Bi-directional regulation of cognitive control by distinct prefrontal cortical output neurons to thalamus and striatum

Abstract

The medial prefrontal cortex (mPFC) steers goal-directed actions and withholds inappropriate behavior. Dorsal and ventral mPFC (dmPFC/vmPFC) circuits have distinct roles in cognitive control, but underlying mechanisms are poorly understood. Here we use neuroanatomical tracing techniques, in vitro electrophysiology, chemogenetics and fiber photometry in rats engaged in a 5-choice serial reaction time task to characterize dmPFC and vmPFC outputs to distinct thalamic and striatal subdomains. We identify four spatially segregated projection neuron populations in the mPFC. Using fiber photometry we show that these projections distinctly encode behavior. Postsynaptic striatal and thalamic neurons differentially process synaptic inputs from dmPFC and vmPFC, highlighting mechanisms that potentially amplify distinct pathways underlying cognitive control of behavior. Chemogenetic silencing of dmPFC and vmPFC projections to lateral and medial mediodorsal thalamus subregions oppositely regulate cognitive control. In addition, dmPFC neurons projecting to striatum and thalamus divergently regulate cognitive control. Collectively, we show that mPFC output pathways targeting anatomically and functionally distinct striatal and thalamic subregions encode bi-directional command of cognitive control.

A thalamo-centric neural signature for restructuring negative self-beliefs

“…Findings from our DCM analysis endorse the ventral MPFC as the primary conduit for prefrontal input onto the MD during higher-order cognition. This result aligns with recent in-vitro electrophysiological research identifying distinct roles of prefrontal-MD pathways in shaping behavior, with inhibition of ventral MPFC-to-MD pathways impacting the encoding and maintenance of contingencies [43]. The fact that the modulation of ventral MPFC-to-MD effective connectivity during cognitive restructuring was able to reliably predict participants' tendency to engage in repetitive negative thinking suggests that this pathway may contribute to sustaining mental self-representations and, when having exaggerated impact, to rumination.…”

Communication between the mediodorsal thalamus and prelimbic cortex regulates timing performance in rats

“…However, data supporting this hypothesis have been primarily correlative, monitoring changes in purported task-related activity in one area after inactivating the other. The data presented here contributes to the recent, but growing, body of causal data showing that MD-PFC interactions mediate cognitive function (Bolkan et al, 2017;de Kloet et al, 2021).…”

Organization and engagement of a prefrontal-olfactory network during olfactory selective attention

“…This approach allowed us to observe fluorescent puncta (which can more confidently be attributed to synaptic terminals, rather than fibers of passage) in olfactory regions receiving input from either the PrL or IL cortex. Importantly, because Cre expression was driven by the CaMKII promotor, we can specifically assess excitatory projections which make up >80% of mPFC neurons (Erö et al 2018) and are major regulators of the PFC's effects (de Kloet et al 2021). We quantified puncta in three structures recipient of dense olfactory bulb input: the AON, PCX and TuS (Fig.…”

“…The copyright holder for this preprint this version posted September 6, 2021. ; https://doi.org/10.1101/2021.09.04.458996 doi: bioRxiv preprint 5 Kloet et al 2021;Luchicchi et al 2016). Specifically, the PrL appears important for setshifting and selective attention (Marquis et al 2007;Schmitt et al 2017;Kim et al 2016;Rodgers and DeWeese 2014), while the IL is implicated in behavioral flexibility and extinction (Barker et al 2014).…”

“…mPFC neurons are modulated as animals attentively await a stimulus (Rodgers and DeWeese 2014;Kim et al 2016), and disruptions to the mPFC impair attentional set-shifting (Birrell and Brown 2000;Ragozzino et al 2003), sustained attention (Kim et al 2016), and selective attention (Wimmer et al 2015). mPFC subdivisions include the prelimbic (PrL) and infralimbic (IL) cortices, which seem to possess dissociable behavioral functions (Hardung et al 2017;Marquis et al 2007;de Kloet et al 2021;Luchicchi et al 2016). Specifically, the PrL appears important for setshifting and selective attention (Marquis et al 2007;Schmitt et al 2017;Kim et al 2016;Rodgers and DeWeese 2014), while the IL is implicated in behavioral flexibility and extinction (Barker et al 2014).…”