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Late-adolescent onset of prefrontal endocannabinoid control of hippocampal and amygdalar inputs and its impact on trace-fear conditioning behavior

Neuropsychopharmacology (2024)Cite this article

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Abstract

Prefrontal cortex (PFC) maturation during adolescence is characterized by structural and functional changes, which involve the remodeling of GABA and glutamatergic synapses, as well as changes in the endocannabinoid system. Yet, the way PFC endocannabinoid signaling interacts with local GABA and glutamatergic function to impact its processing of afferent transmission during the adolescent transition to adulthood remains unknown. Here we combined PFC local field potential recordings with local manipulations of 2-AG and anandamide levels to assess how PFC endocannabinoid signaling is recruited to modulate ventral hippocampal and basolateral amygdalar inputs in vivo in adolescent and adult male rats. We found that the PFC endocannabinoid signaling does not fully emerge until late-adolescence/young adulthood. Once present, both 2-AG and anandamide can be recruited in the PFC to limit the impact of hippocampal drive through a CB1R-mediated mechanism whereas basolateral amygdalar inputs are only inhibited by 2-AG. Similarly, the behavioral effects of increasing 2-AG and anandamide in the PFC do not emerge until late-adolescence/young adulthood. Using a trace fear conditioning paradigm, we found that elevating PFC 2-AG levels preferentially reduced freezing behavior during acquisition without affecting its extinction. In contrast, increasing anandamide levels in the PFC selectively disrupted the extinction of trace fear memory without affecting its acquisition. Collectively, these results indicate a protracted recruitment of PFC endocannabinoid signaling, which becomes online in late adolescence/young adulthood as revealed by its impact on hippocampal and amygdalar-evoked local field potential responses and trace fear memory behavior.

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Fig. 1: PFC infusion of the CB1R agonist WIN limits the impact of ventral hippocampal and basolateral amygdalar-evoked LFP responses.
Fig. 2: PFC infusion of JZL184 and URB597 blocks the LFP suppression elicited from the ventral hippocampus.
Fig. 3: PFC infusion of JZL184 (but not URB597) diminishes the LFP potentiation elicited from the ventral hippocampus.
Fig. 4: PFC infusion of JZL184 (but not URB597) diminishes the LFP response elicited from the basolateral amygdala.
Fig. 5: Differential impact of PFC infusion of JZL184 and URB on the level of freezing response during the acquisition and extinction of trace fear memory in adult rats (P75-95).

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All data supporting the conclusions of this manuscript will be made available to any qualified researcher without undue reservation.

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Funding

Supported by NIH Grants (R01-MH086507, R01-MH105488, R01-DA056447 to KYT) and Institutional startup funds from the College of Medicine – University of Illinois Chicago to KYT.

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  1. Department of Anatomy and Cell Biology, University of Illinois Chicago – College of Medicine, Chicago, IL, 60612, USA

    Hanna M. Molla, Anabel M. M. Miguelez Fernández & Kuei Y. Tseng

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Contributions

Hanna M. Molla and Kuei Y. Tseng designed the study, wrote the manuscript, and prepared the figures. Hanna M. Molla performed all electrophysiological and behavioral experiments and data analyses under the supervision of Kuei Y. Tseng. Anabel M. M. Miguelez Fernández assisted Hanna M. Molla with the execution of the behavioral experiments.

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Correspondence to Kuei Y. Tseng.

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Molla, H.M., Miguelez Fernández, A.M.M. & Tseng, K.Y. Late-adolescent onset of prefrontal endocannabinoid control of hippocampal and amygdalar inputs and its impact on trace-fear conditioning behavior. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01844-z

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