Mechanisms of Memory Disruption in Depression

Abstract

Depressed individuals typically show poor memory for positive events, potentiated memory for negative events, and impaired recollection. These phenomena are clinically important but poorly understood. Compelling links between stress and depression suggest promising candidate mechanisms. Stress can suppress hippocampal neurogenesis, inhibit dopamine neurons, and sensitize the amygdala. We argue that these phenomena may impair pattern separation, disrupt the encoding of positive experiences, and bias retrieval toward negative events, respectively, thus recapitulating core aspects of memory disruption in depression. Encouragingly, optogenetic reactivation of cells engaged during the encoding of positive memories rapidly reduces depressive behavior in preclinical models. Thus, many memory deficits in depression appear to be downstream consequences of chronic stress, and addressing memory disruption can have therapeutic value.

Keywords: autobiographical memory; depression; encoding; episodic memory; retrieval.

Figure 1. Chronic stress induces physiological changes that disrupt basic neurocognitive processes, contributing to the specific memory deficits observed in depression

Key references for the effects summarized in the flow diagram are noted in the following sentences. Physiological impact of chronic stress on: suppression of hippocampal neurogenesis [15], inhibition of midbrain dopamine (DA) neurons [87], and sensitization of the amygdala [14]. Basic processes affected by chronic stress: impaired pattern separation [21], weak dopaminergic reward responses [88], and exaggerated amygdala responses to emotional stimuli [14]. The putative effects on memory are discussed in the main text; the link between impaired pattern separation and reduced recollection is speculative, the hypothesized relationship between disrupted dopaminergic reward responses and poor encoding and consolidation of positive events in depression is developed in [39], and the amygdala’s role in negatively biased memory retrieval in depression is described in [58,59].

Figure 2. Evidence supportive of adult hippocampal neurogenesis in humans

Black line shows atmospheric concentration of ¹⁴C by year; the spike reflects above-ground nuclear bomb tests between 1945 and 1963. Blue dots reflect hippocampal ¹⁴C concentrations from postmortem tissue, plotted by birth date. The presence of dots above the line for individuals born before the spike, but below the line for individuals born after it, strongly suggests adult hippocampal neurogenesis. Humans take up ¹⁴C from the plants and animals they eat, and the ¹⁴C is incorporated into the DNA when the cells in the body divide to form new cells (neurons). Thus, the fact that adults born before the spike have higher than expected hippocampal ¹⁴C concentrations suggests that new hippocampal neurons were added later in their lives, when atmospheric concentrations of ¹⁴C were elevated. By the same token, the fact that adults born after the spike have lower than expected levels is consistent with the hypothesis that hippocampal neurons were added in adulthood as ¹⁴C concentrations fell. Image adapted from [18], with permission.

Figure 3. Electroconvulsive therapy (ECT) increases hippocampal volumes bilaterally in patients with major depressive disorder (MDD)

Compared to healthy controls (n = 32), bilateral hippocampal volume (left hemisphere = left column, right hemisphere = right column) was significantly smaller in the MDD group at baseline (T1; MDD, n = 43). Significant volumetric increases were observed after just two ECT sessions (T2; MDD, n = 36), and after four weeks of treatment (T3; MDD, n = 29) hippocampal volume was comparable in patients and controls. Controls were scanned twice (C1, C2) about four weeks apart and did not show volumetric changes over time. Image adapted from [29], with permission.

Figure 4. Association between blunted reward responses and poor memory for rewarded stimuli in depression

(A) Healthy controls showed a source memory advantage for objects paired with reward vs. non-reward (“zero”) tokens, but adults with Major Depressive Disorder (MDD) did not. (B) At encoding, reward tokens elicited a stronger VTA/SN response in healthy controls than in depressed adults. (C) In controls, but not depressed adults, the size of the reward (vs. zero) memory advantage was positively correlated with the reward (vs. zero) activation difference scores in the VTA/SN. Image adapted from [54], with permission.

Figure 5. Abnormal amygdala responses during autobiographical memory retrieval in adults who are depressed or at elevated risk for depression

Amygdala activation was studied in healthy controls, currently depressed adults, formerly depressed adults (“remitted group”), and healthy adults at high risk of depression due to family history. During retrieval of positive autobiographical memories (left), depressed adults showed left amygdala hypoactivation relative to all other groups, indicating that such blunting may represent a state-related dysfunction associated with the disorder. By contrast, during retrieval of negative autobiographical memories (right), healthy controls showed significantly weaker activation than all other groups, suggesting that an exaggerated amygdala response to negative material may be a trait-like phenomenon related to depression vulnerability. The letters “b” and “c” denote significant differences from the depressed and control groups, respectively. Image adapted from [58], with permission.