Abstract
The mediodorsal nucleus of the thalamus (MD) is a rich source of afferents to the medial prefrontal cortex (mPFC). Dysfunctions in the thalamo-prefrontal connections can impair networks implicated in working memory, some of which are affected in Alzheimer disease and schizophrenia. Considering the importance of the cholinergic system to cortical functioning, our study aimed to investigate the effects of global cholinergic activation of the brain on MD-mPFC synaptic plasticity by measuring the dynamics of long-term potentiation (LTP) and depression (LTD) in vivo. Therefore, rats received intraventricular injections either of the muscarinic agonist pilocarpine (PILO; 40 nmol/µL), the nicotinic agonist nicotine (NIC; 320 nmol/µL), or vehicle. The injections were administered prior to either thalamic high-frequency (HFS) or low-frequency stimulation (LFS). Test pulses were applied to MD for 30 min during baseline and 240 min after HFS or LFS, while field postsynaptic potentials were recorded in the mPFC. The transient oscillatory effects of PILO and NIC were monitored through recording of thalamic and cortical local field potentials. Our results show that HFS did not affect mPFC responses in vehicle-injected rats, but induced a delayed-onset LTP with distinct effects when applied following PILO or NIC. Conversely, LFS induced a stable LTD in control subjects, but was unable to induce LTD when applied after PILO or NIC. Taken together, our findings show distinct modulatory effects of each cholinergic brain activation on MD-mPFC plasticity following HFS and LFS. The LTP-inducing action and long-lasting suppression of cortical LTD induced by PILO and NIC might implicate differential modulation of thalamo-prefrontal functions under low and high input drive.
Highlights
In the prefrontal cortex (PFC), the rescaling of synaptic weights mediated by long-term potentiation (LTP) and long-term depression (LTD) is thought to play an important role in working memory, decision-making, behavioral inhibition and attention shifting [1,2,3]
Accuracy of implants All animals included in our analysis had the stimulation electrode tips positioned within the mediodorsal thalamic nucleus (MD), most often in its anterior and medial aspects, which contain the highest density of mPFCprojecting cells according to retrograde tracing [60]
The prefrontal field post-synaptic potentials (fPSPs) obtained by stimulation throughout the hippocampus may occur due to the activation of passing fibers, since retrograde tracing data from the literature do not show hippocampal cells projecting to the medial prefrontal cortex (mPFC) at the anteroposterior level where our stimulation electrodes were implanted [59]
Summary
In the prefrontal cortex (PFC), the rescaling of synaptic weights mediated by long-term potentiation (LTP) and long-term depression (LTD) is thought to play an important role in working memory, decision-making, behavioral inhibition and attention shifting [1,2,3]. Electrophysiological studies in rodents have shown that changes in PFC responses mediated by MD stimulation are involved in the modulation of hippocampusevoked activity in the PFC [21], fear extinction [22,23], and propagation of limbic seizures [24,25,26,27]. Several studies have shown that cholinergic activation regulates synaptic plasticity in adult thalamocortical loops comprising sensorial areas of the cortex [44,45,46,47,48]. The authors did not evaluate long-term synaptic plasticity in the MD-mPFC pathway Synaptic plasticity in this pathway was shown to occur associated with fear learning in mice in the absence of any pharmacological treatment [22,23]
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