Prefrontal cortex modulates firing pattern in the nucleus reuniens of the midline thalamus via distinct corticothalamic pathways

Abstract

The thalamus has long been recognized for its role in relaying sensory information from the periphery, a function accomplished by its "first-order" nuclei. However, a second category of thalamic nuclei, termed "higher-order" nuclei, have been shown instead to mediate communication between cortical areas. The nucleus reuniens of the midline thalamus (RE) is a higher-order nucleus known to act as a conduit of reciprocal communication between the medial prefrontal cortex (mPFC) and hippocampus. While anatomical and behavioural studies of RE are numerous, circuit-based electrophysiological studies, particularly those examining the impact of cortical input and the thalamic reticular nucleus (TRN) on RE neuron firing, are sparse. To characterize RE neuron firing properties and dissect the circuit dynamics of the infralimbic subdivision of the mPFC (ilPFC), the TRN and RE, we used in vivo, extracellular, single-unit recordings in male Sprague Dawley rats and manipulated neural activity using targeted pharmacological manipulations, electrical stimulation and a projection-specific implementation of designer receptors exclusively activated by designer drugs (DREADDs). We show that ilPFC inhibition reduces multiple burst firing parameters in RE, whereas ilPFC stimulation drives burst firing and dampens tonic firing. In addition, TRN inhibition reduces the number of spontaneously active neurons in RE. Finally, inhibition of ilPFC terminals in RE selectively enhances a subset of burst firing parameters. These findings demonstrate that ilPFC input, both via direct projections and via the TRN, can modulate RE neuron firing pattern in nuanced and complex ways. They also highlight the ilPFC-TRN-RE circuit as a likely critical component of prefrontal-hippocampal interactions.

The nucleus reuniens of the thalamus sits at the nexus of a hippocampus and medial prefrontal cortex circuit enabling memory and behavior

“…While direct mPFC-RE input is glutamatergic, feedforward inhibition of RE occurs via GABAergic input from the TRN (Halassa and Acsády 2016). Muscimol inhibition of TRN, had no effects on the spontaneous firing rate, bursting or spike counts in RE cells, but it did reduce the number of spontaneously active cells (Zimmerman and Grace 2018). These results, although puzzling, indicate distinct roles of the TRN → RE, and mPFC (IL) → TRN → RE pathways.…”

“…Thus, mPFC input to RE appeared to have shifted the firing mode from tonic to burst firing, followed by silence. Zimmerman and Grace (2018) hypothesized that the mPFC → RE input may entrain bursting in RE neurons, with silencing effects achieved via the mPFC → TRN → RE pathway (Fig. 2B).…”

The Reuniens Nucleus of the Thalamus Has an Essential Role in Coordinating Slow-Wave Activity between Neocortex and Hippocampus

“…The mPFC (and the IL in particular) has also been shown to alter the firing of RE cells (Zimmerman and Grace, 2018). Our findings suggest that the mPFC provides a rhythmic input to RE during SO states, the timing of which is then relayed to CA1.…”

Dysregulation of Midbrain Dopamine System and the Pathophysiology of Schizophrenia

“…These findings suggest that 1) the ilPFC potently regulates the vHipp via nucleus reuniens and 2) the ilPFC inhibition leads to disinhibition of nucleus reuniens, likely due to deactivation of the thalamic reticular nucleus, which in turn, via its excitatory projections to the vHipp, enhances VTA DA system activity. The ilPFC was found to modulate several aspects of the firing pattern of neurons in the nucleus reuniens (119). Thus, the nucleus reuniens may mediate the regulation of the VTA DA system activity by the ilPFC.…”