep changes are in line with human MDD.…”

“…Chronic restraint stress leads to dendritic atrophy in the rat medial PFC (mPFC), including reduced length and total branch numbers of apical dendrites in pyramidal cells (Brown, 2005; Cook and Wellman, 2004; Izquierdo et al , 2006; Radley et al , 2004), while antidepressant treatment increases markers of neuroplasticity (Sairanen et al , 2007) and changes in cell morphology in the PFC (Benes and Vincent, 1991; Li et al , 2010). Our recent study shows that the lesioning the vmPFC reduces REM sleep latency, increases REM sleep amounts, and increases immobile time in forced swim test (FST) in rats (Chang et al , 2014). These changes of REM sleep and hopelessness are consistent in behaviors of unipolar and bipolar depression in human.…”

VGF and its C-terminal peptide TLQP-62 in ventromedial prefrontal cortex regulate depression-related behaviors and the response to ketamine

“…Reduced volume in subgenual anterior cingulate cortex (sgACC; a portion of human vmPFC), which includes Brodmann area (BA) 25 posteriorly and parts of BA24 and BA32 anteriorly [3] has been observed in depressed patients [4], and spine loss and decreased dendritic arborization in the vmPFC (including prelimbic and infralimbic cortexes) have been reported in rodents following chronic stress exposure [5]. Recent preclinical studies also revealed that vmPFC stimulation [6] and lesion [7] induce antidepressant and prodepressant effects in rodents, respectively. VGF (non-acronymic) is a neuropeptide precursor that is robustly regulated by neurotrophic growth factors [8], including brain-derived neurotrophic factor (BDNF).…”

Efficacy of an Integrative Treatment for Tinnitus Combining Music and Cognitive-Behavioral Therapy—Assessed With Behavioral and EEG Data

“…It is suggested that a limbic-auditory interaction could have constituted a ''noise-cancelling'' system, comprising mainly nodes of the thalamus, nucleus accumbens (NAc) and vMPFC, in which the vMPFC specializes in orienting attentional and emotional modulation into inhibiting the unwanted sensory signals through NAc and thalamus (Rauschecker et al, 2010;Leaver et al, 2011). Furthermore, activities in this region have been found to be related to processing the pleasantness of the stimuli (Sabatinelli et al, 2007;Junghofer et al, 2017), and animal studies have found that lesions to this region could induce depression-like behaviors in rat (Chang et al, 2014). VMPFC abnormalities have also been found in tinnitus patients with both structural (Mühlau et al, 2006;Leaver et al, 2011) and functional evidences (Seydell-Greenwald et al, 2012).…”