Plasticity in prefrontal cortex induced by coordinated nucleus reuniens and hippocampal synaptic transmission

Abstract

The nucleus reuniens of the thalamus (NRe) is reciprocally connected to a range of higher order cortices including hippocampus (HPC) and medial prefrontal cortex (mPFC). The physiological function of NRe is well predicted by requirement for interactions between mPFC and HPC, including associative recognition memory, spatial navigation and working memory. Although anatomical and electrophysiological evidence suggests NRe makes excitatory synapses in mPFC there is little data on the physiological properties of these projections, or whether NRe and HPC target overlapping cell populations and, if so, how they interact. We demonstrate in ex vivo mPFC slices that NRe and HPC afferent inputs converge onto more than two-thirds of layer 5 pyramidal neurons, show that NRe, but not HPC, undergoes marked short-term plasticity at theta, and that HPC, but not NRe, afferents are subject to neuromodulation by acetylcholine acting via muscarinic receptor M2. Finally, we demonstrate that pairing HPC followed by NRe (but not pairing NRe followed by HPC) at theta frequency induces associative, NMDA receptor dependent synaptic plasticity in both inputs to mPFC. These data provide vital physiological phenotypes of the synapses of this circuit and provide a novel mechanism for HPC-NRe-mPFC encoding.

Changes in Representation of Thalamic Projection Neurons within Prefrontal-Thalamic-Hippocampal Circuitry in a Rat Model of Third Trimester Binge Drinking

“…Changes in timing between mono- (Re→mPFC) and disynaptic (Re→vCA1→mPFC) inputs to mPFC could result in impairments in input timing-dependent plasticity (ITDP) (e.g., [ 70 , 71 ]) and ultimately learning. In a recent first investigation of this phenomenon, Banks, Warburton [ 19 ] demonstrated that the majority of layer 5 pyramidal neurons in the prelimbic subregion of mPFC receive input from both Re and vCA1. The same study further demonstrated (in ex vivo brain slices) that precise temporal coordination of vCA1→mPFC and Re→mPFC inputs resulted in NMDA-mediated ITDP.…”

“…Given this precise regulation of differential timing between HPC and Re inputs to mPFC necessary for ITDP (approximately 10ms according to Banks, Warburton [ 19 ]), it follows that damaging Re and altering the proportion of projection neurons in Re that collaterally innervate vCA1 and mPFC would be likely to influence EF through impaired mPFC function (e.g., [ 13 , 20 ]). This would also account for sparing of orbitofrontal function of any behaviorally-relevant wave of secondary damage from developmental AE (i.e., lack of reversal learning deficit in [ 13 ]), as there have been no observations of Re neurons collaterally projecting to both vHPC and orbitofrontal cortex.…”

“…There is evidence (albeit limited) that the mPFC-Re-HPC system is at a similar stage of development and susceptibility to AE (which targets synaptogenic neurons [ 66 ]) as PFC spine density and synaptogenesis are similar between this model and the human at the aforementioned developmental stages [ 72 , 73 ]. While there is currently no literature comparing development of Re (selectively within thalamus) between humans and rodents, limiting the translatability of the current study, the critical role of Re in rodent EF [ 15 , 16 , 19 , 20 , 67 , 74 , 75 ] and its susceptibility to developmental AE [ 21 , 22 ] results in a need to address this gap in knowledge.…”

“…Re also uniquely innervates HPC in a way that allows for precise timing differences between direct (i.e., monosynaptic) Re→mPFC and indirect (i.e., disynaptic) Re→HPC→mPFC input to mPFC. This phenomenon has lately gained attention as a recent study identified that ventral HPC (vHPC) and Re inputs to the prelimbic subregion of mPFC frequently converge and precise timing of these inputs is necessary for plasticity in mPFC [ 19 ]. Re is essential for the long-term maintenance of learning-related changes in mPFC anatomy [ 20 ], suggesting that disruption of the connectivity and balance of projections within the mPFC-Re-HPC circuit early in life is likely to have deleterious long-term consequences.…”

NMDARs in prefrontal cortex – Regulation of synaptic transmission and plasticity

“…ReRh are involved in associative recognition memory and working memory and have strong reciprocal connections with both HPC and mPFC (Barker & Warburton 2018, Cassel et al 2013, Dolleman-van der Weel et al 2019, Hallock et al 2016 but little is known of how HPC and ReRh inputs converge onto cells in mPFC and how this regulates synaptic plasticity within mPFC (Viana Di Prisco & Vertes 2006). By using a combination of optogenetic stimulation of ReRh inputs and electrical stimulation of HPC inputs (Fig 3A ) we were able to investigate in slices of mPFC whether HPC and NRe inputs converge at the single cell level, characterise receptor physiology at these synapses and determine whether interaction of these inputs results in synaptic plasticity which may allow encoding of information in mPFC (Banks et al 2020).…”