Person:

Dillon, Daniel

Adults with unipolar depression typically show poor episodic memory for positive material, but the neuroscientific mechanisms responsible for this deficit have not been characterized. I suggest a simple hypothesis: weak memory for positive material in depression reflects disrupted communication between the mesolimbic dopamine pathway and medial temporal lobe (MTL) memory systems during encoding. This proposal draws on basic research showing that dopamine release in the hippocampus is critical for the transition from early- to late-phase long-term potentiation (LTP) that marks the conversion of labile, short-term memories into stable, long-term memories. Neuroimaging and pharmacological data from healthy humans paint a similar picture: activation of the mesolimbic reward circuit enhances encoding and boosts retention. Unipolar depression is characterized by anhedonia–loss of pleasure–and reward circuit dysfunction, which is believed to reflect negative effects of stress on the mesolimbic dopamine pathway. Thus, I propose that the MTL is deprived of strengthening reward signals in depressed adults and memory for positive events suffers accordingly. Although other mechanisms are important, this hypothesis holds promise as an explanation for positive memory deficits in depression.

Anhedonia (hyposensitivity to rewards) and negative bias (hypersensitivity to punishments) are core features of major depressive disorder (MDD), which could stem from abnormal reinforcement learning. Emerging evidence highlights blunted reward learning and reward prediction error (RPE) signaling in the striatum in MDD, although inconsistencies exist. Preclinical studies have clarified that ventral tegmental area (VTA) neurons encode RPE and habenular neurons encode punishment prediction error (PPE), which are then transmitted to the striatum and cortex to guide goal-directed behavior. However, few studies have probed striatal activation, and functional connectivity between VTA-striatum and VTA-habenula during reward and punishment learning respectively, in unmedicated MDD. To fill this gap, we acquired fMRI data from 25 unmedicated MDD and 26 healthy individuals during a monetary instrumental learning task and utilized a computational modeling approach to characterize underlying neural correlates of RPE and PPE. Relative to controls, MDD individuals showed impaired reward learning, blunted RPE signal in the striatum and overall reduced VTA-striatal connectivity to feedback. Critically, striatal RPE signal was increasingly blunted with more major depressive episodes (MDEs). No group differences emerged in PPE signals in the habenula and VTA or in connectivity between these regions. However, PPE signals in the habenula correlated positively with number of MDEs. These results highlight impaired reward learning, disrupted RPE signaling in the striatum (particularly among individuals with more lifetime MDEs) as well as reduced VTA-striatal connectivity in MDD. Collectively, these findings highlight reward-related learning deficits in MDD and their underlying pathophysiology.