Leal, S. L. | Search bioRxiv

bioRxiv2026

Antidepressant mechanism and treatment response define distinct hippocampal-amygdala circuit biomarkers during emotional memory in humans

Antidepressant efficacy varies widely, yet the circuit-level mechanisms that distinguish treatment responders from non-responders remain poorly understood in humans. Here, we used high-resolution neuroimaging of hippocampal-amygdala networks during an emotional mnemonic discrimination task that taxes hippocampal pattern separation to examine how antidepressant mechanism of action and perceived treatment response shape emotional memory circuitry (N = 117). Participants included individuals taking single-action antidepressants (selective serotonin reuptake inhibitors), multi-action antidepressants (serotonin-norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, or polypharmacy), and unmedicated controls matched on current depression severity. Antidepressant mechanism and treatment response were associated with distinct patterns of activity in hippocampal subfields (dentate gyrus (DG)/CA3 and CA1) and amygdala subnuclei, including the basolateral amygdala (BLA) and central amygdala (CEA), during emotional mnemonic discrimination. Among non-responders, the relative balance of hippocampal activity differed by antidepressant mechanism: those taking single-action antidepressants showed greater DG/CA3 than CA1 activity, whereas those taking multi-action antidepressants showed the opposite pattern. This suggests mechanistically specific differences in hippocampal computations associated with ineffective treatment. These effects were localized to the anterior hippocampus, with no significant effects observed in posterior regions. In contrast, responders exhibited stronger DG/CA3-BLA coactivation during negative mnemonic discrimination, a pattern absent in non-responders and unmedicated controls. Antidepressant-associated differences in amygdala subnuclei activity persisted beyond current symptom severity, suggesting medication-related modulation of emotional memory circuits rather than effects driven solely by depression severity. These findings provide evidence in humans that antidepressant use is associated with altered hippocampal-amygdala circuitry in a manner that depends on both pharmacological mechanism and treatment efficacy. Identifying circuit-level signatures of treatment response may inform mechanistically guided approaches to antidepressant selection and monitoring.

neuroscience↗

bioRxiv2019

Integrity of the Uncinate Fasciculus Predicts Emotional Pattern Separation-Related fMRI Signals in the Hippocampal Dentate and CA3

Alterations in white matter integrity have been demonstrated in a number of psychiatric disorders that involve disruptions in emotional processing. One such pathway - the uncinate fasciculus (UF) - connects the orbitofrontal cortex (OFC) to the medial temporal lobes (MTL) and has been associated with early life adversity, maltreatment, anxiety, and depression. While it is purported to play a role in episodic memory and discrimination, its exact function remains poorly understood. We have previously described the role of the amygdala and dentate (DG)/CA3 fields of the hippocampus in the mnemonic discrimination of emotional experiences (i.e. emotional pattern separation). However, how this computation may be modulated by connectivity between the medial temporal lobes and the orbitofrontal cortex remains unknown. Here we ask the question of whether the uncinate fasciculus plays a role in influencing MTL subregional activity during emotional pattern separation. By combining diffusion imaging with high-resolution functional MRI, we found that reduced integrity of the UF is related to higher activation in the DG/CA3 subregions of the hippocampus during an emotional pattern separation task. We additionally report that higher levels of DG/CA3 activity are associated with poorer memory performance, suggesting that hyperexcitability in this network (which may be driven by CA3 recurrent collaterals) is associated with memory errors and that the UF may allow the OFC to exert inhibitory control on this network and improve discrimination of emotional experiences. This work provides novel mechanistic insight into the role of prefrontal interactions with the MTL, particularly in the context of emotional memory.

neuroscience↗