The prefrontal cortex (PFC) plays a pivotal role in orchestrating higher-order emotional and cognitive processes, a function that depends on the precise modulation of synaptic activity. Although pharmacological studies have demonstrated that dopamine signaling through dopamine D1 receptor (DRD1) in the PFC is essential for these functions, the cell-type-specific and molecular mechanisms underlying the neuromodulatory effects remain elusive. Using cell-type-specific knockout mice and patch-clamp recordings, we investigated the regulatory role of DRD1 on neurons and astrocytes in synaptic transmission and plasticity. Furthermore, we explored the mechanisms by which DRD1 on astrocytes regulate synaptic transmission and plasticity at the cellular level, as well as emotional and cognitive functions at the behavioral level, through two-photon imaging, microdialysis, high-performance liquid chromatography, transcriptome sequencing, and behavioral testing. We found that conditional knockout of the Drd1 in astrocytes (CKO^AST) increased glutamatergic synaptic transmission and long-term potentiation (LTP) in the medial prefrontal cortex (mPFC), whereas Drd1 deletion in pyramidal neurons did not affect synaptic transmission. The elevated level of d-serine in the mPFC of CKO^AST mice increased glutamatergic transmission and LTP through NMDA receptors. In addition, CKO^AST mice exhibited abnormal emotional and cognitive function. Notably, these behavioral changes in CKO^AST mice could be reversed through the administration of d-serine degrease to the mPFC. These results highlight the critical role of the astrocytic DRD1 in modulating mPFC synaptic transmission and plasticity, as well as higher brain functions through d-serine, and may shed light on the treatment of mental disorders.

Pathological anxiety is among the most difficult neuropsychiatric diseases to treat pharmacologically, and it represents a major societal problem. Studies have implicated structural changes within the prefrontal cortex (PFC) and functional changes in the communication of the PFC with distal brain structures in anxiety disorders. Treatments that affect the activity of the PFC, including cognitive therapies and transcranial magnetic stimulation, reverse anxiety- and fear-associated circuit abnormalities through mechanisms that remain largely unclear. While the subjective experience of a rodent cannot be precisely determined, rodent models hold great promise in dissecting well-conserved circuits. Newly developed genetic and viral tools and optogenetic and chemogenetic techniques have revealed the intricacies of neural circuits underlying anxiety and fear by allowing direct examination of hypotheses drawn from existing psychological concepts. This review focuses on studies that have used these circuit-based approaches to gain a more detailed, more comprehensive, and more integrated view on how the PFC governs anxiety and fear and orchestrates adaptive defensive behaviors to hopefully provide a roadmap for the future development of therapies for pathological anxiety.
Anxiety ; Anxiety Disorders/therapy* ; Fear/psychology* ; Humans ; Neural Pathways ; Prefrontal Cortex