Pattern Separation: A Potential Marker of Impaired Hippocampal Adult Neurogenesis in Major Depressive Disorder

Abstract

Adult neurogenesis involves the generation of new neurons, particularly in the dentate gyrus of the hippocampus. Decreased hippocampal neurogenesis has been implicated in both animal models of depression and in patients with major depressive disorder (MDD), despite some inconsistency in the literature. Here, we build upon current models to generate a new testable hypothesis, linking impaired neurogenesis to downstream psychological outcomes commonly observed in MDD. We contend that disruption in adult neurogenesis impairs pattern separation, a hippocampus-dependent function requiring the careful discrimination and storage of highly similar, but not identical, sensory inputs. This, in turn, can affect downstream processing and response selection, of relevance to emotional wellbeing. Specifically, disrupted pattern separation leads to misperceived stimuli (i.e., stimulus confusion), triggering the selection and deployment of established responses inappropriate for the actual stimuli. We speculate that this may be akin to activation of automatic thoughts, described in the Cognitive Behavior Theory of MDD. Similarly, this impaired ability to discriminate information at a fundamental sensory processing level (e.g., impaired pattern separation) could underlie impaired psychological flexibility, a core component of Acceptance and Commitment Therapy of MDD. We propose that research is needed to test this model by examining the relationship between cognitive functioning (e.g., pattern separation ability), psychological processes (e.g., perseveration and psychological inflexibility), and neurogenesis, taking advantage of emerging magnetic resonance spectroscopy-based imaging that measures neurogenesis in-vivo.

Mentalization as Mediator between Adult Attachment and Interpersonal Distress

“…An explanation for the eminently high correlations regarding interpersonal distress and symptom severity may be the high number of depressed patients. Since approximately 60% of the sample had depressive disorders as main diagnoses (Table 2), the mental inflexibility that goes along with the disorder may have affected the data [50, 51]. …”

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

“…Pattern separation is a competence that avoids confusion between similar memories by transforming similar input patterns of neural activity into dissimilar output patterns before their long-term storage in the hippocampus [103]. Since pattern separation function requires maintenance of DG neurogenesis at certain levels [104][105] and the integrity of DG circuitry [106], the results pointed to abnormalities in neurogenesis and alterations in DG network activity. Indeed, neurogenesis was substantially reduced, and a portion of newly born neurons continued to migrate into the dentate hilus in CERs, a feature also noted in previous KA models [32,39].…”

Adult Hippocampal Neurogenesis: Regulation and Possible Functional and Clinical Correlates

“…Depression is also associated with a decrease in declarative memory and to worse performances on hippocampal-dependent tasks, including pattern separation (Dere et al, 2010 ; Shelton and Kirwan, 2013 ). Altogether, memory impairments and altered interpretation of ambiguous contexts may be related to a decrease in hippocampal neurogenesis (Gandy et al, 2017 ). Indeed, impaired cognitive flexibility and pattern separation inefficiency, which leads to overgeneralization (Sahay et al, 2011b ), are commonly seen in depressed patients (Sumner et al, 2010 ; Belzung et al, 2015 ).…”