Serotonin 1B Receptors Regulate Prefrontal Function by Gating Callosal and Hippocampal Inputs

Abstract

SUMMARY Both the medial prefrontal cortex (mPFC) and serotonin play key roles in anxiety, however, specific mechanisms through which serotonin might act on the mPFC to modulate anxiety-related behavior remain unknown. Here, we use a combination of optogenetics and synaptic physiology to show that serotonin acts presynaptically via 5-HT1B receptors to selectively suppress inputs from the contralateral mPFC and ventral hippocampus (vHPC), while sparing those from mediodorsal thalamus. To elucidate how these actions could potentially regulate prefrontal circuit function, we infused a 5-HT1B agonist into the mPFC of freely behaving mice. Consistent with previous studies that have optogenetically inhibited vHPC-mPFC projections, activating prefrontal 5-HT1B receptors suppressed theta-frequency (4–12 Hz) mPFC activity, and also reduced avoidance of anxiogenic regions in the elevated plus maze. These findings suggest a potential mechanism, linking specific receptors, synapses, patterns of circuit activity, and behavior, through which serotonin may regulate prefrontal circuit function including anxiety-related behaviors.

Transient and sustained effects of dopamine and serotonin signaling in motivation‐related behavior

“…Glutamatergic and GABAergic axons can also be inhibited by dopamine and serotonin through G i/o ‐protein signaling. For example, in axonal inputs to pyramidal neurons in the PFC from the contralateral pyramidal neurons and ventral hippocampus but not from mediodorsal thalamus, serotonin suppressed synaptic inputs in 5‐HT 1B ‐receptor‐dependent ways at temporal scales ranging from 3 to 5 min . In addition to presynaptic mechanisms, the axon initial segment is a subcellular target of modulation.…”

“…For example, serotonin activates the presynaptic 5‐HT 1B receptor of glutamatergic inputs from the neocortex and causes persistent suppression, or long‐term depression (LTD), which has been suggested to underlie social reward conditioning . Notably, the same presynaptic action of 5‐HT 1B receptor was transient in PFC inputs, indicating that the same receptor controls transient and sustained mechanisms differentially depending on the respective brain regions. In the postsynapse of SPN in the NAc, the 5‐HT 4 receptor inhibits LTD when coupled with repeated stimulation with glutamate and action potentials .…”

“…For example, in axonal inputs to pyramidal neurons in the PFC from the contralateral Transient and sustained monoamine effects PCN Psychiatry and Clinical Neurosciences pyramidal neurons and ventral hippocampus but not from mediodorsal thalamus, serotonin suppressed synaptic inputs in 5-HT 1B -receptor-dependent ways at temporal scales ranging from 3 to 5 min. 81 In addition to presynaptic mechanisms, the axon initial segment is a subcellular target of modulation. Although hyperpolarization and cyclic-nucleotide-gated (HCN) channels regulated by cytosolic cAMP signals generally enhance the excitability of cells at resting membrane potentials, one study has reported that HCN channels also reduce the excitability of cells at the axon initial segment by upregulating spike threshold downstream of 5-HT 1A receptors in principle neurons of the medial superior olive.…”

The Brain, Explained: A Comprehensive Theory of Brain Function

“…Thus, SER cooperates with the response suppression network. SER also suppresses contralateral and ventral hippocampal inputs onto the mPFC execution networks via presynaptic SER1bRs, while not harming BU thalamocortical flow [Kjaerby et al, 2016]. Similarly, SER2a excites cell body-targetting IINs, including those in the response suppression network [Jakab and Goldman-Rakic, 2000].…”

Medial prefrontal cortical NMDA receptors regulate depression-like behavior and dictate limbic thalamus innervation

“…The ventral hippocampus (vHipp) is a spatially and functionally distinct section of the hippocampal formation 52 . It has established roles in the expression of social behavior 53 , anxiety [54][55][56][57] , and depression-related behavior 58 . In order to verify that our mPFC coordinates do in fact receive inputs form MDT and vHipp, we injected canine adenovirus type 2 expressing Cre recombinase (CAV-Cre) 59,60 into the mPFC of the Ai14 Cre-dependent reporter mouse line 61 to selectively label neurons that send axonal inputs into mPFC (Supplemental Figure 3A).…”