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. 2025 Mar 27:S0006-3223(25)01099-6.
doi: 10.1016/j.biopsych.2025.03.011. Online ahead of print.

Neurochemical and Circuit Heterogeneity of Cognition-Modulating Prefrontal Corticotropin-Releasing Factor Neurons

Spencer K Cooke  1 , Andrea J Martin  1 , Robert C Spencer  1 , Shannon E Nicol  1 , Craig W Berridge  2
Affiliations

Neurochemical and Circuit Heterogeneity of Cognition-Modulating Prefrontal Corticotropin-Releasing Factor Neurons

Spencer K Cooke et al. Biol Psychiatry. .

Abstract

Background: Impairment of prefrontal cortex (PFC)-dependent cognition is associated with multiple psychiatric disorders. Development of more effective treatments for this form of cognitive dysfunction is hindered by our limited understanding of the neurobiology underlying PFC-dependent cognition. We previously identified a robust population of corticotropin-releasing factor (CRF) neurons in the caudal dorsomedial PFC (dmPFC) of rats that impair both working memory and sustained attention. Although the working memory actions of these neurons involved local CRF release, the sustained attention actions did not. These results suggest potential heterogeneity within this population of CRF neurons, including the potential existence of both GABAergic (gamma-aminobutyric acidergic) (CRFGABA) interneurons and glutamatergic (CRFGlu) CRF projection neurons.

Methods: Immunohistochemical analyses first identified both CRFGABA and CRFGlu neurons in the caudal dmPFC. Intersectional viral vector chemogenetic approaches were then used to assess the effects of activating caudal dmPFC CRFGlu and CRFGABA neurons on working memory and sustained attention in males and females (tested outside of proestrus).

Results: CRFGlu neurons comprised a majority (85%) of caudal dmPFC CRF neurons, while the remaining were identified as CRFGABA neurons. For both females and males, activation of caudal dmPFC CRFGABA neurons impaired working memory but not sustained attention, while activation of CRFGlu neurons impaired both working memory and sustained attention. Interestingly, the working memory actions of both CRFGABA and CRFGlu neurons were dependent on local CRF receptors.

Conclusions: These results advance our understanding of the neurobiology of PFC-dependent cognition and potential mechanisms through which cognitive dysfunction could arise.

Keywords: CRF; CRH; Executive function; PFC; Sustained attention; Working memory.

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Conflict of interest statement

Disclosures

The authors report no biomedical financial interests or potential conflicts of interest.

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