Depressive mood modulates the anterior lateral CA1 and DG/CA3 during a pattern separation task in cognitively intact individuals: A functional MRI study

Abstract

Although patients with major depressive disorder typically have a reduced hippocampal volume, particularly in the cornu ammonis 1 (CA1), animal studies suggest that depressive mood is related to the dentate gyrus (DG). In this study, our objective was to clarify which hippocampal subregions are functionally associated with depressive mood in humans. We conducted a functional MRI (fMRI) study on 27 cognitively intact volunteers. Subjects performed a modified version of a delayed matching-to-sample task in an MRI scanner to investigate pattern separation-related activity during each phase of encoding, delay, and retrieval. In each trial, subjects learned a pair of sample cues. Functional MR images were acquired at a high spatial resolution, focusing on the hippocampus. Subjects also completed the Beck Depression Inventory (BDI), a questionnaire about depressive mood. Depending on the similarity between sample cues, activity in the DG/CA3 and medial CA1 in the anterior hippocampus changed only during encoding. Furthermore, the DG/CA3 region was more active during successful encoding trials compared to false trials. Activity in the DG/CA3 and lateral CA1 was negatively correlated with BDI scores. These results suggest that the DG/CA3 is the core region for pattern separation during the encoding phase and interacts with the medial CA1, depending on the similarity of the stimuli, to achieve effective encoding. Impaired activity in the DG/CA3, as well as in the lateral CA1, was found to be associated with depressive symptoms, even at a subclinical level.

Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

“…Within the hippocampal formation, DG-CA3 volume is decreased in individuals with early life stress history (Teicher et al, 2012) and in PTSD . A recent study found impaired pattern separation in the DG of individuals with elevated depression scores (Fujii et al, 2014). Although it is not clear if stress contributes to the higher depression scores (or depressed mood) in these individuals, these observations suggest, albeit indirectly, that stress alters pattern separation in the DG-CA3 circuit.…”

Integrating new findings and examining clinical applications of pattern separation

“…This behavioral difference is accompanied by increased amygdala activity and decreased DG/CA3 activity in high-resolution fMRI. Furthermore, the level of DG/CA3 activity is negatively correlated with depressive symptom severity, which indicates that reduced DG/CA3 activity may be a pathological condition 51,113 . Older adults experiencing late-life depression also show enhanced discrimination of negative scenes, in addition to alterations in their amygdala–entorhinal–hippocampal network 114 (Fig.…”

GABAergic Control of Depression-Related Brain States

“…Moreover, in mice this task is critically dependent on adult hippocampal neurogenesis (reviewed in Aimone, Deng, & Gage, 2011; Clelland et al, 2009). Importantly, defects in pattern separation of emotionally relevant stimuli have emerged as a cognitive phenotype of MDD (Fujii et al, 2014; Leal, Tighe, Jones, & Yassa, 2014). In the context of anxiety disorders defects in pattern separation have been proposed to underlie the commonly observed phenomenon of stimulus generalization (Kheirbek, Klemenhagen, Sahay, & Hen, 2012).…”

“…Moreover, disinhibition of HPA axis function correlates with depressive-like increases in emotional reactivity of mice with impaired hippocampal neurogenesis (Shen et al, 2010; Snyder et al, 2011). Although several studies have reported normal emotional behavior following ablation of hippocampal neurogenesis in mice (reviewed in Petrik, Lagace, & Eisch, 2012), hippocampal neurogenesis is also essential for hippocampus-dependent pattern separation, a cognitive task that is impaired in MDD (Fujii et al, 2014; Leal et al, 2014). …”

“…A. Murray, Wise, & Drevets, 2011), regional brain volume loss (i.e. Bell-McGinty et al, 2002; Hickie et al, 2005; Koolschijn, van Haren, Lensvelt-Mulders, Hulshoff Pol, & Kahn, 2009; Sacher et al, 2012; Steffens et al, 2000), circuits underlying cognitive impairments (Fujii, Saito, Yanaka, Kosaka, & Okazawa, 2014), and brain regions and their functional connections that respond to therapeutically effective deep brain stimulation (Holtzheimer & Mayberg, 2011). …”