HMN 2025: How Distinct prefrontal pathways shown to separate reward motivation from threat reactivity

University of Cambridge researchers report that inactivating dorsolateral prefrontal cortex area 46 in marmosets blunts appetitive motivation and heightens threat reactivity, with effects mediated through asymmetric left-hemisphere pathways.

The dorsolateral prefrontal cortex (dlPFC) is implicated in higher-order processes such as attention, abstract thought, working memory, and inhibitory control. It is also a target for noninvasive brain stimulation in treatment-resistant depression.

Previous studies have shown that dlPFC transcranial magnetic stimulation improves depressive and comorbid anxiety symptoms and modulates activity in subcallosal cingulate cortex area 25, a region linked to therapeutic success.

Hemispheric asymmetry has been observed, with left dlPFC activation associated with antidepressant responses and right dlPFC with inhibitory control. While neuroimaging studies further implicate dlPFC in emotion regulation, its causal role has remained unclear.

In the study, “Dysfunction in primate dorsolateral prefrontal area 46 affects motivation and anxiety,” published in Science, researchers used chemogenetic and pharmacological inactivation to investigate dlPFC area 46 function in marmosets.

Six marmosets were used in experiments assessing motivation and pathway manipulations, while a separate cohort of seven marmosets was used in hemispheric asymmetry experiments involving intracerebral pharmacological inactivation.

Motivation was assessed using a progressive ratio task requiring escalating touchscreen responses for milkshake rewards, and consummatory behavior was measured with sucrose preference tests. Threat reactivity was tested with a human intruder paradigm.

Additional manipulations infused drugs into connected regions, area 32, ventral area 32 (A32v), and area 25, using surgically implanted cannulae. Ketamine was administered systemically or directly into area 25 to assess treatment interactions.

In this six-animal cohort, inactivation of area 46 reduced total responses and rewards received in the progressive ratio task without altering sucrose preference. Systemic ketamine and intra-A25 ketamine infusion blocked the motivational deficit.

Pathway-specific manipulations revealed that inactivation of area 46 terminals in dorsal area 32, but not direct projections to area 25, reduced motivation, and this effect was reversed by ketamine infusion into area 25. Inactivation of area 46 also increased threat reactivity, with effects localized to projections to ventral area 32.

A separate cohort of seven marmosets was used to test hemispheric asymmetry. Intracerebral infusions of muscimol and baclofen were administered unilaterally or bilaterally into area 46.

Inactivation of left or bilateral area 46 increased threat reactivity scores, whereas right area 46 inactivation had no effect. Additional pathway-specific experiments confirmed that left A32v mediated heightened threat reactivity, while left and bilateral A32 mediated motivational deficits.

Researchers conclude that area 46 forms a functional network with area 32 and area 25 that together regulate positive and negative emotion-related behaviors. Inactivation produced anhedonia-like and anxiety-like phenotypes that were mediated by distinct pathways: dorsal area 32 for motivation and ventral area 32 for threat reactivity.

Ketamine reversed motivational deficits via mechanisms in area 25, consistent with clinical evidence linking dlPFC stimulation and subcallosal cingulate activity to treatment response.

Findings provide causal evidence for asymmetric prefrontal networks underlying emotion regulation, offering mechanistic insight into therapeutic strategies for treatment-resistant depression and anxiety.

© 2025 Science X Network