The Thalamic Nucleus Reuniens Facilitates Communication Between Prefrontal Cortex and Hippocampus
Creators: Hauer, Brandon Evan
Publisher: name: University of Alberta Library
Year: 2022

<p>Decades of research have established that two brain regions, the medial prefrontal cortex (mPFC) and hippocampus (HPC), have dissociable but critical roles in memory. Often, these roles are co-operative and enable for the richness of episodic remembrances. It has remained relatively elusive, however, how these distant sites communicate to achieve this. To this end, I have investigated an anatomically interposed but somewhat understudied brain region: the thalamic nucleus reuniens (RE). The overall goal of this thesis was to understand how mPFC and HPC coordinate their activity, particularly during slow oscillations (SOs, ~1 Hz). SOs were of particular interest given their implication in the sleep-dependent consolidation of episodic memories, a process that involves bidirectional communication between these sites. I learned, however, that the mPFC-HPC circuitry operates in fundamentally different ways, both as a function of forebrain state, and of the activity patterns of RE neurons.<br>
In Chapter 2, I first showed that neuronal activity in the RE is intimately coupled to the ongoing mPFC SO. As well, optogenetic activation of the RE, or of its ipsilateral afferent fibers to the HPC, reliably produced a robust excitation at the site of RE terminals in CA1, the stratum lacunosum moleculare (SLM), which also happens to be the locus of SO generation in HPC. Electrical stimulation of the mPFC produced a similar pattern of short-latency excitation in HPC. Crucially, when the RE was chemogenetically inactivated, the mPFC-evoked excitation at SLM was selectively eliminated and SO coherence between these sites dropped significantly. The RE as such plays an essential role in mediating the coupled SO dialogue between mPFC and HPC.<br>
In Chapter 3, I explored how overall brain state affects the responses in HPC following stimulation of either RE or mPFC. Optogenetic activation of the RE, or its fibers targeting the HPC, consistently evoked a larger response at SLM during SO as compared to theta states.<br>
Similarly, excitation of RE yielded a larger mPFC field response during SO states. While electrical stimulation of mPFC produced a similar short-latency pattern of SLM responding during SO, this response appeared surprisingly delayed during theta. Interestingly, stimulation of the mPFC also evoked excitation in the dentate gyrus (DG) which did not change across states. Chemogenetic inhibition of RE abolished the mPFC responses in SLM during SO, leaving the DG responses intact, while no differences were observed during theta. The magnitude of responding in HPC via both RE and mPFC stimulation was additionally shown to be modified by the phase of the ongoing oscillation, whether during SO or theta. The way mPFC and HPC communicate and therefore process information is variable by brain state. The interposed RE acts as a crucial hub for biasing the preferred circuitry of information transfer, and is as such posed to be a key modulator in timing-dependent mnemonic processes.<br>
In Chapter 4, I investigated the role of neuronal activity states within the RE in mediating both mPFC-HPC SO dialogue, as well as the larger evoked responses observed during SO. Specifically, I tested the functional circuit implications of up-regulating RE activity using optogenetics. Optogenetically stimulating the RE robustly and tonically increased its multiunit activity, in a manner comparable to that observed during spontaneous theta. Interestingly, performing this manipulation decreased the amplitude of excitatory SLM responses to mPFC stimulation, specifically during SO states. Consistent with this, tonic upregulation of RE activity also decreased SO coherence between mPFC and HPC. Thus, modulating the activity dynamics of the RE to mimic those observed during theta, despite the forebrain otherwise exhibiting an SO state, was sufficient to disrupt mPFC-HPC coupling. It thus appears that during SO, the RE is primed by the mPFC-HPC circuitry to both receive and transmit SO information, whereas this is not the case during the particular activity patterns shown during theta.<br>
Finally, in Chapter 5, I showed that brief optogenetic stimulation of the RE was sufficient to reset the ongoing HPC theta rhythm. This was true both with direct RE stimulation during theta states, as well as with stimulation of its HPC-projecting afferents. The RE therefore has the ability to fundamentally affect the internal oscillator of the HPC, the resetting of which may mechanistically underlie its capacity to synchronize mPFC and HPC at theta frequencies and augment activity-dependent mnemonic processes.<br>
Taken all together, the results in this thesis show that the thalamic nucleus reuniens is a fundamentally important processing node for mPFC-HPC information exchange, a circuit crucially involved in episodic memory.</p>