Prefrontal GABAergic Interneurons Gate Long-Range Afferents to Regulate Prefrontal Cortex-Associated Complex Behaviors

Abstract

Prefrontal cortical GABAergic interneurons (INs) and their innervations are essential for the execution of complex behaviors such as working memory, social behavior, and fear expression. These behavior regulations are highly dependent on primary long-range afferents originating from the subcortical structures such as mediodorsal thalamus (MD), ventral hippocampus (vHPC), and basolateral amygdala (BLA). In turn, the regulatory effects of these inputs are mediated by activation of parvalbumin-expressing (PV) and/or somatostatin expressing (SST) INs within the prefrontal cortex (PFC). Here we review how each of these long-range afferents from the MD, vHPC, or BLA recruits a subset of the prefrontal interneuron population to exert precise control of specific PFC-dependent behaviors. Specifically, we first summarize the anatomical connections of different long-range inputs formed on prefrontal GABAergic INs, focusing on PV versus SST cells. Next, we elaborate on the role of prefrontal PV- and SST- INs in regulating MD afferents-mediated cognitive behaviors. We also examine how prefrontal PV- and SST- INs gate vHPC afferents in spatial working memory and fear expression. Finally, we discuss the possibility that prefrontal PV-INs mediate fear conditioning, predominantly driven by the BLA-mPFC pathway. This review will provide a broad view of how multiple long-range inputs converge on prefrontal interneurons to regulate complex behaviors and novel future directions to understand how PFC controls different behaviors.

Social play behavior shapes the development of prefrontal inhibition in a region-specific manner

“…Around this time, white matter volume increases because of myelination, and grey matter volume in the PFC starts to decrease due to synaptic pruning and apoptosis (Markham et al, 2007). In addition, at the onset of adolescence (around P30 – P42), the PFC starts to receive long-range afferents from sensory and subcortical brain regions including the amygdala, ventral hippocampus and mediodorsal thalamus (Hoover and Vertes, 2007, 2011; Murphy and Deutch, 2018; Yang et al, 2021). During adolescence (P35-P60), local interneurons are undergoing important remodeling (Caballero et al, 2014a; Cass et al, 2014; Caballero and Tseng, 2016), which is critical for the maturation of the PFC network (Tseng et al, 2008).…”

Sex-dependent effects of angiotensin type 2 receptor expressing medial prefrontal cortex (mPFC) interneurons in fear extinction learning

“…In both males and females, AT2R primarily colocalized with somatostatin-expressing interneurons, and females had greater co-expression with somatostatin than males across the PL and IL ( Fig. 4 ), indicating that AT2R preferentially modulates the activity of somatostatin interneurons, a key population in regulating cognition(38,65,66) and fear learning(39–41). The minimal levels of AT2R colocalization with other interneuron populations ( Fig.…”

“…2 ), indicating that their function is likely through modulating the action of interneurons. Though the smaller (10-20%) class of mPFC neurons, several overlapping and non-overlapping interneuron types are vital to modulating the activity of excitatory projection neurons to regulate fear memory and extinction(26,36,38,39,41,43,61). However, these populations often have opposing or additive effects on mPFC output.…”

Prefrontal Cortical Control of Anxiety: Recent Advances

“…The diverse population of GABAergic INs are crucial for information processing within the mPFC by gating long-range afferent inputs and allowing for dynamic modulation of the gain of PC responses (see section “Definition, Anatomy, and Physiology of the Rodent Prefrontal Cortex”) which, in turn, regulates multiple complex behaviors (Yang and others 2021). A key question of interest that can now be addressed with newly emergent techniques is what distinct roles genetically defined populations of mPFC INs play in modulating prefrontal activity and subsequent anxiety-related behaviors.…”